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

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

High Cardiovascular Risk in Older Men with Poor Bone Microarchitecture—The Prospective STRAMBO Study

Data on the association between bone microarchitecture and cardiovascular disease (CVD) in men are scarce. We studied the link of bone microarchitecture and areal bone mineral density (aBMD) with the risk of major adverse coronary event (MACE) in a cohort of men aged 60 to 87 years followed prospectively for 8 years. At baseline, aBMD was measured using a Hologic Discovery-A device. Bone microarchitecture was assessed at distal radius and tibia by high-resolution peripheral quantitative computed tomography (XtremeCT Scanco device). During the study, 53 men had incident MACE. The analyses were adjusted for confounders related to bone and CVD. In 813 men (53 MACEs), higher aBMD at the lumbar spine, hip, whole body, and radius was associated with lower risk of MACE (hazard ratio [HR] = 0.44–0.71/SD, p < .025 to < .001). In 745 men having valid distal radius scan (47 MACEs), higher cortical density (Ct.BMD) and higher cortical thickness (Ct.Th^d) were associated with lower risk of MACE. This risk was higher in men in the lowest quintile of cortical measures versus the four upper quintiles combined (Ct.BMD: HR = 2.12, 95% confidence interval [CI] 1.08–4.17, p < .025). Findings were similar in 779 men having valid distal tibia scan (48 MACEs). At both sites, higher estimated stiffness and higher failure load were associated with a lower risk of MACE. The risk of MACE was higher in men in the lowest quintile of the measures of bone strength versus four upper quintiles jointly (distal radius stiffness: HR = 2.46, 95% CI 1.27–4.74, p < .01). Similar results were obtained in 638 men without prior fragility fracture and in 689 men without ischemic heart disease at baseline. Thus, in older men followed prospectively for 8 years, higher aBMD, preserved cortical bone status, and higher estimated bone strength were associated with lower risk of MACE after adjustment for relevant confounders. © 2021 American Society for Bone and Mineral Research (ASBMR).     

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

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

Correlates of bone microarchitectural parameters and serum sclerostin levels in men: The STRAMBO study

Sclerostin is predominantly expressed by osteocytes. Serum sclerostin levels are positively correlated with areal bone mineral density (aBMD) measured by dual‐energy X‐ray absorptiometry (DXA) and bone microarchitecture assessed by high‐resolution peripheral quantitative computed tomography (HR‐pQCT) in small studies. We assessed the relation of serum sclerostin levels with aBMD and microarchitectural parameters based on HR‐pQCT in 1134 men aged 20 to 87 years using multivariable models adjusted for confounders (age, body size, lifestyle, comorbidities, hormones regulating bone metabolism, muscle mass and strength). The apparent age‐related increase in serum sclerostin levels was faster before the age of 63 years than afterward (0.43 SD versus 0.20 SD per decade). In 446 men aged ≤63 years, aBMD (spine, hip, whole body), trabecular volumetric BMD (Tb.vBMD), and trabecular number (Tb.N) at the distal radius and tibia were higher in the highest sclerostin quartile versus the three lower quartiles combined. After adjustment for aBMD, men in the highest sclerostin quartile had higher Tb.vBMD (mainly in the central compartment) and Tb.N at both skeletal sites (p < 0.05 to 0.001). In 688 men aged >63 years, aBMD was positively associated with serum sclerostin levels at all skeletal sites. Cortical vBMD (Ct.vBMD) and cortical thickness (Ct.Th) were lower in the first sclerostin quartile versus the three higher quartiles combined. Tb.vBMD increased across the sclerostin quartiles, and was associated with lower Tb.N and more heterogeneous trabecular distribution (higher Tb.Sp.SD) in men in the lowest sclerostin quartile. After adjustment for aBMD, men in the lowest sclerostin quartile had lower Tb.vBMD and Tb.N, but higher Tb.Sp.SD (p < 0.05 to 0.001) at both the skeletal sites. In conclusion, serum sclerostin levels in men are strongly positively associated with better bone microarchitectural parameters, mainly trabecular architecture, regardless of the potential confounders.     

Effect of Total Hip Bone Area on Osteoporosis Diagnosis and Fractures

DXA is affected by skeletal size, with smaller bones giving lower areal BMD despite equal material density. Whether this size effect confounds the use of BMD as a diagnostic and fracture risk assessment tool is unclear. We identified 16,205 women of white ethnicity ≥50 yr of age undergoing baseline hip assessment with DXA (1998–2002) from a population‐based database that contains all clinical DXA test results for the Province of Manitoba, Canada. Total hip measurements were categorized according to quartile in total hip bone area (Q1 = smallest, Q4 = largest). Longitudinal health service records were assessed for the presence of nontraumatic osteoporotic fracture codes during a mean of 3.2 yr of follow‐up after BMD testing (757 osteoporotic fractures, 186 hip fractures). Total hip bone area strongly affected osteoporosis diagnosis with much higher rates in Q1 (14.4%) than Q4 (8.9%). However, incident fracture rates were constant across all area quartiles, and prevalent fractures were paradoxically fewer in smaller area quartiles (p < 0.001 for trend). Age was a potential confounder that correlated positively with area (r = 0.12, p < 0.0001). When age was not included in a Cox regression model, Q1 seemed to have a lower rate of incident osteoporotic fractures (HR = 0.80, 95% CI = 0.66–0.98, reference Q4) and hip fractures (HR = 0.63, 95% CI = 0.43–0.94) for a given level of BMD. In age‐adjusted regression models, total hip BMD was strongly predictive of incident osteoporotic fractures (HR per SD = 1.83, 95% CI = 1.68–1.99) and hip fractures (HR per SD = 2.80, 95% CI = 2.33–3.35), but there was no independent effect of bone area (categorical or continuous). Nested matched subgroup analysis and ROC analysis confirmed that bone area had no appreciable effect on incident fractures. We conclude that total hip areal BMD categorizes a substantially higher fraction of women with smaller bone area as being osteoporotic despite younger age. Incident fracture rates correlate equally well with BMD across all bone area quartiles when adjusted for age.     

Methylation of Bone SOST,Its mRNA,and Serum Sclerostin Levels Correlate Strongly With Fracture Risk in Postmenopausal Women

Inhibition of sclerostin, a glycoprotein secreted by osteocytes, offers a new therapeutic paradigm for treatment of osteoporosis (OP) through its critical role as Wnt/catenin signaling regulator. This study describes the epigenetic regulation of SOST expression in bone biopsies of postmenopausal women. We correlated serum sclerostin to bone mineral density (BMD), fractures, and bone remodeling parameters, and related these findings to epigenetic and genetic disease mechanisms. Serum sclerostin and bone remodeling biomarkers were measured in two postmenopausal groups: healthy (BMD T‐score > –1) and established OP (BMD T‐score < –2.5, with at least one low‐energy fracture). Bone specimens were used to analyze SOST mRNAs, single nucleotide polymorphisms (SNPs), and DNA methylation changes. The SOST gene promoter region showed increased CpG methylation in OP patients (n = 4) compared to age and body mass index (BMI) balanced controls (n = 4) (80.5% versus 63.2%, p = 0.0001) with replication in independent cohorts (n = 27 and n = 36, respectively). Serum sclerostin and bone SOST mRNA expression correlated positively with age‐adjusted and BMI‐adjusted total hip BMD (r = 0.47 and r = 0.43, respectively; both p < 0.0005), and inversely to serum bone turnover markers. Five SNPs, one of which replicates in an independent population‐based genomewide association study (GWAS), showed association with serum sclerostin or SOST mRNA levels under an additive model (p = 0.0016 to 0.0079). Genetic and epigenetic changes in SOST influence its bone mRNA expression and serum sclerostin levels in postmenopausal women. The observations suggest that increased SOST promoter methylation seen in OP is a compensatory counteracting mechanism, which lowers serum sclerostin concentrations and reduces inhibition of Wnt signaling in an attempt to promote bone formation. © 2014 American Society for Bone and Mineral Research.     

Importance of Albumin, 25(OH)-Vitamin D and IGFBP-3 as Risk Factors in Elderly Women and Men with Hip Fracture

The relative importance of vitamin D deficiency, secondary hyperparathyroidism, nutritional deficiency and low bone mineral density (BMD) as risk factors for hip fracture is not definitely established. In the framework of a case-control study of risk factors for hip fractured, biochemical markers of bone metabolism and nutrition and femoral BMD data were compared in 136 female and 43 male hip fracture patients, 126 female and 44 male age-matched hospitalized controls, and 47 healthy elderly women (8 men). Patients with hip fracture had lower albumin (−10%9 and 25(OH)-vitamin D (25(OH)D; −19%) compared with hospitalized controls, and lower albumin (−28%) and 25(OH)D levels (−52%) compared with the elderly controls. Serum values of IGFBP-3 were also significantly lower (−33%) in hip fracture patients than in community controls. BMD of femoral neck was lower (p < 0.001) in patients than in hospitalized and community controls. In hip fracture patients, parathyroid hormone (PTH) correlated weakly with BMD (neck: r = −0.19, trochanter: r = −0.17; both p < 0.05). When all women were pooled (n = 233), albumin correlated significantly (age-adjusted) with BMD at all sites (neck: r = 0.27, trochanter: r = 0.25; all p < 0.001). Albumin, but not 25(OH)D, also correlated with skinfold thickness (r = 0.19, p < 0.0025) and with body mass index (BMI) (r = 0.14, p < 0.05). Male patients with hip fracture had lower BMD and albumin (both p < 0.001), 25(OH)D (p = 0.02) and IGFBP-3 levels (p <: 0.005) compared with the controls. When male patients and controls were pooled together, albumin, skinfold thickness and BMI were significantly correlated with each other, but not with BMD. IGFBP-3 was highly correlated with albumin (p < 0.0001), 25(OH)D (p < 0.005) and, less significantly, with PTH (p < 0.05), but not with BMI or skinfold thickness. IGFBP-3 was significantly correlated with BMD at all sites (neck: r = 0.27, p < 0.05); trochanter: r = 0.40, p < 0.0005). In conclusion, low albumin and low BMD were both important risk factors for hip fracture. Low serum albumin was the strongest independent variable correlated with hip fractures. In men, IGFBP-3 was correlated with BMD. The femoral BMD depended only weakly on PTH and 25(OH)D, but was correlated at all sites with albumin, a non-specific parameter of nutrition and general health.     

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

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

Relationship Between Body Mass Index and Fracture Risk Is Mediated by Bone Mineral Density

The relationship between body mass index (BMI) and fracture risk is controversial. We sought to investigate the effect of collinearity between BMI and bone mineral density (BMD) on fracture risk, and to estimate the direct and indirect effect of BMI on fracture with BMD being the mediator. The study involved 2199 women and 1351 men aged 60 years or older. BMI was derived from baseline weight and height. Femoral neck BMD was measured by dual‐energy X‐ray absorptiometry (DXA; GE‐LUNAR, Madison, WI, USA). The incidence of fragility fracture was ascertained by X‐ray reports from 1991 through 2012. Causal mediation analysis was used to assess the mediated effect of BMD on the BMI‐fracture relationship. Overall, 774 women (35% of total women) and 258 men (19%) had sustained a fracture. Approximately 21% of women and 20% of men were considered obese (BMI ≥ 30). In univariate analysis, greater BMI was associated with reduced fracture risk in women (hazard ratio [HR] 0.92; 95% confidence interval [CI], 0.85 to 0.99) and in men (HR 0.77; 95% CI, 0.67 to 0.88). After adjusting for femoral neck BMD, higher BMI was associated with greater risk of fracture in women (HR 1.21; 95% CI, 1.11 to 1.31) but not in men (HR 0.96; 95% CI, 0.83 to 1.11). Collinearity had minimal impact on the BMD‐adjusted results (variance inflation factor [VIF] = 1.2 for men and women). However, in mediation analysis, it was found that the majority of BMI effect on fracture risk was mediated by femoral neck BMD. The overall mediated effect estimates were ?0.048 (95% CI, ?0.059 to ?0.036; p < 0.001) in women and ?0.030 (95% CI, ?0.042 to ?0.018; p < 0.001) in men. These analyses suggest that there is no significant direct effect of BMI on fracture, and that the observed association between BMI and fracture risk is mediated by femoral neck BMD in both men and women. © 2014 American Society for Bone and Mineral Research.     

Relation of age,gender, and bone mass to circulating sclerostin levels in women and men

Sclerostin is a potent inhibitor of Wnt signaling and bone formation. However, there is currently no information on the relation of circulating sclerostin levels to age, gender, or bone mass in humans. Thus we measured serum sclerostin levels in a population‐based sample of 362 women [123 premenopausal, 152 postmenopausal not on estrogen treatment (ET), and 87 postmenopausal on ET] and 318 men, aged 21 to 97 years. Sclerostin levels (mean ± SEM) were significantly higher in men than women (33.3 ± 1.0 pmol/L versus 23.7 ± 0.6 pmol/L, p < .001). In pre‐ and postmenopausal women not on ET combined (n = 275) as well as in men, sclerostin levels were positively associated with age (r = 0.52 and r = 0.64, respectively, p < .001 for both). Over life, serum sclerostin levels increased by 2.4‐ and 4.6‐fold in the women and men, respectively. Moreover, for a given total‐body bone mineral content, elderly subjects (age ≥ 60 years) had higher serum sclerostin levels than younger subjects (ages 20 to 39 years). Our data thus demonstrate that (1) men have higher serum sclerostin levels than women, (2) serum sclerostin levels increase markedly with age, and (3) compared with younger subjects, elderly individuals have higher serum sclerostin levels for a given amount of bone mass. Further studies are needed to define the cause of the age‐related increase in serum sclerostin levels in humans as well as the potential role of this increase in mediating the known age‐related impairment in bone formation. © 2011 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.     

Do Both Areal BMD and Injurious Falls Explain the Higher Incidence of Fractures in Women than in Men?

The higher incidence of fractures in women than in men is generally attributed to the lower areal bone mineral density (areal BMD, g/cm²) of the former. The purpose of the present study was to investigate both areal BMD and injurious falls as risk factors for fractures. In a first cohort, areal BMD was measured in 5,131 men and women (age range 40–95 years). In a second cohort, consisting of 26,565 men and women (age range 40–69 years), a health survey was conducted including questions about lifestyle and medication. Main outcome measures included validated prospective injurious falls and fractures in both cohorts. The higher areal BMD and femoral neck BMD in men compared to women (P < 0.001) were explained by a higher diameter of the femoral neck. Importantly, the diameter of the femoral neck was not associated with fractures in either sex (hazard ratio [HR] 0.94–1.04, P > 0.05 for all), suggesting that a higher areal BMD and lower incidence of osteoporosis in men do not explain their lower incidence of fractures. In contrast, women were more prone to sustain injurious falls than men in both cohorts investigated (HR for women = 1.61 and 1.84, P < 0.001 for both), resulting in a higher incidence of fractures (HR for women = 2.24 and 2.36, P < 0.001 for both). The number of injurious falls and fractures occurring each month during the study period showed a very strong correlation in both women (r = 0.95, P < 0.00001) and men (r = 0.97, P < 0.00001). In summary, low areal BMD, and thus osteoporosis, may not explain the higher fracture incidence in women than in men. Instead, a higher incidence of injurious falls in women was strongly associated with the higher fracture risk.     

Men with metabolic syndrome have lower bone mineral density but lower fracture risk—the MINOS study

Data on the association of the metabolic syndrome (MetS) with bone mineral density (BMD) and fracture risk in men are inconsistent. We studied the association between MetS and bone status in 762 older men followed up for 10 years. After adjustment for age, body mass index, height, physical activity, smoking, alcohol intake, and serum 25‐hydroxycholecalciferol D and 17β‐estradiol levels, men with MetS had lower BMD at the hip, whole body, and distal forearm (2.2% to 3.2%, 0.24 to 0.27 SD, p < .05 to .005). This difference was related to abdominal obesity (assessed by waist circumference, waist‐hip ratio, or central fat mass) but not other MetS components. Men with MetS had lower bone mineral content (3.1% to 4.5%, 0.22 to 0.29 SD, p < .05 to 0.001), whereas differences in bone size were milder. Men with MetS had a lower incidence of vertebral and peripheral fractures (6.7% versus 12.0%, p < .05). After adjustment for confounders, MetS was associated with a lower fracture incidence [odds ratio (OR) = 0.33, 95% confidence interval (CI) 0.15–0.76, p < .01]. Among the MetS components, hypertriglyceridemia was most predictive of the lower fracture risk (OR = 0.25, 95%CI 0.10–0.62, p < .005). Lower fracture risk in men with MetS cannot be explained by differences in bone size, rate of bone turnover rate and bone loss, or history of falls or fractures. Thus older men with MetS have a lower BMD related to the abdominal obesity and a lower risk of fracture related to hypertriglyceridemia. MetS probably is not a meaningful concept in the context of bone metabolism. Analysis of its association with bone‐related variables may obscure the pathophysiologic links of its components with bone status. © 2010 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.     

Association of serum sclerostin with bone mineral density, bone turnover, steroid and parathyroid hormones, and fracture risk in postmenopausal women: the OFELY study

Summary

Sclerostin is a key regulator of bone formation. In a population of 572 postmenopausal women (mean age, 67 years) followed prospectively for a median of 6 years, there was no significant association between baseline levels of serum sclerostin and incidence of all fractures which occurred in 64 subjects.

Introduction

Sclerostin, an osteocyte soluble factor, is a major negative regulator of osteoblastic activity. Circulating sclerostin levels were reported to increase with age and to be modestly associated with bone mineral density (BMD) and bone turnover, but there are no data on the association with fracture risk.

Methods

We investigated 572 postmenopausal women (mean age, 67?±?8.5 years) from the OFELY population-based cohort. The associations of serum sclerostin measured with a new two-site ELISA and spine and hip BMD by DXA, serum β-isomerized C-terminal crosslinking of type I collagen (CTX), intact N-terminal propeptide of type I collagen (PINP), intact PTH, 25-hydroxyvitamin D [25(OH)D], estradiol, testosterone, and fracture risk were analyzed. At the time of sclerostin measurements, 98 postmenopausal women had prevalent fractures. After a median of 6 years (interquartile range, 5–7 years) follow-up, 64 postmenopausal sustained an incident fracture.

Results

Serum sclerostin correlated positively with spine (r?=?0.35, p?<?0.0001) and total hip (r?=?0.25, <0.0001) BMD. Conversely, serum sclerostin was weakly negatively associated with the bone markers PINP (r?=??0.10, p?=?0.014) and CTX (r?=??0.13, p?=?0.0026) and with intact PTH (r?=??0.13, p?=?0.0064). There was no significant association of serum sclerostin with 25(OH)D, estradiol, free estradiol index, or testosterone. Serum sclerostin considered as a continuous variable or in quartiles was not significantly associated with the risk of prevalent or incident fracture.

Conclusion

Serum sclerostin is weakly correlated with BMD, bone turnover, and PTH in postmenopausal women. It was not significantly associated with the risk of all fractures, although the number of incident fractures recorded may not allow detecting a modest association.     

Levels of serotonin,sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high‐bone‐mass phenotype due to a mutation in Lrp5

Patients with an activation mutation of the Lrp5 gene exhibit high bone mass (HBM). Limited information is available regarding compartment‐specific changes in bone. The relationship between the phenotype and serum serotonin is not well documented. To evaluate bone, serotonin, and bone turnover markers (BTM) in Lrp5‐HBM patients, we studied 19 Lrp5‐HBM patients (T253I) and 19 age‐ and sex‐matched controls. DXA and HR‐pQCT were used to assess BMD and bone structure. Serum serotonin, sclerostin, dickkopf‐related protein 1 (DKK1), and BTM were evaluated. Z‐scores for the forearm, total hip, lumbar spine, forearm, and whole body were significantly increased (mean ± SD) between 4.94 ± 1.45 and 7.52 ± 1.99 in cases versus ?0.19 ± 1.19 to 0.58 ± 0.84 in controls. Tibial and radial cortical areas, thicknesses, and BMD were significantly higher in cases. In cases, BMD at the lumbar spine and forearm and cortical thickness were positively associated and trabecular area negatively associated with age (r = 0.49, 0.57, 0.74, and ?0.61, respectively, p < .05). Serotonin was lowest in cases (69.5 [29.9–110.4] ng/mL versus 119.4 [62.3–231.0] ng/mL, p < .001) and inversely associated with tibial cortical density (r = ?0.49, p < .05) and directly with osteocalcin (OC), bone‐specific alkaline phosphatase (B‐ALP), and procollagen type 1 amino‐terminal propeptide (PINP) (r = 0.52–0.65, p < .05) in controls only. OC and S‐CTX were lower and sclerostin higher in cases, whereas B‐ALP, PINP, tartrate‐resistant acid phosphatase (TRAP), and dickkopf‐related protein 1 (DKK1) were similar in cases and controls. In conclusion, increased bone mass in Lrp5‐HBM patients seems to be caused primarily by changes in trabecular and cortical bone mass and structure. The phenotype appeared to progress with age, but BTM did not suggest increased bone formation. © 2011 American Society for Bone and Mineral Research     

Serum 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density in men: the Rancho Bernardo study

Introduction This study examined the distribution and determinants of serum 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) and their associations with bone mineral density (BMD) at the hip and spine in 414 older men (mean age 74 years) living in southern California.Methods At a clinic visit (1997–2000), demographic and lifestyle information, fracture history, and medication use were recorded; venous blood for serum 25OHD and PTH was obtained; and BMD was measured at the hip and spine.Results Only one man had vitamin D deficiency (25OHD <20 nmol/l), but 15.5% of the men had high parathyroid levels (PTH ≥65 pg/ml). The mean 25OHD and PTH levels were 109.0 nmol/l and 50.3 pg/ml, respectively. Overall, 21.5% used calcium and 9.7% used vitamin D supplements. Serum 25OHD decreased with age and was lowest in the winter; levels were higher in supplement users (vitamin D and/or calcium; p<0.01). Serum PTH did not vary by age or season, and it was lower in supplement users (p<0.01). After excluding 12 men who were outliers for serum 25OHD and PTH, there was no significant correlation between serum 25OHD and PTH (r=−0.05, p=0.3). In multiple adjusted models, serum 25OHD was positively associated with BMD at the hip (p=0.01) and spine (p=0.001). Serum PTH was moderately and inversely associated with BMD at the hip (p=0.04) but not at the spine (p=0.77).Conclusion We conclude that serum 25OHD is associated with bone health in older, community-dwelling men.     

Association of Trabecular Bone Score (TBS) With Incident Clinical and Radiographic Vertebral Fractures Adjusted for Lumbar Spine BMD in Older Men: A Prospective Cohort Study

The association of trabecular bone score (TBS) with incident clinical and radiographic vertebral fractures in older men is uncertain. TBS was estimated from baseline spine dual‐energy X‐ray absorptiometry (DXA) scans for 5831 older men (mean age 73.7 years) enrolled in the Osteoporotic Fractures in Men (MrOS) study. Cox proportional hazard models were used to determine the association of TBS (per 1 SD decrease) with incident clinical vertebral fractures. Logistic regression was used to determine the association between TBS (per 1 SD decrease) and incident radiographic vertebral fracture among the subset of 4309 men with baseline and follow‐up lateral spine radiographs (mean 4.6 years later). We also examined whether any associations varied by body mass index (BMI) category. TBS was associated with a 1.41‐fold (95% confidence interval [CI] 1.23 to 1.63) higher aged‐adjusted odds of incident radiographic fracture, and this relationship did not vary by BMI (p value = 0.22 for interaction term). This association was no longer significant with further adjustment for lumbar spine bone mineral density (BMD; odds ratio [OR] = 1.11, 95% CI 0.94 to 1.30). In contrast, the age‐adjusted association of TBS with incident clinical vertebral fracture was stronger in men with lower BMI (≤ median value of 26.8 kg/m²; hazard ratio [HR] = 2.28, 95% CI 1.82 to 2.87) than in men with higher BMI (> median; HR = 1.60, 95% CI 1.31 to 1.94; p value = 0.0002 for interaction term). With further adjustment for lumbar spine BMD, the association of TBS with incident clinical vertebral fracture was substantially attenuated in both groups (HR = 1.30 [95% CI 0.99 to 1.72] among men with lower BMI and 1.11 [95% CI 0.87 to 1.41] among men with higher BMI). In conclusion, TBS is not associated with incident clinical or radiographic vertebral fracture after consideration of age and lumbar spine BMD, with the possible exception of incident clinical vertebral fracture among men with lower BMI. © 2017 American Society for Bone and Mineral Research.     

Sclerostin Regulation,Microarchitecture, and Advanced Glycation End-Products in the Bone of Elderly Women With Type 2 Diabetes

Increased circulating sclerostin and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk in type 2 diabetes (T2D). Whether the expression of the sclerostin-encoding SOST gene is altered in T2D, and whether it is associated with AGEs accumulation or regulation of other bone formation-related genes is unknown. We hypothesized that AGEs accumulate and SOST gene expression is upregulated in bones from subjects with T2D, leading to downregulation of bone forming genes (RUNX2 and osteocalcin) and impaired bone microarchitecture and strength. We obtained bone tissue from femoral heads of 19 T2D postmenopausal women (mean glycated hemoglobin [HbA1c] 6.5%) and 73 age- and BMI-comparable nondiabetic women undergoing hip replacement surgery. Despite similar bone mineral density (BMD) and biomechanical properties, we found a significantly higher SOST (p = .006) and a parallel lower RUNX2 (p = .025) expression in T2D compared with non-diabetic subjects. Osteocalcin gene expression did not differ between T2D and non-diabetic subjects, as well as circulating osteocalcin and sclerostin levels. We found a 1.5-fold increase in total bone AGEs content in T2D compared with non-diabetic women (364.8 ± 78.2 versus 209.9 ± 34.4 μg quinine/g collagen, respectively; p < .001). AGEs bone content correlated with worse bone microarchitecture, including lower volumetric BMD (r = −0.633; p = .02), BV/TV (r = −0.59; p = .033) and increased trabecular separation/spacing (r = 0.624; p = .023). In conclusion, our data show that even in patients with good glycemic control, T2D affects the expression of genes controlling bone formation (SOST and RUNX2). We also found that accumulation of AGEs is associated with impaired bone microarchitecture. We provide novel insights that may help understand the mechanisms underlying bone fragility in T2D. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Van Buchem disease: Clinical,biochemical, and densitometric features of patients and disease carriers

Van Buchem disease (VBD) is a rare bone sclerosing dysplasia caused by the lack of a regulatory element of the SOST gene, which encodes for sclerostin, an osteocyte‐derived negative regulator of bone formation. We studied the demographic, clinical, biochemical, and densitometric features of 15 patients with VBD (12 adults and 3 children) and 28 related carriers of the gene mutation. The most common clinical findings in patients were facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%. The clinical course of the disease appeared to stabilize in adulthood, with the majority of patients reporting no progression of symptoms or development of complications with time. Carriers of the disease had none of the clinical features or complications of the disease. Sclerostin could be detected in the serum in all but 1 VBD patients (mean 8.0 pg/mL; 95% confidence interval [CI], 4.9–11.0 pg/mL), and were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5–32.9 pg/mL; p < 0.001) and healthy controls (mean 40.0 pg/mL; 95% CI, 34.5–41.0 pg/mL; p < 0.). Serum procollagen type 1 amino‐terminal propeptide (P1NP) levels were also significantly higher in adult patients (mean 96.0; 95% CI, 54.6–137.4 ng/mL versus mean 47.8; 95% CI, 39.4–56.2 ng/mL, p = 0.003 in carriers and mean 37.8; 95% CI, 34.5–41.0 ng/mL, p = 0.028 in healthy controls) and declined with age. Bone mineral density (BMD) was markedly increased in all patients (mean Z‐score 8.7 ± 2.1 and 9.5 ± 1.9 at the femoral neck and spine, respectively); BMD of carriers was significantly lower than that of patients but varied widely (mean Z‐scores 0.9 ± 1.0 and 1.3 ± 1.5 at the femoral neck and spine, respectively). Serum sclerostin levels were inversely correlated with serum P1NP levels (r = –0.39, p = 0.018) and BMD values (femoral neck r = –0.69, p < 0.001; lumbar spine r = –0.78, p < 0.001). Our results show that there is a gene‐dose effect of the VBD deletion on circulating sclerostin and provide further in vivo evidence of the role of sclerostin in bone formation in humans. The small amounts of sclerostin produced by patients with VBD may explain their milder phenotype compared to that of patients with sclerosteosis, in whom serum sclerostin is undetectable. © 2013 American Society for Bone and Mineral Research.