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1.  Percutaneous Vertebroplasty for Treatment of Painful Osteoporotic Vertebral Compression Fractures 
Executive Summary
Objective of Analysis
The objective of this analysis is to examine the safety and effectiveness of percutaneous vertebroplasty for treatment of osteoporotic vertebral compression fractures (VCFs) compared with conservative treatment.
Clinical Need and Target Population
Osteoporosis and associated fractures are important health issues in ageing populations. Vertebral compression fracture secondary to osteoporosis is a cause of morbidity in older adults. VCFs can affect both genders, but are more common among elderly females and can occur as a result of a fall or a minor trauma. The fracture may occur spontaneously during a simple activity such as picking up an object or rising up from a chair. Pain originating from the fracture site frequently increases with weight bearing. It is most severe during the first few weeks and decreases with rest and inactivity.
Traditional treatment of painful VCFs includes bed rest, analgesic use, back bracing and muscle relaxants. The comorbidities associated with VCFs include deep venous thrombosis, acceleration of osteopenea, loss of height, respiratory problems and emotional problems due to chronic pain.
Percutaneous vertebroplasty is a minimally invasive surgical procedure that has gained popularity as a new treatment option in the care for these patients. The technique of vertebroplasty was initially developed in France to treat osteolytic metastasis, myeloma, and hemangioma. The indications were further expanded to painful osteoporotic VCFs and subsequently to treatment of asymptomatic VCFs.
The mechanism of pain relief, which occurs within minutes to hours after vertebroplasty, is still not known. Pain pathways in the surrounding tissue appear to be altered in response to mechanical, chemical, vascular, and thermal stimuli after the injection of the cement. It has been suggested that mechanisms other than mechanical stabilization of the fracture, such as thermal injury to the nerve endings, results in immediate pain relief.
Percutaneous Vertebroplasty
Percutaneous vertebroplasty is performed with the patient in prone position and under local or general anesthesia. The procedure involves fluoroscopic imaging to guide the injection of bone cement into the fractured vertebral body to support the fractured bone. After injection of the cement, the patient is placed in supine position for about 1 hour while the cement hardens.
Cement leakage is the most frequent complication of vertebroplasty. The leakages may remain asymptomatic or cause symptoms of nerve irritation through compression of nerve roots. There are several reports of pulmonary cement embolism (PCE) following vertebroplasty. In some cases, the PCE may remain asymptomatic. Symptomatic PCE can be recognized by their clinical signs and symptoms such as chest pain, dyspnea, tachypnea, cyanosis, coughing, hemoptysis, dizziness, and sweating.
Research Methods
Literature Search
A literature search was performed on Feb 9, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 to February 9, 2010.
Studies were initially reviewed by titles and abstracts. For those studies meeting the eligibility criteria, full-text articles were obtained and reviewed. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Data extraction was carried out by the author.
Inclusion Criteria
Study design: Randomized controlled trials (RCTs) comparing vertebroplasty with a control group or other interventions
Study population: Adult patients with osteoporotic vertebral fractures
Study sample size: Studies included 20 or more patients
English language full-reports
Published between Jan 1 2005 and Feb 9, 2010
(eligible studies identified through the Auto Alert function of the search were also included)
Exclusion Criteria
Non-randomized studies
Studies on conditions other than VCF (e.g. patients with multiple myeloma or metastatic tumors)
Studies focused on surgical techniques
Studies lacking outcome measures
Results of Evidence-Based Analysis
A systematic search yielded 168 citations. The titles and the abstracts of the citations were reviewed and full text of the identified citations was retrieved for further consideration. Upon review of the full publications and applying the inclusion and exclusion criteria, 5 RCTs were identified. Of these, two compared vertebroplasty with sham procedure, two compared vertebroplasty with conservative treatment, and one compared vertebroplasty with balloon kyphoplasty.
Randomized Controlled Trials
Recently, the results of two blinded randomized placebo-controlled trials of percutaneous vertebroplasty were reported. These trials, providing the highest quality of evidence available to date, do not support the use of vertebroplasty in patients with painful osteoporotic vertebral compression fractures. Based on the results of these trials, vertebroplasty offer no additional benefit over usual care and is not risk free.
In these trials the treatment allocation was blinded to the patients and outcome assessors. The control group received a sham procedure simulating vertebroplasty to minimize the effect of expectations and to reduce the potential for bias in self-reporting of outcomes. Both trials applied stringent exclusion criteria so that the results are generalizable to the patient populations that are candidates for vertebroplasty. In both trials vertebroplasty procedures were performed by highly skilled interventionists. Multiple valid outcome measures including pain, physical, mental, and social function were employed to test the between group differences in outcomes.
Prior to these two trials, there were two open randomized trials in which vertebroplasty was compared with conservative medical treatment. In the first randomized trial, patients were allowed to cross over to the other arm and had to be stopped after two weeks due to the high numbers of patients crossing over. The other study did not allow cross over and recently published the results of 12 months follow-up.
The following is the summary of the results of these 4 trials:
Two blinded RCTs on vertebroplasty provide the highest level of evidence available to date. Results of these two trials are supported by findings of an open randomized trial with 12 months follow-up. Blinded RCTs showed:
No significant differences in pain scores of patients who received vertebroplasty and patients who received a sham procedure as measured at 3 days, 2 weeks and 1 month in one study and at 1 week, 1 month, 3 months, and 6 months in the other.
The observed differences in pain scores between the two groups were neither statistically significant nor clinically important at any time points.
The above findings were consistent with the findings of an open RCT in which patients were followed for 12 months. This study showed that improvement in pain was similar between the two groups at 3 months and were sustained to 12 months.
In the blinded RCTs, physical, mental, and social functioning were measured at the above time points using 4-5 of the following 7 instruments: RDQ, EQ-5D, SF-36 PCS, SF-36 MCS, AQoL, QUALEFFO, SOF-ADL
There were no significant differences in any of these measures between patients who received vertebroplasty and patients who received a sham procedure at any of the above time points (with a few exceptions in favour of control intervention).
These findings were also consistent with the findings of an open RCT which demonstrated no significant between group differences in scores of ED-5Q, SF-36 PCS, SF 36 MCS, DPQ, Barthel, and MMSE which measure physical, mental, and social functioning (with a few exceptions in favour of control intervention).
One small (n=34) open RCT with a two week follow-up detected a significantly higher improvement in pain scores at 1 day after the intervention in vertebroplasty group compared with conservative treatment group. However, at 2 weeks follow-up, this difference was smaller and was not statistically significant.
Conservative treatment was associated with fewer clinically important complications
Risk of new VCFs following vertebroplasty was higher than those in conservative treatment but it requires further investigation.
PMCID: PMC3377535  PMID: 23074396
2.  Metal-on-Metal Total Hip Resurfacing Arthroplasty 
Executive Summary
Objective
The objective of this review was to assess the safety and effectiveness of metal on metal (MOM) hip resurfacing arthroplasty for young patients compared with that of total hip replacement (THR) in the same population.
Clinical Need
Total hip replacement has proved to be very effective for late middle-aged and elderly patients with severe degenerative diseases of the hips. As indications for THR began to include younger patients and those with a more active life style, the longevity of the implant became a concern. Evidence suggests that these patients experience relatively higher rates of early implant failure and the need for revision. The Swedish hip registry, for example, has demonstrated a survival rate in excess of 80% at 20 years for those aged over 65 years, whereas this figure was 33% by 16 years in those aged under 55 years.
Hip resurfacing arthroplasty is a bone-conserving alternative to THR that restores normal joint biomechanics and load transfer. The technique has been used around the world for more than 10 years, specifically in the United Kingdom and other European countries.
The Technology
Metal-on-metal hip resurfacing arthroplasty is an alternative procedure to conventional THR in younger patients. Hip resurfacing arthroplasty is less invasive than THR and addresses the problem of preserving femoral bone stock at the initial operation. This means that future hip revisions are possible with THR if the initial MOM arthroplasty becomes less effective with time in these younger patients. The procedure involves the removal and replacement of the surface of the femoral head with a hollow metal hemisphere, which fits into a metal acetabular cup.
Hip resurfacing arthroplasty is a technically more demanding procedure than is conventional THR. In hip resurfacing, the femoral head is retained, which makes it much more difficult to access the acetabular cup. However, hip resurfacing arthroplasty has several advantages over a conventional THR with a small (28 mm) ball. First, the large femoral head reduces the chance of dislocation, so that rates of dislocation are less than those with conventional THR. Second, the range of motion with hip resurfacing arthroplasty is higher than that achieved with conventional THR.
A variety of MOM hip resurfacing implants are used in clinical practice. Six MOM hip resurfacing implants have been issued licences in Canada.
Review Strategy
A search of electronic bibliographies (OVID Medline, Medline In-Process and Other Non-Indexed Citations, Embase, Cochrane CENTRAL and DSR, INAHTA) was undertaken to identify evidence published from Jan 1, 1997 to October 27, 2005. The search was limited to English-language articles and human studies. The literature search yielded 245 citations. Of these, 11 met inclusion criteria (9 for effectiveness, 2 for safety).
The result of the only reported randomized controlled trial on MOM hip resurfacing arthroplasty could not be included in this assessment, because it used a cemented acetabular component, whereas in the new generation of implants, a cementless acetabular component is used. After omitting this publication, only case series remained.
Summary of Findings
 
Health Outcomes
The Harris hip score and SF-12 are 2 measures commonly used to report health outcomes in MOM hip resurfacing arthroplasty studies. Other scales used are the Oxford hip score and the University of California Los Angeles hip score.
The case series showed that the mean revision rate of MOM hip resurfacing arthroplasty is 1.5% and the incidence of femoral neck fracture is 0.67%. Across all studies, 2 cases of osteonecrosis were reported. Four studies reported improvement in Harris hip scores. However, only 1 study reported a statistically significant improvement. Three studies reported improvement in SF-12 scores, of which 2 reported a significant improvement. One study reported significant improvement in UCLA hip score. Two studies reported postoperative Oxford hip scores, but no preoperative values were reported.
None of the reviewed studies reported procedure-related deaths. Four studies reported implant survival rates ranging from 94.4% to 99.7% for a follow-up period of 2.8 to 3.5 years. Three studies reported on the range of motion. One reported improvement in all motions including flexion, extension, abduction-adduction, and rotation, and another reported improvement in flexion. Yet another reported improvement in range of motion for flexion abduction-adduction and rotation arc. However, the author reported a decrease in the range of motion in the arc of flexion in patients with Brooker class III or IV heterotopic bone (all patients were men).
Safety of Metal-on-Metal Hip Resurfacing Arthroplasty
There is a concern about metal wear debris and its systemic distribution throughout the body. Detectable metal concentrations in the serum and urine of patients with metal hip implants have been described as early as the 1970s, and this issue is still controversial after 35 years.
Several studies have reported high concentration of cobalt and chromium in serum and/or urine of the patients with metal hip implants. Potential toxicological effects of the elevated metal ions have heightened concerns about safety of MOM bearings. This is of particular concern in young and active patients in whom life expectancy after implantation is long.
Since 1997, 15 studies, including 1 randomized clinical trial, have reported high levels of metal ions after THR with metal implants. Some of these studies have reported higher metal levels in patients with loose implants.
Adverse Biological Effects of Cobalt and Chromium
Because patients who receive a MOM hip arthroplasty are shown to be exposed to high concentrations of metallic ions, the Medical Advisory Secretariat searched the literature for reports of adverse biological effects of cobalt and chromium. Cobalt and chromium make up the major part of the metal articulations; therefore, they are a focus of concern.
Risk of Cancer
To date, only one study has examined the incidence of cancer after MOM and polyethylene on metal total hip arthroplasties. The results were compared to that of general population in Finland. The mean duration of follow-up for MOM arthroplasty was 15.7 years; for polyethylene arthroplasty, it was 12.5 years. The standardized incidence ratio for all cancers in the MOM group was 0.95 (95% CI, 0.79–1.13). In the polyethylene on metal group it was 0.76 (95% CI, 0.68–0.86). The combined standardized incidence ratio for lymphoma and leukemia in the patients who had MOM THR was 1.59 (95% CI, 0.82–2.77). It was 0.59 (95% CI, 0.29–1.05) for the patients who had polyethylene on metal THR. Patients with MOM THR had a significantly higher risk of leukemia. All patients who had leukemia were aged over than 60 years.
Cobalt Cardiotoxicity
 
Epidemiological Studies of Myocardiopathy of Beer Drinkers
An unusual type of myocardiopathy, characterized by pericardial effusion, elevated hemoglobin concentrations, and congestive heart failure, occurred as an epidemic affecting 48 habitual beer drinkers in Quebec City between 1965 and 1966. This epidemic was directly related the consumption of a popular beer containing cobalt sulfate. The epidemic appeared 1 month after cobalt sulfate was added to the specific brewery, and no further cases were seen a month after this specific chemical was no longer used in making this beer. A beer of the same name is made in Montreal, and the only difference at that time was that the Quebec brand of beer contained about 10 times more cobalt sulphate. Cobalt has been added to some Canadian beers since 1965 to improve the stability of the foam but it has been added in larger breweries only to draught beer. However, in small breweries, such as those in Quebec City, separate batches were not brewed for bottle and draught beer; therefore, cobalt was added to all of the beer processed in this brewery.
In March 1966, a committee was appointed under the chairmanship of the Deputy Minister of Health for Quebec that included members of the department of forensic medicine of Quebec’s Ministry of Justice, epidemiologists, members of Food and Drug Directorate of Ottawa, toxicologists, biomedical researchers, pathologists, and members of provincial police. Epidemiological studies were carried out by the Provincial Ministry of Health and the Quebec City Health Department.
The association between the development of myocardiopathy and the consumption of the particular brand of beer was proven. The mortality rate of this epidemic was 46.1% and those who survived were desperately ill, and recovered only after a struggle for their lives.
Similar cases were seen in Omaha (Nebraska). The epidemic started after a cobalt additive was used in 1 of the beers marketed in Nebraska. Sixty-four patients with the clinical diagnosis of alcoholic myocardiopathy were seen during an 18-month period (1964–1965). Thirty of these patients died. The first patient became ill within 1 month after cobalt was added to the beer, and the last patient was seen within 1 month of withdrawal of cobalt.
A similar epidemic occurred in Minneapolis, Minnesota. Between 1964 and 1967, 42 patients with acute heart failure were admitted to a hospital in Minneapolis, Minnesota. Twenty of these patients were drinking 6 to 30 bottles per day of a particular brand of beer exclusively. The other 14 patients also drank the same brand of beer, but not exclusively. The mortality rate from the acute illness was 18%, but late deaths accounted for a total mortality rate of 43%. Examination of the tissue from these patients revealed markedly abnormal changes in myofibrils (heart muscles), mitochondria, and sarcoplasmic reticulum.
In Belgium, a similar epidemic was reported in 1966, in which, cobalt was used in some Belgian beers. There was a difference in mortality between the Canadian or American epidemic and this series. Only 1 of 24 patients died, 1.5 years after the diagnosis. In March 1965, at an international meeting in Brussels, a new heart disease in chronic beer drinkers was described. This disease consists of massive pericardial effusion, low cardiac output, raised venous pressure, and polycythemia in some cases. This syndrome was thought to be different from the 2 other forms of alcoholic heart disease (beriberi and a form characterized by myocardial fibrosis).
The mystery of the above epidemics as stated by investigators is that the amount of cobalt added to the beer was below the therapeutic doses used for anemia. For example, 24 pints of Quebec brand of beer in Quebec would contain 8 mg of cobalt chloride, whereas an intake of 50 to 100 mg of cobalt as an antianemic agent has been well tolerated. Thus, greater cobalt intake alone does not explain the occurrence of myocardiopathy. It seems that there are individual differences in cobalt toxicity. Other features, like subclinical alcoholic heart disease, deficient diet, and electrolyte imbalance could have been precipitating factors that made these patients susceptible to cobalt’s toxic effects.
In the Omaha epidemic, 60% of the patients had weight loss, anorexia, and occasional vomiting and diarrhea 2 to 6 months before the onset of cardiac symptoms. In the Quebec epidemic, patients lost their appetite 3 to 6 months before the diagnosis of myocardiopathy and developed nausea in the weeks before hospital admission. In the Belgium epidemic, anorexia was one of the most predominant symptoms at the time of diagnosis, and the quality and quantity of food intake was poor. Alcohol has been shown to increase the uptake of intracoronary injected cobalt by 47%. When cobalt enters the cells, calcium exits; this shifts the cobalt to calcium ratio. The increased uptake of cobalt in alcoholic patients may explain the high incidence of cardiomyopathies in beer drinkers’ epidemics.
As all of the above suggest, it may be that prior chronic exposure to alcohol and/or a nutritionally deficient diet may have a marked synergistic effect with the cardiotoxicity of cobalt.
Conclusions
MOM hip resurfacing arthroplasty has been shown to be an effective arthroplasty procedure as tested in younger patients.
However, evidence for effectiveness is based only on 7 case series with short duration of follow-up (2.8–3.5 years). There are no RCTs or other well-controlled studies that compare MOM hip resurfacing with THR.
Revision rates reported in the MOM studies using implants currently licensed in Canada (hybrid systems, uncemented acetabular, and cemented femoral) range from 0.3% to 3.6% for a mean follow-up ranging from 2.8 to 3.5 years.
Fracture of femoral neck is not very common; it occurs in 0.4% to 2.2% of cases (as observed in a short follow-up period).
All the studies that measured health outcomes have reported improvement in Harris Hip and SF-12 scores; 1 study reported significant reduction in pain and improvement in function, and 2 studies reported significant improvement in SF-12 scores. One study reported significant improvement in UCLA Hip scores.
Concerns remain on the potential adverse effects of metal ions. Longer-term follow-up data will help to resolve the inconsistency of findings on adverse effects, including toxicity and carcinogenicity.
Ontario-Based Economic Analysis
The device cost for MOM ranges from $4,300 to $6,000 (Cdn). Traditional hip replacement devices cost about $2,000 (Cdn). Using Ontario Case Costing Initiative data, the total estimated costs for hip resurfacing surgery including physician fees, device fees, follow-up consultation, and postsurgery rehabilitation is about $15,000 (Cdn).
Cost of Total Hip Replacement Surgery in Ontario
MOM hip arthroplasty is generally recommended for patients aged under 55 years because its bone-conserving advantage enables patients to “buy time” and hence helps THRs to last over the lifetime of the patient. In 2004/2005, 15.9% of patients who received THRs were aged 55 years and younger. It is estimated that there are from 600 to 1,000 annual MOM hip arthroplasty surgeries in Canada with an estimated 100 to 150 surgeries in Ontario. Given the increased public awareness of this device, it is forecasted that demand for MOM hip arthroplasty will steadily increase with a conservative estimate of demand rising to 1,400 cases by 2010 (Figure 10). The net budget impact over a 5-year period could be $500,000 to $4.7 million, mainly because of the increasing cost of the device.
Projected Number of Metal-on-Metal Hip Arthroplasty Surgeries in Ontario: to 2010
PMCID: PMC3379532  PMID: 23074495
3.  The Risk of Fractures Associated with Thiazolidinediones: A Self-controlled Case-Series Study 
PLoS Medicine  2009;6(9):e1000154.
Ian Douglas and colleagues analyze records from the UK General Practice Research Database, and find that among individuals prescribed thiazolidinediones who develop a fracture, fractures are more common during periods of thiazolidinedione exposure than unexposed periods.
Background
The results of clinical trials have suggested that the thiazolidinedione antidiabetic agents rosiglitazone and pioglitazone are associated with an increased risk of fractures, but such studies had limited power. The increased risk in these trials appeared to be limited to women and mainly involved fractures of the arm, wrist, hand, or foot: risk patterns that could not be readily explained. Our objective was to further investigate the risk of fracture associated with thiazolidinedione use.
Methods and Findings
The self-controlled case-series design was used to compare rates of fracture during thiazolidinedione exposed and unexposed periods and thus estimate within-person rate ratios. We used anonymised primary care data from the United Kingdom General Practice Research Database (GPRD). All patients aged 40 y or older with a recorded fracture and at least one prescription for a thiazolidinedione were included (n = 1,819). We found a within-person rate ratio of 1.43 (95% confidence interval [CI] 1.25–1.62) for fracture at any site comparing exposed with unexposed periods among patients prescribed any thiazolidinedione. This association was similar in men and women and in patients treated with either rosiglitazone or pioglitazone. The increased risk was also evident at a range of fracture sites, including hip, spine, arm, foot, wrist, or hand. The risk increased with increasing duration of thiazolidinedione exposure: rate ratio 2.00 (95% CI 1.48–2.70) for 4 y or more of exposure.
Conclusion
Within individuals who experience a fracture, fracture risk is increased during periods of exposure to thiazolidinediones (both rosiglitazone and pioglitazone) compared with unexposed periods. The increased risk is observed in both men and women and at a range of fracture sites. The risk also increases with longer duration of use.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, nearly 250 million people have diabetes and this number is increasing rapidly, particularly in developing countries. Diabetes is a chronic disease characterized by dangerous amounts of sugar (glucose) in the blood. Blood-sugar levels are normally controlled by insulin, a hormone that the pancreas releases when blood-sugar levels rise after eating (the digestion of food produces glucose). Blood-sugar control fails in people with diabetes because they make no insulin (type 1 diabetes) or because the fat cells and muscle cells that usually respond to insulin by removing sugar from the blood have become insulin insensitive (type 2 diabetes). Type 1 diabetes is treated with insulin injections; type 2 diabetes—the most common type of diabetes—is controlled with diet, exercise, and antidiabetic pills, drugs that help the pancreas make more insulin (for example, sulfonylureas) or that make cells more sensitive to insulin (for example, thiazolidinediones). Long-term complications of diabetes include kidney failure, blindness, and nerve damage, and an increased risk of developing cardiovascular problems, including heart disease and strokes.
Why Was This Study Done?
Thiazolidinediones are widely used to treat type 2 diabetes but, worryingly, these drugs seem to increase people's risk of developing cardiovascular problems. In addition, they may increase the risk of bone fractures although the evidence for this particular association is limited. Given the large number of people with diabetes, it is important to understand the benefits and risks of thiazolidinedione treatment of diabetes as fully as possible. In this self-controlled case-series study, therefore, the researchers investigate the risk of fracture associated with the use of rosiglitazone and pioglitazone (two thiazolidinedione antidiabetic agents). A “self-controlled case-series study” compares how often an event (in this case, a fracture) occurs (the event's “rate”) in a population of individuals during a period of time when the individuals are not exposed to a medical intervention (in this case, treatment with thiazolidinediones) to its rate during a period when they are exposed to the intervention. Because each person acts as their own control, this study design helps to eliminate the possibility that unrecognized characteristics that vary between people (“confounders”) are responsible for differences in the event rate rather than the intervention itself.
What Did the Researchers Do and Find?
The researchers identified 1,819 people aged 40 years or older with a recorded fracture and at least one prescription for a thiazolidinedione by searching the UK General Practice Research Database, which contains personal and health data for more than 6 million UK residents. They compared these people's fracture rate during periods when they were taking a thiazolidinedione to their fracture rate when they weren't taking one of these drugs. After adjusting for age (age is a potential confounder because the risk of fractures increases with age and all the patients were older during their exposed period than during their unexposed period), the rate ratio for fracture at any site in patients during thiazolidinedione-exposed periods compared with thiazolidinedione-unexposed periods was 1.43. That is, nearly one and half times as many fractures occurred when people were taking thiazolidinediones than when they were not taking these drugs. The association between taking thiazolidinediones and the risk of fracture was similar in men and women and at several fracture sites but increased with the length of thiazolidinedione exposure.
What Do These Findings Mean?
These findings suggest that taking thiazolidinediones is associated with an increased risk of fracture at a wide range of sites in both men and women. They also suggest that the risk of fracture increases with treatment duration. These findings do not prove that thiazolidinediones cause fractures because, despite the self-controlled case-series design of this study, it remains possible that the people who have fractures share some unknown characteristic that affects their chances of breaking a bone. The accuracy of the findings is also dependent on the quality of the data in the General Practice Research Database. Nonetheless, these results are in keeping with the findings of clinical trials and other observational studies, suggesting they represent a real effect of treatment with thiazolidinediones. Although it is not clear yet how thiazolidinediones weaken bones, these findings need to be included in the ongoing debate about the risks and benefits of the treatment of type 2 diabetes with thiazolidinediones.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000154.
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information ClearingHouse provides detailed information about diabetes (including information on medicines for diabetes) for patients, health-care professionals, and the general public (in English and Spanish)
The UK National Health Service also provides information for patients and carers about type 2 diabetes (in several languages)
MedlinePlus provides links to further resources and advice about diabetes and diabetes medicines (in English and Spanish)
Information about the UK General Practice Research Database and about the self-controlled case-series method is available
More information is available where the research was done at The London School of Hygiene & Tropical Medicine
doi:10.1371/journal.pmed.1000154
PMCID: PMC2741577  PMID: 19787025
4.  A phase II trial for the efficacy of physiotherapy intervention for early-onset hip osteoarthritis: study protocol for a randomised controlled trial 
Trials  2015;16:26.
Background
Early-onset hip osteoarthritis is commonly seen in people undergoing hip arthroscopy and is associated with increased pain, reduced ability to participate in physical activity, reduced quality of life and reduced range of motion and muscle strength. Despite this, the efficacy of non-surgical interventions such as exercise therapies remains unknown. The primary aim is to establish the feasibility of a phase III randomised controlled trial investigating a targeted physiotherapy intervention for people with early-onset hip osteoarthritis. The secondary aims are to determine the size of treatment effects of a physiotherapy intervention, targeted to improve hip joint range and hip-related symptoms in early-onset hip osteoarthritis following hip arthroscopy, compared to a health-education control.
Methods
This protocol describes a randomised, assessor- and participant-blind, controlled clinical trial. We will include 20 participants who are (i) aged between 18 and 50 years; (ii) have undergone hip arthroscopy during the past six to 12 months; (iii) have early-onset hip osteoarthritis (defined as chondrolabral pathology) at the time of hip arthroscopy; and (iv) experience hip-related pain during activities. Primary outcome will be the feasibility of a phase III clinical trial. Secondary outcomes will be (i) perceived global change score; (ii) hip-related symptoms (measured using the Hip disability and Osteoarthritis Outcome Score (HOOS) pain subscale, activity subscale, and sport and recreation subscale); (iii) hip quality of life (measured using the HOOS quality of life subscale and International Hip Outcome tool; (iv) hip muscle strength and (v) hip range of motion. The physiotherapy intervention is semi-standardised, including joint and soft tissue mobilisation and stretching, hip and trunk muscle retraining and functional and activity-specific retraining and education. The control intervention encompasses individualised health education, with the same frequency and duration as the intervention. The trial primary end-point is the conclusion of the 12-week intervention, and follow-up measures will be collected at the 12-week post-baseline assessment.
Discussion
The findings of this study will provide guidance regarding the feasibility of a full-scale phase III randomised controlled trial, prior to its undertaking.
Trial registration
The trial protocol was registered with the Australian Clinical Trials Registry (number: 12614000426684) on 17 April 2014.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0543-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-014-0543-7
PMCID: PMC4318367  PMID: 25622524
Osteoarthritis; Hip joint; Hip arthroscopy; Randomised controlled trial; Physiotherapy
5.  Hip Fracture Incidence in Relation to Age, Menopausal Status, and Age at Menopause: Prospective Analysis 
PLoS Medicine  2009;6(11):e1000181.
Using data from the UK Million Women Study, Emily Banks and colleagues investigate the relationships between the incidence of hip fracture and a woman's age, menopausal status, and age at menopause.
Background
Bone mineral density is known to decrease rapidly after the menopause. There is limited evidence about the separate contributions of a woman's age, menopausal status and age at menopause to the incidence of hip fracture.
Methods and Findings
Over one million middle-aged women joined the UK Million Women Study in 1996–2001 providing information on their menopausal status, age at menopause, and other factors, which was updated, where possible, 3 y later. All women were registered with the UK National Health Service (NHS) and were routinely linked to information on cause-specific admissions to NHS hospitals. 561,609 women who had never used hormone replacement therapy and who provided complete information on menopausal variables (at baseline 25% were pre/perimenopausal and 75% postmenopausal) were followed up for a total of 3.4 million woman-years (an average 6.2 y per woman). During follow-up 1,676 (0.3%) were admitted to hospital with a first incident hip fracture. Among women aged 50–54 y the relative risk (RR) of hip fracture risk was significantly higher in postmenopausal than premenopausal women (adjusted RR 2.22, 95% confidence interval [CI] 1.22–4.04; p = 0.009); there were too few premenopausal women aged 55 y and over for valid comparisons. Among postmenopausal women, hip fracture incidence increased steeply with age (p<0.001), with rates being about seven times higher at age 70–74 y than at 50–54 y (incidence rates of 0.82 versus 0.11 per 100 women over 5 y). Among postmenopausal women of a given age there was no significant difference in hip fracture incidence between women whose menopause was due to bilateral oophorectomy compared to a natural menopause (adjusted RR 1.20, 95% CI 0.94–1.55; p = 0.15), and age at menopause had little, if any, effect on hip fracture incidence.
Conclusions
At around the time of the menopause, hip fracture incidence is about twice as high in postmenopausal than in premenopausal women, but this effect is short lived. Among postmenopausal women, age is by far the main determinant of hip fracture incidence and, for women of a given age, their age at menopause has, at most, a weak additional effect.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Anyone can break a hip but most hip fractures occur in elderly people. As people age, their bones gradually lose minerals and become less dense, which weakens the bones and makes them more susceptible to fracture. Because women lose bone density faster than men as they age and because women constitute the majority of the elderly, three-quarters of hip fractures occur in women. Hip fractures can cause long-term health problems and premature death. Thus, although surgical repair of a broken hip usually only requires a hospital stay of about a week, a quarter of elderly people who were living independently before their fracture have to stay in a nursing home for at least a year after their injury and a fifth of elderly people who break a hip die within the year. Most hip fractures are caused by falls. Regular exercise to improve strength and balance combined with review of medicines (to reduce side effects and interactions), regular eye examinations, and the removal of fall hazards from the home can help to prevent hip fractures in elderly people.
Why Was This Study Done?
Bone density decreases very rapidly in women immediately after menopause—the time when menstruation permanently stops—and then continues to decrease more slowly with age. Most women have their menopause in their early 50s but menopause can occur in younger women. Early menopause is thought to be a risk factor for osteoporosis (thinning of the bones) and fractures later in life but little is known about how menopause influences hip fracture risk as women age. In this prospective study (a type of study in which a group of people is followed for several years to see whether they develop a particular condition), the researchers investigate the incidence of hip fractures in relation to age, menopausal status, and age at menopause among the participants of the Million Women Study. This study, which recruited 1.3 million women aged 50–64 years who attended UK breast cancer screening clinics between 1996 and 2001, has been investigating how reproductive and lifestyle factors affect women's health.
What Did the Researchers Do and Find?
At enrollment and three years later, the study participants provided information about their menopausal status and other health and lifestyle factors likely to affect their fracture risk. From these data, the researchers identified more than half a million women who had never used hormone replacement therapy (which reduces fracture risk) and who had given complete information about their menopausal status. They then looked for statistical associations between the occurrence of a first hip fracture in these women over the next few years and their age, menopausal status, and age at menopause. Among women aged 50–54 years, postmenopausal women were twice as likely to have a hip fracture as premenopausal women. Among postmenopausal women, the incidence of hip fractures increased steeply with age and was seven times higher in 70–74-year olds than in 50–54-year olds. Women who had their menopause before age 45 had a slightly increased risk of hip fracture but any effect of age at menopause on the risk of hip fracture was small compared to the effect of age itself, and the slightly increased risk may have been due to other factors that could not be fully accounted for in the analysis.
What Do These Findings Mean?
These findings indicate that around the time of menopause, although hip fractures are rare, the risk of a fracture in postmenopausal women is twice that in premenopausal women. The findings also show that among postmenopausal women, age is the major determinant of hip fracture risk and that for women of a given age, their age at menopause has little effect on hip fracture risk. Women attending breast cancer screening clinics and completing questionnaires about their health may not be representative of the general population. Furthermore, these findings rely on women self-reporting their menopausal status accurately. Nevertheless, the results of this study suggest that clinicians advising women about hip fracture prevention should probably base their advice on the woman's age and on age-related factors such as frailty rather than on factors related to menopause. Clinicians can also now reassure elderly women who had an early menopause that their risk of hip fracture is unlikely to be higher than that of similar women who had a later menopause.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000181.
The American Academy of Orthopaedic Surgeons has detailed information about hip fractures
The US National Institute of Arthritis and Muscoloskeletal and Skin Diseases has an interactive feature called “Check up on your bones and provides detailed information about osteoporosis, including advice on fall prevention
The US Centers for Disease Control and Prevention has a fact sheet about hip fractures among older adults
MedlinePlus has links to resources about hip fracture, osteoporosis, and menopause (in English and Spanish)
More information on the Million Women Study is available
doi:10.1371/journal.pmed.1000181
PMCID: PMC2766835  PMID: 19901981
6.  Hip fracture epidemiological trends, outcomes, and risk factors, 1970–2009 
Hip fractures – which commonly lead to premature death, high rates of morbidity, or reduced life quality – have been the target of a voluminous amount of research for many years. But has the lifetime risk of incurring a hip fracture decreased sufficiently over the last decade or are high numbers of incident cases continuing to prevail, despite a large body of knowledge and a variety of contemporary preventive and refined surgical approaches? This review examines the extensive hip fracture literature published in the English language between 1980 and 2009 concerning hip fracture prevalence trends, and injury mechanisms. It also highlights the contemporary data concerning the personal and economic impact of the injury, plus potentially remediable risk factors underpinning the injury and ensuing disability. The goal was to examine if there is a continuing need to elucidate upon intervention points that might minimize the risk of incurring a hip fracture and its attendant consequences. Based on this information, it appears hip fractures remain a serious global health issue, despite some declines in the incidence rate of hip fractures among some women. Research also shows widespread regional, ethnic and diagnostic variations in hip fracture incidence trends. Key determinants of hip fractures include age, osteoporosis, and falls, but some determinants such as socioeconomic status, have not been well explored. It is concluded that while more research is needed, well-designed primary, secondary, and tertiary preventive efforts applied in both affluent as well as developing countries are desirable to reduce the present and future burden associated with hip fracture injuries. In this context, and in recognition of the considerable variation in manifestation and distribution, as well as risk factors underpinning hip fractures, well-crafted comprehensive, rather than single solutions, are strongly indicated in early rather than late adulthood.
PMCID: PMC2866546  PMID: 20463818
epidemiology; disability; hip fractures; injury; prevention; risk factors
7.  Surgery Versus Epilation for the Treatment of Minor Trichiasis in Ethiopia: A Randomised Controlled Noninferiority Trial 
PLoS Medicine  2011;8(12):e1001136.
In this randomized, non-inferiority trial, Saul Rajak et al compare epilation and surgery for the management of minor trichiasis in Ethiopia, the country with the most cases of trachomatous trichiasis.
Background
Trachomatous trichiasis can cause corneal damage and visual impairment. WHO recommends surgery for all cases. However, in many regions surgical provision is inadequate and patients frequently decline. Self-epilation is common and was associated with comparable outcomes to surgery in nonrandomised studies for minor trichiasis (
Methods and Findings
1,300 individuals with minor trichiasis from Amhara Regional State, Ethiopia were recruited and randomly assigned (1∶1) to receive trichiasis surgery or epilation. The epilation group were given new forceps and epilation training. The surgical group received trichiasis surgery. Participants were examined every 6 months for 2 years by clinicians masked to allocation, with 93.5% follow-up at 24 months. The primary outcome measure (“failure”) was ≥five lashes touching the eye or receiving trichiasis surgery during 24 months of follow-up, and was assessed for noninferiority with a 10% prespecified noninferiority margin. Secondary outcomes included number of lashes touching, time to failure, and changes in visual acuity and corneal opacity.
Cumulative risk of failure over 24 months was 13.2% in the epilation group and 2.2% in the surgical group (risk difference = 11%). The 95% confidence interval (8.1%–13.9%) includes the 10% noninferiority margin. Mean number of lashes touching the eye was greater in the epilation group than the surgery group (at 24 months 0.95 versus 0.09, respectively; p<0.001); there was no difference in change in visual acuity or corneal opacity between the two groups.
Conclusions
This trial was inconclusive regarding inferiority of epilation to surgery for the treatment of minor trichiasis, relative to the prespecified margin. Epilation had a comparable effect to surgery on visual acuity and corneal outcomes. We suggest that surgery be performed whenever possible but epilation be used for treatment of minor trichiasis patients without access to or declining surgery.
Trial registration
ClinicalTrials.gov NCT00522912
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 40 million people are affected at any one time by active trachoma, an infectious eye disease caused by the bacterium Chlamydia trachomatis. Trachoma, which is responsible for more than 3% of the world's blindness, mostly affects people living in rural areas in developing countries where there are water shortages, poor personal hygiene, and crowded living conditions. C. trachomatis is spread through contact with infected eye secretions or with contaminated towels or clothes, and by flies. Recurrent infections with C. trachomatis during childhood cause inflammation of the lining of the eye lid (chronic conjunctival inflammation), which can lead to conjunctival scarring. If this scarring is severe, the eyelids turn inwards and the eye lashes rub across the eye's surface (the cornea). This condition—trachomatous trichiasis—is extremely painful. Patients describe the pain like having thorns scraping their eyes when they blink. If left untreated, trichiasis can lead to irreversible corneal opacities and visual impairment.
Why Was This Study Done?
The SAFE strategy—surgery for trichiasis, antibiotics for infection, and facial cleanliness and environmental improvements to reduce transmission—aims to control trachoma in countries where it is common. Unfortunately, current surgical activity is only keeping up with new cases of trichiasis; it is not clearing the backlog. The reasons for this treatment gap are complex but in many regions surgical provision is inadequate. Moreover, although the World Health Organization recommends surgery for all cases of trachomatous trichiasis, people with minor trichiasis (only a few eyelashes touching the cornea) often decline surgery, preferring to pull out their eyelashes (epilation), an intervention that has to be repeated when the eyelashes regrow. In this randomized, noninferiority trial, the researchers compare epilation and surgery for the management of minor trichiasis in Ethiopia, the country with the most cases of trachomatous trichiasis. In a randomized trial, randomly chosen groups of patients are given different treatments for a disease and then followed to compare the outcomes of these interventions. A noninferiority trial investigates whether one treatment is not worse than another treatment.
What Did the Researchers Do and Find?
The researchers randomly assigned 1,300 Ethiopians with minor trichiasis to receive surgery or to be given epilation training and good quality epilation forceps. The primary trial outcome was “failure”—five or more lashes touching the eye or receiving trichiasis surgery during the 24-month follow-up period. The researchers decided in advance that epilation would be deemed noninferior to surgery if its failure rate was less than 10% greater than that of surgery (a noninferiority margin of 10%). Secondary outcomes included the number of lashes touching the eye and changes in visual acuity and corneal opacity. The cumulative risk of failure over 24 months was 13.2% in the epilation group and 2.2% in the surgical group, a difference of 11%. The 95% confidence interval for this difference was 8.1%–13.9%. That is, there was a 95% probability that the true failure rate lay within this range. The mean number of lashes touching the eye at 24 months was 0.95 and 0.09 in the epilation and surgery groups, respectively, a significant difference (that is, a difference unlikely to have occurred by chance). Finally, the changes in visual acuity or corneal opacity during the trial were similar in the two groups.
What Do These Findings Mean?
Because the 95% confidence interval for the difference in failure rate of the two interventions included the preset inferiority margin, these findings provide no evidence that epilation is noninferior to surgery for the management of minor trichiasis. That is, statistically speaking, this trial is inconclusive. Thus, if one were to consider only the primary clinical outcome when deciding whether to include epilation in the management of mild trichiasis, one would reject it because this trial indicates that surgery is better than epilation at preventing lashes touching the eye. However, epilation had a comparable effect to surgery on visual acuity and corneal opacity changes and, importantly, in real life, surgical services are likely to remain unacceptable, unavailable, inaccessible, or prohibitively expensive for many people with trachomatous trichiasis in the medium term. The researchers suggest, therefore, that surgery should be performed for minor trachomatous trichiasis whenever possible but that epilation should be considered when surgery is not available or is declined by the patient.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001136.
An accompanying PLoS Medicine Research Article by Saul Rajak et al. describes another randomized trial undertaken by these researchers that compares the use of absorbable and silk sutures for the surgical treatment of trachomatous trichiasis in Ethiopia
The World Health Organization has information on trachoma (in several languages), including details of the Alliance for Global Elimination of Trachoma by the year 2020 (GET 2020) and a personal story about blinding trachoma
The UK National Health Service Choices web site also provides information on trachoma
Orbis, an international nonprofit organization devoted to blindness prevention and treatment in developing countries, provides information about trachoma
The International Trachoma Initiative provides detailed personal story about trichiasis surgery in Ethiopia information about trachoma and a personal story about trichiasis surgery in Ethiopia
The Global Atlas of Trachoma is an open-access resource on the geographical distribution of trachoma
Light for the World is a nonprofit organization dedicated to ensuring the rights of persons with disabilities in developing countries, including people in Ethiopia with trachoma
doi:10.1371/journal.pmed.1001136
PMCID: PMC3236738  PMID: 22180731
Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture and has been linked with poorer lower extremity functioning, falls, and fractures. There is evidence that disability severity and fall rates may be reduced by adequate vitamin D replacement. However, the ideal regimen for vitamin D administration to have these benefits in older people who have been in the hospital has not been established. This randomized controlled trial will investigate the effects of an oral vitamin D loading dose with maintenance oral vitamin D and calcium on lower extremity function (gait velocity), correction of hypovitaminosis D, falls, and fractures among older people after hip fracture surgery. The cost-effectiveness of the REVITAHIP program from the health and community service provider’s perspective will also be established, as will predictors of adherence with the treatment. A total of 450 older people who have recently had a hip fracture requiring surgical intervention will be screened to achieve 250 participants for the study. Participants will have no medical contraindications to vitamin D replacement. The primary outcome measure will be mobility-related disability as measured with the 2.4-m gait velocity test. Secondary measures will be 25-hydroxyvitamin D (25-OHD) levels at 2, 4, and 26 weeks, number of falls and fractures, and additional measures of mobility, disability, quality of life, health system and community–service contact, adherence to the intervention, and adverse events. After surgical fixation and being deemed medically stable, participants will be randomly allocated to an intervention or placebo-control group. Participants of the intervention group will receive initial oral 250 000 IU (5 × 50 000 IU) vitamin D3 tablets. Both groups will receive oral maintenance vitamin D3 and calcium and will follow the usual hip fracture rehabilitation pathway. The study will determine the impact of a vitamin D loading dose on mobility-related disability in older people following hip fracture and will discuss the efficacy and cost-effectiveness of a loading dose vitamin D replacement more generally. The results will have direct implications for future use of vitamin D therapy for this high-risk group.
doi:10.1177/2151458511406723
PMCID: PMC3597307  PMID: 23569677
fragility fractures; geriatric medicine; hospitalist; metabolic bone disorders; osteoporosis; physical medicine and rehabilitation; trauma surgery
PLoS Medicine  2008;5(10):1-12.
Background
Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.
Methods and Findings
This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.
Conclusions
Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.
Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)
Angela Cheung and colleagues investigate whether vitamin K1 can prevent bone loss among postmenopausal women with osteopenia.
Editors' Summary
Background.
Osteoporosis is a bone disease in which the bones gradually become less dense and more likely to break. In the US, 10 million people have osteoporosis and 18 million have osteopenia, a milder condition that precedes osteoporosis. In both conditions, insufficient new bone is made and/or too much old bone is absorbed. Although bone appears solid and unchanging, very little bone in the human body is more than 10 y old. Old bone is continually absorbed and new bone built using calcium, phosphorous, and proteins. Because the sex hormones control calcium and phosphorous deposition in the bones and thus bone strength, the leading cause of osteoporosis in women is reduced estrogen levels after menopause. In men, an age-related decline in testosterone levels can cause osteoporosis. Most people discover they have osteoporosis only when they break a bone, but the condition can be diagnosed and monitored using bone mineral density (BMD) scans. Treatments can slow down or reverse bone loss (antiresorptive therapies) and some (bone formation therapies) can even make bone and build bone tissue.
Why Was This Study Done?
Although regular exercise and a healthy diet can help to keep bones strong, other ways of preventing osteoporosis are badly needed. Recently, the lay media has promoted vitamin K supplements as a way to reduce bone loss in postmenopausal women. Vitamin K (which is found mainly in leafy green vegetables) is required for a chemical modification of proteins called carboxylation. This modification is essential for the activity of three bone-building proteins. In addition, there is some evidence that low bone density and fractures are associated with a low vitamin K intake. However, little is known about the long-term benefits or harms of vitamin K supplements. In this study, the researchers investigate whether a high-dose daily vitamin K supplement can safely reduce bone loss, bone turnover, and fractures in postmenopausal women with osteopenia in a randomized controlled trial called the “Evaluation of the Clinical Use of Vitamin K Supplementation in Post-Menopausal Women With Osteopenia” (ECKO) trial.
What Did the Researchers Do and Find?
In the study, 440 postmenopausal women with osteopenia were randomized to receive 5mg of vitamin K1 (the type of vitamin K in North American food; the recommended daily adult intake of vitamin K1 is about 0.1 mg) or an inactive tablet (placebo) daily for 2 y; 261 of the women continued their treatment for 2 y to gather information about the long-term effects of vitamin K1 supplementation. All the women had regular bone density scans of their lower back and hips and were examined for fractures and for changes in bone turnover. After 2 y and after 4 y, lower back and hip bone density measurements had decreased by similar amounts in both treatment groups. The women who took vitamin K1 had 10-fold higher amounts of vitamin K1 in their blood than the women who took placebo and lower amounts of a bone formation marker; the levels of a bone resorption marker were similar in both groups. Over the 4-y period, fewer women in the vitamin K group had fractures (nine versus 20 women in the placebo group), and fewer had cancer (three versus 12). Finally, vitamin K supplementation was well tolerated over the 4-y period and adverse health effects were similar in the two treatment groups.
What Do These Findings Mean?
These findings indicate that a high daily dose of vitamin K1 provides no protection against the age-related decline in bone density in postmenopausal women with osteopenia, but that vitamin K1 supplementation may protect against fractures and cancers in these women. The apparent contradiction between the effects of vitamin K1 on bone density and on fractures could mean that vitamin K1 supplements strengthen bone by changing factors other than bone density, e.g., by changing its fine structure rather than making it denser. However, because so few study participants had fractures, the difference in the fracture rate between the two treatment groups might have occurred by chance. Larger studies are therefore needed to examine the effect of vitamin K1 on fractures (and on cancer) and, until these are done, high-dose vitamin K1 supplementation should not be recommended for the prevention of osteoporosis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050196.
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides detailed information about osteoporosis (in English and Spanish) and links to other resources, including an interactive web tool called Check Up On Your Bones
MedlinePlus provides links to additional information about osteoporosis (in English and Spanish)
The MedlinePlus Encyclopedia has a page about vitamin K
The UK Food Standards Agency provides information about vitamin K
Full details about the ECKO trial are available on the ClinicalTrials.gov Web site
The Canadian Task Force for Preventive Health Care provides recommendations on the prevention of osteoporosis and osteoporotic fractures in postmenopausal women
Osteoporosis Canada provides information on current topics related to osteoporosis
doi:10.1371/journal.pmed.0050196
PMCID: PMC2566998  PMID: 18922041
BMC Geriatrics  2011;11:30.
Background
Fall-related hip fractures result in significant personal and societal consequences; importantly, up to half of older adults with hip fracture never regain their previous level of mobility. Strategies of follow-up care for older adults after fracture have improved investigation for osteoporosis; but managing bone health alone is not enough. Prevention of fractures requires management of both bone health and falls risk factors (including the contributing role of cognition, balance and continence) to improve outcomes.
Methods/Design
This is a parallel group, pragmatic randomized controlled trial to test the effectiveness of a post-fracture clinic compared with usual care on mobility for older adults following their hospitalization for hip fracture. Participants randomized to the intervention will attend a fracture follow-up clinic where a geriatrician and physiotherapist will assess and manage their mobility and other health issues. Depending on needs identified at the clinical assessment, participants may receive individualized and group-based outpatient physiotherapy, and a home exercise program. Our primary objective is to assess the effectiveness of a novel post-discharge fracture management strategy on the mobility of older adults after hip fracture.
We will enrol 130 older adults (65 years+) who have sustained a hip fracture in the previous three months, and were admitted to hospital from home and are expected to be discharged home. We will exclude older adults who prior to the fracture were: unable to walk 10 meters; diagnosed with dementia and/or significant comorbidities that would preclude their participation in the clinical service.
Eligible participants will be randomly assigned to the Intervention or Usual Care groups by remote allocation. Treatment allocation will be concealed; investigators, measurement team and primary data analysts will be blinded to group allocation. Our primary outcome is mobility, operationalized as the Short Physical Performance Battery at 12 months. Secondary outcomes include frailty, rehospitalizations, falls risk factors, quality of life, as well as physical activity and sedentary behaviour. We will conduct an economic evaluation to determine health related costs in the first year, and a process evaluation to ascertain the acceptance of the program by older adults, as well as clinicians and staff within the clinic.
Trial registration number
ClinicalTrials.gov: NCT01254942
doi:10.1186/1471-2318-11-30
PMCID: PMC3132160  PMID: 21651819
Executive Summary
Issue
Systematic reviews and analyses of administrative data were performed to determine the appropriate use of bone mineral density (BMD) assessments using dual energy x-ray absorptiometry (DXA), and the associated trends in wrist and hip fractures in Ontario.
Background
Dual Energy X-ray Absorptiometry Bone Mineral Density Assessment
Dual energy x-ray absorptiometry bone densitometers measure bone density based on differential absorption of 2 x-ray beams by bone and soft tissues. It is the gold standard for detecting and diagnosing osteoporosis, a systemic disease characterized by low bone density and altered bone structure, resulting in low bone strength and increased risk of fractures. The test is fast (approximately 10 minutes) and accurate (exceeds 90% at the hip), with low radiation (1/3 to 1/5 of that from a chest x-ray). DXA densitometers are licensed as Class 3 medical devices in Canada. The World Health Organization has established criteria for osteoporosis and osteopenia based on DXA BMD measurements: osteoporosis is defined as a BMD that is >2.5 standard deviations below the mean BMD for normal young adults (i.e. T-score <–2.5), while osteopenia is defined as BMD that is more than 1 standard deviation but less than 2.5 standard deviation below the mean for normal young adults (i.e. T-score< –1 & ≥–2.5). DXA densitometry is presently an insured health service in Ontario.
Clinical Need
 
Burden of Disease
The Canadian Multicenter Osteoporosis Study (CaMos) found that 16% of Canadian women and 6.6% of Canadian men have osteoporosis based on the WHO criteria, with prevalence increasing with age. Osteopenia was found in 49.6% of Canadian women and 39% of Canadian men. In Ontario, it is estimated that nearly 530,000 Ontarians have some degrees of osteoporosis. Osteoporosis-related fragility fractures occur most often in the wrist, femur and pelvis. These fractures, particularly those in the hip, are associated with increased mortality, and decreased functional capacity and quality of life. A Canadian study showed that at 1 year after a hip fracture, the mortality rate was 20%. Another 20% required institutional care, 40% were unable to walk independently, and there was lower health-related quality of life due to attributes such as pain, decreased mobility and decreased ability to self-care. The cost of osteoporosis and osteoporotic fractures in Canada was estimated to be $1.3 billion in 1993.
Guidelines for Bone Mineral Density Testing
With 2 exceptions, almost all guidelines address only women. None of the guidelines recommend blanket population-based BMD testing. Instead, all guidelines recommend BMD testing in people at risk of osteoporosis, predominantly women aged 65 years or older. For women under 65 years of age, BMD testing is recommended only if one major or two minor risk factors for osteoporosis exist. Osteoporosis Canada did not restrict its recommendations to women, and thus their guidelines apply to both sexes. Major risk factors are age greater than or equal to 65 years, a history of previous fractures, family history (especially parental history) of fracture, and medication or disease conditions that affect bone metabolism (such as long-term glucocorticoid therapy). Minor risk factors include low body mass index, low calcium intake, alcohol consumption, and smoking.
Current Funding for Bone Mineral Density Testing
The Ontario Health Insurance Program (OHIP) Schedule presently reimburses DXA BMD at the hip and spine. Measurements at both sites are required if feasible. Patients at low risk of accelerated bone loss are limited to one BMD test within any 24-month period, but there are no restrictions on people at high risk. The total fee including the professional and technical components for a test involving 2 or more sites is $106.00 (Cdn).
Method of Review
This review consisted of 2 parts. The first part was an analysis of Ontario administrative data relating to DXA BMD, wrist and hip fractures, and use of antiresorptive drugs in people aged 65 years and older. The Institute for Clinical Evaluative Sciences extracted data from the OHIP claims database, the Canadian Institute for Health Information hospital discharge abstract database, the National Ambulatory Care Reporting System, and the Ontario Drug Benefit database using OHIP and ICD-10 codes. The data was analyzed to examine the trends in DXA BMD use from 1992 to 2005, and to identify areas requiring improvement.
The second part included systematic reviews and analyses of evidence relating to issues identified in the analyses of utilization data. Altogether, 8 reviews and qualitative syntheses were performed, consisting of 28 published systematic reviews and/or meta-analyses, 34 randomized controlled trials, and 63 observational studies.
Findings of Utilization Analysis
Analysis of administrative data showed a 10-fold increase in the number of BMD tests in Ontario between 1993 and 2005.
OHIP claims for BMD tests are presently increasing at a rate of 6 to 7% per year. Approximately 500,000 tests were performed in 2005/06 with an age-adjusted rate of 8,600 tests per 100,000 population.
Women accounted for 90 % of all BMD tests performed in the province.
In 2005/06, there was a 2-fold variation in the rate of DXA BMD tests across local integrated health networks, but a 10-fold variation between the county with the highest rate (Toronto) and that with the lowest rate (Kenora). The analysis also showed that:
With the increased use of BMD, there was a concomitant increase in the use of antiresorptive drugs (as shown in people 65 years and older) and a decrease in the rate of hip fractures in people age 50 years and older.
Repeat BMD made up approximately 41% of all tests. Most of the people (>90%) who had annual BMD tests in a 2-year or 3-year period were coded as being at high risk for osteoporosis.
18% (20,865) of the people who had a repeat BMD within a 24-month period and 34% (98,058) of the people who had one BMD test in a 3-year period were under 65 years, had no fracture in the year, and coded as low-risk.
Only 19% of people age greater than 65 years underwent BMD testing and 41% received osteoporosis treatment during the year following a fracture.
Men accounted for 24% of all hip fractures and 21 % of all wrist fractures, but only 10% of BMD tests. The rates of BMD tests and treatment in men after a fracture were only half of those in women.
In both men and women, the rate of hip and wrist fractures mainly increased after age 65 with the sharpest increase occurring after age 80 years.
Findings of Systematic Review and Analysis
Serial Bone Mineral Density Testing for People Not Receiving Osteoporosis Treatment
A systematic review showed that the mean rate of bone loss in people not receiving osteoporosis treatment (including postmenopausal women) is generally less than 1% per year. Higher rates of bone loss were reported for people with disease conditions or on medications that affect bone metabolism. In order to be considered a genuine biological change, the change in BMD between serial measurements must exceed the least significant change (variability) of the testing, ranging from 2.77% to 8% for precisions ranging from 1% to 3% respectively. Progression in BMD was analyzed, using different rates of baseline BMD values, rates of bone loss, precision, and BMD value for initiating treatment. The analyses showed that serial BMD measurements every 24 months (as per OHIP policy for low-risk individuals) is not necessary for people with no major risk factors for osteoporosis, provided that the baseline BMD is normal (T-score ≥ –1), and the rate of bone loss is less than or equal to 1% per year. The analyses showed that for someone with a normal baseline BMD and a rate of bone loss of less than 1% per year, the change in BMD is not likely to exceed least significant change (even for a 1% precision) in less than 3 years after the baseline test, and is not likely to drop to a BMD level that requires initiation of treatment in less than 16 years after the baseline test.
Serial Bone Mineral Density Testing in People Receiving Osteoporosis Therapy
Seven published meta-analysis of randomized controlled trials (RCTs) and 2 recent RCTs on BMD monitoring during osteoporosis therapy showed that although higher increases in BMD were generally associated with reduced risk of fracture, the change in BMD only explained a small percentage of the fracture risk reduction.
Studies showed that some people with small or no increase in BMD during treatment experienced significant fracture risk reduction, indicating that other factors such as improved bone microarchitecture might have contributed to fracture risk reduction.
There is conflicting evidence relating to the role of BMD testing in improving patient compliance with osteoporosis therapy.
Even though BMD may not be a perfect surrogate for reduction in fracture risk when monitoring responses to osteoporosis therapy, experts advised that it is still the only reliable test available for this purpose.
A systematic review conducted by the Medical Advisory Secretariat showed that the magnitude of increases in BMD during osteoporosis drug therapy varied among medications. Although most of the studies yielded mean percentage increases in BMD from baseline that did not exceed the least significant change for a 2% precision after 1 year of treatment, there were some exceptions.
Bone Mineral Density Testing and Treatment After a Fragility Fracture
A review of 3 published pooled analyses of observational studies and 12 prospective population-based observational studies showed that the presence of any prevalent fracture increases the relative risk for future fractures by approximately 2-fold or more. A review of 10 systematic reviews of RCTs and 3 additional RCTs showed that therapy with antiresorptive drugs significantly reduced the risk of vertebral fractures by 40 to 50% in postmenopausal osteoporotic women and osteoporotic men, and 2 antiresorptive drugs also reduced the risk of nonvertebral fractures by 30 to 50%. Evidence from observational studies in Canada and other jurisdictions suggests that patients who had undergone BMD measurements, particularly if a diagnosis of osteoporosis is made, were more likely to be given pharmacologic bone-sparing therapy. Despite these findings, the rate of BMD investigation and osteoporosis treatment after a fracture remained low (<20%) in Ontario as well as in other jurisdictions.
Bone Mineral Density Testing in Men
There are presently no specific Canadian guidelines for BMD screening in men. A review of the literature suggests that risk factors for fracture and the rate of vertebral deformity are similar for men and women, but the mortality rate after a hip fracture is higher in men compared with women. Two bisphosphonates had been shown to reduce the risk of vertebral and hip fractures in men. However, BMD testing and osteoporosis treatment were proportionately low in Ontario men in general, and particularly after a fracture, even though men accounted for 25% of the hip and wrist fractures. The Ontario data also showed that the rates of wrist fracture and hip fracture in men rose sharply in the 75- to 80-year age group.
Ontario-Based Economic Analysis
The economic analysis focused on analyzing the economic impact of decreasing future hip fractures by increasing the rate of BMD testing in men and women age greater than or equal to 65 years following a hip or wrist fracture. A decision analysis showed the above strategy, especially when enhanced by improved reporting of BMD tests, to be cost-effective, resulting in a cost-effectiveness ratio ranging from $2,285 (Cdn) per fracture avoided (worst-case scenario) to $1,981 (Cdn) per fracture avoided (best-case scenario). A budget impact analysis estimated that shifting utilization of BMD testing from the low risk population to high risk populations within Ontario would result in a saving of $0.85 million to $1.5 million (Cdn) to the health system. The potential net saving was estimated at $1.2 million to $5 million (Cdn) when the downstream cost-avoidance due to prevention of future hip fractures was factored into the analysis.
Other Factors for Consideration
There is a lack of standardization for BMD testing in Ontario. Two different standards are presently being used and experts suggest that variability in results from different facilities may lead to unnecessary testing. There is also no requirement for standardized equipment, procedure or reporting format. The current reimbursement policy for BMD testing encourages serial testing in people at low risk of accelerated bone loss. This review showed that biannual testing is not necessary for all cases. The lack of a database to collect clinical data on BMD testing makes it difficult to evaluate the clinical profiles of patients tested and outcomes of the BMD tests. There are ministry initiatives in progress under the Osteoporosis Program to address the development of a mandatory standardized requisition form for BMD tests to facilitate data collection and clinical decision-making. Work is also underway for developing guidelines for BMD testing in men and in perimenopausal women.
Conclusion
Increased use of BMD in Ontario since 1996 appears to be associated with increased use of antiresorptive medication and a decrease in hip and wrist fractures.
Data suggest that as many as 20% (98,000) of the DXA BMD tests in Ontario in 2005/06 were performed in people aged less than 65 years, with no fracture in the current year, and coded as being at low risk for accelerated bone loss; this is not consistent with current guidelines. Even though some of these people might have been incorrectly coded as low-risk, the number of tests in people truly at low risk could still be substantial.
Approximately 4% (21,000) of the DXA BMD tests in 2005/06 were repeat BMDs in low-risk individuals within a 24-month period. Even though this is in compliance with current OHIP reimbursement policies, evidence showed that biannual serial BMD testing is not necessary in individuals without major risk factors for fractures, provided that the baseline BMD is normal (T-score < –1). In this population, BMD measurements may be repeated in 3 to 5 years after the baseline test to establish the rate of bone loss, and further serial BMD tests may not be necessary for another 7 to 10 years if the rate of bone loss is no more than 1% per year. Precision of the test needs to be considered when interpreting serial BMD results.
Although changes in BMD may not be the perfect surrogate for reduction in fracture risk as a measure of response to osteoporosis treatment, experts advised that it is presently the only reliable test for monitoring response to treatment and to help motivate patients to continue treatment. Patients should not discontinue treatment if there is no increase in BMD after the first year of treatment. Lack of response or bone loss during treatment should prompt the physician to examine whether the patient is taking the medication appropriately.
Men and women who have had a fragility fracture at the hip, spine, wrist or shoulder are at increased risk of having a future fracture, but this population is presently under investigated and under treated. Additional efforts have to be made to communicate to physicians (particularly orthopaedic surgeons and family physicians) and the public about the need for a BMD test after fracture, and for initiating treatment if low BMD is found.
Men had a disproportionately low rate of BMD tests and osteoporosis treatment, especially after a fracture. Evidence and fracture data showed that the risk of hip and wrist fractures in men rises sharply at age 70 years.
Some counties had BMD utilization rates that were only 10% of that of the county with the highest utilization. The reasons for low utilization need to be explored and addressed.
Initiatives such as aligning reimbursement policy with current guidelines, developing specific guidelines for BMD testing in men and perimenopausal women, improving BMD reports to assist in clinical decision making, developing a registry to track BMD tests, improving access to BMD tests in remote/rural counties, establishing mechanisms to alert family physicians of fractures, and educating physicians and the public, will improve the appropriate utilization of BMD tests, and further decrease the rate of fractures in Ontario. Some of these initiatives such as developing guidelines for perimenopausal women and men, and developing a standardized requisition form for BMD testing, are currently in progress under the Ontario Osteoporosis Strategy.
PMCID: PMC3379167  PMID: 23074491
PLoS Medicine  2012;9(9):e1001313.
Lieven Huybregts and colleagues investigate how supplementing a general food distribution with a fortified lipid-based spread during a seasonal hunger gap in Chad affects anthropometric and morbidity outcomes for children aged 6 to 36 months.
Background
Recently, operational organizations active in child nutrition in developing countries have suggested that blanket feeding strategies be adopted to enable the prevention of child wasting. A new range of nutritional supplements is now available, with claims that they can prevent wasting in populations at risk of periodic food shortages. Evidence is lacking as to the effectiveness of such preventive interventions. This study examined the effect of a ready-to-use supplementary food (RUSF) on the prevention of wasting in 6- to 36-mo-old children within the framework of a general food distribution program.
Methods and Findings
We conducted a two-arm cluster-randomized controlled pragmatic intervention study in a sample of 1,038 children aged 6 to 36 mo in the city of Abeche, Chad. Both arms were included in a general food distribution program providing staple foods. The intervention group was given a daily 46 g of RUSF for 4 mo. Anthropometric measurements and morbidity were recorded monthly. Adding RUSF to a package of monthly household food rations for households containing a child assigned to the intervention group did not result in a reduction in cumulative incidence of wasting (incidence risk ratio: 0.86; 95% CI: 0.67, 1.11; p = 0.25). However, the intervention group had a modestly higher gain in height-for-age (+0.03 Z-score/mo; 95% CI: 0.01, 0.04; p<0.001). In addition, children in the intervention group had a significantly higher hemoglobin concentration at the end of the study than children in the control group (+3.8 g/l; 95% CI: 0.6, 7.0; p = 0.02), thereby reducing the odds of anemia (odds ratio: 0.52; 95% CI: 0.34, 0.82; p = 0.004). Adding RUSF also resulted in a significantly lower risk of self-reported diarrhea (−29.3%; 95% CI: 20.5, 37.2; p<0.001) and fever episodes (−22.5%; 95% CI: 14.0, 30.2; p<0.001). Limitations of this study include that the projected sample size was not fully attained and that significantly fewer children from the control group were present at follow-up sessions.
Conclusions
Providing RUSF as part of a general food distribution resulted in improvements in hemoglobin status and small improvements in linear growth, accompanied by an apparent reduction in morbidity.
Trial registration
ClinicalTrials.gov NCT01154595
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
Good nutrition during childhood is essential for health and survival. Undernourished children are more susceptible to infections and are more likely to die from common ailments such as diarrhea than well-nourished children. Globally, undernutrition contributes to about a third of deaths among children under five years old. Experts use three physical measurements to determine whether a child is undernourished. An “underweight” child has a low weight for his or her age and gender when compared to the World Health Organization Child Growth Standards, which chart the growth of a reference population. A “stunted” child has a low height for his or her age; stunting indicates chronic undernutrition. A “wasted” child has a low weight for his or her height; wasting indicates acute undernutrition and can be caused by disasters or seasonal food shortages. Recent estimates indicate that about a fifth of young children in developing countries are underweight, and one third are stunted; in south Asia and west/central Africa, more than one tenth of children are wasted, a condition that markedly increases the risk of death.
Why Was This Study Done?
In emergency situations, international organizations support affected populations by providing “general food distributions.” Recently, there have been claims that the provision of targeted nutritional supplements within a general food distribution framework effectively prevents child wasting, but there is little evidence to support these claims. In this cluster-randomized controlled trial, the researchers investigate the effect of a targeted daily dose of a “ready-to-use supplementary food” (RUSF; a lipid-based nutrient supplement) on indicators of undernutrition in 6- to 36-month-old, non-wasted children in Chad, a country beset by a severe food crisis. Political instability in this central African country has severely reduced the nutritional status of children, and annual droughts, which affect crop production, cause a “hunger gap” between June and October. In a recent survey, one fifth of children in Chad were wasted at the beginning of this hunger gap. A cluster-randomized trial randomly assigns groups of people to receive alternative interventions and compares the outcomes in the differently treated “clusters.”
What Did the Researchers Do and Find?
The researchers randomly assigned fourteen household clusters in the city of Abeche, Chad, to the trial's intervention or control arm. All the households received a general food distribution that included staple foods; eligible children in the intervention households were also given a daily RUSF ration between June and September 2010. The researchers regularly measured the children's weights and heights, recorded illnesses reported by caregivers, and measured each child's blood hemoglobin level before and after the intervention to assess their risk of anemia, an indicator of poor nutrition. The addition of RUSF to the household food rations did not significantly reduce the cumulative incidence of wasting. That is, although fewer children in the intervention group became wasted during the trial than in the control group, this difference was not statistically significant—it could have happened by chance. However, compared to the children in the control group, those in the intervention group had a significantly greater gain in height-for-age (equivalent to a difference in height gain of 0.09 cm/month), slightly higher hemoglobin levels at the end of the study, which significantly reduced their anemia risk, and a significantly lower risk of self-reported diarrhea and fever.
What Do These Findings Mean?
Although targeted RUSF provided as part of a general food distribution had no significant effect on wasting in young children in Abeche, Chad, the intervention improved their hemoglobin status and linear growth, and reduced illness among them. Why didn't targeted RUSF prevent wasting effectively in this trial? Maybe the effect of RUSF was diluted out by the effect of the general food distribution or maybe the trial was too short to see a clear effect. Most importantly, though, the trial may have been too small to see a clear effect—the researchers were unable to enroll as many children into their trial as they had planned because of political instability in Chad, and this probably limited the trial's ability to detect small differences between the control and intervention groups. Nevertheless, because these findings provide no clear evidence that adding RUSF to a household food ration effectively prevents wasting, alternative ways to prevent acute malnutrition in Chad and other vulnerable regions of the world should be investigated.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001313.
This study is further discussed in a PLOS Medicine Perspective by Kathryn Dewey and Mary Arimond
Action Contra la Faim–France has a web page that describes the situation in Chad
The United Nations Childrens Fund, which protects the rights of children and young people around the world, provides detailed statistics on child undernutrition; it has detailed information, including videos, about the current food crisis in Chad and the Sahel
The WHO Child Growth Standards are available (in several languages)
The United Nations provides information on ongoing world efforts to reduce hunger and child mortality
The World Food Programme is the world's largest humanitarian agency fighting hunger worldwide; its website provides detailed information about malnutrition in Chad, including a video of the current food crisis in the country
Starved for Attention is an international multimedia campaign launched in 2010 by Médecins Sans Frontiéres (MSF) and the VII Photo agency to rewrite the story of childhood malnutrition; information about MSFs work in Chad to tackle malnutrition is available
doi:10.1371/journal.pmed.1001313
PMCID: PMC3445445  PMID: 23028263
Journal of Athletic Training  2006;41(4):466-469.
Reference/Citation: Rome K, Handoll HH, Ashford R. Interventions for preventing and treating stress fractures and stress reactions of bone of the lower limbs in young adults. Cochrane Database Syst Rev.20052:CD000450. Update from Gillespie WJ, Grant I. Interventions for preventing and treating stress fractures and stress reactions of bone of the lower limbs in young adults. Cochrane Database Syst Rev.20002: CD000450.
Clinical Question: Do evidence-based interventions exist for the prevention and treatment of stress reactions and stress fractures in young active adults?
Data Sources: This systematic review is an update of the original article, which was published in 2000. The authors conducted a literature review of computerized databases that included the Cochrane Musculoskeletal Injuries Group Specialized Register (April 2004), the Cochrane Central Register of Controlled Trials, MEDLINE (1966 to September 2004), EMBASE (1988 to 2004, week 36), CINAHL (1982 to 2004, September, week 1), Index to Theses (1990 to 2004), and Dissertation Abstracts (1990 to 2004). In addition, the authors searched the Current Controlled Trials at http://www.controlled-trials.com (June 2004, week 1) and the United Kingdom National Research Registrar at http://www.update-software.com/national/ (to issue 1, 2004) for current or recently completed studies. They also reviewed the British Journal of Podiatry, International Journal of Podiatric Biomechanics, Physiotherapy, and the Australian Journal of Podiatric Medicine for relevant studies. Furthermore, they contacted the Medical Departments of Defense Forces in Europe and North America to identify unpublished or unlisted military studies. Reference lists of all identified studies and Cochrane reviews were also investigated. The computer search strategy included 61 separate entries and included such terms as stress fractures, stress reactions, shin splints, overuse, athletic injuries, cumulative trauma disorders, running, and randomized controlled trial. The 3 authors of this updated review independently selected new articles for inclusion. Furthermore, the 12 articles that were included in the original systematic review were also reevaluated to ensure they met the defined inclusion criteria.
Study Selection: To qualify for inclusion, studies had to be randomized or quasirandomized control trials, involve interventions to prevent or treat lower extremity stress reactions and fractures, and include physically active adults (adolescence to middle age) who were involved in athletics or military training. Clinical and radiographic (bone scan or x-ray) evidence of a lower extremity stress reaction or stress fracture was also required for inclusion of treatment-based studies. Specifically, skeletal overuse injuries are considered the result of a cumulative and repetitive process that produces initial microstructural changes or stress reactions that are identified by bone scans or magnetic resonance imaging but not conventional radiographs. If cumulative stresses continue, structural changes are visualized on radiographs and are referred to as stress fractures. In addition, research studies involving the treatment of medial tibial stress syndrome or shin splints were excluded. Desired outcome measures for treatment studies included return to training time, return to normal physical activity, functional performance, quality of life measures, resource management (eg, costs, health care visits, diagnostic procedures), adverse effects, and compliance.
The inclusion criteria for stress fracture prevention studies were similar, except that the authors did not have to provide radiographic evidence of a stress fracture or stress reaction. Prevention studies included a combination of the following outcome measures: occurrence and location of stress fracture, stratification of diagnosis, incidence of other lower limb injuries, complications and adverse effects of prevention techniques, resource management, and compliance with the prevention strategy.
Data Extraction: At least 2 reviewers independently extracted the demographic and outcome data from the newly identified studies, and 1 author verified the data and results from the 12 studies included in the 2000 Cochrane review. Inconsistencies from the original review and data from all new studies were also checked by an additional reviewer. All 3 reviewers then independently evaluated the quality of inclusion studies using a quality scoring scheme ( Table). The categories considered included randomization or group allocation (A), intention-to-treat analysis (B), examiner blinding (C), comparison of experimental and control groups at baseline (D), use of a placebo treatment (E), clearly defined subject inclusion and exclusion criteria (F), and methods of outcome assessments (G). Items A through F were scored from 0 to 2 and item G from 0 to 3, for a total “best” quality assessment score (QAS) of 15. Inconsistencies among reviewers' QAS scores were resolved by discussion and with the aid of a discrepancies form.
Main Results: Search criteria identified 24 new studies since the previous review, 8 of which fulfilled the inclusion criteria. In addition, 4 of the 12 studies included in the original 2000 review were excluded. Three were excluded as a result of insufficient indication of subject or group randomization or quasirandomization, and the fourth excluded study included subjects with the diagnosis of medial tibial stress syndrome. Overall, 16 studies were included.
The authors of 13 studies focused on prevention, and 3 groups evaluated the treatment of stress fractures and reactions. The average number of subjects for prevention and treatment studies, respectively, was 1091 (range = 206 to 3025) and 34 (range = 21 to 60). All 13 prevention studies involved military personnel who performed physical training over a 9-to-14–week period. Quality assessment scores for prevention studies ranged from 4 to 10 (mean score = 7). In 9 prevention studies, the effectiveness of insoles or orthoses was evaluated, and the QAS for these studies ranged from 4 to 9 (mean = 6.2). The investigators in 4 studies assessed “shock-absorbing” insoles or orthoses in shoes or boots versus a control (shoes or boots alone), and an additional 5 groups compared insoles and orthoses against one another. One study's authors also evaluated military training in a modified high-top shoe versus standard military boots (QAS = 8). Two groups assessed the influence of pre-exercise stretching (QAS = 8 and 9, respectively), and one investigated the effects of calcium supplementation (QAS = 10).
In none of the prevention studies were adequate randomization and concealment of treatment before group allocation (item A) accomplished, and the researchers in 3 studies randomized groups (team or platoon) instead of individual participants. Attrition rates exceeded 50% in 2 studies, and missing subjects' data were unaccounted for in the final analysis of 3 studies (item B, intention-to-treat analysis). Also, in only 2 of 13 studies were examiners blinded to group assignment (item C). Radiographic (bone scan or x-ray) evidence for diagnostic confirmation of a stress reaction or fracture was used in 12 studies. The method of diagnosis (item G) was based solely on clinical examination or a self-report questionnaire in 2 studies, and diagnostic methods were not described in 2 studies.
Overall fewer osseous stress injuries were reported in the experimental groups for all 4 studies comparing military personnel in “shock absorbing insoles” with controls (no insoles). However, none of these 4 studies demonstrated a statistically significant reduction in lower extremity overuse osseous injuries. In addition, statistically significant results were reported in only 1 of 5 studies that compared various orthoses and insoles. The authors reported a significant reduction in tibial stress fractures for soldiers wearing custom-made semirigid or soft-foot orthoses versus those wearing standard insoles (relative risk = 0.46, 95% confidence interval = 0.22 to 0.93). In a follow-up study, no significant difference in stress fracture rates was seen between subjects who wore custom-made semirigid orthoses and those who wore biomechanical soft orthoses, thus precluding the ability to identify one best design for stress fracture reduction. No significant stress fracture or lower extremity injury rate differences were seen between the control and experimental groups involved in lower extremity stretching studies. Participants taking calcium supplements did not demonstrate a significant reduction in stress fractures (tibial only) versus controls. The differences among the prevention studies prohibited pooling of the data and subsequent meta-analysis. Authors of all 3 treatment studies investigated the effects of a pneumatic ankle foot orthosis (Aircast Corp, Summit, NJ). Follow-up for outcome measures ranged from 78 days to 6 months. Two studies were conducted with military recruits, and the other was conducted with competitive and recreational athletes (n = 18, age range = 18 to 45 years). Treatment QASs ranged from 7/15 to 11/ 15, with an average score of 9.3/15. Proper randomization (item A) and evaluator blinding (item C) were confirmed in 1 of the 3 treatment studies. Data pooled from all 3 studies reached statistical significance for mean number of days until returning to full activities (weighted mean difference with brace versus without brace = −33.39 days, 95% confidence interval = −44.18 to −22.59 days).
Conclusions: Currently, no solid evidence-based interventions to prevent lower extremity stress reactions or fractures exist. Limited evidence suggests that “shock absorbing” insoles may reduce the overall incidence of lower extremity osseous injuries in military personnel. Unfortunately, research does not support the best design for inserts or footwear modifications. There is also insufficient evidence to determine if pre-performance stretching or calcium supplementation offers added protection from lower extremity osseous overuse injuries. Initial evidence supports the use of a pneumatic brace and early mobilization for the treatment of tibal stress reactions and fractures, but additional studies are required to validate these findings. Further investigation concerning the prevention and treatment of lower extremity stress fractures is needed and would assist researchers in establishing and clarifying evidence-based intervention guidelines. Future randomized control trials that clearly define (ie, provide clinical and radiographic evidence for) the diagnosis of a stress fracture or reaction, implement appropriate randomization, and use intervention and outcome measures (functional and performance measurements) that are appropriate for active adults would assist this ongoing and necessary process.
PMCID: PMC1748425  PMID: 17273474
athletic injuries; outcomes assessment
PLoS ONE  2014;9(4):e93332.
Importance
Patients with a hip fracture lose more than 50% knee-extension strength in the fractured limb within one week of surgery. Hence, immediate progressive strength training following hip fracture surgery may be rational, but the feasibility unknown.
Objective
To examine the feasibility of in-hospital progressive strength training implemented in the acute ward following hip fracture surgery, based on pre-specified criteria for feasibility.
Design, Setting and Patients
A prospective cohort study conducted in an acute orthopedic hip fracture unit at a university hospital. A consecutive sample of 36 patients, 18 with a cervical and 18 with a trochanteric hip fracture (27 women and 9 men, mean (SD) age of 79.4 (8.3) years) were included between June and December 2012.
Intervention
A daily (on weekdays) program of progressive knee-extension strength training for the fractured limb, using ankle weight cuffs in 3 sets of 10 repetition maximum loadings.
Main outcomes and Measures
The primary outcome was the change in training load (kg) during the knee-extension strength training. The secondary outcomes were changes in hip fracture-related pain and maximal isometric knee-extension strength.
Results
The strength training was commenced at a mean of 2.4 (0.7) days after surgery. The training loads (kilograms lifted) increased from 1.6 (0.8) to 4.3 (1.7) kg over 4.3 (2.2) training sessions (P<.001). The maximal isometric knee-extension strength of the fractured limb increased from 0.37 (0.2) to 0.61 (0.3) Nm/kg (P<.001), while the average strength deficit in the fractured limb decreased from 50% to 32% (% non-fractured, P<.001). Only 3 of 212 sessions were not performed because of severe hip fracture-related pain.
Conclusion and Relevance
Progressive knee-extension strength training of the fractured limb commenced in the acute ward seems feasible, and may reduce strength asymmetry between limbs without hip pain interfering. The clinical efficacy needs confirmation in a randomized controlled design.
Trial Registration
ClinicalTrials.gov ID: NCT01616030
doi:10.1371/journal.pone.0093332
PMCID: PMC3974729  PMID: 24699276
PLoS Medicine  2013;10(8):e1001497.
Sophie Boisson and colleagues conducted a double-blind, randomized placebo-controlled trial in Orissa, a state in southeast India, to evaluate the effect of household water treatment in preventing diarrheal illnesses in children aged under five years of age.
Please see later in the article for the Editors' Summary
Background
Boiling, disinfecting, and filtering water within the home can improve the microbiological quality of drinking water among the hundreds of millions of people who rely on unsafe water supplies. However, the impact of these interventions on diarrhoea is unclear. Most studies using open trial designs have reported a protective effect on diarrhoea while blinded studies of household water treatment in low-income settings have found no such effect. However, none of those studies were powered to detect an impact among children under five and participants were followed-up over short periods of time. The aim of this study was to measure the effect of in-home water disinfection on diarrhoea among children under five.
Methods and Findings
We conducted a double-blind randomised controlled trial between November 2010 and December 2011. The study included 2,163 households and 2,986 children under five in rural and urban communities of Orissa, India. The intervention consisted of an intensive promotion campaign and free distribution of sodium dichloroisocyanurate (NaDCC) tablets during bi-monthly households visits. An independent evaluation team visited households monthly for one year to collect health data and water samples. The primary outcome was the longitudinal prevalence of diarrhoea (3-day point prevalence) among children aged under five. Weight-for-age was also measured at each visit to assess its potential as a proxy marker for diarrhoea. Adherence was monitored each month through caregiver's reports and the presence of residual free chlorine in the child's drinking water at the time of visit. On 20% of the total household visits, children's drinking water was assayed for thermotolerant coliforms (TTC), an indicator of faecal contamination. The primary analysis was on an intention-to-treat basis. Binomial regression with a log link function and robust standard errors was used to compare prevalence of diarrhoea between arms. We used generalised estimating equations to account for clustering at the household level. The impact of the intervention on weight-for-age z scores (WAZ) was analysed using random effect linear regression.
Over the follow-up period, 84,391 child-days of observations were recorded, representing 88% of total possible child-days of observation. The longitudinal prevalence of diarrhoea among intervention children was 1.69% compared to 1.74% among controls. After adjusting for clustering within household, the prevalence ratio of the intervention to control was 0.95 (95% CI 0.79–1.13). The mean WAZ was similar among children of the intervention and control groups (−1.586 versus −1.589, respectively). Among intervention households, 51% reported their child's drinking water to be treated with the tablets at the time of visit, though only 32% of water samples tested positive for residual chlorine. Faecal contamination of drinking water was lower among intervention households than controls (geometric mean TTC count of 50 [95% CI 44–57] per 100 ml compared to 122 [95% CI 107–139] per 100 ml among controls [p<0.001] [n = 4,546]).
Conclusions
Our study was designed to overcome the shortcomings of previous double-blinded trials of household water treatment in low-income settings. The sample size was larger, the follow-up period longer, both urban and rural populations were included, and adherence and water quality were monitored extensively over time. These results provide no evidence that the intervention was protective against diarrhoea. Low compliance and modest reduction in water contamination may have contributed to the lack of effect. However, our findings are consistent with other blinded studies of similar interventions and raise additional questions about the actual health impact of household water treatment under these conditions.
Trial Registration
ClinicalTrials.gov NCT01202383
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Millennium Development Goal 7 calls for halving the proportion of the global population without sustainable access to safe drinking water between 1990 and 2015. Although this target was met in 2010, according to latest figures, 768 million people world-wide still rely on unimproved drinking water sources. Access to clean drinking water is integral to good health and a key strategy in reducing diarrhoeal illness: Currently, 1.3 million children aged less than five years die of diarrhoeal illnesses every year with a sixth of such deaths occurring in one country—India. Although India has recently made substantial progress in improving water supplies throughout the country, currently almost 90% of the rural population does not have a water connection to their house and drinking water supplies throughout the country are extensively contaminated with human waste. A strategy internationally referred to as Household Water Treatment and Safe Storage (HWTS), which involves people boiling, chlorinating, and filtering water at home, has been recommended by the World Health Organization and UNICEF to improve water quality at the point of delivery.
Why Was This Study Done?
The WHO and UNICEF strategy to promote HWTS is based on previous studies from low-income settings that found that such interventions could reduce diarrhoeal illnesses by between 30%–40%. However, these studies had several limitations including reporting bias, short follow up periods, and small sample sizes; and importantly, in blinded studies (in which both the study participants and researchers are unaware of which participants are receiving the intervention or the control) have found no evidence that HWTS is protective against diarrhoeal illnesses. So the researchers conducted a blinded study (a double-blind, randomized placebo-controlled trial) in Orissa, a state in southeast India, to address those shortcomings and evaluate the effect of household water treatment in preventing diarrhoeal illnesses in children under five years of age.
What Did the Researchers Do and Find?
The researchers conducted their study in 11 informal settlements (where the inhabitants do not benefit from public water or sewers) in the state's capital city and also in 20 rural villages. 2,163 households were randomized to receive the intervention—the promotion and free distribution of sodium dichloroisocyanurate (chlorine) disinfection tablets with instruction on how to use them—or placebo tablets that were similar in appearance and had the same effervescent base as the chlorine tablets. Trained field workers visited households every month for 12 months (between December 2010 and December 2011) to record whether any child had experienced diarrhoea in the previous three days (as reported by the primary care giver). The researchers tested compliance with the intervention by asking participants if they had treated the water and also by testing for chlorine in the water.
Using these methods, the researchers found that over the 12-month follow-up period, the longitudinal prevalence of diarrhoea among children in the intervention group was 1.69% compared to 1.74% in the control group, a non-significant finding (a finding that could have happened by chance). There was also no difference in diarrhoea prevalence among other household members in the two groups and no difference in weight for age z scores (a measurement of growth) between children in the two groups. The researchers also found that although just over half (51%) of households in the intervention group reported treating their water, on testing, only 32% of water samples tested positive for chlorine. Finally, the researchers found that water quality (as measured by thermotolerant coliforms, TTCs) was better in the intervention group than the control group.
What Do These Findings Mean?
These findings suggest that treating water with chlorine tablets has no effect in reducing the prevalence of diarrhoea in both children aged under five years and in other household members in Orissa, India. However, poor compliance was a major issue with only a third of households in the intervention group confirmed as treating their water with chlorine tablets. Furthermore, these findings are limited in that the prevalence of diarrhoea was lower than expected, which may have also reduced the power of detecting a potential effect of the intervention. Nevertheless, this study raises questions about the health impact of household water treatment and highlights the key challenge of poor compliance with public health interventions.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001497.
The website of the World Health Organization has a section dedicated to household water treatment and safe storage, including a network to promote the use of HWTS and a toolkit to measure HWTS
The Water Institute hosts the communications portal for the International Network on Household Water Treatment and Safe Storage
doi:10.1371/journal.pmed.1001497
PMCID: PMC3747993  PMID: 23976883
PLoS Medicine  2011;8(4):e1001018.
Philip Ayieko and colleagues report the outcomes of a cluster-randomized trial carried out in eight Kenyan district hospitals evaluating the effects of a complex intervention involving improved training and supervision for clinicians. They found a higher performance of hospitals assigned to the complex intervention on a variety of process of care measures, as compared to those receiving the control intervention.
Background
In developing countries referral of severely ill children from primary care to district hospitals is common, but hospital care is often of poor quality. However, strategies to change multiple paediatric care practices in rural hospitals have rarely been evaluated.
Methods and Findings
This cluster randomized trial was conducted in eight rural Kenyan district hospitals, four of which were randomly assigned to a full intervention aimed at improving quality of clinical care (evidence-based guidelines, training, job aides, local facilitation, supervision, and face-to-face feedback; n = 4) and the remaining four to control intervention (guidelines, didactic training, job aides, and written feedback; n = 4). Prespecified structure, process, and outcome indicators were measured at baseline and during three and five 6-monthly surveys in control and intervention hospitals, respectively. Primary outcomes were process of care measures, assessed at 18 months postbaseline.
In both groups performance improved from baseline. Completion of admission assessment tasks was higher in intervention sites at 18 months (mean = 0.94 versus 0.65, adjusted difference 0.54 [95% confidence interval 0.05–0.29]). Uptake of guideline recommended therapeutic practices was also higher within intervention hospitals: adoption of once daily gentamicin (89.2% versus 74.4%; 17.1% [8.04%–26.1%]); loading dose quinine (91.9% versus 66.7%, 26.3% [−3.66% to 56.3%]); and adequate prescriptions of intravenous fluids for severe dehydration (67.2% versus 40.6%; 29.9% [10.9%–48.9%]). The proportion of children receiving inappropriate doses of drugs in intervention hospitals was lower (quinine dose >40 mg/kg/day; 1.0% versus 7.5%; −6.5% [−12.9% to 0.20%]), and inadequate gentamicin dose (2.2% versus 9.0%; −6.8% [−11.9% to −1.6%]).
Conclusions
Specific efforts are needed to improve hospital care in developing countries. A full, multifaceted intervention was associated with greater changes in practice spanning multiple, high mortality conditions in rural Kenyan hospitals than a partial intervention, providing one model for bridging the evidence to practice gap and improving admission care in similar settings.
Trial registration
Current Controlled Trials ISRCTN42996612
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, nearly 10 million children died in early childhood. Nearly all these deaths were in low- and middle-income countries—half were in Africa. In Kenya, for example, 74 out every 1,000 children born died before they reached their fifth birthday. About half of all childhood (pediatric) deaths in developing countries are caused by pneumonia, diarrhea, and malaria. Deaths from these common diseases could be prevented if all sick children had access to quality health care in the community (“primary” health care provided by health centers, pharmacists, family doctors, and traditional healers) and in district hospitals (“secondary” health care). Unfortunately, primary health care facilities in developing countries often lack essential diagnostic capabilities and drugs, and pediatric hospital care is frequently inadequate with many deaths occurring soon after admission. Consequently, in 1996, as part of global efforts to reduce childhood illnesses and deaths, the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) introduced the Integrated Management of Childhood Illnesses (IMCI) strategy. This approach to child health focuses on the well-being of the whole child and aims to improve the case management skills of health care staff at all levels, health systems, and family and community health practices.
Why Was This Study Done?
The implementation of IMCI has been evaluated at the primary health care level, but its implementation in district hospitals has not been evaluated. So, for example, interventions designed to encourage the routine use of WHO disease-specific guidelines in rural pediatric hospitals have not been tested. In this cluster randomized trial, the researchers develop and test a multifaceted intervention designed to improve the implementation of treatment guidelines and admission pediatric care in district hospitals in Kenya. In a cluster randomized trial, groups of patients rather than individual patients are randomly assigned to receive alternative interventions and the outcomes in different “clusters” of patients are compared. In this trial, each cluster is a district hospital.
What Did the Researchers Do and Find?
The researchers randomly assigned eight Kenyan district hospitals to the “full” or “control” intervention, interventions that differed in intensity but that both included more strategies to promote implementation of best practice than are usually applied in Kenyan rural hospitals. The full intervention included provision of clinical practice guidelines and training in their use, six-monthly survey-based hospital assessments followed by face-to-face feedback of survey findings, 5.5 days training for health care workers, provision of job aids such as structured pediatric admission records, external supervision, and the identification of a local facilitator to promote guideline use and to provide on-site problem solving. The control intervention included the provision of clinical practice guidelines (without training in their use) and job aids, six-monthly surveys with written feedback, and a 1.5-day lecture-based seminar to explain the guidelines. The researchers compared the implementation of various processes of care (activities of patients and doctors undertaken to ensure delivery of care) in the intervention and control hospitals at baseline and 18 months later. The performance of both groups of hospitals improved during the trial but more markedly in the intervention hospitals than in the control hospitals. At 18 months, the completion of admission assessment tasks and the uptake of guideline-recommended clinical practices were both higher in the intervention hospitals than in the control hospitals. Moreover, a lower proportion of children received inappropriate doses of drugs such as quinine for malaria in the intervention hospitals than in the control hospitals.
What Do These Findings Mean?
These findings show that specific efforts are needed to improve pediatric care in rural Kenya and suggest that interventions that include more approaches to changing clinical practice may be more effective than interventions that include fewer approaches. These findings are limited by certain aspects of the trial design, such as the small number of participating hospitals, and may not be generalizable to other hospitals in Kenya or to hospitals in other developing countries. Thus, although these findings seem to suggest that efforts to implement and scale up improved secondary pediatric health care will need to include more than the production and dissemination of printed materials, further research including trials or evaluation of test programs are necessary before widespread adoption of any multifaceted approach (which will need to be tailored to local conditions and available resources) can be contemplated.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001018.
WHO provides information on efforts to reduce global child mortality and on Integrated Management of Childhood Illness (IMCI); the WHO pocket book “Hospital care for children contains guidelines for the management of common illnesses with limited resources (available in several languages)
UNICEF also provides information on efforts to reduce child mortality and detailed statistics on child mortality
The iDOC Africa Web site, which is dedicated to improving the delivery of hospital care for children and newborns in Africa, provides links to the clinical guidelines and other resources used in this study
doi:10.1371/journal.pmed.1001018
PMCID: PMC3071366  PMID: 21483712
PLoS Medicine  2009;6(12):e1000195.
In a randomized trial of elementary schools in Toronto, Andrew Howard and colleagues show that granitic sand playground surfaces reduce the risk of arm fractures from playground falls when compared with wood fiber surfaces.
Background
The risk of playground injuries, especially fractures, is prevalent in children, and can result in emergency room treatment and hospital admissions. Fall height and surface area are major determinants of playground fall injury risk. The primary objective was to determine if there was a difference in playground upper extremity fracture rates in school playgrounds with wood fibre surfacing versus granite sand surfacing. Secondary objectives were to determine if there were differences in overall playground injury rates or in head injury rates in school playgrounds with wood fibre surfacing compared to school playgrounds with granite sand surfacing.
Methods and Findings
The cluster randomized trial comprised 37 elementary schools in the Toronto District School Board in Toronto, Canada with a total of 15,074 students. Each school received qualified funding for installation of new playground equipment and surfacing. The risk of arm fracture from playground falls onto granitic sand versus onto engineered wood fibre surfaces was compared, with an outcome measure of estimated arm fracture rate per 100,000 student-months. Schools were randomly assigned by computer generated list to receive either a granitic sand or an engineered wood fibre playground surface (Fibar), and were not blinded. Schools were visited to ascertain details of the playground and surface actually installed and to observe the exposure to play and to periodically monitor the depth of the surfacing material. Injury data, including details of circumstance and diagnosis, were collected at each school by a prospective surveillance system with confirmation of injury details through a validated telephone interview with parents and also through collection (with consent) of medical reports regarding treated injuries. All schools were recruited together at the beginning of the trial, which is now closed after 2.5 years of injury data collection. Compliant schools included 12 schools randomized to Fibar that installed Fibar and seven schools randomized to sand that installed sand. Noncompliant schools were added to the analysis to complete a cohort type analysis by treatment received (two schools that were randomized to Fibar but installed sand and seven schools that were randomized to sand but installed Fibar). Among compliant schools, an arm fracture rate of 1.9 (95% confidence interval [CI] 0.04–6.9) per 100,000 student-months was observed for falls into sand, compared with an arm fracture rate of 9.4 (95% CI 3.7–21.4) for falls onto Fibar surfaces (p≤0.04905). Among all schools, the arm fracture rate was 4.5 (95% CI 0.26–15.9) per 100,000 student-months for falls into sand compared with 12.9 (95% CI 5.1–30.1) for falls onto Fibar surfaces. No serious head injuries and no fatalities were observed in either group.
Conclusions
Granitic sand playground surfaces reduce the risk of arm fractures from playground falls when compared with engineered wood fibre surfaces. Upgrading playground surfacing standards to reflect this information will prevent arm fractures.
Trial Registration
Current Controlled Trials ISRCTN02647424
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Playgrounds and outdoor play equipment provide children with a place to let steam off, play creatively, socialize, and learn new skills. And, in a world where childhood obesity is a burgeoning problem, playgrounds provide a place where children can be encouraged to exercise. But playgrounds are not without hazards. Even in well-maintained and well-run facilities, children can hurt themselves by falling off climbing frames, monkey bars, and other equipment or by falling from standing height during playground games such as tag. In the US alone, more than 200,000 children are treated in emergency departments for injuries sustained in playgrounds every year and about 6,400 children are admitted to hospitals because of playground injuries, most of which are bone fractures (broken bones). In fact, playground injuries in the US are more severe and have a higher hospital admission rate than any other sort of child injury except those involving vehicles.
Why Was This Study Done?
Children who fall off playground equipment are nearly four times as likely to break a bone (often in an arm) as children who fall from standing height. To reduce the number of fractures that occur in playgrounds, some governments have limited the height of playground equipment. Some have also set standards for the type of surfaces installed in playgrounds and for the depth of sand or engineered wood fiber in loose fill surfaces. These standards are based on laboratory tests in which headforms (artificial heads) are dropped onto surfaces. However, these tests provide no information about the ability of different surfaces to prevent broken arms and other specific injuries in the real world. In this cluster randomized trial (a study in which groups of people are randomly assigned to receive different interventions), the researchers compare the rates of arm fractures in elementary (primary) school playgrounds in Toronto (Canada) that have wood fiber surfacing with the rates in playgrounds that have granite sand surfacing.
What Did the Researchers Do and Find?
The researchers randomly assigned 37 elementary schools that had qualified for school board funding for replacement playground equipment to receive either wood fiber (19 schools) or granite sand surfacing (18 schools) in their playgrounds. 19 of the schools complied with their randomization (12 installed fiber and seven installed sand); two schools installed sand although they were randomized to install fiber and seven schools installed fiber instead of sand. The researchers evaluated the playgrounds and their surfaces several times during the 2.5-year study and collected data on how playground injuries happened and types of injuries from the schools, parents, and medical reports. Among the schools that complied with randomization, falls from height into sand resulted in 1.9 arm fractures per 100,000 student-months whereas falls into fiber resulted in 9.4 arm fractures per 100,000 student-months. Arm fracture rates and other injury rates were also higher for falls from height into fiber than into sand when all the schools that had installed new surfaces were considered. However, the rates of arm fracture and other injuries that did not involve a fall from height did not vary between surfaces.
What Do These Findings Mean?
The accuracy of these findings is limited by the small number of arm fractures that occurred during the trial—only 20 children who fell into fiber and two who fell into sand broke an arm. The accuracy of the findings may also be limited by the failure of many schools to comply with randomization although the researchers found no obvious differences between the schools that did and did not comply with randomization that might have affected the trial's outcome. However, even with these limitations, the findings of this real-world study indicate that granitic sand surfaces substantially reduce the risk of arm fractures and other injuries caused by falls from playground equipment when compared with wood fiber surfaces. Thus, because falls from playground equipment are more likely to cause a fracture than falls from standing height, if playground surfacing standards are adjusted to reflect the findings of this study (that is, if sand surfaces are recommended in preference to wood fiber surfaces), many arm fractures in children should be prevented.
Additional Information
Please access these Web sites via the online version of this summary at ttp://dx.doi.org/10.1371/journal.pmed.1000195.
Safe Kids Canada provides information about playground safety and other aspects of childhood safety (in English and French)
Safe Kids Worldwide is a global network of organizations whose mission is to prevent accidental childhood injury (in English and Spanish)
The Nemours Foundation, a nonprofit organization for child health, provides information for parents on playground safety
The Royal Society for the Prevention of Accidents provides information on the safety of indoor and outdoor play areas
The US Centers for Disease Control and Prevention provides fact sheets on playground injuries
The US Consumer Product Safety Commission also has information on playground safety, including resources designed for children such as The Further Adventures of Kidd Safety and Little Big Kids, a booklet on play safety written by children for children
doi:10.1371/journal.pmed.1000195
PMCID: PMC2784292  PMID: 20016688
BMC Geriatrics  2014;14:101.
Background
Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture. There are currently no agreed strategies for vitamin D replenishment after hip fracture surgery. The REVITAHIP Study is a multisite, double-blinded randomized-controlled trial investigating the effects of an oral vitamin D loading dose on gait velocity after hip fracture surgery. We describe the baseline characteristics of participants, aiming to document hypovitaminosis D and its associations after hip fracture.
Methods
Participants, over 65, recruited within 7 days following hip fracture surgery from 3 Australia hospitals, were randomly allocated to receive a loading dose of vitamin D3 (250,000IU) or placebo, followed by oral maintenance vitamin D3/calcium (800 IU/500 mg) and the usual hip fracture rehabilitation pathway. Demographic and clinical data were collected, including surgical procedure, pre-fracture functional status, Mini Mental State Examination (MMSE) score, serum 25-hydroxyvitamin D (25-OHD), Verbal Rating Scale (VRS) for pain, grip strength and gait velocity. The associations of baseline 25-OHD levels with demographic and clinical data were assessed using Pearson’s correlation, ANOVA and regression analyses.
Results
Two-hundred-and-eighteen people with hip fracture participated in the study. Mean age was 83.9+/-7.2 years, 77% were women and 82% lived in private homes. Fifty-six percent had a subcapital fracture. Mean comorbidity count was 3.13+/-2.0. Mean MMSE was 26.1+/-3.9. Forty-seven percent of participants had hypovitaminosis D (<50 nmol/L). Multivariate regression models demonstrated higher baseline vitamin D levels were significantly associated with higher premorbid Barthel index scores, lower post-operative VRS pain levels and use of vitamin D.
Conclusion
This study cohort shared similar demographic characteristics and comorbidities with other cohorts of people with hip fracture, with the probable exception of less cognitive impairment. Hypovitaminosis D was not as prevalent as previously documented. Patients taking vitamin D supplements and with higher premorbid Barthel index, reflecting greater independence and activity, tended to have higher 25-OHD levels at baseline. Further, lower VRS pain ratings following surgery were associated with higher vitamin D levels. Such associations will need further investigation to determine causation. (ANZCTR number, ACTRN12610000392066).
Trial registration
The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry ANZCTRN ACTRN12610000392066.
doi:10.1186/1471-2318-14-101
PMCID: PMC4164764  PMID: 25200552
Fragility fractures; Hip fracture; Vitamin D; Aged care; Metabolic bone disorders; Osteoporosis; Rehabilitation; Trauma surgery
Executive Summary
Objective
To assess the efficacy of osteogenic protein-1 (OP-1) for long bone nonunion.
Clinical Need
Although most fractures heal within a normal period, about 5% to 10% do not heal and are classified as delayed or nonunion fractures. Nonunion and segmental bone loss after fracture, reconstructive surgery, or lesion excision can present complex orthopedic problems, and the multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life.
Many factors contribute to the pathogenesis of a delayed union or nonunion fractures, including deficiencies of calcium, vitamin D, or vitamin C, and side effects of medications such as anticoagulants, steroids, some anti-inflammatory drugs, and radiation. It has been shown that smoking interferes with bone repair in several ways.
Incidence of Nonunion and Delayed Union Cases
An estimated 5% to 10% of fractures do not heal properly and go on to delayed union or nonunion. If this overall estimate of incidence were applied to the Ontario population1, the estimated number of delayed union or nonunion in the province would be between 3,863 and 7,725.
Treatment of Nonunion Cases
The treatment of nonunion cases is a challenge to orthopedic surgeons. However, the basic principle behind treatment is to provide both mechanical and biological support to the nonunion site.
Fracture stabilization and immobilization is frequently used with the other treatment modalities that provide biological support to the fractured bone. Biological support includes materials that could be served as a source of osteogenic cells (osteogenesis), a stimulator of mesenchymal cells (osteoinduction), or a scaffold-like structure (osteoconduction).
The capacity to heal a fracture is a latent potential of the stromal stem cells, which synthesize new bone. This process has been defined as osteogenesis. Activation of the stem cells to initiate osteogenic response and to differentiate into bone-forming osteoblasts is called osteoinduction. These 2 properties accelerate the rate of fracture healing or reactivate the ineffective healing process. Osteoconduction occurs when passive structures facilitate the migration of osteoprogenitor cells, the perivascular tissue, and capillaries into these structures.
Bone Grafts and Bone Graft Substitutes
Bone graft and bone graft substitutes have one or more of the following components:
Undifferentiated stem cells
Growth factors
Structural lattice
Undifferentiated stem cells are unspecialized, multipotential cells that can differentiate into a variety of specialized cells. They can also replicate themselves. The role of stem cells is to maintain and repair the tissue in which they are residing. A single stem cell can generate all cell types of that tissue. Bone marrow is a source of at least 2 kinds of stem cells. Hematopoietic stem cells that form all types of blood cells, and bone marrow stromal stem cells that have osteogenic properties and can generate bone, cartilage, and fibrous tissue.
Bone marrow has been used to stimulate bone formation in bone defects and cases of nonunion fractures. Bone marrow can be aspirated from the iliac crest and injected percutaneously with fluoroscopic guidance into the site of the nonunion fracture. The effectiveness of this technique depends on the number and activity of stem cells in the aspirated bone marrow. It may be possible to increase the proliferation and speed differentiation of stem cells by exposing them to growth factor or by combining them with collagen.
Many growth factors and cytokines induced in response to injury are believed to have a considerable role in the process of repair. Of the many bone growth factors studied, bone morphogenetics (BMPs) have generated the greatest attention because of their osteoinductive potential. The BMPs that have been most widely studied for their ability to induce bone regeneration in humans include BMP-2 and BMP-7 (osteogenic protein). Human osteogenic protein-1 (OP-1) has been cloned and produced with recombinant technology and is free from the risk of infection or allergic reaction.
The structural lattice is osteoconductive; it supports the ingrowth of developing capillaries and perivascular tissues. Three distinct groups of structural lattice have been identified: collagen, calcium sulphate, and calcium phosphate. These materials can be used to replace a lost segment of bone.
Grafts Used for Nonunion
Autologous bone graft is generally considered the gold standard and the best material for grafting because it contains several elements that are critical in promoting bone formation, including osteoprogenitor cells, the matrix, and bone morphogenetic proteins. The osteoconductive property of cancellous autograft is related to the porosity of bone. The highly porous, scaffold-like structure of the graft allows host osteoblasts and host osteoprogenitor cells to migrate easily into the area of the defect and to begin regeneration of bone. Sources of cancellous bone are the iliac crest, the distal femur, the greater trochanter, and the proximal tibia. However, harvesting the autologous bone graft is associated with postoperative pain at the donor site, potential injury to the surrounding arteries, nerves, and tissues, and the risk of infection. Thus the development of synthetic materials with osteoconductive and osteoinductive properties that can eliminate the need for harvesting has become a major goal of orthopedic research.
Allograft is the graft of tissue between individuals who are of the same species but are of a disparate genotype. Allograft has osteoconductive and limited osteoinductive properties. Demineralized bone matrix (DBM) is human cortical and cancellous allograft. These products are prepared by acid extraction of allograft bone, resulting in the loss of most of the mineralized component while collagen and noncollagenous proteins, including growth factors, are retained. Figures 1 to 5 demonstrate the osteogenic, osteoinduction, and osteoconduction properties of autologous bone graft, allograft, OP-1, bone graft substitutes, and bone marrow.
Autologous Bone Graft
Osteogenic Protein-1
Allograft bone and Demineralized Bone Matrix
Bone Graft Substitutes
Autologous Bone Marrow Graft
New Technology Being Reviewed: Osteogenic Protein-1
Health Canada issued a Class IV licence for OP-1 in June 2004 (licence number 36320). The manufacturer of OP-1 is Stryker Biotech (Hapkinton, MA).
The United States Food and Drug Administration (FDA) issued a humanitarian device exemption for the application of the OP-1 implant as an “alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed.” Regulatory agencies in Europe, Australia, and New Zealand have permitted the use of this implant in specific cases, such as in tibial nonunions, or in more general cases, such as in long bone nonunions.
According to the manufacturer, OP-1 is indicated for the treatment of long bone nonunions. It is contraindicated in the patient has a hypersensitivity to the active substance or collagen, and it should not be applied at the site of a resected tumour that is at or near the defect or fracture. Finally, it should not be used in patients who are skeletally immature (< 18 years of age), or if there is no radiological evidence of closure of epiphysis.
Review Strategy
Objective
To summarize the safety profile and effectiveness of OP-1 in the treatment of cases of long bone nonunion and bone defects
To compare the effectiveness and cost effectiveness of OP-1 in the treatment of long bone nonunions and bone defects with the alternative technologies, particularly the gold standard autologous bone graft.
Literature Search
International Network of Agencies for Health Technology Assessments (INAHTA), the Cochrane Database of Systematic Reviews and the CCTR (formerly Cochrane Controlled Trials Register) were searched for health technology assessments. MEDLINE, EMBASE, Medline In Process and Other Non-Indexed Citations were searched from January 1, 1996 to January 27, 2004 for studies on OP-1. The search was limited to English-language articles and human studies. The search yielded 47 citations. Three studies met inclusion criteria (2 RCTs and 1 Ontario-based study presented at an international conference.
Summary of Findings
Friedlaender et al. conducted a prospective, randomized, partially blinded clinical trial on the treatment tibial nonunions with OP-1. Tibial nonunions were chosen for this study because of their high frequency, challenging treatment requirements, and substantial morbidity. All of the nonunions were at least 9 months old and had shown no progress toward healing over the previous 3 months. The patients were randomized to receive either treatment with autologous bone grafting or treatment with OP-1 in a type-1 collagen carrier. Both groups received reduction and fixation with an intramedullary rod. Table 1 summarizes the clinical outcomes of this study.
Outcomes in a Randomized Clinical Trial on Tibial Nonunions: Osteogenic Protein-1 versus Autologous Bone Grafting
Clinical success was defined as full weight-bearing, loss of severe pain at the fracture site on weight-bearing, and no further surgical treatment to enhance fracture repair.
The results of this study demonstrated that recombinant OP-1 is associated with substantial clinical and radiographic success for the treatment of tibial nonunions when used with intramedullary rod fixation. No adverse event related to sensitization was reported. Five per cent of the patients in the OP-1 group had circulating antibodies against type 1 collagen. Only 10% of the patients had a low level of anti-OP-1 antibodies, and all effects were transient. Furthermore, the success rate with the OP-1 implant was comparable with those achieved with autograft at 9 and 24 months follow-up. Eighty-two per cent of patients were successful at 24 months follow-up in both groups.
Statistically significant increased blood loss in the group treated with the autograft was observed (P = .049). Patients treated with autograft had longer operation and hospitalization times. All patients in the autograft group had pain at the donor site after surgery, and more than 80% judged their postoperative pain as moderate or severe. At their 6-month visit, 20% of the patients in the autograft group had persistent pain, mild or moderate in nature, at the donor site. This number fell to 13% at 12 months.
All patients in each of the groups had at least 1 adverse event that wasn’t serious, such as fever, nausea and vomiting, leg edema, discomfort, and bruising at the operative site. The incidence of these events was similar in both groups. Serious adverse events were observed in 44% of both groups, none of which were considered related to the OP-1 implant or autograft.
On the basis of this data, the FDA issued a humanitarian device exemption for the application of OP-1 implant as an alternative to autograft in recalcitrant long bone nonunions when the use of autograft is unfeasible and alternative treatments have failed.
Study on Fibular Defects
Geesink et al. investigated the osteogenic activity of OP-1 by assessing its value in bridging fibular defects made at the time of tibial osteotomy for varus or valgus deformity of the knee. This study had 2 phases and included 12 patients in each phase. Each phase included 12 patients (6 in each group). Patients in the first phase received either DBM or were left untreated. Patients in the second phase received either OP-1 on collagen type-1 or collagen type-1 alone.
Radiological and Dual Energy X-ray Absorptiometry (DEXA) evaluation showed that in patients in whom the defect was left untreated, no formation of bone occurred. At 12 months follow-up, new bone formation with bridging occurred in 4 of the 6 patients in DMB group, and 5 of the 6 patients in OP-1 group. One patient in OP-1 group did not show any evidence of new bone formation at any point during the study.
Ontario Pilot Study
A prospective pilot study was conducted in Ontario, Canada to investigate the safety and efficacy of OP-1 for the treatment of recalcitrant long bone nonunions. The study looked at 15 patients with complex, recalcitrant, long bone nonunions whose previous treatment had failed. The investigators concluded that this bone graft substitute appears to be safe and effective in providing sufficient biological stimulation in difficult to treat nonunions. Results of a more complete study on 70 patients are ready for publication. According to the principal investigator, OP-1 was 90% effective in inducing bone formation and bone healing in this sample.
Alternative Technologies
The Medical Advisory Secretariat conducted a literature search from January 1, 2000 to February 28, 2005 to identify studies on nonunions/bone defects that had been treated with alternative technologies. A review of these studies showed that, in addition to the gold standard autologous bone marrow grafting, bone allografts, demineralized bone matrices, bone graft substitutes, and autologous bone marrow have been used for treatment of nonunions and bone defects. These studies were categorized according to the osteoinductive, osteoconductive, and osteogenesis properties of the technologies studied.
A review of these studies showed that bone allografts have been used mostly in various reconstruction procedures to restore the defect after excavating a bone lesion. Two studies investigated the effectiveness of DBM in healing fracture nonunions. Calcium phosphate and calcium sulphate have been used mostly for repair of bone defects.
Several investigators have looked at the use of autologous bone marrow for treatment of long bone nonunions. The results of these studies show that method of percutaneous bone marrow grafting is highly effective in the treatment of long bone nonunions. In a total of 301 fractures across all studies, 268 (89%) healed with a mean healing time of 2.5 to 8 months. This healing time as derived from these case series is less than the timing of the primary end point in Friedlaender’s study (9 months). Table 2 summarizes the results of these studies. Table 2 summarizes the results of these studies.
Studies that used Percutaneous Bone Marrow Grafting for Treatment of Nonunions
Economic Analysis
Based on annual estimated incidence of long-bone nonunion of 3,863 - 7,725, the annual hospitalization costs associated with this condition is between $21.2 and $42.3 million based on a unit cost of $5,477 per hospital separation. When utilized, the device, a single vial of OP-1, is approximately $5,000 and if adopted universally in Ontario, the total device costs would be in the range of $19.3 - $38.6 million annually. The physician fee for harvest, insertion of bone, or OP-1 is $193 and is $193 for autologous bone marrow transplantation. Total annual physician costs are expected to be in the range of from $0.7 million to $1.3 million per year. Expenditures associated with long-bone nonunion are unlikely to increase since incidence of long-bone nonunion is unlikely to change in the future. However, the rate of uptake of OP-1 could have a significant impact on costs if the uptake were large.
The use of OP-1 and autologous bone marrow transplantation may offset pain medication costs compared with those associated with autologous bone harvest given that the former procedures do not involve the pain associated with the bone harvest site. However, given that this pain is normally not permanent, the overall offset is likely to be small. There are likely to be smaller OHIP costs associated with OP-1 than bone-harvest procedures given that only 1, rather than 2, incisions are needed when comparing the former with the latter procedure. This offset could amount to between $0.3 million to $0.7 million annually.
No data on the cost-effectiveness of OP-1 is available.
PMCID: PMC3382627  PMID: 23074475
PLoS Medicine  2009;6(1):e1000007.
Background
Delays in accessing care for malaria and other diseases can lead to disease progression, and user fees are a known barrier to accessing health care. Governments are introducing free health care to improve health outcomes. Free health care affects treatment seeking, and it is therefore assumed to lead to improved health outcomes, but there is no direct trial evidence of the impact of removing out-of-pocket payments on health outcomes in developing countries. This trial was designed to test the impact of free health care on health outcomes directly.
Methods and Findings
2,194 households containing 2,592 Ghanaian children under 5 y old were randomised into a prepayment scheme allowing free primary care including drugs, or to a control group whose families paid user fees for health care (normal practice); 165 children whose families had previously paid to enrol in the prepayment scheme formed an observational arm. The primary outcome was moderate anaemia (haemoglobin [Hb] < 8 g/dl); major secondary outcomes were health care utilisation, severe anaemia, and mortality. At baseline the randomised groups were similar. Introducing free primary health care altered the health care seeking behaviour of households; those randomised to the intervention arm used formal health care more and nonformal care less than the control group. Introducing free primary health care did not lead to any measurable difference in any health outcome. The primary outcome of moderate anaemia was detected in 37 (3.1%) children in the control and 36 children (3.2%) in the intervention arm (adjusted odds ratio 1.05, 95% confidence interval 0.66–1.67). There were four deaths in the control and five in the intervention group. Mean Hb concentration, severe anaemia, parasite prevalence, and anthropometric measurements were similar in each group. Families who previously self-enrolled in the prepayment scheme were significantly less poor, had better health measures, and used services more frequently than those in the randomised group.
Conclusions
In the study setting, removing out-of-pocket payments for health care had an impact on health care-seeking behaviour but not on the health outcomes measured.
Trial registration: ClinicalTrials.gov (#NCT00146692).
Evelyn Ansah and colleagues report on whether removing user fees has an impact on health care-seeking behavior and health outcomes in households with children in Ghana.
Editors' Summary
Background.
Every year, about 10 million children worldwide die before their fifth birthday. About half these deaths occur in developing countries in sub-Saharan Africa. Here, 166 children out of every 1,000 die before they are five. A handful of preventable diseases—acute respiratory infections, diarrhea, malaria, measles, and HIV/AIDS—are responsible for most of these deaths. For all these diseases, delays in accessing medical care contribute to the high death rate. In the case of malaria, for example, children are rarely taken to a clinic or hospital (formal health care) when they first develop symptoms, which include fever, chills, and anemia (lack of red blood cells). Instead, they are taken to traditional healers or given home remedies (informal health care). When they are finally taken to a clinic, it is often too late to save their lives. Many factors contribute to this delay in seeking formal health care. Sometimes, health care simply isn't available. In other instances, parents may worry about the quality of the service provided or may not seek formal health care because of their sociocultural beliefs. Finally, many parents cannot afford the travel costs and loss of earnings involved in taking their child to a clinic or the cost of the treatment itself.
Why Was This Study Done?
The financial cost of seeking formal health care is often the major barrier to accessing health care in poor countries. Consequently, the governments of several developing countries have introduced free health care in an effort to improve their nation's health. Such initiatives have increased the use of formal health care in several African countries; the introduction of user fees in Ghana in the early 1980s had the opposite effect. It is generally assumed that an increase in formal health care utilization improves health—but is this true? In this study, the researchers investigate the effect of removing direct payment for health care on health service utilization and health outcomes in Ghanaian children in a randomized controlled trial (a trial in which participants are randomly assigned to an “intervention” group or “control” group and various predefined outcomes are measured).
What Did the Researchers Do and Find?
The researchers enrolled nearly 2,600 children under the age of 5 y living in a poor region of Ghana. Half were assigned to the group in which a prepayment scheme (paid for by the trial) provided free primary and basic secondary health care—this was the intervention arm. The rest were assigned to the control group in which families paid for health care. The trial's main outcome was the percentage of children with moderate anemia at the end of the malaria transmission season, an indicator of the effect of the intervention on malaria-related illness. Other outcomes included health care utilization (calculated from household diaries), severe anemia, and death. The researchers report that the children in the intervention arm attended formal health care facilities slightly more often and informal health care providers slightly less often than those in the control arm. About 3% of the children in both groups had moderate anemia at the end of the malaria transmission season. In addition, similar numbers of deaths, cases of severe anemia, fever episodes, and known infections with the malaria parasite were recorded in both groups of children.
What Do These Findings Mean?
These findings show that, in this setting, the removal of out-of-pocket payments for health care changed health care-seeking behavior but not health outcomes in children. This lack of a measured effect does not necessarily mean that the provision of free health care has no effect on children's health—it could be that the increase in health care utilization in the intervention arm compared to the control arm was too modest to produce a clear effect on health. Alternatively, in Ghana, the indirect costs of seeking health care may be more important than the direct cost of paying for treatment. Although the findings of this trial may not be generalizable to other countries, they nevertheless raise the possibility that providing free health care might not be the most cost-effective way of improving health in all developing countries. Importantly, they also suggest that changes in health care utilization should not be used in future trials as a proxy measure of improvements in health.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000007.
This research article is further discussed in a PLoS Medicine Perspective by Valéry Ridde and Slim Haddad
The World Health Organization provides information on child health and on global efforts to reduce child mortality, Millennium Development Goal 4; it also provides information about health in Ghana
The United Nations Web site provides further information on all the Millennium Development Goals, which were agreed to by the nations of the world in 2000 with the aim of ending extreme poverty by 2015 (in several languages)
The UK Department for International Development also provides information on the progress that is being made toward reducing child mortality
doi:10.1371/journal.pmed.1000007
PMCID: PMC2613422  PMID: 19127975
Journal of orthopaedic trauma  2009;23(6):479-484.
Summary
Hip fractures are a significant cause of morbidity and mortality worldwide and the burden of disability associated with hip fractures globally vindicates the need for high-quality research to advance the care of patients with hip fractures. Historically, large, multi-centre randomized controlled trials have been rare in the orthopaedic trauma literature. Similar to other medical specialties, orthopaedic research is currently undergoing a paradigm shift from single centre initiatives to larger collaborative groups. This is evident with the establishment of several collaborative groups in Canada, in the United States, and in Europe, which has proven that multi-centre trials can be extremely successful in orthopaedic trauma research.
Despite ever increasing literature on the topic of his fractures, the optimal treatment of hip fractures remains unknown and controversial. To resolve this controversy large multi-national collaborative randomized controlled trials are required. In 2005, the International Hip Fracture Research Collaborative was officially established following funding from the Canadian Institute of Health Research International Oppurtunity Program with the mandate of resolving controversies in hip fracture management. This manuscript will describe the need, the information, the organization, and the accomplishments to date of the International Hip Fracture Research Collaborative.
doi:10.1097/BOT.0b013e3181a772e3
PMCID: PMC2954961  PMID: 19550238 CAMSID: cams321
hip fracture; multicenter collaboratives
BMJ : British Medical Journal  2003;326(7380):76.
Objective
To assess the effects of an intervention programme designed to increase use of hip protectors in elderly people in nursing homes.
Design
Cluster randomised controlled trial with 18 months of follow up.
Setting
Nursing homes in Hamburg (25 clusters in intervention group; 24 in control group).
Participants
Residents with a high risk of falling (459 in intervention group; 483 in control group).
Intervention
Single education session for nursing staff, who then educated residents; provision of three hip protectors per resident in intervention group. Usual care optimised by brief information to nursing staff about hip protectors and provision of two hip protectors per cluster for demonstration purposes.
Main outcome measure
Incidence of hip fractures.
Results
Mean follow up was 15 months for the intervention group and 14 months for the control group. In total 167 residents in the intervention group and 207 in the control group died or moved away. There were 21 hip fractures in 21 (4.6%) residents in the intervention group and 42 hip fractures in 39 (8.1%) residents in the control group (relative risk 0.57, absolute risk difference −3.5%, 95% confidence interval −7.3% to 0.3%, P=0.072). After adjustment for the cluster randomisation the proportions of fallers who used a hip protector were 68% and 15% respectively (mean difference 53%, 38% to 67%, P=0.0001). There were 39 other fractures in the intervention group and 38 in the control group.
Conclusion
The introduction of a structured education programme and the provision of free hip protectors in nursing homes increases the use of protectors and may reduce the number of hip fractures.
What is already known on this topicNursing home residents are at particularly high risk of fracturing a hipHip protectors can effectively prevent hip fracturesAdherence to the use of hip protectors is poorWhat this study addsThe use of hip protectors in nursing homes can be substantially increased by a single session education targeted at nursing staff and residents and provision of free hip protectorsIncreasing the use of hip protectors resulted in a relative reduction of hip fractures of about 40%
PMCID: PMC139934  PMID: 12521969
Trials  2011;12:213.
Background
Approximately 70,000 patients/year undergo surgery for repair of a fractured hip in the United Kingdom. This is associated with 30-day mortality of 9% and survivors have a considerable length of acute hospital stay postoperatively (median 26 days). Use of oesophageal Doppler monitoring to guide intra-operative fluid administration in hip fracture repair has previously been associated with a reduction in hospital stay of 4-5 days. Most hip fracture surgery is now performed under spinal anaesthesia. Oesophageal Doppler monitoring may be unreliable in the presence of spinal anaesthesia and most patients would not tolerate the probes. An alternative method of guiding fluid administration (minimally-invasive arterial pulse contour analysis) has been shown to reduce length of stay in high-risk surgical patients but has never been studied in hip fracture surgery.
Methods
Single-centre randomised controlled parallel group trial. Randomisation by website using computer generated concealed tables. Setting: University hospital in UK. Participants: 128 patients with acute primary hip fracture listed for operative repair under spinal anaesthesia and aged > 65 years. Intervention: Stroke volume guided intra-operative fluid management. Continuous measurement of SV recorded by a calibrated cardiac output monitor (LiDCOplus). Maintenance fluid and 250 ml colloid boluses given to achieve sustained 10% increases in stroke volume. Control group: fluid administration at the responsible (blinded) anaesthetist's discretion. The intervention terminates at the end of the surgical procedure and post-operative fluid management is at the responsible anaesthetist's discretion. Primary outcome: length of acute hospital stay is determined by a blinded team of clinicians. Secondary outcomes include number of complications and total cost of care.
Funding NIHR/RfPB: PB-PG-0407-13073.
Trial registration number
Trial registration: Current Controlled Trials ISRCTN88284896.
doi:10.1186/1745-6215-12-213
PMCID: PMC3191355  PMID: 21955538
PLoS ONE  2010;5(3):e9515.
Background
Elderly nursing home residents are at increased risk of hip fracture; however, the efficacy of fracture prevention strategies in this population is unclear.
Objective
We performed a scoping review of randomized controlled trials of interventions tested in the long-term care (LTC) setting, examining hip fracture outcomes.
Methods
We searched for citations in 6 respective electronic searches, supplemented by hand searches. Two reviewers independently reviewed all citations and full-text papers; consensus was achieved on final inclusion. Data was abstracted in duplicate.
Findings
We reviewed 22,349 abstracts or citations and 949 full-text papers. Data from 20 trials were included: 7 - vitamin D (n = 12,875 participants), 2 - sunlight exposure (n = 522), 1 - alendronate (n = 327), 1 - fluoride (n = 460), 4 – exercise or multimodal interventions (n = 8,165), and 5 - hip protectors (n = 2,594). Vitamin D, particularly vitamin D3 ≥800 IU orally daily, reduced hip fracture risk. Hip protectors reduced hip fractures in included studies, although a recent large study not meeting inclusion criteria was negative. Fluoride and sunlight exposure did not significantly reduce hip fractures. Falls were reduced in three studies of exercise or multimodal interventions, with one study suggesting reduced hip fractures in a secondary analysis. A staff education and risk assessment strategy did not significantly reduce falls or hip fractures. In a study underpowered for fracture outcomes, alendronate did not significantly reduce hip fractures in LTC.
Conclusions
The intervention with the strongest evidence for reduction of hip fractures in LTC is Vitamin D supplementation; more research on other interventions is needed.
doi:10.1371/journal.pone.0009515
PMCID: PMC2831075  PMID: 20209088
PLoS Medicine  2011;8(12):e1001137.
In this randomized trial, Saul Rajak et al. compare silk sutures (removed at 7–10 days) or absorbable sutures (left in place) during surgery for the management of trachomatous trichiasis.
Background
Trachoma causes blindness through an anatomical abnormality called trichiasis (lashes touching the eye). Trichiasis can recur after corrective surgery. We tested the hypothesis that using absorbable sutures instead of silk sutures might reduce the risk of recurrent disease among patients with major trichiasis in a randomised trial.
Methods and Findings
1,300 individuals with major trichiasis from rural villages in the Amhara Region of Ethiopia were recruited and assigned (1∶1) by computer-generated randomisation sequence to receive trichiasis surgery using either an absorbable suture (polyglactin-910) or silk sutures (removed at 7–10 days) in an otherwise identical surgical technique. Participants were examined every 6 months for 2 years by clinicians masked to allocation. The primary outcome measure was recurrent trichiasis (≥one lash touching the eye) at 1 year. There was no difference in prevalence of recurrent trichiasis at 1 year (114 [18.2%] in the absorbable suture group versus 120 [19.7%] in the silk suture group; odds ratio = 0.90, 95% CI 0.68–1.20). The two groups also did not differ in terms of corneal opacification, visual acuity, conjunctival inflammation, and surgical complications.
Conclusions
There was no evidence that use of absorbable polyglactin-910 sutures was associated with a lower prevalence of trichiasis recurrence at 1 year postsurgery than silk sutures. However, from a programmatic perspective, polyglactin-910 offers the major advantage that patients do not have to be seen soon after surgery for suture removal. The postoperative review after surgery using absorbable polyglactin-910 sutures can be delayed for 3–6 months, which might allow us to better determine whether a patient needs additional surgery.
Trial registration
ClinicalTrials.gov NCT00522860
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, around 40 million people—mostly people living in rural areas in developing countries where there are water shortages, poor personal hygiene, and crowded living conditions—have active trachoma, an infectious eye disease that is caused by Chlamydia trachomatis. This bacterium is spread through contact with infected eye secretions or with contaminated towels or clothes, and by flies. Recurrent infections with C. trachomatis during early childhood cause inflammation of the tissue lining the eye lid (chronic conjunctival inflammation), which can lead to conjunctival scarring. If this scarring is severe, the eyelids turn inwards (entropion) and the lashes rub across the eye's surface (the cornea). This condition—trachomatous trichiasis—is extremely painful and, if not treated with surgery, can lead to irreversible corneal opacities and visual impairment by middle age. It is estimated that 8 million people have trichiasis and that an additional 8 million people are blind or visually impaired as a result of the condition.
Why Was This Study Done?
Surgery for trichiasis, antibiotics for infection, and facial cleanliness and environmental improvements to reduce transmission together constitute the SAFE strategy for the control of blinding trachoma. Unfortunately, trichiasis recurs in nearly two-thirds of patients within 3 years of surgery, often within the first year. How the surgery is performed, its quality, and the severity of entropion and conjunctival scarring at the time of surgery all contribute to trichiasis recurrence. In this randomized trial (a study in which randomly chosen groups of patients receive different treatments for a disease and are followed to compare the outcomes of these interventions), the researchers investigate whether using absorbable sutures instead of silk sutures reduces the risk of recurrent disease among patients with major trichiasis (more than five lashes touching the cornea). Sutures are used to sew up surgical incisions. Silk sutures, which are used routinely during trichiasis surgery, have to be removed 7–10 days after surgery when the incision may not have stably healed. Absorbable sutures might provide more stable fixation of the eye tissue while healing is taking place and might, therefore, reduce the recurrence of trichiasis after surgery.
What Did the Researchers Do and Find?
The researchers randomly assigned 1,300 people living in Ethiopia (the country with the highest rates of trachoma and trichiasis) to receive trichiasis surgery using silk sutures (removed at 7–10 days) or absorbable sutures (left in place); the other details of the surgery were identical for all the patients. The trial's primary outcome was recurrent trichiasis (one or more lash touching the eye) at 1 year. Secondary outcomes included the rate of recurrence, visual acuity, corneal opacity, and conjunctival inflammation at 2 years, and surgical complications. At 1 year, 18.2% of the patients in the absorbable suture group and 19.7% in the silk suture group had developed recurrent trichiasis. That is, the prevalence of recurrence in the two groups was similar. There was also no difference in the rate of trichiasis recurrence between the groups 2 years after surgery. Moreover, the two groups did not differ in terms of corneal opacity and visual acuity, conjunctival inflammation, or surgical complications.
What Do These Findings Mean?
These findings provide no evidence to suggest that the use of absorbable sutures during trichiasis surgery is clinically better than the use of silk sutures. However, the researchers note that the use of absorbable sutures would eliminate the need for patients to return to the clinic soon after their operation to have their sutures removed. In remote rural settings, it can be difficult for patients, who are often elderly and poor, to attend clinics. Thus, it might be better for trachoma services to concentrate on encouraging patients to return 3–6 months after surgery when the need for additional surgery can be determined rather than trying to encourage them to come back after 7–10 days for suture removal. The use of absorbable sutures would also avoid any complications arising from patients failing to come back to have their stitches removed. The researchers suggest, therefore, that trachoma control programs should now consider the potential logistical advantages of using absorbable sutures rather than silk sutures during trichiasis surgery despite the lack of any apparent clinical difference between the two suture types.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001137.
An accompanying PLoS Medicine Research Article by Saul Rajak et al. describes another randomized trial undertaken by these researchers that compares surgery and epilation (eyelash removal) for the treatment of trichiasis in Ethiopia
The World Health Organization has information on trachoma (in several languages), including details of the Alliance for Global Elimination of Trachoma by the year 2020 (GET 2020) and a personal story about blinding trachoma
The UK National Health Service Choices website also provide information on trachoma
Orbis, an international nonprofit organization devoted to blindness prevention and treatment in developing countries, provides information about trachoma
The International Trachoma Initiative provides detailed information about trachoma and a personal story about trichiasis surgery in Ethiopia
The Global Atlas of Trachoma is an open-access resource on the geographical distribution of trachoma
Light for the World is a nonprofit organization dedicated to ensuring the rights of persons with disabilities in developing countries, including people in Ethiopia with trachoma
doi:10.1371/journal.pmed.1001137
PMCID: PMC3236737  PMID: 22180732

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