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Context Bisphosphonates have been reported to be cardioprotective in some, but not all, studies. It is unknown whether denosumab (Dmab) use protects against cardiovascular events (CVEs). Objective To determine whether oral bisphosphonate (oBP) or Dmab use is associated with CVEs in persons with incident fracture. Methods Participants with an incident minimal trauma fracture from the Sax Institute’s 45 and Up Study, a population-based cohort from NSW, Australia, were followed between 2005/2009 and 2017. Questionnaire data were linked to hospital admissions (Admitted Patients Data Collection [APDC]) by the Centre for Health Record Linkage). Medicare Benefit Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS) data sets were provided by Services Australia. Data was stored in a secure computing environment (Secure Unified Research Environment). Fractures, CVEs, and comorbidities were identified from the APDC and oBP and Dmab medication from the PBS. oBP and Dmab users were matched to never users (NoRx) by propensity scores. The main outcome measures were association between oBP and Dmab with CVE (acute myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) and were determined using a stratified Cox's proportional hazards model. Results There were 880 pairs of oBP and NoRx (616 women) and 770 pairs of Dmab and NoRx (615 women) followed for ∼4.3 years. CVE risk was similar for oBP and NoRx Hazard Ratios (HR) women, 0.88 [95% CI 0.65-1.18]; men, 1.07 [95% CI 0.72-1.57]). Similar findings were obtained for Dmab (Hazard Ratios (HR) women, 1.08 [95% CI 0.78-1.50]; men, 1.55 [95% CI 0.96-2.48]). Conclusion oBP and Dmab use was not associated with CVEs.

Muscle strength and physical performance are associated with incident fractures and mortality. However, their role in the risk of subsequent fracture and postfracture mortality is not clear. We assessed the association between muscle strength (grip strength) and performance (gait speed and chair stands time) and the risk of subsequent fracture and mortality in 830 men with low-trauma index fracture, who participated in the Osteoporotic Fractures in Men (MrOS) USA Study and had their index measurements assessed within 5 years prior to the index fracture. The annual decline in muscle strength and performance following index fracture, estimated using linear mixed-effects regression, was also examined in relation to mortality. The associations were assessed using Cox proportional hazards models adjusted for age, femoral neck bone mineral density (FN BMD), prior fractures, falls, body mass index (BMI), index fracture site, lifestyle factors, and comorbidities. Over a median follow-up of 3.7 (interquartile range [IQR], 1.3-8.1) years from index fracture to subsequent fracture, 201 (24%) men had a subsequent fracture and over 5.1 (IQR, 1.8-9.6) years to death, and 536 (65%) men died. Index measurements were not associated with subsequent fracture (hazard ratios [HRs] ranging from 0.97 to 1.07). However, they were associated with postfracture mortality. HR (95% confidence interval [CI]) per 1 standard deviation (1-SD) decrement in grip strength: HR 1.12 (95% CI, 1.01-1.25) and gait speed: HR 1.14 (95% CI, 1.02-1.27), and 1-SD increment in chair stands time: HR 1.08 (95% CI, 0.97-1.21). Greater annual declines in these measurements were associated with higher mortality risk, independent of the index values and other covariates. HR (95% CI) per 1-SD annual decrement in change in grip strength: HR 1.15 (95% CI, 1.01-1.33) and in gait speed: HR 1.38 (95% CI, 1.13-1.68), and 1-SD annual increment in chair stands time: HR 1.28 (95% CI, 1.07-1.54). Men who were unable to complete one or multiple tests had greater risk of postfracture mortality (24%-109%) compared to those performed all tests. It remains to be seen whether improvement in these modifiable factors can reduce postfracture mortality. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

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. (c) 2021 American Society for Bone and Mineral Research (ASBMR). The Canadian Multicentre Osteoporosis Study was funded by the Canadian Institutes of Health Research (CIHR); Merck Frosst Canada Ltd.; Eli Lilly Canada Inc.; Novartis Pharmaceuticals Inc.; The Alliance: sanofi-aventis & Procter and Gamble Pharmaceuticals Canada Inc.; Servier Canada Inc.; Amgen Canada Inc.; The Dairy Farmers of Canada; and The Arthritis Society. This work was supported by the National Health Medical Research Council Australia Projects 1070187, 1008219, and 1073430. Other funding bodies were an Osteoporosis Australia-Amgen grant; the Bupa Health Foundation (formerly MBF Foundation); the Mrs Gibson and Ernst Heine Family Foundation; and untied grants from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Servier, and Novartis

ImportanceLimited knowledge about interactions among health disorders impedes optimal patient care. Because comorbidities are common among patients 50 years and older with fractures, these fractures provide a useful setting for studying interactions among disorders.ObjectiveTo define multimorbidity clusters at the time of fracture and quantify the interaction between multimorbidity and fracture in association with postfracture excess mortality.Design, Setting, and ParticipantsThis nationwide cohort study included 307 870 adults in Denmark born on or before January 1, 1951, who had an incident low-trauma fracture between January 1, 2001, and December 31, 2014, and were followed up through December 31, 2016. Data were analyzed from February 1 to March 31, 2022.Main Outcomes and MeasuresFracture and 32 predefined chronic diseases recorded within 5 years before the index fracture were identified from the Danish National Hospital Discharge Register. Death was ascertained from the Danish Register on Causes of Death. Latent class analysis was conducted to identify multimorbidity clusters. Relative survival analysis was used to quantify excess mortality associated with the combination of multimorbidity and fractures at specific sites.ResultsAmong the 307 870 participants identified with incident fractures, 95 372 were men (31.0%; mean [SD] age at fracture, 72.3 [11.2] years) and 212 498 were women (69.0%; mean [SD] age at fracture, 74.9 [11.2] years). During a median of 6.5 (IQR, 3.0-11.0) years of follow-up, 41 017 men (43.0%) and 81 727 women (38.5%) died. Almost half of patients with fractures (42.9%) had at least 2 comorbidities. Comorbidities at fracture were categorized as low-multimorbidity (60.5% in men and 66.5% in women), cardiovascular (23.7% in men and 23.5% in women), diabetic (5.6% in men and 5.0% in women), malignant (5.1% in men and 5.0% in women), and mixed hepatic and/or inflammatory (5.1% in men only) clusters. These clusters distinguished individuals with advanced, complex, or late-stage disease from those with earlier-stage disease. Multimorbidity and proximal or lower leg fractures were associated with increased mortality risk, with the highest excess mortality found in patients with hip fracture in the malignant cluster (1-year excess mortality: 40.8% [95% CI: 38.1%-43.6%]). The combination of multimorbidity and fracture compounded the association with mortality, conferring much greater risk than either alone.Conclusions and RelevanceConcomitant illnesses were common and clustered into distinct multimorbidity clusters that were associated with excess postfracture mortality. The compound contribution of multimorbidity to postfracture excess mortality highlights the need for more comprehensive approaches in these high-risk patients. The analytical approach applied to fracture could also be used to examine other sentinel health events.

ObjectivesTo evaluate the risk of subsequent fractures in patients who attended the Fracture Liaison Service (FLS), with and without incident falls after the index fracture.DesignA 3-year prospective observational cohort study.SettingAn outpatient FLS in the Netherlands.ParticipantsPatients aged 50+ years with a recent clinical fracture.Outcome measuresIncident falls and subsequent fractures.ResultsThe study included 488 patients (71.9% women, mean age: 64.6±8.6 years). During the 3-year follow-up, 959 falls had been ascertained in 296 patients (60.7%) (ie, fallers), and 60 subsequent fractures were ascertained in 53 patients (10.9%). Of the fractures, 47 (78.3%) were fall related, of which 25 (53.2%) were sustained at the first fall incident at a median of 34 weeks. An incident fall was associated with an approximately 9-fold (HR: 8.6, 95% CI 3.1 to 23.8) increase in the risk of subsequent fractures.ConclusionThese data suggest that subsequent fractures among patients on treatment prescribed in an FLS setting are common, and that an incident fall is a strong predictor of subsequent fracture risk. Immediate attention for fall risk could be beneficial in an FLS model of care.Trial registration numberNL45707.072.13.

Existing fracture risk assessment tools are not designed to predict fracture-associated consequences, possibly contributing to the current undermanagement of fragility fractures worldwide. We aimed to develop a risk assessment tool for predicting the conceptual risk of fragility fractures and its consequences. The study involved 8965 people aged >= 60 years from the Dubbo Osteoporosis Epidemiology Study and the Canadian Multicentre Osteoporosis Study. Incident fracture was identified from X-ray reports and questionnaires, and death was ascertained though contact with a family member or obituary review. We used a multistate model to quantify the effects of the predictors on the transition risks to an initial and subsequent incident fracture and mortality, accounting for their complex interrelationships, confounding effects, and death as a competing risk. There were 2364 initial fractures, 755 subsequent fractures, and 3300 deaths during a median follow-up of 13 years (interquartile range [IQR] 7-15). The prediction model included sex, age, bone mineral density, history of falls within 12 previous months, prior fracture after the age of 50 years, cardiovascular diseases, diabetes mellitus, chronic pulmonary diseases, hypertension, and cancer. The model accurately predicted fragility fractures up to 11 years of follow-up and post-fracture mortality up to 9 years, ranging from 7 years after hip fractures to 15 years after non-hip fractures. For example, a 70-year-old woman with aT-score of -1.5 and without other risk factors would have 10% chance of sustaining a fracture and an 8% risk of dying in 5 years. However, after an initial fracture, her risk of sustaining another fracture or dying doubles to 33%, ranging from 26% after a distal to 42% post hip fracture. A robust statistical technique was used to develop a prediction model for individualization of progression to fracture and its consequences, facilitating informed decision making about risk and thus treatment for individuals with different risk profiles. (c) 2020 American Society for Bone and Mineral Research.

Little is known about the long-term skeletal impact of bariatric procedures, particularly the increasingly commonly performed gastric sleeve surgery (GS). We examined bone density (BMD) change following three types of bariatric surgery Roux-en-Y gastric bypass (RYGB), GS and laparoscopic adjustable gastric banding (LAGB), compared with diet, over 36 months. Non-randomized, prospective study of participants with severe obesity (n = 52), undergoing weight-loss interventions: RYGB (n = 7), GS (n = 21), LAGB (n = 11) and diet (n = 13). Measurements of calciotropic indices, gut hormones (fasting and post prandial) peptide YY (PYY), glucagon-like peptide 1 (GLP1) and adiponectin together with dual-X-ray absorptiometry and quantitative computed tomography scans were performed thorough the study. All groups lost weight during the first 12 months. Despite weight stability from 12 to 36 months and supplementation of calcium and vitamin D, there was progressive bone loss at the total hip (TH) over 36 months in RYGB −14% (95% CI: −12, −17) and GS −9% (95% CI: −7, −10). In RYGB forearm BMD also declined over 36 months −9% (95% CI: −6, −12) and LS BMD declined over the first 12 months −7% (95% CI: −3, −12). RYGB and GS groups experienced significantly greater bone loss until 36 months than LAGB and diet groups, which experienced no significant BMD loss. These bone losses remained significant after adjustment for weight loss and age. RYGB and GS procedures resulted in elevated postprandial PYY, adiponectin and bone turnover markers up to 36 months without such changes among LAGB and diet participants. RYGB and GS but not LAGB resulted in ongoing TH bone loss for three postoperative years. For RYGB, bone loss was also observed at LS and non-weight-bearing forearms. These BMD changes were independent of weight and age differences. We, therefore, recommend close monitoring of bone health following RYGB and GS surgeries.

Muscle strength and physical performance are associated with fracture risk in men. However, it is not known whether these measurements enhance fracture prediction beyond Garvan and FRAX tools. A total of 5665 community-dwelling men, aged ≥65 years, from the Osteoporotic Fractures in Men (MrOS) Study, who had data on muscle strength (grip strength) and physical performance (gait speed and chair stand tests), were followed from 2000 to 2019 for any fracture, major osteoporotic fracture (MOF), initial hip, and any hip fracture. The contributions to different fracture outcomes were assessed using Cox's proportional hazard models. Tool-specific analysis approaches and outcome definitions were used. The added predictive values of muscle strength and physical performance beyond Garvan and FRAX were assessed using categorical net reclassification improvement (NRI) and relative importance analyses. During a median follow-up of 13 (interquartile range 7-17) years, there were 1014 fractures, 536 MOFs, 215 initial hip, and 274 any hip fractures. Grip strength and chair stand improved prediction of any fracture (NRI for grip strength 3.9% and for chair stand 3.2%) and MOF (5.2% and 6.1%). Gait speed improved prediction of initial hip (5.7%) and any hip (7.0%) fracture. Combining grip strength and the relevant performance test further improved the models (5.7%, 8.9%, 9.4%, and 7.0% for any, MOF, initial, and any hip fractures, respectively). The improvements were predominantly driven by reclassification of those with fracture to higher risk categories. Apart from age and femoral neck bone mineral density, muscle strength and performance were ranked equal to or better than the other risk factors included in fracture models, including prior fractures, falls, smoking, alcohol, and glucocorticoid use. Muscle strength and performance measurements improved fracture risk prediction in men beyond Garvan and FRAX. They were as or more important than other established risk factors. These measures should be considered for inclusion in fracture risk assessment tools. © 2021 American Society for Bone and Mineral Research (ASBMR).

Bisphosphonates, potent antiresorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population-based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non-users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox's proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR] = 0.61 [95% confidence interval 0.39-0.96] and 1.35 [95% CI 0.86-2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than 2-fold increased mortality risk compared with no loss. Mediation analysis indicated that 39% (95% CI 7%-84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients. (c) 2019 American Society for Bone and Mineral Research.

Background: Management of osteoporosis following fracture is suboptimal. Multimorbidity adds to clinical management complexity in the elderly but its contribution to the osteoporosis treatment gap has never been investigated. Objectives: To determine the impact of multimorbidity on fracture risk and on osteoporosis investigation and treatment in patients at high fracture risk. Design and Setting: The 45 and Up Study is a prospective population-based cohort study in NSW, Australia with questionnaire data linked to hospital records by the Centre for Health Record Linkage (CHeReL) and the Pharmaceutical Benefits Scheme (PBS) and Medicare Benefits Scheme (MBS) data provided by Department of Human Services. Fractures identified from hospital records, comorbidities from questionnaires, hospital and PBS records. Bone mineral density (BMD) investigation obtained from MBS and treatment for osteoporosis from PBS. Participants: 16191 women and 9089 men with incident low-trauma fracture (2000 - 2017) classified in a high and low-risk group based on 10-year fracture risk threshold of 20% from the Garvan Fracture Risk Calculator (age, gender, prior fracture and falls). Main Outcome Measurements: Association of Charlson comorbidity index (CCI) with fracture. Likelihood of BMD investigation and treatment initiation. Outcomes ascertained by logistic regression and re-fracture risk by Cox models. Results: Individuals at high fracture risk were significantly older [women (mean age ±SD) 77 ± 10 vs 57 ±4 for high- vs low risk and men 86±5 vs 65±8 for high vs low risk] and had a higher morbidity burden [women, CCI ≥ 2 40% vs 12% for high- vs low-risk and men 53% vs 26% for high vs low risk]. Being in the high-risk group as well as a higher CCI were independently associated with > 2-fold higher risk of re-fracture. However, in the high-risk group, only 28% (48% women and 17% men) had a BMD investigation and 31% (24% women and 14% men) received anti-osteoporosis medication post-fracture. A higher CCI was associated with a lower probability of both BMD investigation [CCI 2–3 vs 0–1, RR 0.73 (0.65–0.82) for women, and 0.50 (0.40–0.64) for men and CCI ≥4 vs 0–1, RR 0.50 (0.41- 0.62) for women and 0.36 (0.25–0.52) for men] and treatment initiation [CCI 2–3 vs 0–1, RR 0.88 (0.77–0.98) for women and 0.75 (0.60–0.95) for men and CCI ≥4 vs 0–1, RR 0.75 (0.59- 0.95) for women and 0.35 (0.23–0.53) for men]. Conclusion: Multimorbidity, despite being associated with the highest fracture risk, significantly lowers the likelihood of osteoporosis investigation and treatment. These findings suggest that fracture risk is either under-estimated or under-prioritized in the context of multimorbidity. Our findings highlight the need for improved delivery of fracture preventive care in this setting. More generally, they also point out the need for a better understanding of how problems are prioritized in complex clinical situations.

PURPOSE: Diabetes and fractures are both associated with increased mortality, however the effect of the combination is not well-established. We examined the mortality risk following all types of fractures in type 2 diabetes (T2D). METHODS: In the Dubbo Osteoporosis Epidemiology Study (1989-2017), participants were grouped according to T2D and/or incident fracture. Study outcome was all-cause mortality. First incident radiological fragility fracture and incident T2D diagnosis were time-dependent variables. Cox's proportional hazards models quantified mortality risk associated with T2D and incident fracture overall, as well as by fracture site, T2D duration and T2D medication type. RESULTS: In 3618 participants (62% women), 272 had baseline and 179 developed T2D over median 13.0 years (IQR 8.2-19.6). 796 women (56 with T2D) and 240 men (25 with T2D) sustained a fracture. Compared to those without T2D or fracture, mortality risk increased progressively, in T2D without fracture, then no T2D with fracture, and was highest in those with T2D with fracture (adjusted hazard ratio (aHR) (95% CI) for women 2.62 (1.75-3.93) and men 2.61 (1.42-4.81)). Within T2D participants, incident fracture was associated with increased mortality (aHR for women 1.87 (1.10-3.16) and men 2.83 (1.41-5.68)), especially following hip/vertebral fractures in men (aHR 2.97 (1.29-6.83)) and non-hip non-vertebral fractures in women (aHR 2.42 (1.24-4.75)), and in T2D duration >5 years. CONCLUSION: Any fracture in T2D conferred significant excess mortality. Individuals with T2D should be carefully monitored post-fracture, especially if T2D >5 years. Optimising fracture prevention and post-fracture management in T2D is critical and warrants further studies.

Osteoporotic fracture represents a growing public health problem worldwide. Fracture is not benign, being associated with significant risk of future fracture, disability, loss of independence, and premature mortality. This chapter reviews the epidemiology of imminent fracture risk, and its associated outcomes, including disability, institutionalizations, and premature mortality. Imminent fracture risk occurs predominantly following a prior fracture. Virtually all types of fractures are associated with at least twofold risk of a subsequent fracture, and this risk is highest in the first 2 years following the initial fracture. As well as increased risk of imminent fracture, all fractures are associated with significant disability and premature mortality. While these outcomes are worse for hip and vertebral fractures, nonhip and nonvertebral fractures contribute to a greater population burden due to their high prevalence (>50% of all fractures) and constitute up to 40% of the overall excess mortality. Antiosteoporosis treatment not only reduces fracture risk but may also decrease mortality.

Muscle strength and physical performance are associated with fracture risk in men. However, it is not known whether these measurements enhance fracture prediction beyond Garvan and FRAX tools. A total of 5665 community-dwelling men, aged 65+, from the Osteoporotic Fractures in Men (MrOS) Study, who had data on muscle strength (grip strength) and physical performance (gait speed and chair stand tests), were followed from 2000 to 2019 for any fracture, major osteoporotic fracture (MOF), initial hip and any hip fracture. The contributions to different fracture outcomes were assessed using Cox's proportional hazard models. Tool-specific analysis approaches and outcome definitions were used. The added predictive values of muscle strength and physical performance beyond Garvan and FRAX were assessed using categorical net reclassification improvement (NRI) and relative importance analyses. During a median follow-up of 13 (IQR: 7-17) years, there were 1014 fractures, 536 MOFs, 215 initial hip and 274 any hip fractures. Grip strength and chair stand improved prediction of any fracture (NRI for grip strength: 3.9% and for chair stand: 3.2%) and MOF (5.2% and 6.1%). Gait speed improved prediction of initial hip (5.7%) and any hip (7.0%) fracture. Combining grip strength and the relevant performance test further improved the models (5.7%, 8.9%, 9.4% and 7.0% for any, MOF, initial, and any hip fractures, respectively). The improvements were predominantly driven by reclassification of those with fracture to higher risk categories. Apart from age and FNBMD, muscle strength and performance were ranked equal to or better than the other risk factors included in fracture models including prior fractures, falls, smoking, alcohol, and glucocorticoid use. Muscle strength and performance measurements improved fracture risk prediction in men beyond Garvan and FRAX. They were as or more important than other established risk factors. These measures should be considered for inclusion in fracture risk assessment tools. This article is protected by copyright. All rights reserved.

A proportion of circulating 25-hydroxy vitamin D3 (25(OH)D3)) undergoes epimerization to form C3-epi 25(OH)D3 and C3-epi 1,25(OH)2D3. These epimers have less calcaemic activity than non-epimerized metabolites and are not differentiated by many immunoassays when reporting total 25(OH)D3 levels. This study aimed to compare the effect of exposure to ultraviolet radiation (UVR) and oral vitamin D3 supplementation on vitamin D C3-epimer levels. C57Bl/6 female mice were fed either vitamin D-sufficient (vitamin D3 2000 IU/kg) or -deficient diets (no vitamin D3) for 4 weeks. Among the vitamin D-deficient group, the shaved backs of half were irradiated daily for 4 days with 1 kJ/m2 UVR, followed by twice weekly irradiation for 4 weeks. Despite similar 25(OH)D3 levels, the UV-irradiated group had a lower proportion of C3-epi 25(OH)D3 at week 7 (p < 0.05) and week 9 (p < 0.01). C3-epimer concentrations and %C3-epi 25(OH)D3 were also analysed in serum samples from two human clinical trials. These trials investigated the effect of high dose oral vitamin D3 supplementation and narrowband UVB phototherapy, respectively. Serum 25(OH)D3 and the %C3-epi 25(OH)D3 levels measured at 12 months after oral vitamin D3 supplementation were not significantly different to those measured at the time of maximal effect of phototherapy (2 months). Thus, the proportion of 25(OH)D3 that undergoes epimerization is greater with oral vitamin D3 supplementation than exposure to UVR in mice, but not in humans. This important difference between human and murine vitamin D metabolism warrants consideration when interpreting animal studies.

There is increasing evidence that all proximal and not just hip fractures are associated with increased mortality risk. However, the cause of this increased mortality is unknown. We sought to determine the post-fracture trajectories of subsequent hospital admissions and mortality to develop an understanding of why patients with non-hip fractures die prematurely. This nationwide Danish population-based study included all individuals aged 50+ years who sustained an incident fragility fracture between 2001 and 2014. High-trauma fractures or individuals with fracture prior to 2001 were excluded. Fracture patients were matched 1:4 by sex, age and comorbidity status with non-fracture subjects alive at the time of fracture. Comorbidities included 33 unique medical conditions of the Charlson or Elixhauser comorbidity index. We modelled the contribution of specific fractures on the risk of subsequent admissions or death within the following 2 years. There were 212,498 women and 95,372 men with fracture followed by 30,677 and 19,519 deaths, respectively over 163,482 and 384,995 person-years of follow up. Mean age at fracture was 72± 11 for women and 75± 11 for men. Proximal fractures including hip, femur, pelvis, rib, clavicle and humerus had increased mortality compared with their matched non-fracture counterparts with HRs ranging from 1.5-4.0, while distal fractures such as ankle, forearm, hand or foot fractures had similar or lower mortality risk. Almost 75% of men and 60% of women had ≥1 comorbidity. For every additional comorbidity, risk of mortality increased for all fracture types. However, only for proximal fractures did the fracture itself independently increase mortality risk over and above co-morbidity status. The 2-yr post fracture admission and mortality patterns differed between proximal and distal fractures. Proximal, but not distal fracture subjects had greater risk of any major hospital admission (including cardiovascular disease, cancer, stroke, diabetes, pneumonia and pulmonary disease) within 2 years compared with their non-fracture counterparts. Distal fractures in general had similar admission patterns as their non-fractured matched counterparts. Furthermore, 2 year mortality risk was increased for proximal fractures whether or not they were admitted to hospital post fracture. By contrast, mortality risk was similar or reduced for distal fractures compared with non-fracture controls. This study has not only confirmed the increased mortality following proximal fractures but has demonstrated differing clinical trajectories between proximal and distal fractures that contribute to this increased mortality. These findings provide important insights as to why proximal fracture subjects die prematurely that may lead to specific avenues for intervention.

Bisphosphonates are first line agents used to treat osteoporosis and reduce fracture rate. They bind to areas of exposed calcium in the skeleton and cause osteoclast apoptosis, thereby leading to a reduction in remodelling rates. They are also used to decrease skeletal complications of some cancers including a reduction in bone metastases. Following the landmark randomised controlled trial of zoledronate post hip fracture (HORIZON) in which an unexpected survival benefit was found, there has been increasing interest in their potential ability to increase lifespan. This review will consider the clinical evidence for their effect on mortality in both the osteoporosis and non-osteoporosis settings, the latter including studies in intensive care, cancer and cardiovascular disease. Where evidence exists, this review will briefly discuss some of the postulated mechanisms for this survival benefit.

Pharmacoepidemiology is used extensively in osteoporosis research and involves the study of the use and effects of drugs in large numbers of people. Randomized controlled trials are considered the gold standard in assessing treatment efficacy and safety. However, their results can have limited external validity when applied to day‐to‐day patients. Pharmacoepidemiological studies aim to assess the effect/s of treatments in actual practice conditions, but they are limited by the quality, completeness, and inherent bias due to confounding. Sources of information include prospectively collected (primary) as well as readily available routinely collected (secondary) (eg, electronic medical records, administrative/claims databases) data. Although the former enable the collection of ad hoc measurements, the latter provide a unique opportunity for the study of large representative populations and for the assessment of rare events at relatively low cost. Observational cohort and case‐control studies, the most commonly implemented study designs in pharmacoepidemiology, each have their strengths and limitations. However, the choice of the study design depends on the research question that needs to be answered. Despite the many advantages of observational studies, they also have limitations. First, missing data is a common issue in routine data, frequently dealt with using multiple imputation. Second, confounding by indication arises because of the lack of randomization; multivariable regression and more specific techniques such as propensity scores (adjustment, matching, stratification, trimming, or weighting) are used to minimize such biases. In addition, immortal time bias (time period during which a subject is artefactually event‐free by study design) and time‐varying confounding (patient characteristics changing over time) are other types of biases usually accounted for using time‐dependent modeling. Finally, residual “uncontrolled” confounding is difficult to assess, and hence to account for it, sensitivity analyses and specific methods (eg, instrumental variables) should be considered. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Femoral neck (FN) bone mineral density (BMD) is the most commonly used skeletal site to estimate fracture risk. The role of lumbar spine (LS) BMD in fracture risk prediction is less clear due to osteophytes that spuriously increase LS BMD, particularly at lower levels. The aim of this study was to compare fracture predictive ability of upper L1-L2 BMD with standard L2-L4 BMD and assess whether the addition of either LS site could improve fracture prediction over FN BMD. This study comprised a prospective cohort of 3016 women and men over 60 yr from the Dubbo Osteoporosis Epidemiology Study followed up for occurrence of minimal trauma fractures from 1989 to 2014. Dual-energy X-ray absorptiometry was used to measure BMD at L1-L2, L2-L4, and FN at baseline. Fracture risks were estimated using Cox proportional hazards models separately for each site. Predictive performances were compared using receiver operating characteristic curve analyses. There were 565 women and 179 men with a minimal trauma fracture during a mean of 11 ± 7 yr. L1-L2 BMD T-score was significantly lower than L2-L4 T-score in both genders (p 0.0001). L1-L2 and L2-L4 BMD models had a similar fracture predictive ability. LS BMD was better than FN BMD in predicting vertebral fracture risk in women [area under the curve 0.73 (95% confidence interval, 0.68-0.79) vs 0.68 (95% confidence interval, 0.62-0.74), but FN was superior for hip fractures prediction in both women and men. The addition of L1-L2 or L2-L4 to FN BMD in women increased overall and vertebral predictive power compared with FN BMD alone by 1% and 4%, respectively (p 0.05). In an elderly population, L1-L2 is as good as but not better than L2-L4 site in predicting fracture risk. The addition of LS BMD to FN BMD provided a modest additional benefit in overall fracture risk. Further studies in individuals with spinal degenerative disease are needed.

Data on long-term consequences of non-hip non-vertebral (NHNV) fractures, accounting for approximately two-thirds of all fragility fractures, are scanty. Our study aimed to quantify the population-wide impact of NHNV fractures on mortality. The national population-based prospective cohort study (Canadian Multicentre Osteoporosis Study) included 5526 community dwelling women and 2163 men aged 50 years or older followed from July 1995 to September 2013. Population impact number was used to quantify the average number of people for whom one death would be attributable to fracture and case impact number to quantify the number of deaths out of which one would be attributable to a fracture. There were 1370 fragility fractures followed by 296 deaths in women (mortality rate: 3.49; 95% CI, 3.11 to 3.91), and 302 fractures with 92 deaths in men (5.05; 95% CI, 4.12 to 6.20). NHNV fractures accounted for three-quarters of fractures. In women, the population-wide impact of NHNV fractures on mortality was greater than that of hip and vertebral fractures because of the greater number of NHNV fractures. Out of 800 women, one death was estimated to be attributable to a NHNV fracture, compared with one death in 2000 women attributable to hip or vertebral fracture. Similarly, out of 15 deaths in women, one was estimated to be attributable to a NHNV fracture, compared with one in over 40 deaths for hip or vertebral fracture. The impact of forearm fractures (ie, one death in 2400 women and one out of 42 deaths in women attributable to forearm fracture) was similar to that of hip, vertebral, or rib fractures. Similar, albeit not significant, results were noted for men. The study highlights the important contribution of NHNV fractures on mortality because many NHNV fracture types, except for the most distal fractures, have serious adverse consequences that affect a significant proportion of the population. © 2017 American Society for Bone and Mineral Research.

Context Muscle strength and performance are associated with fractures. However, the contribution of their rate of decline is unclear. Objective To assess the independent contribution of the rate of decline in muscle strength and performance to fracture risk. Design, Setting, and Participants Community-dwelling women (n = 811) and men (n = 440) aged 60 years or older from the prospective Dubbo Osteoporosis Epidemiology Study followed from 2000 to 2018 for incident fracture. Clinical data, appendicular lean mass/height2 (ht)2, bone mineral density, quadricep strength/ht (QS), timed get-up-and-go (TGUG), 5 times repeated sit-to-stand (5xSTS), and gait speed (GS) measured biennially. Rates of decline in muscle parameters were calculated using ordinary least squares regression and fracture risk was assessed using Cox’s models. Main Outcome Incident low-trauma fracture ascertained by x-ray report. Results Apart from lean mass in women, all muscle parameters declined over time. Greater rates of decline in physical performance were associated with increased fracture risk in women (Hazard ratios [HRs] ranging from 2.1 (95% CI: 1.5–2.9) for GS to 2.7 (95% CI: 1.9–3.6) for 5xSTS, while in men only the decline in GS was associated with fracture risk (HR: 3.4 [95% CI: 1.8–6.3]). Baseline performance and strength were also associated with increased fracture risk in men (HRs ranging from 1.8 (95% CI: 1.1–3.0) for QS to 2.5 (95% CI: 1.5–4.1) for TGUG, but not in women. Conclusion Rate of decline in physical performance in both genders, and baseline strength and performance in men, contributed independently to fracture risk. Sit-to-stand and GS were the tests most consistently associated with fractures. Further studies are required to determine whether muscle strength and/or performance improve the predictive accuracy of fracture prediction models.

Oral bisphosphonates (oBPs) have been associated with reduced fractures and mortality. However, their risks and benefits are unclear in patients with moderate–severe CKD. This study examined the association between oBPs and all-cause mortality in G3B-5D CKD. This is a population-based cohort study including all subjects with an estimated glomerular filtration rate (eGFR) 2 (G3B: eGFR 2 G4: eGFR 15–29/mL/min/1.73 m 2 G5: eGFR 2 G5D: hemodialysis) aged 40+ years from the UK Clinical Practice Research Datalink (CPRD) and the Catalan Information System for Research in Primary Care (SIDIAP). Previous and current users of other anti-osteoporosis drugs were excluded. oBP use was modeled as a time-varying exposure to avoid immortal time bias. Treatment episodes in oBP users were created by concatenating prescriptions until patients switched or stopped therapy or were censored or died. A washout period of 180 days was added to (date of last prescription +180 days). Propensity scores (PSs) were calculated using prespecified predictors of mortality including age, gender, baseline eGFR, socioeconomic status, comorbidities, previous fracture, co-medications, and number of hospital admissions in the previous year. Cox models were used for PS adjustment before and after PS trimming (the first and last quintiles). In the CPRD, of 19,351 oBP users and 210,954 non-oBP users, 5234 (27%) and 85,105 (40%) deaths were recorded over 45,690 and 915,867 person-years of follow-up, respectively. oBP users had 8% lower mortality risk compared to non-oBP users (hazard ratio [HR] 0.92; 95% CI, 0.89 to 0.95). Following PS trimming, this became nonsignificant (HR 0.98; 95% CI, 0.94 to 1.04). In the SIDIAP, of 4146 oBP users and 86,127 non-oBP users, 1330 (32%) and 36,513 (42%) died, respectively. oBPs were not associated with mortality in PS adjustment and trimming (HR 1.04; 95% CI, 0.99 to 1.1 and HR 0.95; 95% CI, 0.89 to 1.01). In this observational, patient-based cohort study, oBPs were not associated with increased mortality among patients with moderate–severe CKD. However, further studies are needed on other effects of oBPs in CKD patients.

Increased mortality risk is accepted for hip and vertebral fracture. Recent data suggest that other fracture types have also been linked to excess mortality. This article reviews the existing evidence on the pattern and determinants of postfracture mortality.The pattern of mortality over time following hip and vertebral fractures has recently been clarified. Nonhip nonvertebral fractures at major, and even minor sites in older individuals have also been associated with excess mortality. Studies have revealed the higher excess mortality in men and in younger age groups for all fracture types. Despite the increasing knowledge on the fracture-mortality association, little is known about its cause. The role of co-morbidities is inconsistent across studies. Recent findings suggest low bone mass, bone loss and muscle weakness are linked to both fracture and mortality risk, and thus may play a role in postfracture mortality.Nonhip nonvertebral fractures have recently been associated with mortality risk. Larger studies are needed to better understand which specific fractures and factors contribute to fracture-associated mortality risk. The role of bone loss in postfracture mortality needs to be validated in more studies, because of its potential reversibility with antifracture therapies.

Context: Hip fracture incidence has been declining and life expectancy improving. However, trends of postfracture outcomes are unknown. Objectives: The objective of the study was to compare the refracture risk and excess mortality after osteoporotic fracture between two birth cohorts, over 2 decades. Design: Prospective birth cohorts were followed up over 2 decades (1989–2004 and 2000–2014). Setting: The study was conducted in community-dwelling participants in Dubbo, Australia. Participants: Women and men aged 60–80 years, participating in Dubbo Osteoporosis Epidemiology Study 1 (DOES 1; born before 1930) and Dubbo Osteoporosis Epidemiology Study 2 (DOES 2; born after 1930) participated in the study. Main Outcome Measure: Age-standardized fracture and mortality over two time intervals: (1989–2004 [DOES 1] and 2000–2014 [DOES 2]) were measured. Results: The DOES 2 cohort had higher body mass index and bone mineral density and lower initial fracture rate than DOES 1, but similar refracture rates [age-standardized refracture rates per 1000 person-years: women: 53 (95% confidence interval [CI] 42–63) and 51 (95% CI 41–60) and men: 53 (95% CI 38–69) and 55 (95% CI 40–71) for DOES 2 and DOES 1, respectively). Absolute postfracture mortality rates declined in DOES 2 compared with DOES 1, mirroring the improvement in general-population life expectancy. However, when compared with period-specific general-population mortality, there was a similar 2.1- to 2.6-fold increased mortality risk after a fracture in both cohorts (age-adjusted standardized mortality ratio, women: 2.05 [95% CI 1.43–2.83] and 2.43 [95% CI 1.95–2.99] and men: 2.56 [95% CI 1.78–3.58] and 2.48 [95% CI 1.87–3.22] for DOES 2 and DOES 1, respectively). Conclusion: Over the 2 decades, despite the decline in the prevalence of fracture risk factors, general-population mortality, and initial fracture incidence, there was no improvement in postfracture outcomes. Refracture rates were similar and fracture-associated mortality was 2-fold higher than expected. These data indicate that the low postfracture treatment rates are still a major problem.

Osteoporotic fracture is a growing public health problem worldwide. Because of the ageing of most populations, the number of people who will sustain a fracture is predicted to increase significantly over the next few decades. This chapter reviews the epidemiology of osteoporotic fracture and its outcomes, including subsequent fracture and associated premature mortality. All osteoporotic fractures are associated with an approximate twofold increased risk of a subsequent fracture, with the greatest risk of refracture occurring close in time to the initial fracture. This risk is higher in men than in women. Although hip and vertebral fractures are considered the most serious of fracture types, nonhip nonvertebral fractures account for more than 50% of initial and subsequent fractures. In addition, all proximal fractures are associated with an increased mortality risk, which is highest close to the fracture event and persists for at least 5 years before declining to the background population mortality rate. A subsequent fracture further increases this risk. Antiresorptive medication may be associated with improved survival in those at fracture risk. It is now clear that osteoporotic fracture is associated with poor outcomes, and early intervention is essential to reduce the subsequent fracture and possibly also mortality risk.

Context: Little is known about long-term excess mortality following fragility nonhip fractures. Objective: The study aimed to determine which fracture was associated with excess mortality and for how long the postfracture excess mortality persisted. Design, Setting, and Patients: This nationwide registry-based follow-up study included all individuals in Denmark aged 50+ years who first experienced fragility fractures in 2001 and were followed up for up to 10 years for their mortality risk. Main Outcome Measure: The contribution of fracture to mortality at precise postfracture time intervals was examined using relative survival analysis, accounting for time-related mortality changes in the background population. Results: There were 21,123 women (aged 72 +/- 13 years) and 9481 men (aged 67 +/- 12 years) with an incident fragility fracture in 2001, followed by 10,668 and 4745 deaths, respectively. Excess mortality was observed following all proximal and lower leg fractures. The majority of deaths occurred within the first year after fracture, and thereafter excess mortality gradually declined. Hip fractures were associated with the highest excess mortality (33% and 20% at 1 year after fracture in men and women, respectively). One-year excess mortality after fracture of a femur or pelvis was 20% to 25%; vertebrae, 10%; humerus, rib, or clavicle, 5% to 10%; and lower leg, 3%. A significant although smaller excess mortality was still observed until 10 years for hip fractures and -5 years after femur, other proximal, and lower leg fractures. Conclusion: This study highlights the important contribution of a wide variety of fragility fractures to long-term excess mortality and thus the potential for benefit from early intervention. This work was supported by the National Health Medical Research Council Australia Project Grants nos.1070187 (to T.T., D.B., J.A.E, T.V.N, and J.R.C), 1008219 (to J.R.C.), and 1073430 (to D.B.). Other funding sources were an Osteoporosis Australia-Amgen grant, the Bupa Health Foundation (formerly MBE Foundation), the Mrs. Gibson and Ernest Heine Family Foundation, and untied grants from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Servier, and Novartis. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

© 2019, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: In this prospective cohort of 6120 participants aged 50+, nitrogen-bisphosphonates but not non-nitrogen bisphosphonates were associated with a significant 34% mortality risk reduction compared to non-treated propensity score matched controls. These findings open new avenues for research into mechanistic pathways. Introduction: Emerging evidence suggests that bisphosphonates (BP), first-line treatment of osteoporosis, are associated with reduced risks for all-cause mortality. This study aimed to determine the association between different BP types and mortality risk in participants with or without a fracture. Methods: A prospective cohort study of users of different BPs matched to non-users by propensity score (age, gender, co-morbidities, fragility fracture status) and time to starting the BP medication from the population-based Canadian Multicentre Osteoporosis Study from nine Canadian centres followed from 1995 to 2013. Mortality risk for bisphosphonate users vs matched non-users was assessed using pairwise multivariable Cox proportional hazards models. Results: There were 2048 women and 308 men on BP and 1970 women and 1794 men who did not receive medication for osteoporosis. The relationship between BP and mortality risk was explored in three separate 1:1 propensity score-matched cohorts of BP users and no treatment (etidronate, n = 599, alendronate, n = 498, and risedronate n = 213). Nitrogen BP (n-BP) (alendronate and risedronate) was associated with lower mortality risks [pairwise HR, 0.66 (95% CI, 0.48–0.91)] while the less potent non-n-BP, etidronate, was not [pairwise HR: 0.89 (95% CI, 0.66–1.20)]. A direct comparison between n-BP and etidronate (n = 340 pairs) also suggested a better survival for n-BP [paired HR, 0.47 (95%CI, (95% CI, 031–0.70)] for n-BP vs. etidronate]. Conclusion: Compared to no treatment, nitrogen but not non-nitrogen bisphosphonates appear to be associated with better survival.

Fracture risk estimates are usually based on femoral neck (FN) BMD. It is unclear how to address T-score discordance, where lumbar spine (LS) T-score is lower than FN T-score. The objective of this work was to examine the impact of LS BMD on fracture risk, in individuals with lower LS T-score than FN T-score. Participants aged 60+ years from the Dubbo Osteoporosis Epidemiology Study with LS and FN BMD measured at first visit, and were followed from 1989 to 2014. Five-hundred and seventy-three (573) of 2270 women and 131 of 1373 men had lower LS than FN T-score by ≥ 0.6 standard deviation (SD) (low-LS group based on least significant change). In low-LS women, each 1 SD lower LS T-score than FN was associated with a 30% increase in fracture risk (hazard ratio [HR] 1.30; 95% CI, 1.11 to 1.45). For low-LS men there was a 20% nonsignificant increase in fracture risk for each 1 SD lower LS than FN T-score (HR 1.20; 95% CI, 0.10 to 1.67). Low-LS women had greater absolute fracture risks than the rest of the women. This increased risk was more apparent for lower levels of FN T-score and in older age groups. At an FN T-score of -2, low-LS women had a 3%, 10%, and 23% higher 5-year absolute fracture risk than non-low LS women in the 60 to 69 year, 70 to 79 year, and 80+ years age-groups, respectively. Furthermore, an osteoporotic LS T-score increased 5-year absolute fracture risk for women with normal or osteopenic FN T-score by 10% to 13%. Men in the low-LS group had very few fractures; therefore, a meaningful analyses of fracture risk could not be conducted. This study shows the significant contribution of lower LS BMD to fracture risk over and above FN BMD in women. A LS BMD lower than FN BMD should be incorporated into fracture risk calculators at least for women in older age-groups.

Half of fragility fractures occur in individuals with nonosteoporotic BMD (BMD T-score > -2.5); however, there is no information on postfracture adverse events of subsequent fracture and mortality for different BMD levels. The objective of this work was to determine the risk and predictors of subsequent fracture and excess mortality following initial fracture according to BMD. The subjects were community-dwelling participants aged 60+ years from the Dubbo Osteoporosis Epidemiology Study with incident fractures followed from 1989 to 2011. The outcome measurements were as follows: risk of subsequent fracture and mortality according to BMD categorized as normal (T-score -2.5), and osteoporosis (T-score ≤ -2.5). There were 528 low-trauma fractures in women and 187 in men. Of these, 12% occurred in individuals with normal BMD (38 women, 50 men) and 42% in individuals with osteopenia (221 women, 76 men). The relative risk (RR) of subsequent fracture was >2.0-fold for all levels of BMD (normal BMD: 2.0 [1.2 to 3.3] for women and 2.1 [1.2 to 3.8] for men; osteopenia: 2.1 [1.7 to 2.6] for women and 2.5 [1.6 to 4.1] for men; and osteoporosis 3.2 [2.7 to 3.9] for women and 2.1 [1.4 to 3.1] for men. The likelihood of falling and reduced quadriceps strength contributed to subsequent fracture risk in women with normal BMD. By contrast with subsequent fracture risk, postfracture mortality was increased particularly in individuals with low BMD (age-adjusted standardized mortality ratio [SMR] for osteopenia 1.3 [1.1 to 1.7] and 2.2 [1.7 to 2.9] for women and men, respectively, and osteoporosis 1.7 [1.5 to 2.0] and 2.7 [2.0 to 3.6] for women and men, respectively). This study demonstrates the high burden of subsequent fracture in individuals with normal BMD and osteopenia, and excess mortality particularly for those with osteopenia (and osteoporosis). These findings highlight the importance of these fractures and underscore the gap in evidence for benefit of antiosteoporotic treatment for fragility fracture, in those with only mildly low BMD.

Bone loss, a fracture risk factor, may play a role in post-fracture mortality. We found accelerated bone loss (≥1.31 % bone loss/year for women and ≥1.35 % bone loss/year for men) associated with 44–77 % increased mortality. It remains unclear whether bone loss is a marker or plays a role in mortality. Osteoporotic fractures are associated with increased mortality although the cause is unknown. Bone loss, a risk factor for osteoporotic fracture is also associated with increased mortality, but its role in mortality risk post-fracture is unclear. This study aimed to examine post-fracture mortality risk according to levels of bone loss. Community-dwelling participants aged 60+ from Dubbo Osteoporosis Epidemiology Study with incident fractures were followed from 1989 to 2011. Kaplan-Meier survival curves were constructed according to bone loss quartiles. Cox proportional hazard models were used to determine the effect of bone loss on mortality. There were 341 women and 106 men with ≥2 BMD measurements. The rate of bone loss was similar for women and men (women mean −0.79 %/year, highest bone loss quartile −1.31 %/year; men mean −0.74 %/year, highest quartile −1.35 %/year). Survival was lowest for the highest quartile of bone loss for women (p

Nonhip, nonvertebral (NHNV) fractures constitute the majority of osteoporotic fractures, but few studies have examined the association between these fractures, comorbidity, and mortality. Our objective was to examine the relationship between individual nonhip, nonvertebral fractures, comorbidities, and mortality. The prospective population-based cohort of 267,043 subjects (45 and Up Study, Australia) had baseline questionnaires linked to hospital administrative and all-cause mortality data from 2006 to 2013. Associations between fracture and mortality were examined using multivariate, time-dependent Cox models, adjusted for age, prior fracture, body mass index, smoking, and comorbidities (cardiovascular disease, diabetes, stroke, thrombosis, and cancer), and survival function curves. Population attributable fraction was calculated for each level of risk exposure. During 1,490,651 person-years, women and men experienced 7571 and 4571 fractures and 7064 deaths and 11,078 deaths, respectively. In addition to hip and vertebral fractures, pelvis, humerus, clavicle, rib, proximal tibia/fibula, elbow and distal forearm fractures in both sexes, and ankle fractures in men were associated with increased multivariable-adjusted mortality hazard ratios ranging from 1.3 to 3.4. Comorbidity independently added to mortality such that a woman with a humeral fracture and 1 comorbidity had a similarly reduced 5-year survival as that of a woman with a hip fracture and no comorbidities. Population mortality attributable to any fracture without comorbidity was 9.2% in women and 5.3% in men. All proximal nonhip, nonvertebral fractures in women and men were associated with increased mortality risk. Coexistent comorbidities independently further increased mortality. Population attributable risk for mortality for fractures was similar to cardiovascular disease and diabetes, highlighting their importance and potential benefit for early intervention and treatment. © 2018 American Society for Bone and Mineral Research.