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1.  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
2.  Bone density in transfusion dependent thalassemia patients in Urmia, Iran 
Background
Patients with thalassemia major and intermedia are susceptible to osteopenia and osteoporosis. The mechanism of osteoporosis in these patients is multifactorial. Transfusion related iron overload in endocrine organs leads to impaired growth hormone secretion, diabetes mellitus, hypothyroidism, hypoparathyroidism, lack of sex steroids and vitamin D deficiency that contribute to impairment in achieving an adequate bone mass .The aim of this study was assessment of frequency of bone loss in patients with thalassemia major and intermedia in Urmia City of West Azerbaijan, Iran
Materials and Methods
In this cross sectional descriptive study,10 patients (lower than 18 y/o)with transfusion dependent thalassemia attending to Motahari and Emam Khomeini hospitals in Urmia city of Iran were enrolled and scanned for Bone Mineral Density (BMD) starting at around 10 years old.
Results
Tenatients (6 male and 4 female) with transfusion dependent thalassemia (β-thalassemia major and intermedia) aged 13to 17 years in Urmia city of Iran were enrolled. Mean age of patients was 15.1±.37year old. Among them, 8 patients (80%)had low BMD and2 of them (20%) had normal BMD in lumbar spine. Only 30% of patients had low BMD in the neck of femur.
Conclusion
We should perform annual BMD in patients with thalassemia major and intermedia and hemoglobin H disease in age of higher than 8 year old and treat low BMD with administration of bisphosphonate, calcium and vitamin D supplements. Medical consultation with a rheumatologist and /or an endocrinologist should be performed in these patients. Changing lifestyle with mild daily exercise, adequate calcium containing foods, avoiding heavy activities, stop smoking, iron chelation therapy in adequate dosage, early diagnosis and treatment of endocrine insufficiency and regular blood transfusions can help to achieve an optimal bone density in these patients.
PMCID: PMC4083203  PMID: 25002928
Thalassemia; Bone mineral density; Osteoporosis; Bone Loss
3.  Multifactorial analysis of risk factors for reduced bone mineral density among postmenopausal women 
Introduction
The study aimed to determine the risk factors for reduced bone mineral density (BMD) among postmenopausal women.
Material and methods
Two hundred and fifty-three postmenopausal women were included to the study. The study group consisted of 85 women with osteoporosis (mean age: 59.9 years) and 168 with osteopenia (mean age: 57.8 years). Patients were assigned to groups according to their BMD measured in the lumbar spine, hip and femoral neck by dual X-ray absorptiometry. Bone formation was assessed by measuring serum osteocalcin and bone resorption by measuring serum C-terminal type I α-collagen chain telopeptide.
Results
Multiple regression analysis for lumbar spine showed association of age (p = 0.001), parental history of fracture (p = 0.05), use of hormone replacement therapy (p = 0.034), bisphosphonates therapy (p < 0.001), calcium and vitamin D supplements therapy (p = 0.001), oestradiol level (p = 0.007) and body mass index (p < 0.001). Multiple regression analysis for femoral neck and hip total showed association of age (p = 0.001), parental history of fracture (p = 0.049), use of bisphosphonates (p < 0.03)) use of calcium and vitamin D supplements (p = 0.039), oestradiol level (p = 0.047). All the variables together explain 40.4% of variance in BMD for the lumbar spine and 25.6% of variance in BMD for femoral neck and hip total.
Conclusions
The present study demonstrated correlations between the variables and BMD, which are known and widely described in the literature. Osteoporosis and osteopenia in Polish subjects appear to be associated with several known risk factors that are well described in the literature.
doi:10.5114/aoms.2012.28562
PMCID: PMC3361047  PMID: 22662008
bone mineral density; postmenopausal women; osteoporosis; osteopenia; multifactorial analysis
4.  Osteoporosis and osteopenia in adults and adolescents with cystic fibrosis: prevalence and associated factors 
Thorax  2000;55(9):798-804.
BACKGROUND—Patients with cystic fibrosis (CF) have many risk factors for reduced bone mineral density (BMD). The aim of this study was to determine the prevalence of osteoporosis and osteopenia in a large cross section of patients and to identify risk factors.
METHODS—All patients attending the regional centre were invited to participate in the study. Bone mineral density was measured at the lumbar spine, femoral neck, and for total body with a Lunar DPX-L densitometer. Multiple indices of disease severity were investigated, and liver and thyroid function, blood calcium, phosphate, 25-OH vitamin D, follicle stimulating and luteinising hormone, oestradiol, and testosterone levels were measured. Patients completed a four day prospective dietary diary. Exercise was assessed by a seven day activity recall questionnaire. Sexual development and treatment histories were obtained. The relationship between all these variables and BMD measurements was analysed.
RESULTS—Sixty six percent of 114 patients assessed had osteopenia or osteoporosis. The Shwachman-Kulczycki (SK) clinical score (higher score = less severe disease) correlated significantly with BMD at the lumbar spine and femoral neck, and with total body BMD (p<0.001). There was a predicted increase of 0.0032 g/cm2 in lumbar spine BMD for every unit increase in the SK score. Oral steroid use was significantly associated with reduced BMD at the lumbar spine (p = 0.017) and femoral neck (p = 0.027).
CONCLUSIONS—Osteopenia and osteoporosis are common findings in a heterogeneous population of adults with CF. Patients at most risk are those with severe disease and those who have used corticosteroids.


doi:10.1136/thorax.55.9.798
PMCID: PMC1745849  PMID: 10950902
5.  High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review 
Clinical Rheumatology  2012;31(11):1529-1535.
Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease. Decreased bone mineral density (BMD) is a common complication of AS, with a prevalence range of 19 to 62 %. Many studies have shown decreased BMD in AS with long disease duration, but only a few studies investigated BMD in early AS. The prevalence of decreased BMD in early disease stages of AS has not yet been clearly described, and for that reason, we reviewed the literature which describes the prevalence of decreased BMD in AS patients with a short disease duration (<10 years). In this review, we included articles which used the modified New York criteria for the diagnosis of AS, included patients with a disease duration of less than 10 years, and used the WHO criteria for osteopenia and osteoporosis. Decreased BMD was defined as a T score < −1.0, including both osteopenia and osteoporosis. For this review, only articles that acquired BMD data of lumbar spine and femoral neck by DXA were used. The literature search provided us 35 articles of which 7 matched all our criteria, and they will be further outlined in this review. The overall prevalence of decreased BMD of the articles reviewed is 54 % (n = 229/424) for lumbar spine and 51 % (n = 224/443) for femoral neck. The prevalence of osteopenia vs. osteoporosis for lumbar spine is 39 vs. 16 % and for femoral neck, 38 vs. 13 %. This review showed a high total prevalence of 51–54 % decreased BMD and 13–16 % osteoporosis in AS with a short disease duration. This high prevalence was not to be expected in a relatively young and predominantly male population. Further research is needed to determine the clinical relevance of this low BMD by investigating the relation between low BMD and vertebral and nonvertebral fractures at this early stage in AS.
doi:10.1007/s10067-012-2018-0
PMCID: PMC3483100  PMID: 22706444
Ankylosing spondylitis; Bone mineral density; Osteopenia; Osteoporosis; Vertebral fractures
6.  Effects of the anti-receptor activator of nuclear factor kappa B ligand denusomab on beta thalassemia major-induced osteoporosis 
Introduction:
Osteoporosis represents the second most common cause of endocrinopathy in patients with beta thalassemia major (BTM). Some drugs proved effective to reduce vertebral and non-vertebral fracture risk. Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor kappa B ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. The efficacy and safety of denosumab in BTM-induced osteoporosis has not been tested.
Objective:
To evaluate the efficacy and safety of anti-RANKL on the biochemical and radiological parameters of bone mineralization in patients with BTM-induced osteoporosis.
Design:
The study population was selected using the random sampling method from the patient's database of our thalassemia clinic. Transfusion-dependent BTM patients above 18 years with no history of treatment with bisphosphonates were randomly selected. Bone mineral density (BMD) of the lumbar spine (LS) and right femoral neck (FN) were measured by dual energy X-ray absorption (DEXA) scan using a calibrated method. Independent factors likely to be associated with low bone mass were determined and included in the analysis to ascertain possible associations.
Patients and Methods:
We studied 30 patients with BTM-induced osteoporosis as per World Health Organization criteria (T Score of less than − 1.0 being defined as osteopenic and a T Score of less than − 2.5 being referred as osteoporotic). 19 males and 11 females aged between 18 and 32 years, with full pubertal development (Tanner's stage 5) at the time of the study. Their mean serum ferritin concentration was 3557 ng ± 1488 ng/ml. Every patient underwent DEXA scan as a baseline and after 12 months of denosumab therapy. Biochemical evaluation including serum concentrations of creatinine, Na, K, calcium, phosphorus, parathormone, bone specific alkaline phosphatase and type 1 collagen carboxy telopetide (ICCT) using enzyme-linked immunosorbent assay (Nordic Bioscience Diagnostics A/S) was done at baseline, after a month and then every 3 months for 12 months after starting denosumab. 60 mg of denosumab was administered subcutaneously twice yearly for a year. The mean BMD T Scores at baseline were −2.7 at the LS and −2.1 at the FN.
Results:
Denosumab therapy for a year was associated with a significant increase in BMD of 9.2% (95% confidence interval [CI], 8.2-10.1) at the LS and 6.0% (95% CI, 5.2-6.7) at the FN. Denosumab treatment decreased serum ICCT levels by 56% at 1 month and normalized them in all patients at 1 year. Significant correlations were found between BMD T Score before and 1 year after denosumab in LS (r = 0.752, P < 0.001) and FN (r = 0.758 P < 0.001), respectively. The most common side effects were pain in the back and extremities (12%) and nausea (10%). Asymptomatic hypocalcaemia occurred in two patients.
Conclusion:
Denosumab therapy for a year significantly increased BMD density at LS and FN of patients with BTM and was associated with a rapid and sustained reduction in ICCT levels. Further studies are required to confirm long-term effects of this therapy.
doi:10.4103/2230-8210.137516
PMCID: PMC4138914  PMID: 25143915
Bone alkaline phosphatase; bone mineral density; denosumab; osteoporosis; thalassemia; type 1 collagen carboxy telopetide
7.  Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial 
PLoS Medicine  2008;5(10):1-12.
Background
Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures.
Methods and Findings
This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small.
Conclusions
Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers.
Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)
Angela Cheung and colleagues investigate whether vitamin K1 can prevent bone loss among postmenopausal women with osteopenia.
Editors' Summary
Background.
Osteoporosis is a bone disease in which the bones gradually become less dense and more likely to break. In the US, 10 million people have osteoporosis and 18 million have osteopenia, a milder condition that precedes osteoporosis. In both conditions, insufficient new bone is made and/or too much old bone is absorbed. Although bone appears solid and unchanging, very little bone in the human body is more than 10 y old. Old bone is continually absorbed and new bone built using calcium, phosphorous, and proteins. Because the sex hormones control calcium and phosphorous deposition in the bones and thus bone strength, the leading cause of osteoporosis in women is reduced estrogen levels after menopause. In men, an age-related decline in testosterone levels can cause osteoporosis. Most people discover they have osteoporosis only when they break a bone, but the condition can be diagnosed and monitored using bone mineral density (BMD) scans. Treatments can slow down or reverse bone loss (antiresorptive therapies) and some (bone formation therapies) can even make bone and build bone tissue.
Why Was This Study Done?
Although regular exercise and a healthy diet can help to keep bones strong, other ways of preventing osteoporosis are badly needed. Recently, the lay media has promoted vitamin K supplements as a way to reduce bone loss in postmenopausal women. Vitamin K (which is found mainly in leafy green vegetables) is required for a chemical modification of proteins called carboxylation. This modification is essential for the activity of three bone-building proteins. In addition, there is some evidence that low bone density and fractures are associated with a low vitamin K intake. However, little is known about the long-term benefits or harms of vitamin K supplements. In this study, the researchers investigate whether a high-dose daily vitamin K supplement can safely reduce bone loss, bone turnover, and fractures in postmenopausal women with osteopenia in a randomized controlled trial called the “Evaluation of the Clinical Use of Vitamin K Supplementation in Post-Menopausal Women With Osteopenia” (ECKO) trial.
What Did the Researchers Do and Find?
In the study, 440 postmenopausal women with osteopenia were randomized to receive 5mg of vitamin K1 (the type of vitamin K in North American food; the recommended daily adult intake of vitamin K1 is about 0.1 mg) or an inactive tablet (placebo) daily for 2 y; 261 of the women continued their treatment for 2 y to gather information about the long-term effects of vitamin K1 supplementation. All the women had regular bone density scans of their lower back and hips and were examined for fractures and for changes in bone turnover. After 2 y and after 4 y, lower back and hip bone density measurements had decreased by similar amounts in both treatment groups. The women who took vitamin K1 had 10-fold higher amounts of vitamin K1 in their blood than the women who took placebo and lower amounts of a bone formation marker; the levels of a bone resorption marker were similar in both groups. Over the 4-y period, fewer women in the vitamin K group had fractures (nine versus 20 women in the placebo group), and fewer had cancer (three versus 12). Finally, vitamin K supplementation was well tolerated over the 4-y period and adverse health effects were similar in the two treatment groups.
What Do These Findings Mean?
These findings indicate that a high daily dose of vitamin K1 provides no protection against the age-related decline in bone density in postmenopausal women with osteopenia, but that vitamin K1 supplementation may protect against fractures and cancers in these women. The apparent contradiction between the effects of vitamin K1 on bone density and on fractures could mean that vitamin K1 supplements strengthen bone by changing factors other than bone density, e.g., by changing its fine structure rather than making it denser. However, because so few study participants had fractures, the difference in the fracture rate between the two treatment groups might have occurred by chance. Larger studies are therefore needed to examine the effect of vitamin K1 on fractures (and on cancer) and, until these are done, high-dose vitamin K1 supplementation should not be recommended for the prevention of osteoporosis.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050196.
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases provides detailed information about osteoporosis (in English and Spanish) and links to other resources, including an interactive web tool called Check Up On Your Bones
MedlinePlus provides links to additional information about osteoporosis (in English and Spanish)
The MedlinePlus Encyclopedia has a page about vitamin K
The UK Food Standards Agency provides information about vitamin K
Full details about the ECKO trial are available on the ClinicalTrials.gov Web site
The Canadian Task Force for Preventive Health Care provides recommendations on the prevention of osteoporosis and osteoporotic fractures in postmenopausal women
Osteoporosis Canada provides information on current topics related to osteoporosis
doi:10.1371/journal.pmed.0050196
PMCID: PMC2566998  PMID: 18922041
8.  Zinc and Copper Status in Children with Beta-Thalassemia Major  
Iranian Journal of Pediatrics  2010;20(3):297-302.
Objective
There are some reports in which a condition of zinc deficiency and its associated outcomes with a change in concentration of serum copper among the thalassemic patients has been highlighted. The aim of this prospective study was to determine the serum zinc and copper levels in children with beta-thalassemia major.
Methods
In this cross sectional study all children under 12 years affected by beta thalassemia major (40 patients) were evaluated for serum zinc and copper levels in Qazvin thalassemia center (Qazvin, Iran) in 2007. Serum measurements for zinc and copper were performed by atomic absorption spectrophotometer.
Findings
The mean concentrations of serum zinc and copper levels were 67.35±20.38 and 152.42±24.17 µg/dl respectively. Twenty-six (65%) of thalassemic patients had zinc concentration under 70 µg/dl (hypozincemia). None of the thalassemic children had copper deficiency. No significant correlation between serum zinc level with age, weight, height, body mass index, duration of blood transfusion, desferrioxamine dose and ferritin level was observed in thalassemic patients (P=0.3).
Conclusion
This study revealed that hypozincemia is common in thalassemic patients, but in contrast, there is no copper deficiency. Further evaluation in this regard is recommended.
PMCID: PMC3446035  PMID: 23056720
Beta-thalassemia; Zinc; Copper; Children
9.  Correlation of vitamin D, bone mineral density and parathyroid hormone levels in adults with low bone density 
Indian Journal of Orthopaedics  2013;47(4):402-407.
Background:
Bone mineral densiy (BMD) is known to be affected by serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels. Indian data pertinent to above observation is scant. Our study aimed to investigate the relationships between serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels and bone mineral density (BMD) in a cohort of Indian patients.
Materials and Methods:
Adults with or without fragility fractures with low BMD at the hip or lumbar spine were evaluated clinically along with laboratory investigations. T-scores of the hip and spine were derived from BMD-DEXA (dual-energy X-ray absorptiometry). Multivariate regression models were used to investigate the relationships between serum 25(OH) D, iPTH and BMD.
Results:
Total of 102 patients (male:female = 38:64) with a mean age of 62.5 ± 6.4 years were included in the study. Forty-four patients had osteopenia. Osteoporosis was present in 58 patients. The mean values for serum 25(OH) D and iPTH levels were 21.3 ± 0.5 ng/ml and 53.1 ± 22.3 pg/ml, respectively. In 84.3% of patients, serum 25(OH) D levels were below 30 ng/ml (Normal = 30-74 ng/ml), confirming vitamin D deficiency. There was no association between 25(OH) D levels and BMD at the hip or lumbar spine (P = 0.473 and 0.353, respectively). Both at the hip and lumbar spine; iPTH levels, male gender, body mass index (BMI) and age were found to be significant predictors of BMD. Patients with higher BMI had significantly lower BMD and T-score. At levels <30 ng/ml, 25(OH) D was negatively associated with iPTH (P = 0.041).
Conclusion:
Among our cohort of patients with low BMD, no direct relationship between serum 25(OH) D levels and BMD was observed. However, a negative correlation between iPTH and 25(OH) D at serum 25(OH) D concentrations <30 ng/ml. Serum iPTH levels showed a significant negative association with BMD at the hip and lumbar spine. Our findings underscore the critical role of parathyroid hormone in bone metabolism and health.
doi:10.4103/0019-5413.114932
PMCID: PMC3745696  PMID: 23960286
Bone mineral density; osteoporosis; parathyroid hormone; vitamin D
10.  Prevalence of Vitamin D insufficiency and low bone mineral density in elderly Thai nursing home residents 
BMC Geriatrics  2012;12:49.
Background
Numerous emerging data from research on osteoporosis among Asians found differences from Caucasians. Therefore, the aim of this study was to determine the prevalence of vitamin D insufficiency and osteoporosis in elderly participants from two nursing homes in Thailand, a country located near the equator.
Methods
The subjects of this cross-sectional study comprised 93 elderly Thai women who were living in institutional long-term nursing homes for the aged. Demographic data, daily food and calcium intake, physical activity, and sunlight exposure were measured. Lumbar spine and femoral neck bone mineral density (BMD) and biochemical levels including serum 25 hydroxyvitamin D [25(OH)D] and bone turnover markers were assessed. Vitamin D insufficiency was defined as 25(OH)D level < 70 nmol/l.
Results
The mean age of subjects was 75.2 ± 6.0 (SD) years. Dietary calcium intake was low (322 ± 158 mg/day) The mean 25(OH)D level was 64.3 ± 14.9 nmol/L and the prevalence of vitamin D insufficiency was 38.7% (95% CI: 28.8%, 49.4%). There was no correlation between serum 25(OH)D concentrations and age (r = −.11, p = 0.3). The mean BMD of lumbar spine and femoral neck were 0.92 ± 0.19 and 0.65 ± 0.10 g/cm2, respectively. Nearly a half of the subjects had osteopenia (44.1%, 95% CI: 33.8%, 54.8%) and osteoporosis (47.3%, 95% CI: 36.9%, 57.9%). Circulating C-terminal telopeptide of type I collagen (CTx) level correlated significantly with both lumbar spine (r = −0.26, p = 0.01) and femoral neck BMD (r = −0.25, p = 0.02).
Conclusions
More than one-third of Thai elderly women residing in nursing homes had vitamin D insufficiency. Almost all nursing home residents had osteoporosis and/or osteopenia.
doi:10.1186/1471-2318-12-49
PMCID: PMC3490934  PMID: 22938528
Vitamin D; Osteoporosis; Bone density; Aged; Nursing homes; Collagen type I trimeric cross-linked peptide
11.  Clinical Efficacy and Safety of Pamidronate Therapy on Bone Mass Density in Early Post-Renal Transplant Period: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2014;9(9):e108106.
Introduction
The overall effect of pamidronate on bone mass density (BMD) in the early renal transplant period varies considerably among studies. The effects of pamidronate on graft function have not been determined.
Materials and Methods
A comprehensive search was conducted in PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and Embase independently by two authors. Randomized controlled trials of pamidronate evaluating bone loss in the first year of renal transplantation were included. Methods reported in the “Cochrane Handbook for Systematic Reviews of Interventions 5.0.2” were used to evaluate changes of lumbar spine and femoral neck BMD, and serum creatinine, calcium and intact parathyroid hormone (iPTH) levels. Fixed or random effect models were used as appropriate.
Results
Six randomized trials evaluating 281 patients were identified. One hundred forty-four were treated with pamidronate and 137 were control patients. Administration of pamidronate was associated with significant reduction of bone loss in the lumbar spine, compared to the control group (standardized mean difference (SMD)  = 24.62 [16.25, 32.99]). There was no difference between the pamidronate treated and control femoral neck BMD (SMD  = 3.53 [−1.84, 8.90]). A significant increase in the serum creatinine level of the intervention group was seen, compared to the control group. The serum calcium and iPTH of the pamidronate and control groups were not different after 1 year (serum creatinine: SMD  = −3.101 [−5.33, −0.89]; serum calcium: SMD  = 2.18 [−0.8, 5.16]; serum iPTH: SMD  = 0.06 [−0.19, 0.31]). Heterogeneity was low for serum calcium and iPTH and high for serum creatinine.
Conclusions
This meta-analysis demonstrated the beneficial clinical efficacy of pamidronate on BMD with no association with any alteration in graft function during the first year of renal transplantation. Significant heterogeneity precludes the conclusion of the relationship between serum creatinine and pamidronate.
doi:10.1371/journal.pone.0108106
PMCID: PMC4180498  PMID: 25265508
12.  Osteoporosis in ankylosing spondylitis - prevalence, risk factors and methods of assessment 
Arthritis Research & Therapy  2012;14(3):R108.
Introduction
Osteoporosis can be a complication of ankylosing spondylitis (AS), but diagnosing spinal osteoporosis can be difficult since pathologic new bone formation interferes with the assessment of the bone mineral density (BMD). The aims of the current study were to investigate prevalence and risk factors for reduced BMD in a Swedish cohort of AS patients, and to examine how progressive ankylosis influences BMD with the use of dual-energy x-ray absorptiometry (DXA) of the lumbar spine in different projections.
Methods
Methods of assessment were questionnaires, back mobility tests, blood samples, lateral spine radiographs for syndesmophyte grading (mSASSS), DXA of the hip, radius and lumbar spine in anteroposterior (AP) and lateral projections with estimation of volumetric BMD (vBMD).
Results
AS patients (modified New York criteria), 87 women and 117 men, mean age 50 ± 13 years and disease duration 15 ± 11 years were included. According to World Health Organization (WHO) criteria 21% osteoporosis and 44% osteopenia was diagnosed in patients > = 50 years. Under age 50 BMD below expected range for age was found in 5%. Interestingly lateral lumbar DXA showed significantly lower BMD and revealed significantly more cases with osteoporosis as compared with AP DXA. Lumbar vBMD was not different between sexes, but women had significantly more lumbar osteoporosis measured with AP DXA (P < 0.001). Men had significantly higher mSASSS (P < 0.001). Low BMD was associated with high age, disease duration, mSASSS, Bath Ankylosing Spondylitis Metrology Index (BASMI), inflammatory parameters and low body mass index (BMI). Increasing mSASSS correlated significantly with decreasing lateral and volumetric lumbar BMD, while AP lumbar BMD showed tendency to increase.
Conclusions
Osteoporosis and osteopenia is common in AS and associated with high disease burden. Lateral and volumetric lumbar DXA are more sensitive than AP DXA in detecting osteoporosis and are less affected by syndesmophyte formation.
doi:10.1186/ar3833
PMCID: PMC3446485  PMID: 22569245
13.  Prevalence of low bone mineral density among HIV patients on long-term suppressive antiretroviral therapy in resource limited setting of western India 
Journal of the International AIDS Society  2014;17(4Suppl 3):19567.
Introduction
Bone mineral density (BMD) assessment in HIV patients is sparsely done in resource limited settings.
Materials and Methods
We conducted a cross-sectional study of BMD amongst HIV patients following up in our clinic from 1 June to 1 December 2013 by performing dual-energy X-ray absorptiometry scan (Lunar Prodigy Advanced DXA System, GE Healthcare) of lumbar spine and hip. Patients on long term (≥12 months), virologically suppressive antiretroviral therapy (ART) were included. Patients who were ART naïve were included as control population. Virologic failures were excluded. Low BMD was defined by WHO T-score criteria (normal: T score ≥−1;osteopenia: T score between −1 and −2.5 SD; osteoporosis: T score ≤−2.5 SD). Baseline risk factors associated with low BMD like age, low BMI, lipoatrophy, diabetes mellitus, current smoking, current alcohol intake, steroid exposure and menopause were recorded. ART-related factors associated with low BMD like ART duration, exposure to tenofovir and exposure to protease inhibitors (PI) were studied.
Results
A total of 536 patients (66% males, 496 ART experienced and 40 ART naïve) were included in this analysis. Median age was 42 years, mean BMI 23.35 kg/m2 and median CD4 count 146 cells/mm3. All ART experienced patients had plasma viral load<400 copies/ml.
Prevalence of low BMD amongst ART naive and ART experienced patients was 67% (osteopenia: 70.4%, osteoporosis: 29.6%) and 80.4% (osteopenia: 63.4%, osteoporosis: 36.6%), respectively (p=0.05). Mean T scores at lumbar spine and hip for ART naive and ART experienced patients were −1.37 and −0.9 versus −1.56 and −1.48 (p=0.05), respectively. Age, low BMI, current smoking, menopause, baseline CD4 count and exposure to ART were factors significantly associated with low overall BMD on univariate regression analysis. On multivariable logistic regression analysis age (p<0.001), low BMI (p<0.001), current smoking (0.05) and menopause (0.03) were associated with low BMD. BMI decrease of 1 kg/m2 and baseline CD4 decline of 50 cells/mm3 lead to 14% and 4% increased probability of low BMD, respectively. Choice of antiretroviral use (tenofovir vs non-tenofovir, PI vs No PI) did not influence loss of BMD.
Conclusions
Extremely high prevalence of accelerated BMD loss amongst ART naïve and ART experienced patients in our cohort is a matter of deep concern due to its association with pathological fractures. Bone mineral loss was seen irrespective of ART used. Association of low BMD with low baseline CD4 count strengthens the case for early ART.
doi:10.7448/IAS.17.4.19567
PMCID: PMC4224871  PMID: 25394074
14.  Relationship between body mass index and bone mineral density in HIV-infected patients referred for DXA 
Journal of the International AIDS Society  2014;17(4Suppl 3):19569.
Introduction
Reduced bone mass density (BMD) is a frequent observation in HIV-infected persons. Relationship between body mass index (BMI), weight, height and BMD was reported for many populations. In particular, BMI has been found to be inversely related to the risk of osteoporosis.
Methods
This is a cross-sectional, monocentric study where all HIV-infected patients referred to first DXA scan in clinical routine during 2010–2013 were included. Osteopenia and osteoporosis were defined by T- score <−1 and <−2.5, respectively. Patients were categorized according to WHO BMI classification: underweight <18.5 kg/m2; normal weight 18.5–24.9 kg/m2; over weight 25–29.9 kg/m2; obese >30 kg/m2. Statistical analysis was carried using logistic regression.
Results
A total of 918 patients were included: median age 49 years (IQR, 44–55); 59.4% male; 93% Caucasian. Median anthrometric characteristics were: 68 kg (IQR, 59–78); 1.7 m (IQR, 1.6–1.75); 23.5 kg/m2 (IQR, 21.4–26.2). Underweight was found in 5%, normal weight in 61%, overweight in 26% and obesity in 8% of patients. According to T-scores, 110 (11.2%) patients were osteoporotic and 502 (54.7%) had osteopenia. In the femoral neck area, the prevalence of osteoporosis was slightly lower (5.7%) than lumbar spine site (9.2%). Agreements between sites of T-scores for the diagnosis of osteoporosis were 26 and 172 and 346 for osteopenia and normal BMD values, respectively. T-scores at femoral neck or lumbar spine positively correlated with BMI (p<0.001) (Figure 1). Among predictors of osteopenia/osteoporosis, univariable analysis showed: older age (p<0.0001); lower weight (p<0.0001); increasing height (p<0.002). Patients underweight had a higher risk of osteopenia (p=0.02) as well as of osteoporosis (p=0.003). Patients with BMI above normal had a reduced risk of low BMD (osteopenia p<0.0001; osteoporosis p<0.03). Controlling for calendar year, gender, ethnicity, and age, BMI was confirmed as risk factor if below normal (AdjOR of osteopenia 2.42 [95% CI 1.16–5.07] p=0.02; AdjOR of osteoporosis 3.22 [95% CI 1.60–6.49] p=0.001).
Conclusions
Our findings indicate that almost 66% of HIV-infected patients have subnormal bone mass. Further, as in other patient populations, in the HIV infection also low BMI is an important risk factor for osteopenia/osteoporosis. This finding highlights the compelling need for standardized screening actions, particularly in patients weighting below normal.
doi:10.7448/IAS.17.4.19569
PMCID: PMC4224848  PMID: 25394076
15.  Prevalence and determinants of osteoporosis in patients with type 1 and type 2 diabetes mellitus 
Background
Increased risk of osteoporosis and its clinical significance in patients with diabetes is controversial. We analyze osteoporosis prevalence and determinants of bone mineral density (BMD) in patients with type 1 and 2 diabetes.
Methods
Three hundred and ninety-eight consecutive diabetic patients from a single outpatient clinic received a standardized questionnaire on osteoporosis risk factors, and were evaluated for diabetes-related complications, HbA1c levels, and lumbar spine (LS) and femoral neck (FN) BMD. Of these, 139 (71 men, 68 women) type 1 and 243 (115 men, 128 women) type 2 diabetes patients were included in the study. BMD (T-scores and values adjusted for age, BMI and duration of disease) was compared between patient groups and between patients with type 2 diabetes and population-based controls (255 men, 249 women).
Results
For both genders, adjusted BMD was not different between the type 1 and type 2 diabetes groups but was higher in the type 2 group compared with controls (p < 0.0001). Osteoporosis prevalence (BMD T-score < −2.5 SD) at FN and LS was equivalent in the type 1 and type 2 diabetes groups, but lower in type 2 patients compared with controls (FN: 13.0% vs 21.2%, LS: 6.1% vs 14.9% men; FN: 21.9% vs 32.1%, LS: 9.4% vs 26.9% women). Osteoporosis prevalence was higher at FN-BMD than at LS-BMD. BMD was positively correlated with BMI and negatively correlated with age, but not correlated with diabetes-specific parameters (therapy, HbBA1c, micro- and macrovascular complications) in all subgroups. Fragility fracture prevalence was low (5.2%) and not different between diabetes groups. Fracture patients had lower BMDs compared with those without fractures; however, BMD T-score was above −2.5 SD in most patients.
Conclusions
Diabetes-specific parameters did not predict BMD. Fracture occurrence was similar in both diabetes groups and related to lower BMD, but seems unrelated to the threshold T-score, <−2.5 SD. These results suggest that osteoporosis, and related fractures, is a clinically significant and commonly underestimated problem in diabetes patients.
doi:10.1186/1472-6823-14-33
PMCID: PMC4021186  PMID: 24721668
Bone mineral density; Diabetes mellitus; Fractures; Osteoporosis; Vascular complications
16.  Copper deficit as a potential pathogenic factor of reduced bone mineral density and severe tooth wear 
Osteoporosis International  2013;25(2):447-454.
Summary
The study evaluated if men and women with severe tooth wear were at increased risk of general bone loss. Enamel biopsies obtained from 50 subjects aged 47.5 ± 5 years showed decreased copper content, which was associated with reduced spine bone mineral density, suggesting deficits of this trace element contributing to bone demineralization, enamel attrition, and deteriorated quality of mineralized tissues.
Introduction
The objective of this cross-sectional study was to assess associations between enamel trace minerals and bone mineral density (BMD) in severe tooth wear. We hypothesized that similar factors contributed to both the excessive abrasion of dental enamel and reduced BMD in subjects with tooth wear.
Methods
Fifty patients aged 47.5 ± 5 years with severe tooth wear and 20 age-, sex-, and body mass index (BMI)-matched healthy volunteers with normal dental status were studied regarding dietary intakes of trace elements, serum and salivary copper (Cu), zinc (Zn), and calcium (Ca) concentrations, and serum PTH, osteocalcin, and hydroxyvitamin D levels. Tooth wear was determined using clinical examination based on standard protocol according to Smith and Knight. In all subjects, acid biopsies of the maxillary central incisors were carried out to assess mineral composition of the enamel. Atomic absorption spectroscopy with an air/acetylene flame was used to measure Ca and Zn, and graphite furnace atomic absorption spectroscopy was used to analyze Cu content. BMD was examined using dual energy X-ray absorptiometry.
Results
Tooth wear patients had reduced lumbar spine, but not femoral, BMD relative to controls (p < 0.001). No differences were found in enamel Ca concentration and Zn content was slightly higher in tooth wear patients than in controls whereas Cu content was significantly decreased in the patients: 19.59 ± 16.4 vs 36.86 ± 26.1 μg/l (p = 0.01) despite similar levels of Cu in serum and saliva. The differences were independent of serum 25-OH-D, osteocalcin concentrations or PTH either.
Conclusion
Severe tooth wear is associated with reduced spinal BMD. Enamel in adult individuals with severe tooth wear is low in copper content. Therefore, further work is needed to determine whether copper plays a role in bone pathophysiology in these patients.
doi:10.1007/s00198-013-2410-x
PMCID: PMC3906556  PMID: 23797848
Bone mineral density; Copper deficit; Dental status; Enamel attrition; Enamel composition; Microelements
17.  Prevalence and correlates of osteoporosis in chronic obstructive pulmonary disease patients in India 
Background:
Chronic obstructive pulmonary disease (COPD) is a syndrome of progressive airflow limitation caused by the abnormal inflammatory reaction of the airway and lung parenchyma. Osteoporosis is one of the major extrapulmonary manifestations of COPD. The, prevalence of osteoporosis in COPD patients in Indian population is unknown.
Objectives:
To study the prevalence of osteoporosis in COPD and to define various risk factors associated with reduced bone mineral density (BMD) in COPD.
Materials and Methods:
The study was done in the department of Pulmonary Medicine of a tertiary care hospital. All the diagnosed cases of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) guidelines were included in this study. The present study was a prospective study in for a period of 1 year. A brief history of the patients was taken, especially regarding duration of illness, number of exacerbations in the past 3 years, smoking in pack years, and history of steroid use (both systemic and inhaled steroids) after which cumulative dose of steroids was calculated. Spirometry was done in all these patients to stage the severity of COPD according to GOLD criteria. DEXA scan of the lumbar spine was done using bone densitometer to determine osteoporosis. A world Health Organization (WHO) criterion for definition of osteoporosis was applied and patients with T-score of > –2.5 standard deviation (SD) were diagnosed to have osteoporosis, –1 SD to –2.5 SD were diagnosed to have osteopenia and < –1 SD as normal. Statistical analysis for association of COPD with osteoporosis was done using chi-square test. Risk factors for osteoporosis were identified by univariate and multivariate logistic regression analysis.
Results:
A total of 102 COPD patients were included in the study. Among these, 68 patients (66.6%) had osteoporosis and 20 patients (19.6%) had osteopenia. Majority (64.7%) of the patients who had osteoporosis had stage III and stage IV COPD disease. It was observed that as the severity grade of COPD increased, the risk of osteoporosis also increased. The bone mineral density (BMD) showed a significant difference among different stages of COPD. As the severity of the stage of COPD increased, BMD decreased. It was also observed that patients with lower body mass index (BMI) had higher prevalence of osteoporosis (37.3%) as compared to overweight patients. On univariate analysis, it was observed that risk factors for osteoporosis were female sex, higher number of exacerbations, BMI, and severity of COPD. After using multivariate logistic regression analysis, stage IV COPD (odds ratio (OR): 34.48, 95% confidence interval (CI): 1.59–1,000, P < 0.02), number of acute exacerbations >3 (OR: 30.3, 95% CI: 4.74–200, P < 0.01), and steroid cumulative dose >1,000 mg (OR: 7.35, 95% CI: 0.92–58.5, P < 0.04) were observed to be significant risk factors for osteoporosis in COPD patients.
Conclusions:
In the present study, the prevalence of osteoporosis was 66.6% and another 19.6% had osteopenia. As the severity of COPD increased, the risk of osteoporosis increased. GOLD stage III and stage IV patient had significantly lower BMD as compared to stage I and stage II of COPD disease. Stage IV COPD disease, use of oral or parenteral glucocorticoids, and repeated number of exacerbations were found to be independent risk factors for osteoporosis in COPD patients. Thus, high clinical suspicion and early diagnosis and treatment is required in the evaluation of osteoporosis in COPD patients so that the quality of life can be improved in these patients.
doi:10.4103/0970-2113.135759
PMCID: PMC4129592  PMID: 25125807
COPD; correlates; DEXA scan; osteoporosis; repeated exacerbations; risk factors
18.  Testosterone Replacement and Bone Mineral Density in Male Pituitary Tumor Patients 
Endocrinology and Metabolism  2014;29(1):48-53.
Background
Hypopituitarism is associated with osteoporosis and osteopenia especially when hypogonadotropic hypogonadism is present. Despite hypopituitarism being an important cause of secondary osteoporosis, osteoporosis in patients receiving surgery for pituitary tumors in Korea has not been studied. In this study, we evaluated the effects of testosterone replacement therapy (TRT) on bone mineral density (BMD) in postoperative hypogonadal patients with pituitary tumors.
Methods
To examine the effect of TRT on BMD, we performed a retrospective observational study in 21 postoperative male patients who underwent pituitary tumor surgery between 2003 and 2012 at the Ajou University Hospital. Testosterone was replaced in postoperative hypogonadal patients by regular intramuscular injection, daily oral medication, or application of transdermal gel. BMD (g/cm2) measurements of central skeletal sites (lumbar spine, femoral neck, and total femur) were obtained using dual-energy X-ray absorptiometry (GE Lunar). For lumbar spine BMD, L1 to L4 values were chosen for analysis. Femur neck and total femur were also analyzed.
Results
During the follow-up period (mean, 56 months; range, 12 to 99 months) serum testosterone levels increased with the administration of TRT (P=0.007). There was significant improvement (4.56%±9.81%) in the lumbar spine BMD compared to baseline BMD. There were no significant changes in the femur neck BMD or total femur BMD. We did not find any statistically significant relationships between changes in testosterone levels and BMD using Spearman correlation analysis.
Conclusion
Our results indicated that TRT used in the postoperative period for hypogonadal pituitary tumor surgery patients may have beneficial effects on the BMD of the spine.
doi:10.3803/EnM.2014.29.1.48
PMCID: PMC3970284  PMID: 24741454
Osteoporosis; Bone density; Pituitary neoplasms; Hypogonadism; Testosterone; Male
19.  Growth hormone – insulin-like growth factor-I axis and bone mineral density in adults with thalassemia major 
Introduction:
Bone disease and short stature are frequent clinical features of patients with beta-thalassaemia major. Dysfunction of the GH-IGF-1 axis has been described in many thalassemics children and adolescents with short stature and reduced growth velocity. Assessment of the GH-IGF-1 axis in short adults with TM after attainment of final height may be required to select those who are candidates for replacement therapy and to prevent the development of bone disease. The aim of our study was to investigate GH secretion in adult thalassemic patients in relation to their bone mineral density (BMD) and serum ferritin concentrations.
Materials and Methods:
We performed clonidine stimulation test in 30 thalassemic patients (18 males, 12 females) with a mean age of 31.5± 7.2 years. The cut-off level for GH response was set at 7ug/l, according to the literature. Serum ferritin, IGF-I, liver enzymes, alkaline phosphatase (ALP) and type 1 Collagen Carboxy Telopeptide (CCT1) were also determined.
Results:
We diagnosed GH deficiency (GHD) in 12 patients (40%) and IGF-I deficiency (IGF-I SDS <-2) was diagnosed in 20 patients (67%). Adult patients with TM had significantly decreased IGF-I concentrations and bone mineral density (BMD) at the femur neck and lumbar spine compared to normal controls. Thalassemic patients with GHD and IGF-I deficiency had significantly lower BMD T score at the lumbar spine compared to patients with normal GH and IGF-I levels. Thalassemic patients had higher serum CCT1 concentrations compared to normal controls. Peak GH levels were correlated significantly with IGF- I concentrations and IGF-I levels were correlated significantly with the height SDS (HtSDS) of thalassemic patients. Neither GH peak nor IGF-I concentrations were correlated to serum ferritin concentrations.
Conclusions:
We conclude that GH status should be tested in adult thalassemic patients especially those with short stature and/or decreased BMD. Clonidine test appears to be effective and safe in adults with TM. If the diagnosis of adult GHD is established, GH treatment may be considered for possible improvement of bone mineral density and heart function in patients with TM.
doi:10.4103/2230-8210.126525
PMCID: PMC3968729  PMID: 24701427
Bone mineral density; ferritin; GH deficiency GHD; insulin like growth factor –I; growth; growth hormone; prevalence; thalassemia
20.  Relationship between bone mineral density and the frequent administration of epidural steroid injections in postmenopausal women with low back pain 
BACKGROUND:
Epidural steroid injection (ESI) is one of the most common nonsurgical treatments for low back pain. In general, corticosteroid therapy often results in bone loss and osteoporosis. In previous studies, bone mineral density (BMD) was evaluated after epidural injections of relatively small numbers and relatively low total doses of corticosteroids. However, the relationship between BMD and multiple ESIs remains to be elucidated.
OBJECTIVE:
To explore the relationship between BMD and multiple ESIs in postmenopausal women with low back pain.
METHODS:
Medical records of postmenopausal women with low back pain treated with or without ESIs were reviewed. BMD was measured in the lumbar spine, femoral neck and total femur after the treatments. A total of 71 patients were divided into two groups: group 1 included patients who had received non-ESI medications; and group 2 included those who had received ESIs >10 times, with a cumulative administered triamcinolone dose >200 mg.
RESULTS:
Patients in group 2 showed lower BMD in the femoral neck and total femur. However, no significant intergroup differences in the BMD of the lumbar spine were observed. The prevalences of osteoporosis and osteopenia in the lumbar spine and femoral neck were significantly higher in group 2; these patients also had lower femoral neck BMD Z-scores.
CONCLUSIONS:
Multiple ESIs (approximately 14 injections with a cumulative triamcinolone dose of approximately 400 mg) can reduce BMD in postmenopausal women with low back pain.
PMCID: PMC3938340  PMID: 24404559
Bone mineral density; Corticosteroid; Epidural steroid injection; Low back pain; Postmenopausal women; Triamcinolone
21.  DETERMINANTS OF CIRCULATING 25-HYDROXYVITAMIN D AND BONE MINERAL DENSITY IN YOUNG PHYSICIANS 
Objective
To examine determinants of serum 25-hydroxyvitamin D [25(OH)D] and bone mineral density (BMD) in young physicians, a group not well studied previously.
Methods
We analyzed data from a questionnaire completed by young physicians as well as results of serum 25(OH)D, serum parathyroid hormone, and BMD measurements.
Results
Among 104 study subjects, 42% were white, 46% were Asian, 12% were “other” (10 Hispanic and 2 African American subjects), and 75% were women. The mean age and body mass index (BMI) were 28.1 years and 23.0 kg/m2, respectively. White subjects had a higher mean serum 25(OH)D level (27.3 ng/mL) than did Asian subjects (15.9 ng/mL) and other subjects (22.3 ng/mL) (P<.0001). White subjects tended to have higher Z-scores than Asian subjects and other subjects for the hip (P = .06), trochanter (P = .08), and lumbar spine (P = .08). The serum 25(OH)D level was negatively associated with serum parathyroid hormone (r = -0.44; P<.01) but not with BMD. The prevalence of vitamin D insufficiency [serum 25(OH)D <30 ng/mL, 77% for the entire group] was higher (P<.01) in Asian subjects (93%) than in white subjects (61%) and other subjects (73%). Significant determinants of serum 25(OH)D included age, ethnicity, exposure to sunlight, use of vita-min D supplements, and family history of osteoporosis (P<.05 for all), and together with sex, calcium supplements, exercise, and BMI, these factors explained 49% of serum 25(OH)D level variability. Significant determinants of low BMD (osteopenia plus osteoporosis, prevalence 37.5%) included sex (P = .002) and BMI (P<.0001) but not serum 25(OH)D; Asian ethnicity reached borderline significance (P = .088). Age, sex, ethnicity, smoking, and BMI explained 20% to 30% of the Z-score variations.
Conclusion
In young physicians with a healthful lifestyle, determinants of low serum 25(OH)D and BMD included modifiable risk factors. Vitamin D insufficiency and low BMD could be important contributors to future osteoporotic fractures in this population.
doi:10.4158/EP11269.OR
PMCID: PMC4151555  PMID: 22440992
22.  Nutritional Biomarkers in Children and Adolescents with Beta-Thalassemia-Major: An Egyptian Center Experience 
BioMed Research International  2014;2014:261761.
Background and Aim. Trace elements and vitamins play a vital role in human body to perform its function properly. Thalassemic patients are at risk of micronutrient deficiency. This study estimated levels of vitamins A, C, E, B12, folic acid, total homocysteine (tHcy), and methylmalonic acid (MMA) along with trace elements, zinc, copper, and selenium in Beta-thalassemia-major patients. Methods. This study included 108 patients with Beta-thalassemia-major and 60 age and sex matched healthy children. Serum levels of vitamin A, E, C, tHcy, and MMA were estimated by high pressure liquid chromatography while serum levels of folic acid and B12 were estimated by thin layer chromatography. Serum zinc, copper, and selenium were determined by atomic absorption spectrometry. Results. There was a significant decrease of vitamins A, C, E, and B12 and trace elements zinc, copper, and selenium in thalassemic patients as compared to controls. tHcy and MMA were significantly elevated in patients. No significant correlations were found between the serum levels of the studied vitamins and trace elements as regards age, frequency of transfusion, duration of transfusion, and serum ferritin. Conclusion. The level of various nutritional biomarkers (vitamins A, C, E, and B12 and trace elements zinc, copper, selenium) was reduced in chronically transfused Egyptian thalassemic patient. These patients should have periodic nutritional evaluation and supplementation. Multicenter studies are highly recommended.
doi:10.1155/2014/261761
PMCID: PMC4000941  PMID: 24812610
23.  Prevalence of osteoporosis and vertebral fractures in acromegalic patients 
Summary
Growth Hormone (GH) and Insulin-like Growth Factor (IGF-1) stimulate proliferation, differentiation and extracellular matrix production in osteoblastic cells. GH and IGF-1 also stimulate recruitment and bone resorption activity in osteoclastic cells. A chronic systemic GH and IGF-1 excess produces an increased bone turn over in acromegalic patients (pts). Osteoporosis, joint alterations and bone deformities have a great clinical relevance in acromegalic pts and favour mortality and morbility. In the present study we evaluate the still unclear GH/IGF-1 activity on bone, Bone Mineral Density (BMD) and risk of osteoporotic Vertebral Fractures (VF), in relation to gender and gonadal status in acromegalic pts.
Twenty acromegalic pts (12 F, 8 M) ranging 26–64 years were studied. Four pts were hypogonadic (1 F, 3 M), seven women were in post-menopause (PM) and four women eugonadic. The disease was active in twelve pts and inactive in eight pts. Serum and urinary 24/hrs calcium and phosphate and serum PTH, bone formation (P1NP) and resorption (beta-CTX) markers were assayed. BMD was measured using dual energy X ray absorptiometry (DXA) at the lumbar spine and femoral neck and bone quantitative ultrasonography (QUS) at phalanges. Osteoporotic VF were assessed by antero-posterior and lateral x-ray examinations of the thoracic and lumbar spine.
Serum IGF-1, calcium and phosphate and 24-hours urinary calcium were significantly higher in pts with active disease in respect to pts with inactive disease. BMD was reduced in more of 50% of pts, in each skeletal sites measured. Z-score values were lower in males than in females. VF prevalence was 39% (43% in women, 57% in men). Fractured and non-fractured pts were not significantly different for BMD, T-score and Z-score.
In conclusion, VF are frequent in acromegaly and, even mild and asymptomatic, play an important role on life quality and survival, already decreased in acromegalic pts. DXA and QUS methods are not sufficient for identifying pts at risk for fracture, due to the many possible interferences (bone deformities, osteoarthritis, joint rigidity and soft tissue tickening), since BMD is just one determinant of bone fracture. In the screening of acromegalic complications, it is necessary to perform a radiographic study of the spine at the time of diagnosis and during follow up.
PMCID: PMC3279059  PMID: 22461828
acromegaly; osteoporosis
24.  Factors associated with low bone mass in the hemodialysis patients – a cross-sectional correlation study 
Background
Low bone mass is common in end-stage renal disease patients, especially those undergoing hemodialysis. It can lead to serious bone health problems such as fragility fractures. The purpose of this study is to investigate the risk factors of low bone mass in the hemodialysis patients.
Methods
Sixty-three subjects on hemodialysis for at least 6 months were recruited from a single center for this cross-sectional study. We collected data by questionnaire survey and medical records review. All subjects underwent a bone mineral density (BMD) assay with dual-energy x-ray absorptiometry at the lumbar spine and right hip. Data were statistically analyzed by means of descriptive analysis, independent t test and one way analysis of variance for continuous variables, Pearson product-moment correlation to explore the correlated factors of BMD, and stepwise multiple linear regression to identify the predictors of low bone mass.
Results
Using WHO criteria as a cutoff point, fifty-one subjects (81%) had a T-score lower than -1, of them 8 subjects (13%) had osteoporosis with the femoral neck most commonly affected. Regarding risk factors, age, serum alkaline phosphatase (ALP) level, and intact parathyroid hormone (iPTH) level had significant negative correlations with the femoral neck and lumbar spine BMD. On the other hand, serum albumin level, effective exercise time, and body weight (BW) had significant positive correlations with the femoral neck and lumbar spine BMD. Age, effective exercise time, and serum albumin level significantly predicted the femoral neck BMD (R2 × 0.25), whereas BW and the ALP level significantly predicted the lumbar spine BMD (R2 × 0.20).
Conclusion
This study showed that advanced age, low BW, low serum albumin level, and high ALP and iPTH levels were associated with a low bone mass in the hemodialysis patients. We suggest that regular monitoring of the femoral neck BMD, maintaining an adequate serum albumin level and BW, and undertaking an exercise program are important to improve bone health in the patients undergoing hemodialysis.
doi:10.1186/1471-2474-10-60
PMCID: PMC2700075  PMID: 19497099
25.  Bone health in phenylketonuria: a systematic review and meta-analysis 
Patients with Phenylketonuria (PKU) reportedly have decreased bone mineral density (BMD). The primary aim of this study was to perform a systematic review and meta-analysis to determine the extent and significance of low BMD in early treated patients with PKU. Secondary aims were to assess other bone status indicators including bone turnover markers (BTM) and to define areas for future research. Two research teams (Amsterdam, Netherlands and Atlanta, USA) performed literature searches for articles reporting data on BMD, osteopenia and osteoporosis, BTM or other bone indicators in patients with PKU. Included articles were compared between research teams and assessed for quality and risk of bias. A total of 13 unique articles were included; 11/13 articles reported BMD including a total of 360 patients. Ten out of 11 articles found BMD was significantly lower in patients with PKU. Meta-analyses for total BMD (TBMD; 3 studies; n = 133), lumbar spine BMD (LBMD; 7 studies; n = 247), and femoral neck BMD (FBMD; 2 studies; n = 78) Z-scores were performed. Overall effect sizes were: TBMD −0.45 (95% CI −0.61, −0.28); LBMD −0.70 (95% CI −0.82, −0.57); FBMD −0.96 (95% CI −1.42, −0.49). Definitions of osteopenia and osteoporosis were highly heterogeneous between studies and did not align with World Health Organization standards and the International Society for Clinical Densitometry positions on BMD measurement. Despite individual study findings of low BMD indicating higher risk of osteoporosis, pooled available data suggest reduction in BMD is not clinically important when using standard definitions of low BMD. Results from studies evaluating BTM are inconclusive. Phenylalanine concentration, vitamin D, PTH, and nutrient intake do not correlate with BMD or BTM. We recommend forthcoming studies use standard definitions of low BMD to determine clinical implications of BMD Z-scores below 0, explore cause of low BMD in the subset of patients with low BMD for chronological age (Z-score < −2) and assess fracture risk in patients with PKU.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0232-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-015-0232-y
PMCID: PMC4340652  PMID: 25758373
Phenylketonuria; PKU; Bone mineral density; BMD; Bone turnover markers; Phenylalanine; Osteopenia; Osteoporosis; Meta-analysis; Systematic review

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