Serum uric acid is associated with bone health in older men: A cross‐sectional population‐based study

Serum uric acid (UA) is a strong endogenous antioxidant. Since oxidative stress has been linked to osteoporosis, we examined the association between serum UA levels and bone mineral density (BMD), prevalent vertebral and nonvertebral fractures, and laboratory measures such as calcitropic hormones and bone turnover marker levels. This cross‐sectional analysis consisted of 1705 community‐dwelling men aged 70 years or over who participated in the baseline part of the Concord Health and Ageing in Men Project (CHAMP), a population‐based study of older men in Sydney, Australia. BMD at all sites was significantly higher among men with serum UA levels above the group median than among men with UA levels below the median. In multiple regression analyses adjusted for potential confounders, serum UA remained associated with BMD at all sites (β = 0.12 to 0.14, p < .001), serum calcium (β = 0.11, p = .001), parathyroid hormone (β = 0.09, p = .002), 25‐hydroxyvitamin D (β = 0.09, p = .005), and was negatively associated with urinary excretion amino‐terminal cross‐linked telopeptide of type 1 collagen (β = –0.09, p = .006). Overall, serum UA accounted for 1.0% to 1.44% of the variances in BMD (R² = 0.10 to 0.22). In multiple logistic regression analyses, above‐median serum UA levels were associated with a lower prevalence of osteoporosis at the femoral neck [odds ratio (OR) = 0.42, 95% confidence interval (CI) 0.22–0.81, p = .010) and lumbar spine (OR = 0.44, 95% CI 0.23–0.86, p = .016) and a lower prevalence of vertebral (OR = 0.62, 95% CI 0.43–0.91, p = .015) and nonvertebral (OR = 0.51, 95% CI 0.29–0.89, p = .018) fractures. In conclusion, higher serum UA levels are associated with higher BMD at all skeletal sites and with a lower prevalence of vertebral and nonvertebral fractures in older men. © 2011 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.     

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.     

Meta‐analysis of genome‐wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women

Previous genome‐wide association studies (GWAS) have identified common variants in genes associated with variation in bone mineral density (BMD), although most have been carried out in combined samples of older women and men. Meta‐analyses of these results have identified numerous single‐nucleotide polymorphisms (SNPs) of modest effect at genome‐wide significance levels in genes involved in both bone formation and resorption, as well as other pathways. We performed a meta‐analysis restricted to premenopausal white women from four cohorts (n = 4061 women, aged 20 to 45 years) to identify genes influencing peak bone mass at the lumbar spine and femoral neck. After imputation, age‐ and weight‐adjusted bone‐mineral density (BMD) values were tested for association with each SNP. Association of an SNP in the WNT16 gene (rs3801387; p = 1.7 × 10^?9) and multiple SNPs in the ESR1/C6orf97 region (rs4870044; p = 1.3 × 10^?8) achieved genome‐wide significance levels for lumbar spine BMD. These SNPs, along with others demonstrating suggestive evidence of association, were then tested for association in seven replication cohorts that included premenopausal women of European, Hispanic‐American, and African‐American descent (combined n = 5597 for femoral neck; n = 4744 for lumbar spine). When the data from the discovery and replication cohorts were analyzed jointly, the evidence was more significant (WNT16 joint p = 1.3 × 10^?11; ESR1/C6orf97 joint p = 1.4 × 10^?10). Multiple independent association signals were observed with spine BMD at the ESR1 region after conditioning on the primary signal. Analyses of femoral neck BMD also supported association with SNPs in WNT16 and ESR1/C6orf97 (p < 1 × 10^?5). Our results confirm that several of the genes contributing to BMD variation across a broad age range in both sexes have effects of similar magnitude on BMD of the spine in premenopausal women. These data support the hypothesis that variants in these genes of known skeletal function also affect BMD during the premenopausal period. © 2013 American Society for Bone and Mineral Research.     

Catch up in bone acquisition in young adult men with late normal puberty

The aim of this study was to investigate the development of bone mineral density (BMD) and bone mineral content (BMC) in relation to peak height velocity (PHV), and to investigate whether late normal puberty was associated with remaining low BMD and BMC in early adulthood in men. In total, 501 men (mean ± SD, 18.9 ± 0.5 years of age at baseline) were included in this 5‐year longitudinal study. Areal BMD (aBMD) and BMC, volumetric BMD (vBMD) and cortical bone size were measured using dual‐energy X‐ray absorptiometry (DXA) and pQCT. Detailed growth and weight charts were used to calculate age at PHV, an objective assessment of pubertal timing. Age at PHV was a strong positive predictor of the increase in aBMD and BMC of the total body (R² aBMD 11.7%; BMC 4.3%), radius (R² aBMD 23.5%; BMC 22.3%), and lumbar spine (R² aBMD 11.9%; BMC 10.5%) between 19 and 24 years (p < 0.001). Subjects were divided into three groups according to age at PHV (early, middle, and late). Men with late puberty gained markedly more in aBMD and BMC at the total body, radius, and lumbar spine, and lost less at the femoral neck (p < 0.001) than men with early puberty. At age 24 years, no significant differences in aBMD or BMC of the lumbar spine, femoral neck, or total body were observed, whereas a deficit of 4.2% in radius aBMD, but not in BMC, was seen for men with late versus early puberty (p < 0.001). pQCT measurements of the radius at follow‐up demonstrated no significant differences in bone size, whereas cortical and trabecular vBMD were 0.7% (p < 0.001) and 4.8% (p < 0.05) lower in men with late versus early puberty. In conclusion, our results demonstrate that late puberty in males was associated with a substantial catch up in aBMD and BMC in young adulthood, leaving no deficits of the lumbar spine, femoral neck, or total body at age 24 years. © 2012 American Society for Bone and Mineral Research.     

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.     

Amino Acid Intakes Are Associated With Bone Mineral Density and Prevalence of Low Bone Mass in Women: Evidence From Discordant Monozygotic Twins

Although a higher protein intake, particularly from vegetable sources, has been shown to be associated with higher bone mineral density (BMD) the relative impact of specific amino acids on BMD and risk of osteoporosis remains to be determined. Mechanistic research suggests that a number of specific amino acids, including five nonessential amino acids—alanine, arginine, glutamic acid, glycine, and proline—may play a role in bone health, principally through improved production of insulin and insulin‐like growth factor 1 and the synthesis of collagen and muscle protein. However to date, no previous studies have examined the associations between habitual intake of amino acids and direct measures of BMD and prevalence of osteoporosis or osteopenia, and no studies have examined this relationship in discordant identical twin‐pairs. In these analyses of female monozygotic twin‐pairs discordant for amino acid intake (n = 135), twins with higher intakes of alanine and glycine had significantly higher BMD at the spine than their co‐twins with within‐pair differences in spine‐BMD of 0.012 g/cm² (SE 0.01; p = 0.039) and 0.014 g/cm² (SE 0.01; p = 0.026), respectively. Furthermore, in cross‐sectional multivariable analyses of 3160 females aged 18 to 79 years, a higher intake of total protein was significantly associated with higher DXA‐measured BMD at the spine (quartile Q4 to quartile Q1: 0.017 g/cm², SE 0.01, p = 0.035) and forearm (Q4 to Q1: 0.010 g/cm², SE 0.003, p = 0.002). Intake of six amino acids (alanine, arginine, glutamic acid, leucine, lysine, and proline) were associated with higher BMD at the spine and forearm with the strongest association observed for leucine (Q4 to Q1: 0.024 g/cm², SE 0.01, p = 0.007). When intakes were stratified by protein source, vegetable or animal, prevalence of osteoporosis or osteopenia was 13% to 19% lower comparing extreme quartiles of vegetable intake for five amino acids (not glutamic acid or proline). These data provide evidence to suggest that intake of protein and several amino acids, including alanine and glycine, may be beneficial for bone health, independent of genetic background. © 2015 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.     

Quantitative and Qualitative Changes of Bone in Psoriasis and Psoriatic Arthritis Patients

Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by periarticular bone loss and new bone formation. Current data regarding systemic bone loss and bone mineral density (BMD) in PsA are conflicting. The aim of this study was to evaluate bone microstructure and volumetric BMD (vBMD) in patients with PsA and psoriasis. We performed HR‐pQCT scans at the ultradistal and periarticular radius in 50 PsA patients, 30 psoriasis patients, and 70 healthy, age‐ and sex‐related controls assessing trabecular bone volume (BV/TV), trabecular number (Tb.N), inhomogeneity of the trabecular network, cortical thickness (Ct.Th), and cortical porosity (Ct.Po), as well as vBMD. Trabecular BMD (Tb.BMD, p = 0.021, 12.0%), BV/TV (p = 0.020, –11.9%), and Tb.N (p = 0.035, 7.1%) were significantly decreased at the ultradistal radius and the periarticular radius in PsA patients compared to controls. In contrast, bone architecture of the ultradistal radius and periarticular radius was similar in patients with psoriasis and healthy controls. Duration of skin disease was associated with low BV/TV and Tb.N in patients with PsA. These data suggest that trabecular BMD and bone microstructure are decreased in PsA patients. The observation that duration of skin disease determines bone loss in PsA supports the concept of subclinical musculoskeletal disease in psoriasis patients. © 2015 American Society for Bone and Mineral Research.     

Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: A three‐year study

The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual‐energy X‐ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean ± SD) were similar between groups in terms of age, 76.8 ± 5.0 years; body mass index (BMI), 24.5 ± 3.6 kg/m²; TBS, 1.178 ± 0.1 but for LS T‐score (ZOL–2.9 ± 1.5 versus PLB–2.1 ± 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus–0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once‐yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years. © 2013 American Society for Bone and Mineral Research.     

Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa

Women with anorexia nervosa (AN) have elevated marrow fat mass despite low visceral and subcutaneous fat depots, which is inversely associated with bone mineral density (BMD). Whether marrow fat mass remains persistently elevated or decreases with recovery from AN is currently unknown. In this study, we investigated changes in marrow fat in women who have recovered from AN (AN-R). We also studied the relationship between preadipocyte factor (Pref)-1—a member of the EGF-like family of proteins and regulator of adipocyte and osteoblast differentiation—and fat depots and BMD in AN-R compared with women with AN and healthy controls (HC). We studied 29 women: 14 with active or recovered AN (30.7 + 2.2 years [mean ± SEM]) and 15 normal-weight controls (27.8 ± 1.2 years). We measured marrow adipose tissue (MAT) of the L4 vertebra and femur by ¹H-magnetic resonance spectroscopy; BMD of the spine, hip, and total body by DXA; and serum Pref-1 and leptin levels. We found that MAT of the L4 vertebra was significantly lower in AN-R compared with AN (p = 0.03) and was comparable to levels in HC. Pref-1 levels were also significantly lower in AN-R compared with AN (p = 0.02) and comparable to levels in healthy controls. Although Pref-1 was positively associated with MAT of the L4 vertebra in AN (R = 0.94; p = 0.002), we found that it was inversely associated with MAT of the L4 vertebra in HC (R = −0.71; p = 0.004). Therefore, we have shown that MAT and Pref-1 levels decrease with recovery from AN. Our data suggest that Pref-1 may have differential effects in states of nutritional deprivation compared with nutritional sufficiency. © 2012 American Society for Bone and Mineral Research.     

Multiscale Predictors of Femoral Neck In Situ Strength in Aging Women: Contributions of BMD,Cortical Porosity,Reference Point Indentation,and Nonenzymatic Glycation

The diagnosis of fracture risk relies almost solely on quantifying bone mass, yet bone strength is governed by factors at multiple scales including composition and structure that contribute to fracture resistance. Furthermore, aging and conditions such as diabetes mellitus alter fracture incidence independently of bone mass. Therefore, it is critical to incorporate other factors that contribute to bone strength in order to improve diagnostic specificity of fracture risk. We examined the correlation between femoral neck fracture strength in aging female cadavers and areal bone mineral density, along with other clinically accessible measures of bone quality including whole‐bone cortical porosity (Ct.Po), bone material mechanical behavior measured by reference point indentation (RPI), and accumulation of advanced glycation end‐products (AGEs). All measurements were found to be significant predictors of femoral neck fracture strength, with areal bone mineral density (aBMD) being the single strongest correlate (aBMD: r = 0.755, p < 0.001; Ct.Po: r = –0.500, p < 0.001; RPI: r = –0.478, p < 0.001; AGEs: r = –0.336, p = 0.016). RPI‐derived measurements were not correlated with tissue mineral density or local cortical porosity as confirmed by micro–computed tomography (μCT). Multiple reverse stepwise regression revealed that the inclusion of aBMD and any other factor significantly improve the prediction of bone strength over univariate predictions. Combining bone assays at multiple scales such as aBMD with tibial Ct.Po (r = 0.835; p < 0.001), tibial difference in indentation depth between the first and 20th cycle (IDI) (r = 0.883; p < 0.001), or tibial AGEs (r = 0.822; p < 0.001) significantly improves the prediction of femoral neck strength over any factor alone, suggesting that this personalized approach could greatly enhance bone strength and fracture risk assessment with the potential to guide clinical management strategies for at‐risk populations. © 2015 American Society for Bone and Mineral Research.     

An investigation into the relationship between soft tissue body composition and bone mineral density in a young adult twin sample

The purpose of this study was to investigate the relationship of fat mass (FM) and lean mass (LM) with bone mineral density (BMD) independent of genetic effects. We also assessed the extent to which genetic and environmental influences explain the associations between these phenotypes. Body composition and BMD were measured using dual‐energy X‐ray absorptiometry in 57 monozygotic and 92 same‐sex dizygotic twin pairs, aged 23 to 31 years, chosen to represent a wide range of intrapair differences in body mass index (BMI; 0 to 15.2 kg/m²). Heritability estimates were adjusted for height and gender. In multiple linear regression analysis, intrapair differences in both FM and LM were independently associated with intrapair differences in BMD at most skeletal sites after adjustment for gender and differences in height. Within monozygotic and dizygotic pairs, LM was a significantly stronger predictor of whole‐body BMD than FM (p < .01). Additive genetic factors explained 87% [95% confidence interval (CI) 80%–91%), 81% (95% CI 70%–88%), and 61% (95% CI 41%–75%) of the variation in whole‐body BMD, LM, and FM, respectively. Additive genetic factors also accounted for 69% to 88% of the covariance between LM and BMD and for 42% to 72% of the covariance between FM and BMD depending on the skeletal site. The genetic correlation between LM and whole‐body BMD (r_g = 0.46, 95% CI 0.32–0.58) was greater than that of FM and whole‐body BMD (r_g = 0.25, 95% CI 0.05–0.42). In conclusion, our data indicate that peak BMD is influenced by acquired body weight as well as genetic factors. In young adulthood, LM and BMD may have more genes in common than do FM and BMD. © 2011 American Society for Bone and Mineral Research.     

Associations between dietary flavonoid intakes and bone health in a scottish population

Flavonoids are bioactive polyphenols found particularly in fruit and vegetables, but little is known about their role in bone health in humans. The aim of this observational study was to investigate whether dietary flavonoid intake was associated with bone mineral density (BMD) and bone resorption in a large group of perimenopausal Scottish women. Over 3000 women completed a food frequency questionnaire as part of an osteoporosis screening study. The diets were analyzed for flavonoid intake using a food composition database. BMD was measured at the femoral neck (FN) and lumbar spine (LS) by dual‐energy X‐ray absorptiometry (DXA). Free pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by high‐performance liquid chromatography (HPLC) in second early morning fasted urine samples. The mean flavonoid intake of the diet was 307 ±199 mg/d. The catechin family contributed the most to flavonoid intakes (55%), and the flavones the least (<1%). Associations were found between energy‐adjusted total flavonoid intakes and BMD at the FN and LS (FN r = 0.054, LS r = 0.036, p ≤ .05). Annual percent change in BMD was associated with intakes of procyanidins and catechins (p ≤ .05), and flavanones were negatively associated with bone‐resorption markers (PYD r = ?0.049, DPD r = –0.057, p ≤ .001). These associations were still seen after adjusting for confounders. It is concluded that dietary flavonoid intakes are associated with BMD, supporting the evidence from animal and cellular studies. © 2011 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.     

Bone Density,Microstructure and Strength in Obese and Normal Weight Men and Women in Younger and Older Adulthood

Obesity is associated with greater areal BMD (aBMD) and is considered protective against hip and vertebral fracture. Despite this, there is a higher prevalence of lower leg and proximal humerus fracture in obesity. We aimed to determine if there are site‐specific differences in BMD, bone structure, or bone strength between obese and normal‐weight adults. We studied 100 individually‐matched pairs of normal (body mass index [BMI] 18.5 to 24.9 kg/m²) and obese (BMI >30 kg/m²) men and women, aged 25 to 40 years or 55 to 75 years. We assessed aBMD at the whole body (WB), hip (TH), and lumbar spine (LS) with dual‐energy X‐ray absorptiometry (DXA), LS trabecular volumetric BMD (Tb.vBMD) by quantitative computed tomography (QCT), and vBMD and microarchitecture and strength at the distal radius and tibia with high‐resolution peripheral QCT (HR‐pQCT) and micro–finite element analysis. Serum type 1 procollagen N‐terminal peptide (P1NP) and collagen type 1 C‐telopeptide (CTX) were measured by automated electrochemiluminescent immunoassay (ECLIA). Obese adults had greater WB, LS, and TH aBMD than normal adults. The effect of obesity on LS and WB aBMD was greater in older than younger adults (p < 0.01). Obese adults had greater vBMD than normal adults at the tibia (p < 0.001 both ages) and radius (p < 0.001 older group), thicker cortices, higher cortical BMD and tissue mineral density, lower cortical porosity, higher trabecular BMD, and higher trabecular number than normal adults. There was no difference in bone size between obese and normal adults. Obese adults had greater estimated failure load at the radius (p < 0.05) and tibia (p < 0.01). Differences in HR‐pQCT measurements between obese and normal adults were seen more consistently in the older than the younger group. Bone turnover markers were lower in obese than in normal adults. Greater BMD in obesity is not an artifact of DXA measurement. Obese adults have higher BMD, thicker and denser cortices, and higher trabecular number than normal adults. Greater differences between obese and normal adults in the older group suggest that obesity may protect against age‐related bone loss and may increase peak bone mass. © 2014 American Society for Bone and Mineral Research.     

Association Between the Metabolome and Low Bone Mineral Density in Taiwanese Women Determined by 1H NMR Spectroscopy

Osteoporosis is related to the alteration of specific circulating metabolites. However, previous studies on only a few metabolites inadequately explain the pathogenesis of this complex syndrome. To date, no study has related the metabolome to bone mineral density (BMD), which would provide an overview of metabolism status and may be useful in clinical practice. This cross‐sectional study involved 601 healthy Taiwanese women aged 40 to 55 years recruited from MJ Health Management Institution between 2009 and 2010. Participants were classified according to high (2nd tertile plus 3rd tertile) and low (1st tertile) BMD groups. The plasma metabolome was evaluated by proton nuclear magnetic resonance spectroscopy (¹H NMR). Principal components analysis (PCA), partial least‐squares discriminant analysis (PLS‐DA), and logistic regression analysis were used to assess the association between the metabolome and BMD. The high and low BMD groups could be differentiated by PLS‐DA but not PCA in postmenopausal women (Q² = 0.05, p_permutation = 0.04). Among postmenopausal women, elevated glutamine was significantly associated with low BMD (adjusted odds ratio [AOR] = 5.10); meanwhile, elevated lactate (AOR = 0.55), acetone (AOR = 0.51), lipids (AOR = 0.04), and very low‐density lipoprotein (AOR = 0.49) protected against low BMD. To the best of our knowledge, this study is the first to identify a group of metabolites for characterizing low BMD in postmenopausal women using a ¹H NMR–based metabolomic approach. The metabolic profile may be useful for predicting the risk of osteoporosis in postmenopausal women at an early age. © 2014 American Society for Bone and Mineral Research.     

Low‐Magnitude Mechanical Stimulation to Improve Bone Density in Persons of Advanced Age: A Randomized,Placebo‐Controlled Trial

Nonpharmacologic approaches to preserve or increase bone mineral density (BMD) include whole‐body vibration (WBV), but its efficacy in elderly persons is not clear. Therefore, we conducted the Vibration to Improve Bone in Elderly Subjects (VIBES) trial, a randomized, placebo‐controlled trial of 10 minutes of daily WBV (0.3g at 37 Hz) in seniors recruited from 16 independent living communities. The primary outcomes were volumetric BMD of the hip and spine measured by quantitative computed tomography (QCT) and biochemical markers of bone turnover. We randomized 174 men and women (89 active, 85 placebo) with T‐scores –1 to –2.5 who were not taking bone active drugs and had no diseases affecting the skeleton (mean age 82 ± 7 years, range 65 to 102). Participants received daily calcium (1000 mg) and vitamin D (800 IU). Study platforms were activated using radio frequency ID cards providing electronic adherence monitoring; placebo platforms resembled the active platforms. In total, 61% of participants in the active arm and 73% in the placebo arm completed 24 months. The primary outcomes, median percent changes (interquartile range [IQR]) in total volumetric femoral trabecular BMD (active group (2.2% [–0.8%, 5.2%]) versus placebo 0.4% [–4.8%, 5.0%]) and in mid‐vertebral trabecular BMD of L₁ and L₂ (active group (5.3% [–6.9%, 13.3%]) versus placebo (2.4% [–4.4%, 11.1%]), did not differ between groups (all p values > 0.1). Changes in biochemical markers of bone turnover (P1NP and sCTX) also were not different between groups (p = 0.19 and p = 0.97, respectively). In conclusion, this placebo‐controlled randomized trial of daily WBV in older adults did not demonstrate evidence of significant beneficial effects on volumetric BMD or bone biomarkers; however, the high variability in vBMD changes limited our power to detect small treatment effects. The beneficial effects of WBV observed in previous studies of younger women may not occur to the same extent in elderly individuals. © 2015 American Society for Bone and Mineral Research.     

Bone Mineral Density Is Positively Related to Carotid Intima‐Media Thickness: Findings From a Population‐Based Study in Adolescents and Premenopausal Women

Osteoporosis and cardiovascular disease (CVD) are both common causes of morbidity and mortality. Previous studies, mainly of people older than 60 years, suggest a relationship between these conditions. Our aim was to determine the association between bone characteristics and CVD markers in younger and middle‐aged individuals. Women (n = 3366) and their adolescent offspring (n = 4368) from the UK population‐based cohort study, Avon Longitudinal Study of Parents and Children (ALSPAC), were investigated. We measured total body (TB) and hip bone mineral density (BMD), TB bone area (BA) and bone mineral content (BMC) by dual‐energy X‐ray absorptiometry (DXA), and carotid intima‐media thickness (cIMT) by high‐resolution ultrasound. Arterial distensibility was calculated as the difference between systolic and diastolic arterial diameters. Linear regression determined associations between bone exposures and cIMT (in adolescents) and both cIMT and arterial distensibility (in women), generating partial correlation coefficients. Mean (SD) age of women was 48 (4.2) years, body mass index (BMI) was 26.2 (5.0) kg/m², and 71% were premenopausal. In confounder‐adjusted analyses (age, height, lean mass, fat mass, menopause, smoking, estrogen replacement, calcium/vitamin D supplementation, and education) TB and hip BMD were both positively associated with cIMT (0.071 [0.030, 0.112], p = 0.001; 0.063 [0.025, 0.101], p = 0.001, respectively). Femoral neck BMD and TB BMD, BMC, and BA were positively associated with arterial distensibility. Mean (SD) age of adolescents was 17 (0.4) years, BMI was 23 (4.1) kg/m², and 44.5% were male. Total hip and TB measurements were positively associated with cIMT, with similar magnitudes of association to those found in their mothers. In contrast to most published findings, we identified weak positive associations between BMD and cIMT in predominantly premenopausal women and their adolescent offspring. We found greater femoral neck BMD and TB DXA measurements to be associated with reduced arterial stiffness. Rather than a relationship with preclinical atherosclerosis, in these relatively young populations, we speculate our associations between BMD, cIMT, and arterial distensibility may reflect a shared relationship between bone and vascular growth and development. © 2016 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.     

Relationship Between Pretreatment Rate of Bone Loss and Bone Density Response to Once‐Yearly ZOL: HORIZON‐PFT Extension Study

Several studies have shown that high bone turnover is associated with greater rates of bone loss and greater bone mineral density (BMD) response to antiresorptive therapy in postmenopausal osteoporosis. However, it is not known whether greater rates of bone loss before therapy are associated with greater BMD response to antiresorptive therapy. In the HORIZON‐PFT study and its extension, one group of women who were randomized to receive placebo for 3 years (years 1, 2, and 3) were then switched to zoledronic acid (ZOL) 5 mg annually for up to three injections (years 4, 5, and 6, P3Z3 arm) (n = 1223). We measured total hip BMD at baseline, 1, 2, and 3 years on placebo and at 4.5 and 6 years on ZOL. The procollagen type I N‐terminal propeptide (PINP) was measured at 3, 4.5, and 6 years. By design, not all subjects were followed for as long as 6 years, so this analysis focused on the results at 4.5 years. Those with the largest loss in total hip BMD on placebo in years 0 to 3 had the largest gain during ZOL (years 3 to 4.5): (r = –0.39, p < 0.0001). The change in total hip BMD in years 0 to 3 on placebo was related to the serum PINP at the end of the 3‐year period (r = –0.24, p < 0.0001). The change in total hip BMD on ZOL from year 3 to 4.5 was related to the serum PINP at the end of the 3‐year period (r = 0.26, p < 0.0001). We conclude that BMD response to ZOL is greater in postmenopausal women who had larger loss before treatment. This association may result from higher bone turnover being associated with both greater bone loss on placebo and greater BMD response to ZOL. © 2014 American Society for Bone and Mineral Research.     

Motor Competence in Early Childhood Is Positively Associated With Bone Strength in Late Adolescence

The onset of walking in early childhood results in exposure of the lower limb to substantial forces from weight bearing activity that ultimately contribute to adult bone strength. Relationships between gross motor score (GMS), at 18 months and bone outcomes measured at age 17 years were examined in 2327 participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Higher GMS indicated greater motor competence in weight‐bearing activities. Total hip bone mineral density (BMD) and hip cross‐sectional moment of inertia (CSMI) were assessed from dual‐energy X‐ray absorptiometry (DXA). Bone measures including cortical bone mineral content (BMC), periosteal circumference (PC), cortical thickness (CT), cortical bone area (CBA), cortical BMD (BMD_C) and cross‐sectional moment of inertia (CSMI) were assessed by peripheral quantitative computed tomography (pQCT) at 50% distal‐proximal length. Before adjustment, GMS was associated with hip BMD, CSMI, and tibia BMC, PC, CT, CBA and CSMI (all p < 0.001) but not BMD_C (p > 0.25). Strongest associations (standardized regression coefficients with 95% CI) were between GMS and hip BMD (0.086; 95% CI, 0.067 to 0.105) and tibia BMC (0.105; 95% CI, 0.089 to 0.121). With the exception of hip BMD, larger regression coefficients were observed in males (gender interactions all p < 0.05). Adjustment for lean mass resulted in substantial attenuation of regression coefficients, suggesting associations between impaired motor competence and subsequent bone development are partly mediated by alterations in body composition. In conclusion, impaired motor competence in childhood is associated with lower adolescent bone strength, and may represent a risk factor for subsequent osteoporosis. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).