Juvenile Paget's disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation

Juvenile Paget's disease (JPD) is a rare heritable osteopathy characterized biochemically by markedly increased serum alkaline phosphatase (ALP) activity emanating from generalized acceleration of skeletal turnover. Affected infants and children typically suffer bone pain and fractures and deformities, become deaf, and have macrocranium. Some who survive to young adult life develop blindness from retinopathy engendered by vascular microcalcification. Most cases of JPD are caused by osteoprotegerin (OPG) deficiency due to homozygous loss‐of‐function mutations within the TNFRSF11B gene that encodes OPG. We report a 3‐year‐old Iranian girl with JPD and craniosynostosis who had vitamin D deficiency in infancy. She presented with fractures during the first year‐of‐life followed by bone deformities, delayed development, failure‐to‐thrive, and pneumonias. At 1 year‐of‐age, biochemical studies of serum revealed marked hyperphosphatasemia together with low‐normal calcium and low inorganic phosphate and 25‐hydroxyvitamin D levels. Several family members in previous generations of this consanguineous kindred may also have had JPD and vitamin D deficiency. Mutation analysis showed homozygosity for a unique missense change (c.130T>C, p.Cys44Arg) in TNFRSF11B that would compromise the cysteine‐rich domain of OPG that binds receptor activator of NF‐κB ligand (RANKL). Both parents were heterozygous for this mutation. The patient's serum OPG level was extremely low and RANKL level markedly elevated. She responded well to rapid oral vitamin D repletion followed by pamidronate treatment given intravenously. Our patient is the first Iranian reported with JPD. Her novel mutation in TNFRSF11B plus vitamin D deficiency in infancy was associated with severe JPD uniquely complicated by craniosynostosis. Pamidronate treatment with vitamin D sufficiency can be effective therapy for the skeletal disease caused by the OPG deficiency form of JPD.     

Higher premenarcheal bone mass in elite gymnasts is maintained into young adulthood after long‐term retirement from sport: A 14‐year follow‐up

Sports that impact‐load the skeleton during childhood and adolescence increase determinants of bone strength such as bone mineral content and density; however, it is unclear if this benefit is maintained after retirement from the sport. The purpose of this study was to assess whether the previously reported higher bone mass in a group of premenarcheal gymnasts was still apparent 10 years after the cessation of participation and withdrawal of the gymnastics loading stimulus. In 1995, 30 gymnasts 8 to 15 years of age were measured and compared with 30 age‐matched nongymnasts. Twenty‐five former gymnasts and 22 nongymnasts were measured again 14 years later (2009 to 2010). Gymnasts had been retired from gymnastics training and competition for an average of 10 years. Total body (TB), lumbar spine (LS), and femoral neck (FN) bone mineral content (BMC) was assessed at both measurement occasions by dual‐energy X‐ray absorptiometry (DXA). Multivariate analysis of covariance (MANCOVA) was used to compare former gymnasts' and nongymnasts' BMC while controlling for differences in body size and maturation (covariates: age, height, weight, and years from menarche [1995] or age at menarche [2009 to 2010]). Premenarcheal gymnasts (measured in 1995) had significantly greater size‐adjusted TB, LS, and FN BMC (p < 0.05) (15%, 17%, and 12%, respectively) than nongymnasts. Ten years after retirement, gymnasts had maintained similar size‐adjusted TB, LS, and FN BMC differences (p < 0.05) (13%, 19%, and 13%, respectively) when compared with nongymnasts. Bone mass benefits in premenarcheal gymnasts were still apparent even after long‐term (10 years) removal of the gymnastics loading stimulus. © 2012 American Society for Bone and Mineral Research     

Central DXA utilization shifts from office-based to hospital-based settings among medicare beneficiaries in the wake of reimbursement changes

In the United States, Medicare gradually reduced payments for central dual-energy X-ray absorptiometry (DXA) performed at physician offices (or other nonhospital settings) from an average of $139 in 2006 to about $82 in 2007 and 2008 and $72 in 2009. Reimbursement for hospital outpatient DXA service was unchanged. We investigated the utilization of hip and spine (central) DXA in the Medicare population before and after the reduction. We identified individuals from the national 5% random sample of Medicare beneficiaries who were ≥65 years of age and enrolled in Medicare Parts A and B but not in a Medicare Advantage plan from 2002 through 2009. For each calendar year, we calculated the proportion of beneficiaries who submitted claims for DXA, the proportions of DXAs performed in hospitals and in physician offices and the number of physician office-based practices that discontinued or started to provide DXA services. From 2002 to 2006, the proportion of beneficiaries who had at least one central DXA increased from 7.9% to 9.6% at an annual increase of 0.4% and from 2006 to 2009, the annual increase dropped to 0.1%. The number of DXAs performed in physician offices dropped from 1,643,720 (69% of 2,363,500 total DXAs) in 2006 to 1,534,240 (66% of 2,338,240) in 2009. This decline was offset by an increase in the number of DXAs performed in hospitals, which increased from 719,780 (31%) in 2006 to 804,000 (34%) in 2009. Among physician office-based practices, more practices initiated than discontinued DXA service each year from 2002 to 2006. However, the trend was reversed since 2007 such that in 2009, 1876 practices discontinued and only 1394 initiated DXA service. The reduction in DXA reimbursement was associated with a decrease in the number of DXAs performed in physician offices and fewer physician offices that provided DXA services.     

Bone attenuation on routine chest CT correlates with bone mineral density on DXA in patients with COPD

Chronic obstructive pulmonary disease (COPD), although primarily a disease of the lungs, is associated with extrapulmonary effects such as muscle weakness and osteoporosis. Fractures owing to osteoporosis cause significant morbidity and mortality, particularly in patients with COPD. To prevent osteoporotic fractures, it is important to diagnose osteoporosis in an early stage and to start anti‐osteoporotic therapy in at‐risk patients. Because routine chest computed tomography (CT) is increasingly used to assess the extent of emphysema and airways disease in patients with COPD, we investigated whether simple attenuation measurement of the thoracic spine on routine chest CT may provide useful information on bone health in patients with COPD. Fifty‐eight patients with moderate to very severe COPD were included in our study. The average attenuation of thoracic vertebrae 4, 7, and 10 on chest CT was correlated with the lowest bone mineral density (BMD) of the hip and lumbar spine (L₁ to L₄) on dual‐energy X‐ray absorptiometry (DXA) in patients with COPD. The inter‐ and intra‐observer variabilities of the attenuation measurements were low as shown by Bland‐Altman plots. Pearson's correlation coefficient between the average attenuation of the three thoracic vertebrae and the lowest BMD of the hip and lumbar spine was high (r = 0.827, p < 0.001). A receiver‐operating characteristic (ROC) analysis of the area under the curve for osteoporosis was 0.969 (p < 0.001), corresponding to an attenuation threshold of 147 Hounsfield Units (HU). In conclusion, our data demonstrated that bone attenuation measured on routine chest CT correlated strongly with BMD assessed on DXA in patients with COPD. Routine chest CT may provide useful information on bone health in patients with COPD. © 2012 American Society for Bone and Mineral Research.     

Absolute fracture risk assessment using lumbar spine and femoral neck bone density measurements: Derivation and validation of a hybrid system

The World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) computes 10‐year probability of major osteoporotic fracture from multiple risk factors, including femoral neck (FN) T‐scores. Lumbar spine (LS) measurements are not currently part of the FRAX formulation but are used widely in clinical practice, and this creates confusion when there is spine‐hip discordance. Our objective was to develop a hybrid 10‐year absolute fracture risk assessment system in which nonvertebral (NV) fracture risk was assessed from the FN and clinical vertebral (V) fracture risk was assessed from the LS. We identified 37,032 women age 45 years and older undergoing baseline FN and LS dual‐energy X‐ray absorptiometry (DXA; 1990–2005) from a population database that contains all clinical DXA results for the Province of Manitoba, Canada. Results were linked to longitudinal health service records for physician billings and hospitalizations to identify nontrauma vertebral and nonvertebral fracture codes after bone mineral density (BMD) testing. The population was randomly divided into equal‐sized derivation and validation cohorts. Using the derivation cohort, three fracture risk prediction systems were created from Cox proportional hazards models (adjusted for age and multiple FRAX risk factors): FN to predict combined all fractures, FN to predict nonvertebral fractures, and LS to predict vertebral (without nonvertebral) fractures. The hybrid system was the sum of nonvertebral risk from the FN model and vertebral risk from the LS model. The FN and hybrid systems were both strongly predictive of overall fracture risk (p < .001). In the validation cohort, ROC analysis showed marginally better performance of the hybrid system versus the FN system for overall fracture prediction (p = .24) and significantly better performance for vertebral fracture prediction (p < .001). In a discordance subgroup with FN and LS T‐score differences greater than 1 SD, there was a significant improvement in overall fracture prediction with the hybrid method (p = .025). Risk reclassification under the hybrid system showed better alignment with observed fracture risk, with 6.4% of the women reclassified to a different risk category. In conclusion, a hybrid 10‐year absolute fracture risk assessment system based on combining FN and LS information is feasible. The improvement in fracture risk prediction is small but supports clinical interest in a system that integrates LS in fracture risk assessment. © 2011 American Society for Bone and Mineral Research.     

Effect of low‐dose calcium supplements on bone loss in perimenopausal and postmenopausal Asian women: A randomized controlled trial

Current standard‐dose calcium supplements (eg, 1000 mg/d) may increase the risk for cardiovascular events. Effectiveness of lower‐dose supplements in preventing bone loss should thus be considered. This study aimed to assess whether calcium supplements of 500 or 250 mg/d effectively prevent bone loss in perimenopausal and postmenopausal Japanese women. We recruited 450 Japanese women between 50 and 75 years of age. They were randomly assigned to receive 500 mg of calcium (as calcium carbonate), 250 mg of calcium, or placebo daily. Medical examinations conducted three times over a 2‐year follow‐up period assessed bone mineral density (BMD) of the lumbar spine and femoral neck. One‐factor repeated measures ANOVA was used for statistical tests. Subgroup analyses were also conducted. Average total daily calcium intake at baseline for the 418 subjects who underwent follow‐up examinations was 493 mg/d. Intention‐to‐treat analysis showed less dramatic decreases in spinal BMD for the 500‐mg/d calcium supplement group compared to the placebo group (1.2% difference over 2 years, p = 0.027). Per‐protocol analysis (≥80% compliance) revealed that spinal BMD for the 500‐mg/d and 250‐mg/d calcium supplement groups decreased less than the placebo group (1.6%, p = 0.010 and 1.0%, p = 0.078, respectively), and that femoral neck BMD for the 500‐mg/d calcium supplement group decreased less relative to the placebo group (1.0%, p = 0.077). A low‐dose calcium supplement of 500 mg/d can effectively slow lumbar spine bone loss in perimenopausal and postmenopausal women with habitually low calcium intake, but its effect on the femoral neck is less certain. Calcium supplementation dosage should thus be reassessed. (Clinical Trials Registry number: UMIN000001176). © 2012 American Society for Bone and Mineral Research.     

Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: A three‐year study

The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual‐energy X‐ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean ± SD) were similar between groups in terms of age, 76.8 ± 5.0 years; body mass index (BMI), 24.5 ± 3.6 kg/m²; TBS, 1.178 ± 0.1 but for LS T‐score (ZOL–2.9 ± 1.5 versus PLB–2.1 ± 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus–0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once‐yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years. © 2013 American Society for Bone and Mineral Research.     

Hip Fractures Risk in Older Men and Women Associated With DXA‐Derived Measures of Thigh Subcutaneous Fat Thickness,Cross‐Sectional Muscle Area,and Muscle Density

Mid‐thigh cross‐sectional muscle area (CSA), muscle attenuation, and greater trochanter soft tissue thickness have been shown to be independent risk factors of hip fracture. Our aim was to determine whether muscle and adipose tissue measures derived from dual‐energy X‐ray absorptiometry (DXA) scans would have a similar risk association as those measured using other imaging methods. Using a case‐cohort study design, we identified 169 incident hip fracture cases over an average of 13.5 years among participants from the Health ABC Study, a prospective study of 3075 individuals initially aged 70 to 79 years. We modeled the thigh 3D geometry and compared DXA and computed tomography (CT) measures. DXA‐derived thigh CSA, muscle attenuation, and subcutaneous fat thickness were found to be highly correlated to their CT counterparts (Pearson's r = 0.82, 0.45, and 0.91, respectively; p < 0.05). The fracture risk of men and women were calculated separately. We found that decreased subcutaneous fat, CT thigh muscle attenuation, and appendicular lean mass by height squared (ALM/Ht²) were associated with fracture risk in men; hazard ratios (HR) = 1.44 (1.02, 2.02), 1.40 (1.05, 1.85), and 0.58 (0.36, 0.91), respectively, after adjusting for age, race, clinical site, body mass index (BMI), chronic disease, hip bone mineral density (BMD), self‐reported health, alcohol use, smoking status, education, physical activity, and cognitive function. In a similar model for women, only decreases in subcutaneous fat and DXA CSA were associated with hip fracture risk; HR = 1.39 (1.07, 1.82) and 0.78 (0.62, 0.97), respectively. Men with a high ALM/Ht² and low subcutaneous fat thickness had greater than 8 times higher risk for hip fracture compared with those with low ALM/Ht² and high subcutaneous fat. In women, ALM/Ht² did not improve the model when subcutaneous fat was included. We conclude that the DXA‐derived subcutaneous fat thickness is a strong marker for hip fracture risk in both men and women, especially in men with high ALM/Ht². © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research     

Managing Osteoporosis in Patients on Long‐Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk‐benefit perspective. Two trials provided evidence for long‐term BP use. In the Fracture Intervention Trial Long‐term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T‐score, between –2 and –2.5 in FLEX and below –2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T‐score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high‐risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long‐term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid‐induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations. © 2015 American Society for Bone and Mineral Research.     

Long‐term cadmium exposure and the association with bone mineral density and fractures in a population‐based study among women

All people are exposed to cadmium (Cd) via food; smokers are additionally exposed. High Cd exposure is associated with severe bone damage, but the public health impact in relation to osteoporosis and fractures at low environmental exposure remains to be clarified. Within the population‐based Swedish Mammography Cohort, we assessed urinary Cd [U‐Cd, µg/g of creatinine (cr)] as a marker of lifetime exposure and bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA) among 2688 women. Register‐based information on fractures was retrieved from 1997 to 2009. Associations were evaluated by multivariable regression analyses. In linear regression, U‐Cd was inversely associated with BMD at the total body (p < .001), femoral neck (p = .025), total hip (p = .004), lumbar spine (p = .088), and volumetric femoral neck (p = .013). In comparison with women with U‐Cd < 0.50 µg/g of cr, those with U‐Cd ≥ 0.75 µg/g of cr had odds ratios (ORs) of 2.45 [95% confidence interval (CI) 1.51–3.97] and 1.97 (95% CI 1.24–3.14) for osteoporosis at the femoral neck and lumbar spine, respectively. Among never‐smokers, the corresponding ORs were 3.47 (95% CI 1.46–8.23) and 3.26 (95% CI 1.44–7.38). For any first fracture (n = 395), the OR was 1.16 (95% CI 0.89–1.50) comparing U‐Cd ≥ 0.50 µg/g of cr with lower levels. Among never‐smokers, the ORs (95% CIs) were 2.03 (1.33–3.09) for any first fracture, 2.06 (1.28–3.32) for first osteoporotic fracture, 2.18 (1.20–3.94) for first distal forearm fracture, and 1.89 (1.25–2.85) for multiple incident fractures. U‐Cd at low environmental exposure from food in a general population of women showed modest but significant association with both BMD and fractures, especially in never‐smokers, indicating a larger concern than previously known. © 2011 American Society for Bone and Mineral Research.     

Iron overload accelerates bone loss in healthy postmenopausal women and middle‐aged men: A 3‐year retrospective longitudinal study

Despite extensive experimental and animal evidence about the detrimental effects of iron and its overload on bone metabolism, there have been no clinical studies relating iron stores to bone loss, especially in nonpathologic conditions. In the present study, we performed a large longitudinal study to evaluate serum ferritin concentrations in relation to annualized changes in bone mineral density (BMD) in healthy Koreans. A total of 1729 subjects (940 postmenopausal women and 789 middle‐aged men) aged 40 years or older who had undergone comprehensive routine health examinations with an average 3 years of follow‐up were enrolled. BMD in proximal femur sites (ie, the total femur, femur neck, and trochanter) was measured with dual‐energy X‐ray absorptiometry using the same equipment at baseline and follow‐up. The mean age of women and men in this study was 55.8 ± 6.0 years and 55.5 ± 7.8 years, respectively, and serum ferritin levels were significantly higher in men than in women (p < 0.001). The overall mean annualized rates of bone loss in the total femur, femur neck, and trochanter were ?1.14%/year, ?1.17%/year, and ?1.51%/year, respectively, in women, and ?0.27%/year, ?0.34%/year, and ?0.41%/year, respectively, in men. After adjustment for potential confounders, the rates of bone loss in all proximal femur sites in both genders were significantly accelerated in a dose‐response fashion across increasing ferritin quartile categories (p for trend = 0.043 to <0.001). Consistently, compared with subjects in the lowest ferritin quartile category, those in the third and/or highest ferritin quartile category showed significantly faster bone loss in the total femur and femur neck in both genders (p = 0.023 to <0.001). In conclusion, these data provide the first clinical evidence that increased total body iron stores could be an independent risk factor for accelerated bone loss, even in healthy populations. © 2012 American Society for Bone and Mineral Research.     

A longitudinal HR‐pQCT study of alendronate treatment in postmenopausal women with low bone density: Relations among density,cortical and trabecular microarchitecture,biomechanics, and bone turnover

The goal of this study was to characterize longitudinal changes in bone microarchitecture and function in women treated with an established antifracture therapeutic. In this double‐blind, placebo‐controlled pilot study, 53 early postmenopausal women with low bone density (age = 56 ± 4 years; femoral neck T‐score = ?1.5 ± 0.6) were monitored by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) for 24 months following randomization to alendronate (ALN) or placebo (PBO) treatment groups. Subjects underwent annual HR‐pQCT imaging of the distal radius and tibia, dual‐energy X‐ray absorptiometry (DXA), and determination of biochemical markers of bone turnover (BSAP and uNTx). In addition to bone density and microarchitecture assessment, regional analysis, cortical porosity quantification, and micro‐finite‐element analysis were performed. After 24 months of treatment, at the distal tibia but not the radius, HR‐pQCT measures showed significant improvements over baseline in the ALN group, particularly densitometric measures in the cortical and trabecular compartments and endocortical geometry (cortical thickness and area, medullary area) (p < .05). Cortical volumetric bone mineral density (vBMD) in the tibia alone showed a significant difference between treatment groups after 24 months (p < .05); however, regionally, significant differences in Tb.vBMD, Tb.N, and Ct.Th were found for the lateral quadrant of the radius (p < .05). Spearman correlation analysis revealed that the biomechanical response to ALN in the radius and tibia was specifically associated with changes in trabecular microarchitecture (|ρ| = 0.51 to 0.80, p < .05), whereas PBO progression of bone loss was associated with a broad range of changes in density, geometry, and microarchitecture (|ρ| = 0.56 to 0.89, p < .05). Baseline cortical geometry and porosity measures best predicted ALN‐induced change in biomechanics at both sites (ρ > 0.48, p < .05). These findings suggest a more pronounced response to ALN in the tibia than in the radius, driven by trabecular and endocortical changes. © 2010 American Society for Bone and Mineral Research.     

A comparison of parathyroid hormone‐related protein (1‐36) and parathyroid hormone (1‐34) on markers of bone turnover and bone density in postmenopausal women: The PrOP study

Parathyroid hormone‐related protein (PTHrP)(1‐36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but it has not been directly compared with parathyroid hormone (PTH)(1‐34). We performed a 3‐month randomized, prospective study in 105 postmenopausal women with low bone density or osteoporosis, comparing daily subcutaneous injections of PTHrP(1‐36) to PTH(1‐34). Thirty‐five women were randomized to each of three groups: PTHrP(1‐36) 400 µg/day; PTHrP(1‐36) 600 µg/day; and PTH(1‐34) 20 µg/day. The primary outcome measures were changes in amino‐terminal telopeptides of procollagen 1 (PINP) and carboxy‐terminal telopeptides of collagen 1 (CTX). Secondary measures included safety parameters, 1,25(OH)₂ vitamin D, and BMD. The increase in bone resorption (CTX) by PTH(1‐34) (92%) (p < 0.005) was greater than for PTHrP(1‐36) (30%) (p < 0.05). PTH(1‐34) also increased bone formation (PINP) (171%) (p < 0.0005) more than either dose of PTHrP(1‐36) (46% and 87%). The increase in PINP was earlier (day 15) and greater than the increase in CTX for all three groups. LS BMD increased equivalently in each group (p < 0.05 for all). Total hip (TH) and femoral neck (FN) BMD increased equivalently in each group but were only significant for the two doses of PTHrP(1‐36) (p < 0.05) at the TH and for PTHrP(1‐36) 400 (p < 0.05) at the FN. PTHrP(1‐36) 400 induced mild, transient (day 15) hypercalcemia. PTHrP(1‐36) 600 required a dose reduction for hypercalcemia in three subjects. PTH(1‐34) was not associated with hypercalcemia. Each peptide induced a marked biphasic increase in 1,25(OH)₂D. Adverse events (AE) were similar among the three groups. This study demonstrates that PTHrP(1‐36) and PTH(1‐34) cause similar increases in LS BMD. PTHrP(1‐36) also increased hip BMD. PTH(1‐34) induced greater changes in bone turnover than PTHrP(1‐36). PTHrP(1‐36) was associated with mild transient hypercalcemia. Longer‐term studies using lower doses of PTHrP(1‐36) are needed to define both the optimal dose and full clinical benefits of PTHrP. © 2013 American Society for Bone and Mineral Research. © 2013 American Society for Bone and Mineral Research.     

Effect of alendronate and vitamin D3 on fractional calcium absorption in a double‐blind,randomized, placebo‐controlled trial in postmenopausal osteoporotic women

Menopause and increasing age are associated with a decrease in calcium absorption that can contribute to the pathogenesis of osteoporosis. We hypothesized that alendronate plus vitamin D₃ (ALN + D) would increase fractional calcium absorption (FCA). In this randomized, double‐blind, placebo‐controlled multicenter clinical trial, 56 postmenopausal women with 25‐hydroxyvitamin D [25(OH)D] concentrations of 25 ng/mL or less and low bone mineral density (BMD) received 5 weekly doses of placebo or alendronate 70 mg plus vitamin D₃ 2800 IU (ALN + D). Calcium intake was stabilized to approximately 1200 mg/d prior to randomization. FCA was determined using a dual‐tracer stable‐calcium isotope method. FCA and 25(OH)D were similar between treatment groups at baseline (0.31 ± 0.12 ng/mL and 19.8 ± 4.7 ng/mL, respectively). After 1 month of treatment, subjects randomized to ALN + D experienced a significant least squares (LS) mean [95% confidence interval (CI)] increase in FCA [0.070 (0.042, 0.098)], whereas FCA did not change significantly in the placebo group [?0.016 (?0.044, 0.012)]. After ALN + D treatment, patients had higher 25(OH)D levels (LS mean difference 7.3 ng/mL, p < .001). The rise in serum 1,25‐dihydroxyvitamin D₃ (p < .02) and parathyroid hormone (p < .001) were greater in the ALN + D group than in placebo‐treated patients. ALN + D was associated with an increase in FCA of 0.07. To our knowledge, there is no other trial showing such a marked rise in calcium absorption owing to treatment with a bisphosphonate or owing to a small rise in 25(OH)D. This unique response of ALN + D is important for the treatment of osteoporosis, but the exact mechanism requires further study. © 2011 American Society for Bone and Mineral Research     

The vitamin D analogue 2MD increases bone turnover but not BMD in postmenopausal women with osteopenia: Results of a 1‐year phase 2 double‐blind,placebo‐controlled,randomized clinical trial

Most osteoporosis drugs act by inhibiting bone resorption. A need exists for osteoporosis therapies that stimulate new bone formation. 2‐Methylene‐19‐nor‐(20S)‐1α,25‐dihydroxyvitamin D₃ (2MD) is a vitamin D analogue that potently stimulates bone formation activity in vitro and in the ovariectomized rat model. In this randomized, double‐blind, placebo‐controlled study of osteopenic women, the effect of daily oral treatment with 2MD on bone mineral density (BMD), serum markers of bone turnover, and safety were assessed over 1 year. Volunteers were randomly assigned to three treatment groups: placebo (n = 50), 220 ng of 2MD (n = 54), and 440 ng of 2MD (n = 53). In general, 2MD was well tolerated. Although 2MD caused a marked increase in markers of bone formation, it did not significantly increase BMD. Since 2MD also shows marked activity on bone resorption (as revealed by dose‐dependent increases in serum C‐telopeptide cross‐links of type I collagen in this study), 2MD likely stimulated both bone formation and bone resorption, thereby increasing bone remodeling. © 2011 American Society for Bone and Mineral Research.     

Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three‐year continued therapy and resolution of effect

The selective cathepsin K inhibitor odanacatib (ODN) progressively increased bone mineral density (BMD) and decreased bone‐resorption markers during 2 years of treatment in postmenopausal women with low BMD. A 1‐year extension study further assessed ODN efficacy and safety and the effects of discontinuing therapy. In the base study, postmenopausal women with BMD T‐scores between ?2.0 and ?3.5 at the lumbar spine or femur received placebo or ODN 3, 10, 25, or 50 mg weekly. After 2 years, patients (n = 189) were rerandomized to ODN 50 mg weekly or placebo for an additional year. Endpoints included BMD at the lumbar spine (primary), total hip, and hip subregions; levels of bone turnover markers; and safety assessments. Continued treatment with 50 mg of ODN for 3 years produced significant increases from baseline and from year 2 in BMD at the spine (7.9% and 2.3%) and total hip (5.8% and 2.4%). Urine cross‐linked N‐telopeptide of type I collagen (NTx) remained suppressed at year 3 (?50.5%), but bone‐specific alkaline phosphatase (BSAP) was relatively unchanged from baseline. Treatment discontinuation resulted in bone loss at all sites, but BMD remained at or above baseline. After ODN discontinuation at month 24, bone turnover markers increased transiently above baseline, but this increase largely resolved by month 36. There were similar overall adverse‐event rates in both treatment groups. It is concluded that 3 years of ODN treatment resulted in progressive increases in BMD and was generally well tolerated. Bone‐resorption markers remained suppressed, whereas bone‐formation markers returned to near baseline. ODN effects were reversible: bone resorption increased transiently and BMD decreased following treatment discontinuation. © 2011 American Society for Bone and Mineral Research.     

Cognitive decline is associated with an accelerated rate of bone loss and increased fracture risk in women: a prospective study from the Canadian Multicentre Osteoporosis Study

Cognitive decline and osteoporosis often coexist and some evidence suggests a causal link. However, there are no data on the longitudinal relationship between cognitive decline, bone loss and fracture risk, independent of aging. This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline (≥3 points) on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged ≥65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Association between cognitive decline and (i) bone loss was estimated using mixed-effects models; and (ii) fracture risk was estimated using adjusted Cox models. Over 95% of participants had normal cognition at baseline (MMSE ≥ 24). The annual % change in MMSE was similar for both genders (women −0.33, interquartile range [IQR] −0.70 to +0.00; and men −0.34, IQR: −0.99 to 0.01). After multivariable adjustment, cognitive decline was associated with bone loss in women (6.5%; 95% confidence interval [CI], 3.2% to 9.9% for each percent decline in MMSE from baseline) but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly (multivariable hazard ratio [HR], 1.61; 95% CI, 1.11 to 2.34). There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women. Further studies are needed to determine mechanisms that link these common conditions. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Relationship of changes in total hip bone mineral density to vertebral and nonvertebral fracture risk in women with postmenopausal osteoporosis treated with once-yearly zoledronic acid 5 mg: the HORIZON-Pivotal Fracture Trial (PFT)

Measurements of change in bone mineral density (BMD) are thought to be weak predictors of treatment effect on the reduction of fracture risk. In this study we report an alternative year-on-year approach for the estimation of treatment effect explained by BMD in which we examine the relationship between fracture risk and the most recent change in BMD. We studied 7736 postmenopausal women (ages 65 to 89 years) who were participants in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) and were randomized to either intravenous administration of zoledronic acid or placebo. The percentage of treatment effect explained by change in total hip BMD was estimated using the alternative year-on-year approach and the standard approach of looking at change over 3 years. We also studied a subset of 1132 women in whom procollagen type 1 amino-terminal propeptide (PINP) was measured at baseline and 12 months, to estimate the percentage of treatment effect explained by change in PINP. Regardless of the method used, the change in total hip BMD explained a large percentage of the effect of zoledronic acid in reducing new vertebral fracture risk (40%; 95% CI, 30% to 54%; for the 3-year analysis). The treatment effects for nonvertebral fracture were not statistically significant for the year-on-year analysis but 3-year change in BMD explained 61% (95% CI, 24% to 156%) of treatment effect. Change in PINP explained 58% (95% CI, 15% to 222%) of the effect of zoledronic acid in reducing new vertebral fracture risk. We conclude that our estimates of the percentage of treatment effect explained may be higher than in previous studies because of high compliance with zoledronic acid (due to its once-yearly intravenous administration). Previous studies may have underestimated the relationship between BMD change and the effect of treatment on fracture risk.     

Degree of biological apatite c‐axis orientation rather than bone mineral density controls mechanical function in bone regenerated using recombinant bone morphogenetic protein‐2

The aim of the present study was to assess the bone regeneration process in defects introduced into rabbit long bones, which were regenerated with controlled release of recombinant bone morphogenetic protein‐2 (rBMP‐2). The orientation of the biological apatite (BAp) c‐axis and bone mineral density (BMD) were compared as predictors of bone mechanical function. A 20‐mm‐long defect was introduced in rabbit ulnas, and 17 µg of rBMP‐2 was controlled‐released into the defect using a biodegradable gelatin hydrogel as the carrier. In the bone regeneration process, two characteristic phases may have been governed by different factors. First, new bone formation actively occurred, filling the bone defect with newly formed bone tissue and increasing the BMD. This process was regulated by the strong osteoinductive capacity of rBMP‐2. Second, after filling of the defect and moderate BMD restoration, preferential BAp c‐axis orientation began to increase, coincident with initiation of remodeling. In addition, the BAp c‐axis orientation, rather than BMD, was strongly correlated with Young's modulus, an important index of bone mechanical function, particularly in the later stage of bone regeneration. Thus, preferential BAp c‐axis orientation is a strong determinant and predictor of the mechanical function of tissue‐engineered bone. Therefore, analysis of BAp preferential c‐axis orientation in addition to measurement of BMD is crucial in assessment of bone mechanical function. © 2013 American Society for Bone and Mineral Research © 2013 American Society for Bone and Mineral Research     

Trabecular and cortical bone density and architecture in women after 60 days of bed rest using high‐resolution pQCT: WISE 2005

Prolonged bed rest is used to simulate the effects of spaceflight and causes disuse‐related loss of bone. While bone density changes during bed rest have been described, there are no data on changes in bone microstructure. Twenty‐four healthy women aged 25 to 40 years participated in 60 days of strict 6‐degree head‐down tilt bed rest (WISE 2005). Subjects were assigned to either a control group (CON, n = 8), which performed no countermeasures; an exercise group (EXE, n = 8), which undertook a combination of resistive and endurance training; or a nutrition group (NUT, n = 8), which received a high‐protein diet. Density and structural parameters of the distal tibia and radius were measured at baseline, during, and up to 1 year after bed rest by high‐resolution peripheral quantitative computed tomography (HR‐pQCT). Bed rest was associated with reductions in all distal tibial density parameters (p < 0.001), whereas only distal radius trabecular density decreased. Trabecular separation increased at both the distal tibia and distal radius (p < 0.001), but these effects were first significant after bed rest. Reduction in trabecular number was similar in magnitude at the distal radius (p = 0.021) and distal tibia (p < 0.001). Cortical thickness decreased at the distal tibia only (p < 0.001). There were no significant effects on bone structure or density of the countermeasures (p ≥ 0.057). As measured with HR‐pQCT, it is concluded that deterioration in bone microstructure and density occur in women during and after prolonged bed rest. The exercise and nutrition countermeasures were ineffective in preventing these changes. © 2011 American Society for Bone and Mineral Research