Diabetes and Deficits in Cortical Bone Density,Microarchitecture, and Bone Size: Framingham HR‐pQCT Study

Older adults with type 2 diabetes (T2D) tend to have normal or greater areal bone mineral density (aBMD), as measured by DXA, than those who do not have diabetes (non‐T2D). Yet risk of fracture is higher in T2D, including 40% to 50% increased hip fracture risk. We used HR‐pQCT to investigate structural mechanisms underlying skeletal fragility in T2D. We compared cortical and trabecular bone microarchitecture, density, bone area, and strength in T2D and non‐T2D. In secondary analyses we evaluated whether associations between T2D and bone measures differed according to prior fracture, sex, and obesity. Participants included 1069 members of the Framingham Study, who attended examinations in 2005 to 2008 and underwent HR‐pQCT scanning in 2012 to 2015. Mean age was 64 ± 8 years (range, 40 to 87 years), and 12% (n = 129) had T2D. After adjustment for age, sex, weight, and height, T2D had lower cortical volumetric BMD (vBMD) (p < 0.01), higher cortical porosity (p = 0.02), and smaller cross‐sectional area (p = 0.04) at the tibia, but not radius. Trabecular indices were similar or more favorable in T2D than non‐T2D. Associations between T2D and bone measures did not differ according to sex or obesity status (all interaction p > 0.05); however, associations did differ in those with a prior fracture and those with no history of fracture. Specifically, cortical vBMD at the tibia and cortical thickness at the radius were lower in T2D than non‐T2D, but only among those individuals with a prior fracture. Cortical porosity at the radius was higher in T2D than non‐T2D, but only among those who did not have a prior fracture. Findings from this large, community‐based study of older adults suggest that modest deterioration in cortical bone and reductions in bone area may characterize diabetic bone disease in older adults. Evaluation of these deficits as predictors of fracture in T2D is needed to develop prevention strategies in this rapidly increasing population of older adults. © 2017 American Society for Bone and Mineral Research.     

Bone Density Loss Is Associated With Blood Cell Counts

Hematopoiesis depends on a supportive microenvironment. Preclinical studies in mice have demonstrated that osteoblasts influence the development of blood cells, particularly erythrocytes, B lymphocytes, and neutrophils. However, it is unknown whether osteoblast numbers or function impact blood cell counts in humans. We tested the hypothesis that men with low BMD or greater BMD loss have decreased circulating erythrocytes and lymphocytes and increased myeloid cells. We performed a cross‐sectional analysis and prospective analysis in the Osteoporotic Fractures in Men (MrOS) study, a multisite longitudinal cohort study. A total of 2571 community‐dwelling men (≥65 years) who were able to walk without assistance, did not have a hip replacement or fracture, and had complete blood counts (CBCs) at the third study visit were analyzed. Multivariable (MV)‐adjusted logistic regression estimated odds of white blood cell (WBC) subtypes (highest and lowest quintile versus middle), and anemia (clinically defined) associated with BMD by DXA scan (at visit 3), annualized percent BMD change (baseline to visit 3), and high BMD loss (>0.5%/year, from baseline to visit 3) at the femoral neck (FN) and total hip (TH). MV‐adjusted models included age, BMI, cancer history, smoking status, alcohol intake, corticosteroid use, self‐reported health, thiazide use, and physical activity. At visit 3 greater TH BMD loss (per 1 SD) was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Annualized BMD loss of >0.5% was associated with increased odds of anemia, high neutrophils, and low lymphocytes. Similar results were observed for FN BMD regarding anemia and lymphocytes. We conclude that community‐dwelling older men with declining hip BMD over about 7 years had increased risks of anemia, lower lymphocyte count, and higher neutrophil count, consistent with preclinical studies. Bone health and hematopoiesis may have greater interdependency than previously recognized. © 2016 American Society for Bone and Mineral Research.     

Systematic review of major osteoporotic fracture to hip fracture incidence rate ratios worldwide: implications for Fracture Risk Assessment Tool (FRAX)-derived estimates

The Fracture Risk Assessment Tool (FRAX) is the most widely used tool for fracture prediction. It provides 10-year probabilities for hip and major osteoporotic fracture (MOF). It uses country-specific hip fracture incidence and life expectancy data, and for most countries, MOF/hip fracture incidence rate ratios (IRRs) from Malmo Sweden. However, the risk of MOF varies by age, sex, and geography. The objective is to compare the MOF/hip IRRs across countries, by sex and age. This systematic review targeted observational studies of MOF and hip fractures in individuals >50 years (PROSPERO 2019 CRD42019129259). One reviewer screened potential articles. Two reviewers completed duplicate and independent data abstraction, and assessed study quality based on population representativeness, study design and duration, definition of ethnicity, and fracture characteristics. We calculated the MOF/hip IRRs (95% confidence interval) and Z-values to compare IRRs in various countries to those for Sweden. We included 27 studies, of fair to good quality in the majority, from Europe (15), US and Canada (7), Asia (3), and Australia (2). The IRRs were twofold to 10-fold higher in younger compared to older age categories, and in women compared to men, with few exceptions. Within Europe, and using Sweden as a reference, MOF/Hip IRRs in women 50–54 years from Finland, Italy, Netherlands, Denmark, and UK were significantly lower by 38% to 60%. Findings were similar in men. At older ages, MOF/Hip IRRs were consistently lower in women from European countries compared to Sweden, by 10%–40% and 11%–51%, at 75–79 years and 85–89 years, respectively. Findings were heterogenous in men and in non-European countries. In conclusion, the MOF/hip fracture IRR may vary between countries. The variability at older ages may affect FRAX prediction when country-specific fracture IRRs are not used. Further research is needed to elucidate the implication of our findings to FRAX-derived MOF estimates in various countries. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Prioritization of Genes Relevant to Bone Fragility Through the Unbiased Integration of Aging Mouse Bone Transcriptomics and Human GWAS Analyses

Identifying new genetic determinants of bone mineral density (BMD) and fracture promises to yield improved diagnostics and therapies for bone fragility. However, prioritizing candidate genes from genome-wide screens can be challenging. To overcome this challenge, we prioritized mouse genes that are differentially expressed in aging mouse bone based on whether their human homolog is associated with human BMD and/or fracture. Unbiased RNA-seq analysis of young and old male C57BL/6 mouse cortical bone identified 1499, 1685, and 5525 differentially expressed genes (DEGs) in 1, 2, and 2.5-year-old bone, relative to 2-month-old bone, respectively. Gene-based scores for heel ultrasound bone mineral density (eBMD) and fracture were estimated using published genome-wide association studies (GWAS) results of these traits in the UK Biobank. Enrichment analysis showed that mouse bone DEG sets for all three age groups, relative to young bone, are significantly enriched for eBMD, but only the oldest two DEG sets are enriched for fracture. Using gene-based scores, this approach prioritizes among thousands of DEGs by a factor of 5- to 100-fold, yielding 10 and 21 genes significantly associated with fracture in the two oldest groups of mouse DEGs. Though these genes were not the most differentially expressed, they included Sost, Lrp5, and others with well-established functions in bone. Several others have, as yet, unknown roles in the skeleton. Therefore, this study accelerates identification of new genetic determinants of bone fragility by prioritizing a clinically relevant and experimentally tractable number of candidate genes for functional analysis. Finally, we provide a website ( www.mouse2human.org ) to enable other researchers to easily apply our strategy. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Energy Excess,Glucose Utilization,and Skeletal Remodeling: New Insights

Skeletal complications have recently been recognized as another of the several comorbidities associated with diabetes. Clinical studies suggest that disordered glucose and lipid metabolism have a profound effect on bone. Diabetes‐related changes in skeletal homeostasis result in a significant increased risk of fractures, although the pathophysiology may differ from postmenopausal osteoporosis. Efforts to understand the underlying mechanisms of diabetic bone disease have focused on the direct interaction of adipose tissue with skeletal remodeling and the potential influence of glucose utilization and energy uptake on these processes. One aspect that has emerged recently is the major role of the central nervous system in whole‐body metabolism, bone turnover, adipose tissue remodeling, and beta cell secretion of insulin. Importantly, the skeleton contributes to the metabolic balance inherent in physiologic states. New animal models have provided the insights necessary to begin to dissect the effects of obesity and insulin resistance on the acquisition and maintenance of bone mass. In this Perspective, we focus on potential mechanisms that underlie the complex interactions between adipose tissue and skeletal turnover by focusing on the clinical evidence and on preclinical studies indicating that glucose intolerance may have a significant impact on the skeleton. In addition, we raise fundamental questions that need to be addressed in future studies to resolve the conundrum associated with glucose intolerance, obesity, and osteoporosis. © 2015 American Society for Bone and Mineral Research.     

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.     

Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Antiresorptive Drugs: Proportion of Treatment Effect Explained

Few analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction seeking to estimate the proportion of treatment effect explained (PTE) by BTMs. Pooling such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from up to 62,000 participants enrolled in 12 bisphosphonate (BP) and four selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and one bone resorption marker (C-terminal telopeptide of type I collagen [CTX]) and incident fracture outcome data, we estimated the PTE using two different models. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 5 years of follow-up. For vertebral fracture, the results showed that changes in all three BTMs at 6 months explained a large proportion of the treatment effect of ARs (57 to >100%), but not for and non-vertebral or hip fracture. We conclude that short-term AR treatment-related changes in bone ALP, PINP, and CTX account for a large proportion of the treatment effect for vertebral fracture. Change in BTMs is a useful surrogate marker to study the anti-fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Analysis of the Associations Between the Human Fecal Microbiome and Bone Density,Structure, and Strength: The Osteoporotic Fractures in Men (MrOS) Cohort

In preclinical models, the composition and function of the gut microbiota have been linked to bone growth and homeostasis, but there are few available data from studies of human populations. In a hypothesis-generating experiment in a large cohort of community-dwelling older men (n = 831; age range, 78–98 years), we explored the associations between fecal microbial profiles and bone density, microarchitecture, and strength measured with total hip dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HRpQCT) (distal radius, distal and diaphyseal tibia). Fecal samples were collected and the 16S rRNA gene V4 hypervariable region sequenced. Sequences were bioinformatically processed through the DADA2 pipeline and then taxonomically assigned using SILVA. Generalized linear models as implemented in microbiome multivariable association with linear models (MaAsLin 2) were used to test for associations between skeletal measures and specific microbial genera. The abundances of four bacterial genera were weakly associated with bone density, structure, or strength (false discovery rate [FDR] ≤ 0.05), and the measured directions of associations of genera were generally consistent across multiple bone measures, supporting a role for microbiota on skeletal homeostasis. However, the associated effect sizes were small (log2 fold change < ±0.35), limiting power to confidently identify these associations even with high resolution skeletal imaging phenotypes, and we assessed the resulting implications for the design of future cohort-based studies. As in analogous examples from genomewide association studies, we find that larger cohort sizes will likely be needed to confidently identify associations between the fecal microbiota and skeletal health relying on 16S sequencing. Our findings bolster the view that the gut microbiome is associated with clinically important measures of bone health, while also indicating the challenges in the design of cohort-based microbiome studies. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Saturated and Unsaturated Bone Marrow Lipids Have Distinct Effects on Bone Density and Fracture Risk in Older Adults

Greater bone marrow adiposity (BMAT) is associated with lower bone mineral density (BMD) and vertebral fractures; less is known about BMAT composition and bone. We studied BMAT composition and bone outcomes in 465 participants from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study. BMAT saturation and unsaturation, measured with magnetic resonance spectroscopy, were defined as the ratio of saturated (1.3 ppm peak) or unsaturated (5.3 ppm peak) lipid to total marrow contents, respectively. At baseline and follow-up visits, spine and hip BMD were assessed with quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA) and vertebral fractures were identified with DXA. Incident clinical fractures were identified through medical records for up to 8.8 years of follow-up. Associations between BMAT composition and BMD, bone loss, and fractures were evaluated in adjusted regression models. At baseline, mean ± standard deviation (SD) participant age was 81.7 ± 4.3 years, mean BMAT unsaturation was 3.5% ± 1.0%, and mean saturation was 46.3% ± 7.2% in the full cohort (47.7% women). Each SD increase in BMAT saturation was associated with lower trabecular BMD: −23.6% (spine) and −13.0% (total hip) (all p < 0.0001). Conversely, BMAT unsaturation (per SD increase) was associated with higher trabecular BMD: +17.5% (spine) and +11.5% (total hip) (all p < 0.001). BMAT saturation (per SD increase) was associated with greater risk for prevalent (odds ratio [OR] 1.46; 95% confidence interval [CI], 1.11–1.92) and incident (OR 1.55; 95% CI, 1.03–2.34) vertebral fracture. BMAT unsaturation (per SD increase) was associated with lower risk for incident vertebral fracture (OR 0.58; 95% CI, 0.38–0.89). In gender stratified analyses, BMAT saturation and unsaturation had opposite associations with incident clinical fracture among men. In general, saturated marrow lipids were associated with worse skeletal outcomes, whereas unsaturated lipids were associated with better outcomes. We recommend that future studies of marrow fat and skeletal health report measurements of saturated and unsaturated marrow lipids, rather than total marrow fat content alone. © 2022 American Society for Bone and Mineral Research (ASBMR).     

Long Bone Fractures in Fibrous Dysplasia/McCune-Albright Syndrome: Prevalence,Natural History,and Risk Factors

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder arising along a broad spectrum. Long-bone fractures are a common, painful, and potentially disabling complication. However, fracture prevalence and risk factors have not been well-established, making it difficult to predict which patients are at risk for a severe course. Clinical and imaging data were reviewed from two large, well-phenotyped cohorts (National Institutes of Health [NIH] in the United States and the Leiden University Medical Center [LUMC] in the Netherlands) to identify long-bone fractures at FD sites. Skeletal burden score was quantified using bone scintigraphy. Multiple linear regressions were performed to identify clinical associations with fractures. A total of 419 patients were included (186 NIH, 233 LUMC); 194 (46%) had MAS endocrinopathies. Median age at last follow-up was 30.2 years (range 3.2–84.6, interquartile range [IQR] 25.5), and median skeletal burden score was 16.6 (range 0–75, IQR 33). A total of 48 (59%) patients suffered one or more lifetime fracture (median 1, range 0–70, IQR 4). Median age at first fracture was 8 years (range 1–76, IQR 10). Fracture rates peaked between 6 and 10 years of age and decreased thereafter. Lifetime fracture rate was associated with skeletal burden score (β = 0.40, p < 0.01) and MAS hyperthyroidism (β = 0.22, p = 0.01). Younger age at first fracture was associated with skeletal burden score (β = −0.26, p = 0.01) and male sex (β = −0.23, p = 0.01). Both skeletal burden score >25 and age at first fracture ≤7 years were associated with a higher total number of lifetime fractures (median 4, range 1–70, IQR 5 versus median 1, range 1–13, IQR 1) (p < 0.01). In conclusion, higher skeletal burden score and MAS hyperthyroidism are associated with long-bone fractures in FD/MAS. Both skeletal burden score ≥25 and age at first fracture ≤7 years are associated with a higher lifetime long-bone fracture risk and may predict a more severe clinical course. These results may allow clinicians to identify FD/MAS patients at risk for severe disease who may be candidates for early therapeutic interventions. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.     

Low‐Level Cadmium Exposure Is Associated With Decreased Bone Mineral Density and Increased Risk of Incident Fractures in Elderly Men: The MrOS Sweden Study

One risk factor for osteoporosis that has attracted increasing attention in recent years is exposure to cadmium. The aim of this study was to examine the associations between low‐level cadmium exposure, from diet and smoking, and bone mineral density (BMD) and incident fractures in elderly men. The study population consisted of 936 men from the Swedish cohort of the Osteoporotic Fractures in Men (MrOS) study, aged 70 to 81 years at inclusion (years 2002 to 2004), with reliable data on cadmium in urine (U‐Cd) analyzed using inductively coupled plasma mass spectrometry in baseline samples. The participants also answered a questionnaire on lifestyle factors and medical history. BMD was measured at baseline using dual‐energy X‐ray absorptiometry (DXA) in the total body, hip, and lumbar spine. During the follow‐up period (until 2013), all new fractures were registered by date and type. Associations between BMD and U‐Cd were assessed using multiple linear regression, and associations between incident fractures and baseline U‐Cd were analyzed using Cox regression. In both cases, a number of potential confounders and other risk factors (eg, age, smoking, body mass index [BMI], and physical activity) were included in the models. We found significant negative associations between U‐Cd and BMD, with lower BMD (4% to 8%) for all sites in the fourth quartile of U‐Cd, using the first quartile as the reference. In addition, we found positive associations between U‐Cd and incident fractures, especially nonvertebral osteoporosis fractures in the fourth quartile of U‐Cd, with hazard ratios of 1.8 to 3.3 in the various models. U‐Cd as a continuous variable was significantly associated with nonvertebral osteoporosis fractures (adjusted hazard ratio 1.3 to 1.4 per μg Cd/g creatinine), also in never‐smokers, but not with the other fracture groups (all fractures, hip fractures, vertebral fractures, and other fractures). Our results indicate that even relatively low cadmium exposure through diet and smoking increases the risk of low BMD and osteoporosis‐related fractures in elderly men. © 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).     

Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density

Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 μg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a −0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (−4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Propranolol Promotes Bone Formation and Limits Resorption Through Novel Mechanisms During Anabolic Parathyroid Hormone Treatment in Female C57BL/6J Mice

Although the nonselective β-blocker, propranolol, improves bone density with parathyroid hormone (PTH) treatment in mice, the mechanism of this effect is unclear. To address this, we used a combination of in vitro and in vivo approaches to address how propranolol influences bone remodeling in the context of PTH treatment. In female C57BL/6J mice, intermittent PTH and propranolol administration had complementary effects in the trabecular bone of the distal femur and fifth lumbar vertebra (L₅), with combination treatment achieving microarchitectural parameters beyond that of PTH alone. Combined treatment improved the serum bone formation marker, procollagen type 1 N propeptide (P1NP), but did not impact other histomorphometric parameters relating to osteoblast function at the L₅. In vitro, propranolol amplified the acute, PTH-induced, intracellular calcium signal in osteoblast-like cells. The most striking finding, however, was suppression of PTH-induced bone resorption. Despite this, PTH-induced receptor activator of nuclear factor κ-B ligand (RANKL) mRNA and protein levels were unaltered by propranolol, which led us to hypothesize that propranolol could act directly on osteoclasts. Using in situ methods, we found Adrb2 expression in osteoclasts in vivo, suggesting β-blockers may directly impact osteoclasts. Consistent with this, we found propranolol directly suppresses osteoclast differentiation in vitro. Taken together, this work suggests a strong anti-osteoclastic effect of nonselective β-blockers in vivo, indicating that combining propranolol with PTH could be beneficial to patients with extremely low bone density. © 2022 American Society for Bone and Mineral Research (ASBMR).