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1.  Surgical approach to bone healing in osteoporosis 
Osteoporotic fractures represent one of the most common cause of disability and one of the major voice in the health economic budget in many countries of the world. Fragility fractures are especially meta-epiphyseal fractures, in skeletal sites with particular biomechanic characteristic (hip, vertebrae), complex and with more fragments, with slow healing process (mineralization and remodeling) and co-morbidity. The healing of a fracture in osteoporotic bone passes through the normal stages and concludes with union of the fracture although the healing process is prolonged. Fractures in the elderly osteoporotic patients represent a challenge to the orthopaedic surgeons. Osteoporosis does not only increase the risk of fracture but also represents a problem in osteofixation of fractures in fracture treatment. The major technical problem that surgeons face, is the difficulty to obtain a stable fixation of an implant due to osteoporotic bone. The load transmitted at the bone-implant interface can often exceed the reduced strain tolerance of osteoporotic bone.
In the treatment of osteoporotic fractures it is important to consider different aspects: general conditions of elderly patient and comorbidity, the reduced muscular and bone mass and the increased bone fragility, structural modifications as medullary expansion.
The aim of surgical treatment is to obtain a stable fixation that reduces pain and permits an early mobilization.
PMCID: PMC2781233  PMID: 22461162
osteoporosis, bone healing, fractures fixation.
2.  Orthopaedic surgeons’ strategies in pharmacological treatment of fragility fractures 
Summary
Fragility fractures are the most severe complications of osteoporosis and the poor mechanical properties of bone can make fixation and healing of these fracture extremely difficult. The role of orthopaedic surgeons does not end in skillful fixation of the fractures, but they have the unique opportunity to prevent complications which can negatively affect the patient’s quality of life. The best practice for preventing the risk of further fractures in patients presenting fragility fractures includes fall prevention, investigation of possible causes underlying osteoporosis, attention to exercise, calcium and vitamin D supplementation as well as prescription of drugs. Actually two classes of agents can be used for their effect on fracture prevention: antiresorptive and bone forming agents. Systemic therapy reduces the risk of vertebral (30–70%) and non-vertebral fractures (12–53%), depending on agents and patients’ compliance.
Preclinical and clinical studies have shown that pharmacological agents involved in osteoporosis can also influence the phases of fracture repair. Preclinical studies and evidences from case reports showed a positive effect of anabolic drugs on bone healing and implant osseointegration.
The interventions in the process of fracture healing had evolved from a diamond to a pentagon concept, with interactions between the mechanical environment, the local therapies, the vascularity of the fracture site, the biology of the host and the systemic therapy which has the potential to represent the fifth interaction factor.
The orthopaedic surgeon plays a central role in clinical setting to evaluate the efficacy of systemic anti-fracture drugs for improving fracture repair and preventing complications.
PMCID: PMC4172175  PMID: 25285136
anabolics; bisphosphonates; bone healing; fracture; osteoporosis; prevention
3.  Knowledge of orthopaedic surgeons in managing patients with fragility fracture 
International Orthopaedics  2012;36(6):1275-1279.
Purpose
Fragility fractures represent a major health problem, as they cause deformity, disability and increased mortality rates. Orthopaedic surgeons should identify patients with fragility fractures and manage their osteoporosis in order to reduce the risk of future fracture; therefore, orthopaedic surgeons’ knowledge about managing fragile fracture should be evaluated.
Methods
A questionnaire was administered to 2,910 orthopaedic surgeons to address the respondents’ knowledge. The questions covered the topics of diagnosis, treatment and approach to a patient with a fragility fracture. The data-collection period for this survey spanned one year.
Results
There were 2,021 orthopaedic surgeons who participated in this study. Less than 10% of the respondents included bone mass densitometry (BMD) when evaluating patients with fragile fractures 32% prescribed proper dosage of calcium and vitamin D; approximately 30% would refer if falling from a height was suspected.
Conclusions
The majority of orthopaedic surgeons questioned lacked knowledge of fragility fracture management. This is reflected by limited knowledge of osteoporosis assessment and treatment in most areas. An appropriate method should be created to manage patients with fragility fractures to guarantee the patient the best possible care.
doi:10.1007/s00264-012-1482-0
PMCID: PMC3353064  PMID: 22281934
4.  Utilization of DXA Bone Mineral Densitometry in Ontario 
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
5.  Osteogenic Protein-1 for Long Bone Nonunion 
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
6.  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
7.  Clinical and surgical approach of severe bone fragility fracture: clinical case of 4 fragility fracture in patient with heavy osteoporosis 
Summary
An accurate diagnosis of osteoporosis and a proper treatment are today recognized to be the most important facts for prevention and for a correct arrangement and treatment of fragility fractures. In the text the Authors describe a case of severe osteoporosis aggravated by 2 femur fractures and 2 periprosthetic fractures occurred in 2 months. In such cases the orthopaedic surgeon needs to formulate first a clinical osteoporotic pattern, than its treatment together with a surgery suitable choice, that has to take into consideration of the bone structural characteristics. In the case described one can note that fractures healing occurred thanks to both an improvement in surgical techniques and antiosteoporotic pharmacological support; in the specific case the Authors used strontium ranelate for its osteoinductive capacity. In our opinion is crucial that the treatment used by orthopaedic surgeons is not related only to the “by-hand” treatment but take into consideration both the underlying disease and the possibility of positively affect bone healing with specific drug therapy.
doi:10.11138/ccmbm/2013.10.1.052
PMCID: PMC3710011  PMID: 23858312
osteoporosis; periprosthetic fractures; bone healing
8.  Does osteoporosis increase complication risk in surgical fracture treatment? A protocol combining new endpoints for two prospective multicentre open cohort studies 
Background
With an ever-increasing elderly population, orthopaedic surgeons are faced with treating a high number of fragility fractures. Biomechanical tests have demonstrated the potential role of osteoporosis in the increased risk of fracture fixation complications, yet this has not been sufficiently proven in clinical practice. Based on this knowledge, two clinical studies were designed to investigate the influence of local bone quality on the occurrence of complications in elderly patients with distal radius and proximal humerus fractures treated by open reduction and internal fixation.
Methods/Design
The studies were planned using a prospective multicentre open cohort design and included patients between 50 and 90 years of age. Distal radius and proximal humerus fractures were treated with locking compression 2.4 mm and proximal humerus internal locking plates, respectively. Follow-up examinations were planned for 6 weeks, 3 and 12 months as well as a telephone interview at 6 months. The primary outcome focuses on the occurrence of at least one local bone quality related complication. Local bone quality is determined by measuring bone mineral density and bone mineral content at the contralateral radius. Primary complications are categorised according to predefined factors directly related to the bone/fracture or the implant/surgical technique. Secondary outcomes include the documentation of soft tissue/wound or general/systemic complications, clinical assessment of range of motion, and patient-rated evaluations of upper limb function and quality of life using both objective and subjective measures.
Discussion
The prospective multicentre open cohort studies will determine the value of local bone quality as measured by bone mineral density and content, and compare the quality of local bone of patients who experience a complication (cases) following surgery with that of patients who do not (controls). These measurements are novel and objective alternatives to what is currently used.
Trial registration numbers
Clinical Trials.gov NCT01144208 and NCT01143675
doi:10.1186/1471-2474-11-256
PMCID: PMC2992478  PMID: 21062463
9.  Established Osteoporosis and Gaps in the Management: Review from a Teaching hospital 
Background:
International osteoporosis foundation described severe or established osteoporosis as an osteoporotic individual with a fragility fracture. Orthopaedic surgeons frequently manage fractures, but we believe that large gaps are prevalent in the medical management of osteoporosis after fractures are fixed.
Aim:
The aim of this analysis is to assess the investigations and gaps in the management of osteoporosis in patients admitted with a fragility fracture of femur at King Fahd Hospital of the University, AlKhobar, Saudi Arabia.
Materials and Methods:
A retrospective analysis of all admission and discharge; medical and pharmacy records database of patients over ≥ 50 years with fragility fracture between January 2001 and December 2011. The outcome measures assessed were investigations such as serum calcium, phosphorous, alkaline phosphatase, parathormone, 25 hydroxy vitamin D (25OHD) levels and a dual energy X-ray absorptiometry (DEXA). Secondly once the fracture was fixed what medications were prescribed, calcium and vitamin D, antiresorptives and anabolic agents.
Results:
There were 207 patients admitted during the study period with an average age of 69.2 (12.1) years and 118 were females. In 169 (81.6%) patients, the fracture site was proximal femur. Vitamin D (25OHD) was requested in 31/207 (14.9%). DEXA scan was ordered in 49/207 (24.1%). A total of 78/207 (37.6%) patients received calcium and vitamin D3 and 94/207 (45.4%) either got calcium or vitamin D3. Bisphosphonates was used in 35, miacalcic nasal spray in 25 and anabolic agent teriparatide was prescribed in 21 patients. Post-fixation 126/207 (60.8%) patients did not receive any anti-osteoporotic medication. In untreated group, there were 87 males and 39 females.
Conclusions:
The study found that in patients, who sustained a fragility fracture, confirmation of osteoporosis by DEXA was very low and ideal treatment for severe osteoporosis was given out to few patients. More efforts are needed to fill this large gap in the correct management of osteoporosis related fractures by orthopaedic surgeons.
doi:10.4103/2141-9248.129038
PMCID: PMC3991939  PMID: 24761237
Fragility fractures; Management; Osteoporosis; Saudi Arabia
10.  The Role of the Orthopaedic Surgeon 
Treatment for patients with vertebral compression fractures (VCFs) should address pain and mobility, and aim to prevent further fractures. Restoration of vertebral height to improve the spinal deformity is also of primary importance. Traditionally, osteoporosis-induced VCFs have been treated with bed rest, narcotic analgesics, braces, and physical therapy. However, immobility is known to have a negative impact on muscle strength and bone mass and may cause serious general health complications, narcotics can worsen mood and mentation problems, and brace wear is not well tolerated by the elderly. These fractures have a considerable impact on quality of life, and although most of them heal, the height loss and deformity remain uncorrected. Vertebroplasty and balloon kyphoplasty are minimally invasive treatment options for VCFs. Kyphoplasty is designed to reduce and stabilise the fracture in a controlled way, to correct the spinal deformity and to provide immediate pain relief, mobility, and an improved quality of life. The main differences between balloon kyphoplasty and vertebroplasty are the greater potential of the kyphoplasty procedure to restore the vertebral height and kyphosis angle of the fractured vertebra and (although the clinical significance of this has not yet been demonstrated) its lower percentage of cement extravasation; the latter is related to lower injection pressures, and facilitated by a higher cement viscosity and by the cavity created in the fractured vertebrae.
Worldwide, over 95,000 VCFs in 75,000 patients have been treated with balloon kyphoplasty. Accordingly, the orthopaedic surgeon today plays a leading role in the “Fracture Unit”, not only on the therapeutic side, but also on the diagnostic side. The kyphoplasty kit can allow percutaneous bone biopsy, often very important in order to obtain a correct diagnosis. In order to justify resource allocation and patient selection for new osteoporotic fracture treatment technologies, it is also becoming increasingly important to determine the cost-effectiveness of treatments. In a recent study we highlighted why spine surgery is important in VCFs, comparing the efficacy and safety of kyphoplasty and of non-surgical management for the treatment of acute osteoporotic VCFs. Our aim was to test the hypothesis that kyphoplasty would result in greater improvement in quality of life with a better cost-effectiveness ratio at 24 months’ follow up. Between January 2005 and September 2008, we randomly assigned 60 patients with one fresh (< 6 weeks) painful osteoporotic VCF to undergo either percutaneous surgical treatment with Medtronic Kyphoplasty (Group A, n=32) or conservative treatment (Group B, n=28), preceded by 40 days of bed rest and followed by 40 days of hyperextension back brace wear (type C35). The baseline characteristics were similar in the two groups: the average age was 67 years and 7 months, min. 62 - max. 89 years, in Group A, and 66 years and 5 months, min. 64 - max. 78 years, in Group B. The fractured levels were T12=10, L1=11, L2=5, L3=6 in Group A and T12=7, L1=13, L2=5, L3=3 in Group B. According to the Magerl classification the VCFs in both groups were prevalently A1.2 (13 cases in A and 16 in B) and A1.3 (14 cases in A and 8 in B). In all cases standing lateral spinal radiographs were taken at baseline, 3 months, 6 months, 12 months and 24 months to evaluate vertebral kyphosis (VK) and regional kyphosis (RK). Vertebral kyphosis was measured from the superior endplate to the inferior endplate of the fractured vertebra. Regional kyphosis was measured from the inferior endplate of the intact adjacent distal vertebra to the superior endplate of the intact adjacent proximal vertebra. Pain was evaluated at baseline, 3 months, 6 months, 12 months and 24 months with the VAS pain scale. Each patient had a card to be used for recording medical and non-medical costs sustained in the course of the 24 months.
The primary endpoint was the difference, between the groups, in VK and VAS pain scale score changes from baseline to 3, 6, 12 and 24 months: the surgical treatment group always showed better results. Mean VK was 11.50 degrees at baseline, 6.50 degrees at 3 months, 6.37 degrees at 6 months, and 6.38 degrees at 12 and 24 months in Group A and 12.6 degrees at baseline, 10.50 degrees at 3 months, 10.70 degrees at 6 months, and 11.80 degrees at 12 and 24 months in Group B. The VAS pain score was 9 (baseline), 2 (3 mths), 1 (6 mths), 2 (12 and 24 mths) in Group A and 9 (baseline), 7 (3 mths), 4 (6 mths), 5 (12 and 24 mths) in Group B.
The secondary endpoint was the difference, between surgical and conservative treatments, in medical (hospitalisation, surgical procedure, convalescence and 24-months follow up) and non-medical costs sustained. Group A recorded higher hospitalisation costs (average 9 days, € 4551) than Group B (average 5 days, € 2681). For the surgically treated group there was also an additional surgical procedure cost (average € 4,483.09).
The convalescence was longer in Group B (average 95 days, medical costs: € 2018,59) than in Group A (average 15 days, medical costs: € 192,92). Obviously, non-medical costs were also higher in Group B (€ 3390,00) than in Group A (€ 210,00). Between 3 and 24 months we recorded three cases of back pain Group A and 17 in Group B, with an additional cost of € 47,53 in the first group and € 1319,56 in the second. Therefore, on the whole, the surgical treatment had an average cost of € 9484,54 while the conservative treatment had an average cost of € 9409,15. However it is important to underline that in the second group there was also another non-medical cost that is difficult to quantify: that of family caregiving, which corresponds to 1 person’s days of absence from work (average 14 days, min. 5, max. 22).
The cost-effectiveness relationship becomes even better for the surgically treated group if we analyse the complications. In the first group we recorded seven asymptomatic minor complications (3 cases of vein leakage and 4 of intradiscal leakage) that did not generate supplementary medical or non-medical costs; instead, in the second group we recorded 13 complications (6 cases of decubitus ulcers and 7 cases of bronchitis) generating an additional cost of ⇔ 4325. Therefore, this study confirmed that kyphoplasty may today be the gold standard in the treatment of fresh osteoporotic VCFs. Accordingly, orthopaedic surgeon is destined to play an ever more important role within a superspecialist team.
PMCID: PMC3213845
11.  Management pitfalls of fractured neck of femur in osteogenesis imperfecta 
Introduction
Fractured neck of femur in osteogenesis imperfecta is rarely reported. Its management is always difficult because of bone fragility and the outcome is not well known. We, therefore, aimed to study the management pitfalls in this group of patients.
Methods
We retrospectively reviewed five cases of fractured neck of femur in four patients treated in our hospital between 2006 and 2009. The demographic data, mode of injury, fracture configuration, treatment, complications, clinical and radiological outcome were reviewed.
Results
According to the Sillence classification, one patient was type I, two were type III and one was type IV. There were two children (aged 8 and 15 years) and two adults (aged 21 and 22 years), with the 8 year-old girl suffering from hip fracture on different sides in two accidents. All five hip fractures were the result of low-energy injury and were associated with other fractures. Two undisplaced fractures required intra-operative fluoroscopic confirmation to demonstrate movement at the fracture site. The interval between the injury and fixation ranged from 6 h to 3 days. One hip required secondary surgery to openly reduce the fracture due to inadequate primary fixation and reduction. Two hips were fixed with paediatric dynamic hip screws and three hips were fixed with cannulated screws. All patients were immobilised in hip spica for 6 weeks. The average follow-up was 4 years (3–5 years). All patients had satisfactory union and none of them developed radiological evidence of avascular necrosis at the latest follow-up. All patients returned to their pre-injury functional level.
Conclusion
Fractured neck of femur is rare given the high prevalence of long bone fractures in osteogenesis imperfecta. They all have characteristic associated fractures of the extremity at the time of injury and neck of femur fractures could be easily missed. Fracture fixation is a great challenge to the orthopaedic surgeons because of the small size of the patients, poor bone quality with suboptimal imaging intra-operatively and compromised purchase of fixation devices. The choice of implants should be determined by the size of the patients and the presence of prior instrumentation close to the hip joint.
doi:10.1007/s11832-013-0495-6
PMCID: PMC3672462  PMID: 24432078
Osteogenesis imperfecta; Fractured neck of femur; Operative challenge
12.  Pharmacological agents and bone healing 
Osteoporosis is the most common alteration of bone metabolism. It derives from an increase in bone resorption with respect to bone formation and is characterized by microarchitectural alterations, decreased bone mass and increased risk of fracture. The coupling between bone formation and resorption is a fundamental concept in skeletal metabolism, and it explains how a certain amount of removed tissue can be replaced by the same amount of new bone. Various substances used to treat osteoporosis may also be used for orthopaedic conditions such as fracture healing, implant fixation, bone grafts and osteonecrosis. Fracture healing consists in the replacement of the lost bone by a tissue that has the same biomechanical properties as those preceding the fracture. The repair process is triggered by the local response to the tissue injury that damaged the continuity of bone. The duration of each phase of the healing process can vary significantly, depending on the site and characteristics of the fracture, on patient related factors and on the treatment choice. While most of the fractures heal with conventional treatment, they can also cause permanent damage and complications, especially in a certain kind of patients. Osteoporosis and old age may contribute in delaying or impairing the reparative process. In animal models the healing process is slower in older and/or ovariectomized animals. Biomechanical tests have also shown that bone strength is compromised in human osteoporotic cadaver bone. The same problems were highlighted in the surgical treatment of fractures in osteoporotic patients. Mainly in the treatment of hip fractures there is an increased risk of cut-out, re-fractures and implant failure in patients with osteoporosis. Preclinical studies have shown that certain pharmacological agents (bisphosphonates, strontium ranelate, teriparatide) may enhance osseointegration and stimulate reparative processes. They may be administered systemically and/or used locally at the fracture site on the implant surface. The aim of fracture treatment is to restore bone biomechanical properties and to allow restoring normal function at the affected site. If the new pharmacological approaches could be translated into clinical benefit and offered to patients with osteoporosis or other factors that put at risk the process of healing (subjects with severe loss of substance or fractures at high risk of complications), they could represent a valuable aid in the treatment of fractures.
PMCID: PMC2781222  PMID: 22461164
fracture healing, bone remodeling, osteoporosis treatment.
13.  Leisure Physical Activity and the Risk of Fracture in Men 
PLoS Medicine  2007;4(6):e199.
Background
Data from previous studies are inconsistent, and it is therefore uncertain whether, to what extent, and at what level leisure physical activity influences the risk of osteoporotic fractures in men.
Methods and Findings
A cohort of 2,205 men, 49–51 y of age, was enrolled in a longitudinal, population-based study. Leisure physical activity and other lifestyle habits were established at baseline and at ages 60, 70, 77, and 82 y. During 35 y of follow-up, 482 men had at least one fracture. Cox's proportional hazards regression was used to determine hazard ratios (HRs) of fracture associated with time-dependent physical activity habits and covariates. Men with a sedentary lifestyle (HR 2.56, 95% confidence interval 1.55–4.24) or men who walked or bicycled only for pleasure (HR 1.61, 95% confidence interval 1.10–2.36) had an increased adjusted risk of hip fracture compared with men who participated in regular sports activities for at least 3 h/wk. At the end of follow-up, 8.4% of the men with a high physical activity, 13.3% of the men with a medium physical activity, and 20.5% of the men with a low physical activity had suffered a hip fracture. According to the estimation of population-attributable risk, one third of all hip fractures could be prevented by participation in regular sports activities. High activity also conferred a reduced overall fracture risk.
Conclusions
Our data indicate that regular sports activities can reduce the risk of fractures in older men.
From a large cohort study with 35 years of follow-up, Michaelsson and colleagues conclude that regular sport activities can reduce the risk of fractures in older men.
Editors' Summary
Background.
One of the hazards of old age is that the bones become less dense—and therefore weaker—so when an elderly person falls, the result is often a broken bone. As many as half of all women and a quarter of men older than 50 y will break a bone because of this, and the consequences can be serious, particularly if the hip is broken. The thinning of bones, which is known as osteoporosis, does affect all people as they age, but the degree to which it occurs varies greatly between individuals. A priority area for medical research is finding ways in which osteoporosis can be reduced, with the aim of improving the lives of older people and reducing their risk of “osteoporotic fractures.” It is known that genetic and environmental factors can both play a part in how rapidly osteoporosis develops, but it is generally agreed that personal lifestyle factors are also important. Osteoporosis develops over many years; in most people bone density starts to decline after the age of about 30 y. Preventive action should therefore begin early.
Most research so far has focused on women, who are more at risk as the thinning of their bones increases after the menopause. (Indeed osteoporosis has sometimes been wrongly described as a “woman's disease.”) It is now accepted that women who are more physically active reduce the rate of decline in their bone density and, as a result, are less likely to break bones when they are elderly. There has been little research in men and the results have not been consistent.
Why Was This Study Done?
In order to provide better evidence as to whether men who do more physical activity have fewer osteoporotic fractures than those with lower activity levels, the researchers wanted to complete a study that was larger and was conducted over a longer period of time than previous research.
What Did the Researchers Do and Find?
Between 1970 and 1973, the researchers invited all those men living in Uppsala, Sweden, who were aged between 49 and 51 y to participate in a health survey. Most of them (2,205) agreed to do so. When the study began, they were asked questions about the amount of physical activity they took outside working hours. They were asked the same questions again when they were aged 60, 70, 77, and 82 y. A record was also kept of the number of fractures the men had suffered during the 35-y study period. (Although some of the men died before the end of the study, about half were still alive at the end.) On the basis of the answers to the questions on physical activity at the start of the study, the researchers divided the men into three categories: those whose lifestyle was considered to be “sedentary,” those whose leisure activities included some walking and cycling, and those who participated in sports for at least 3 h a week. These were referred to as the low, medium, and high activity groups. Over the 35-y period, 428 men had at least one fracture and 134 broke a hip, but there were big differences between the groups—20% of the low-activity men had fractures compared with 13% of those with medium activity and only 8% of those in the high-activity group. In particular, the chance of having a hip fracture was reduced by increased activity.
What Do These Findings Mean?
Taking exercise reduces the risk of an osteoporotic fracture. Participating in sports seems to be particularly effective; the researchers calculate that one-third of fractures could be prevented if men could be persuaded to take part in sports regularly. The researchers do note that the very best evidence always comes from studies where people are assigned at random to receive a particular “treatment” (in this case, it would be exercise) and are compared with others who did not receive the treatment. This is known as a “randomized controlled trial.” Such a trial would be difficult, if not impossible, to organize on this topic, and the approach adopted by the researchers, which is known as a “cohort study,” does provide very strong evidence. There are many other benefits from increased exercise (for example, in reducing the risk of heart attacks and strokes), and most governments are now promoting sports and other active leisure pursuits. This study adds further weight to support such policies.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040199.g002.
There are many free sources of information about osteoporosis on the Web, and many organizations exist to support people with the condition. For example, the National Osteoporosis Society (UK) has useful information about the condition
In the USA, there is the Nationtal Osteoporosis Foundation (USA)
The equivalent organization in Australia is Osteoporosis Australia
The UK National Health Service's NHS Direct Health Encyclopedia has an entry on osteoporosis
MedlinePlus is an excellent source of information
doi:10.1371/journal.pmed.0040199
PMCID: PMC1892039  PMID: 17579509
14.  Strontium Ranelate: The Pathophysiological Rationale 
Skeletal metabolism and the replacement of damaged tissue with the same amount of intact bone depends on the correct balance between bone formation and bone resorption.
The existence of an imbalance between bone formation and resorption is a concept central to understanding of the pathophysiology of osteoporosis and the reduction of fracture risk.
With aging, the volume of bone that is formed during the bone remodelling process and after injury is less than the volume absorbed during the bone resorption phase; this results in bone loss and increased bone fragility. In addition to bone mineral density, many other properties of bone are determined by the balance between bone formation and bone resorption. A bone that is biomechanically more fragile is also a bone that consolidates more slowly after a fracture event. Although the fracture healing stages are the same even in the presence of osteoporosis, recent studies have shown a slowdown in the process of consolidation when osteoporosis is present. In particular, strategies to reduce fracture risk and facilitate the process of consolidation of the fracture may be a primary criterion for selection.
The ability to modulate anabolic and catabolic phenomena in the skeleton, both locally and systemically, opens up a new horizon for the reduction of fracture risk and the enhancement of bone healing, particularly when the bone is qualitatively and/or quantitatively compromised.
Clinical research has recently allowed the development of therapies, such as treatment with strontium ranelate, able to increase production of bone matrix by osteoblasts and to act positively on the distribution of the skeletal microarchitecture. Strontium ranelate is able to rebalance bone turnover in favour of the formation of more resistant and elastic bone, by stimulating osteoblasts and inhibiting the resorptive activity of osteoclasts, thereby ensuring rapid and lasting protection against the risk of fractures. In vitro studies have shown that the drug is able to promote replication of the first pre-osteoblasts and their differentiation into mature osteoblasts and osteocytes interacting with the receptor CaSR and through the increased synthesis of OPG. Thanks, again, to the participation of the CaSR receptor, but also by reducing the production of RANKL, strontium ranelate decreases the resorptive activity of osteoclasts. The anabolic action of strontium ranelate in terms of mineral apposition rate in both cortical and trabecular bone was demonstrated on bone biopsies analysed by three-dimensional micro-CT. The drug was shown to increase the number of trabeculae, the cortical thickness, and the total bone volume. The bone-forming activity of strontium ranelate was also demonstrated in comparative studies versus teriparatide and antiresorptive agents. In experimental studies the bone-forming effect of strontium ranelate leads to an increase in the bone callus volume and its maturation and, in turn, to an acceleration of the consolidation of the fracture and better implant osteointegration.
In conclusion, the mechanism of action of strontium ranelate, which inhibits bone resorption in favour of new bone formation, is able to counteract, in a physiological manner, the bone loss associated with advancing age. The net effect is an increase in bone mass, trabecular and cortical bone, which explains its anti-fracture efficacy. The drug’s ability to stimulate bone formation seems to unfold at the level of the callus allowing improved fracture healing and in the case of implants potential improvement of implant osteointegration.
PMCID: PMC3213810
15.  Optimizing Screening for Osteoporosis in Patients With Fragility Hip Fracture 
Background
Osteoporosis, the underlying cause of most hip fractures, is underdiagnosed and undertreated. The 2008 Joint Commission report Improving and Measuring Osteoporosis Management showed only an average of 20% of patients with low-impact fracture are ever tested or treated for osteoporosis. We developed an integrated model utilizing hospitalists and orthopaedic surgeons to improve care of osteoporosis in patients with hip fracture.
Questions/purposes
Does our integrated model combining hospitalists and orthopaedic surgeons improve the frequency of evaluation for osteoporosis, screening for secondary causes, and patients’ education on osteoporosis?
Patients and Methods
Our Hospitalist-Orthopaedic Surgeon Integrated Model of Care was implemented in September 2009. We compared the rate of evaluation and treatment of osteoporosis in 140 patients admitted with fragility hip fracture at our institution before (70 patients) and after (70 patients) implementation of the care plan.
Results
Evaluation of patients for osteoporosis was higher in the postimplementation group compared to the preimplementation group (89% versus 24%). Screening of patients for secondary causes of osteoporosis was also improved in the postimplementation group (89% versus 0%), as was the proportion of patients who received education for osteoporosis management (89% versus 0%).
Conclusion
Our model of integrated care by hospitalists and orthopaedic surgeons resulted in improvement in the evaluation for osteoporosis, screening for secondary causes of osteoporosis, and education on osteoporosis management in patients with hip fracture at our institution. This may have important implications for treatment of these patients.
Level of Evidence
Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-011-1839-5
PMCID: PMC3111791  PMID: 21387105
16.  Are osteoporotic fractures being adequately investigated?: A questionnaire of GP & orthopaedic surgeons 
Background
To investigate the current practice of Orthopaedic Surgeons & General Practitioners (GP) when presented with patients who have a fracture, with possible underlying Osteoporosis.
Methods
Questionnaires were sent to 140 GPs and 140 Orthopaedic Surgeons. The participants were asked their routine clinical practice with regard to investigation of underlying osteoporosis in 3 clinical scenarios.
55 year old lady with a low trauma Colles fracture
60 year old lady with a vertebral wedge fracture
70 year old lady with a low trauma neck of femur fracture.
Results
Most doctors agreed that patients over 50 years old with low trauma fractures required investigation for osteoporosis, however, most surgeons (56%, n = 66) would discharge patients with low trauma Colles fracture without requesting or initiating investigation for osteoporosis. Most GPs (67%, n = 76) would not investigate a similar patient for osteoporosis, unless prompted by the Orthopaedic Surgeon or patient.
More surgeons (71%, n= 83) and GPs (64%, n = 72) would initiate investigations for osteoporosis in a vertebral wedge fracture, but few surgeons (35%, n = 23) would investigate a neck of femur fracture patient after orthopaedic treatment.
Conclusion
Most doctors know that fragility fractures in patients over 50 years old require investigation for Osteoporosis; however, a large population of patients with osteoporotic fractures are not being given the advantages of secondary prevention.
doi:10.1186/1471-2296-7-7
PMCID: PMC1388220  PMID: 16464250
17.  Breakout Session: Sex/Gender and Racial/Ethnic Disparities in the Care of Osteoporosis and Fragility Fractures 
Background
Recent epidemiologic and clinical data suggest men and racial and ethnic minorities may receive lower-quality care for osteoporosis and fragility fractures than female and nonminority patients. The causes of such differences and optimal strategies for their reduction are unknown.
Questions/purposes
A panel was convened at the May 2010 American Academy of Orthopaedic Surgeons/Orthopaedic Research Society/Association of Bone and Joint Surgeons Musculoskeletal Healthcare Disparities Research Symposium to (1) assess current understanding of sex/gender and racial/ethnic disparities in the care of osteoporosis and after fragility fractures, (2) define goals for improving the equity and quality of care, and (3) identify strategies for achieving these goals.
Where are we now?
Participants identified shortcomings in the quality of care for osteoporosis and fragility fractures among male and minority populations and affirmed a need for novel strategies to improve the quality and equity of care.
Where do we need to go?
Participants agreed opportunities exist for health professionals to contribute to improved osteoporosis management and secondary fracture prevention. They agreed on a need to define standards of care and management for osteoporosis and fragility fractures and develop strategies to involve physicians and other health professionals in improving care.
How do we get there?
The group proposed strategies to improve the quality and equity of osteoporosis and care after fragility fractures. These included increased patient and physician education, with identification of “champions” for osteoporosis care within and outside of the healthcare workforce; creation of incentives for hospitals and physicians to improve care; and research comparing the effectiveness of approaches to osteoporosis screening and fracture management.
doi:10.1007/s11999-011-1859-1
PMCID: PMC3111803  PMID: 21424834
18.  Managing osteoporosis in ulcerative colitis: Something new? 
World Journal of Gastroenterology : WJG  2014;20(39):14087-14098.
The authors revise the latest evidence in the literature regarding managing of osteoporosis in ulcerative colitis (UC), paying particular attention to the latest tendency of the research concerning the management of bone damage in the patient affected by UC. It is wise to assess vitamin D status in ulcerative colitis patients to recognize who is predisposed to low levels of vitamin D, whose deficiency has to be treated with oral or parenteral vitamin D supplementation. An adequate dietary calcium intake or supplementation and physical activity, if possible, should be guaranteed. Osteoporotic risk factors, such as smoking and excessive alcohol intake, must be avoided. Steroid has to be prescribed at the lowest possible dosage and for the shortest possible time. Moreover, conditions favoring falling have to been minimized, like carpets, low illumination, sedatives assumption, vitamin D deficiency. It is advisable to assess the fracture risk in all UC patient by the fracture assessment risk tool (FRAX® tool), that calculates the ten years risk of fracture for the population aged from 40 to 90 years in many countries of the world. A high risk value could indicate the necessity of treatment, whereas a low risk value suggests a follow-up only. An intermediate risk supports the decision to prescribe bone mineral density (BMD) assessment and a subsequent patient revaluation for treatment. Dual energy X-ray absorptiometry bone densitometry can be used not only for BMD measurement, but also to collect data about bone quality by the means of trabecular bone score and hip structural analysis assessment. These two indices could represent a method of interesting perspectives in evaluating bone status in patients affected by diseases like UC, which may present an impairment of bone quality as well as of bone quantity. In literature there is no strong evidence for instituting pharmacological therapy of bone impairment in UC patients for clinical indications other than those that are also applied to the patients with osteoporosis. Therefore, a reasonable advice is to consider pharmacological treatment for osteoporosis in those UC patients who already present fragility fractures, which bring a high risk of subsequent fractures. Therapy has also to be considered in patients with a high risk of fracture even if it did not yet happen, and particularly when they had long periods of corticosteroid therapy or cumulative high dosages. In patients without fragility fractures or steroid treatment, a medical decision about treatment could be guided by the FRAX tool to determine the intervention threshold. Among drugs for osteoporosis treatment, the bisphosphonates are the most studied ones, with the best and longest evidence of efficacy and safety. Despite this, several questions are still open, such as the duration of treatment, the necessity to discontinue it, the indication of therapy in young patients, particularly in those without previous fractures. Further, it has to be mentioned that a long-term bisphosphonates use in primary osteoporosis has been associated with an increased incidence of dramatic side-effects, even if uncommon, like osteonecrosis of the jaw and atypical sub-trochanteric and diaphyseal femoral fractures. UC is a long-lasting disease and the majority of patients is relatively young. In this scenario primary prevention of fragility fracture is the best cost-effective strategy. Vitamin D supplementation, adequate calcium intake, suitable physical activity (when possible), removing of risk factors for osteoporosis like smoking, and avoiding falling are the best medical acts.
doi:10.3748/wjg.v20.i39.14087
PMCID: PMC4202340  PMID: 25339798
Ulcerative colitis; Osteoporosis; Fragility fracture; Bone mineral density; Trabecular bone score; Hip structural analysis; Fracture assessment risk tool; Dual energy X-ray absorptiometry
19.  The clinical utility of bone marker measurements in osteoporosis 
Osteoporosis is characterised by low bone mass and structural deterioration of bone tissue, resulting in increased fragility and susceptibility to fracture. Osteoporotic fractures are a significant cause of morbidity and mortality. Direct medical costs from such fractures in the UK are currently estimated at over two billion pounds per year, resulting in a substantial healthcare burden that is expected to rise exponentially due to increasing life expectancy. Currently bone mineral density is the WHO standard for diagnosis of osteoporosis, but poor sensitivity means that potential fractures will be missed if it is used alone. During the past decade considerable progress has been made in the identification and characterisation of specific biomarkers to aid the management of metabolic bone disease. Technological developments have greatly enhanced assay performance producing reliable, rapid, non-invasive cost effective assays with improved sensitivity and specificity. We now have a greater understanding of the need to regulate pre-analytical sample collection to minimise the effects of biological variation. However, bone turnover markers (BTMs) still have limited clinical utility. It is not routinely recommended to use BTMs to select those at risk of fractures, but baseline measurements of resorption markers are useful before commencement of anti-resorptive treatment and can be checked 3–6 months later to monitor response and adherence to treatment. Similarly, formation markers can be used to monitor bone forming agents. BTMs may also be useful when monitoring patients during treatment holidays and aid in the decision as to when therapy should be recommenced. Recent recommendations by the Bone Marker Standards Working Group propose to standardise research and include a specific marker of bone resorption (CTX) and bone formation (P1NP) in all future studies. It is hoped that improved research in turn will lead to optimised markers for the clinical management of osteoporosis and other bone diseases.
doi:10.1186/1479-5876-11-201
PMCID: PMC3765909  PMID: 23984630
Bone turnover markers; Bone formation; Bone resorption; Osteoporosis; Biological variability
20.  Prevalence and Predictors of Osteoporosis Risk in Orthopaedic Patients 
Background
Current physician practices are not effective in adequately evaluating and treating patients for osteoporosis. While dual-energy xray absorptiometry is the gold standard in evaluating bone mineral density, calcaneal quantitative ultrasound has emerged as a low-risk and low-cost alternative.
Questions/purposes
We estimated the prevalence of abnormal bone mineral density with calcaneal quantitative ultrasound and developed criteria for risk stratification in female and male orthopaedic patients.
Methods
We enrolled 500 patients (331 women, 169 men) with a mean age of 67 years (range, 55–94 years) and screened them for osteoporosis with calcaneal quantitative ultrasound. Multivariate logistic regression was used to identify predictors of low bone mineral density and a risk model was developed.
Results
Quantitative ultrasound identified 154 patients with low bone mineral density at the time of enrollment. The prevalence of abnormal bone mineral density was 31% (women: 38%, men: 17%). Multivariate analysis demonstrated age, female gender, smoking, wrist fracture, and spinal deformities independently predicted low bone mineral density. The probability of low bone mineral density among patients with more than one risk factor was greater than 50% among women and greater than 30% among men.
Conclusions
Low bone mineral density is common among orthopaedic outpatients. Age, female gender, smoking, wrist fractures, and spinal deformities are independent risk factors for osteoporosis. We present a probability model designed to assist orthopaedic surgeons in identifying high-risk patients and initiating adequate preventative measures.
Level of Evidence
Level I, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-009-1162-6
PMCID: PMC2881983  PMID: 19911243
21.  Beta-Catenin Signaling Plays a Disparate Role in Different Phases of Fracture Repair: Implications for Therapy to Improve Bone Healing 
PLoS Medicine  2007;4(7):e249.
Background
Delayed fracture healing causes substantial disability and usually requires additional surgical treatments. Pharmacologic management to improve fracture repair would substantially improve patient outcome. The signaling pathways regulating bone healing are beginning to be unraveled, and they provide clues into pharmacologic management. The β-catenin signaling pathway, which activates T cell factor (TCF)-dependent transcription, has emerged as a key regulator in embryonic skeletogenesis, positively regulating osteoblasts. However, its role in bone repair is unknown. The goal of this study was to explore the role of β-catenin signaling in bone repair.
Methods and Findings
Western blot analysis showed significant up-regulation of β-catenin during the bone healing process. Using a β-Gal activity assay to observe activation during healing of tibia fractures in a transgenic mouse model expressing a TCF reporter, we found that β-catenin-mediated, TCF-dependent transcription was activated in both bone and cartilage formation during fracture repair. Using reverse transcription-PCR, we observed that several WNT ligands were expressed during fracture repair. Treatment with DKK1 (an antagonist of WNT/β-catenin pathway) inhibited β-catenin signaling and the healing process, suggesting that WNT ligands regulate β-catenin. Healing was significantly repressed in mice conditionally expressing either null or stabilized β-catenin alleles induced by an adenovirus expressing Cre recombinase. Fracture repair was also inhibited in mice expressing osteoblast-specific β-catenin null alleles. In stark contrast, there was dramatically enhanced bone healing in mice expressing an activated form of β-catenin, whose expression was restricted to osteoblasts. Treating mice with lithium activated β-catenin in the healing fracture, but healing was enhanced only when treatment was started subsequent to the fracture.
Conclusions
These results demonstrate that β-catenin functions differently at different stages of fracture repair. In early stages, precise regulation of β-catenin is required for pluripotent mesenchymal cells to differentiate to either osteoblasts or chondrocytes. Once these undifferentiated cells have become committed to the osteoblast lineage, β-catenin positively regulates osteoblasts. This is a different function for β-catenin than has previously been reported during development. Activation of β-catenin by lithium treatment has potential to improve fracture healing, but only when utilized in later phases of repair, after mesenchymal cells have become committed to the osteoblast lineage.
In a study in mice Benjamin Alman and colleagues show that β-catenin functions differently in different stages of fracture repair; moreover, activation of β-catenin by lithium improves fracture healing when used in later phases of repair.
Editors' Summary
Background.
Most people break at least one bone during their life. If the damaged bone is immobilized with a plaster cast or with metal plates and pins, most fractures heal naturally and quickly. Soon after a bone is damaged, cells called pluripotent mesenchymal cells collect at the injury site. Here, they multiply and change (differentiate) into osteoblasts (cells that make bone) and chondrocytes (cells that make cartilage, the dense connective tissue that covers joints). Osteoblasts and chondrocytes mend the fracture by making new bone, a process called ossification. Bone healing involves two types of ossification. In intramembranous ossification, mesenchymal cells and osteoblast progenitor cells make bone directly, forming a hard “callus” within the fracture. In endochondral ossification, mesenchymal cells differentiate into chondrocytes and make cartilage at the fracture site, which osteoblasts turn into bone. Finally, the bone made by both types of ossification is remodeled so that it closely resembles the damaged bone's original shape and strength.
Why Was This Study Done?
Unfortunately, fractures do not always heal efficiently. If healing is delayed, additional surgery may be needed to repair the break. But surgery can be risky, so drug-based ways of encouraging bone repair would be very useful. To develop such treatments, researchers need to understand what controls the differentiation and activity of osteoblasts and chondrocytes during normal healing. In this study, the researchers have investigated the role of the β-catenin signaling pathway in bone repair. This pathway regulates bone formation during embryonic development, a process that closely resembles bone healing. β-catenin is usually degraded rapidly in cells. However, if a member of a particular family of proteins known as the WNT family binds to a WNT receptor on the surface of a cell, β-catenin moves into the cell's nucleus where it interacts with a protein called T cell factor (TCF). This interaction activates the transcription (the copying of DNA into messenger RNA, which is used to make proteins) of numerous genes and alters the behavior of the cell.
What Did the Researchers Do and Find?
The researchers first measured β-catenin levels in mouse and human bones. In both species, much more β-catenin was made in bones undergoing repair than in intact bones. Then they studied TCF reporter mice—animals in which TCF controls the expression of a marker gene. β-catenin-mediated TCF-dependent transcription, they report, was activated during both bone and cartilage formation after a fracture in these mice. Next, the researchers made mice that could be induced to express an inactive form of β-catenin or a stabilized (permanently active) form of β-catenin in all the cells in a bone fracture. Expression of inactive β-catenin slowed the rate of healing but, unexpectedly, so did expression of stabilized β-catenin. Osteoblast-specific expression of inactive β-catenin also delayed bone healing, whereas osteoblast-specific expression of stabilized β-catenin enhanced the process. Finally, treatment of wild-type mice with lithium (which prevents the degradation of β-catenin) enhanced bone healing if given after a fracture, but interfered with it if given before.
What Do These Findings Mean?
These findings indicate that β-catenin signaling (which, the researchers show, is mainly activated by WNT signaling) has different effects at different stages of bone repair. Early in the process, it controls the ratio of osteoblasts and chondrocytes made from the pluripotent mesenchymal cells. Consequently, too much or too little β-catenin interferes with bone healing at this stage. Later on, β-catenin promotes the differentiation of osteoblasts and enhances their ability to make bone, and so too little β-catenin at this stage prevents healing, whereas increased β-catenin levels stimulate healing. These findings need to be confirmed in people before testing agents that affect β-catenin signaling for their effects on human bone healing. Nevertheless, the researchers' final discovery that lithium improves bone healing if given at the right time is particularly encouraging; lithium is widely used to treat one form of depression so could be readily tested in clinical trials.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040249.
MedlinePlus encyclopedia contains pages on broken bones and on bone fracture repair (in English and Spanish)
Wikipedia has pages on bone fracture and on bone healing (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The UK National Health Service Direct encyclopedia provides pages on broken bones
Animations of intramembranous and endochondral ossification are available from the Ministry of Advanced Education, Training and Technology, Province of British Columbia, Canada
The American Academy of Orthopedic Surgeons has an informative discussion of fractures
The Hospital for Sick Children in Toronto (where the authors of this study are affiliated) has a Web site called SickKids, which contains a page on child physiology, including diagrams of bone development
doi:10.1371/journal.pmed.0040249
PMCID: PMC1950214  PMID: 17676991
22.  Fractures of the Femur. End Results* 
Melvin Starkey Henderson was born in St. Paul, Minnesota and received his early schooling there and in Winnipeg, Manitoba [4]. He received his undergraduate and medical degrees from the University of Toronto. He then interned in the City and County Hospital in his home town of St. Paul, and in 1907 went to work as an assistant with the founders of the recently formed Mayo Clinic, William James and Charles Horace Mayo. To further his training and evidently at the suggestion of the Mayo brothers, in 1911 Dr. Henderson went abroad to work under Sir Robert Jones in Liverpool and then Sir Harold Stiles in Edinburgh. He returned to organize and direct the section of orthopaedic surgery at the Mayo Clinic and spent his entire professional career there.
Dr. Henderson was involved in many national and international organizations, and was a founder and first President of the American Board of Orthopaedic Surgeons when it was established at the Kahler Hotel in Rochester, Minnesota, on June 5, 1934, after several previous organizational meetings [5]. Wickstrom [5], describing the organization of the Board, commented, “After all, in the opinion of the East coast establishment, Dr. Henderson (who was born in St. Paul, was educated in Canada, and had his beginning with the Mayo brothers as a clinical assistant riding a bicycle around Rochester, making house calls on the Mayo brothers’ patients) was a mere upstart.” However, at the time Dr. Henderson was 50 years old and had been President of the American Orthopaedic Association and Clinical Orthopaedic Society, as well as prominent in the American Medical Association and other organizations. Dr. Henderson was one of three of the first 15 AAOS Presidents (the other two being Drs. Philip D. Wilson and John C. Wilson, Sr.) who had a son who succeeded him as President. He was greatly respected for his organizational abilities, particularly at the Board, whose objectives were uncertain in the beginning and required sage guidance [5].
We reproduce here an article in which Dr. Henderson reviewed 222 consecutive cases of femur fractures, 165 of which had been referred late because of complications of fractures treated elsewhere (clearly, by 1921, the Mayo Clinic was a referral source for others) [2]. Followup could not have been easy at a time when patients often came from a distance and travel was difficult, but it was described when available and in 40 of the 57 recent fractures, Henderson reported 87.5% were “cured.” Of the 165 old fractures, he was able to trace 143 (87%), a remarkable figure even today. He reported 90% of the femoral neck fractures were cured by various sorts of nonsurgical (6 patients) or surgical reconstructive (39 patients) means; 85% of the femoral shaft fractures were cured by either nonoperative (29 patients) or operative (69 patients) means. While he did not use the sort of outcomes we use today (the earliest orthopaedic outcome instruments were not introduced for four more decades: by Carroll B. Larson in 1963 [3] and William H. Harris in 1969 [1]), we can only presume Henderson meant union was achieved when patients were “cured” since nonunion or malunion would not have likely produced good results. That being the case, his rate of union was remarkable and would be enviable today in these sometimes difficult situations, attesting to his understanding of the individual situations and his skills. Melvin S. Henderson, MD is shown. Photograph is reproduced with permission and ©American Academy of Orthopaedic Surgeons. Fifty Years of Progress, 1983.
References
Harris WH. Traumatic arthritis of the hip after dislocation and acetabular fractures: treatment by mold arthroplasty: an end-result study using a new method of result evaluation. J Bone Joint Surg Am. 1969;51:737–755.Henderson MS. Fractures of the femur: end results. J Bone Joint Surg Am. 1921;3:520–528.Larson CB. Rating scale for hip disabilities. Clin Orthop Relat Res. 1963;31:85–93.Mostofi SB. Who's Who in Orthopedics. London, UK: Springer; 2005.Wickstrom JK. Fifty years of the American Board of Orthopaedic Surgery: 1934. Clin Orthop Relat Res. 1990;257:3–10.
doi:10.1007/s11999-007-0033-2
PMCID: PMC2505283  PMID: 18196372
23.  Secondary Prevention of Fragility Fractures: Are We Following the Guidelines? 
INTRODUCTION
The aim of this study was to determine whether orthopaedic surgeons follow the British Orthopaedic Association (BOA) guidelines for secondary prevention of fragility fractures.
PATIENTS AND METHODS
A retrospective audit was conducted on patients with neck of femur fractures treated in our hospital between October and November 2003. A re-audit was conducted during the period August to October 2004.
RESULTS
There were 27 patients in the initial study period. Twenty-six patients (96%)had full blood count measured with LFT and bone-profile measured in 18 patients (66%). Only nine patients (30%)had treatment for osteoporosis (calcium and vitamin D). Only one patient was referred for DEXA scan. Steps were taken in the form of creating better awareness among the junior doctors and nurse practitioners of the BOA guidelines. In patients above 80 years of age, it was decided to use abbreviated mental score above 7 as a clinical criteria for DEXA referral. A hospital protocol based on BOA guidelines was made. A re-audit was conducted during the period August to October 2004. There were 37 patients. All had their full blood count and renal profile checked (100%). The bone-profile was measured in 28 (75.7%) and LFT in 34 (91.9%)patients. Twenty-four patients (65%) received treatment in the form of calcium + vitamin D (20) and bisphosphonate (4). DEXA-scan referral was not indicated in 14 patients as 4 were already on bisphosphonates and for 10 patients their abbreviated mental score was less than 7. Among the remaining 23 patients, 9 patients (40%) were referred for DEXA scan. This improvement is statistically significant (P = 0.03, chi square test).
DISCUSSION AND CONCLUSIONS
The re-audit shows that, although there is an improvement in the situation, we are still below the standards of secondary prevention of fragility fractures with 60% of femoral fragility fracture patients not being referred for DEXA scan. A pathway lead by a fracture liaison nurse dedicated to osteoporotic fracture patients should improve the situation.
doi:10.1308/003588406X116891
PMCID: PMC1964691  PMID: 17002853
Osteoporosis; Secondary prevention; Guidelines
24.  The Fracture Unit Model. A Model for Implementation in Italy: “Multidisciplinary Approach for the Prevention and Treatment of Osteoporotic Vertebral Compression Fractures: VCF Unit” 
Reduced BMD is a risk factor for vertebral fractures (VFs). Every one SD increase in BMD is associated with a 2- to 2.5-fold increase in the risk of VFs. The presence of a previous fracture, vertebral or of other districts, is another important predictor of an increased risk of future fractures, independently of the association between BMD and fracture risk. Thus, the presence of both a low BMD and a previous fracture dramatically increases fracture risk. The definition of osteopo-rotic VFs has undergone considerable variations over the years, going from initial clinical sign of OP, through the now superseded definition of VFs as a disease, to a complication of OP resulting from bone fragility. The prevalence of VFs increases with age in both sexes, and it is calculated that at the age of 80 years, 37% of Caucasian women will have at least one radiographically evident VF. It has been estimated, again in Caucasian women, that the percentage incidence of fractures is 0.5% in those aged 50-55 years, 1.4% in those aged 65-69 years, and over 2% in women older than 75. However, two factors prevent an accurate assessment of the epidemiology of VFs. First, most VFs escape clinical diagnosis. Second, the absence of a “gold standard” radiographic definition of VFs has given rise to different ways of defining these lesions. VFs are rarely a cause of mortality, but they are associated with increased impairment of general conditions. Recurrent VFs have irreversible clinical consequences, such as reduction of height and chronic vertebral pain, which provoke an intensification of the pain and a greater degree of disability due to accentuation of kyphosis. The presence of VFs and kyphosis leads to a reduced thoracic volume and, consequently, to a loss of lung volume, in some cases severe enough to result in respiratory insufficiency. The consequences of the intense pain are: reduced range of motion, loss of balance, slowed gait and greater difficulty carrying out normal daily activities. In rare cases, lower limb pain and weakness may appear, caused by compression of the spinal medulla by the deformed vertebral body. The main aim of treatment is to restore the patient to his/her pre-trauma levels of functioning. This can be achieved through recourse to mini-invasive percutaneous techniques, vertebroplasty and kyphoplasty, with the aim of reducing the pain caused by osteo-porotic vertebral compression fractures, of preventing progression of the vertebral collapse and of rapidly re-establishing functional activity. Most fracture patients are discharged without undergoing a thorough bone metabolism assessment that could identify the causal factor of the fracture. In a high percentage (up to 95%) of patients with recent fractures, BMD is not measured and, therefore, a diagnosis of OP is not made. Consequently, these patients are not prescribed drugs capable of effectively reducing the risk of further fractures. Specialist orthopaedic centres need to introduce protocols designed to ensure application of the current procedures for diagnosing and treating OP.
On the basis of these considerations, we undertook to develop, in collaboration with the Department of Specialist Surgical Sciences of the University of Florence, the Orthopaedics and Traumatology Units 1, 2 and 3, the Recovery and Functional Re-education Unit, the Neurosurgery Unit, and the third Radiodiagnostics Unit of the Careggi Hospital in Floren-ce, a protocol that involves a range of specialists in assessing the introduction of variable, outcome-targeted medical therapies for osteoporotic patients submitted to kyphoplasty following fragility fractures of the vertebra. To choose the appropriate medical therapy, and to monitor its effects, the patients will be submitted to a series of clinical investigations. The “appropriate” therapy could include calcium and vitamin D supplementation, biphosphonates, SERMs, bone anabolic agents and combinations of drugs. The safety of the medical therapy and any adverse effects will be monitored at each follow-up visit through an appropriate questionnaire. This study aims to compare the outcomes of the group following a traditional pathway with those following a modified pathway (prescription of a targeted medical therapy), by means of metabolic, instrumental and functional tests performed at 2 months, 6 months, 1 year and 2 years. The general aim of the study will be to evaluate the efficacy and safety of a modified versus a traditional pathway in the care of osteoporotic patients undergoing kyphoplasty for VFs. The primary endpoint of the study will be the percentage of successes in the modified compared with the traditional pathway group. Secondary endpoints will be: change in femoral and lumbar BMD, changes in biochemical markers of bone remodelling and quality of life, assessment of safety parameters: overall and symptomatic cement leakage, pulmonary embolism, spinal medulla compression, radicular pain, radiculopathies and assessment of total procedure-related, cement-related and access-related adverse events. The ultimate aim of the study will be to prepare guidelines for the management, in terms of metabolic diagnosis and relative medical therapy, of patients with OP complicated by VFs.
PMCID: PMC3213825
25.  Efficacy of Alendronate in the Management of Fragility Fractures 
Osteoporosis, particularly common in post-menopausal women, is a disease characterised by altered bone turnover, progressive loss of bone mass, deterioration of bone architecture and increased fracture risk. Precisely in order to prevent fractures, it is useful to administer osteotropic drugs that act on the altered bone metabolism in order to slow down bone resorption.
Biphosphonates are the drugs most commonly prescribed to prevent and treat post-menopausal osteoporosis and they have been shown to exert important effects on bone tissue, preventing excessive weakening, preferentially localising to sites of bone resorption, and provoking osteoclast inhibition without any direct effect on new bone formation. This results in an uncoupling of anabolic and catabolic processes that translates into increased bone mass.
Alendronate, a powerful inhibitor of bone resorption that belongs to the biphosphonate class of drugs, was shown, in a heterogeneous cohort of patients, to produce significant reductions in markers of bone resorption and considerable, dose-related increases in bone mineral density (BMD). Alendronate, at a mimumum dose of 10 mg/day, has been shown to increase BMD values by 7.5% in the lumbar spine after two-three years of treatment, by 5.6% at the neck of the femur after three-four years of treatment, and by 2.1% at forearm level after treatment lasting two-four years; instead, at 5 mg/day it was found to increase BMD levels by 5.8%, 4.6% and 1.8%, respectively. Furthermore, the drug has been widely shown to be effective in preventing both vertebral and non-vertebral fractures (including hip fractures) and was also found to be effective in reducing the incidence of vertebral fractures in corticosteroid-induced osteoporosis. These effects have been demonstrated in numerous studies, which have shown that drug is able to significantly reduce the risk of vertebral, non-vertebral and hip fractures (level IA evidence) compared with placebo, and to conserve bone mass (level IA evidence), with an increase in BMD within three months of the start of treatment, both at spinal and at hip level, and even in women and men taking corticosteroids. These effects were confirmed in studies with follow ups as long as ten years, providing evidence of the long-term efficacy of the drug and its high level of tolerability throughout the duration of treatment.
Weekly dosing (70 mg) of alendronate can increase compliance in poorly collaborating patients or patients with numerous comorbidities. With this dosing regimen, the drug was also shown to be effective in improving screw fixation in cancellous bone in a group of elderly patients with confirmed poor bone quality.
PMCID: PMC3213791

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