Successful Skeletal Aging: A Marker of Low Fracture Risk and Longevity. The Study of Osteoporotic Fractures (SOF)

Successful aging is multidimensional, and many phenotypes have been proposed. We examined a biomarker of aging based on repeated measures of BMD for up to 15 yr and hypothesized that maintenance of BMD will be associated with low fracture risk and disability and improved survival. We studied 9704 women recruited at four U.S. clinical centers and enrolled in the Study of Osteoporotic Fractures, a longitudinal cohort study. Of these, 8224 women had at least one hip BMD measurement. Hip BMD was measured a maximum of five times over 15 yr. Random effects regression was used to determine a BMD slope for each subject. Three groups were formed—“maintained” BMD: slope ≥0, n = 724 (9%); “expected” BMD loss: slope <0 to <1 SD below mean, n = 6478 (79%); and “accelerated” BMD loss: slope ≥1 SD below mean, n = 1022 (12%). Cox proportional hazards models were used to compare the relative hazard (RH; 95% CI) of fracture, incident mobility disability, and mortality in the maintained and accelerated groups compared with the expected. A 1 SD decrease in the BMD slope was associated with an increased risk of all outcomes. In multivariate models, the RH of nonspine fracture was 0.81 (0.71–0.93) and of hip fracture was 0.36 (0.25–0.53) for women in the maintained compared with the expected group. The incidence of mobility disability was lower in the maintained versus expected group (RH = 0.70; 95% CI = 0.59–0.83), but this was largely explained by other factors. Women who experienced accelerated bone loss were more likely to develop disability (RH = 1.56; 95% CI: 1.33–1.84). Mortality risks were lower in the maintained compared with the expected group (RH = 0.49; 95% CI: 0.42–0.58). In conclusion, a subset of older women maintained their BMD up to 15 yr, suggesting that bone loss is not an inevitable consequence of aging. These women experienced a lower risk of fractures, disability, and mortality, suggesting that this phenotype may be a marker of successful aging.     

Height loss in older women: Risk of hip fracture and mortality independent of vertebral fractures

We examined if height loss in older women predicts risk of hip fractures, other nonspine fractures, and mortality, and whether this risk is independent of both vertebral fractures (VFx) and bone mineral density (BMD) by dual‐energy X‐ray absorptiometry. Among 3124 women age 65 and older in the Study of Osteoporotic Fractures, we assessed the association with measured height change between year 0 (1986–1988) and year 15 (2002–2004) and subsequent risk of radiologically confirmed hip fractures, other nonspine fractures, and mortality assessed via death certificates. Follow‐up occurred every 4 months for fractures and vital status (>95% contacts complete). Cox proportional hazards models assessed risk of hip fracture, nonspine fracture, and mortality over a mean of 5 years after height change was assessed (ie, after final height measurement). After adjustment for VFx, BMD, and other potential covariates, height loss >5 cm was associated with a marked increased risk of hip fracture [hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.06, 2.12], nonspine fracture (HR 1.48; 95% CI 1.20, 1.83), and mortality (1.45; 95% CI 1.21, 1.73). Although primary analyses were a subset of 3124 survivors healthy enough to return for a year 15 height measurement, a sensitivity analysis in the entire cohort (n = 9677) using initial height in earlier adulthood [self‐reported height at age 25 (?40 years) to measured height age >65 years (Year 0)] demonstrated consistent results. Height loss >5 cm (2″) in older women was associated with a nearly 50% increased risk of hip fracture, nonspine fracture, and mortality—independent of incident VFx and BMD. © 2012 American Society for Bone and Mineral Research     

Association of Serum Uric Acid and Incident Nonspine Fractures in Elderly Men: The Osteoporotic Fractures in Men (MrOS) Study

Uric acid (UA) is produced from purines by the enzyme xanthine oxidase, and elevated levels may cause arthritis and kidney stones. Conversely, UA also appears to function as an antioxidant and may protect against the oxidative stress associated with aging and disease. We performed a prospective fracture case‐cohort study to understand the relation of UA and fracture risk in older men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men aged 65 years and older attending the baseline MrOS examination, we evaluated a subgroup 1680 men in a case‐cohort study design. The analytic group included 387 men with incident nonspine fractures (73 hip) and a random sample of 1383. Serum UA was measured in baseline serum samples. Modified proportional hazards models that account for case‐cohort study design were used to estimate the relative hazards (RH) of hip and nonspine fracture in men for serum UA. Models were adjusted for age, race, clinic site, body mass index, vitamin D, parathyroid hormone, walking speed, Physical Activity Scale for the Elderly (PASE) score, frailty, and total. Subjects with incident nonspine fractures were older, had lower total hip bone mineral density (BMD), and higher serum phosphorus. There was an 18% decreased risk of nonspine fractures (95% confidence interval [CI] 0.71–0.93; p = 0.003) per 1 SD increase of baseline serum and 34% decreased risk of nonspine fractures in quartile 4 of UA versus quartiles 1, 2, and 3 (95% CI 0.49–0.89; p = 0.028) compared with nonfracture cases after multivariate adjustment. Hip fractures were not significantly associated with UA. Total hip BMD was significantly higher in the group of men with high UA levels compared with lower UA levels and increased linearly across quartiles of UA after multivariate adjustment (p for trend = 0.002). In summary, higher serum UA levels were associated with a reduction in risk of incident nonspine fractures but not hip fractures and higher hip BMD. © 2014 American Society for Bone and Mineral Research.     

Biochemical Markers of Bone Turnover,Hip Bone Loss,and Fracture in Older Men: The MrOS Study

We used data from the Osteoporotic Fractures in Men (MrOS) study to test the hypothesis that men with higher levels of bone turnover would have accelerated bone loss and an elevated risk of fracture. MrOS enrolled 5995 subjects >65 yr; hip BMD was measured at baseline and after a mean follow‐up of 4.6 yr. Nonspine fractures were documented during a mean follow‐up of 5.0 yr. Using fasting serum collected at baseline and stored at ?190°C, bone turnover measurements (type I collagen N‐propeptide [PINP]; β C‐terminal cross‐linked telopeptide of type I collagen [βCTX]; and TRACP5b) were obtained on 384 men with nonspine fracture (including 72 hip fractures) and 947 men selected at random. Among randomly selected men, total hip bone loss was 0.5%/yr among those in the highest quartile of PINP (>44.3 ng/ml) and 0.3%/yr among those in the lower three quartiles (p = 0.01). Fracture risk was elevated among men in the highest quartile of PINP (hip fracture relative hazard = 2.13; 95% CI: 1.23, 3.68; nonspine relative hazard = 1.57, 95% CI: 1.21, 2.05) or βCTX (hip fracture relative hazard = 1.76, 95 CI: 1.04, 2.98; nonspine relative hazard = 1.29, 95% CI: 0.99, 1.69) but not TRACP5b. Further adjustment for baseline hip BMD eliminated all associations between bone turnover and fracture. We conclude that higher levels of bone turnover are associated with greater hip bone loss in older men, but increased turnover is not independently associated with the risk of hip or nonspine fracture.     

Strontium Ranelate Reduces the Risk of Vertebral Fractures in Patients With Osteopenia

Many fractures occur in women with moderate fracture risk caused by osteopenia. Strontium ranelate was studied in 1431 postmenopausal women with osteopenia. Vertebral fracture risk reduction of 41–59% was shown depending on the site and fracture status at baseline. This is the first report of antivertebral fracture efficacy in women with vertebral osteopenia. Introduction: Women with osteoporosis are at high risk for fracture. However, more than one half of all fractures in the community originate from the larger population at more moderate risk of fracture caused by osteopenia. Despite this, evidence for antifracture efficacy in these persons is limited. The aim of this study was to determine whether strontium ranelate, a new drug that reduces fracture risk in women with osteoporosis, is also effective in women with osteopenia. Materials and Methods: Data from the Spinal Osteoporosis Therapeutic Intervention study (SOTI; n = 1649) and the TReatment Of Peripheral OSteoporosis (TROPOS; n = 5091) were pooled to evaluate the antivertebral fracture efficacy of strontium ranelate in women with lumbar spine (LS) osteopenia with any BMD value at the femoral neck (FN; N = 1166) and in 265 women with osteopenia at both sites (intention‐to‐treat analysis). The women were randomized to strontium ranelate 2 g/d orally or placebo for 3 yr. Results: No group differences were present in baseline characteristics that may influence fracture outcome independent of therapy. In women with LS osteopenia, treatment reduced the risk of vertebral fracture by 41% (RR = 0.59; 95% CI, 0.43–0.82), by 59% (RR = 0.41; 95% CI, 0.17–0.99) in the 447 patients with no prevalent fractures, and by 38% (RR = 0.62; 95% CI, 0.44–0.88) in the 719 patients with prevalent fractures. In women with osteopenia at both sites, treatment reduced the risk of fracture by 52% (RR = 0.48; 95% CI, 0.24–0.96). Conclusions: Strontium ranelate safely reduces the risk of vertebral fractures in women with osteopenia with or without a prevalent fracture.     

Change in hip bone mineral density and risk of subsequent fractures in older men

Low bone mineral density (BMD) increases fracture risk; how changes in BMD influence fracture risk in older men is uncertain. BMD was assessed at two to three time points over 4.6 years using dual‐energy X‐ray absorptiometry (DXA) for 4470 men aged ≥65 years in the Osteoporotic Fractures in Men (MrOS) Study. Change in femoral neck BMD was estimated using mixed effects linear regression models. BMD change was categorized as “accelerated” (≤?0.034 g/cm²), “expected” (between 0 and ?0.034 g/cm²), or “maintained” (≥0 g/cm²). Fractures were adjudicated by central medical record review. Multivariate proportional hazards models estimated the risk of hip, nonspine/nonhip, and nonspine fracture over 4.5 years after the final BMD measure, during which time 371 (8.3%) men experienced at least one nonspine fracture, including 78 (1.7%) hip fractures. Men with accelerated femoral neck BMD loss had an increased risk of nonspine (hazard ratio [HR] = 2.0; 95% confidence interval [CI] 1.4–2.8); nonspine/nonhip (HR = 1.6; 95% CI 1.1–2.3); and hip fracture (HR = 6.3; 95% CI 2.7–14.8) compared with men who maintained BMD over time. No difference in risk was seen for men with expected loss. Adjustment for the initial BMD measure did not alter the results. Adjustment for the final BMD measure attenuated the change in BMD‐nonspine fracture and the change in BMD‐nonspine/nonhip relationships such that they were no longer significant, whereas the change in the BMD‐hip fracture relationship was attenuated (HR = 2.6; 95% CI 1.1–6.4). Total hip BMD change produced similar results. Accelerated decrease in BMD is a strong, independent risk factor for hip and other nonspine fractures in men. © 2012 American Society for Bone and Mineral Research.     

High Serum Serotonin Predicts Increased Risk for Hip Fracture and Nonvertebral Osteoporotic Fractures: The MrOS Sweden Study

Because several studies have implicated serotonin as a regulator of bone mass, we here explore its potential association on fracture risk and falls, as on bone mineral density (BMD) and muscle strength, in humans. Serum levels of serotonin were analyzed in 950 men (aged 69 to 81 years), participating in the Gothenburg part of the population‐based study MrOS Sweden. Men taking selective serotonin reuptake inhibitors (SSRIs) had a mean value of 31.2 μg/L compared with 159.4 μg/L in those not taking SSRIs. SSRI users were excluded from further analysis. During 10‐year follow‐up, 224 men exhibited fractures, including 97 nonvertebral osteoporotic fractures (57 hip fractures), and 86 vertebral fractures. Serotonin was associated with hip fracture in linear analysis (hazard ratio [HR] = 1.27, 95% confidence interval [CI] 1.03–1.58) and to all fractures in a nonlinear manner, when quintiles of serotonin was included in quadratic terms (HR = 1.12, 95% CI 1.04–1.21). Men in serotonin quintile 5 had, in multivariable analysis, a HR of 2.30 (95% CI 1.31–4.02) for hip fracture and 1.82 (95% CI 1.17–2.85) for nonvertebral fractures compared with men in quintiles 1 to 4. Men in quintile 1 had, in multivariable analysis, a HR of 1.76 (95% CI 1.03–2.99) for nonvertebral fractures compared with men in quintiles 2 to 4. No association was found with vertebral fractures. Individuals in serotonin quintile 1 had higher prevalence of falls compared with quintiles 2 to 5 (odds ratio = 1.90, 95% CI 1.26–2.87). Serotonin was positively associated with hand‐grip strength (r = 0.08, p = 0.02) and inversely with hip BMD (r = ?0.10, p = 0.003). To assess the association between SSRIs and falls and fractures, the total MrOS Sweden cohort was examined (n = 3014). SSRI users (n = 90) had increased prevalence of falls (16% versus 33%, p = 0.0001) and increased rate of incident fractures (28.0 versus 44.7 per 1000 person‐years, p = 0.018). We present novel data showing that high levels of serotonin predict an increased risk for hip fracture and nonvertebral osteoporotic fractures. © 2018 American Society for Bone and Mineral Research.     

Prevalent Vertebral Fractures in Black Women and White Women

Vertebral fractures are the most common osteoporotic fracture. Hip and clinical fractures are less common in black women, but there is little information on vertebral fractures. We studied 7860 white and 472 black women ≥65 yr of age enrolled in the Study of Osteoporotic Fractures. Prevalent vertebral fractures were identified from lateral spine radiographs using vertebral morphometry and defined if any vertebral height ratio was >3 SD below race‐specific means for each vertebral level. Information on risk factors was obtained by questionnaire or examination. Lumbar spine, total hip, and femoral neck BMD and BMC were measured by DXA. The prevalence of vertebral fractures was 10.6% in black and 19.1% in white women. In age‐adjusted logistic regression models, a 1 SD decrease in femoral neck BMD was associated with 47% increased odds of fracture in black women (OR = 1.47; 95% CI, 1.12–1.94) and 80% increased odds in white women (OR = 1.80; 95% CI, 1.68–1.94; interaction p = 0.14). The overall lower odds of fracture among black women compared with white women was independent of femoral neck BMD and other risk factors (OR = 0.51; 95% CI, 0.37–0.72). However, the prevalence of vertebral fractures increased with increasing number of risk factors in both groups. The prevalence of vertebral fractures is lower in black compared with white women but increases with age, low BMD, and number of risk factors.     

The Effect of a Screening and Treatment Program for the Prevention of Fractures in Older Women: A Randomized Pragmatic Trial

Population screening for fracture risk may reduce the fracture incidence. In this randomized pragmatic trial, the SALT Osteoporosis Study (SOS), we studied whether screening for fracture risk and subsequent treatment in primary care can reduce fractures compared with usual care. A total of 11,032 women aged 65 to 90 years with ≥1 clinical risk factor for fractures were individually randomized to screening (n = 5575) or usual care (n = 5457). Participants in the screening group underwent a screening program, including bone densitometry and vertebral fracture assessment. Participants with a high 10-year fracture probability (FRAX) or a vertebral fracture were offered treatment with anti-osteoporosis medication by their general practitioner. Incident fractures as reported by questionnaires were verified with medical records. Follow-up was completed by 94% of the participants (mean follow-up = 3.7 years). Of the 5575 participants in the screening group, 1417 (25.4%) had an indication for anti-osteoporosis medication. Screening and subsequent treatment had no statistically significant effect on the primary outcome fracture (hazard ratio [HR] = 0.97; 95% confidence interval [CI] 0.87–1.08), nor on the secondary outcomes osteoporotic fractures (HR = 0.91; 95% CI 0.81–1.03), major osteoporotic fractures (HR = 0.91; 95% CI 0.80–1.04), hip fractures (HR = 0.91; 95% CI 0.71–1.15), falls (odds ratio [OR] = 0.91; 95% CI 0.72–1.15), or mortality (HR = 1.03; 95% CI 0.91–1.17). Post hoc explorative finding suggested that screening might be most effective after a recent fracture (HR = 0.65; 95% CI 0.44–0.96 for major osteoporotic fractures and HR = 0.38; 95% CI 0.18–0.79 for hip fractures). The results of this study might have been compromised by nonparticipation and medication nonadherence in the screening group. Overall, this study does not provide sufficient indications to consider screening for fracture prevention. However, we cannot exclude its clinical relevance to reduce (major) osteoporotic fractures and hip fractures because of the relatively small number of women with a treatment indication in the intervention group. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.     

Older Men With Low Serum Estradiol and High Serum SHBG Have an Increased Risk of Fractures

Osteoporosis‐related fractures constitute a major health concern not only in women but also in men. To study the predictive role of serum sex steroids for fracture risk in men, serum sex steroids were analyzed by the specific gas chromatography‐mass spectrometry technique at baseline in older men (n = 2639; mean, 75 yr of age) of the prospective population‐based MrOS Sweden cohort. Fractures occurring after baseline were validated (average follow‐up of 3.3 yr). The incidence for having at least one validated fracture after baseline was 20.9/1000 person‐years. Estradiol (E2; hazard ratio [HR] per SD decrease, 1.34; 95% CI, 1.22–1.49), free estradiol (fE2; HR per SD decrease, 1.41; 95% CI, 1.28–1.55), testosterone (T; HR per SD decrease, 1.27; 95% CI, 1.16–1.39), and free testosterone (fT; HR per SD decrease, 1.32; 95% CI, 1.21–1.44) were all inversely, whereas sex hormone–binding globulin (SHBG; HR per SD increase, 1.41; 95% CI, 1.22–1.63) was directly related to fracture risk. Multivariable proportional hazards regression models, adjusted for age, suggested that fE2 and SHBG (p < 0.001), but not fT, were independently associated with fracture risk. Further subanalyses of fracture type showed that fE2 was inversely associated with clinical vertebral fractures (HR per SD decrease, 1.57; 95% CI, 1.36–1.80), nonvertebral osteoporosis fractures (HR per SD decrease, 1.42; 95% CI, 1.23–1.65), and hip fractures (HR per SD decrease, 1.44; 95% CI, 1.18–1.76). The inverse relation between serum E2 and fracture risk was nonlinear with a strong relation <16 pg/ml for E2 and 0.3 pg/ml for fE2. In conclusion, older Swedish men with low serum E2 and high SHBG levels have an increased risk of fractures.     

High hip fracture risk in men with severe aortic calcification: MrOS study

A significant link between cardiovascular disease and osteoporosis is established in postmenopausal women, but data for men are scarce. We tested the hypothesis that greater severity of abdominal aortic calcification (AAC) was associated with an increased risk of nonspine fracture in 5994 men aged ≥65 years. AAC was assessed on 5400 baseline lateral thoracolumbar radiographs using a validated visual semiquantitative score. Total hip bone mineral density (BMD) was measured using dual‐energy X‐ray absorptiometry. Incident nonspine fractures were centrally adjudicated. After adjustment for age, body mass index (BMI), total hip BMD, fall history, prior fracture, smoking status, comorbidities, race, and clinical center, the risk of nonspine fracture (n = 805) was increased among men with higher AAC (hazard ratio [HR] quartile 4 [Q4] [AAC score ≥9] versus quartile 1 [Q1] [0–1], 1.36; 96% confidence interval [CI], 1.10–1.68). This association was due to an increased risk of hip fracture (n = 178) among men with higher AAC (HR Q4 versus Q1, 2.33; 95% CI, 1.41–3.87). By contrast, the association between AAC and the risk of nonspine, nonhip fracture was weaker and not significant (HR Q4 versus Q1, 1.22; 95% CI, 0.96–1.55). The findings regarding higher AAC and increased risk of fracture were not altered in additional analyses accounting for degree of trauma, estimated glomerular filtration rate, presence of lumbar vertebral fractures (which may bias AAC assessment), preexisting cardiovascular disease, ankle brachial index, or competing risk of death. Thus, in this large cohort of elderly men, greater AAC was independently associated with an increased risk of hip fracture, but not with other nonspine fractures. These findings suggest that AAC assessment may be a useful method for identification of older men at high risk of hip fracture. © 2014 American Society for Bone and Mineral Research.     

Optimism,Cynical Hostility,Falls, and Fractures: The Women's Health Initiative Observational Study (WHI‐OS)

Traits of optimism and cynical hostility are features of personality that could influence the risk of falls and fractures by influencing risk‐taking behaviors, health behaviors, or inflammation. To test the hypothesis that personality influences falls and fracture risk, we studied 87,342 women enrolled in WHI‐OS. Optimism was assessed by the Life Orientation Test–Revised and cynical hostility, the cynicism subscale of the Cook‐Medley questionnaire. Higher scores indicate greater optimism and hostility. Optimism and hostility were correlated at r = –0. 31, p < 0.001. Annual self‐report of falling ≥2 times in the past year was modeled using repeated measures logistic regression. Cox proportional hazards models were used for the fracture outcomes. We examined the risk of falls and fractures across the quartiles (Q) of optimism and hostility with tests for trends; Q1 formed the referent group. The average follow‐up for fractures was 11.4 years and for falls was 7.6 years. In multivariable (MV)‐adjusted models, women with the highest optimism scores (Q4) were 11% less likely to report ≥2 falls in the past year (odds ratio [OR] = 0.89; 95% confidence intervals [CI] 0.85–0.90). Women in Q4 for hostility had a 12% higher risk of ≥2 falls (OR = 1.12; 95% CI 1.07–1.17). Higher optimism scores were also associated with a 10% lower risk of fractures, but this association was attenuated in MV models. Women with the greatest hostility (Q4) had a modest increased risk of any fracture (MV‐adjusted hazard ratio = 1. 05; 95% CI 1.01–1.09), but there was no association with specific fracture sites. In conclusion, optimism was independently associated with a decreased risk of ≥2 falls, and hostility with an increased risk of ≥2 falls, independent of traditional risk factors. The magnitude of the association was similar to aging 5 years. Whether interventions aimed at attitudes could reduce fall risks remains to be determined. © 2016 American Society for Bone and Mineral Research.     

Hyponatremia and Fractures: Findings From the MrOS Study

Hyponatremia may be a risk factor for fracture. To determine the relationship between hyponatremia and fracture we conducted cross‐sectional and longitudinal analyses using data from the Osteoporotic Fractures in Men (MrOS) study. The MrOS study enrolled 5122 community dwelling men aged ≥65 years from six centers across the United States. We excluded men taking bisphosphonates, those with unknown medication history, those without serum sodium measures, or those with out of range assays for serum sodium. Serum sodium was measured at study entry. Subjects were followed for fractures (nonspine [including hip], hip, incident morphometric, and prevalent morphometric) for up to 9 years. We used Cox proportional hazards models to analyze the association between serum sodium levels (<135 mmol/L versus ≥135 mmol/L) and risk of nonspine and hip fractures, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). We examined the association between morphometric vertebral fractures and serum sodium using logistic regression models, presented as odds ratios (ORs) and 95% CI. Hyponatremia was observed in 64 men (1.2% of the cohort). After adjusting for age, BMI, study center, and other covariates, we found that, compared to men with serum sodium ≥135 mmol/L, those with serum sodium <135 mmol/L, had an increased risk of hip fracture (HR = 3.04; 95% CI, 1.37 to 6.75), prevalent morphometric spine fracture (OR = 2.46; 95% CI, 1.22 to 4.95), and incident morphometric spine fracture (OR = 3.53; 95% CI, 1.35 to 9.19), but not nonspine fracture (OR = 1.44; 95% CI, 0.85 to 2.44). Adjusting for bone mineral density (BMD) did not change our findings. Our data show that hyponatremia is associated with up to a doubling in the risk of hip and morphometric spine fractures, independent of BMD. Further studies, to determine how hyponatremia causes fractures and if correction of hyponatremia decreases fractures, are needed. © 2014 American Society for Bone and Mineral Research.     

Effect of Total Hip Bone Area on Osteoporosis Diagnosis and Fractures

DXA is affected by skeletal size, with smaller bones giving lower areal BMD despite equal material density. Whether this size effect confounds the use of BMD as a diagnostic and fracture risk assessment tool is unclear. We identified 16,205 women of white ethnicity ≥50 yr of age undergoing baseline hip assessment with DXA (1998–2002) from a population‐based database that contains all clinical DXA test results for the Province of Manitoba, Canada. Total hip measurements were categorized according to quartile in total hip bone area (Q1 = smallest, Q4 = largest). Longitudinal health service records were assessed for the presence of nontraumatic osteoporotic fracture codes during a mean of 3.2 yr of follow‐up after BMD testing (757 osteoporotic fractures, 186 hip fractures). Total hip bone area strongly affected osteoporosis diagnosis with much higher rates in Q1 (14.4%) than Q4 (8.9%). However, incident fracture rates were constant across all area quartiles, and prevalent fractures were paradoxically fewer in smaller area quartiles (p < 0.001 for trend). Age was a potential confounder that correlated positively with area (r = 0.12, p < 0.0001). When age was not included in a Cox regression model, Q1 seemed to have a lower rate of incident osteoporotic fractures (HR = 0.80, 95% CI = 0.66–0.98, reference Q4) and hip fractures (HR = 0.63, 95% CI = 0.43–0.94) for a given level of BMD. In age‐adjusted regression models, total hip BMD was strongly predictive of incident osteoporotic fractures (HR per SD = 1.83, 95% CI = 1.68–1.99) and hip fractures (HR per SD = 2.80, 95% CI = 2.33–3.35), but there was no independent effect of bone area (categorical or continuous). Nested matched subgroup analysis and ROC analysis confirmed that bone area had no appreciable effect on incident fractures. We conclude that total hip areal BMD categorizes a substantially higher fraction of women with smaller bone area as being osteoporotic despite younger age. Incident fracture rates correlate equally well with BMD across all bone area quartiles when adjusted for age.     

Measured Height Loss Predicts Fractures in Middle‐Aged and Older Men and Women: The EPIC‐Norfolk Prospective Population Study

In this large population‐based prospective study among middle‐aged and older men and women, we found that height loss of >2 cm over a period of 4 yr is a significant predictor of future fractures. Serial measurement of height is, therefore, recommended among the elderly people. Introduction: Height change can be easily measured and may contribute to fracture risk prediction. We assessed measured height loss and fracture incidence in a prospective population study. Materials and Methods: Height was measured in participants in the Norfolk cohort of the European Prospective Investigation into Cancer (EPIC‐Norfolk) between 1993 and 1997 and repeated between 1997 and 2000. Incident fractures to 2006 were ascertained by hospital record linkage. Results: In 14,921 men and women 42–82 yr of age, during a mean follow‐up period of 7.1 yr, there were 390 fractures, including 122 hip fractures. Prior annual height loss in those who had an incident fracture (1.8 ± 0.3 [SD] mm) was significantly greater than other participants (0.9 ± 0.2 mm; p < 0.001). Participants with annual height loss >0.5 cm had an age‐ and sex‐adjusted hazard ratio of any fracture of 1.76 (95% CI, 1.16–2.67) and of hip fracture of 2.08 (95% CI, 1.07–4.05) compared with those with no height loss. Each 1 cm/yr height loss was associated with a hazard ratio of 1.86 (95% CI, 1.28–2.72) for all fractures and 2.24 (95% CI, 1.23–4.09) for hip fracture after adjustment for age, sex, past history of fracture, smoking, body mass index, alcohol intake, and heel ultrasound measures. Annual height loss of 1 cm was comparable to having a past history of fracture and equivalent to being ～14 yr older in chronological age in terms of the magnitude of relationship with fracture risk. Conclusions: Middle‐aged and older men and women with annual height loss >0.5 cm are at increased risk of hip and any fracture. Serial height measurements can contribute to fracture risk prediction.     

Vertebral Fracture Assessment (VFA) With a Densitometer Predicts Future Fractures in Elderly Women Unselected for Osteoporosis

Low radiation dose imaging of the lateral spine acquired with a bone densitometer for vertebral fracture assessment (VFA) has great potential for clinical use. We have undertaken an evaluation of VFA in a prospective population cohort of elderly women to examine the prevalence of vertebral fractures, their ability to predict incident fractures, and their use in targeting therapy. Women (n = 5157) ≥75 yr of age living in the general community in the United Kingdom underwent posteroanterior and lateral imaging of the spine (T₄–L₄) with a densitometer (Hologic QDR4500A) at entry to a randomized, double‐blind, controlled trial of 800 mg oral clodronate (Bonefos) or matching placebo daily over 3 yr. The women were identified from general practice registers and recruited by letter of invitation regardless of skeletal status. The proportion of vertebrae interpretable varied from 98.2% at T₁₂ to 57.1% at T₄, with >92% interpretable at levels between T₈ and L₃. As judged by BMD at the total hip, 19.6% of the women had osteoporosis, and the prevalence of vertebral fracture was 14.5%. Women with one or more vertebral fractures had a relative risk (RR) for incident osteoporotic fractures of 2.01 (95% CI, 1.64–2.47). The RR for hip fractures was 2.29 (95% CI, 1.63–3.21). After adjustment for age, femoral neck BMD, weight, and treatment, the RR was 1.50 (95% CI, 1.21–1.86) for osteoporotic fractures, with similar results for hip fractures (RR, 1.41; 95% CI, 0.99–2.02). For women with two or more vertebral fractures, the adjusted RRs were 1.97 (95% CI, 1.24–2.72) and 1.86 (95% CI, 1.14–3.03) for osteoporotic and hip fractures, respectively. We conclude that VFA can frequently detect vertebral fractures in a population cohort of elderly women. These fractures, like radiographic fractures, predict future clinical fractures independent of age, weight, and BMD. Having multiple vertebral fractures was associated with greater risk of incident osteoporotic fractures and hip fractures.     

Quantitative Ultrasound and Bone Densitometry to Evaluate the Risk of Nonspine Fractures: A Prospective Study

The ability of quantitative ultrasound (QUS) to estimate the risk of osteoporotic fractures was evaluated in a prospective study over a mean time of 5.47 years in 254 postmenopausal women (mean age 58.06 ± 7.67 years). Baseline measurements of ultrasound transmission velocity (UTV) and bone mineral density (BMD) were taken at the distal radius (DR). UTV was also measured at the patella (P). Fifty nonspine fractures due to minor trauma were detected during annual check-ups with an incidence of 3.59/year. Fractures occurred in older women with a lower BMD and QUS. Using Cox regression analysis the relative risk (RR) per 1 standard deviation (SD) decrease in the unadjusted QUS and BMD measurements was: BMD-DR = 3.56, 95% confidence interval (CI) 1.57–8.09; UTV-DR = 5.35, 95% CI 2.07–13.83; UTV-P = 4.49, 95% CI 2.08–9.68. The relationship between BMD and QUS variables and fracture risk persisted after adjusting for potential confounders apart from previous fractures, giving the following RR: BMD-DR = 2.99, 95% CI 1.06–8.41; UTV-DR = 3.69, 95% CI 1.18–11.49; UTV-P = 3.89, 95% CI 1.53–9.90. Correcting also for previous fractures, only UTV-P remained an effective predictor of fracture risk even after QUS measurement correction for BMD. Wrist fractures were best related to BMD-DR (RR 7.33, 95% CI 1.43–37.50) and UTV-DR (RR 10.94, 95% CI 1.10–108.45), while hip and ankle fractures were significantly associated only with UTV-P (hip: RR 32.14, 95% CI 1.83–562.80; ankle: RR 17.60, 95% CI 1.78–173.79). The combined use of BMD and QUS is a better predictor of fracture risk than either technique used separately. Comparison of the areas under the receiver operating characteristic (ROC) curves did not show differences in the ability of BMD and QUS to correctly distinguish fractures. In conclusion, QUS predicts fracture risk in osteoporotic women at least as well as BMD. UTV-DR and BMD-DR are good predictors of wrist fractures, while UTV-P is strongly related to hip and ankle fractures. QUS and BMD combined improve the diagnostic ability of each technique individually. Received: 27 April 1999 / Accepted: 3 December 1999     

The Effect of Fall Biomechanics on Risk for Hip Fracture in Older Adults: A Cohort Study of Video-Captured Falls in Long-Term Care

Over 95% of hip fractures in older adults are caused by falls, yet only 1% to 2% of falls result in hip fracture. Our current understanding of the types of falls that lead to hip fracture is based on reports by the faller or witness. We analyzed videos of real-life falls in long-term care to provide objective evidence on the factors that separate falls that result in hip fracture from falls that do not. Between 2007 and 2018, we video-captured 2377 falls by 646 residents in two long-term care facilities. Hip fracture was documented in 30 falls. We analyzed each video with a structured questionnaire, and used generalized estimating equations (GEEs) to determine relative risk ratios (RRs) for hip fracture associated with various fall characteristics. All hip fractures involved falls from standing height, and pelvis impact with the ground. After excluding falls from lower than standing height, risk for hip fracture was higher for sideways landing configurations (RR = 5.50; 95% CI, 2.36–12.78) than forward or backward, and for falls causing hip impact (3.38; 95% CI, 1.49–7.67). However, hip fracture risk was just as high in falls initially directed sideways as forward (1.14; 95% CI, 0.49–2.67), due to the tendency for rotation during descent. Falling while using a mobility aid was associated with lower fracture risk (0.30; 95% CI, 0.09–1.00). Seventy percent of hip fractures involved impact to the posterolateral aspect of the pelvis. Hip protectors were worn in 73% of falls, and hip fracture risk was lower in falls where hip protectors were worn (0.45; 95% CI, 0.21–0.99). Age and sex were not associated with fracture risk. There was no evidence of spontaneous fractures. In this first study of video-captured falls causing hip fracture, we show that the biomechanics of falls involving hip fracture were different than nonfracture falls for fall height, fall direction, impact locations, and use of hip protectors. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

The Importance of Previous Fracture Site on Osteoporosis Diagnosis and Incident Fractures in Women

Previous fracture increases the risk of subsequent fractures regardless of the site of the initial fracture. Fracture risk assessment tools have been developed to guide clinical management; however, no discrimination is made as to the site of the prior fracture. Our objective was to determine which sites of previous nontraumatic fractures are most strongly associated with a diagnosis of osteoporosis, defined by a bone mineral density (BMD) T‐score of ≤ ?2.5 at the femoral neck, and an incident major osteoporotic fracture. Using administrative health databases, we conducted a retrospective historical cohort study of 39,991women age 45 years and older who had BMD testing with dual‐energy X‐ray absorptiometry (DXA). Logistic regression and Cox proportional multivariate models were used to test the association of previous fracture site with risk of osteoporosis and incident fractures. Clinical fractures at the following sites were strongly and independently associated with higher risk of an osteoporotic femoral neck T‐score after adjustment for age: hip (odds ratio [OR], 3.58; 95% confidence interval [CI], 3.04–4.21), pelvis (OR, 2.23; 95% CI, 1.66–3.0), spine (OR, 2.16; 95% CI, 1.77–2.62), and humerus (OR, 1.74; 95% CI, 1.49–2.02). Cox proportional hazards models, with adjustment for age and femoral neck BMD, showed the greatest increase in risk for a major osteoporotic fracture for women who had sustained previous fractures of the spine (hazard ratio [HR], 2.08; 95% CI, 1.72–2.53), humerus (HR, 1.70; 95% CI, 1.44–2.01), patella (HR, 1.54; 95% CI, 1.10–2.18), and pelvis (HR, 1.45; 95% CI, 1.04–2.02). In summary, our results confirm that nontraumatic fractures in women are associated with osteoporosis at the femoral neck and that the site of previous fracture impacts on future osteoporotic fracture risk, independent of BMD. © 2014 American Society for Bone and Mineral Research.     

Serum 25‐hydroxyvitamin D and the risk of hip and nonspine fractures in older men

The association between vitamin D levels and incident fractures in older men is uncertain. To test the hypothesis that low serum 25‐hydroxyvitamin D [(25(OH)D] levels are associated with an increased risk of fracture, we performed a case‐cohort study of 436 men with incident nonspine fractures, including 81 hip fractures, and a random subcohort of 1608 men; average follow‐up time 5.3 years. Serum vitamin D₂ and vitamin D₃ were measured on baseline sera using mass spectrometry and summed for total vitamin D. Modified Cox proportional hazards models were used to estimate the hazard ratio (HR) of fracture with 95% confidence intervals (CIs). Multivariable models included age, clinic, season, race, height, weight, and physical activity. The mean (SD) total 25(OH)D was 24.6 (7.8) ng/mL in nonspine fracture subjects, 21.5 (7.9) ng/mL in hip fracture subjects, and 25.2 (7.8) ng/mL in controls (nonspine fracture subjects versus nonpatients, p = .14; hip fracture subjects versus controls, p < .0001). 25(OH)D levels were unrelated to nonspine fractures. One SD decrease in total 25(OH)D was associated with an increased risk of hip fracture (multivariate HR = 1.60; 95% CI 1.18–2.17). Compared with men in the top quartile of total 25(OH)D (≥28), the HR of hip fracture was 2.36 (95% CI 1.08–5.15) for men in the lowest quartile (<20) (p = .009 for trend). Adjusting for hip bone mineral density attenuated the association by more than 50% (p = .065 for trend). Low serum 25(OH)D concentrations are associated with a higher risk of hip fracture in older men. Measurement of 25(OH)D may be useful in identifying men at high risk of hip fracture. © 2010 American Society for Bone and Mineral Research.