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issn:0937-941
1.  [No title available] 
PMCID: PMC3903658  PMID: 23892583
2.  [No title available] 
PMCID: PMC3946739  PMID: 23925651
3.  [No title available] 
PMCID: PMC4100956  PMID: 23948876
4.  Efficacy of combined treatment with alendronate (ALN) and eldecalcitol, a new active vitamin D analog, compared to that of concomitant ALN, vitamin D plus calcium treatment in Japanese patients with primary osteoporosis 
Osteoporosis International  2015;26(3):1193-1202.
Summary
Combined treatment with alendronate and eldecalcitol was found to be more effective in reducing the bone turnover markers and increasing bone mineral density than alendronate treatment with vitamin D3 and calcium supplementation in the osteoporotic patients.
Introduction
We compared the clinical efficacy and safety of combined treatment with alendronate plus eldecalcitol (ALN + ELD) with those of treatment with ALN plus vitamin D and calcium (ALN + VitD).
Methods
Osteoporotic 219 patients were randomly assigned to the ALN + ELD, or the ALN + VitD group. Primary endpoint was the inter-group differences in lumbar spine BMD (L-BMD) at patient’s last visit. Secondary endpoints included the differences in BMD at other sites and the bone turnover marker (BTM) levels.
Results
L-BMD, total hip BMD and femoral neck (FN-BMD) increased from baseline by 7.30, 2.41, and 2.70 % in the ALN + ELD group, and by 6.52, 2.27, and 1.18 % in the ALN + VitD group, respectively. Inter-group differences of the L-BMD and total hip BMD values were not significant. The increase of the FN-BMD was larger in the ALN + ELD group than the ALN + VitD group. Reductions of the BTMs were greater in the ALN + ELD group than the ALN + VitD group. Interaction of the percent increase of the L-BMD with the baseline values of the BTMs was observed in the ALN + VitD group only. The increases of the FN-BMD in patients with lower baseline values of type-I-collagen C-telopeptide (sCTX) and serum 25(OH) D levels <20 ng/mL were significantly larger in the ALN + ELD group than the other group.
Conclusion
Combination treatment of ALN plus ELD was more effective in reducing the BTMs and increasing the FN-BMD than ALN treatment with vitamin D3 and calcium.
doi:10.1007/s00198-014-2991-z
PMCID: PMC4331603  PMID: 25592133
Bisphosphonate; Bone mineral density; Bone turnover markers; Eldecalcitol; Vitamin D
5.  Teriparatide treatment patterns in osteoporosis and subsequent fracture events: a US claims analysis 
Osteoporosis International  2015;26(3):1203-1212.
Summary
The objective of this study was to describe the risk of fragility-related fractures in the 2 years following teriparatide initiation. In an administrative claims analysis of over 11,407 patients, approximately one in eight patients had a new or recurrent fragility-related fracture in the 2 years following teriparatide initiation.
Introduction
The objective of this study was to describe the risk of fragility-related fractures in the 2 years following the initiation of teriparatide in a real-world setting.
Methods
This retrospective study used data from the 2002 to 2011 MarketScan® Commercial and Medicare Supplemental Databases to identify patients 50 years and older with a diagnosis of osteoporosis (ICD-9-CM code 733.0x) who were initiating teriparatide. Patients were required to have continuous medical and pharmacy benefit coverage for the 12 months prior to and 24 months following teriparatide initiation (index event). Teriparatide treatment patterns (persistence and adherence) were described, as was the use of antiresorptive therapy. The primary study outcome was the presence of a new or recurring fragility fracture following the initiation of teriparatide.
Results
A total of 11,407 patients met the study criteria (mean age = 69.5, standard deviation = 10.6 years; 92.0 % female). One in four (25.6 %) patients had fragility fracture claims in the year prior to teriparatide initiation, of which 64.0 % were on existing antiresorptive therapy. Overall, 13.4 % (n = 1527) of patients had a new or recurrent fracture during the 2-year follow-up period. Forty-eight percent of patients on teriparatide treatment were considered persistent; fragility fractures were more common among patients nonpersistent with teriparatide (15.2 %) than among those persistent with teriparatide (11.4 %). A higher fracture rate (35.7 %) was observed in the cohort with previous fragility fracture then those without pre-index fractures (24 %).
Conclusion
More than 13.4 % of patients had new or recurrent fragility-related fractures during the 2 years following the initiation of teriparatide; these fractures were more in common in patients with pre-existing fractures and the patients who were nonpersistent with teriparatide.
doi:10.1007/s00198-014-2971-3
PMCID: PMC4331607  PMID: 25567774
Antiresorptive; Claims; Fracture; Osteoporosis; Teriparatide; Treatment persistence
6.  Performance of risk assessment instruments for predicting osteoporotic fracture risk: a systematic review 
Summary
We systematically reviewed the literature on the performance of osteoporosis absolute fracture risk assessment instruments. Relatively few studies have evaluated the calibration of instruments in populations separate from their development cohorts, and findings are mixed. Many studies had methodological limitations making susceptibility to bias a concern.
Introduction
The aim of this study was to systematically review the literature on the performance of osteoporosis clinical fracture risk assessment instruments for predicting absolute fracture risk, or calibration, in populations other than their derivation cohorts.
Methods
We performed a systematic review, and MEDLINE, Embase, Cochrane Library, and multiple other literature sources were searched. Inclusion and exclusion criteria were applied and data extracted, including information about study participants, study design, potential sources of bias, and predicted and observed fracture probabilities.
Results
A total of 19,949 unique records were identified for review. Fourteen studies met inclusion criteria. There was substantial heterogeneity among included studies. Six studies assessed the WHO's Fracture Risk Assessment (FRAX) instrument in five separate cohorts, and a variety of risk assessment instruments were evaluated in the remainder of the studies. Approximately half found good instrument calibration, with observed fracture probabilities being close to predicted probabilities for different risk categories. Studies that assessed the calibration of FRAX found mixed performance in different populations. A similar proportion of studies that evaluated simple risk assessment instruments (≤5 variables) found good calibration when compared with studies that assessed complex instruments (>5 variables). Many studies had methodological features making them susceptible to bias.
Conclusions
Few studies have evaluated the performance or calibration of osteoporosis fracture risk assessment instruments in populations separate from their development cohorts. Findings are mixed, and many studies had methodological limitations making susceptibility to bias a possibility, raising concerns about use of these tools outside of the original derivation cohorts. Further studies are needed to assess the calibration of instruments in different populations prior to widespread use.
doi:10.1007/s00198-013-2504-5
PMCID: PMC3962543  PMID: 24105431
Calibration; Fracture; Osteoporosis; Risk assessment; Systematic review
7.  Fracture risk following bariatric surgery: a population-based study 
Summary
The effects of bariatric surgery on skeletal health are poorly understood. We found that bariatric surgery patients are more prone to fracture when compared to the general population. While further studies of fracture risk in this population are needed, bone health should be discussed in bariatric surgery clinics.
Introduction
Bariatric surgery is an increasingly common treatment for medically complicated obesity. Adverse skeletal changes after bariatric surgery have been reported, but their clinical importance remains unknown. We hypothesized that bariatric surgery patients are at increased risk of fracture.
Methods
We conducted a historical cohort study of fracture incidence among 258 Olmsted County, Minnesota, residents who underwent a first bariatric surgery in 1985–2004. Relative fracture risk was expressed as standardized incidence ratios (SIRs), while potential risk factors were evaluated by hazard ratios (HR) obtained from a time-to-fracture regression model.
Results
The mean (±SD) body mass index at bariatric surgery was 49.0±8.4 kg/m2, with an average age of 44±10 years and 82 % (212) females. Gastric bypass surgery was performed in 94 % of cases. Median follow-up was 7.7 years (range, 6 days to 25 years), during which 79 subjects experienced 132 fractures. Relative risk for any fracture was increased 2.3-fold (95 % confidence interval (CI), 1.8–2.8) and was elevated for a first fracture at the hip, spine, wrist, or humerus (SIR, 1.9; 95 % CI, 1.1–2.9), as well as for a first fracture at any other site (SIR, 2.5; 95 % CI, 2.0–3.2). Better preoperative activity status was associated with a lower age-adjusted risk (HR, 0.4; 95 % CI, 0.2–0.8) while prior fracture history was not associated with postoperative fracture risk.
Conclusions
Bariatric surgery, which is accompanied by substantial biochemical, hormonal, and mechanical changes, is associated with an increased risk of fracture.
doi:10.1007/s00198-013-2463-x
PMCID: PMC3939838  PMID: 23912559
Bariatric surgery; Cohort study; Fractures; Obesity; Population based
8.  Adherence to oral bisphosphonates and the risk of subtrochanteric and femoral shaft fractures among female medicare beneficiaries 
Summary
Previous studies have shown an association between duration of bisphosphonate use and atypical femur fractures. This cohort study showed an increasingly higher risk of subtrochanteric and femoral shaft fractures among those who were more adherent to oral bisphosphonates.
Introduction
Long-term use of oral bisphosphonates has been implicated in an increased risk of atypical femur fractures located in subtrochanteric and femoral shaft regions. Another measure of drug exposure, medication adherence, however, has not been investigated.
Methods
Among all Medicare fee-for-service female beneficiaries from 2006–2010, we followed 522,287 new bisphosphonate users from their index prescription until being censored or having a primary diagnosis of closed subtrochanteric/ femoral shaft or intertrochanteric/femoral neck fractures. Data about radiographs of fracture site and features were not available. Adherence was classified according to the medication possession ratio (MPR) as the following: MPR<1/3 as less compliant, MPR≥1/3–<2/3 as compliant, and MPR≥2/3 as highly compliant. Alternative cutoff points at 50 and 80 % were also used. Survival analysis was used to determine the cumulative incidence and hazard of subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures.
Results
There was a graded increase in incidence of subtrochanteric/femoral shaft fractures as the level of adherence increased (Gray’s test, P<0.001). The adjusted hazard ratio (HR) for the highly compliant vs. the less compliant was 1.23 (95 % Confidence Interval [CI] 1.06–1.43) overall, became significant after 2 years of follow-up (HR=1.51, 95 % CI 1.06–2.15) and reached the highest risk in the fifth year (HR=4.06, 95 % CI 1.47–11.19). However, age-adjusted incidence rates of intertrochanteric/femoral neck fractures were significantly lower among highly compliant beneficiaries, compared to less compliant users (HR=0.69, 95 % CI 0.66–0.73). Similar results were obtained when the cutoff points for being compliant and highly compliant were set at 50 and 80 %, respectively.
Conclusions
Subtrochanteric/femoral shaft fractures, unlike intertrochanteric/femoral neck fractures, are positively associated with higher adherence to long-term (≥3 years) oral bisphosphonates in the elderly female Medicare population.
doi:10.1007/s00198-014-2738-x
PMCID: PMC4254800  PMID: 24846316
Bisphosphonates; Fracture; Osteoporosis; Atypical femur fracture
9.  Incorporating bazedoxifene into the treatment paradigm for postmenopausal osteoporosis in Japan 
Osteoporosis International  2014;26(3):849-863.
The incidence of osteoporosis-related fractures in Asian countries is steadily increasing. Optimizing osteoporosis treatment is especially important in Japan, where the rate of aging is increasing rapidlyelderly population is increasing rapidly and life expectancy is among the longest in the world. There are several therapies currently available in Japan for the treatment of postmenopausal osteoporosis, each with a unique risk/benefit profile. A novel selective estrogen receptor modulator, bazedoxifene (BZA), was recently approved for the treatment of postmenopausal osteoporosis in Japan. Results from a 2-year, phase 2 trial in postmenopausal Japanese women showed that BZA significantly improved lumbar spine and total hip bone mineral density compared with placebo, while maintaining endometrial and breast safety, consistent with results from 2 global, phase 3 trials including a 2-year osteoporosis prevention study and a 3-year osteoporosis treatment study. In the pivotal 3-year treatment study, BZA significantly reduced the incidence of new vertebral fractures compared with placebo; in a post hoc analysis of a subgroup of women at higher risk of fractures, BZA significantly reduced the risk of nonvertebral fractures compared with placebo and raloxifene. A 2-year extension of the 3-year treatment study demonstrated the sustained efficacy of BZA over 5 years of treatment. BZA was generally safe and well tolerated in these studies. In a “super-aging” society such as Japan, long-term treatment for postmenopausal osteoporosis is a considerable need. BZA may be considered as a first choice for younger women anticipating long-term treatment, and also an appropriate option for older women who are unable or unwilling to take bisphosphonates.
doi:10.1007/s00198-014-2940-x
PMCID: PMC4331605  PMID: 25448837
Bazedoxifene; Fracture; Japan; Osteoporosis; Selective estrogen receptor modulator (SERM)
10.  Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial 
Osteoporosis International  2014;26:699-712.
Summary
Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial.
Introduction
Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN.
Methods
The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤−1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg.
Results
Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension.
Conclusions
This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.
Electronic supplementary material
The online version of this article (doi:10.1007/s00198-014-2944-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00198-014-2944-6
PMCID: PMC4312384  PMID: 25432773
Cathepsin K; Fracture; Odanacatib; Osteoporosis; Postmenopausal
11.  Polymorphism of vitamin D3 receptor and its relation to mineral bone density in perimenopausal women 
Osteoporosis International  2014;26(3):1045-1052.
Summary
Postmenopausal osteoporosis is the most common metabolic bone disease with important genetic factors. We evaluated the frequency of polymorphism 283G/A of the vitamin D3VDR gene receptor. The study included 800 women at the postmenopausal (505) and reproductive (295) age. Statistically significant changes, depending on the genotype, were shown.
Introduction
Postmenopausal osteoporosis is the most common metabolic bone disease of strong genetic origin with population variability determined by the interaction of genetic and environmental factors. Recognition of different genetic variants underlying development of osteoporosis would make it possible to administer individual symptomatic treatment as well as early prophylactics of osteoporosis.
Methods
The aim of the study was to evaluate the frequency of polymorphism 283G/A of the vitamin D3VDR gene receptor and assessment of its relations with the clinical parameters of osseous turnover and degree of postmenopausal osteoporosis.
The study included 800 women at the postmenopausal (505) and reproductive (295) age throughout the Wielkopolska region in Poland. The postmenopausal group included women with osteoporosis and osteopenia and the healthy ones. Women at the reproductive age were healthy. Frequency of the tested gene polymorphism was evaluated in the group where bone mineral density (BMD) was marked and in the control group.
Results
The obtained test results pointed to correlation of polymorphism VDR 283G/A with the BMD scores for the lumbar vertebrae in women with osteopenia and osteoporosis, therefore the ones at risk of fractures. Vitamin D receptor (VDR) polymorphism correlated with reduced BMD values.
Conclusions
Polymorphism 283G/A of the vitamin D3 receptor gene has been proved to be the genetic factor of postmenopausal osteoporosis. The polymorphism mentioned above has been proved to be a factor of mineral bone density changes of women.
doi:10.1007/s00198-014-2947-3
PMCID: PMC4331595  PMID: 25407264
Age; Females; Osteoporosis; Polymorphism; VDR gene
12.  Isolation and characterization of human osteoblasts from needle biopsies without in vitro culture 
Summary
We isolate and characterize osteoblasts from humans without in vitro culture. These techniques should be broadly applicable to studying the pathogenesis of osteoporosis and other bone disorders.
Introduction
There is currently no data regarding the expression of specific genes or pathways in human osteoblasts that have not been subjected to extensive in vitro culture. Thus, we developed methods to rapidly isolate progressively enriched osteoblast populations from humans and characterized these cells.
Methods
Needle bone biopsies of the posterior iliac crest were subjected to sequential collagenase digests. The cells from the second digest were stained with an alkaline phosphatase (AP) antibody, and the AP+ cells were isolated using magnetic cell sorting.
Results
Relative to AP− cells, the AP+ cells contained virtually all of the mineralizing cells and were enriched for key osteoblast marker genes. The AP+ cells were further purified by depletion of cells expressing CD45, CD34, or CD31 (AP+/CD45/34/31− cells), which represented a highly enriched human osteoblast population devoid of hematopoietic/endothelial cells. These cells expressed osteoblast marker genes but very low to undetectable levels of SOST. We next used high-throughput RNA sequencing to compare the transcriptome of the AP+/CD45/34/31− cells to human fibroblasts and identified genes and pathways expressed only in human osteoblasts in vivo, but not in fibroblasts, including 448 genes unique to human osteoblasts.
Conclusions
We provide a detailed characterization of highly enriched human osteoblast populations without in vitro culture. These techniques should be broadly applicable to studying the pathogenesis of osteoporosis and other bone disorders.
doi:10.1007/s00198-013-2529-9
PMCID: PMC4216562  PMID: 24114401
Bone biopsy; Osteoblasts; Osteoporosis
13.  Ovariectomy and genes encoding core circadian regulatory proteins in murine bone 
Summary
This study investigated the influence of ovarian hormone deficiency on core circadian regulatory protein (CCRP) in the context of bone loss. Our data suggest that ovarian hormone deficiency disrupts diurnal rhythmicity and CCRP expression in bone. Further studies should determine if chronobiology provides a novel therapeutic target for osteoporosis intervention.
Introduction
CCRP synchronize metabolic activities and display an oscillatory expression profile in murine bone. In vitro studies using bone marrow mesenchymal stromal/stem cells have demonstrated that the CCRP is present and can be regulated within osteoblast progenitors. In vivo studies have shown that the CCRP regulates bone mass via leptin/neuroendocrine pathways. The current study used an ovariectomized murine model to test the hypothesis that ovarian hormone deficiency is associated with either an attenuation and/or temporal phase shift of the CCRP oscillatory expression in bone and that these changes are correlated with the onset of osteoporosis.
Methods
Sham-operated controls and ovariectomized female C57BL/6 mice were euthanized at 4-h intervals 2 weeks post-operatively.
Results
Ovariectomy attenuated the oscillatory expression of CCRP mRNAs in the femur and vertebra relative to the controls and reduced the wheel-running activity profile.
Conclusion
Ovarian hormone deficiency modulates the expression profile of the CCRP with potential impact on bone marrow mesenchymal stem cell lineage commitment.
doi:10.1007/s00198-010-1325-z
PMCID: PMC4215737  PMID: 20593165
Diurnal; Estrogen; Mesenchymal stem cell; Osteoporosis
14.  Dietary intake of polyunsaturated fatty acids and risk of hip fracture in men and women 
Introduction
Polyunsaturated fatty acids (PUFA) are important in the prevention of chronic diseases, but studies of bone health report inconsistent results. Our aim was to investigate the association between dietary PUFA intake and risk of hip fracture in two large prospective cohorts of men and women with long follow-up times and frequently updated dietary data.
Methods
The study population included 75878 women and 46476 men free of osteoporosis at baseline. Dietary intakes were assessed by a food frequency questionnaire at baseline and several times during the follow-up. Multivariable-adjusted Cox proportional hazards models were used to estimate relative risks (RR).
Results
During 24 years of follow-up, we identified 1051 hip fracture cases due to low or moderate trauma among the women and 529 cases among the men. In the pooled analyses, no statistically significant associations were found between intakes of total PUFA [RR in the highest vs. lowest quintile: 0.99, 95% confidence interval (CI) 0.69, 1.43; p for trend=0.83], total n-3 PUFA (RR 0.89, 95% CI 0.75, 1.06; p for trend=0.26), total n-6 PUFA (RR 0.99, 95% CI 0.71, 1.38; p for trend=0.82), n-6/n-3 PUFA ratio or individual PUFAs and hip fracture risk. However, in women low intakes of total PUFA, total n-6 PUFA and linoleic acid intakes were associated with higher risk.
Conclusions
This study does not support a significant role for PUFA intake in the prevention of hip fractures, although low total PUFA, n-6 PUFA or linoleic acid intakes may increase the risk in women.
doi:10.1007/s00198-012-1903-3
PMCID: PMC4213390  PMID: 22270860
fatty acids; fish; hip fracture; population studies; men; women
15.  Overuse of short-interval bone densitometry: assessing rates of low-value care 
Summary
We evaluated the prevalence and geographic variation of short-interval (repeated in under 2 years) dual-energy X-ray absorptiometry tests (DXAs) among Medicare beneficiaries. Short-interval DXA use varied across regions (coefficient of variation=0.64), and unlike other DXAs, rates decreased with payment cuts.
Introduction
The American College of Rheumatology, through the Choosing Wisely initiative, identified measuring bone density more often than every 2 years as care “physicians and patients should question.” We measured the prevalence and described the geographic variation of short-interval (repeated in under 2 years) DXAs among Medicare beneficiaries and estimated the cost of this testing and its responsiveness to payment change.
Methods
Using 100 % Medicare claims data, 2006–2011, we identified DXAs and short-interval DXAs for female Medicare beneficiaries over age 66. We determined the population rate of DXAs and short-interval DXAs, as well as Medicare spending on short-interval DXAs, nationally and by hospital referral region (HRR).
Results
DXA use was stable 2008–2011 (12.4 to 11.5 DXAs per 100 women). DXA use varied across HRRs: in 2011, overall DXA use ranged from 6.3 to 23.0 per 100 women (coefficient of variation = 0.18), and short-interval DXAs ranged from 0.3 to 8.0 per 100 women (coefficient of variation=0.64). Short-interval DXA use fluctuated substantially with payment changes; other DXAs did not. Short-interval DXAs, which represented 10.1 % of all DXAs, cost Medicare approximately US$16 million in 2011.
Conclusions
One out of ten DXAs was administered in a time frame shorter than recommended and at a substantial cost to Medicare. DXA use varied across regions. Short-interval DXA use was responsive to reimbursement changes, suggesting carefully designed policy and payment reform may reduce this care identified by rheumatologists as low value.
doi:10.1007/s00198-014-2725-2
PMCID: PMC4210629  PMID: 24809808
Bone densitometry; Health services research; Medicare
16.  Ethnic differences in urinary calcium and phosphate excretion between Gambian and British older adults 
Osteoporosis International  2014;26(3):1125-1135.
Summary
Ethnic differences in renal calcium and phosphate excretion exist, which may depend on differences in their dietary intakes and regulatory factors. We report highly significant differences in urinary calcium and phosphate excretion between white British and Gambian adults after statistical adjustment for mineral intakes, indicating an independent effect of ethnicity.
Introduction
Populations vary in their risk of age-related osteoporosis. There are racial or ethnic differences in the metabolism of the bone-forming minerals calcium (Ca) and phosphate (P), with a lower renal Ca and P excretion in African-Americans compared to white counterparts, even at similar intakes and rates of absorption. Also, Africans in The Gambia have a lower Ca excretion compared to white British subjects, groups known to differ in their dietary Ca intake. Here, we report on differences in urinary Ca and P excretion between Gambian and white British adults while allowing for known predictors, including dietary intakes.
Methods
Participants were healthy white British (n = 60) and Gambian (n = 61) men and women aged 60–75 years. Fasting blood and 2-h urine samples were collected. Markers of Ca and P metabolism were analysed. Dietary intake was assessed with country-specific methods.
Results
White British older adults had higher creatinine-corrected urinary Ca and P excretion (uCa/uCr, uP/uCr) and lower tubular maximum of Ca and P compared to Gambian counterparts. The predictors of urinary Ca and P differed between groups. Multiple regression analysis showed that dietary Ca and Ca/P were predictors of uCa/uCr and uP/uCr, respectively. Ethnicity remained a significant predictor of uCa/uCr and uP/uCr after adjustment for diet and other factors.
Conclusions
Gambian older adults have higher renal Ca conservation than British counterparts. Dietary mineral intakes were predictors of the differences in urinary Ca and P excretion, but ethnicity remained a highly significant predictor after statistical adjustment. This suggests that ethnicity has an independent effect on renal Ca and P handling.
doi:10.1007/s00198-014-2926-8
PMCID: PMC4331615  PMID: 25311107
Bone; Calcium; Diet; Ethnicity; Kidney; Phosphate
17.  Predictors of 25(OH)D half-life and plasma 25(OH)D concentration in The Gambia and the UK 
Osteoporosis International  2014;26(3):1137-1146.
Summary
Predictors of 25(OH)D3 half-life were factors associated with vitamin D metabolism, but were different between people in The Gambia and the UK. Country was the strongest predictor of plasma 25(OH)D concentration, probably as a marker of UVB exposure. 25(OH)D3 half-life may be applied as a tool to investigate vitamin D expenditure.
Introduction
The aim of this study was to investigate predictors of 25(OH)D3 half-life and plasma 25(OH)D concentration.
Methods
Plasma half-life of an oral tracer dose of deuterated-25(OH)D3 was measured in healthy men aged 24–39 years, resident in The Gambia, West Africa (n = 18) and in the UK during the winter (n = 18), countries that differ in calcium intake and vitamin D status. Plasma and urinary markers of vitamin D, calcium, phosphate and bone metabolism, nutrient intakes and anthropometry were measured.
Results
Normally distributed data are presented as mean (SD) and non-normal data as geometric mean (95 % CI). Gambian compared to UK men had higher plasma concentrations of 25(OH)D (69 (13) vs. 29 (11) nmol/L; P < 0.0001); 1,25(OH)2D (181 (165, 197) vs. 120 (109, 132) pmol/L; P < 0.01); and parathyroid hormone (PTH) (50 (42, 60) vs. 33 (27, 39); P < 0.0001). There was no difference in 25(OH)D3 half-life (14.7 (3.5) days vs. 15.6 (2.5) days) between countries (P = 0.2). In multivariate analyses, 25(OH)D, 1,25(OH)2D, vitamin D binding protein and albumin-adjusted calcium (Caalb) explained 79 % of variance in 25(OH)D3 half-life in Gambians, but no significant predictors were found in UK participants. For the countries combined, Caalb, PTH and plasma phosphate explained 39 % of half-life variability. 1,25(OH)2D, weight, PTH and country explained 81 % of variability in 25(OH)D concentration; however, country alone explained 74 %.
Conclusion
Factors known to affect 25(OH)D metabolism predict 25(OH)D3 half-life, but these differed between countries. Country predicted 25(OH)D, probably as a proxy measure for UVB exposure and vitamin D supply. This study supports the use of 25(OH)D half-life to investigate vitamin D metabolism.
doi:10.1007/s00198-014-2905-0
PMCID: PMC4331602  PMID: 25278297
24,25(OH)2D; Gambia; Half-life; Vitamin D binding protein; Vitamin D metabolism
18.  Genetic variants in the SOX6 gene are associated with bone mineral density in both Caucasian and Chinese populations 
Summary
Given the biological function of SOX6 and recent genome-wide association finding, we performed a fine-mapping association analyses to investigate the relationship between SOX6 and BMD both in Caucasian and Chinese populations. We identified many single-nucleotide polymorphisms (SNPs) within or near the SOX6 gene to be significantly associated with hip bone mineral density (BMD).
Introduction
SOX6 gene is an essential transcription factor in chondrogenesis and cartilage formation. Recent genome-wide association studies (GWAS) detected a SNP (rs7117858) located at the downstream of SOX6 significantly associated with hip BMD.
Methods
Given the biological function of SOX6 and the GWAS finding, we considered SOX6 as a new candidate for BMD and osteoporosis. Therefore, in this study, we performed a fine-mapping association analyses to investigate the relationship between SNPs within and near the SOX6 gene and BMD at both hip and spine. A total of 301 SNPs were tested in two independent US Caucasian populations (2,286 and 1,000 unrelated subjects, respectively) and a Chinese population (1,627 unrelated Han subjects).
Results
We confirmed that the previously reported rs7117858-A was associated with reduced hip BMD, with combined P value of 2.45×10−4. Besides this SNP, we identified another 19 SNPs within or near the SOX6 gene to be significantly associated with hip BMD after false discovery rate adjustment. The most significant SNP was rs1347677 located at the intron 3 (P=3.15×10−7). Seven additional SNPs in high linkage disequilibrium with rs1347677 were also significantly associated with hip BMD. SNPs in SOX6 showed significant skeletal site specificity since no SNP was detected to be associated with spine BMD.
Conclusion
Our study identified many SNPs in the SOX6 gene associated with hip BMD even across different ethnicities, which further highlighted the importance of the SOX6 gene influencing BMD variation and provided more information to the understanding of the genetic architecture of osteoporosis.
doi:10.1007/s00198-011-1626-x
PMCID: PMC4171834  PMID: 21625884
Association; BMD; Osteoporosis; SOX6
19.  Persistence at 12 months with denosumab in postmenopausal women with osteoporosis: interim results from a prospective observational study 
Osteoporosis International  2014;26:361-372.
Summary
To determine persistence with subcutaneous denosumab every 6 months in women being treated for osteoporosis, we conducted a single-arm prospective, observational study in the United States and Canada. Among 935 patients enrolled, 12-month persistence was 82 %, with 66 patients (7 %) reporting serious adverse events and 19 patients (2 %) reporting fractures.
Introduction
Increased persistence with osteoporosis therapy is associated with reduced fracture risk. Denosumab reduced fracture risk in clinical trials; persistence in community settings is undetermined. This study evaluates persistence with denosumab in community practice in the United States (US) and Canada.
Methods
In a 24-month multicenter, prospective, single-arm, observational study, women being treated for osteoporosis were enrolled ≤4 weeks after the first subcutaneous injection of denosumab. For this 12-month prespecified interim analysis, endpoints include persistence (one injection at study entry and another within 6 months + 8 weeks), attributes associated with persistence (univariate analysis), and serious adverse events (SAEs).
Results
Among 935 patients (mean age 71 years), mean baseline T-scores were −2.18 (femoral neck) and −2.00 (lumbar spine); 50 % of patients had experienced osteoporotic fracture(s). At 12 months, 82 % of patients were persistent with denosumab. Baseline factors significantly (p < 0.05) associated with higher persistence included use of osteoporosis medications >5 years previously, lumbar spine T-score > −2.5, and treatment by female physicians (US). Lower persistence was associated (p < 0.05) with psychiatric diagnoses including depression, southern US residence, being divorced, separated, or widowed (US), and prior hip fracture (Canada). SAEs were reported in 66 patients (7 %); no SAEs of osteonecrosis of the jaw, atypical femoral fracture, fracture healing complications, hypocalcemia, eczema, or hypersensitivity were reported. Nineteen patients (2 %) reported osteoporotic fractures.
Conclusions
The 12-month persistence observed in this single-arm open-label study of US and Canadian community practice extends the evidence regarding denosumab’s potential role in reducing fracture risk in postmenopausal women with osteoporosis.
Electronic supplementary material
The online version of this article (doi:10.1007/s00198-014-2871-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00198-014-2871-6
PMCID: PMC4286624  PMID: 25236877
Adherence; Compliance; Denosumab; Observational study; Osteoporosis; Persistence
20.  Racial differences in cortical bone and their relationship to biochemical variables in black and white children in the early stages of puberty 
Introduction
Racial differences in bone structure likely have roots in childhood as bone size develops predominantly during growth. This study aimed to compare cortical bone health within the tibial diaphysis of black and white children in the early stages of puberty, and explore the contributions of biochemical variables in explaining racial variation in cortical bone properties.
Methods
A cross-sectional study was performed comparing peripheral quantitative computed tomography-derived cortical bone measures of the tibial diaphysis and biochemical variables in 314 participants (n=155 males; n=164 blacks) in the early stages of puberty.
Results
Blacks had greater cortical volumetric bone mineral density, mass and size compared to whites (all p<0.01), contributing to blacks having 17.0% greater tibial strength (polar strength-strain index [SSIP]) (p<0.001). Turnover markers indicated blacks had higher bone formation (osteocalcin [OC] and bone specific alkaline phosphatase) and lower bone resorption (N-terminal telopeptide) than whites (all p<0.01). Blacks also had lower 25-hydroxyvitamin D [25(OH)D], and higher 1,25-dihydroxyvitamin D [1,25(OH)2D] and parathyroid hormone (PTH) (all p<0.05). There were no correlations between tibial bone properties, and 25(OH)D and PTH in whites (all p≥0.10); however, SSIP was negatively and positively correlated with 25(OH)D and PTH in blacks, respectively (all p≤0.02). Variation in bone cross-sectional area and SSIP attributable to race was partially explained by tibial length, 25(OH)D/PTH and OC.
Conclusions
Divergence in tibial cortical bone properties between blacks and whites is established by the early stages of puberty with the enhanced cortical bone properties in black children possibly being explained by higher PTH and OC.
doi:10.1007/s00198-012-2174-8
PMCID: PMC4163020  PMID: 23093348
peripheral quantitative computed tomography; 25 hydroxy vitamin D; 1,25 dihydroxy vitamin D; PTH; bone turnover; race
21.  Decreased cortical thickness, as estimated by a newly developed ultrasound device, as a risk for vertebral fracture in type 2 diabetes mellitus patients with eGFR of less than 60 mL/min/1.73 m2 
Osteoporosis International  2014;26:229-236.
Summary
Cortical porosity is increasingly recognized as an important risk for fracture in DM patients. The present study demonstrated that decreased cortical thickness, assessed using a newly developed quantitative ultrasonic bone densitometry, is a significant risk factor for vertebral fractures in type 2 diabetes mellitus patients with stage 3 or higher chronic kidney disease, but not in those without.
Introduction
Cortical porosity is increasingly recognized as an important risk factor for fracture in type 2 diabetes mellitus (T2DM) patients as well as in stage 3 chronic kidney disease (CKD) patients in whom serum parathyroid hormone (PTH) starts to increase. The present study aimed to clarify whether the coexistence of CKD might affect the relationship of decreased cortical thickness (CoTh) in the development of vertebral fractures (VF) in T2DM patients.
Methods
In this cross-sectional study, trabecular bone mineral density (TrBMD), elastic modulus of trabecular bone (EMTb), and CoTh were estimated with a new quantitative ultrasound bone densitometry in 173 T2DM patients. VFs were identified radiographically.
Results
Thirty-nine patients (22.5 %) had VF. Those with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (low eGFR) showed a significantly higher VF rate (32.4 %) than those with eGFR ≥60 mL/min/1.73 m2 (high eGFR, 16.2 %). Serum PTH was significantly higher with low eGFR than with high eGFR. In those with high eGFR, EMTb was significantly lower in VF(+) than VF(−). In those with low eGFR, TrBMD, EMTb, and CoTh were significantly lower in VF(+) than in VF(−). In a multivariate logistic regression analysis, EMTb was independently and significantly associated with VF in T2DM patients with a high eGFR, in contrast to those with only CoTh with VF in T2DM with low eGFR.
Conclusion
This study demonstrated CoTh as a factor independently associated with VF in T2DM patients with low eGFR and increasing serum PTH levels.
Electronic supplementary material
The online version of this article (doi:10.1007/s00198-014-2843-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00198-014-2843-x
PMCID: PMC4286635  PMID: 25187117
Bone fracture; Bone mineral density; Chronic kidney disease; Cortical thickness; Type 2 diabetes
22.  Evaluation of the effect of selective serotonin reuptake inhibitors on bone mineral density: an observational cross-sectional study 
Osteoporosis International  2014;26:273-279.
Summary
Sixty patients diagnosed with generalized anxiety disorder and treated with either paroxetine, sertraline, or citalopram for at least 12 months were enrolled in this study, and the bone mineral density (BMD) of the patients was compared with that of 40 healthy volunteers. Selective serotonin reuptake inhibitor (SSRI) therapy in generalized anxiety disorder was found to be related with decreased BMD values.
Introduction
The objectives of this study were to evaluate the effect of SSRI therapy on BMD in postmenopausal women diagnosed with generalized anxiety disorder (GAD) and to identify the effects of the duration of disease and treatment on risk factors for osteoporosis.
Methods
Sixty patients diagnosed with GAD and treated with paroxetine, sertraline, or citalopram from the SSRI group for at least 12 months were enrolled. Social demographic features, the Hamilton Anxiety Scale (HAS) results, and the Hamilton Depression Scale (HDS) scores of all the patients were assessed. The BMD of the patients was measured by dual-energy X-ray absorptiometry (DXA) at the femoral and lumbar regions. The patients were divided into three groups which are the paroxetine, sertraline, and citalopram groups. The BMD of the patients was compared with that of 40 healthy volunteers.
Results
The L2–L4, total lumbar vertebrae, femoral intertrochanteric, total femoral Z-scores, and femoral Ward’s region T-scores of the treatment group were lower than the median T- and Z-scores of the control group (p < 0.05). Of the treatment groups, the femoral neck, trochanteric and intertrochanteric T- and Z-scores, total femoral T- and Z-scores, and femoral Ward’s T- and Z-scores of the sertraline group were significantly lower than the BMD values measured at the identical regions in the paroxetine and citalopram groups (p < 0.05).There was a significant negative correlation between the duration of treatment and the BMD values.
Conclusion
SSRI therapy in GAD was found to be related with decreased BMD values. Further randomized controlled studies are warranted to determine whether SSRI use is a risk factor for osteoporosis; such studies should investigate these factors by performing BMD assessments before treatment.
doi:10.1007/s00198-014-2859-2
PMCID: PMC4286623  PMID: 25187118
BMD; GAD; Osteoporosis; SSRI
23.  Sclerostin and Pref-1 have differential effects on bone mineral density and strength parameters in adolescent athletes compared with non-athletes 
Purpose
Exercise activity is common in female adolescents, however, excessive exercise can have detrimental effects on bone mineral density (BMD). Mechanisms underlying this decrease in bone mass are not well understood. We investigated the effects of sclerostin, a potent inhibitor of bone formation via WNT signaling inhibition, and pre-adipocyte factor (Pref)-1, a suppressor of osteoblast differentiation, on BMD, bone turnover markers and bone strength in adolescent athletes.
Methods
We studied 50 adolescents between 15-21 years of age: 17 amenorrheic athletes (AA), 17 eumenorrheic athletes (EA) and 16 nonathletic controls (NA). We measured spine and hip BMD by dual energy x-ray absorptiometry and estimated failure load and stiffness at the distal radius and tibia using micro-finite element analysis. We also measured fasting sclerostin, Pref-1, N-terminal propeptide of type 1 procollagen (P1NP) and C-terminal collagen crosslinks (CTX) levels.
Results
Sclerostin levels were higher in AA and EA compared with NA (AA: 0.42 ± 0.15 ng/mL, EA: 0.44 ± 0.09 ng/mL, NA: 0.33 ± 0.14 ng/mL; p=0.047). In EA, sclerostin was positively associated with lumbar spine (LS) BMD and its Z-score (R=0.52, p=0.03 and R=0.55, p=0.02, respectively) whereas in NA, sclerostin was inversely associated with LS BMD (R=−0.61, p=0.01). Pref-1 levels were similar in all three groups and there were significant inverse associations between Pref-1, BMD and estimated bone strength in NA.
Conclusions
Sclerostin and Pref-1 may have differential effects on bone in adolescent athletes compared to non-athletes.
doi:10.1007/s00198-013-2353-2
PMCID: PMC3740025  PMID: 23579340
Sclerostin; Pref-1; Bone strength; Adolescent athletes
24.  Vitamin D in organ transplantation 
Vitamin D deficiency is prevalent among patients with end-stage organ failure awaiting transplant. Low serum 25-hydroxyvitamin D (25-OHD) levels in these patients may be related to many disease-specific factors, as well as decreased sunlight exposure and limited intake of foods containing vitamin D. Low serum 25-OHD levels are also extremely common following solid organ transplantation, both during the immediate postoperative period and in long-term graft recipients. Demographic and lifestyle factors are important in determining D status in transplant recipients. Worse vitamin D status is associated with poorer general health, lower albumin, and even decreased survival among these patients. Although several studies have demonstrated that active forms of vitamin D and its analogues prevent bone loss following transplantation, the data do not show consistent benefit. These therapies may have particular utility after renal transplantation. However, given the narrow therapeutic window with respect to hypercalcemia and hypercalciuria, and the demonstrated efficacy of bisphosphonates to prevent post-transplantation bone loss, we regard these agents as adjunctive rather than primary therapy for transplantation osteoporosis. The effects of 1,25(OH)2D on the immune system, which are still being elucidated, may have potential for reducing infections and preventing allograft rejection after transplantation.
doi:10.1007/s00198-010-1523-8
PMCID: PMC4139072  PMID: 21207011
Bone loss; Fracture; Organ transplantation; Osteoporosis; Vitamin D deficiency
25.  Clinician’s Guide to Prevention and Treatment of Osteoporosis 
Osteoporosis International  2014;25(10):2359-2381.
The Clinician’s Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteoporosis Foundation (NOF) in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF. Readers are urged to consult current prescribing information on any drug, device, or procedure discussed in this publication.
doi:10.1007/s00198-014-2794-2
PMCID: PMC4176573  PMID: 25182228
Diagnosis; Guide; Osteoporosis; Prevention; Treatment

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