Fracture Risk In Older Men Research Articles

The observation that older men suffer from hip fracture at DXA T-scores higher than older women and a proposal of a new low BMD category, osteofrailia, for predicting fracture risk in older men.

The clinical significance of osteoporosis lies in the occurrence of fragility fractures (FFx), and the most relevant fracture site is the hip. The T-score is defined as follows: (BMDpatient-BMDyoung adult mean)/SDyoung adult population, where BMD is bone mineral density and SD is the standard deviation. When the femoral neck (FN) is measured in adult Caucasian women, a cutpoint value of patient BMD of 2.5 SD below the young adult mean BMD results in a prevalence the same as the lifetime risk of hip FFx for Caucasian women. The FN T-score criterion for classifying osteoporosis in older Caucasian men has been provisionally recommended to be - 2.5, but debates remain. Based on a systematic literature review, we noted that older men suffer from hip FFx at aFN T-score approximately 0.5-0.6 higher than older women. While the mean hip FFx FN T-score of around - 2.9 for women lies below - 2.5, the mean hip FF FN T-score of around - 2.33 for men lies above - 2.5. This is likely associated with that older male populations have a higher mean T-score than older female populations. We propose a new category of low BMD status, osteofrailia, for older Caucasian men with T-score ≤ - 2 (T-score ≤ - 2.1 for older Chinese men) who are likely to suffer from hip FFx. The group withT-score ≤ - 2 for older Caucasian men is comparable in prevalence to the group withT-score ≤ - 2.5 for older Caucasian women. However, older men in such category on average have only half the FFx risk as that of older women with osteoporotic T-score.

Association of serum phosphate, calcium and alkaline phosphatase with risk of incident fractures in healthy older adults.

Aging increases fracture risk through bone loss and microarchitecture deterioration due to an age-related imbalance in bone resorption and formation during bone remodelling. We examined the associations between levels of phosphate, calcium, and alkaline phosphatase, and fracture risk in initially-healthy older individuals. A post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial recruited 16,703 Australian participants aged ≥70 years and 2,411 US participants aged ≥65 years. Analyses were conducted on ASPREE-Fracture substudy participants from Australia with serum calcium, phosphate, and alkaline phosphatase measurement. Fracture data were collected post-randomization. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs). Phosphate, calcium, and alkaline phosphatase were analysed in deciles (D1-D10), with deciles 4-7 (31-70%) as the reference category. Restricted cubic spline curves were used to identify nonlinear associations. Of the 9915 participants, 907 (9·2%) persons had incident fractures recorded over 3·9 (SD 1·4) years. In the fully adjusted model, males in the top decile (D10) of phosphate had 78% higher risk of incident fracture (HR 1·78, 95% CI 1·25-2·54). No such association was observed for females (HR 1·09, 95% CI 0·83-1·44). The population attributable fraction in men within the D10 phosphate category is 6·9%. This result confirms that, high-normal serum phosphate levels are associated with increased fracture risk in older men.

Breaking Up Sedentary Time Reduces Recurrent Fall Risk, but Not Incident Fracture Risk in Older Men.

Apart from physical activity volume, frequent breaks from sedentary bouts and active bouts may differentially reduce fall and fracture risk. We assessed the longitudinal relationship between frequency of breaks from time spent sedentary and frequency of active bouts with recurrent falls and fractures. The sample included 2918 men aged 79.0 ± 5.1 years with free-living activity (SenseWear Armband) at the Osteoporotic Fractures in Men Study (MrOS) year 7 (2007-2009) visit. Men were divided into quartiles by the number of breaks from sedentary bouts (sedentary bout: 5+ minutes sedentary; <1.5 metabolic equivalents of task [METS]) and separately by active bout frequency (active bout: 5+ minutes of activity; ≥1.5 METS). Recurrent falls (2+ falls/year) and fractures were ascertained by self-report; fractures were radiographically confirmed. Generalized estimating equations estimated the recurrent fall odds, with restricted cubic splines applied to assess nonlinear relationships. Cox proportional hazards models estimated fracture risk. Over 4 years of follow-up after year 7, 1025 (35.1%) men were fallers. Over 8.40 ± 4.10 years of follow-up, 640 (21.9%) men experienced a fracture. There was a significant nonlinear U-shaped relationship between number of breaks from sedentary bouts and recurrent falls (p < 0.001); compared with men with few breaks from sedentary bouts (1.4-<13.6), the odds of recurrent falls were lower with a moderate number (13.6-<17.0, odds ratio [OR] = 0.82, 95% confidence interval [CI] 0.66, 1.01; 17.0-<20.4, OR = 0.79, 95% CI 0.64, 0.99), but not with the highest number of breaks from sedentary bouts (20.4-34.6, OR = 1.01, 95% CI 0.81, 1.27). Results remained borderline significant after adjusting for total sedentary time. Men with the highest compared with the lowest number of breaks from sedentary bouts had a lower fracture risk, but the association was attenuated after adjustment for total sedentary time. No associations were observed for active bout frequency. In conclusion, breaking up extended periods of sedentary time reduces fall risk regardless of total sedentary time. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

C-reactive protein predicts endocortical expansion but not fracture in older men: the prospective STRAMBO study.

Data on the link of the high-sensitivity C-reactive protein (hsCRP) with bone loss and fracture risk are discordant. We studied the association of the hsCRP with the prospectively assessed decrease in areal bone mineral density (aBMD), bone microarchitecture decline, and fracture risk in older men. At baseline, hsCRP was measured in 823 men aged 60-88. Areal BMD and bone microarchitecture (distal radius, distal tibia) were assessed by dual-energy X-ray absorptiometry and high-resolution peripheral QCT, respectively, at baseline and after 4 and 8years. Data on incident fractures were collected for 8years. Higher hsCRP concentration was associated with faster increase in aBMD at the whole body and lumbar spine, but not other sites. Higher hsCRP levels were associated with faster decrease in cortical area and more rapid increase in trabecular area at the distal radius (0.048 mm2/year/SD, p < 0.05) and distal tibia (0.123 mm2/year/SD, p < 0.001). At the distal tibia, high hsCRP level was associated with greater decrease in total and cortical volumetric BMD (vBMD) and in failure load. The hsCRP levels were not associated with the fracture risk, even after accounting for competing risk of death. Higher hsCRP levels were associated with greater endocortical expansion at the distal radius and tibia. Higher hsCRP was associated with slightly faster decrease in total and cortical vBMD and failure load at distal tibia, but not with the fracture risk. Thus, high hsCRP levels are associated with faster cortical bone loss, but not with fracture risk in older men.

Anaemia Is Associated with an Increased Risk of Fractures, a Systematic Review, and Meta-Analysis

Background: Anaemia and osteoporotic fractures are both major health problems among older adults worldwide. Objectives: Previous studies suggest that anaemia may be associated with elevated fracture risk among older adults; however, the exact relationship between them is unknown. We aimed to investigate the association between anaemia and fracture risk. Methods: A comprehensive literature search was performed in four medical databases. We included articles that were published from inception to February 18, 2021. Odds ratios (ORs), hazard ratios (HRs) with 95% confidence intervals (CIs), and original raw incidences from studies comparing fracture rates in anaemic versus non-anaemic patients were extracted and pooled with the random-effects model. I2 test was used to assess heterogeneity. Risk of bias assessment was performed using the Quality of Prognostic Studies tool. PROSPERO: CRD42021241109. Results: A total of 13 studies were identified; 8 of them were included in the quantitative synthesis. Anaemia was found to be a risk factor for fracture compared to non-anaemia. Anaemia increased hip fracture risk in both older men (HR = 1.71; CI: 1.46–2.00, p< 0.001, I2 = 83.2%) and women (HR = 1.31; CI: 1.13–1.52, p< 0.001), but the fracture risk was more increased among men. There was also an increased chance of hip fracture in the presence of anaemia in populations, including both older men and women (OR = 1.64; CI: 1.35–2.01, p< 0.001, I2 = 61.1%). Anaemia was also associated with increased vertebral (HR = 1.21; CI: 1.04–1.40, p = 0.012) and all-type (HR = 1.49; CI: 1.19–1.86, p< 0.001) fracture risk in older men. Conclusion: Our results suggest that there is a significant relationship between anaemia and fracture risk in older adults. This association is stronger among older men than women and differs in the different types of fractures.

Rapid Cortical Bone Loss at the Distal Radius Is Associated With Higher Risk of Fracture in Older Men - The STRAMBO Study.

Rapid loss of areal bone mineral density (aBMD) is associated with higher fracture risk after adjustment for confounders including initial aBMD. However, the link between bone microarchitecture decline and fracture is not clear. We studied the association between bone microarchitecture deterioration assessed prospectively over 4 years and the subsequent fracture risk in older men. Bone microarchitecture at the distal radius and tibia was assessed by high-resolution peripheral QCT (HR-pQCT; XtremeCT, Scanco Medical) (baseline, 4 years) in 732 men aged 60-87 years. During the 8-year follow-up, 109 men had fragility fractures. Areal BMD was assessed by dual-energy X-ray absorptiometry. After adjustment for age, weight, prior falls and fractures, distal radius aBMD (baseline, slope), and baseline distal radius total volumetric BMD (Tt.BMD), a faster decrease in distal radius Tt.BMD was associated with higher fracture risk (hazard ratio [HR] = 1.54/SD, 95% confidence interval: 1.20-1.95, p < .005). Rapid cortical bone loss was associated with higher fracture risk (cortical thickness: HR = 1.48; 1.15-1.90, p < .01; cortical BMD: HR = 1.38; 1.11-1.72, p < .01). The rate of trabecular bone loss at the distal radius and the rate of bone microarchitecture decline at the distal tibia were not associated with fracture risk. After adjustment for aBMD and distal radius HR-pQCT measures assessed after 4 years, changes in Tt.BMD were associated with higher fracture risk (e.g., Tt.BMD: HR = 1.37; 1.11-1.69, p < .005). Compared with the reference model (age, weight, prior fractures and falls, baseline and slope of aBMD, baseline HR-pQCT value), further addition of the slope of the HR-pQCT measure did not improve the fracture prediction. Thus, rapid cortical bone loss at the distal radius is associated with higher fracture risk in the multivariable models including baseline values of the HR-pQCT measure. However, repeated HR-pQCT measurements did not improve the assessment of the fracture risk in older men (compared with the reference model defined earlier). © 2023 American Society for Bone and Mineral Research (ASBMR).

Advanced Glycation End Products and esRAGE Are Associated With Bone Turnover and Incidence of Hip Fracture in Older Men.

Diabetes mellitus is associated with increased fracture risk despite preservation of bone density and reduced bone turnover. We tested the hypothesis that circulating advanced glycation end products (AGEs) and endogenous secretory receptor for AGEs (esRAGE) differentially modulate bone turnover and predict fracture risk in older men. A total of 3384 community-dwelling men aged 70 to 89 years. Collagen type I C-terminal cross-linked telopeptide, N-terminal propeptide of type I collagen (P1NP), and total osteocalcin (TOC) were assayed using immunoassay and undercarboxylated osteocalcin (ucOC) following hydroxyapatite binding. Plasma N-carboxymethyllysine (CML) and esRAGE were assayed using immunoassay. Methylglyoxal and glyoxal were assayed using mass spectrometry. Incident hip fractures were ascertained. Median age was 76.3 years (interquartile range, 74.2 to 79.1 years). Plasma CML was measured in 3011 men, methylglyoxal and glyoxal in 766 men, and esRAGE in 748 men. Plasma CML, methylglyoxal, glyoxal, and esRAGE were similar in men without and with diabetes (all P > 0.05). CML was positively associated with fasting glucose (r = 0.06, P < 0.001), and esRAGE was inversely associated (r = -0.08, P = 0.045). esRAGE was positively associated with bone formation (P1NP, r = 0.17, P < 0.001; ucOC, r = 0.11, P = 0.008; TOC, r = 0.16, P < 0.001). Incident hip fractures occurred in 106 men during follow-up. Men with CML in the third quartile of values had reduced incidence of hip fracture compared with men in the lowest quartile (hazard ratio, 0.49; 95% CI, 0.24 to 0.99; P = 0.045). Glycemia associates positively with CML and reciprocally with esRAGE in older men. Circulating esRAGE modulates bone turnover in older men, whereas CML predicts incidence of hip fracture.

Areal and volumetric bone mineral density and risk of multiple types of fracture in older men

Although many studies have examined the association between low bone mineral density (BMD) and fracture risk in older men, none have simultaneously studied the relationship between multiple BMD sites and risk of different types of fractures. Using data from the Osteoporotic Fractures in Men study, we evaluated the association between areal BMD (aBMD) by dual-energy X-ray absorptiometry (DXA) and volumetric BMD (vBMD) by quantitative computed tomography (QCT) measurements, and different types of fractures during an average of 9.7years of follow-up. Men answered questionnaires about fractures every 4months (>97% completions). Fractures were confirmed by centralized review of radiographic reports; pathological fractures were excluded. Risk of fractures was assessed at the hip, spine, wrist, shoulder, rib/chest/sternum, ankle/foot/toe, arm, hand/finger, leg, pelvis/coccyx, skull/face and any non-spine fracture. Age and race adjusted Cox proportional-hazards modeling was used to assess the risk of fracture in 3301 older men with both aBMD (at the femoral neck (FN) and lumbar spine) and vBMD (at the trabecular spine and FN, and cortical FN) measurements, with hazard ratios (HRs) expressed per standard deviation (SD) decrease. Lower FN and spine aBMD were associated with an increased risk of fracture at the hip, spine, wrist, shoulder, rib/chest/sternum, arm, and any non-spine fracture (statistically significant HRs per SD decrease ranged from 1.24–3.57). Lower trabecular spine and FN vBMD were associated with increased risk of most fractures with statistically significant HRs ranging between 1.27 and 3.69. There was a statistically significant association between FN cortical vBMD and fracture risk at the hip (HR=1.55) and spine sites (HR=1.26), but no association at other fracture sites. In summary, both lower aBMD and vBMD were associated with increased fracture risk. The stronger associations observed for trabecular vBMD than cortical vBMD may reflect the greater metabolic activity of the trabecular compartment.

Progressive Temporal Change in Serum SHBG, But Not in Serum Testosterone or Estradiol, Is Associated With Bone Loss and Incident Fractures in Older Men: The Concord Health and Ageing in Men Project.

This study aimed to examine progressive temporal relationships between changes in major reproductive hormones across three waves of a cohort study of older men and (1) changes in bone mineral density (BMD) and (2) incident fractures (any, hip or non-vertebral) over an average of 6 years of follow-up. The CHAMP cohort of men aged 70 years and older were assessed at baseline (2005 to 2007, n = 1705), 2-year follow-up (n = 1367), and 5-year follow-up (n = 958). Serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) (by liquid chromatography-tandem mass spectrometry [LC-MS/MS]), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) (by immunoassay) were measured at all time-points, whereas free testosterone (cFT) was calculated using a well-validated formula. Hip BMD was measured by dual-energy X-ray absorptiometry (DXA) at all three time-points, and fracture data were verified radiographically. Statistical modeling was done using general estimating equations (GEEs). For total hip BMD, univariable analyses revealed inverse associations with temporal changes in serum SHBG, FSH, and LH and positive associations for serum E1 and cFT across the three time-points. In models adjusted for multiple covariables, serum SHBG (β = -0.029), FSH (β = -0.065), LH (β = -0.049), E1 (β = 0.019), and cFT (β = 0.033) remained significantly associated with hip BMD. However for femoral neck BMD, only FSH (β = -0.048) and LH (β = -0.036) remained associated in multivariable-adjusted models. Temporal change in serum SHBG, but not T, E2, or other hormonal variables, was significantly associated with any, nonvertebral or hip fracture incidence in univariable analyses. In multivariable-adjusted models, temporal increase in serum SHBG over time remained associated with any fracture (β = 0.060) and hip fracture (β = 0.041) incidence, but not nonvertebral fracture incidence. These data indicate that a progressive increase in circulating SHBG over time predicts bone loss and fracture risk in older men. Further studies are warranted to further characterize changes in circulating SHBG as a mechanism and/or biomarker of bone health during male ageing. © 2016 American Society for Bone and Mineral Research.

Association of bone turnover markers with volumetric bone loss, periosteal apposition, and fracture risk in older men and women: the AGES-Reykjavik longitudinal study.

We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93years from the AGES-Reykjavik study. The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7years (range 5.4-12.5), 54 (11.4%) men and 182 (30.6%) women sustained at least one fracture of any type. Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

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.

Risk of fragility fracture in older men with severe spine osteoarthritis

Purpose: Data on the association of osteoarthritis (OA) with bone mass and fragility are limited. In particular, data on the fracture risk in older men with spine OA are scarce. Our aim was to study the association of baseline severity of spine OA with bone mineral density (BMD), bone loss and risk of fragility fracture in a cohort of older men. Methods: Men aged >50 (n=766) had lateral spine radiographs at baseline. Spine OA was assessed by Lane's score (J Rheumatol, 1993). We calculated the total osteophyte score by adding up osteophyte scores for 6 intervertebral levels. We calculated total disc narrowing score (DSN) and total overall grade score similarly. BMD was measured by DXA using a HOLOGIC QDR1500 device. Abdominal aortic calcification (AAC) was assessed by Kauppila's semiquantitative score (Atherosclerosis, 1997). Men were followed up for 7.5 yr to assess bone loss (every 18 mo) and incident vertebral fractures. Incident peripheral fractures were assessed for 10 yr. Results: Moderate and severe osteophytes were found in 85% of men, 72% of men had DSN. After adjustment for age and weight, BMD was 2-7% higher (p<0.05 to <0.001) in men with severe spine OA in comparison with men without or with mild spine OA. For instance, men with severe DSN (total score>4, highest quartile) had 5% (0.4SD, p<0.001) higher total hip BMD compared with men without DSN. The rate of bone loss did not differ according to the severity of spine OA regardless of the measure of the spine OA (DSN, osteophytosis) and regardless of the skeletal site (p>0.4). During the follow-up, 27 men sustained radiographic vertebral fractures. After adjustment for age, BMI, lumbar spine BMD, AAC, prior falls and fractures, risk of vertebral fracture increased with the DSN severity (HR= 1.15 per increase by 1 unit, 95%CI: 1.01-1.31, p<0.05). In the multivariable model, the risk of vertebral fracture was higher in the highest quartile of total DSN score vs. the three lower quartiles combined (HR= 2.47, 95%CI: 1.04-5.86, p<0.05). During the follow-up, 61 men sustained peripheral fragility fractures. The incidence of peripheral fracture was lower above the median of total DSN score (4.6 vs 10.2%, p<0.005). After adjustment for the confounders (including hip BMD and leg disability), the risk of peripheral fracture was lower in men above the median total DSN score vs. below the median (HR= 0.44, 95%CI: 0.24-0.80, p<0.01). Other measures of spine OA were not associated with the risk of fracture. Conclusions: Men with severe spine OA had higher BMD vs. men without spine OA. Spine OA had no impact on the rate of bone loss. Men with severe multi-level DSN had higher risk of vertebral fracture, but lower risk of peripheral fracture.

Reproductive Hormones and Longitudinal Change in Bone Mineral Density and Incident Fracture Risk in Older Men: The Concord Health and Aging in Men Project.

The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (1) change in bone mineral density (BMD) over 5 years and (2) incident fractures over an average of 6 years' follow-up. A total of 1705 men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005-2007), 2 years follow-up (2007-2009), and 5 years follow-up (2010-2013). At baseline, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by immunoassay. Hip BMD was measured by dual X-ray absorptiometry (DXA) at all three time-points. Fracture data were collected at 4-monthly phone calls and verified radiographically. Statistical modeling was by general estimating equations and Cox model regression. Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip across the three time points. Serum levels of SHBG (β = -0.071), FSH (β = -0.085), LH (β = -0.070), and E1 (β = 0.107) remained significantly associated with BMD loss in multivariate-adjusted models; however, we were unable to identify any thresholds for accelerated BMD loss according to reproductive steroids. Incident fractures (all, n = 171; hip, n = 44; and nonvertebral, n = 139) were all significantly associated with serum SHBG, FSH, and LH levels in univariate models but none remained significantly associated in multivariate-adjusted model. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate-adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. This means these reproductive variables may be considered as novel biomarkers of bone health during male aging.

Reference intervals for bone turnover markers and their association with incident hip fractures in older men: the Health in Men study.

Reference intervals for bone turnover markers (BTMs) and relationships between BTM and fracture risk in older men are not well characterized. The purpose of this article was to determine the reference intervals for serum total osteocalcin (tOC), undercarboxylated osteocalcin (ucOC), N-terminal propeptide of type I collagen (PINP), and collagen type I C-terminal cross-linked telopeptide (CTX-I) in healthy older men and to explore factors associated with BTMs, including hip fracture risk. We studied a population-based cohort of 4248 men aged 70 to 89 years, 4008 of whom had serum samples available for analysis. Morning blood samples were collected at the study visit. Comorbid conditions were assessed by questionnaire. The reference sample comprised fasting men (n = 298, median age 75.3 years [interquartile range 73.9-78.1 years) reporting excellent or very good health, without a history of diabetes, cardiovascular disease, cancer, depression, or dementia. Serum tOC, PINP, and CTX-I were estimated by automated electrochemiluminescence immunoassays, ucOC was estimated using hydroxyapatite binding, and incident hip fractures were captured from hospital admission data. Reference intervals for tOC, ucOC, PINP, and CTX-I were 10.2 to 41.0, 5.2 to 21.9, 18 to 129 μg/L, and 117 to 740 ng/L, respectively. tOC, ucOC and CTX-I were associated with hip fracture incidence, but after adjustment for other risk factors only tOC remained significantly associated. Reference intervals for BTMs in older men have been defined. tOC may be more informative for hip fracture risk in older men than CTX-I and PINP. Further studies are needed to clarify the utility of BTM reference intervals in the management of aging men at risk of osteoporosis.

Development and validation of a prognostic index for fracture risk in older men undergoing prostate cancer treatment.

Men treated with androgen deprivation therapy (ADT) or radiation therapy (RT) for prostate cancer have an increased risk for fractures. Given uncertainty as to whether specific clinical factors can identify men at increased risk, we sought to develop a prognostic index for risk of fracture in this population. We used the Surveillance, Epidemiology, and End Results-Medicare database to identify men who received ADT or RT after being diagnosed with localized prostate cancer in 2007-2009. Cox proportional hazards models tested the association of potential risk factors with fracture. In a derivation group, hazard ratios were used to assign points for factors independently related to fracture. The prognostic index was then applied to a validation group. The sample of 5824 men had a median age of 73.0 years; 82.9% were white and 8.6% had a fracture within 2 years of treatment for prostate cancer. The Cox model identified 8 variables (age, race, hormone treatment, Elixhauser score, anxiety, Parkinson's, fall-inducing medications and disability status) independently associated with fracture. In the derivation cohort, 4.3% of the sample experienced a fracture in the low-risk group, 8.9% in the intermediate group, and 19.2% in the high-risk group (C statistic, 0.749). The index was applied to the validation cohort (C statistic, 0.782). The prognostic index can help to identify patients at increased risk for fracture. This underscores the importance of identifying risk factors for fracture, given the substantial variation in fracture risk in men treated with ADT or RT.

Development and validation of a prognostic index for fracture risk in older men undergoing prostate cancer treatment.

5056 Background: Although men treated with androgen deprivation therapy (ADT) or radiation therapy (RT) for prostate cancer are at an increased risk for fractures, it is unclear whether specific fa...

Serum Estradiol Levels Are Inversely Associated With Cortical Porosity in Older Men

Context:The key role of serum estradiol (E2) for bone health in men is well established. The effect of serum sex steroids on bone microstructure, measured by high-resolution peripheral quantitative computed tomography, remains unknown in elderly men.Objective:The objective of the study was to examine the associations between serum sex steroids and bone microstructural parameters in older men.Methods:Trabecular and cortical bone microstructure at the tibia was measured by high-resolution peripheral quantitative computed tomography in 440 men (mean 80 y of age) participating in the population-based Osteoporotic Fractures in Men Sweden cohort. Serum levels of E2 and T were analyzed with mass spectrometry and free E2 and free T levels were calculated using law-of-mass-action equations.Results:Age-adjusted models demonstrated that E2 and free E2 but not T or free T associated significantly inversely with cortical porosity. The associations between E2 and free E2 and cortical porosity remained significant after further adjustment for height, weight, physical activity, calcium intake, and smoking. Models including both serum E2 and T demonstrated that E2 (standardized β = −.12, P < .05) but not T associated independently with cortical porosity. A similar independent association was found for free E2 (standardized β = −.12, P < .05) but not free T. Free E2 associated significantly with trabecular bone volume fraction in the age-adjusted models, but this association did not remain significant after further adjustment.Conclusions:Serum E2 levels associated inversely with cortical porosity in 80-year-old men. We propose that low serum E2 may reduce cortical bone strength, at least partly, by increasing cortical porosity and thereby increase fracture risk in older men.

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.

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.

A prospective study of thyroid function, bone loss, and fractures in older men: The MrOS study

Excess thyroid hormone is associated with increased bone loss and fracture risk in older women, but few data exist for men. We sought to determine if thyroid function is independently associated with bone loss and fracture risk in older men. Data were analyzed from the Osteoporotic Fractures in Men (MrOS) study, a cohort of community-dwelling U.S. men aged 65 years and older. Using a case-cohort design, fasting baseline serum archived at -80°C was assayed for thyroid-stimulating hormone (thyrotropin) (TSH) and free thyroxine (FT4) in 397 men with confirmed nonspine fracture, including 157 hip fractures, and 1420 randomly selected men without fracture. TSH and FT4 were analyzed as continuous variables and as thyroid function categories (subclinical hyperthyroid, euthyroid, and subclinical hypothyroid). Hip dual-energy X-ray absorptiometry (DXA) (Hologic QDR4500) was measured at baseline and after a mean follow-up of 4.6 years. Incident nonspine fractures were centrally adjudicated. Bone loss was evaluated with multivariate regression methods and fractures risk was evaluated using hazard models that accounted for the case-cohort sampling, adjusted for age, clinic-site, body mass index (BMI), race, physical activity, corticosteroid use, smoking, alcohol intake, and thyroid medication use. In fully adjusted analyses, TSH was not associated with risk of nonspine fracture (relative hazard [RH] 0.92 per SD decrease in TSH; 95% confidence interval [CI], 0.74-1.14), but was significantly associated with risk of hip fracture (RH 1.31; 95% CI, 1.01-1.71), which persisted among normal range TSH values (RH 1.21; 95% CI, 1.00-1.47). There was no association between TSH or FT4 and bone loss, and fracture risk did not differ significantly by thyroid function category. We conclude that although neither TSH nor FT4 are associated with bone loss, lower serum TSH may be associated with an increased risk of hip fractures in older men.