Bone Mineral Density Predicts Fractures in Chronic Kidney Disease

Fractures are common in chronic kidney disease (CKD). The optimal methods by which to assess fracture risk are unknown, in part, due to a lack of prospective studies. We determined if bone mineral density (BMD) by dual‐energy X‐ray absorptiometry (DXA), and/or high‐resolution peripheral quantitative computed tomography (HRpQCT) could predict fractures in men and women ≥18 years old with stages 3 to 5 CKD. BMD was measured by DXA (at the total hip, lumbar spine, ultradistal, and 1/3 radius) and by HRpQCT (at the radius), and subjects were followed for 2 years for incident morphometric spine fractures and low‐trauma clinical fractures. The mean age of the subjects was 62 years with equal numbers having stages 3, 4, and 5 CKD. Over 2 years there were 51 fractures in 35 subjects. BMD by DXA at baseline was significantly lower at all sites among those with incident fractures versus those without. For example, the mean BMD at the total hip in those with incident fractures was 0.77 g/cm² (95% confidence interval [CI], 0.73 to 0.80) and in those without fracture was 0.95 g/cm² (95% CI, 0.92 to 0.98). Almost all baseline HRpQCT measures were lower in those with incident fracture versus those without. For example, volumetric BMD in those with incident fractures was 232 mg HA/cm³ (95% CI, 213 to 251) and in those without fracture was 317.6 mg HA/cm³ (95% CI, 306 to 329.1). Bone loss occurred in all subjects, but was significantly greater among those with incident fractures. Our data demonstrate that low BMD (by DXA and HRpQCT) and a greater annualized percent decrease in BMD are risk factors for subsequent fracture in men and women with predialysis CKD. © 2014 American Society for Bone and Mineral Research.     

Relationship Between Low Bone Mineral Density and Fractures With Incident Cardiovascular Disease: A Systematic Review and Meta‐Analysis

An increasing evidence base suggests that low bone mineral density (BMD) and fractures are associated with cardiovascular disease (CVD). We conducted a systematic review and meta‐analysis summarizing the evidence of low BMD and fractures as risk factors for future CVD. Two independent authors searched major databases from inception to August 1, 2016, for longitudinal studies reporting data on CVD incidence (overall and specific CVD) and BMD status and fractures. The association between low BMD, fractures, and CVD across longitudinal studies was explored by calculating pooled adjusted hazard ratios (HRs) ±95% confidence intervals (CIs) with a random‐effects meta‐analysis. Twenty‐eight studies (18 regarding BMD and 10 fractures) followed a total of 1,107,885 participants for a median of 5 years. Taking those with higher BMD as the reference, people with low BMD were at increased risk of developing CVD during follow‐up (11 studies; HR = 1.33; 95%CI, 1.27 to 1.38; I² = 53%), after adjusting for a median of eight confounders. This finding was confirmed using a decrease in one standard deviation of baseline BMD (9 studies; HR = 1.16; 95% CI, 1.09 to 1.24; I² = 69%). The presence of fractures at baseline was associated with an increased risk of developing CVD (HR = 1.20; 95% CI, 1.06 to 1.37; I² = 91%). Regarding specific CVDs, low BMD was associated with an increased risk of developing coronary artery disease, cerebrovascular conditions, and CVD‐associated death. Fractures at baseline was associated with an increased risk of cerebrovascular conditions and death due to CVD. In conclusion, low BMD and fractures are associated with a small, but significant increased risk of CVD risk and possibly death. © 2017 American Society for Bone and Mineral Research.     

Associations of 25‐Hydroxyvitamin D and 1,25‐Dihydroxyvitamin D With Bone Mineral Density,Bone Mineral Density Change,and Incident Nonvertebral Fracture

Relationships between 1,25‐dihydroxyvitamin D (1,25(OH)₂D) and skeletal outcomes are uncertain. We examined the associations of 1,25(OH)₂D with bone mineral density (BMD), BMD change, and incident non‐vertebral fractures in a cohort of older men and compared them with those of 25‐hydroxyvitamin D (25OHD). The study population included 1000 men (aged 74.6 ± 6.2 years) in the Osteoporotic Fractures in Men (MrOS) study, of which 537 men had longitudinal dual‐energy X‐ray absorptiometry (DXA) data (4.5 years of follow‐up). A case‐cohort design and Cox proportional hazards models were used to test the association between vitamin D metabolite levels and incident nonvertebral and hip fractures. Linear regression models were used to estimate the association between vitamin D measures and baseline BMD and BMD change. Interactions between 25OHD and 1,25(OH)₂D were tested for each outcome. Over an average follow‐up of 5.1 years, 432 men experienced incident nonvertebral fractures, including 81 hip fractures. Higher 25OHD was associated with higher baseline BMD, slower BMD loss, and lower hip fracture risk. Conversely, men with higher 1,25(OH)₂D had lower baseline BMD. 1,25(OH)₂D was not associated with BMD loss or nonvertebral fracture. Compared with higher levels of calcitriol, the risk of hip fracture was higher in men with the lowest 1,25(OH)₂D levels (8.70 to 51.60 pg/mL) after adjustment for baseline hip BMD (hazard ratio [HR] = 1.99, 95% confidence interval [CI] 1.19–3.33). Adjustment of 1,25(OH)₂D data for 25OHD (and vice versa) had little effect on the associations observed but did attenuate the hip fracture association of both vitamin D metabolites. In older men, higher 1,25(OH)₂D was associated with lower baseline BMD but was not related to the rate of bone loss or nonvertebral fracture risk. However, with BMD adjustment, a protective association for hip fracture was found with higher 1,25(OH)₂D. The associations of 25OHD with skeletal outcomes were generally stronger than those for 1,25(OH)₂D. These results do not support the hypothesis that measures of 1,25(OH)₂D improve the ability to predict adverse skeletal outcomes when 25OHD measures are available. © 2015 American Society for Bone and Mineral Research.     

Temporal Trends in Obesity,Osteoporosis Treatment,Bone Mineral Density,and Fracture Rates: A Population‐Based Historical Cohort Study

Diverging international trends in fracture rates have been observed, with most reports showing that fracture rates have stabilized or decreased in North American and many European populations. We studied two complementary population‐based historical cohorts from the Province of Manitoba, Canada (1996–2006) to determine whether declining osteoporotic fracture rates in Canada are attributable to trends in obesity, osteoporosis treatment, or bone mineral density (BMD). The Population Fracture Registry included women aged 50 years and older with major osteoporotic fractures, and was used to assess impact of changes in osteoporosis treatment. The BMD Registry included all women aged 50 years and older undergoing BMD tests, and was used to assess impact of changes in obesity and BMD. Model‐based estimates of temporal changes in fracture rates (Fracture Registry) were calculated. Temporal changes in obesity and BMD and their association with fracture rates (BMD Registry) were estimated. In the Fracture Registry (n = 27,341), fracture rates declined 1.6% per year (95% confidence interval [CI], 1.3% to 2.0%). Although osteoporosis treatment increased from 5.6% to 17.4%, the decline in fractures was independent of osteoporosis treatment. In the BMD Registry (n = 36,587), obesity increased from 12.7% to 27.4%. Femoral neck BMD increased 0.52% per year and lumbar spine BMD increased 0.32% per year after covariate adjustment (p < 0.001). Major osteoporotic fracture rates decreased in models that did not include femoral neck BMD (fully adjusted annual change –1.8%; 95% CI, –2.9 to –0.5), but adjusting for femoral neck BMD accounted for the observed reduction (annual change –0.5%; 95% CI, –1.8 to +1.0). In summary, major osteoporotic fracture rates declined substantially and linearly from 1996 to 2006, and this was explained by improvements in BMD rather than greater rates of obesity or osteoporosis treatment. © 2014 American Society for Bone and Mineral Research.     

Plasma Choline,Nicotine Exposure,and Risk of Low Bone Mineral Density and Hip Fracture: The Hordaland Health Study

Choline, obtained from diet and formed by biosynthesis, is the immediate precursor of betaine. Animal studies suggest an impact of choline on bone metabolism. We examined the associations of plasma choline and betaine with bone mineral density (BMD), the risk of hip fractures, and possible effect‐modification by nicotine exposure. The Hordaland Health Study (1998 to 2000) included 7074 women and men (ages 46 to 49 or 71 to 74 years). In 5315, BMD was measured. The oldest (n = 3311) were followed for hip fractures through 2009. Risk associations were studied by logistic and Cox regression by comparing the lowest and middle tertiles with the highest, as well as trends across tertiles of plasma choline and betaine. In analyses adjusted for sex and age, participants in the lowest (odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.69–2.37) and middle (OR = 1.39, CI 1.17–1.66) tertiles of plasma choline had an increased risk of low BMD (lowest quintile) (p trend < 0.001). Separate analyses for sex and age groups revealed the strongest relations in elderly women (lowest tertile: OR = 2.84, CI 1.95–4.14; middle tertile: OR = 1.80, CI 1.22–2.67, p trend < 0.001), and highest OR among those in the lowest tertile who were exposed to nicotine (OR = 4.56, CI 1.87–11.11). Low plasma choline was also associated with an increased risk of hip fracture in elderly women and men (lowest tertile: hazard ratio [HR] = 1.45, CI 1.08–1.94; middle tertile: HR = 1.13, CI 0.83–1.54, p trend = 0.012). In elderly women, the HR for hip fracture was 1.90 (CI 1.32–2.73) and 1.36 (CI 0.92–1.99) (p trend < 0.001) for lowest and middle tertiles of choline, and the highest HR was found among women in the lowest tertile exposed to nicotine (HR = 2.68, CI 1.16–6.19). Plasma betaine was not related to BMD or hip fracture. Low plasma choline was associated with low BMD in both sexes and increased the risk of hip fracture in elderly women. These results should motivate further studies on choline, nicotine exposure, and bone metabolism. © 2014 American Society for Bone and Mineral Research.     

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

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

Identifying Causes of Fracture Beyond Bone Mineral Density: Evidence From Human Genetics

New therapies may help to prevent osteoporotic fractures other than through increasing bone mineral density (BMD). Because fracture risk has an important genetic component, we aim to identify loci increasing fracture risk that do not decrease BMD, using a recently-proposed structural equation model adapted to remove genetic influences of BMD on fracture risk. We used summary statistics of the largest genome-wide association studies (GWASs) for BMD and for fracture in these analyses. We next estimated the genetic correlation between the non-BMD or BMD-related genetic effects and other clinical risk factors for fracture. Last, based on white British participants in the UK Biobank, we conducted genetic risk score analyses to assess whether the aggregated genetic effects conferred increased major osteoporotic fracture risk. We found that only three loci affecting fracture risk exhibited genetic effects not mediated by BMD: SOST, CPED1-WNT16, and RSPO3, while these three loci simultaneously conferred BMD-related effects. No strong genetic associations between non-BMD or BMD-related effects and 16 clinical risk factors were observed. However, non-BMD effects might be genetic correlated with hip bone size. In the UK Biobank, a 1 standard deviation (1-SD) increase in the non-BMD genetic risk score conferred an odds ratio of 1.17 for incident major osteoporotic fracture, compared to 1.29 by a BMD-related genetic risk score. Our study suggests that the majority of common genetic predisposition toward fracture risk acts upon BMD. Although non-BMD genetic effects may exist, they are not strongly correlated with most traditional clinical risk factors. Risk loci harboring non-BMD genetic effects may influence other perspectives of bone quality, or confer effects that existing GWASs fail to capture, but they demonstrate weaker impact on fracture risk than BMD-related genetic effects. These findings suggest that most successful drug development programs for osteoporosis should focus on pathways identified through BMD-associated loci. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Effects of a Targeted Multimodal Exercise Program Incorporating High‐Speed Power Training on Falls and Fracture Risk Factors in Older Adults: A Community‐Based Randomized Controlled Trial

Multimodal exercise programs incorporating traditional progressive resistance training (PRT), weight‐bearing impact training and/or balance training are recommended to reduce risk factors for falls and fracture. However, muscle power, or the ability to produce force rapidly, has emerged as a more crucial variable to functional decline than muscle strength or mass. The aim of this 12‐month community‐based randomized controlled trial, termed Osteo‐cise: Strong Bones for Life, was to evaluate the effectiveness and feasibility of a multimodal exercise program incorporating high‐velocity (HV)‐PRT, combined with an osteoporosis education and behavioral change program, on bone mineral density (BMD), body composition, muscle strength and functional muscle performance in older adults. Falls incidence was evaluated as a secondary outcome. A total of 162 older adults (mean ± SD; 67 ± 6 years) with risk factors for falls and/or low BMD were randomized to the Osteo‐cise program (n = 81) or a control group (n = 81). Exercise consisted of fitness center‐based HV‐PRT, weight‐bearing impact and challenging balance/mobility activities performed three times weekly. After 12 months, the Osteo‐cise program led to modest but significant net gains in femoral neck and lumbar spine BMD (1.0% to 1.1%, p < 0.05), muscle strength (10% to 13%, p < 0.05), functional muscle power (Timed Stair Climb, 5%, p < 0.05) and dynamic balance (Four Square Step Test 6%, p < 0.01; Sit‐to‐Stand, 16%, p < 0.001) relative to controls. There was no effect on total body lean mass or mobility (timed‐up‐and‐go), and no difference in falls rate (incidence rate ratio [IRR], 1.22; 95% confidence interval [CI], 0.72–2.04). In conclusion, this study demonstrates that the Osteo‐cise: Strong Bones for Life community‐based, multimodal exercise program represents an effective approach to improve multiple musculoskeletal and functional performance measures in older adults with risk factors for falls and/or low BMD. Although this did not translate into a reduction in the rate of falls, further large‐scale trials are needed to evaluate the efficacy of this multimodal approach on reducing falls and fracture. © 2014 American Society for Bone and Mineral Research.     

Physical Activity Benefits the Skeleton of Children Genetically Predisposed to Lower Bone Density in Adulthood

Both genetics and physical activity (PA) contribute to bone mineral density (BMD), but it is unknown if the benefits of physical activity on childhood bone accretion depend on genetic risk. We, therefore, aimed to determine if PA influenced the effect of bone fragility genetic variants on BMD in childhood. Our sample comprised US children of European ancestry enrolled in the Bone Mineral Density in Childhood Study (N = 918, aged 5 to 19 years, and 52.4% female). We used a questionnaire to estimate hours per day spent in total, high‐, and low‐impact PA. We calculated a BMD genetic score (% BMD lowering alleles) using adult genome‐wide association study (GWAS)‐implicated BMD variants. We used dual‐energy X‐ray absorptiometry to estimate femoral neck, total hip, and spine areal‐BMD and total body less head (TBLH) bone mineral content (BMC) Z‐scores. The BMD genetic score was negatively associated with each bone Z‐score (eg, TBLH‐BMC: estimate = –0.03, p = 1.3 × 10^?6). Total PA was positively associated with bone Z‐scores; these associations were driven by time spent in high‐impact PA (eg, TBLH‐BMC: estimate = 0.05, p = 4.0 × 10^?10) and were observed even for children with lower than average bone Z‐scores. We found no evidence of PA‐adult genetic score interactions (p interaction > 0.05) at any skeletal site, and there was no evidence of PA‐genetic score–Tanner stage interactions at any skeletal site (p interaction > 0.05). However, exploratory analyses at the individual variant level revealed that PA statistically interacted with rs2887571 (ERC1/WNT5B) to influence TBLH‐BMC in males (p interaction = 7.1 × 10^?5), where PA was associated with higher TBLH‐BMC Z‐score among the BMD‐lowering allele carriers (rs2887571 AA homozygotes: estimate = 0.08 [95% CI 0.06, 0.11], p = 2.7 × 10^?9). In conclusion, the beneficial effect of PA on bone, especially high‐impact PA, applies to the average child and those genetically predisposed to lower adult BMD (based on GWAS‐implicated BMD variants). Independent replication of our exploratory individual variant findings is warranted. © 2016 American Society for Bone and Mineral Research.     

Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures

In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (β = 0.20, p = 4.6 × 10⁻⁴⁹) and GALNT1 (β = 0.11 per G allele, p = 4.4 × 10⁻¹¹). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (β = –0.12, 95% confidence interval [CI] –0.20 to –0.05) and eBMD (β = –0.12, 95% CI –0.14 to –0.10), and a positive relationship with fracture risk (β = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. © 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.     

Bone Mineral Density in Females after Jejunoileal Bypass: A 25-year Follow-up Study

Background: Jejunoileal (JI) bypass was a widely performed operation for morbid obesity in the 1970s.The aim of this study was to investigate the long-term status of bone mineral density (BMD) after weight loss induced by this technique. Subjects and Methods: 18 female patients (age 48-79 y, BMI 23-43 kg/m2) had BMD measurements performed 25 years after JI bypass. Dual energy x-ray absorptiometry was used, and measured sites were the lumbar spine L2-L4, left femoral neck and total hip. Vitamin and mineral supplementation had not routinely been prescribed. An assessment was made on age-adjusted BMD values, and as to whether present BMD was related to present demographic and biochemical variables. Results: No significant reduction of BMD was found beyond that which was expected for age. BMD was inversely and separately related to age and body weight. The serum level of vitamin D was low in 45% of the patients, and inversely correlated to body weight and BMI. Alk phosphatase and parathyroid hormone were the best markers for low BMD. Conclusion: These results suggest that JI bypass has not been detrimental to bone density in females. We recommend, however, vitamin D and calcium supplements after malabsorptive procedures for morbid obesity.     

Prolonged Effect of Zoledronic Acid on Bone Mineral Density and Turnover in HIV-Infected Adults on Tenofovir: A Randomized,Open-Label Study

Zoledronic acid (ZOL) 5 mg annually was more effective than tenofovir disoproxil fumarate (TDF) switching at increasing bone mineral density (BMD) over 24 months in HIV-infected, osteopenic adults. To determine whether the effects of ZOL would persist without further infusions, we compared changes in left hip and spine BMD over 36 months in participants randomized to ZOL 5 mg at baseline and month 12 (and to continue TDF) or to switch TDF (without receiving ZOL). We also compared changes in the plasma bone turnover markers (BTMs) C-terminal telopeptide of type 1 collagen (CTX; bone resorption), and procollagen type 1 N propeptide (P1NP; bone formation) and determined whether CTX and P1NP changes at month 3 predicted BMD changes at month 36. Changes were compared in the per-protocol populations, which included 32 (74%) of 43 participants randomized to ZOL and 37 (88%) of 42 participants who switched TDF. Despite not receiving ZOL after month 12, mean hip and spine BMD change from baseline were stable and remained greater with ZOL at month 36 than with TDF switching (spine: 7.5% versus 2.7%, mean difference 4.7%, p < 0.001; hip: 5.5% versus 1.5%, mean difference 4.0%, p < 0.001). CTX and P1NP levels declined in both groups but significantly more with ZOL. Only percent changes in P1NP at month 3 correlated inversely with BMD changes at month 36 (spine: rho = −0.442, p < 0.001; hip: rho = −0.373, p = 0.002). Two infusions of ZOL (in the presence of ongoing TDF) yielded sustained BMD increases through month 36 that remained greater than with TDF switching. © 2019 American Society for Bone and Mineral Research.     

The Effect of Plasma Lipids and Lipid-Lowering Interventions on Bone Mineral Density: A Mendelian Randomization Study

Several epidemiological studies have reported a relationship between statin treatment and increased bone mineral density (BMD) and reduced fracture risk, but the mechanism underlying the purported relationship is unclear. We used Mendelian randomization (MR) to assess whether this relationship is explained by a specific effect in response to statin use or by a general effect of lipid lowering. We utilized 400 single-nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels as exposure. The outcome results were obtained from a heel estimated BMD (eBMD) genomewide association study (GWAS) from the UK Biobank and dual-energy X-ray absorptiometry (DXA) BMD at four body sites and fracture GWAS from the GEFOS consortium. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels on BMD and fracture. Univariate MR analyses suggested a causal effect of LDL-C on eBMD (β = −0.06; standard deviation change in eBMD per standard deviation change in LDL-C, 95% confidence interval [CI] = –0.08 to −0.04; p = 4 × 10⁻⁶), total body BMD (β = −0.05, 95% CI = –0.08 to −0.01, p = 6 × 10⁻³) and potentially on lumbar spine BMD. Multivariable MR suggested that the effects of LDL-C on eBMD and total body BMD were independent of HDL-C and triglycerides. Sensitivity MR analyses suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in the HMGCR region showed similar effects on eBMD (β = −0.083; −0.132 to −0.034; p = .001) to those excluding these SNPs (β = −0.063; −0.090 to −0.036; p = 8 × 10⁻⁶). Bidirectional MR analyses provided some evidence for a causal effect of eBMD on plasma LDL-C levels. Our results suggest that effects of statins on eBMD and total body BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis. © 2020 American Society for Bone and Mineral Research.     

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. © 2015 American Society for Bone and Mineral Research.     

Association of Bone Density Monitoring in Routine Clinical Practice With Anti-Osteoporosis Medication Use and Incident Fractures: A Matched Cohort Study

Routine bone mineral density (BMD) monitoring of individuals during the initial 5 years of anti-osteoporosis treatment is controversial. Using a registry-based cohort from the Province of Manitoba, Canada, we compared anti-osteoporosis medication use and fracture outcomes in women with versus without BMD monitoring receiving anti-osteoporosis medication. We identified 4559 women aged 40 years and older receiving anti-osteoporosis therapy with serial BMD testing (monitoring) within 5 years (mean interval 3.2 years) and 4559 propensity score–matched women without BMD monitoring. We assessed anti-osteoporosis medication use over 5 years from a population-based retail pharmacy database. Incident fractures to 10 years from health services data. During median 10 years observation, 1225 (13.4%) women developed major osteoporotic fracture, including 382 (4.2%) with hip fractures. Monitored women had significantly better fracture-free survival for major osteoporotic fracture (p = 0.040; 10-year cumulative risk 1.9% lower, 95% confidence interval [CI] 0.3–3.6%) and hip fracture ( p = 0.001; 10-year cumulative risk 1.8% lower, 95% CI 0.7–2.8%) compared with women who were not monitored. Hazard ratios (HRs) were significantly lower in monitored versus not monitored women for major osteoporotic fracture (HR = 0.89, 95% CI 0.80–0.98) and hip fracture (HR = 0.74, 95% CI 0.63–0.87). Days of medication use, medication persistence ratio, and treatment switching over 5 years were greater in monitored versus not monitored women. At the end of 5 years, more women in the monitored group persisted on treatment and more switched treatment, with switching behavior associated with an observed interval reduction in BMD. In conclusion, our findings suggest a possible role for BMD monitoring after initiating anti-osteoporosis therapy in the routine clinical practice setting. © 2019 American Society for Bone and Mineral Research.     

Low Vitamin D Status Is Associated With Impaired Bone Quality and Increased Risk of Fracture-Related Hospitalization in Older Australian Women

The vitamin D debate relates in part to ideal public health population levels of circulating 25-hydroxyvitamin D (25OHD) to maintain bone structure and reduce fracture. In a secondary analysis of 1348 women aged 70 to 85 years at baseline (1998) from the Perth Longitudinal Study of Aging in Women (a 5-year calcium supplementation trial followed by two 5-year extensions), we examined the dose-response relations of baseline plasma 25OHD with hip DXA BMD at year 1, lumbar spine BMD, and trabecular bone score (TBS) at year 5, and fracture-related hospitalizations over 14.5 years obtained by health record linkage. Mean baseline plasma 25OHD was 66.9 ± 28.2 nmol/L and 28.5%, 36.4%, and 35.1% of women had levels <50, 50 to 74.9, and ≥75 nmol/L, respectively. Generalized additive models showed that total hip and femoral neck BMD and TBS, but not spine BMD, were higher with increasing plasma 25OHD up to 100 nmol/L. Compared with those with 25OHD <50 nmol/L, women with 25OHD ≥75 nmol/L had significantly higher total hip and femoral neck BMD at year 1 (3.3% to 3.9%) and TBS at year 5 (2.0%), all P < 0.05. During the follow-up, 27.6% of women experienced any fracture-related hospitalization and 10.6% hip fracture-related hospitalization. Penalized spline regression models showed a decrease in risk with increased 25OHD levels up to 65 nmol/L and 75 nmol/L for hip fracture and any fracture-related hospitalization, respectively. Cox regression grouped analyses showed that compared with women with 25OHD <50 nmol/L, those with 25OHD levels 50 to 74.9 and ≥75 nmol/L had significantly lower risk for hip fracture [HR 0.60 (95% CI, 0.40 to 0.91) and 0.61 (95% CI, 0.40 to 0.92), respectively], and any fracture-related hospitalization [HR 0.77 (95% CI, 0.59 to 0.99) and 0.70 (95% CI, 0.54 to 0.91), respectively]. In older white women, 25OHD levels >50 nmol/L are a minimum public health target and 25OHD levels beyond 75 nmol/L may not have additional benefit to reduce fracture risk. © 2019 American Society for Bone and Mineral Research.     

Prospective Changes in the Distribution of Movement Behaviors Are Associated With Bone Health in the Elderly According to Variations in their Frailty Levels

Frailty is associated with poor bone health and osteoporosis, and physical activity (PA) is one of the best treatments for both pathologies in older adults. Nonetheless, because daily time is limited, how the time is distributed during the waking hours is critical. The waking hours are spent according to different movement behaviors: sedentary behaviors (SB), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA). The aim of this study was to use compositional data analyses to examine the effects of the change in movement behaviors on bone health during aging in older people, related to the changes in their frailty levels. We analyzed 227 older people aged 65 to 94 (125 women and 102 men) over a 4-year period. Movement behaviors were assessed using accelerometry. Both bone mineral density (BMD) and bone mineral content (BMC) were determined using bone densitometry. The Frailty Trait Scale was used to divide the sample by frailty level evolution during aging. The R statistical system was used for the compositional data analysis and, in addition, all models were adjusted for several covariates. The changes in the distribution of all movement behaviors within a waking hour period were significantly associated with spine and femoral neck BMD changes in the subgroup with a positive change in frailty level and spine BMC in the subgroup with no change in frailty level (p ≤ .05). Likewise, MVPA relative to the change in other movement behaviors was also associated in both subgroups with higher BMD and BMC, respectively, in the same body areas (p ≤ .05). No significant associations were found in the negative change in frailty level subgroup. Older people who achieved a positive change in frailty level during a 4-year period showed higher BMD changes compared to those with no changes or increases in their frailty level. Therefore, increasing MVPA relative to the change in the other movement behaviors during a 4-year period could perhaps produce bone health improvements in the elderly that do not worsen their frailty level. © 2020 American Society for Bone and Mineral Research.