Dana Bliuc

Mortality Risk Associated With Low-Trauma Osteoporotic Fracture and Subsequent Fracture in Men and Women

CONTEXT There are few data on long-term mortality following osteoporotic fracture and fewer following subsequent fracture. OBJECTIVES To examine long-term mortality risk in women and men following all osteoporotic fractures and to assess the association of subsequent fracture with that risk. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort from the Dubbo Osteoporosis Epidemiology Study of community-dwelling women and men aged 60 years and older from Dubbo, Australia, who sustained a fracture between April 1989 and May 2007. MAIN OUTCOME MEASURES Age- and sex-specific standardized mortality ratios (SMRs) compared with the overall Dubbo population for hip, vertebral, major, and minor fractures. RESULTS In women, there were 952 low-trauma fractures followed by 461 deaths, and in men, 343 fractures were followed by 197 deaths. Age-adjusted SMRs were increased following hip fractures (SMRs, 2.43 [95% confidence interval [CI], 2.02-2.93] and 3.51 [95% CI, 2.65-4.66]), vertebral fractures (SMRs, 1.82 [95% CI, 1.52-2.17] and 2.12 [95% CI, 1.66-2.72]), major fractures (SMRs, 1.65 [95% CI, 1.31-2.08] and 1.70 [95% CI, 1.23-2.36]), and minor fractures (SMRs, 1.42 [95% CI, 1.19-1.70] and 1.33 [95% CI, 0.99-1.80]) for both women and men, respectively. Mortality was increased for all ages for all fractures except minor fractures for which increased mortality was only apparent for those older than 75 years. Increased mortality risk persisted for 5 years for all fractures and up to 10 years for hip fractures. Increases in absolute mortality that were above expected, for 5 years after fracture, ranged from 1.3 to 13.2 per 100 person-years in women and from 2.7 to 22.3 per 100 person-years in men, depending on fracture type. Subsequent fracture was associated with an increased mortality hazard ratio of 1.91 (95% CI, 1.54-2.37) in women and 2.99 (95% CI, 2.11-4.24) in men. Mortality risk following a subsequent fracture then declined but beyond 5 years still remained higher than in the general population (SMR, 1.41 [95% CI, 1.01-1.97] and SMR, 1.78 [95% CI, 0.96-3.31] for women and men, respectively). Predictors of mortality after any fragility fracture for both men and women included age, quadriceps weakness, and subsequent fracture but not comorbidities. Low bone mineral density, having smoked, and sway were also predictors for women and less physical activity for men. CONCLUSIONS In a sample of older women and men, all low-trauma fractures were associated with increased mortality risk for 5 to 10 years. Subsequent fracture was associated with increased mortality risk for an additional 5 years.

Osteoporosis Medication and Reduced Mortality Risk in Elderly Women and Men

CONTEXT Osteoporotic fractures are associated with premature mortality. Antiresorptive treatment reduces refracture but mortality reduction is unclear. OBJECTIVE The objective of the study was to examine the effect of osteoporosis treatment [bisphosphonates (BP), hormone therapy (HT), and calcium ± vitamin D only (CaD)] on mortality risk. DESIGN This was a prospective cohort study (April 1989 to May 2007). SETTING The study was conducted with community-dwelling elderly (aged 60+ yr) subjects in Dubbo, a semiurban city, Australia. SUBJECTS Subjects included 1223 and 819 women and men in the Dubbo Osteoporosis Epidemiology Study. MAIN OUTCOME MEASURE Mortality according to treatment group was recorded. RESULTS There were 325 (BP, n = 106; HT, n = 77; CaD, n = 142) women and 37 men (BP, n = 15; CaD, n = 22) on treatment. In women, mortality rates were lower with BP 0.8/100 person-years (0.4, 1.4) and HT 1.2/100 person-years (0.7, 2.1) but not CaD 3.2/100 person-years (2.5, 4.1) vs. no treatment 3.5/100 person-years (3.1, 3.8). Accounting for age, fracture occurrence, comorbidities, quadriceps strength, and bone mineral density, mortality risk remained lower for women on BP [hazard ratio (HR) 0.3 (0.2, 0.6)] but not HT [HR 0.8 (0.4, 1.8)]. For 429 women with fractures, mortality risk was still reduced in the BP group [adjusted HR 0.3 (0.2, 0.7)], not accounted for by a reduction in subsequent fractures. In men, lower mortality rates were observed with BP but not CaD [BP 1.0/100 person-years (0.3, 3.9) and CaD 3.1/100 person-years (1.5, 6.6) vs. no treatment 4.3/100 person-years (3.9, 4.8)]. After adjustment, mortality was similar, although not significant [HR 0.5 (0.1, 2.0)]. CONCLUSIONS Osteoporosis therapy appears to reduce mortality risk in women and possibly men.

Compound risk of high mortality following osteoporotic fracture and refracture in elderly women and men

After fracture there is increased risk of refracture and premature mortality. These outcomes, particularly premature mortality following refracture, have not previously been studied together to understand overall mortality risk. This study examined the long‐term cumulative incidence of subsequent fracture and total mortality with mortality calculated as a compound risk and separated according to initial and refracture. Community‐dwelling participants aged 60+ years from Dubbo Osteoporosis Epidemiology Study with incident fractures, followed prospectively for further fractures and deaths from 1989 to 2010. Subsequent fracture and mortality ascertained using cumulative incidence competing risk models allowing four possible outcomes: death without refracture; death following refracture; refracture but alive, and event‐free. There were 952 women and 343 men with incident fracture. Within 5 years following initial fracture, 24% women and 20% men refractured; and 26% women and 37% men died without refracture. Of those who refractured, a further 50% of women and 75% of men died, so that total 5‐year mortality was 39% in women and 51% in men. Excess mortality was 24% in women and 27% in men. Although mortality following refracture occurred predominantly in the first 5 years post–initial fracture, total mortality (post‐initial and refracture) was elevated for 10 years. Most of the 5‐year to 10‐year excess mortality was associated with refracture. The long‐term (>10 years) refracture rate was reduced, particularly in the elderly as a result of their high mortality rate. The 30% alive beyond 10 years postfracture were at low risk of further adverse outcomes. Refractures contribute substantially to overall mortality associated with fracture. The majority of the mortality and refractures occurred in the first 5 years following the initial fracture. However, excess mortality was observed for up to 10 years postfracture, predominantly related to that after refracture.

Risk of subsequent fractures and mortality in elderly women and men with fragility fractures with and without osteoporotic bone density: the Dubbo Osteoporosis Epidemiology Study.

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 < –1), osteopenia (T‐score ≤ –1 and > –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.

The Impact of Nonhip Nonvertebral Fractures in Elderly Women and Men

CONTEXT Nonhip nonvertebral fractures represent half of all osteoporotic fractures; however, their contribution to the burden of refracture and premature mortality is unclear. OBJECTIVES To examine the risk and burden of subsequent fracture and mortality associated with an initial nonhip nonvertebral fracture. SETTING AND PARTICIPANTS This is a prospective cohort from the Dubbo Osteoporosis Epidemiology Study, 1989-2010 of community dwelling participants aged 60+ with incident fractures. OUTCOME MEASURES Relative risk of all subsequent fractures and age-adjusted standardized mortality ratios were calculated according to initial fracture type. The total burden of adverse events was assessed using competing risk models with four potential outcomes: mortality after initial fracture, mortality after subsequent fracture, subsequent fracture and alive, or event-free. RESULTS Of the 952 fractures in women and 343 in men, over half were nonhip nonvertebral fractures (486 in women and 173 in men). Nonhip nonvertebral fractures were associated with increased risk of any subsequent fracture (1.95 [1.67-2.27] for women and 2.47 [1.82-3.35] for men), hip refracture (2.11 [1.04-4.28] for women and 2.63 [1.35-5.13] for men), and vertebral refracture (1.89 [1.43-2.48] for women and 2.13 [1.20-3.79] for men). More importantly, nonhip nonvertebral fractures were associated overall with 20% excess mortality for the first 5 years postfracture, of which approximately half were due to initial fracture and the remaining due to subsequent fractures. Proximal fractures were associated with increased mortality risk per se, whereas distal fractures were associated with increased mortality risk only in the group who sustained subsequent fractures. CONCLUSION Nonhip nonvertebral fractures are associated with significant risk of subsequent fracture including hip and vertebral refracture, and premature mortality. Due to their high prevalence, about half of all subsequent fractures and a quarter of all fracture-related excess mortality were attributable to nonhip nonvertebral fracture. Thus nonhip nonvertebral fracture warrants early investigation and appropriate intervention.

External Validation of the Garvan Nomograms for Predicting Absolute Fracture Risk: The Tromsø Study

Background Absolute risk estimation is a preferred approach for assessing fracture risk and treatment decision making. This study aimed to evaluate and validate the predictive performance of the Garvan Fracture Risk Calculator in a Norwegian cohort. Methods The analysis included 1637 women and 1355 aged 60+ years from the Tromsø study. All incident fragility fractures between 2001 and 2009 were registered. The predicted probabilities of non-vertebral osteoporotic and hip fractures were determined using models with and without BMD. The discrimination and calibration of the models were assessed. Reclassification analysis was used to compare the models performance. Results The incidence of osteoporotic and hip fracture was 31.5 and 8.6 per 1000 population in women, respectively; in men the corresponding incidence was 12.2 and 5.1. The predicted 5-year and 10-year probability of fractures was consistently higher in the fracture group than the non-fracture group for all models. The 10-year predicted probabilities of hip fracture in those with fracture was 2.8 (women) to 3.1 times (men) higher than those without fracture. There was a close agreement between predicted and observed risk in both sexes and up to the fifth quintile. Among those in the highest quintile of risk, the models over-estimated the risk of fracture. Models with BMD performed better than models with body weight in correct classification of risk in individuals with and without fracture. The overall net decrease in reclassification of the model with weight compared to the model with BMD was 10.6% (p = 0.008) in women and 17.2% (p = 0.001) in men for osteoporotic fractures, and 13.3% (p = 0.07) in women and 17.5% (p = 0.09) in men for hip fracture. Conclusions The Garvan Fracture Risk Calculator is valid and clinically useful in identifying individuals at high risk of fracture. The models with BMD performed better than those with body weight in fracture risk prediction.

Population-wide impact of non-hip non-vertebral fractures on mortality

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.

Contribution of Lumbar Spine BMD to Fracture Risk in Individuals With T-Score Discordance

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.

Reduced mortality and subsequent fracture risk associated with oral bisphosphonate recommendation in a fracture liaison service setting: A prospective cohort study

Objective Osteoporotic fragility fractures, that are common in men and women, signal increased risk of future fractures and of premature mortality. Less than one-third of postmenopausal women and fewer men are prescribed active treatments to reduce fracture risk. Therefore, in this study the association of oral bisphosphonate recommendation with subsequent fracture and mortality over eight years in a fracture liaison service setting was analysed. Materials and methods In this prospective cohort study, 5011 men and women aged >50 years, who sustained a clinical fracture, accepted the invitation to attend the fracture liaison service of the West Glasgow health service between 1999 and 2007. These patients were fully assessed and all were recommended calcium and vitamin D. Based on pre-defined fracture risk criteria, 2534 (50.7%) patients were additionally also recommended oral bisphosphonates. Mortality and subsequent fracture risk were the pre-defined outcomes analysed using Cox proportional hazard models. Results Those recommended bisphosphonates were more often female (82.9 vs. 72.4%), were older (73.4 vs. 64.4 years), had lower bone mineral density T-score (-3.1 vs. -1.5) and more had sustained hip fractures (21.7 vs. 6.2%; p < 0.001). After adjustments, patients recommended bisphosphonates had lower subsequent fracture risk (Hazard Ratio (HR): 0.60; 95% confidence interval (CI): 0.49–0.73) and lower mortality risk (HR: 0.79, 95%CI: 0.64–0.97). Conclusion Of the patients, who are fully assessed after a fracture at the fracture liaison service, those with higher fracture risk and a recommendation for bisphosphonates had worse baseline characteristics. However, after adjusting for these differences, those recommended bisphosphonate treatment had a substantially lower risk for subsequent fragility fracture and lower risk for mortality. These community-based data indicate the adverse public health outcomes and mortality impacts of the current low treatment levels post fracture could be improved by bisphosphonate recommendation for both subsequent fracture and mortality.

Secular Changes in Postfracture Outcomes Over 2 Decades in Australia: A Time-Trend Comparison of Excess Postfracture Mortality in Two Birth Controls Over Two Decades

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.