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.     

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.     

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     

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.     

Falls Predict Fractures Independently of FRAX Probability: A Meta‐Analysis of the Osteoporotic Fractures in Men (MrOS) Study

Although prior falls are a well‐established predictor of future fracture, there is currently limited evidence regarding the specific value of falls history in fracture risk assessment relative to that of other clinical risk factors and bone mineral density (BMD) measurement. We therefore investigated, across the three Osteoporotic Fractures in Men (MrOS) Study cohorts, whether past falls predicted future fracture independently of FRAX and whether these associations varied with age and follow‐up time. Elderly men were recruited from MrOS Sweden, Hong Kong, and USA. Baseline data included falls history (over the preceding 12 months), clinical risk factors, BMD at femoral neck, and calculated FRAX probabilities. An extension of Poisson regression was used to investigate the associations between falls, FRAX probability, and incident fracture, adjusting for age, time since baseline, and cohort in base models; further models were used to investigate interactions with age and follow‐up time. Random‐effects meta‐analysis was used to synthesize the individual country associations. Information on falls and FRAX probability was available for 4365 men in USA (mean age 73.5 years; mean follow‐up 10.8 years), 1823 men in Sweden (mean age 75.4 years; mean follow‐up 8.7 years), and 1669 men in Hong Kong (mean age 72.4 years; mean follow‐up 9.8 years). Rates of past falls were similar at 20%, 16%, and 15%, respectively. Across all cohorts, past falls predicted incident fracture at any site (hazard ratio [HR] = 1.69; 95% confidence interval [CI] 1.49, 1.90), major osteoporotic fracture (MOF) (HR = 1.56; 95% CI 1.33, 1.83), and hip fracture (HR = 1.61; 95% CI 1.27, 2.05). Relationships between past falls and incident fracture remained robust after adjustment for FRAX probability: adjusted HR (95% CI) any fracture: 1.63 (1.45, 1.83); MOF: 1.51 (1.32, 1.73); and hip: 1.54 (1.21, 1.95). In conclusion, past falls predicted incident fracture independently of FRAX probability, confirming the potential value of falls history in fracture risk assessment. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Association of 3D Geometric Measures Derived From Quantitative Computed Tomography With Hip Fracture Risk in Older Men

We investigated the associations of 3D geometric measures and volumetric bone mineral density (vBMD) of the proximal femur assessed by quantitative computed tomography (QCT) with hip fracture risk among elderly men. This study was a prospective case‐cohort design nested within the Osteoporotic Fractures in Men Study (MrOS) cohort. QCT scans of 230 men (65 with confirmed hip fractures) were evaluated with Mindways' QCTPRO‐BIT software. Measures that are indicative of bone strength for the femoral neck (FN) and for the trochanteric region (TR) were defined. Bending strength measures were estimated by minimum section modulus, buckling strength by buckling ratio, and a local thinning index (LTI). Integral and trabecular vBMD measures were also derived. Areal BMD (aBMD) of the total proximal femur from dual‐energy X‐ray absorptiometry (DXA) is presented for comparison. Associations of skeletal measures with incident hip fracture were estimated with hazard ratios (HR) per standard deviation and their 95% confidence intervals (CI) from Cox proportional hazard regression models with adjustment for age, body mass index (BMI), site, and aBMD. Men with hip fractures were older than men without fracture (77.1 ± 6.0 years versus 73.3 ± 5.7 years, p < 0.01). Age, BMI, and site‐adjusted HRs were significant for all measures except TR_LTI. Total femural BMD by DXA (HR = 4.9, 95% CI 2.5–9.9) and QCT (HR = 5.5, 95% CI 2.5–11.7) showed the strongest association followed by QCT FN integral vBMD (HR = 3.6, 95% CI 1.8–6.9). In models that additionally included aBMD, FN buckling ratio (HR = 1.9, 95% CI 1.1–3.2) and trabecular vBMD of the TR (HR = 2.0, 95% CI 1.2–3.4) remained associated with hip fracture risk, independent of aBMD. QCT‐derived 3D geometric indices of instability of the proximal femur were significantly associated with incident hip fractures, independent of DXA aBMD. Buckling of the FN is a relevant failure mode not entirely captured by DXA. Further research to study these relationships in women is warranted. © 2016 American Society for Bone and Mineral Research.     

Lower fracture risk in older men with higher sclerostin concentration: A prospective analysis from the MINOS study

Sclerostin is synthesized by osteocytes and inhibits bone formation. We measured serum sclerostin levels in 710 men aged 50 years and older. Bone mineral density (BMD) was measured at the lumbar spine, hip, and distal forearm. Serum sclerostin increased with age (unadjusted r = 0.30, p < 0.001). After adjustment for age, weight, and bioavailable 17β‐estradiol, serum sclerostin correlated positively with BMD (r = 0.24 to 0.35, p < 0.001) and negatively with the levels of bone turnover markers (r = ? 0.09 to ? 0.23, p < 0.05 to 0.001). During a 10‐year follow‐up, 75 men sustained fragility fractures. Fracture risk was lower in the two upper quintiles of sclerostin combined versus three lower quintiles combined (6.1 versus 13.5%, p < 0.01). We compared fracture risk in the two highest quintiles combined versus three lower quintiles combined using the Cox model adjusted for age, weight, leisure physical activity, BMD, bone width (tubular bones), prevalent fracture, prevalent falls, ischemic heart disease, and severe abdominal aortic calcification. Men with higher sclerostin concentration had lower fracture risk (adjusted for hip BMD, hazard ratio [HR] = 0.55, 95% confidence interval [CI] 0.31 to 0.96, p < 0.05). The results were similar in 47 men with major fragility fractures (adjusted for lumbar spine BMD: HR = 0.39, 95% CI 0.17 to 0.90, p < 0.05). Men who had higher sclerostin and higher BMD (two highest quintiles) had lower risk of fracture compared with men who had lower BMD and lower sclerostin levels (three lower quintiles) (HR = 0.24, 95% CI 0.10 to 0.62, p < 0.005). Circulating sclerostin was not associated with mortality rate or the incidence of major cardiovascular events. Thus, in older men, higher serum sclerostin levels are associated with lower risk of fracture, higher BMD, and lower bone turnover rate. © 2013 American Society for Bone and Mineral Research.     

Association of Increased Urinary Albumin With Risk of Incident Clinical Fracture and Rate of Hip Bone Loss: the Osteoporotic Fractures in Men Study

Prior studies suggest that increased urine albumin is associated with a heightened fracture risk in women, but results in men are unclear. We used data from Osteoporotic Fractures in Men (MrOS), a prospective cohort study of community‐dwelling men aged ≥65 years, to evaluate the association of increased urine albumin with subsequent fractures and annualized rate of hip bone loss. We calculated albumin/creatinine ratio (ACR) from urine collected at the 2003–2005 visit. Subsequent clinical fractures were ascertained from triannual questionnaires and centrally adjudicated by review of radiographic reports. Total hip BMD was measured by DXA at the 2003–2005 visit and again an average of 3.5 years later. We estimated risk of incident clinical fracture using Cox proportional hazards models, and annualized BMD change using ANCOVA. Of 2982 men with calculable ACR, 9.4% had ACR ≥30 mg/g (albuminuria) and 1.0% had ACR ≥300 mg/g (macroalbuminuria). During a mean of 8.7 years of follow‐up, 20.0% of men had an incident clinical fracture. In multivariate‐adjusted models, neither higher ACR quintile (p for trend 0.75) nor albuminuria (HR versus no albuminuria, 0.89; 95% CI, 0.65 to 1.20) was associated with increased risk of incident clinical fracture. Increased urine albumin had a borderline significant, multivariate‐adjusted, positive association with rate of total hip bone loss when modeled in ACR quintiles (p = 0.06), but not when modeled as albuminuria versus no albuminuria. Macroalbuminuria was associated with a higher rate of annualized hip bone loss compared to no albuminuria (–1.8% more annualized loss than in men with ACR <30 mg/g; p < 0.001), but the limited prevalence of macroalbuminuria precluded reliable estimates of its fracture associations. In these community‐dwelling older men, we found no association between urine albumin levels and risk of incident clinical fracture, but found a borderline significant, positive association with rate of hip bone loss. © 2016 American Society for Bone and Mineral Research.     

Smoking predicts incident fractures in elderly men: Mr OS Sweden

The aim of this study was to investigate the association between smoking and bone mineral density (BMD) and radiographically verified prevalent vertebral fractures and incident fractures in elderly men. At baseline 3003 men aged 69 to 80 years of age from the Swedish Mr Os Study completed a standard questionnaire concerning smoking habits and had BMD of the hip and spine measured using dual‐energy X‐ray absorptiometry (DXA); 1412 men had an X‐ray of the thoracic‐ and lumbar spine. Radiologic registers were used to confirm reported new fractures after the baseline visit. At baseline, 8.4% were current smokers. Current smokers had a 6.2% lower BMD at the total hip and a 5.4% lower BMD at the lumbar spine (p < .001). Current smoking remained independently inversely associated with BMD at the hip and lumbar spine after adjusting for age, height, weight, calcium intake, physical activity, and centers as covariates. Prevalent vertebral fractures among current smokers were increased in unadjusted analyses [odds ratio (OR) = 1.90, 95% confidence interval (CI) 1.26–2.87] and after adjustment for lumbar BMD (OR = 1.67, 95% CI 1.09–2.55). Smokers had a high risk for two or more prevalent vertebral fractures (OR = 3.18, 95% CI 1.88–5.36). During the average follow‐up of 3.3 years, 209 men sustained an X‐ray‐verified fracture. Incident fracture risk among smokers was calculated with Cox proportional hazard models. Current smokers had an increased risk of all new fractures [hazard ratio (HR) = 1.76, 95% CI 1.19–2.61]; nonvertebral osteoporotic fractures, defined as humerus, radius, pelvis, and hip fractures (HR = 2.14, 95% CI 1.18–3.88); clinical and X‐ray‐verified vertebral fractures (HR = 2.53, 95% CI 1.37–4.65); and hip fractures (HR = 3.16, 95% CI 1.44–6.95). After adjustment for BMD, including other covariates, no significant association between smoking and incident fractures was found. Current tobacco smoking in elderly men is associated with low BMD, prevalent vertebral fractures, and incident fractures, especially vertebral and hip fractures. © 2010 American Society for Bone and Mineral Research     

Serum fibroblast growth factor‐23 (FGF‐23) and fracture risk in elderly men

A normal mineral metabolism is integral for skeletal development and preservation of bone integrity. Fibroblast growth factor 23 (FGF‐23) is a bone‐derived circulating factor that decreases serum concentrations of inorganic phosphorous (P_i) and 1,25‐dihydroxyvitamin D₃ [1,25(OH)₂D₃]. Increased FGF‐23 expression is a direct or indirect culprit in several skeletal disorders; however, the relation between FGF‐23 and fracture risk remains undetermined. We evaluated the prospective relation between serum intact FGF‐23 (measured by a two‐site monoclonal antibody ELISA) and fracture risk employing the Swedish part of the population‐based Osteoporotic Fractures in Men Study (MrOS; n = 2868; mean age 75.4 ± 3.2 years; median follow‐up period 3.35 years). The incidence of at least one validated fracture after baseline was 20.4 per 1000 person‐years. FGF‐23 was directly related to the overall fracture risk [age‐adjusted hazard ratio (HR) per SD increase = 1.20, 95% confidence interval (CI) 1.03–1.40] and vertebral fracture risk (HR = 1.33, 95% CI 1.02–1.75). Spline models revealed a nonlinear relation between FGF‐23 and fracture risk, with the strongest relation at FGF‐23 levels above 55.7 pg/mL. FGF‐23 levels above 55.7 pg/mL also were associated with an increased risk for hip and nonvertebral fractures (HR = 2.30, 95% CI 1.16–4.58, and HR = 1.63, 95% CI 1.01–2.63, respectively). These relations remained essentially unaltered after adjustment for bodymass index (BMI), bone mineral density (BMD), glomerular filtration rate, 25(OH)₂D₃, parathyroid hormone (PTH), and other fracture risk factors. In conclusion, FGF‐23 is a novel predictor of fracture risk in elderly men. © 2011 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.     

Degree of Trauma Differs for Major Osteoporotic Fracture Events in Older Men Versus Older Women

To examine the degree of trauma in major osteoporotic fractures (MOF) in men versus women, we used data from 15,698 adults aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study (5994 men) and the Study of Osteoporotic Fractures (SOF) (9704 women). Participants were contacted tri‐annually to ascertain incident fractures, which were confirmed by radiographic reports and coded according to degree of self‐reported trauma. Trauma was classified as low (fall from ≤ standing height; fall on stairs, steps, or curb; minimal trauma other than fall [coughing, turning over]); moderate (collisions with objects during normal activity without associated fall); or high (fall from > standing height; severe trauma [motor vehicle accident, assault]). MOF included hip, clinical vertebral, wrist, and humerus fractures. Mean fracture follow‐up was 9.1 years in SOF and 8.7 years in MrOS. A total of 14.6% of the MOF in men versus 6.3% of the MOF in women were classified as high trauma (p < 0.001); men versus women more often experienced fractures resulting from severe trauma as well as from fall > standing height. High‐trauma fractures were more significantly common in men versus women at the hip (p = 0.002) and wrist (p < 0.001) but not at the spine or humerus. Among participants with MOF, the odds ratio of a fracture related to high‐trauma fracture among men versus women was 3.12 (95% confidence interval [CI] 1.70–5.71) after adjustment for traditional risk factors. Findings were similar in analyses limited to participants with hip fractures (odds ratio [OR] = 3.34, 95% CI 1.04–10.67) and those with wrist fracture (OR = 5.68, 95% CI 2.03–15.85). Among community‐dwelling older adults, MOF are more likely to be related to high trauma in men than in women. These findings are not explained by sex differences in conventional risk factors and may reflect a greater propensity among men to engage in risky behavior. © 2015 American Society for Bone and Mineral Research.     

Proximal Femoral Structure and the Prediction of Hip Fracture in Men: A Large Prospective Study Using QCT

The structure of the femoral neck contributes to hip strength, but the relationship of specific structural features of the hip to hip fracture risk is unclear. The objective of this study is to determine the contribution of structural features and volumetric density of both trabecular and cortical bone in the proximal femur to the prediction of hip fracture in older men. Baseline QCT scans of the hip were obtained in 3347 men ≥65 yr of age enrolled in the Osteoporotic Fractures in Men Study (MrOS). All men were followed prospectively for an average of 5.5 yr. Areal BMD (aBMD) by DXA was also assessed. We determined the associations between QCT‐derived measures of femoral neck structure, volumetric bone density, and hip fracture risk. Forty‐two men sustained incident hip fractures during follow‐up: an overall rate of 2.3/1000 person‐years. Multivariable analyses showed that, among the QCT‐derived measures, lower percent cortical volume (hazard ratio [HR] per SD decrease: 3.2; 95% CI: 2.2–4.6), smaller minimal cross‐sectional area (HR: 1.6; 95% CI: 1.2–2.1), and lower trabecular BMD (HR: 1.7; 95% CI: 1.2–2.4) were independently related to increased hip fracture risk. Femoral neck areal BMD was also strongly related to hip fracture risk (HR: 4.1; 95% CI: 2.7–6.4). In multivariable models, percent cortical volume and minimum cross‐sectional area remained significant predictors of hip fracture risk after adjustment for areal BMD, but overall prediction was not improved by adding QCT parameters to DXA. Specific structural features of the proximal femur were related to an increased risk of hip fracture. Whereas overall hip fracture prediction was not improved relative to aBMD, by adding QCT parameters, these results yield useful information concerning the causation of hip fracture, the evaluation of hip fracture risk, and potential targets for therapeutic intervention.     

High Plasma Erythropoietin Predicts Incident Fractures in Elderly Men with Normal Renal Function: The MrOS Sweden Cohort

Preclinical studies on the role of erythropoietin (EPO) in bone metabolism are contradictory. Regeneration models indicate an anabolic effect on bone healing, whereas models on physiologic bone remodeling indicate a catabolic effect on bone mass. No human studies on EPO and fracture risk are available. It is known that fibroblast growth factor 23 (FGF23) affects bone mineralization and that serum concentration of FGF23 is higher in men with decreased estimated glomerular filtration rate (eGFR). Recently, a direct association between EPO and FGF23 has been shown. We have explored the potential association between EPO and bone mineral density (BMD), fracture risk, and FGF23 in humans. Plasma levels of EPO were analyzed in 999 men (aged 69 to 81 years), participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) study, MrOS Sweden. The mean ± SD EPO was 11.5 ± 9.0 IU/L. Results were stratified by eGFR 60 mL/min. For men with eGFR ≥60 mL/min (n = 728), EPO was associated with age (r = 0.13, p < 0.001), total hip BMD (r = 0.14, p < 0.001), intact (i)FGF23 (r = 0.11, p = 0.004), and osteocalcin (r = −0.09, p = 0.022). The association between total hip BMD and EPO was independent of age, body mass index (BMI), iFGF23, and hemoglobin (beta = 0.019, p < 0.001). During the 10-year follow-up, 164 men had an X-ray–verified fracture, including 117 major osteoporotic fractures (MOF), 39 hip fractures, and 64 vertebral fractures. High EPO was associated with higher risk for incident fractures (hazard ratio [HR] = 1.43 per tertile EPO, 95% confidence interval [CI] 1.35–1.63), MOF (HR = 1.40 per tertile EPO, 95% CI 1.08–1.82), and vertebral fractures (HR = 1.42 per tertile EPO, 95% CI 1.00–2.01) in a fully adjusted Cox regression model. In men with eGFR<60 mL/min, no association was found between EPO and BMD or fracture risk. We here demonstrate that high levels of EPO are associated with increased fracture risk and increased BMD in elderly men with normal renal function. © 2019 American Society for Bone and Mineral Research.     

The Association Between Protein Intake by Source and Osteoporotic Fracture in Older Men: A Prospective Cohort Study

Dietary protein is a potentially modifiable risk factor for fracture. Our objectives were to assess the association of protein intake with incident fracture among older men and whether these associations varied by protein source or by skeletal site. We studied a longitudinal cohort of 5875 men (mean age 73.6 ± 5.9 years) in the Osteoporotic Fractures in Men (MrOS) study. At baseline, protein intake was assessed as percent of total energy intake (TEI) with mean intake from all sources = 16.1%TEI. Incident clinical fractures were confirmed by physician review of medical records. There were 612 major osteoporotic fractures, 806 low‐trauma fractures, 270 hip fractures, 193 spine fractures, and 919 non‐hip non‐spine fractures during 15 years of follow‐up. We used Cox proportional hazards models with age, race, height, clinical site, TEI, physical activity, marital status, osteoporosis, gastrointestinal surgery, smoking, oral corticosteroids use, alcohol consumption, and calcium and vitamin D supplements as covariates to compute hazard ratios (HRs) with 95% confidence intervals (CIs), all expressed per unit (SD = 2.9%TEI) increase. Higher protein intake was associated with a decreased risk of major osteoporotic fracture (HR = 0.92; 95% CI, 0.84 to 1.00) with a similar association found for low‐trauma fracture. The association between protein and fracture varied by protein source; eg, increased dairy protein and non‐dairy animal protein were associated with a decreased risk of hip fracture (HR = 0.80 [95% CI, 0.65 to 0.98] and HR = 0.84 [95% CI, 0.72 to 0.97], respectively), whereas plant‐source protein was not (HR = 0.99 [95% CI, 0.78 to 1.24]). The association between protein and fracture varied by fracture site; total protein was associated with a decreased risk of hip fracture (HR = 0.84 [95% CI, 0.73 to 0.95]), but not clinical spine fracture (HR = 1.06 [95% CI, 0.92 to 1.22]). In conclusion, those with high protein intake (particularly high animal protein intake) as a percentage of TEI have a lower risk of major osteoporotic fracture. © 2016 American Society for Bone and Mineral Research.     

High Serum SHBG Predicts Incident Vertebral Fractures in Elderly Men

Previous prospective cohort studies have shown that serum levels of sex steroids and sex hormone‐binding globulin (SHBG) associate with nonvertebral fracture risk in men. The predictive value of sex hormones and SHBG for vertebral fracture risk specifically is, however, less studied. Elderly men (aged ≥65 years) from Sweden and Hong Kong participating in the Osteoporotic Fractures in Men (MrOS) study had baseline estradiol and testosterone analyzed by gas chromatography–mass spectrometry (GC‐MS) and SHBG by immunoradiometric assay (IRMA). Incident clinical vertebral fractures (n = 242 cases) were evaluated in 4324 men during an average follow‐up of 9.1 years. In a subsample of these men (n = 2256), spine X‐rays were obtained at baseline and after an average follow‐up of 4.3 years to identify incident radiographic vertebral fractures (n = 157 cases). The likelihood of incident clinical and radiographic vertebral fractures was estimated by Cox proportional hazards models and logistic regression models, respectively. Neither serum estradiol (hazard ratio [HR] per SD increase = 0.93, 95% confidence interval [CI] 0.80–1.08) nor testosterone (1.05, 0.91–1.21) predicted incident clinical vertebral fractures in age‐adjusted models in the combined data set. High serum SHBG, however, associated with increased clinical vertebral fracture risk (1.24, 1.12–1.37). This association remained significant after further adjustment for FRAX with or without bone mineral density (BMD). SHBG also associated with increased incident radiographic vertebral fracture risk (combined data set; odds ratio [OR] per SD increase = 1.23, 95% CI 1.05–1.44). This association remained significant after adjustment for FRAX with or without BMD. In conclusion, high SHBG predicts incident clinical and radiographic vertebral fractures in elderly men and adds moderate information beyond FRAX with BMD for vertebral fracture risk prediction. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.     

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 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.     

Plasma phosphatidylcholine concentrations of polyunsaturated fatty acids are differentially associated with hip bone mineral density and hip fracture in older adults: the Framingham Osteoporosis Study

Polyunsaturated fatty acids (PUFAs) may influence bone health. The objective of this work was to examine associations between plasma phosphatidylcholine (PC) PUFA concentrations and hip measures: (1) femoral neck bone mineral density (FN‐BMD) (n = 765); (2) 4‐year change in FN‐BMD (n = 556); and (3) hip fracture risk (n = 765) over 17‐year follow‐up among older adults in the Framingham Osteoporosis Study. BMD measures were regressed on quintile of plasma PC PUFAs (docosahexaenoic acid [DHA], linoleic acid [LA], and arachidonic acid [AA]), adjusted for covariates. Hazard ratios (HR) and 95% confidence interval (CI) for hip fracture were estimated by quintile of plasma PC PUFAs, adjusted for covariates. Higher concentrations of PC DHA were associated with loss of FN‐BMD over 4 years in women (p‐trend = 0.04), but was protective in men in the uppermost quintile compared to men grouped in the lower four quintiles, in post hoc analysis (p = 0.01). PC LA concentrations were inversely associated with baseline FN‐BMD in women (p‐trend = 0.02), and increased hip fracture risk in women and men (p‐trend = 0.05), but body mass index (BMI) adjustment attenuated these associations (p‐trend = 0.12 and p‐trend = 0.14, respectively). A trend toward a protective association was observed between PC AA and baseline FN‐BMD in men (p‐trend = 0.06). Women and men with the highest PC AA concentrations had 51% lower hip fracture risk than those with the lowest (HR = 0.49, 95% CI = 0.24–1.00). Opposing effects of PC DHA on FN‐BMD loss observed in women and men need further clarification. Bone loss associated with PC LA may be confounded by BMI. High PC AA concentrations may be associated with reduced hip fracture risk. © 2012 American Society for Bone and Mineral Research.     

Association of serum fibroblast growth factor 23 (FGF23) and incident fractures in older men: The Osteoporotic Fractures in Men (MrOS) study

Normal mineral metabolism is critical for skeletal integrity, and recently serum fibroblast growth factor 23 (FGF23) levels were found to be directly related to overall fracture risk in elderly Swedish men. To confirm this association, we performed a prospective case‐cohort study to understand the relation of FGF23 and fracture risk in older white men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men attending the baseline MrOS examination, we evaluated a subgroup of 387 men with incident nonvertebral fracture including 73 hip fractures and a sample of 1385 men randomly selected from the cohort with baseline mineral and calcium hormone measurements. FGF23 was measured in baseline serum samples by ELISA (Millipore, Billerica, MA, USA). Modified Cox proportional hazards models that account for case‐cohort study design were used to estimate the relative hazards (RH) of fracture in men across quartiles of FGF23. Subjects were also stratified by renal function, and RH per strata was estimated in men with the highest quartile of FGF23 compared with quartiles 3, 2, and 1. Overall, there was no difference in risk of nonspine or hip fracture by baseline FGF23. However, associations differed by strata of eGFR_CrCy. Among men with eGFR_CrCys <60 mL/min/1.73 m² (n = 73/313 nonspine fractures), the RH in the highest quartile of FGF23 compared with the rest was 2.02 (95% confidence interval [CI] 1.07–3.79), but in men with eGFR_CrCy, >60 mL/min/1.73 m² (304/1370 fractures) the RH was 0.91 (95% CI 0.66–1.25) after adjustment for age, clinic site, body mass index, race, total hip bone mineral density, vitamin D, parathyroid hormone, alcohol use, physical activity, fracture history, and serum phosphorus. Serum FGF23 levels are not associated with incident fractures in elderly men overall. However, higher levels of serum FGF23 are associated with fracture risk in those with poor renal function. © 2013 American Society for Bone and Mineral Research.