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Our purpose was to assess muscular adaptations during 6 weeks of resistance training in 36 males randomly assigned to supplementation with whey protein (W; 1.2 g/kg/day), whey protein and creatine monohydrate (WC; 0.1 g/kg/day), or placebo (P; 1.2 g/kg/day maltodextrin). Measures included lean tissue mass by dual energy x-ray absorptiometry, bench press and squat strength (1-repetition maximum), and knee extension/flexion peak torque. Lean tissue mass increased to a greater extent with training in WC compared to the other groups, and in the W compared to the P group (p <.05). Bench press strength increased to a greater extent for WC compared to W and P (p <.05). Knee extension peak torque increased with training for WC and W (p <.05), but not for P. All other measures increased to a similar extent across groups. Continued training without supplementation for an additional 6 weeks resulted in maintenance of strength and lean tissue mass in all groups. Males that supplemented with whey protein while resistance training demonstrated greater improvement in knee extension peak torque and lean tissue mass than males engaged in training alone. Males that supplemented with a combination of whey protein and creatine had greater increases in lean tissue mass and bench press than those who supplemented with only whey protein or placebo. However, not all strength measures were improved with supplementation, since subjects who supplemented with creatine and/or whey protein had similar increases in squat strength and knee flexion peak torque compared to subjects who received placebo. [ABSTRACT FROM AUTHOR]

BACKGROUND: Osteoporosis and fragility fractures in men account for substantial health care expenditures and decreased quality of life. OBJECTIVE: This article reviews the most current information about the epidemiology, diagnosis, prevention, and treatment of osteoporosis in men. METHODS: Relevant literature was identified through a search of MEDLINE (1966-June 2003) limited to English-language studies in men. The search terms included fractures, bone density, or osteoporosis plus either epidemiology, diagnosis, prevention, control, or therapy. Additional search terms included specific subtopics (eg, bisphosphonates, calcium, exercise, parathyroid hormone). The authors contributed additional relevant publications. RESULTS: Morbidity after fragility fracture is at least as high in men as in women, and the rate of fracture-related mortality 1 year hip fracture is approximately double in men compared with women. The bioavailable fraction of testosterone slowly declines into the ninth decade in men. There is evidence that the effect of estrogen on bone is greater than that of testosterone in men. Diagnosing osteoporosis in men is complicated by a lack of consensus on how it should be defined. Significant risk factors for osteoporosis or fracture include low bone mineral density, previous fragility fracture, maternal history of fracture, marked hypogonadism, smoking, heavy alcohol intake or alcoholism, low calcium intake, low body mass or body mass index, low physical activity, use of bone-resorbing medication such as glucocorticoids, and the presence of such conditions as hyperthyroidism, hyperparathyroidism, and hypercalciuria. Prevention is paramount and should begin in childhood. During adulthood, calcium (1000-1500 mg/d), vitamin D (400-800 IU/d), and adequate physical activity play crucial preventive roles. When treatment is indicated, the bisphosphonates are the first choice, whereas there is less support for the use of calcitonin or androgen therapy. Parathyroid hormone (1-34) is a promising anabolic therapy. There is also strong evidence for the use of bisphosphonates for the treatment of glucocorticoid-induced osteoporosis. [ABSTRACT FROM AUTHOR]

The design of digital health information systems around a conflated gender/sex binary contributes to health inequities. Lack of specific information that supports affirming communication lead to inappropriate care, disrespectful encounters with healthcare staff, and avoidance of health services by clients who have been harmed by misgendering, deadnaming and being outed. The HL7 International Gender Harmony Model (HL7 GHM) supports the design, implementation and use of DHIS that enable affirming clinical interactions and care. This case study will demonstrate how applying the HL7 GHM can address the harms reported in a recently published account of one patient in Canada.

Sedentary behavior (SB) or sitting is associated with multiple unfavorable health outcomes. Bone tissue responds to imposed gravitational and muscular strain with there being some evidence suggesting a causal link between SB and poor bone health. However, there are no population-based data on the longitudinal relationship between SB, bone change, and incidence of fragility fractures. This study aimed to examine the associations of sitting/SB (defined as daily sitting time), areal BMD (by DXA), and incident low trauma (fragility) osteoporotic fractures (excluding hands, feet, face, and head). We measured baseline (1995-7) and 10-yr self-reported SB, femoral neck (FN), total hip (TH), and lumbar spine (L1-L4) BMD in 5708 women and 2564 men aged 25 to 80+ yr from the population-based, nationwide, 9-center Canadian Multicentre Osteoporosis Study. Incident 10-yr fragility fracture data were obtained from 4624 participants; >80% of fractures were objectively confirmed by medical records or radiology reports. Vertebral fractures were confirmed by qualitative morphological methods. All analyses were stratified by sex. Multivariable regression models assessed SB-BMD relationships; Cox proportional models were fit for fracture risk. Models were adjusted for age, height, BMI, physical activity, and sex-specific covariates. Women in third/fourth quartiles had lower adjusted FN BMD versus women with the least SB (first quartile); women in the SB third quartile had lower adjusted TH BMD. Men in the SB third quartile had lower adjusted FN BMD than those in SB first quartile. Neither baseline nor stable 10-yr SB was related to BMD change nor to incident fragility fractures. Increased sitting (SB) in this large, population-based cohort was associated with lower baseline FN BMD. Stable SB was not associated with 10-yr BMD loss nor increased fragility fracture. In conclusion, habitual adult SB was not associated with subsequent loss of BMD nor increased risk of fracture., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Bispecific antibodies (bsAb) and multispecific antibodies (msAb) encompass a diverse variety of formats that can concurrently bind multiple epitopes, unlocking mechanisms to address previously difficult-to-treat or incurable diseases. Early assessment of candidate developability enables demotion of antibodies with low potential and promotion of the most promising candidates for further development. Protein-based therapies have a stringent set of developability requirements in order to be competitive (e.g. high-concentration formulation, and long half-life) and their assessment requires a robust toolkit of methods, few of which are validated for interrogating bsAbs/msAbs. Important considerations when assessing the developability of bsAbs/msAbs include their molecular format, likelihood for immunogenicity, specificity, stability, and potential for high-volume production. Here, we summarize the critical aspects of developability assessment, and provide guidance on how to develop a comprehensive plan tailored to a given bsAb/msAb.

Introduction: Five-year changes in multisite quantitative ultrasound-assessed speed of sound (SOS in m/s) were studied in a cohort of women and men. The impacts of antiresorptive therapies and menopausal status on SOS were also assessed., Methodology: Two SOS assessments, clinical assessments, and comprehensive questionnaires were completed 5 years apart on 509 women and 211 men. Age at first assessment was grouped into: <40 yr, 40-49 yr, 50-59 yr, 60-69 yr, 70-79 yr and 80+ yr. Mean rate of change in SOS at the distal radius and tibia were calculated for each age grouping by sex. SOS changes were stratified by antiresorptive use (yes, no) or menopausal status (premenopausal, postmenopausal, or bilateral oophorectomy)., Results: Mean losses in SOS occurred over the 5 years in almost all age groupings. In women, mean losses in SOS for the <40 yr, 40-49 yr, 50-59 yr, 60-69 yr, 70-79 yr, and 80+ yr age groupings were -59, -83, -107, -92, -80 and -66 (p = 0.30; differences among age groupings) at the radius and -18, -16, -54, -1, -9 and 31 at the tibia (p < 0.05), respectively. In men, mean SOS losses were -101, -56, -69, -67, -83 and -127 at the radius (p = 0.61) and -46, -61, 0, -35, -29, and -26 at the tibia (p = 0.23). At the tibia, women prescribed antiresorptives had a mean increase in SOS (8.6 m/s) whereas untreated participants had a mean loss (-23.0; p < 0.001); there was no significant impact at the distal radius. There were no significant differences in change in SOS among menopausal groups (p > 0.26)., Conclusions: Mean SOS generally declined over 5 years in all age groupings of both sexes. The consistent mean losses in SOS over the age spans investigated are coincident with increasing fracture risk. Women on antiresorptive therapy had increased mean SOS over the 5-year assessment period at the tibia, whereas untreated women had mean losses in SOS., (Copyright © 2019 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

We examined the underlying relationship between fracture risk factors and their imminent risk. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher imminent fracture risk. Past year falls indirectly predicted imminent risk through physical functioning and general health., Introduction: This study aimed to examine direct and indirect effects of several factors on imminent (1 year) fracture risk., Methods: Data from women age 65 and older from population-based Canadian Multicentre Osteoporosis Study were used. Predictors were identified from study years 5 and 10, and imminent fracture data (1-year fracture) came from years 6 and 11 (year 5 predicts year 6, year 10 predicts year 11). A structural equation model (SEM) was used to test the theoretical construct. General health and physical functioning were measured as latent variables using items from the 36-Item Short Form Health Survey (SF-36) and bone mineral density (BMD) T-score was a latent variable based on observed site-specific BMD data (spine L1-L4, femoral neck, total hip). Observed variables were fractures and falls. Model fit was evaluated using root mean square error of approximation (RMSEA), Tucker Lewis index (TLI), and comparative fit index (CFI)., Results: The analysis included 3298 women. Model fit tests showed that the SEM fit the data well; χ 2 (172) = 1122.10 < .001, RMSEA = .03, TLI = .99, CFI = .99. Results suggested that having past year fracture, worse past year general health, worse past year physical functioning, and lower past year BMD T-score directly predicted higher risk of fracture in the subsequent year (p < .001). Past year falls had a statistically significant but indirect effect on imminent fracture risk through physical functioning and general health (p < .001)., Conclusions: We found several direct and indirect pathways that predicted imminent fracture risk in elderly women. Future studies should extend this work by developing risk scoring methods and defining imminent risk thresholds.

It is recognized that the trabecular bone score (TBS) provides skeletal information, and frailty measurement is significantly associated with increased risks of adverse health outcomes. Given the suboptimal predictive power in fracture risk assessment tools, we aimed to evaluate the combination of frailty and TBS regarding predictive accuracy for risk of major osteoporotic fracture (MOF). Data from the prospective longitudinal study of CaMos (Canadian Multicentre Osteoporosis Study) were used for this study. TBS values were estimated using lumbar spine (L 1 to L 4 ) dual-energy X-ray absorptiometry (DXA) images; frailty was evaluated by a frailty index (FI) of deficit accumulation. Outcome was time to first incident MOF during the follow-up. We used the Harrell's C-index to compare the model predictive accuracy. The Akaike information criterion, likelihood ratio test, and net reclassification improvement (NRI) were used to compare model performances between the model combining frailty and TBS (subsequently called "FI + TBS"), FI-alone, and TBS-alone models. We included 2730 participants (mean age 69 years; 70% women) for analyses (mean follow-up 7.5 years). There were 243 (8.90%) MOFs observed during follow-up. Participants with MOF had significantly higher FI (0.24 versus 0.20) and lower TBS (1.231 versus 1.285) than those without MOF. FI and TBS were significantly related with MOF risk in the model adjusted for FRAX with bone mineral density (BMD) and other covariates: hazard ratio (HR) = 1.26 (95% confidence interval [CI] 1.11-1.43) for per-SD increase in FI; HR = 1.38 (95% CI 1.21-1.59) for per-SD decrease in TBS; and these associations showed negligible attenuation (HR = 1.24 for per-SD increase in FI, and 1.35 for per-SD decrease in TBS) when combined in the same model. Although the model FI + TBS was a better fit to the data than FI-alone and TBS-alone, only minimal and nonsignificant enhancement of discrimination and NRI were observed in FI + TBS. To conclude, frailty and TBS are significantly and independently related to MOF risk. Larger studies are warranted to determine whether combining frailty and TBS can yield improved predictive accuracy for MOF risk. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)

Patients often start treatment to reduce fracture risk because of a bone mineral density T-score consistent with osteoporosis (≤ -2.5). Others with a T-score above -2.5 may be treated when there is a history of fragility fracture or when a fracture risk algorithm categorizes them as having a high risk for fracture. It is common to initiate therapy with a generic oral bisphosphonate, unless contraindicated, and continue therapy if the patient is responding as assessed by stability or an increase in bone mineral density. However, some patients may respond well to an oral bisphosphonate, yet remain with an unacceptably high risk for fracture. Recognition of this occurrence has led to the development of an alternative strategy: treat-to-target. This involves identifying a biological marker (treatment target) that represents an acceptable fracture risk and then initiating treatment with an agent likely to reach this target. If the patient is on a path to reaching the target with initial therapy, treatment is continued. If it appears the target will not be reached with initial therapy, treatment is changed to an agent more likely to achieve the goal., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Using data from the Canadian Multicentre Osteoporosis Study, several risk factors predictive of imminent (2-year) risk of low-trauma non-vertebral fracture among high-risk women were identified, including history of falls, history of low-trauma fracture, poorer physical function, and lower T score. Careful consideration should be given to targeting this population for therapy., Purpose: Fracture risk assessment has focused on a long-term horizon and populations with a broad risk range. For elderly women with osteoporosis or low bone mass, or a history of fragility fractures ("high-risk women"), risk prediction over a shorter horizon may have greater clinical relevance., Methods: A repeated-observations design and data from the Canadian Multicentre Osteoporosis Study were employed. Study population comprised women aged ≥ 65 years with T score (total hip, femoral neck, spine) ≤ - 1.0 or prior fracture. Hazard ratios (HR) for predictors of low-trauma non-vertebral fracture during 2-year follow-up were estimated using multivariable shared frailty model., Results: The study population included 3228 women who contributed 5004 observations; 4.8% experienced low-trauma non-vertebral fracture during the 2-year follow-up. In bivariate analyses, important risk factors included age, back pain, history of falls, history of low-trauma fracture, physical function, health status, and total hip T score. In multivariable analyses, only four independent predictors were identified: falls in past 12 months (≥ 2 falls: HR = 1.9; 1 fall: HR = 1.5), low-trauma fracture in past 12 months (≥ 1 fracture: HR = 1.7), SF-36 physical component summary score (≤ 42.0: HR = 1.6), and total hip T score (≤ - 3.5: HR = 3.7; > - 3.5 to ≤ - 2.5: HR = 2.5; > - 2.5 to ≤ - 1: HR = 1.3)., Conclusions: Imminent risk of low-trauma non-vertebral fracture is elevated among high-risk women with a history of falls or low-trauma fracture, poorer physical function, and lower T score. Careful consideration should be given to identifying and targeting this population for therapy.

Parity and lactation showed no associations with incident clinical fragility fractures or radiographic vertebral compression fractures in the 16-year CaMos prospective study. Parity was associated with slightly greater decline in femoral neck but not hip or spine areal bone mineral density (aBMD), while lactation showed no associations with aBMD change., Purpose: Pregnancy and especially lactation cause loss of bone mass and microarchitectural changes, which temporarily increase fracture risk. After weaning, aBMD increases but skeletal microarchitecture may be incompletely restored. Most retrospective clinical studies found neutral or even protective associations of parity and lactation with fragility fractures, but prospective data are sparse. CaMos is a randomly selected observational cohort that includes ~ 6500 women followed prospectively for over 16 years., Methods: We determined whether parity or lactation were related to incident clinical fragility fractures over 16 years, radiographic (morphometric and morphologic) vertebral fractures over 10 years, and aBMD change (spine, total hip, and femoral neck) over 10 years. Parity and lactation duration were analyzed as continuous variables in predicting these outcomes using univariate and multivariate regression analyses., Results: Three thousand four hundred thirty-seven women completed 16 years of follow-up for incident clinical fractures, 3839 completed 10 years of morphometric vertebral fracture assessment, 3788 completed 10 years of morphologic vertebral fracture assessment, and 4464 completed 10 years of follow-up for change in aBMD. In the multivariate analyses, parity and lactation duration showed no associations with clinical fragility fractures, radiographic vertebral fractures, or change in aBMD, except that parity associated with a probable chance finding of a slightly greater decline in femoral neck aBMD., Conclusions: Parity and lactation have no adverse associations with clinical fragility or radiographic vertebral fractures, or the rate of BMD decline over 10 years, in this prospective, multicenter study of a randomly selected, population-based cohort of women.

Objective: We aimed to explore whether frailty was associated with fracture risk and whether frailty could modify the propensity of type 2 diabetes toward increased risk of fractures., Research Design and Methods: Data were from a prospective cohort study. Our primary outcome was time to the first incident clinical fragility fracture; secondary outcomes included time to hip fracture and to clinical spine fracture. Frailty status was measured by a Frailty Index (FI) of deficit accumulation. The Cox model incorporating an interaction term (frailty × diabetes) was used for analyses., Results: The analysis included 3,149 (70% women) participants; 138 (60% women) had diabetes. Higher bone mineral density and FI were observed in participants with diabetes compared with control subjects. A significant relationship between the FI and the risk of incident fragility fractures was found, with a hazard ratio (HR) of 1.02 (95% CI 1.01-1.03) and 1.19 (95% CI 1.10-1.33) for per-0.01 and per-0.10 FI increase, respectively. The interaction was also statistically significant ( P = 0.018). The HR for per-0.1 increase in the FI was 1.33 for participants with diabetes and 1.19 for those without diabetes if combining the estimate for the FI itself with the estimate from the interaction term. No evidence of interaction between frailty and diabetes was found for risk of hip and clinical spine fractures., Conclusions: Participants with type 2 diabetes were significantly frailer than individuals without diabetes. Frailty increases the risk of fragility fracture and enhances the effect of diabetes on fragility fractures. Particular attention should be paid to diabetes as a risk factor for fragility fractures in those who are frail., (© 2019 by the American Diabetes Association.)

Amenorrhea is important for women's bone health. However, few have reported reproductive, anthropometric (body mass index [BMI], height) and bone health (areal bone mineral density [BMD], prevalent fractures) in a population-based study. The purposes of this cross-sectional study of women in the randomly-selected Canadian Multicentre Osteoporosis Study (CaM os ) population were: (1) to describe reproductive, demographic, anthropometric and lifestyle variables; and (2) in menstruating women, to relate reproductive and other variables to BMD at the lumbar spine (L1-4, LS), femoral neck (FN) and total hip (TH) sites and to prevalent fragility fractures. This study describes the reproductive characteristics of 1532 women aged 30⁻60 years. BMD relationships with reproductive and other variables were described in the 499 menstruating women. Mean menarche age was 12.8 years, 96% of women were parous and 95% had used combined hormonal contraceptives (CHC). Infertility was reported by 9%, androgen excess by 13%, amenorrhea by 8% and nulliparity by 4%. LS BMD was negatively associated with amenorrhea and androgen excess and positively related to current BMI and height. A later age at menarche negatively related to FN BMD. BMI and height were strongly related to BMD at all sites. Prevalent fragility fractures were significantly associated with quartiles of both LS and TH BMD.

We compared two methods for osteoporotic vertebral fracture (VF) assessment on lateral spine radiographs, the Genant semiquantitative (GSQ) technique and a modified algorithm-based qualitative (mABQ) approach. We evaluated 4465 women and 1771 men aged ≥50 years from the Canadian Multicentre Osteoporosis Study with available X-ray images at baseline. Observer agreement was lowest for grade 1 VFs determined by GSQ. Among physician readers, agreement was greater for VFs diagnosed by mABQ (ranging from 0.62 [95% confidence interval (CI) 0.00-1.00] to 0.88 [0.76-1.00]) than by GSQ (ranging from 0.38 [0.17-0.60] to 0.69 [0.54-0.85]). GSQ VF prevalence (16.4% [95% CI 15.4-17.4]) and incidence (10.2/1000 person-years [9.2; 11.2]) were higher than with the mABQ method (prevalence 6.7% [6.1-7.4] and incidence 6.3/1000 person-years [5.5-7.1]). Women had more prevalent and incident VFs relative to men as defined by mABQ but not as defined by GSQ. Prevalent GSQ VFs were predominantly found in the mid-thoracic spine, whereas prevalent mABQ and incident VFs by both methods co-localized to the junction of the thoracic and lumbar spine. Prevalent mABQ VFs compared with GSQ VFs were more highly associated with reduced adjusted L 1 to L 4 bone mineral density (BMD) (-0.065 g/cm 2 [-0.087 to -0.042]), femoral neck BMD (-0.051 g/cm 2 [-0.065 to -0.036]), and total hip BMD (-0.059 g/cm 2 [-0.076 to -0.041]). Prevalent mABQ VFs compared with prevalent GSQ were also more highly associated with incident VF by GSQ (odds ratio [OR] = 3.3 [2.2-5.0]), incident VF by mABQ (9.0 [5.3-15.3]), and incident non-vertebral major osteoporotic fractures (1.9 [1.2-3.0]). Grade 1 mABQ VFs, but not grade 1 GSQ VFs, were associated with incident non-vertebral major osteoporotic fractures (OR = 3.0 [1.4-6.5]). We conclude that defining VF by mABQ is preferred to the use of GSQ for clinical assessments. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Osteoporosis is a chronic disease that requires life-long strategies to reduce fracture risk. Few trials have investigated the balance of benefits and risk with long-term use of osteoporosis therapies, and fewer still have investigated the consequences of treatment discontinuation. The best available evidence suggests that up to 10 years of treatment with an oral bisphosphonate maintains the degree of fracture risk reduction observed in the 3-year registration trials. With denosumab, 10 years of therapy appears to provide fracture risk reduction similar to or better than that observed in the 3-year registration trial. Available data suggest an increasing but low risk of fractures with atypical features with increasing duration of bisphosphonate therapy. Published data linking duration of therapy to osteonecrosis of the jaw are lacking for bisphosphonates and denosumab. Other side effects associated with denosumab or bisphosphonates do not appear to be related to therapy duration. The antifracture benefits of long-term therapy with bisphosphonates and denosumab in appropriately selected patients outweigh the low risk of serious side effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Comparisons of population health status using self-report measures such as the SF-36 rest on the assumption that the measured items have a common interpretation across sub-groups. However, self-report measures may be sensitive to differential item functioning (DIF), which occurs when sub-groups with the same underlying health status have a different probability of item response. This study tested for DIF on the SF-36 physical functioning (PF) and mental health (MH) sub-scales in population-based data using latent variable mixture models (LVMMs)., Methods: Data were from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective national cohort study. LVMMs were applied to the ten PF and five MH SF-36 items. A standard two-parameter graded response model with one latent class was compared to multi-class LVMMs. Multivariable logistic regression models with pseudo-class random draws characterized the latent classes on demographic and health variables., Results: The CaMos cohort consisted of 9423 respondents. A three-class LVMM fit the PF sub-scale, with class proportions of 0.59, 0.24, and 0.17. For the MH sub-scale, a two-class model fit the data, with class proportions of 0.69 and 0.31. For PF items, the probabilities of reporting greater limitations were consistently higher in classes 2 and 3 than class 1. For MH items, respondents in class 2 reported more health problems than in class 1. Differences in item thresholds and factor loadings between one-class and multi-class models were observed for both sub-scales. Demographic and health variables were associated with class membership., Conclusions: This study revealed DIF in population-based SF-36 data; the results suggest that PF and MH sub-scale scores may not be comparable across sub-groups defined by demographic and health status variables, although effects were frequently small to moderate in size. Evaluation of DIF should be a routine step when analysing population-based self-report data to ensure valid comparisons amongst sub-groups.

Trabecular bone score (TBS) is a gray-level texture measure derived from lumbar spine dual-energy X-ray absorptiometry (DXA) images that predicts fractures independent of bone mineral density (BMD). Increased abdominal soft tissue in individuals with elevated body mass index (BMI) absorbs more X-rays during image acquisition for BMD measurement and must be accommodated by the TBS algorithm. We aimed to determine if the relationship between BMI and TBS varied between 2 major manufacturers' densitometers, because different densitometers accommodate soft tissues differently. We identified 1919 women and 811 men, participants of the Canadian Multicentre Osteoporosis Study, aged ≥40 yr with lumbar spine DXA scans acquired on GE Lunar (4 centers) or Hologic (3 centers) densitometers at year 10 of follow-up. TBS was calculated for L1-L4 (TBS iNsight® software, version 2.1). A significant negative correlation between TBS and BMI was observed when TBS measurements were performed on Hologic densitometers in men (Pearson r = -0.36, p <0.0001) and in women (Pearson r = -0.33, p <0.0001); significant correlations were not seen when TBS was measured on GE Lunar densitometers (Pearson r = 0.00 in men, Pearson r = -0.02 in women). Age-adjusted linear regression models confirmed significant interactions between BMI and densitometer manufacturer for both men and women (p < 0.0001). In contrast, comparable positive correlations were observed between BMD and BMI on both Hologic and GE Lunar densitometers in men and women. In conclusion, BMI significantly affects TBS values in men and women when measured on Hologic but not GE Lunar densitometers. This finding has implications for clinical and research applications of TBS, especially when TBS is measured sequentially on DXA densitometers from different manufacturers or when results from different machines are pooled for analysis., (Copyright © 2016. Published by Elsevier Inc.)

Objective: To determine whether sclerostin is associated with fasting glucose, insulin levels, insulin resistance or increased risk of incident type 2 diabetes., Background: Type 2 diabetic patients have a higher risk of fractures. Recent studies suggest sclerostin, a regulator of osteoblast activity, is associated with diabetes., Materials and Methods: Sclerostin levels were obtained from 1778 individuals with no history of type 2 diabetes participating in the population-based Canadian Multicentre Osteoporosis Study (CaMos) cohort. Participants were followed until diagnosis of type 2 diabetes, death or end of the study period (31 December 2013). The relationship of sclerostin with fasting glucose, insulin levels and homoeostatic model assessment-insulin resistance (HOMA-IR) was studied in linear regression models. Cox proportional hazards models were used to determine the association of sclerostin levels and the risk of incident type 2 diabetes during a mean 7·5 years of follow-up., Results: Fasting glucose, fasting insulin levels and HOMA-IR were weakly correlated with sclerostin levels (Spearman's correlation coefficient: 0·11, P < 0·05; -0·09, P < 0·05; and -0·07, P = 0·02, respectively). Multiple linear regression analyses confirmed a significant association between sclerostin and fasting insulin and HOMA-IR but no significant association with fasting glucose levels. Sclerostin levels were not found to be significantly associated with the risk of incident type 2 diabetes (HR: 1·30; 95% CI: 0·37-4·57)., Conclusions: We observed an association between sclerostin levels with fasting insulin levels and HOMA-IR, but there was no clear association with type 2 diabetes risk. Further studies are needed to understand the role of sclerostin in type 2 diabetes., (© 2017 John Wiley & Sons Ltd.)

Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence., (Copyright © 2017. Published by Elsevier Inc.)

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized., Competing Interests: AA Khan is on the advisory board for Amgen, Eli Lilly, and Merck; has research grants from NPS, Amgen, and Merck; and has received lecture fees from Amgen, Eli Lilly, Warner Chilcott, and Merck; D Hanley has received funding for grants from Amgen, Eli Lilly, Merck, and Novartis; has received funding for lectures from Amgen Eli Lilly and Novartis; and is on the membership board for Amgen, Eli Lilly, Merck, and Novartis; R Rizzoli received consultancy and lecture fees from Amgen, Eli Lilly, MSD, Danone, and Servier; L Rejnmark received consultancy and lecture fees from NPS Pharmaceuticals, Amgen, Eli Lilly, and Novo Nordic; RV Thakker is a chairman of Astra-Zeneca Stratified Medicine Panel and has received lecture and consultancy fees from Novartis, Eli Lilly, AstraZeneca, and Ipsen; S Kaiser has received consultancy fees from Amgen and Eli Lilly and has received lecture fees from Amgen, Eli Lilly, Merck, and NRS; L Mosekilde has received funds for the development of educational presentations; DS Rao is on the advisory board for Diasorin Inc., has received consultancy fees from NPS Pharmaceuticals, has received grants from NIAMS, and has received funding for lectures from Eli Lilly; M Lewiecki has received research grant support from Amgen, Merck, and Eli Lilly and has received consultancy fees from Amgen, Eli Lilly, Merck, Radius Health, AgNovos Healthcare, Theranova, and Alexion; R Eastell received grants, lecture fees, and travel expenses from Amgen, AstraZeneca, IDS, Eli Lilly, Merck, Novartis, Roche, Alexion, Otsuka, IBMS, and Warner Chilcott; KS Davison has received honorarium for lectures from Novartis, Merck, Amgen, and Eli Lilly; and ML Brandi has received consultancy fees and grant funding from Amgen, Eli Lilly, MSD, Novartis, Roche, and Servier. Funding This work was supported by the Calcium Disorders Clinic, McMaster University Hamilton, Ontario, Canada.

Unlabelled: Muscle density is a risk factor for fractures in older adults; however, its association with falls is not well described. After adjusting for biologically relevant confounding factors, a unit decrease in muscle density was associated with a 17 % increase in odds of reporting a fall, independent of functional mobility., Introduction: Falls are the leading cause of injury, disability, and fractures in older adults. Low muscle density (i.e., caused by muscle adiposity) and functional mobility have been identified as risk factors for incident disability and fractures in older adults; however, it is not known if these are also independently associated with falls. The purpose of this study was to explore the associations of muscle density and functional mobility with fall status., Methods: Cross-sectional observational study of 183 men and women aged 60-98 years. Descriptive data, including a 12-month fall recall, Timed Up and Go (TUG) test performance, lower leg muscle area, and density. Odds ratio (OR) of being a faller were calculated, adjusted for age, sex, body mass index, general health status, diabetes, and comorbidities., Results: Every mg/cm(3) increase in muscle density (mean 70.2, SD 2.6 mg/cm(3)) independently reduced the odds of being a faller by 19 % (OR 0.81 [95 % CI 0.67 to 0.97]), and every 1 s longer TUG test time (mean 9.8, SD 2.6 s) independently increased the odds by 17 % (OR 1.17 [95 % CI 1.01 to 1.37]). When both muscle density and TUG test time were included in the same model, only age (OR 0.93 [95 % CI 0.87 to 0.99]) and muscle density (OR 0.83 [95 % CI 0.69 to 0.99]) were independently associated with fall status., Conclusions: Muscle density was associated with fall status, independent of functional mobility. Muscle density may compliment functional mobility tests as a biometric outcome for assessing fall risk in well-functioning older adults.

Dual-energy X-ray absorptiometry (DXA) is an important tool for the estimate of fracture risk through the measurement of bone mineral density (BMD). Similarly, multisite quantitate ultrasound can prospectively predict future fracture through the measurement of speed of sound (SOS). This investigation compared BMD (at the femoral neck, total hip, and lumbar spine) and SOS measures (at the distal radius, tibia, and phalanx sites) in a large sample of randomly-selected and community-based individuals from the Canadian Multicentre Osteoporosis Study. Furthermore, mass, height, and age were also compared with both measures. There were 4123 patients included with an age range of 30-96.8 yr. Pearson product moment correlations between BMD and SOS measures were low (0.21-0.29; all p<0.001), irrespective of site. Mass was moderately correlated with BMD measures (0.40-0.58; p<0.001), but lowly correlated with SOS measures (0.03-0.13; p<0.05). BMD and SOS were negatively correlated to age (-0.17 to -0.44; p<0.001). When regression analyses were performed to predict SOS measures at the 3 sites, the models predicted 20%-23% of the variance, leaving 77%-80% unaccounted for. The SOS measures in this study were found to be largely independent from BMD measures. In areas with no or limited access to DXA, the multisite quantitative ultrasound may act as a valuable tool to assess fracture risk. In locales with liberal access to DXA, the addition of SOS to BMD and other clinical risk factors may improve the identification of those patients at high risk for future fracture., (Copyright © 2016 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

We hypothesized that diet would have direct effects on glucose metabolism with direct and indirect effects on bone metabolism in a cohort of Canadian adults. We assessed dietary patterns (Prudent [fruit, vegetables, whole grains, fish, and legumes] and Western [soft drinks, potato chips, French fries, meats, and desserts]) from a semiquantitative food frequency questionnaire. We used fasting blood samples to measure glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR), 25-hydroxyvitamin D (25OHD), parathyroid hormone, bone-specific alkaline phosphatase (a bone formation marker), and serum C-terminal telopeptide (CTX; a bone resorption marker). We used multivariate regression models adjusted for confounders and including/excluding body mass index. In a secondary analysis, we examined relationships through structural equations models. The Prudent diet was associated with favorable effects on glucose metabolism (lower insulin and HOMA-IR) and bone metabolism (lower CTX in women; higher 25OHD and lower parathyroid hormone in men). The Western diet was associated with deleterious effects on glucose metabolism (higher glucose, insulin, and HOMA-IR) and bone metabolism (higher bone-specific alkaline phosphatase and lower 25OHD in women; higher CTX in men). Body mass index adjustment moved point estimates toward the null, indicating partial mediation. The structural equation model confirmed the hypothesized linkage with strong effects of Prudent and Western diet on metabolic risk, and both direct and indirect effects of a Prudent diet on bone turnover. In summary, a Prudent diet was associated with lower metabolic risk with both primary and mediated effects on bone turnover, suggesting that it is a potential target for reducing fracture risk., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Self-reported health status measures, like the Short Form 36-item Health Survey (SF-36), can provide rich information about the overall health of a population and its components, such as physical, mental, and social health. However, differential item functioning (DIF), which arises when population sub-groups with the same underlying (i.e., latent) level of health have different measured item response probabilities, may compromise the comparability of these measures. The purpose of this study was to test for DIF on the SF-36 physical functioning (PF) and mental health (MH) sub-scale items in a Canadian population-based sample., Methods: Study data were from the prospective Canadian Multicentre Osteoporosis Study (CaMos), which collected baseline data in 1996-1997. DIF was tested using a multiple indicators multiple causes (MIMIC) method. Confirmatory factor analysis defined the latent variable measurement model for the item responses and latent variable regression with demographic and health status covariates (i.e., sex, age group, body weight, self-perceived general health) produced estimates of the magnitude of DIF effects., Results: The CaMos cohort consisted of 9423 respondents; 69.4% were female and 51.7% were less than 65 years. Eight of 10 items on the PF sub-scale and four of five items on the MH sub-scale exhibited DIF. Large DIF effects were observed on PF sub-scale items about vigorous and moderate activities, lifting and carrying groceries, walking one block, and bathing or dressing. On the MH sub-scale items, all DIF effects were small or moderate in size., Conclusions: SF-36 PF and MH sub-scale scores were not comparable across population sub-groups defined by demographic and health status variables due to the effects of DIF, although the magnitude of this bias was not large for most items. We recommend testing and adjusting for DIF to ensure comparability of the SF-36 in population-based investigations.

Vertebral fractures are common and can result in acute and chronic pain, decreases in quality of life, and diminished lifespan. The identification of vertebral fractures is important because they are robust predictors of future fractures. The majority of vertebral fractures do not come to clinical attention. Numerous modalities exist for visualizing suspected vertebral fracture. Although differing definitions of vertebral fracture may present challenges in comparing data between different investigations, at least 1 in 5 men and women aged >50 years have one or more vertebral fractures. There is clinical guidance to target spine imaging to individuals with a high probability of vertebral fracture. Radiology reports of vertebral fracture need to clearly state that the patient has a "fracture," with further pertinent details such as the number, recency, and severity of vertebral fracture, each of which is associated with risk of future fractures. Patients with vertebral fracture should be considered for antifracture therapy. Physical and pharmacologic modalities of pain control and exercises or physiotherapy to maintain spinal movement and strength are important components in the care of vertebral fracture patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Context: PTH is an essential regulator of mineral metabolism; PTH hypersecretion may result in hyperparathyroidism including normocalcaemic, primary and secondary hyperparathyroidism., Objective: To examine the characteristics of participants with hyperparathyroid states and the relationship to bone mineral density (BMD)., Design and Participants: A cross-sectional study of 1872 community-dwelling men and women aged 35+ years (mostly Caucasian) with available serum PTH from Year 10 Canadian Multicentre Osteoporosis Study follow-up (2005-07). PTH was determined using a second-generation chemiluminescence immunoassay., Outcome Measures: L1-L4, femoral neck and total hip BMD., Results: We established a PTH reference range (2·7-10·2 pmol/l) based on healthy participants (i.e. normal serum calcium, serum 25-hydroxyvitamin D, kidney function and body mass index, who were nonusers of antiresorptives, glucocorticoids and diuretics and not diagnosed with diabetes or thyroid disease). Participants with PTH levels in the upper reference range (5·6-10·2 pmol/l), representing a prevalence of 10·7%, had lower femoral neck and total hip BMD, by 0·030 g/cm(2) [95% confidence interval: 0·009; 0·051] and 0·025 g/cm(2) (0·001; 0·049), respectively, than those with levels 2·7-5·6 pmol/l. Participants with normocalcaemic and secondary hyperparathyroidism also had lower total hip BMD than those with levels 2·7-5·6 pmol/l, and CaMos prevalences of normocalcaemic, primary and secondary hyperparathyroidism were 3·3%, 1·4% and 5·2%, respectively., Conclusion: We found reduced BMD in participants with accepted hyperparathyroid states but also a notable proportion of other participants that might benefit from having lower PTH levels., (© 2014 John Wiley & Sons Ltd.)

This work provides a systematic review of the literature from January 2003 to April 2014 pertaining to the incidence, pathophysiology, diagnosis, and treatment of osteonecrosis of the jaw (ONJ), and offers recommendations for its management based on multidisciplinary international consensus. ONJ is associated with oncology-dose parenteral antiresorptive therapy of bisphosphonates (BP) and denosumab (Dmab). The incidence of ONJ is greatest in the oncology patient population (1% to 15%), where high doses of these medications are used at frequent intervals. In the osteoporosis patient population, the incidence of ONJ is estimated at 0.001% to 0.01%, marginally higher than the incidence in the general population (<0.001%). New insights into the pathophysiology of ONJ include antiresorptive effects of BPs and Dmab, effects of BPs on gamma delta T-cells and on monocyte and macrophage function, as well as the role of local bacterial infection, inflammation, and necrosis. Advances in imaging include the use of cone beam computerized tomography assessing cortical and cancellous architecture with lower radiation exposure, magnetic resonance imaging, bone scanning, and positron emission tomography, although plain films often suffice. Other risk factors for ONJ include glucocorticoid use, maxillary or mandibular bone surgery, poor oral hygiene, chronic inflammation, diabetes mellitus, ill-fitting dentures, as well as other drugs, including antiangiogenic agents. Prevention strategies for ONJ include elimination or stabilization of oral disease prior to initiation of antiresorptive agents, as well as maintenance of good oral hygiene. In those patients at high risk for the development of ONJ, including cancer patients receiving high-dose BP or Dmab therapy, consideration should be given to withholding antiresorptive therapy following extensive oral surgery until the surgical site heals with mature mucosal coverage. Management of ONJ is based on the stage of the disease, size of the lesions, and the presence of contributing drug therapy and comorbidity. Conservative therapy includes topical antibiotic oral rinses and systemic antibiotic therapy. Localized surgical debridement is indicated in advanced nonresponsive disease and has been successful. Early data have suggested enhanced osseous wound healing with teriparatide in those without contraindications for its use. Experimental therapy includes bone marrow stem cell intralesional transplantation, low-level laser therapy, local platelet-derived growth factor application, hyperbaric oxygen, and tissue grafting., (© 2014 American Society for Bone and Mineral Research.)

Multisite quantitative ultrasound (mQUS) machines are attractive tools for assessing fragility fracture risk as they are often portable, comparatively inexpensive, require little training for their use, and emit no ionizing radiation. The primary objective of this investigation was to generate an mQUS normative database of speed of sound (SOS, in m/s) measures from a large sample of randomly selected community-based individuals. mQUS (BeamMed Omnisense MultiSite Quantitative Ultrasound 7000 S) measurements were obtained and assessed at the distal radius, tibia, and phalanx. All analyses were made separately for men and women and for each anatomical site. Scatterplots (SOS vs age) identified 30-39 yr of age as periods of both maximal SOS and of relative stability for all 3 sites over the age span investigated (30-96 yr of age; 2948 women and 1176 men) and, thus, was used as the "reference" population. For cross-sectional comparison of trends over aging, a number of age groupings were created: 30-39, 40-49, 50-59, 60-69, 70-79, and 80+ yr. In general, there were decreases in SOS over increasing age groupings. The normative data generated can be used to compare a given patient's mQUS measurement with reference to a young, healthy population, assigning them a gender-appropriate T-score., (Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

The number needed to treat is a valuable metric to determine the benefit of therapy, but it must be viewed against the respective number needed to harm. Denosumab and teriparatide (TPTD) have proven antifracture efficacy at vertebral and nonvertebral sites, whereas raloxifene has proven antifracture efficacy at the spine only. Denosumab use has been associated with a small, yet statistically significant, increased incidence of eczema and serious cellulitis. Raloxifene use has been associated with statistically significant increases in the risk of venous thromboembolism and possibly deadly stroke, although not an increase in total strokes. No significant, nontransient adverse events have been reported with TPTD use. When used for the treatment of postmenopausal osteoporosis, denosumab, raloxifene, and TPTD all generally have favorable risk-to-benefit profiles, but therapy-specific contraindications necessitate thoughtful consideration of all available clinical information and individualization of treatment decisions., (Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Objective: To outline the efficacy and risks of bisphosphonate therapy for the management of osteoporosis and describe which patients might be eligible for bisphosphonate "drug holiday.", Quality of Evidence: MEDLINE (PubMed, through December 31, 2012) was used to identify relevant publications for inclusion. Most of the evidence cited is level II evidence (non-randomized, cohort, and other comparisons trials)., Main Message: The antifracture efficacy of approved first-line bisphosphonates has been proven in randomized controlled clinical trials. However, with more extensive and prolonged clinical use of bisphosphonates, associations have been reported between their administration and the occurrence of rare, but serious, adverse events. Osteonecrosis of the jaw and atypical subtrochanteric and diaphyseal femur fractures might be related to the use of bisphosphonates in osteoporosis, but they are exceedingly rare and they often occur with other comorbidities or concomitant medication use. Drug holidays should only be considered in low-risk patients and in select patients at moderate risk of fracture after 3 to 5 years of therapy., Conclusion: When bisphosphonates are prescribed to patients at high risk of fracture, their antifracture benefits considerably outweigh their potential for harm. For patients taking bisphosphonates for 3 to 5 years, reassess the need for ongoing therapy.

The diagnosis of osteoporosis in men is controversial, although most studies demonstrate similar fracture rates for men and women with the same level of hip bone mineral density (BMD). Whether this applies to the lumbar spine is currently uncertain and has important implications with respect to choice of reference population for T-score calculation and osteoporosis diagnosis. This question was specifically addressed in the population-based Canadian Multicentre Osteoporosis Study cohort of 4745 women and 1887 men ages 50+ yr at the time of baseline lumbar spine dual energy x-ray absorptiometry. In up to 10 yr of observation, incident clinical major osteoporotic fractures occurred in 110 men (5.8%) vs 543 women (11.4%) (p < 0.001). Mean lumbar spine BMD in men was greater than in women, both among those with and those without incident major osteoporotic fracture (p < 0.001). Men were at slightly lower risk for incident major osteoporotic fracture than women for an equivalent lumbar spine BMD (age- and BMD-adjusted rate ratio 0.75, 95% confidence interval 0.60-0.93, p = 0.008) with similar findings after adjustment for the World Health Organization fracture risk assessment clinical risk factors or competing mortality. No significant sex difference in the BMD relationship was seen for vertebral fractures (clinical or radiographic) or for all fractures. In summary, this large population-based longitudinal cohort study found similar or lower fracture risk for men vs women after adjustment for absolute lumbar spine BMD and additional covariates. The least complicated model for describing fracture risk is therefore to use the same reference lumbar spine data for generating T-scores in men and women., (Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

The objective of this study was to compare the disintegration times among Canadian-marketed brand (alendronate 70 mg, alendronate 70 mg plus vitamin D 5600 IU, and risedronate 35 mg) and generic (Novo-alendronate 70 mg and Apo-alendronate 70 mg) once-weekly dosed bisphosphonates. All disintegration tests were performed with a Vanderkamp Disintegration Tester. Disintegration was deemed to have occurred when no residue of the tablet, except fragments of insoluble coating or capsule shell, was visible. Eighteen to 20 samples were tested for each bisphosphonate group. The mean (±standard deviation) disintegration times were significantly (P < 0.05) faster for Apo-alendronate (26 ± 5.6 seconds) and Novo-alendronate (13 ± 1.1 seconds) as compared to brand alendronate (147 ± 50.5 seconds), brand alendronate plus vitamin D (378 ± 60.5 seconds), or brand risedronate (101 ± 20.6 seconds). The significantly faster disintegration of the generic tablets as compared to the brand bisphosphonates may have concerning safety and effectiveness implications for patients administering these therapies.

Genetic, environmental, or hormonal factors may cause heterogeneity in skeletal load response. Individuals with reduced sensitivity to load should require higher strains to generate an adaptive response, consequently have weaker bones and fracture more frequently. The purpose of our study was to determine if stresses (proportional to strains) at the femoral neck under equivalent loads were higher in women with a history of fractures compared with women without fractures. We studied postmenopausal women participating in the Canadian Multicentre Osteoporosis Study who had available hip structure analysis data from dual-energy X-ray absorptiometry scans (n = 2168). Women were categorized into 2 groups based on their number of self-reported fractures. We computed stress (megapascals) at the inferomedial margin of the femoral neck in a one-legged stance mode using a 2-dimensional engineering beam analysis. We used linear regression (SAS 9.3) to determine associations between stress, geometry parameters, and number of fractures. Postmenopausal women with 1 or more fractures had higher stress (2.6%), lower narrow neck bone mineral density (4.2%), cross-sectional area (3.9%), and section modulus (9.6%) than postmenopausal women without fractures (all p < 0.05). These findings provide evidence of heterogeneity in load response and suggest an important role for modeling in the pathogenesis of osteoporotic fracture., (Copyright © 2014 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Unlabelled: We determined the prospective 10-year association among incident fragility fractures and four glucocorticoid (GC) treatment groups (Never GC, Prior GC, Baseline GC, and Ever GC). Results showed that GC treatment is associated with increased 10-year incident fracture risk in ambulatory men and women across Canada., Purpose: Using the Canadian Multicentre Osteoporosis Study dataset, we determined the prospective 10-year association between incident fragility fractures and GC treatment., Methods: We conducted a 10-year prospective observational cohort study at nine sites across Canada. A total of 9,263 ambulatory men and women 25 years of age and older were included in the analysis. Multivariable Cox proportional hazards analyses were conducted to determine the relationship among GC treatment groups in four levels that included Never GC, Prior GC, Baseline GC, and Ever GC (combined baseline and prior groups) and time to fracture., Results: In each of the Never GC, Prior GC, Baseline GC, and Ever GC treatment groups, the number of participants were 8,832 (95.4 %), 303 (3.3 %), 128 (1.4 %), and 431 (4.7 %), respectively. Of the 9,263 individuals enrolled, incident fragility non-spine, hip, spine, and any fractures were experienced by a total of 896 (9.67 %), 157 (1.69 %), 130 (1.40 %), and 1,102 (11.90 %) over 10-years, respectively. For men and women combined, prior GC treatment was associated with a higher hazard ratio (HR) for time to incident non-vertebral (HR = 1.5, 95 % confidence interval [CI] = 1.1, 2.0), hip (HR = 2.1, 95 % CI = 1.1, 4.0), and any fracture (HR = 1.4, 95 % CI = 1.0, 1.8) compared with never GC treatment., Conclusions: GC treatment is associated with increased 10-year incident fracture risk; this highlights the importance of considering therapy to prevent GC-induced fractures for patients who are using GC for various medical conditions., Competing Interests: G. Ioannidis, S. Pallan, M. Mulgund, L. Rios, J. Ma, L. Thabane, K. S. Davison, C. S. Kovacs, N. Kreiger, J. C. Prior, and T. Towheed declare that they have no conflict of interest. A. Papaioannou: Speaker’s bureau: Amgen, Eli Lilly, Merck, Novartis, Procter & Gamble, Sanofi Aventis, Warner Chilcott. Research grants: Amgen, Eli Lilly, Merck, Novartis, Procter & Gamble, Sanofi Aventis, Warner Chilcott. Consulting fees or other remuneration (payment): Amgen, Eli Lilly, Merck, Novartis, Procter & Gamble, Roche, Sanofi Aventis, Warner Chilcott, Wyeth. R. G. Josse: Advisory board member: Amgen, Lilly, Merck, Novartis, BMS/AZ, Janssen. Speaker honoraria: Amgen, Lilly, Merck, Novartis, BMS/AZ, Janssen. Research grants: Amgen, Janssen, BMS/AZ. W. P. Olszynski: Consultant or on a speaker’s bureau for Amgen, Eli Lilly, Merck Frosst Canada, Novartis, Pfizer, Procter & Gamble Pharmaceuticals and sanofi-aventis. J. D. Adachi: Speaker’s bureau: Amgen, Eli Lilly, Merck, Novartis, Procter & Gamble, Roche, Sanofi Aventis, Warner Chilcott. Research grants: Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi Aventis, Warner Chilcott, Wyeth. Consulting fees or other remuneration (payment): Amgen, Eli Lilly, GSK, Merck, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi Aventis, Warner Chilcott, Wyeth.

Objectives: Our objective was to study changes in calcium and vitamin D intakes over time, and their cross-sectional and longitudinal associations with bone mineral density (BMD)., Methods: We followed 9382 women and men aged ≥25 and 899 aged 16-24, for 10 and 2 years respectively., Results: Calcium and vitamin D intakes increased over time in adults, but decreased in women aged 16-18. The increased intakes in adults were largely attributable to the increased use of calcium and/or vitamin D supplements. Both the percentage of supplement users and average dose among users increased over time. There was nevertheless a high prevalence of calcium and vitamin D intake below the estimated average requirement. At baseline, higher calcium and vitamin D intakes were associated with higher total hip and femoral neck BMD in young men, and cumulatively high levels of calcium and vitamin D intakes over time contributed to better BMD maintenance at lumbar spine and hip sites in adult women., Conclusions: Although total intakes, particularly of vitamin D, frequently fell below the Institute of Medicine recommendations despite an increase over time in supplement use, we found some positive associations between total calcium and vitamin D intake and bone health., Competing Interests: D. Goltzman has consulted for: Amgen, Lilly, Merck and Novartis, and/or received some financial support for meetings or research projects from them. C.S. Kovacs was consultant for or received financial support for meetings or grants from Amgen, Danone, Eli Lilly, Merck and Novartis; and S.I. Barr, from Dairy Farmers of Canada. The other authors have no disclosures or conflict of interests.

Objective: Compare in vitro and in vivo characteristics and clinical outcomes of brand and generic alendronate., Research Design and Methods: Relevant search terms were input into Medline ("alendronate" AND "generic" up to August 5, 2013) and any abstracts deemed possibly relevant selected for full paper review and abstraction., Results: Multicentre, randomized, placebo-controlled Phase III clinical trials of substantial size and duration have established the anti-fracture efficacy and safety of brand amino-bisphosphonates. For regulatory approval, generic versions of brand drugs need to demonstrate bioequivalence in young, healthy volunteers and have similar dissolution times. While the potency and amount of active drug within generic formulations must be identical to the brand, differences are permitted in the excipients. Significant differences in tablet disintegration time among different versions of generic and brand alendronate have been reported. Rapidly disintegrating alendronate pills may increase oesophageal bioadhesion and adverse event risk. Oesophageal-bound alendronate or slow disintegrating alendronate tablets may be made inert and ineffective by subsequently ingested food or drink. Investigations have reported a lower persistence to therapy with generic brands of alendronate as compared to brand bisphosphonates and patients switched from brand to generic alendronate have increased adverse event rates and losses in bone mineral density., Conclusion: Numerous differences exist between brand and generic alendronate including: disintegration time, bioadhesion to the oesophagus, patient persistence to therapy, adverse event incidence, and maintenance of bone mineral density. Generic forms of alendronate warrant closer clinical study before they are ascribed the clinical effectiveness and tolerability of brand alendronate.

Objective: Recent data suggest that women with type 2 diabetes mellitus (T2DM) might be more susceptible to fractures due to an impaired adaptive response to mechanical load, despite reportedly higher bone mineral density (BMD). The purpose of this study was to use an engineering beam analysis to calculate and compare the load stresses on the femurs of healthy women and women with T2DM and compare these levels to conventional measures of femoral neck BMD., Materials/methods: We studied 3658 women who participated in the Canadian Multicentre Osteoporosis Study (CaMos), and who had available Hip Structure Analysis (HSA) data from baseline dual energy x-ray absorptiometry (DXA) scans. Women were categorized into two groups based on the presence or absence of self-reported T2DM. We computed stress in megapascals (MPa) at the infero-medial margin of the femoral neck in a one-legged stance using an engineering beam analysis incorporating dimensions and geometry from DXA scans using the HSA method. We used linear regression (SAS 9.3) to determine the association between T2DM status and stress. We also determined the association between T2DM status and femoral neck BMD., Results: Stresses were 4.5% higher in T2DM women than in non-diabetics (11.03±0.18 vs. 10.56±0.04 MPa; p=0.0093). Femoral neck BMD was 4.2% greater in women with T2DM than in non-diabetics (0.74±0.002 vs. 0.71±0.01 g/cm(2); p=0.0008)., Conclusions: Despite higher femoral neck BMD, higher stress indicates weaker skeletal geometry for a given load, and suggests an impaired skeletal adaptive response to load may be present in women with T2DM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This study assessed the ability of multisite quantitative ultrasound (mQUS) to predict fracture over a 5-year follow-up. Participants were a subset of the Canadian Multicentre Osteoporosis Study. mQUS-assessed speed of sound (SOS in m/s) at three sites (distal radius, tibia, and phalanx) and extensive questionnaires were completed, after which participants were followed for 5 years and incident fractures recorded. Two survival analyses were completed for each site--a univariate analysis and an adjusted multivariate analysis controlling for age, antiresorptive use, femoral neck bone mineral density, number of diseases, previous fractures, body mass index (BMI), parental history of hip fracture, current smoking, current alcoholic drinks >3 per day, current use of glucocorticoids, and rheumatoid arthritis diagnosis (variables from the FRAX 10-year fracture risk assessment tool). The unit of change for regression analyses was one standard deviation for all measurement sites, specific to site and sex. Separate analyses were completed for all clinical fractures, nonvertebral fractures, and hip fractures by sex. There were 2633 women and 1108 men included, and they experienced 204 incident fractures over 5 years (5.5% fractured). Univariate models revealed statistically significant (p < 0.05) predictive ability of mQUS for all three measurement sites for women alone for all three fracture types (one standard deviation decrease in SOS was associated with a 52% to 130% increase in the risk of fracture), but not for the men's group. The adjusted model found that measures at the distal radius and tibia in the women's group could significantly (p < 0.05) predict all clinical fractures and nonvertebral fractures within the next 5 years (one standard deviation decrease in SOS was associated with a 25% to 31% increase in the risk of fracture). mQUS provided significant 5-year clinical fracture prediction in women, independent of bone mineral density and other significant risk factors for fracture, when measured at the distal radius and tibia sites., (Copyright © 2013 American Society for Bone and Mineral Research.)

Context: Calcium and vitamin D are recommended for bone health, but there are concerns about adverse risks. Some clinical studies suggest that calcium intake may be cardioprotective, whereas others report increased risk associated with calcium supplements. Both low and high serum levels of 25-hydroxyvitamin D have been associated with increased mortality., Objective: The purpose of this study was to determine the association between total calcium and vitamin D intake and mortality and heterogeneity by source of intake., Design: The Canadian Multicentre Osteoporosis Study cohort is a population-based longitudinal cohort with a 10-year follow-up (1995-2007)., Setting: This study included randomly selected community-dwelling men and women., Participants: A total of 9033 participants with nonmissing calcium and vitamin D intake data and follow-up were studied., Exposure: Total calcium intake (dairy, nondairy food, and supplements) and total vitamin D intake (milk, yogurt, and supplements) were recorded., Outcome: The outcome variable was all-cause mortality., Results: There were 1160 deaths during the 10-year period. For women only, we found a possible benefit of higher total calcium intake, with a hazard ratio of 0.95 (95% confidence interval, 0.89-1.01) per 500-mg increase in daily calcium intake and no evidence of heterogeneity by source; use of calcium supplements was also associated with reduced mortality, with hazard ratio of 0.78 (95% confidence interval, 0.66-0.92) for users vs nonusers with statistically significant reductions remaining among those with doses up to 1000 mg/d. These associations were not modified by levels of concurrent vitamin D intake. No definitive associations were found among men., Conclusions: Calcium supplements, up to 1000 mg/d, and increased dietary intake of calcium may be associated with reduced risk of mortality in women. We found no evidence of mortality benefit or harm associated with vitamin D intake.

Bone structure is an integral determinant of bone strength. The availability of high resolution peripheral quantitative computed tomography (HR-pQCT) has made it possible to measure three-dimensional bone microarchitecture and volumetric bone mineral density in vivo, with accuracy previously unachievable and with relatively low-dose radiation. Recent studies using this novel imaging tool have increased our understanding of age-related changes and sex differences in bone microarchitecture, as well as the effect of different pharmacological therapies. One advantage of this novel tool is the use of finite element analysis modelling to non-invasively estimate bone strength and predict fractures using reconstructed three-dimensional images. In this paper, we describe the strengths and limitations of HR-pQCT and review the clinical studies using this tool.

The purposes of this study were to assess direct medical resource utilization related to the treatment of nonvertebral osteoporotic fractures within 1 year postfracture and to evaluate whether age impacts resource utilization. A previously-validated algorithm for physician claims databases identified 15,327 women aged 50 years or older with incident fracture at nonvertebral osteoporotic sites between January 1, 2004 and December 31, 2005. Administrative databases of the health services available to all residents in Quebec served to study fracture-related health resource utilization in the year after fracture. Data were linked by a unique personal identifier, creating a longitudinal cohort of all fracture cases for health resource utilization. The proportions of fractures treated by open reduction, closed reduction, immobilization or follow-up by an orthopedic surgeon (OS) were evaluated. The mean number of claims for consultation with an OS or other clinicians in inpatient and outpatient visits, the hospitalization rate and length of stay (LOS) were assessed. Hip/femur fractures represented the highest rate of resource utilization because the majority of them required surgery (91.1%) and hospitalization (94.5%) with a mean (median) LOS of 39.2 (31) days. However, other nonvertebral fracture types needed significant clinical care related to surgery (27.9%), follow-up consultation with an OS (77.6%), and hospitalization (27.3% of total LOS). Even pelvic fractures, which often do not require surgical treatment, commanded high resource utilization due to the high hospitalization rate (67.4%) with mean (median) LOS of 34.2 (26) days. Moreover, age was an important determinant of health resource utilization, being associated with an increased number of visits to other physicians, hospitalization, and length of hospitalization (LOS), admissions to long term care (LTC), and death. Osteoporosis-related fractures accounted for substantial healthcare resource utilization. With an aging population and increased prevalence of fractures, strategies for osteoporosis management need to be introduced to reduce the healthcare burden., (Copyright © 2013 American Society for Bone and Mineral Research.)

The amino-bisphosphonates are first-line therapy for the treatment of most patients with osteoporosis, with proven efficacy to reduce fracture risk at the spine, hip, and other nonvertebral skeletal sites. Further, bisphosphonates have been associated with a significant decrease in morbidity and increase in survival. Following the use of bisphosphonates in millions of patients in clinical practice, some unexpected possible adverse effects have been reported, including osteonecrosis of the jaw, atypical femur fractures, atrial fibrillation, and esophageal cancer. Because bisphosphonates are incorporated into the skeleton and continue to exert an antiresorptive effect for a period of time after dosing is discontinued, the concept of a drug holiday has emerged, whereby the risk of adverse effects might be decreased while the patient still benefits from antifracture efficacy. Patients receiving bisphosphonates who are not at high risk for fracture are potential candidates for a drug holiday, while for those with bone mineral density in the osteoporosis range or previous history of fragility fracture, the benefits of continuing therapy probably far outweigh the risk of harm., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: Proton pump inhibitor (PPI) use has been identified as a risk factor for hip and vertebral fractures. Evidence supporting a relationship between PPI use and osteoporosis remains scant. Demonstrating that PPIs are associated with accelerated bone mineral density (BMD) loss would provide supportive evidence for a mechanism through which PPIs could increase fracture risk., Methods: We used the Canadian Multicentre Osteoporosis Study data set, which enrolled a population-based sample of Canadians who underwent BMD testing of the femoral neck, total hip, and lumbar spine (L1-L4) at baseline, and then again at 5 and 10 years. Participants also reported drug use and exposure to risk factors for osteoporosis and fracture. Multivariate linear regression was used to determine the independent association of PPI exposure and baseline BMD, and on change in BMD at 5 and 10 years., Results: In all, 8,340 subjects were included in the baseline analysis, with 4,512 (55%) undergoing year 10 BMD testing. After adjusting for potential confounders, PPI use was associated with significantly lower baseline BMD at the femoral neck and total hip. PPI use was not associated with a significant acceleration in covariate-adjusted BMD loss at any measurement site after 5 and 10 years of follow-up., Conclusions: PPI users had lower BMD at baseline than PPI non-users, but PPI use over 10 years did not appear to be associated with accelerated BMD loss. The reasons for discordant findings between PPI use at baseline and during follow-up require further study., Competing Interests: Guarantor of the article: Laura E. Targownik, MD, MSHS. Specific author contributions: study concept and design, acquisition of database data, analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and statistical analysis: Laura E. Targownik and William D. Leslie; acquisition of participant data, study concept and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content: K. Shawn Davison, David Goltzman, Sophie A. Jamal, Nancy Kreiger, Robert G. Josse, Stephanie M. Kaiser, Chris S. Kovacs, and Jerilynn C. Prior; acquisition of database data and statistical analysis: Wei Zhou. Financial support: Laura E. Targownik is supported by a CIHR/ Osteoporosis Canada New Investigator Award and the American College of Gastroenterology 2011 Clinical Research Award. Potential competing interests: William D. Leslie has served on advisory boards for Novartis, Amgen, and Genzyme; received unrestricted research grants from Merck Frosst, Genzyme, Amgen, Sanofi-Aventis, and Warner-Chilcott (formerly Procter & Gamble); received speaker fees from Merck Frosst and Amgen; received conference expenses from Genzyme. David Goltzman serves as a consultant for Eli Lily, Novartis, Merck, Proctor & Gamble, and Amgen. Sophie A. Jamal has been an advisory board member for Novartis, Amgen, and Warner-Chilcott; received consulting fees from Novartis, Warner-Chilcott, Genzyme, and Shire; speaker fees from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire. Christopher S. Kovacs serves as a consultant or has received honoraria from Amgen, Boehringer Ingelheim, Eli Lilly, Merck, and Novartis. Robert G. Josse serves as a consultant for Amgen, Bayer Corporation, Eli Lilly, GlaxoSmith-Kline, Merck, Novartis, Proctor & Gamble, Sanofi-aventis, Servier, and Wyeth-Ayerst. K. Shawn Davison has served as advisory board member/received honoraria from Amgen, Merck, Proctor & Gamble, Sanofi-aventis, and Servier. Stephanie M. Kaiser has served as advisory board member/received honoraria from Amgen, Eli Lilly, Novartis, Proctor & Gamble, Sanofi-aventis, Servier, and Wyeth-Ayerst. The remaining authors declare no conflict of interest.

Unlabelled: This study determined the cost of treating fractures at osteoporotic sites (except spine fractures) for the year following fracture. While the average cost of treating a hip fracture was the highest of all fractures ($46,664 CAD per fracture), treating other fractures also accounted for significant expenditures ($5,253 to $10,410 CAD per fracture)., Introduction: This study aims to determine the mean direct medical cost of treating fractures at peripheral osteoporotic sites in the year post-fracture (through 2 years post-hip fracture)., Methods: Health administrative databases from the province of Quebec, Canada were used to estimate the cost of treating peripheral fractures at osteoporotic sites for the year following fracture (through 2 years for hip fractures). Included in costs analyses were physician claims, emergency and outpatient clinic costs, hospitalization costs, and subsequent costs for treatment of complications., Results: A total of 15,827 patients (mean age 72 years) who suffered one fracture at an osteoporotic site had data for analyses. Hip/femur fractures had the highest rate of hospital stays related to fracture (91%) and the highest rate of hospital stays associated with a post-fracture complication (8%). In the year following fracture, the mean (SD) costs (2009 Canadian dollars) of treating acute fractures and post-fracture complications were: hip/femur fracture $46,664 ($43,198), wrist fracture $5,253 ($18,982), and fractures at other peripheral sites $10,410 ($27,641). The average (SD) cost of treating post-fracture complications at the hip/femur in the second year post-fracture was $1,698 ($12,462). Hospitalizations associated with the fracture accounted for 88% of the total cost of fracture treatment., Conclusions: The treatment of hip fractures accounts for a significant proportion of the costs associated with the treatment of peripheral osteoporotic fractures. Interventions to reduce the incidence of fractures, particularly hip fractures, would result in significant cost savings to the health care system and would preserve quality of life in many patients.

Vitamin D is essential for facilitating calcium absorption and preventing increases in parathyroid hormone (PTH), which can augment bone resorption. Our objectives were to examine serum levels of 25-hydroxyvitamin D [25(OH)D] and PTH, and factors related to longitudinal change in a population-based cohort. This is the first longitudinal population-based study looking at PTH and 25(OH)D levels. We analyzed 3896 blood samples from 1896 women and 829 men in the Canadian Multicentre Osteoporosis Study over a 10-year period starting in 1995 to 1997. We fit hierarchical models with all available data and adjusted for season. Over 10 years, vitamin D supplement intake increased by 317 (95% confidence interval [CI] 277 to 359) IU/day in women and by 193 (135 to 252) IU/day in men. Serum 25(OH)D (without adjustment) increased by 9.3 (7.3 to 11.4) nmol/L in women and by 3.5 (0.6 to 6.4) nmol/L in men but increased by 4.7 (2.4 to 7.0) nmol/L in women and by 2.7 (-0.6 to 6.2) nmol/L in men after adjustment for vitamin D supplements. The percentage of participants with 25(OH)D levels <50 nmol/L was 29.7% (26.2 to 33.2) at baseline and 19.8% (18.0 to 21.6) at year 10 follow-up. PTH decreased over 10 years by 7.9 (5.4 to 11.3) pg/mL in women and by 4.6 (0.2 to 9.0) pg/mL in men. Higher 25(OH)D levels were associated with summer, younger age, lower body mass index (BMI), regular physical activity, sun exposure, and higher total calcium intake. Lower PTH levels were associated with younger age and higher 25(OH)D levels in both women and men and with lower BMI and participation in regular physical activity in women only. We have observed concurrent increasing 25(OH)D levels and decreasing PTH levels over 10 years. Secular increases in supplemental vitamin D intake influenced both changes in serum 25(OH)D and PTH levels., Competing Interests: The following authors declared potential conflicts of interest as follows: DG (Amgen, Eli Lilly, Merck Frosst, and Novartis), DAH (Amgen, Eli Lilly, Novartis, Procter & Gamble, Sanofi Aventis, Merck Frosst, Servier, Warner Chilcott, and NPS Pharmaceuticals), CSK (Amgen, Eli Lilly, and Novartis), JDA (Amgen, Eli Lilly, GSK, Merck, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi Aventis, Warner Chilcott, and Bristol-Myers Squibb), JPB (Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi Aventis, Servier, and Warner Chilcott). CB, LL, LJ, LG-F, JBR, KS, KSD, JCP, and NK did not have any conflicts of interest., (Copyright © 2012 American Society for Bone and Mineral Research.)