Nulliparity and fracture risk in older women: the study of osteoporotic fractures.

Whether nulliparity increases fracture risk is unclear from prior studies, which are limited by small samples or lack of measured bone mineral density. No study has evaluated whether the effect of parity differs by skeletal site. We prospectively analyzed the relationship of parity to the risk of incident nontraumatic hip, spine, and wrist fractures in 9704 women aged 65 years or older participating in the Study of Osteoporotic Fractures to determine if parity reduces postmenopausal fracture risk, and if so, if this risk reduction is (1) greater at weight-bearing skeletal sites and (2) independent of bone mineral density. Parity was ascertained by self-report. Incident hip and wrist fractures were determined by physician adjudication of radiology reports (mean follow-up, 9.8 years) and spine fractures by morphometric criteria on serial radiographs. The relationship of parity to hip and wrist fracture was assessed by proportional hazards models. Spine fracture risk was evaluated by logistic regression. Compared with parous women, nulliparous women (n = 1835, 19%) had an increased risk of hip and spine, but not wrist, fractures. In multivariate models, parity remained a significant predictor only for hip fracture. Nulliparous women had a 44% increased risk of hip fractures independent of hip bone mineral density (hazards ratio, 1.44; 95% CI, 1.17-1.78). Among parous women, each additional birth reduced hip fracture risk by 9% (p = 0.03). Additionally, there were no differences in mean total hip, spine, or radial bone mineral density values between nulliparous and parous women after multivariate adjustment. In conclusion, childbearing reduces hip fracture risk by means that may be independent of hip bone mineral density.     

Wrist Fracture and Risk of Subsequent Fracture: Findings from the Women's Health Initiative Study

Wrist fractures are common in postmenopausal women and are associated with functional decline. Fracture patterns after wrist fracture are unclear. The goal of this study was to determine the frequency and types of fractures that occur after a wrist fracture among postmenopausal women. We carried out a post hoc analysis of data from the Women's Health Initiative Observational Study and Clinical Trials (1993–2010) carried out at 40 US clinical centers. Participants were postmenopausal women aged 50 to 79 years at baseline. Mean follow‐up duration was 11.8 years. Main measures included incident wrist, clinical spine, humerus, upper extremity, lower extremity, hip, and total non‐wrist fractures and bone mineral density (BMD) in a subset. Among women who experienced wrist fracture, 15.5% subsequently experienced non‐wrist fracture. The hazard for non‐wrist fractures was higher among women who had experienced previous wrist fracture than among women who had not experienced wrist fracture: non‐wrist fracture overall (hazard ratio [HR] = 1.40, 95% confidence interval [CI] 1.33–1.48), spine (HR = 1.48, 95% CI 1.32–1.66), humerus (HR = 1.78, 95% CI 1.57–2.02), upper extremity (non‐wrist) (HR = 1.88, 95% CI 1.70–2.07), lower extremity (non‐hip) (HR = 1.36, 95% CI 1.26–1.48), and hip (HR = 1.50, 95% CI 1.32–1.71) fracture. Associations persisted after adjustment for BMD, physical activity, and other risk factors. Risk of non‐wrist fracture was higher in women who were younger when they experienced wrist fracture (interaction p value 0.02). Associations between incident wrist fracture and subsequent non‐wrist fracture did not vary by baseline BMD category (normal, low bone density, osteoporosis). A wrist fracture is associated with increased risk of subsequent hip, vertebral, upper extremity, and lower extremity fractures. There may be substantial missed opportunity for intervention in the large number of women who present with wrist fractures. © 2015 American Society for Bone and Mineral Research.     

Nitrate Medications,Fractures, and Change in Bone Mineral Density in Postmenopausal Women: Results from the Women's Health Initiative

Nitrate medications may increase bone mineral density (BMD), although information on fracture outcomes is sparse. We examined the association of nitrate medications with fractures (hip, wrist/arm, and total fractures) and changes in BMD (hip, spine, and whole body) in the Women's Health Initiative (WHI) Clinical Trials and Observational Study. A total of 139,211 postmenopausal women 50 to 79 years old without history of hip fracture were included in this prospective study. Medication use was ascertained directly from drug containers at baseline during in‐person interviews in 1993 to 1998. Exposure measures included any use (use/non‐use), type of nitrate (as‐needed, maintenance) and duration of use (≤5 years, >5 years). We used separate multivariable Cox proportional hazard models to analyze associations between each exposure and fracture outcome, with results presented as hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariable linear regression models were used to examine 3‐year and 6‐year changes in BMD. At baseline, 1.2% (n = 1647) women were using a nitrate. During the mean ± SD follow‐up of 7.7 ± 1.5 years through 2005, women experienced 1582 hip fractures, 5156 wrist or arm fractures, and 22, 589 total fractures. After adjustment for confounders, nitrate use was not statistically associated with risk for hip (HR, 0.81; 95% CI, 0.56 to 1.18), wrist/arm (HR, 0.95; 95% CI, 0.74 to 1.23), or total fractures (HR, 0.96; 95% CI, 0.85 to 1.08). As‐needed nitrate use, but not maintenance therapy, was associated with a lower risk of total fractures (HR, 0.77; 95% CI, 0.62 to 0.95) and wrist/arm fractures (HR, 0.57; 95% CI, 0.34 to 0.98). Nitrate use was not associated with 3‐year or 6‐year changes in BMD at any site. We conclude that any nitrate use was not significantly associated with lower risk of fractures or higher BMD; however, as‐needed nitrate use was associated with lower risks of total and wrist/arm fractures. © 2016 American Society for Bone and Mineral Research.     

Celiac Disease Autoimmunity and Hip Fracture Risk: Findings from a Prospective Cohort Study

The impact of celiac disease autoimmunity on bone health is unclear. We investigated the associations of seropositivity for tissue transglutaminase antibodies (tTGA) and endomysial antibodies (EMA) with incident hip fractures using data from a prospective cohort study, Mini‐Finland Health Survey. Baseline serum samples, taken in 1978–80, were tested for tTGA and EMA. Incident hip fractures up to the year 2011 were ascertained from a national hospitalization register. Associations between seropositivity and hip fractures were modeled using Cox proportional hazards regression adjusted for age, sex, body mass index, vitamin D, gamma‐glutamyl transferase, smoking, and self‐rated health. Our analyses were based on 6919 men and women who had no record of celiac disease or hip fracture before the study baseline. A total of 382 individuals had a hip fracture during a median follow‐up of 30 years. Compared with the tTGA‐negative individuals (n = 6350), tTGA‐positive participants (n = 569; with hip fracture, n = 51) had a higher risk of hip fractures (hazard ratio [HR] = 1.59, 95% confidence interval [CI] 1.17, 2.14). The findings were similar for another tTGA test (n 200; with hip fracture, n = 26; HR = 2.23, 95% CI 1.49, 3.34). We found no evidence for an association between EMA positivity and hip fracture risk (HR = 0.92, 95% CI 0.34, 2.47; n = 74; with hip fracture, n = 4). In our prospective population‐based study of Finnish adults, seropositivity for tTGA was associated with an increased hip fracture risk. © 2014 American Society for Bone and Mineral Research.     

Effects of antiresorptive treatment on nonvertebral fracture outcomes

Various definitions of nonvertebral fracture have been used in osteoporosis trials, precluding comparisons of efficacy. Using only subgroups of nonvertebral fractures for trial outcomes may underestimate the benefits and cost‐effectiveness of treatments. The objectives of this study were to determine (1) the effect of antiresorptive treatment on various nonvertebral fracture outcomes, (2) whether risk reduction from antiresorptive treatment is greater for nonvertebral fractures that have stronger associations with low BMD, and (3) sample size estimates for clinical trials of osteoporosis treatments. Study‐level data were combined from five randomized fracture‐prevention trials of antiresorptive agents that reduce the risk of nonvertebral fracture in postmenopausal women: alendronate, clodronate, denosumab, lasofoxifene, and zoledronic acid. Pooled effect estimates were calculated with random‐effects models. The five trials included 30,118 women; 2997 women had at least one nonvertebral fracture. There was no significant heterogeneity between treatments for any outcome (all p > 0.10). Antiresorptive treatment had similar effects on all fractures (summary hazard ratio [HR] = 0.76, 95% CI 0.70–0.81), high‐trauma fractures (HR = 0.74, 95% CI 0.57–0.96), low‐trauma fractures (HR = 0.77, (95% CI 0.71–0.83), nonvertebral six (ie, hip, pelvis, leg, wrist, humerus, and clavicle) fractures (HR = 0.73, 95% CI 0.66–0.80), other than nonvertebral six fractures (HR = 0.78, 95% CI 0.70–0.87), and all fractures other than finger, face, and toe (HR = 0.75, 95% CI 0.70–0.81). Risk reduction was not greater for fractures with stronger associations with low BMD (p = 0.77). A trial of all nonvertebral fractures would require fewer participants (n = 2641 per arm) than one of a subgroup of six fractures (n = 3289), for example. In summary, antiresorptive treatments reduced all nonvertebral fractures regardless of degree of trauma or special groupings, supporting the use of all nonvertebral fractures as a standard endpoint of osteoporosis trials and the basis for estimating the benefits and cost‐effectiveness of treatments. © 2011 American Society for Bone and Mineral Research     

Vitamin D receptor genotype and risk of osteoporotic hip fracture in elderly women of Utah: an effect modified by parity

Introduction The associations between vitamin D receptor (VDR) Bsm I and Fok I genotypes, parity, and risk of osteoporotic hip fracture were evaluated in a statewide population-based case-control study in Utah.Methods Women age 50–89 years with hip fracture (n=882) were ascertained via surveillance of 18 Utah hospitals from 1997 to 2001. Age-matched controls were randomly selected (n=897). Participants were interviewed in their homes, and blood samples were collected for genotyping.Results In logistic regression analyses that controlled for multiple confounders, Bsm I VDR genotype but not Fok I genotype was associated with risk of osteoporotic hip fracture (OR bb vs. BB genotype: 0.68; 95% CI: 0.50, 0.95). In similar analyses, no overall association was observed between parity status and risk of osteoporotic hip fracture. However, the effect of VDR genotype was modified by parity status. Among nulliparous women (n=140), Bsm I genotype was not associated with risk of hip fracture (OR bb vs. BB: 0.82; 95% CI: 0.28, 2.4); among primiparous women (n=133), bb genotype was associated with increased risk of hip fracture (OR bb vs. BB: 3.30; 95% CI: 0.96, 11.29); among multiparous women (n=1,400), bb genotype was associated with decreased risk of hip fracture (OR bb vs. BB: 0.59; 95% CI: 0.42, 0.84).Conclusion VDR Bsm I genotype was associated with risk of hip fracture in Utah women, and this effect was modified by parity status. Hormonal or lifestyle factors related to parity may underlie this interaction.     

Parity and risk of hip fracture in postmenopausal women

Summary

Hip fracture risk was assessed according to parity among postmenopausal women. Compared with nulliparous women, the fracture risk was lower in women with three or more births.

Introduction

Parity was assessed for long-term prediction of hip fracture in postmenopausal women.

Methods

Postmenopausal women (n?=?2,028) aged 45 or over with no history of hip fracture were studied. From 1978 to 1980, all of them had participated in a comprehensive health survey based on a nationally representative population sample. Emerging cases of hip fracture were identified from the National Hospital Discharge Register during a follow-up period extending up to 17?years.

Results

The risk of hip fracture was lower among parous women compared with nulliparous women. The model adjusted for age showed a significant inverse association between parity as a continuous variable and the risk of hip fracture [RR?=?0.74; 95% confidence interval (CI), 0.61?C0.90] per an increment of one standard deviation (2.4 births). Adjusted for age, menopausal age, level of education, body mass index, vitamin D status, alcohol consumption, smoking history, leisure time physical activity, and self-rated health, the relative risk was 0.50 (95% CI, 0.32?C0.79) for women with three or more births and 0.85 (95% CI, 0.55?C1.32) for women with one to two births as compared with nulliparous women.

Conclusion

Parity, three or more births in particular, predicts a lowered risk of hip fracture in the long run.     

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.     

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.     

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     

Relationship of body mass index with main limb fragility fractures in postmenopausal women

Body mass index (BMI) has been found to be related to the risk of osteoporotic hip fractures in women, regardless of bone mineral density (BMD). The same relationship is under debate for other limb fragility fractures. Very few studies have investigated the comparison of fracture risk among BMI categories, classified according to the WHO criteria, despite the potential usefulness of such information for clinical purposes. To address these issues we studied 2,235 postmenopausal women including those with fragility fractures of the hip (187), ankle (108), wrist (226) and humerus (85). Statistical analyses were performed by logistic regression by treating the fracture status as the dependent variable and age, age at menopause, femoral neck BMD and BMI as covariates. BMI was tested as a continuous or categorical variable. As a continuous variable, increased BMI had a protective effect against hip fracture: OR 0.949 (95% CI, 0.900–0.999), but carried a higher risk of humerus fracture: OR 1.077 (95% CI, 1.017–1.141). Among the BMI categories, only leanness: OR 3.819 (95% CI, 2.035–7.168) and obesity: OR 3.481 (95% CI, 1.815–6.678) showed a significantly higher fracture risk for hip and humerus fractures, respectively. There was no relationship between ankle and wrist fractures and BMI. In conclusion, decreasing BMI increases the risk for hip fracture, whereas increasing BMI increases the risk for humerus fractures. Leanness-related low BMD and obesity-related body instability might explain the different BMI relationships with these two types of fracture.     

Fracture Risk After Bariatric Surgery: Roux‐en‐Y Gastric Bypass Versus Adjustable Gastric Banding

The long‐term consequences of bariatric surgery on fracture risk are unclear but are likely to vary by procedure type. In physiologic studies, Roux‐en‐Y gastric bypass (RYGB) and adjustable gastric banding (AGB) have differential effects on rates of bone loss. Therefore, our objective was to compare fracture risk in obese adults after RYGB and AGB procedures. Using claims data from a US commercial health plan, we analyzed rates of nonvertebral fractures within a propensity score–matched cohort (n = 15,032) of morbidly obese adults who received either RYGB or AGB surgery between 2005 and 2013. A total of 281 nonvertebral fractures occurred during a mean follow‐up time of 2.3 ± 1.9 years. RYGB patients had an increased risk of nonvertebral fracture (hazard ratio [HR] = 1.43, 95% confidence interval [CI] 1.13–1.81) compared with AGB patients. In fracture site–specific analyses, RYGB patients had increased risk of fracture at the hip (HR = 1.54, 95% CI 1.03–2.30) and wrist (HR = 1.45, 95% CI 1.01–2.07). Nonvertebral fracture risk associated with RYGB manifested >2 years after surgery and increased in subsequent years, with the highest risk in the fifth year after surgery (HR = 3.91, 95% CI 1.58–9.64). In summary, RYGB is associated with a 43% increased risk of nonvertebral fracture compared with AGB, with risk increasing >2 years after surgery. Fracture risk should be considered in risk/benefit discussions of bariatric surgery, particularly among patients with high baseline risk of osteoporosis who are deciding between RYGB and AGB procedures. © 2017 American Society for Bone and Mineral Research.     

Association between self-reported prior wrist fractures and risk of subsequent hip and radiographic vertebral fractures in older women: a prospective study.

In this large prospective cohort study of elderly women, the relationships between prior wrist fracture and incident hip and radiographic vertebral fractures were significantly attenuated when adjusted for BMD. This study suggests that BMD thresholds for drug therapy to prevent osteoporotic fracture should be only modestly adjusted in those with prior wrist fracture compared with those without prior wrist fracture. Validation of such an approach would require intervention trials in patients with prior wrist fracture. INTRODUCTION: Prior wrist fracture has been identified as a risk factor for incident hip and vertebral fractures and proposed as a criterion for determining who should be offered drug therapy to prevent osteoporotic fracture, even if their hip BMD T score is > -2.5. Previously published studies of the relationships between prior wrist fracture and incident hip and vertebral fractures did not adjust for BMD. MATERIALS AND METHODS: We ascertained prior history of wrist fracture since age 50, measured calcaneal and hip BMD, and performed lateral spine films in a cohort of 9704 elderly community-dwelling women, and then followed them prospectively for incident vertebral and hip fractures. Incident vertebral fractures were defined by morphometry using lateral spine radiography at the first examination and an average of 3.7 years later. Incident hip fractures were confirmed with radiographic reports over a mean follow-up period of 10.1 years. RESULTS: Prior wrist fracture was associated with an age-adjusted 72% increased odds of incident radiographic vertebral fracture (odds ratio [OR], 1.72; 95% CI, 1.31-2.25). After adjustment for calcaneal BMD, the association of prior wrist fracture with incident radiographic vertebral fracture was attenuated (OR, 1.39; 95% CI, 1.05-1.83). Prior wrist fracture was also associated with an age-adjusted 43% excess rate of incident hip fracture (hazards ratio [HR], 1.43; 95% CI, 1.17-1.74). After adjustment for hip BMD, the association of prior wrist fracture with rate of incident hip fracture was no longer statistically significant (HR, 1.12; 95% CI, 0.92-1.38). CONCLUSION: In elderly women, prior wrist fracture is a risk factor for radiographic vertebral fracture independent of BMD. The association between prior wrist fracture and incident hip fracture is largely explained by hip BMD. Modest adjustment of BMD drug treatment thresholds for prevention of osteoporotic fractures in those with prior wrist fracture compared with those without prior wrist fracture may be reasonable, but validation of such an approach would require intervention trials in patients with prior wrist fracture.     

Low Serum DHEAS Predicts Increased Fracture Risk in Older Men: The MrOS Sweden Study

The adrenal‐derived hormones dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are the most abundant circulating hormones and their levels decline substantially with age. DHEAS is considered an inactive precursor, which is converted into androgens and estrogens via local metabolism in peripheral target tissues. The predictive value of serum DHEAS for fracture risk is unknown. The aim of this study was, therefore, to assess the associations between baseline DHEAS levels and incident fractures in a large cohort of older men. Serum DHEAS levels were analyzed with mass spectrometry in the population‐based Osteoporotic Fractures in Men study in Sweden (n = 2568, aged 69 to 81 years). Incident X‐ray validated fractures (all, n = 594; non‐vertebral major osteoporotic, n = 255; hip, n = 175; clinical vertebral, n = 206) were ascertained during a median follow‐up of 10.6 years. DHEAS levels were inversely associated with the risk of any fracture (hazard ratio [HR] per SD decrease = 1.14, 95% confidence interval [CI] 1.05–1.24), non‐vertebral major osteoporotic fractures (HR = 1.31, 95% CI 1.16–1.48), and hip fractures (HR = 1.18, 95% CI 1.02–1.37) but not clinical vertebral fractures (HR = 1.09, 95% CI 0.95–1.26) in Cox regression models adjusted for age, body mass index (BMI) and prevalent fractures. Further adjustment for traditional risk factors for fracture, bone mineral density (BMD), and/or physical performance variables as well as serum sex steroid levels only slightly attenuated the associations between serum DHEAS and fracture risk. Similarly, the point estimates were only marginally reduced after adjustment for FRAX estimates with BMD. The inverse association between serum DHEAS and all fractures or major osteoporotic fractures was nonlinear, with a substantial increase in fracture risk (all fractures 22%, major osteoporotic fractures 33%) for those participants with serum DHEAS levels below the median (0.60 μg/mL). In conclusion, low serum DHEAS levels are a risk marker of mainly non‐vertebral fractures in older men, of whom those with DHEAS levels below 0.60 μg/mL are at highest risk. © 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 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 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.     

Influence of reproductive factors on hip fracture risk in Chinese women

To assess the relationships between reproductive factors and the risk of hip fractures in postmenopausal Chinese women, the authors analyzed data from a matched case-control study conducted in the Beijing metropolitan area among women aged 50 years and older. One hundred and fifty-six cases who sustained a hip fracture after minor trauma between January 1994 and May 1996 were identified from hospital records, of whom 121 could be located (78%). All cases agreed to be interviewed. Two controls were selected from the neighbors of each hip fracture case and matched to the cases by age within a 5-year range. Information on reproductive factors and potential confounders was obtained through personal interviews. Multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. Multiple imputation procedure was also employed to account for item non-response. Although univariate analyses revealed that later age at menopause, parity and breastfeeding were protective factors, only breastfeeding was statistically associated with risk of hip fracture after adjusting for potential confounding in multivariable logistic models. As compared with women with average duration of breastfeeding per child 6 months, women with average duration of breastfeeding per child 7–12 months, 13–23 months, and 24 months had odds ratios of 1.14 (95% CI: 0.48, 2.72), 0.28 (95% CI: 0.10, 0.82) and 0.34 (95% CI: 0.13, 0.92), respectively. Among parous women, 13% reduced risk was associated with every 6 months increase in breastfeeding per child. The authors conclude that extended breastfeeding is associated with a reduced hip fracture risk among Chinese women in Beijing.