Tricyclic antidepressant use and risk of fractures: A meta‐analysis of cohort and case‐control studies

Because studies of the association between tricyclic antidepressant (TCA) treatment and risk of fracture have shown inconsistent findings, we sought to assess whether people who take TCAs are at increased risk of fracture. Relevant studies published by June 2012 were identified through database searches of Scopus, MEDLINE, EMBASE, PsycINFO, ISI Web of Science, and WorldCat Dissertations and Theses from their inception, and manual searching of reference lists. Only original studies that examined the association between TCA treatment and risk of fracture were included. Two investigators independently conducted literature searches, study selection, study appraisal, and data abstraction using a standardized protocol. Disagreements were resolved by consensus. Twelve studies met inclusion criteria. Because of the heterogeneity of these studies, random‐effects models were used to pool estimates of effect. Overall, TCA use was associated with significantly increased fracture risk (relative risk [RR], 1.45; 95% confidence interval [CI], 1.31–1.60; p < 0.001). Increased fracture risk associated with TCA use was also observed in studies that adjusted for bone mineral density (RR, 1.54; 95% CI, 1.24–1.90; p < 0.001) or depression (RR, 1.49; 95% CI, 1.28–1.67; p < 0.001). Strength of association with TCA exposure duration ≥6 weeks (RR, 1.13; 95% CI, 1.00–1.28) was substantially weaker than association with TCA exposure duration <6 weeks (RR, 2.40; 95% CI, 1.41–4.08). Prior TCA exposure had no significant effect on fracture risk (RR, 1.04; 95% CI, 0.86–1.26; p = 0.70). After accounting for publication bias, we found the overall association between TCA use and fracture risk to be slightly weaker (RR, 1.36; 95% CI, 1.24–1.50) but still significant (p < 0.001). Findings of this meta‐analysis indicate that treatment with TCAs may convey an increased risk of fracture, independent of depression and bone mineral density. © 2013 American Society for Bone and Mineral Research.     

Distribution of bone density in the proximal femur and its association with hip fracture risk in older men: The osteoporotic fractures in men (MrOS) study

This prospective case‐cohort study aimed to map the distribution of bone density in the proximal femur and examine its association with hip fracture. We analyzed baseline quantitative computed tomography (QCT) scans in 250 men aged 65 years or older, which comprised a randomly‐selected subcohort of 210 men and 40 cases of first hip fracture during a mean follow‐up period of 5.5 years. We quantified cortical, trabecular, and integral volumetric bone mineral density (vBMD), and cortical thickness (CtTh) in four quadrants of cross‐sections along the length of the femoral neck (FN), intertrochanter (IT), and trochanter (TR). In most quadrants, vBMDs and CtTh were significantly (p < 0.05) lower in cases compared to the subcohort and these deficits were present across the entire proximal femur. To examine the association of QCT measurements with hip fracture, we merged the two quadrants in the medial and lateral aspects of the FN, IT, and TR. At most sites, QCT measurements were associated significantly (p < 0.001) with hip fracture, the hazard ratio (HR) adjusted for age, body mass index (BMI), and clinical site for a 1‐SD decrease ranged between 2.28 (95% confidence interval [CI], 1.44–3.63) to 6.91 (95% CI, 3.11–15.53). After additional adjustment for total hip (TH) areal BMD (aBMD), trabecular vBMDs at the FN, TR, and TH were still associated with hip fracture significantly (p < 0.001), the HRs ranged from 3.21 (95% CI, 1.65–6.24) for the superolateral FN to 6.20 (95% CI, 2.71–14.18) for medial TR. QCT measurements alone or in combination did not predict fracture significantly (p > 0.05) better than TH aBMD. With an area under the receiver operating characteristic curve (AUC) of 0.901 (95% CI, 0.852–0.950), the regression model combining TH aBMD, age, and trabecular vBMD predicted hip fracture significantly (p < 0.05) better than TH aBMD alone or TH aBMD plus age. These findings confirm that both cortical and trabecular bone contribute to hip fracture risk and highlight trabecular vBMD at the FN and TR as an independent risk factor. © 2012 American Society for Bone and Mineral Research.     

Lower fracture risk in older men with higher sclerostin concentration: A prospective analysis from the MINOS study

Sclerostin is synthesized by osteocytes and inhibits bone formation. We measured serum sclerostin levels in 710 men aged 50 years and older. Bone mineral density (BMD) was measured at the lumbar spine, hip, and distal forearm. Serum sclerostin increased with age (unadjusted r = 0.30, p < 0.001). After adjustment for age, weight, and bioavailable 17β‐estradiol, serum sclerostin correlated positively with BMD (r = 0.24 to 0.35, p < 0.001) and negatively with the levels of bone turnover markers (r = ? 0.09 to ? 0.23, p < 0.05 to 0.001). During a 10‐year follow‐up, 75 men sustained fragility fractures. Fracture risk was lower in the two upper quintiles of sclerostin combined versus three lower quintiles combined (6.1 versus 13.5%, p < 0.01). We compared fracture risk in the two highest quintiles combined versus three lower quintiles combined using the Cox model adjusted for age, weight, leisure physical activity, BMD, bone width (tubular bones), prevalent fracture, prevalent falls, ischemic heart disease, and severe abdominal aortic calcification. Men with higher sclerostin concentration had lower fracture risk (adjusted for hip BMD, hazard ratio [HR] = 0.55, 95% confidence interval [CI] 0.31 to 0.96, p < 0.05). The results were similar in 47 men with major fragility fractures (adjusted for lumbar spine BMD: HR = 0.39, 95% CI 0.17 to 0.90, p < 0.05). Men who had higher sclerostin and higher BMD (two highest quintiles) had lower risk of fracture compared with men who had lower BMD and lower sclerostin levels (three lower quintiles) (HR = 0.24, 95% CI 0.10 to 0.62, p < 0.005). Circulating sclerostin was not associated with mortality rate or the incidence of major cardiovascular events. Thus, in older men, higher serum sclerostin levels are associated with lower risk of fracture, higher BMD, and lower bone turnover rate. © 2013 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.     

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).     

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.     

Effects of a 12-Month Supervised,Community-Based,Multimodal Exercise Program Followed by a 6-Month Research-to-Practice Transition on Bone Mineral Density,Trabecular Microarchitecture,and Physical Function in Older Adults: A Randomized Controlled Trial

Multicomponent exercise programs are recommended to reduce fracture risk; however, their effectiveness in real-world community settings remain uncertain. This 18-month randomized controlled trial investigated the effects of a 12-month, community-based, supervised multicomponent exercise program followed by a 6-month “research-to-practice” transition on areal bone mineral density (BMD), trabecular bone microarchitecture, functional performance, and falls in older adults at increased fracture risk. One-hundred and sixty-two adults aged ≥60 years with osteopenia or at increased falls risk were randomized to the Osteo-cise: Strong Bones for Life multicomponent exercise program (n = 81) or a control group (n = 81). Exercise consisted of progressive resistance, weight-bearing impact, and balance training (3-days/week) performed at community leisure centers. Overall 148 (91%) participants completed the trial, and mean exercise adherence was 59% after 12 months and 45% during the final 6 months. After 12 months, there were significant net beneficial effects of exercise on lumbar spine and femoral neck BMD (1.0% to 1.1%, p < 0.05), muscle strength (10% to 13%, p < 0.05), and physical function (timed stair climb 5%; four-square step test 6%; sit-to-stand 16%, p ranging <0.05 to <0.001), which persisted after the 6-month transition. There were no significant effects of the 18-month intervention on distal femur or proximal tibia trabecular bone microarchitecture or falls incidence, but per protocol analysis (≥66% exercise adherence) revealed there was a significant net benefit of exercise (mean [95% confidence interval] 2.8% [0.2, 5,4]) on proximal tibia trabecular bone volume fraction (Osteo-cise 1.5% [−1.2, 4.2]; controls −1.3% [−2.6, 0.1]) after 18 months due to changes in trabecular number (Osteo-cise 1.7% [−0.9, 4.3]; controls −1.1% [−2.4, 0.2]) but not trabecular thickness (Osteo-cise − 0.2% [−0.5, 0.2]; controls −0.2% [−0.4, 0.0]). In conclusion, this study supports the effectiveness of the Osteo-cise: Strong Bones for Life program as a real-world, pragmatic, evidence-based community exercise program to improve multiple musculoskeletal health outcomes in older adults at increased fracture risk. © 2019 American Society for Bone and Mineral Research.     

Bone Mineral Density and Parathyroid Hormone as Independent Risk Factors for Mortality in Community‐Dwelling Older Adults: A Population‐Based Prospective Cohort Study in Brazil. The São Paulo Ageing & Health (SPAH) Study

Previous studies have shown a relationship between osteoporosis and increased mortality risk. However, none of these studies performed a concomitant evaluation of the parathyroid hormone (PTH)‐calcium‐vitamin D axis and bone mass to accurately determine the contribution of each of these parameters to survival in older subjects. Thus, we sought to investigate the association between bone parameters and mortality in a longitudinal, prospective, population‐based cohort of 839 elderly subjects. Clinical data (including history of fractures and cardiovascular events) were assessed using a specific questionnaire. Laboratory exams, including serum 25OHD and PTH, were also performed. Bone mineral density (BMD) at the lumbar spine and hip were evaluated using DXA. All analyses were performed at baseline (2005 to 2007). Mortality was recorded during follow‐up. Multivariate Cox proportional regression was used to compute hazard ratios for all‐cause and cardiovascular mortality. Over a mean 4.06 ± 1.07 years, there were 132 (15.7%) deaths. These individuals were compared to 707 subjects who were alive at the end of the coverage period for mortality data collection. In a multivariate Cox proportional hazards model, age (HR 1.32; 95% CI, 1.13 to 1.55; p = 0.001, for each 5‐year increase), male gender (HR 1.90; 95% CI, 1.30 to 2.79; p = 0.001), recurrent falls (more than two in the previous year; HR 1.65; 95% CI, 1.06 to 2.56; p = 0.026), diabetes mellitus (HR 2.17; 95% CI, 1.46 to 3.21; p < 0.001), low physical activity score (HR 1.78; 95% CI, 1.14 to 2.79; p = 0.011), prior cardiovascular event (HR 1.76; 95% CI, 1.18 to 2.63; p = 0.006), total hip BMD (HR 1.41; 95% CI, 1.15 to 1.72; p = 0.001, per each 1 SD decrease), and intact PTH (iPTH) (HR 1.06; 95% CI, 1.04 to 1.08; p < 0.001, per each 10 pg/mL increase) were independently associated with all‐cause mortality. The subjects in the highest quartile of PTH (>49 pg/mL) were at a higher risk of cardiovascular death (HR 3.09; 95% CI, 1.36 to 6.99; p = 0.007) compared with the subjects in the lowest quartile (<26 pg/mL). Low BMD and higher PTH were significantly associated with mortality in community‐dwelling older adults. These findings support the notion that careful screening of these bone parameters might lead to better management of older patients and improve outcomes in this population. © 2016 American Society for Bone and Mineral Research.     

Identification of quantitative trait loci influencing skeletal architecture in mice: Emergence of Cdh11 as a primary candidate gene regulating femoral morphology

Bone strength is influenced by many properties intrinsic to bone, including its mass, geometry, and mineralization. To further advance our understanding of the genetic basis of bone‐strength‐related traits, we used a large (n = 815), moderately (G₄) advanced intercross line (AIL) of mice derived from a high‐runner selection line (HR) and the C57BL/6J inbred strain. In total, 16 quantitative trait loci (QTLs) were identified that affected areal bone mineral density (aBMD) and femoral length and width. Four significant (p < .05) and one suggestive (p < .10) QTLs were identified for three aBMD measurements: total body, vertebral, and femoral. A QTL on chromosome (Chr.) 3 influenced all three aBMD measures, whereas the other four QTLs were unique to a single measure. A total of 10 significant and one suggestive QTLs were identified for femoral length (FL) and two measures of femoral width, anteroposterior (AP) and mediolateral (ML). FL QTLs were distinct from loci affecting AP and ML width, and of the 7 AP QTLs, only three affected ML. A QTL on Chr. 8 that explained 7.1% and 4.0% of the variance in AP and ML, respectively, was mapped to a 6‐Mb region harboring 12 protein‐coding genes. The pattern of haplotype diversity across the QTL region and expression profiles of QTL genes suggested that of the 12, cadherin 11 (Cdh11) was most likely the causal gene. These findings, when combined with existing data from gene knockouts, identify Cdh11 as a strong candidate gene within which genetic variation may affect bone morphology. © 2011 American Society for Bone and Mineral Research     

Trabecular Bone Score: A Noninvasive Analytical Method Based Upon the DXA Image

The trabecular bone score (TBS) is a gray‐level textural metric that can be extracted from the two‐dimensional lumbar spine dual‐energy X‐ray absorptiometry (DXA) image. TBS is related to bone microarchitecture and provides skeletal information that is not captured from the standard bone mineral density (BMD) measurement. Based on experimental variograms of the projected DXA image, TBS has the potential to discern differences between DXA scans that show similar BMD measurements. An elevated TBS value correlates with better skeletal microstructure; a low TBS value correlates with weaker skeletal microstructure. Lumbar spine TBS has been evaluated in cross‐sectional and longitudinal studies. The following conclusions are based upon publications reviewed in this article: 1) TBS gives lower values in postmenopausal women and in men with previous fragility fractures than their nonfractured counterparts; 2) TBS is complementary to data available by lumbar spine DXA measurements; 3) TBS results are lower in women who have sustained a fragility fracture but in whom DXA does not indicate osteoporosis or even osteopenia; 4) TBS predicts fracture risk as well as lumbar spine BMD measurements in postmenopausal women; 5) efficacious therapies for osteoporosis differ in the extent to which they influence the TBS; 6) TBS is associated with fracture risk in individuals with conditions related to reduced bone mass or bone quality. Based on these data, lumbar spine TBS holds promise as an emerging technology that could well become a valuable clinical tool in the diagnosis of osteoporosis and in fracture risk assessment. © 2014 American Society for Bone and Mineral Research.     

The Association Between Trabecular Bone Score and Lumbar Spine Volumetric BMD Is Attenuated Among Older Men With High Body Mass Index

Trabecular bone score (TBS) has been proposed as a dual‐energy X‐ray absorptiometry (DXA) derived measure of underlying quality of trabecular bone; however, TBS is not considered valid for those with body mass index (BMI) >37 kg/m². Our objective was to determine the association between TBS and lumbar spine (trabecular) volumetric BMD (LS‐VBMD) and to examine whether the association varied by BMI and body composition among older men below this clinical threshold. We used regression models to study 3479 men age ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study who had TBS from spine DXA scans, LS‐VBMD from central quantitative computed tomography, measures of trunk fat and lean mass from DXA, and BMI <37 kg/m². TBS was categorized as normal (n = 925), partially degraded (n = 1747), and degraded (n = 807). TBS was inversely related to BMI, trunk fat mass, and trunk lean mass (all p < 0.001). The relationship between TBS and LS‐VBMD was nonlinear with magnitude of effect (slope of regression line using standardized variables) ranging from 0.07 (95% CI, –0.02 to 0.15) among those with degraded TBS up to 0.71 (95% CI, 0.54 to 0.89) among those with normal TBS. The relationship was still nonlinear after adjusting for age, clinical site, and either BMI, trunk lean mass, or trunk fat mass. The magnitude of effect relating TBS and LS‐VBMD also decreased with increasing BMI (interaction, p = 0.090) and increasing trunk lean mass (interaction, p = 0.001), but not with increasing trunk fat mass (interaction, p = 0.224). In summary, the strength of the association between TBS and LS‐VBMD among older men was variable and dependent on BMI and body composition, particularly trunk lean mass. The clinical utility of TBS among older men may be somewhat limited among men with high BMI or high trunk lean mass. © 2016 American Society for Bone and Mineral Research.     

Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized,Double‐Blind,Phase 2, Parallel Group Study

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T‐score ≤–2.0 and ≥–3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open‐label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker β‐CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and β‐CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.     

Smoking-Induced Risk of Osteoporosis Is Partly Mediated by Cadmium From Tobacco Smoke: The MrOS Sweden Study

Cigarette smoking is a risk factor for osteoporosis and bone fracture. Moreover, smoking causes exposure to cadmium, which is a known risk factor for osteoporosis. It is hypothesized that part of smoking-induced osteoporosis may be mediated via cadmium from tobacco smoke. We investigated this hypothesis using mediation analysis in a Swedish cohort of elderly men. This study was performed in 886 elderly men from the Swedish cohort of the Osteoporotic Fractures in Men (MrOS) study. Urinary samples, bone mineral density (BMD), smoking data, and other background information were obtained at baseline in 2002–2004. Urinary cadmium was analyzed in baseline samples and adjusted for creatinine. The cohort was followed until August 2018 for fracture incidence, based on the X-ray register. Mediation analysis was conducted to evaluate the indirect effect (via cadmium) of smoking on both BMD and fractures. Time to first fracture was analyzed using the accelerated failure time (AFT) model and Aalen's additive hazard model. The mean level of urinary cadmium was 0.25 μg/g creatinine. There were significant inverse associations between smoking and total body, total hip, and trochanter BMD. The indirect effects via cadmium were estimated to be 43% of the total effects of smoking for whole-body BMD, and even more for total hip and trochanter BMD. Smoking was also associated with higher risk of all fractures and major osteoporosis fractures. The indirect effects via cadmium were largest in nonvertebral osteoporosis fractures and hip fractures, constituting at least one-half of the total effects, in both the AFT and Aalen's model. The findings in this study provide evidence that cadmium exposure from tobacco smoke plays an important role in smoking-induced osteoporosis © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: the Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) trial

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double‐blind, double‐dummy, active‐ and placebo‐controlled, multiple‐dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one‐half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis. © 2012 American Society for Bone and Mineral Research.     

T-Score as an Indicator of Fracture Risk During Treatment With Romosozumab or Alendronate in the ARCH Trial

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > −2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with romosozumab versus 2.9% (T-score change 0.15) with alendronate (p < .001). The proportion of patients with TH T-score > −2.5 increased from 34% at baseline to 55% after 1 year of romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data support the use of T-score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Durability and delayed treatment effects of zoledronic acid on bone loss after spinal cord injury: a randomized,controlled trial

A single infusion of zoledronic acid (ZOL) after acute spinal cord injury (SCI) attenuates bone loss at the hip (proximal femur) and knee (distal femur and proximal tibia) for at least 6 months. The objective of this study was to examine the effects of timing and frequency of ZOL over 2 years. In this double-blind, placebo-controlled trial, we randomized 60 individuals with acute SCI (<120 days of injury) to receive either ZOL 5-mg infusion (n = 30) or placebo (n = 30). After 12 months, groups were again randomized to receive ZOL or placebo, resulting in four treatment groups for year 2: (i) ZOL both years; (ii) ZOL year 1, placebo year 2; (iii) placebo year 1, ZOL year 2; and (iv) placebo both years. Our primary outcome was bone loss at 12 months; compared to placebo, a single infusion of ZOL attenuated bone loss at the proximal femur, where median changes relative to baseline were −1.7% to −2.2% for ZOL versus −11.3% to −12.8% for placebo (p < 0.001). Similarly, the distal femur and proximal tibia showed changes of −4.7% to −9.6% for ZOL versus −8.9% to −23.0% for placebo (p ≤ 0.042). After 24 months, differences were significant at the proximal femur only (−3.2% to −6.0% for ZOL vs. −16.8% to −21.8% for placebo; p ≤ 0.018). Although not statistically significant, median bone density losses suggested some benefit from two annual infusions compared to a single baseline infusion, as well as from a single infusion 12 months after baseline compared to 2 years of placebo; therefore, further investigation in the 12-month to 24-month treatment window is warranted. No unanticipated adverse events associated with drug treatment were observed. In summary, ZOL 5-mg infusion after acute SCI was well-tolerated and may provide an effective therapeutic approach to prevent bone loss in the first few years following SCI. © 2021 American Society for Bone and Mineral Research (ASBMR).     

A prospective study of thyroid function,bone loss,and fractures in older men: The MrOS study

Excess thyroid hormone is associated with increased bone loss and fracture risk in older women, but few data exist for men. We sought to determine if thyroid function is independently associated with bone loss and fracture risk in older men. Data were analyzed from the Osteoporotic Fractures in Men (MrOS) study, a cohort of community‐dwelling U.S. men aged 65 years and older. Using a case‐cohort design, fasting baseline serum archived at ?80°C was assayed for thyroid‐stimulating hormone (thyrotropin) (TSH) and free thyroxine (FT4) in 397 men with confirmed nonspine fracture, including 157 hip fractures, and 1420 randomly selected men without fracture. TSH and FT4 were analyzed as continuous variables and as thyroid function categories (subclinical hyperthyroid, euthyroid, and subclinical hypothyroid). Hip dual‐energy X‐ray absorptiometry (DXA) (Hologic QDR4500) was measured at baseline and after a mean follow‐up of 4.6 years. Incident nonspine fractures were centrally adjudicated. Bone loss was evaluated with multivariate regression methods and fractures risk was evaluated using hazard models that accounted for the case‐cohort sampling, adjusted for age, clinic‐site, body mass index (BMI), race, physical activity, corticosteroid use, smoking, alcohol intake, and thyroid medication use. In fully adjusted analyses, TSH was not associated with risk of nonspine fracture (relative hazard [RH] 0.92 per SD decrease in TSH; 95% confidence interval [CI], 0.74–1.14), but was significantly associated with risk of hip fracture (RH 1.31; 95% CI, 1.01–1.71), which persisted among normal range TSH values (RH 1.21; 95% CI, 1.00–1.47). There was no association between TSH or FT4 and bone loss, and fracture risk did not differ significantly by thyroid function category. We conclude that although neither TSH nor FT4 are associated with bone loss, lower serum TSH may be associated with an increased risk of hip fractures in older men. © 2013 American Society for Bone and Mineral Research.     

Bone Mineral Density Is Positively Related to Carotid Intima‐Media Thickness: Findings From a Population‐Based Study in Adolescents and Premenopausal Women

Osteoporosis and cardiovascular disease (CVD) are both common causes of morbidity and mortality. Previous studies, mainly of people older than 60 years, suggest a relationship between these conditions. Our aim was to determine the association between bone characteristics and CVD markers in younger and middle‐aged individuals. Women (n = 3366) and their adolescent offspring (n = 4368) from the UK population‐based cohort study, Avon Longitudinal Study of Parents and Children (ALSPAC), were investigated. We measured total body (TB) and hip bone mineral density (BMD), TB bone area (BA) and bone mineral content (BMC) by dual‐energy X‐ray absorptiometry (DXA), and carotid intima‐media thickness (cIMT) by high‐resolution ultrasound. Arterial distensibility was calculated as the difference between systolic and diastolic arterial diameters. Linear regression determined associations between bone exposures and cIMT (in adolescents) and both cIMT and arterial distensibility (in women), generating partial correlation coefficients. Mean (SD) age of women was 48 (4.2) years, body mass index (BMI) was 26.2 (5.0) kg/m², and 71% were premenopausal. In confounder‐adjusted analyses (age, height, lean mass, fat mass, menopause, smoking, estrogen replacement, calcium/vitamin D supplementation, and education) TB and hip BMD were both positively associated with cIMT (0.071 [0.030, 0.112], p = 0.001; 0.063 [0.025, 0.101], p = 0.001, respectively). Femoral neck BMD and TB BMD, BMC, and BA were positively associated with arterial distensibility. Mean (SD) age of adolescents was 17 (0.4) years, BMI was 23 (4.1) kg/m², and 44.5% were male. Total hip and TB measurements were positively associated with cIMT, with similar magnitudes of association to those found in their mothers. In contrast to most published findings, we identified weak positive associations between BMD and cIMT in predominantly premenopausal women and their adolescent offspring. We found greater femoral neck BMD and TB DXA measurements to be associated with reduced arterial stiffness. Rather than a relationship with preclinical atherosclerosis, in these relatively young populations, we speculate our associations between BMD, cIMT, and arterial distensibility may reflect a shared relationship between bone and vascular growth and development. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.