Antiepileptic drug use,falls, fractures,and BMD in postmenopausal women: Findings from the women's health initiative (WHI)

Antiepileptic drugs (AEDs) are used increasingly in clinical practice to treat a number of conditions. However, the relationship between the use of these medications, particularly the newer AEDs, and fracture risk has not been well characterized. We used data from the Women's Health Initiative (WHI) to determine the relationship bewteen the use of AEDs and falls, fractures, and bone mineral density (BMD) over an average of 7.7 years of follow‐up. We included 138,667 women (1,385 users of AEDs and 137,282 nonusers) aged 50 to 79 years in this longitudinal cohort analyses. After adjustment for covariates, use of AEDs was positively associated with total fractures [hazard ratio (HR) = 1.44, 95% confidence interval (CI) 1.30–1.61], all site‐specific fractures including the hip (HR = 1.51, 95% CI 1.05–2.17), clinical vertebral fractures (HR = 1.60, 95% CI 1.20–2.12), lower arm or wrist fractures (HR = 1.40, 95% CI 1.11–1.76), and other clinical fractures (HR = 1.46, 95% CI 1.29–1.65) and two or more falls (HR = 1.62, 95% CI 1.50–1.74) but not with baseline BMD or changes in BMD (p ≥ .064 for all sites). Use of more than one and use of enzyme‐inducing AEDs were significantly associated with total fractures (HR = 1.55, 95% CI 1.15–2.09 and HR = 1.36, 95% CI 1.09–1.69, respectively). We conclude that in clinical practice, postmenopausal women who use AEDs should be considered at increased risk for fracture, and attention to fall prevention may be particularly important in these women. © 2010 American Society for Bone and Mineral Research.     

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.     

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.     

Risk Factors for Treatment Failure With Antiosteoporosis Medication: The Global Longitudinal Study of Osteoporosis in Women (GLOW)

Antiosteoporosis medication (AOM) does not abolish fracture risk, and some individuals experience multiple fractures while on treatment. Therefore, criteria for treatment failure have recently been defined. Using data from the Global Longitudinal Study of Osteoporosis in Women (GLOW), we analyzed risk factors for treatment failure, defined as sustaining two or more fractures while on AOM. GLOW is a prospective, observational cohort study of women aged ≥55 years sampled from primary care practices in 10 countries. Self‐administered questionnaires collected data on patient characteristics, fracture risk factors, previous fractures, AOM use, and health status. Data were analyzed from women who used the same class of AOM continuously over 3 survey years and had data available on fracture occurrence. Multivariable logistic regression was used to identify independent predictors of treatment failure. Data from 26,918 women were available, of whom 5550 were on AOM. During follow‐up, 73 of 5550 women in the AOM group (1.3%) and 123 of 21,368 in the non‐AOM group (0.6%) reported occurrence of two or more fractures. The following variables were associated with treatment failure: lower Short Form 36 Health Survey (SF‐36) score (physical function and vitality) at baseline, higher Fracture Risk Assessment Tool (FRAX) score, falls in the past 12 months, selected comorbid conditions, prior fracture, current use of glucocorticoids, need of arms to assist to standing, and unexplained weight loss ≥10 lb (≥4.5 kg). Three variables remained predictive of treatment failure after multivariable analysis: worse SF‐36 vitality score (odds ratio [OR] per 10‐point increase, 0.85; 95% confidence interval [CI], 0.76–0.95; p = 0.004); two or more falls in the past year (OR, 2.40; 95% CI, 1.34–4.29; p = 0.011), and prior fracture (OR, 2.93; 95% CI, 1.81–4.75; p < 0.0001). The C statistic for the model was 0.712. Specific strategies for fracture prevention should therefore be developed for this subgroup of patients. © 2014 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.     

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.     

Sarcopenic Obesity and Its Temporal Associations With Changes in Bone Mineral Density,Incident Falls,and Fractures in Older Men: The Concord Health and Ageing in Men Project

Body composition and muscle function have important implications for falls and fractures in older adults. We aimed to investigate longitudinal associations between sarcopenic obesity and its components with bone mineral density (BMD) and incident falls and fractures in Australian community‐dwelling older men. A total of 1486 men aged ≥70 years from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005–2007), 2‐year follow‐up (2007–2009; n = 1238), and 5‐year follow‐up (2010–2013; n = 861). At all three time points, measurements included appendicular lean mass (ALM), body fat percentage and total hip BMD, hand‐grip strength, and gait speed. Participants were contacted every 4 months for 6.1 ± 2.1 years to ascertain incident falls and fractures, the latter being confirmed by radiographic reports. Sarcopenic obesity was defined using sarcopenia algorithms of the European Working Group on Sarcopenia (EWGSOP) and the Foundation for the National Institutes of Health (FNIH) and total body fat ≥30% of total mass. Sarcopenic obese men did not have significantly different total hip BMD over 5 years compared with non‐sarcopenic non‐obese men (p > 0.05). EWGSOP‐defined sarcopenic obesity at baseline was associated with significantly higher 2‐year fall rates (incidence rate ratio [IRR] 1.66; 95% confidence interval [CI] 1.16–2.37), as were non‐sarcopenic obesity (1.30; 1.04–1.62) and sarcopenic non‐obesity (1.58; 1.14–2.17), compared with non‐sarcopenic non‐obese. No association with falls was found for sarcopenic obesity using the FNIH definition (1.01; 0.63–1.60), but after multivariable adjustment, the FNIH‐defined non‐sarcopenic obese group had a reduced hazard for any 6‐year fracture compared with sarcopenic obese men (hazard ratio 0.44; 95% CI 0.23–0.86). In older men, EWGSOP‐defined sarcopenic obesity is associated with increased fall rates over 2 years, and FNIH‐defined sarcopenic obese men have increased fracture risk over 6 years compared with non‐sarcopenic obese men. © 2016 American Society for Bone and Mineral Research.     

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 IGF‐1 have an increased risk of incident fractures: The MrOS Sweden study

Osteoporosis‐related fractures constitute a major health concern not only in women but also in men. Insulin‐like growth factor 1 (IGF‐1) is a key determinant of bone mass, but the association between serum IGF‐1 and incident fractures in men remains unclear. To determine the predictive value of serum IGF‐1 for fracture risk in men, older men (n = 2902, mean age of 75 years) participating in the prospective, population‐based Osteoporotic Fractures in Men (MrOS) Sweden study were followed for a mean of 3.3 years. Serum IGF‐1 was measured at baseline by radioimmunoassay. Fractures occurring after the baseline visit were validated. In age‐adjusted hazards regression analyses, serum IGF‐1 associated inversely with risk of all fractures [hazard ratio (HR) per SD decrease = 1.23, 95% confidence interval (CI) 1.07–1.41], hip fractures (HR per SD decrease = 1.45, 95% CI 1.07–1.97), and clinical vertebral fractures (HR per SD decrease = 1.40, 95% CI 1.10–1‐78). The predictive role of serum IGF‐1 for fracture risk was unaffected by adjustment for height, weight, prevalent fractures, falls, and major prevalent diseases. Further adjustment for bone mineral density (BMD) resulted in an attenuated but still significant association between serum IGF‐1 and fracture risk. Serum IGF‐1 below but not above the median was inversely related to fracture incidence. The population‐attributable risk proportion was 7.5% for all fractures and 22.9% for hip fractures. Taken together, older men with low serum IGF‐1 have an increased fracture risk, especially for the two most important fracture types, hip and vertebral fractures. The association between serum IGF‐1 and fracture risk is partly mediated via BMD. © 2011 American Society for Bone and Mineral Research.     

Long‐Term Proton Pump Inhibitor Therapy and Falls and Fractures in Elderly Women: A Prospective Cohort Study

Proton pump inhibitors (PPIs) are widely used in the elderly. Recent studies have suggested that long‐term PPI therapy is associated with fractures in the elderly, however the mechanism remains unknown. We investigated the association between long‐term PPI therapy ≥1 year and fracture risk factors including bone structure, falls, and balance‐related function in a post hoc analysis of a longitudinal population‐based prospective cohort of elderly postmenopausal women and replicated the findings in a second prospective study of falling in elderly postmenopausal women. Long‐term PPI therapy was associated with increased risk of falls and fracture‐related hospitalizations; adjusted odds ratio (AOR) 2.17; 95% CI, 1.25–3.77; p = 0.006 and 1.95; 95% CI, 1.20–3.16; p = 0.007, respectively. In the replication study, long‐term PPI use was associated with an increased risk of self‐reported falling; AOR, 1.51; 95% CI, 1.00–2.27; p = 0.049. No association of long‐term PPI therapy with bone structure was observed; however, questionnaire‐assessed falls‐associated metrics such as limiting outdoor activity (p = 0.002) and indoor activity (p = 0.001) due to fear of falling, dizziness (p < 0.001) and numbness of feet (p = 0.017) and objective clinical measurement such as Timed Up and Go (p = 0.002) and Romberg eyes closed (p = 0.025) tests were all significantly impaired in long‐term PPI users. Long‐term PPI users were also more likely to have low vitamin B12 levels than non‐users (50% versus 21%, p = 0.003). In conclusion, similar to previous studies, we identified an increased fracture risk in subjects on long‐term PPI therapy. This increase in fracture risk in elderly women, already at high risk of fracture, appears to be mediated via increased falls risk and falling rather than impaired bone structure and should be carefully considered when prescribing long‐term PPI therapy. © 2014 American Society for Bone and Mineral Research.     

Independent predictors of all osteoporosis-related fractures among healthy Saudi postmenopausal women: the CEOR Study

This study was designed to identify independent predictors of all osteoporosis-related fractures (ORFs) among healthy Saudi postmenopausal women. We prospectively followed a cohort of 707 healthy postmenopausal women (mean age, 61.3±7.2 years) for 5.2±1.3 years. Data were collected on demographic characteristics, medical history, personal and family history of fractures, lifestyle factors, daily calcium intake, vitamin D supplementation, and physical activity score. Anthropometric parameters, total fractures (30.01 per 1000 women/year), special physical performance tests, bone turnover markers, hormone levels, and bone mineral density (BMD) measurements were performed. The final model consisted of seven independent predictors of ORFs: [lowest quartile (Q(1)) vs highest quartile (Q(4))] physical activity score (Q(1) vs Q(4): ≤12.61 vs ≥15.38); relative risk estimate [RR], 2.87; (95% confidence interval [CI]: 1.88-4.38); age≥60 years vs age<60 years (RR=2.43; 95% CI: 1.49-3.95); hand grip strength (Q(1) vs Q(4): ≤13.88 vs ≥17.28 kg) (RR=1.88; 95% CI: 1.15-3.05); BMD total hip (Q(1) vs Q(4): ≤0.784 vs 0.973 g/cm(2)) (RR=1.86; 95% CI: 1.26-2.75); dietary calcium intake (Q(1) vs Q(4): ≤391 vs ≥648 mg/day) (RR=1.66; 95% CI: 1.08-2.53); serum 25(OH)D (Q(1) vs Q(4): ≤17.9 vs ≥45.1 nmol/L) (RR=1.63; 95% CI: 1.06-2.51); and past year history of falls (RR=1.61; 95% CI: 1.06-2.48). Compared with having none (41.9% of women), having three or more clinical risk factors (4.8% of women) increased fracture risk by more than 4-fold, independent of BMD. Having three or more risk factors and being in the lowest tertile of T-score of [total hip/lumbar spine (L1-L4)] was associated with a 14.2-fold greater risk than having no risk factors and being in the highest T-score tertile. Several clinical risk factors were independently associated with all ORFs in healthy Saudi postmenopausal women. The combination of multiple clinical risk factors and low BMD is a very powerful indicator of fracture risk.     

Prevalent Vertebral Fractures on Chest CT: Higher Risk for Future Hip Fracture

Subclinical or undiagnosed vertebral fractures on routine chest computed tomography (CT) may be useful for detecting patients at increased risk of future hip fractures who might benefit from preventive interventions. We investigated whether prevalent vertebral fractures on routine chest CT are associated with future hip fractures. From a source population of 5679 patients ≥40 years old undergoing chest CT in one of three Dutch hospitals between 2002 and 2005, patients hospitalized for hip fractures (n = 149) during a median follow‐up of 4.4 years were identified. Following a case‐cohort design, a random sample of 576 patients was drawn from the source population and added to the cases. In this group, the presence and severity of vertebral fractures was determined using semiquantitative vertebral fracture assessment and multivariate case‐cohort appropriate Cox modeling. We found that cases were older (69 versus 63 years) and more often female (48% versus 38%) than the source population. Compared with those with no fracture, patients with any vertebral fracture had triple the risk of future hip fracture (age‐ and gender‐adjusted hazard ratio [HR] = 3.1, 95% confidence interval [CI] 2.1–4.7). This HR rose to 3.8 (CI 2.6–5.6) if mild fractures were discounted. Future fracture risk increased significantly with increasing severity of vertebral fracture status: from mild (HR = 2.4, CI 1.5–3.7) and moderate (HR = 4.8, CI 2.5–9.2) to severe (HR = 6.7, CI 2.9–15.5). The same was true for having higher cumulative fracture grades: 1 to 3 (HR = 2.7, CI 1.8–4.1), 4 to 6 (HR = 4.8, CI 2.2–10.5), or ≥7 (HR = 11.2, CI 3.7–34.6). In conclusion, prevalent vertebral fractures on routine clinical chest CT are associated with future hip fracture risk. © 2014 American Society for Bone and Mineral Research.     

Can Change in FRAX Score Be Used to “Treat to Target”? A Population‐Based Cohort Study

It is unknown how responsive the Fracture Risk Assessment (FRAX) tool is to osteoporosis treatment (OTX) or whether it can serve as a target for “goal‐directed” treatment. We studied 11,049 untreated women aged ≥50 years undergoing baseline and follow‐up DXA examinations in Manitoba, Canada. We identified clinical risk factors, intervening OTX based on medication possession ratios (MPR), and incident fractures. FRAX scores for major osteoporotic and hip fractures were computed for each scan using the most current (updated) FRAX inputs. Over 4 years, median FRAX scores showed an increase of 1.1% for major fractures and 0.3% for hip fractures, including women highly adherent to OTX (0.6% and 0.1% increases). Few (2.2%) highly adherent women had a decrease in major fracture probability exceeding 4%, whereas 9.0% had a decrease in hip fracture probability exceeding 1%. Compared with untreated women, OTX was associated with a higher dose‐dependent likelihood of attenuating the expected increase in major fracture risk: adjusted odds ratios (aOR) 2.3 (95% confidence interval [CI] 1.8–2.9) for MPR <0.50; 7.3 (95% CI 5.6–9.6) for MPR 0.50–0.79; and 12.0 (95% CI 9.5–15.2) for MPR ≥0.80. In the 4 years after the second DXA scan, 620 (6%) women had major fractures (152 hip fractures). FRAX scores were strongly predictive of incident major fractures (adjusted hazard ratios [aHR] per SD increase in FRAX 1.8, 95% CI 1.7–1.9) and hip fractures (aHR per SD 4.5, 95% CI 3.7–5.7); however, change in FRAX score was not independently associated with major fracture (p = 0.8) or hip fracture (p = 0.3). In conclusion, FRAX scores slowly increased over time, and this increase was attenuated but not prevented by treatment. Few women had meaningful reductions in FRAX scores, and change in FRAX score did not independently predict incident fracture, suggesting that FRAX with BMD is not responsive enough to be used as a target for goal‐directed treatment. © 2014 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.     

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.     

Mild hyponatremia as a risk factor for fractures: The rotterdam study

Recent studies suggest that mild hyponatremia is associated with fractures, but prospective studies are lacking. We studied whether hyponatremia is associated with fractures, falls, and/or bone mineral density (BMD). A total of 5208 elderly subjects with serum sodium assessed at baseline were included from the prospective population‐based Rotterdam Study. The following data were analyzed: BMD, vertebral fractures (mean follow‐up 6.4 years), nonvertebral fractures (7.4 years), recent falls, comorbidity, medication, and mortality. Hyponatremia was detected in 399 subjects (7.7%, 133.4 ± 2.0 mmol/L). Subjects with hyponatremia were older (73.5 ± 10.3 years versus 70.0 ± 9.0 years, p < .001), had more recent falls (23.8% versus16.4%, p < .01), higher type 2 diabetes mellitus prevalence (22.2% versus 10.3%, p < .001), and more often used diuretics (31.1% versus 15.0%, p < .001). Hyponatremia was not associated with lower BMD but was associated with increased risk of incident nonvertebral fractures [hazard ratio (HR) =1.39, 95% confidence interval (CI) 1.11–1.73, p = .004] after adjustment for age, sex, and body mass index. Further adjustments for disability index, use of diuretics, use of psycholeptics, recent falls, and diabetes did not modify results. In the fully adjusted model, subjects with hyponatremia also had increased risk of vertebral fractures at baseline [odds ratio (OR) = 1.78, 95% CI 1.04–3.06, p = .037] but not at follow‐up. Finally, all‐cause mortality was higher in subjects with hyponatremia (HR = 1.21, 95% CI 1.03–1.43, p = .022). It is concluded that mild hyponatremia in the elderly is associated with an increased risk of vertebral fractures and incident nonvertebral fractures but not with BMD. Increased fracture risk in hyponatremia also was independent of recent falls, pointing toward a possible effect on bone quality. © 2011 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.     

Inflammatory Markers and the Risk of Hip and Vertebral Fractures in Men: the Osteoporotic Fractures in Men (MrOS)

Cytokines play major roles in regulating bone remodeling, but their relationship to incident fractures in older men is uncertain. We tested the hypothesis that men with higher concentrations of pro‐inflammatory markers have a higher risk of fracture. We used a case‐cohort design and measured inflammatory markers in a random sample of 961 men and in men with incident fractures including 120 clinical vertebral, 117 hip, and 577 non‐spine fractures; average follow‐up 6.13 years (7.88 years for vertebral fractures). We measured interleukin (IL)‐6, C‐reactive protein (CRP), tumor necrosis factor alpha (TNFα), soluble receptors (SR) of IL‐6 (IL‐6SR) and TNF (TNFαSR1 and TNFαSR2), and IL‐10. The risk of non‐spine, hip, and clinical vertebral fracture was compared across quartiles (Q) of inflammatory markers using Cox proportional hazard models with tests for linear trend. In multivariable‐adjusted models, men with the highest (Q4) TNFa cytokine concentrations and their receptors had a 2.0–4.2‐fold higher risk of hip and clinical vertebral fracture than men with the lowest (Q1). Results were similar for all non‐spine fractures, but associations were smaller. There was no association between CRP and IL‐6SR and fracture. Men in the highest Q of IL‐10 had a 49% lower risk of vertebral fracture compared with men in Q1. Among men with ≥3 inflammatory markers in the highest Q, the hazard ratio (HR) for hip fractures was 2.03 (95% confidence interval [CI] 1.11–3.71) and for vertebral fracture 3.06 (1.66–5.63). The HRs for hip fracture were attenuated by 27%, 27%, and 15%, respectively, after adjusting for appendicular lean mass (ALM), disability, and bone density, suggesting mediating roles. ALM also attenuated the HR for vertebral fractures by 10%. There was no association between inflammation and rate of hip BMD loss. We conclude that inflammation may play an important role in the etiology of fractures in older men. © 2016 American Society for Bone and Mineral Research.     

The association between fracture site and obesity in men: A population‐Based cohort study

A site‐dependent association between obesity and fracture has been reported in postmenopausal women. In this study we investigated the relationship between body mass index (BMI) and fracture at different skeletal sites in older men (≥65 years). We carried out a population‐based cohort study using data from the Sistema d‘Informació per al Desenvolupament de l‘Investigació en Atenció Primària (SIDIAP^Q) database. SIDIAP^Q contains the primary care and hospital admission computerized medical records of >1300 general practitioners (GPs) in Catalonia (Northeast Spain), with information on a representative 30% of the population (>2 million people). In 2007, 186,171 men ≥65 years were eligible, of whom 139,419 (74.9%) had an available BMI measurement. For this analysis men were categorized as underweight/normal (BMI < 25 kg/m², n = 26,298), overweight (25 ≤ BMI < 30 kg/m², n = 70,851), and obese (BMI ≥ 30 kg/m², n = 42,270). Incident fractures in the period 2007 to 2009 were ascertained using International Classification of Diseases, 10th edition (ICD‐10) codes. A statistically significant reduction in clinical spine and hip fractures was observed in obese (relative risk [RR], 0.65; 95% confidence interval [CI], 0.53–0.80 and RR, 0.63; 95% CI, 0.54–0.74, respectively), and overweight men (RR, 0.77; 95% CI, 0.64–0.92 and RR, 0.63; 95% CI 0.55–0.72, respectively) when compared with underweight/normal men. Additionally, obese men had significantly fewer wrist/forearm (RR, 0.77; 95% CI, 0.61–0.97) and pelvic (RR, 0.44; 95% CI, 0.28–0.70) fractures than underweight/normal men. Conversely, multiple rib fractures were more frequent in overweight (RR, 3.42; 95% CI, 1.03–11.37) and obese (RR, 3.96; 95% CI, 1.16–13.52) men. In this population‐based cohort of older men, obesity was associated with a reduced risk of clinical spine, hip, pelvis, and wrist/forearm fracture and increased risk of multiple rib fractures when compared to normal or underweight men. Further work is needed to identify the mechanisms underlying these associations.