Search

Objective: Bone turnover, which regulates bone mass, may exert metabolic consequences, particularly on markers of glucose metabolism and adiposity. To better understand these relationships, we examined cross‐sectional associations between bone turnover markers (BTMs) and metabolic traits in a population with high bone mass (HBM, BMD Z‐score ≥+3.2). Design: β‐C‐terminal telopeptide of type‐I collagen (β‐CTX), procollagen type‐1 amino‐terminal propeptide (P1NP) and osteocalcin were assessed by electrochemiluminescence immunoassays. Metabolic traits, including lipids and glycolysis‐related metabolites, were measured using nuclear magnetic resonance spectroscopy. Associations of BTMs with metabolic traits were assessed using generalized estimating equation linear regression, accounting for within‐family correlation, adjusting for potential confounders (age, sex, height, weight, menopause, bisphosphonate and oral glucocorticoid use). Results: A total of 198 adults with HBM had complete data, mean [SD] age 61.6 [13.7] years; 77% were female. Of 23 summary metabolic traits, citrate was positively related to all BTMs: adjusted ββ‐CTX = 0.050 (95% CI 0.024, 0.076), P = 1.71 × 10−4, βosteocalcin = 6.54 × 10−4 (1.87 × 10−4, 0.001), P = .006 and βP1NP = 2.40 × 10−4 (6.49 × 10−5, 4.14 × 10−4), P = .007 (β = increase in citrate (mmol/L) per 1 µg/L BTM increase). Inverse relationships of β‐CTX (β = −0.276 [−0.434, −0.118], P = 6.03 × 10−4) and osteocalcin (−0.004 [−0.007, −0.001], P = .020) with triglycerides were also identified. We explored the generalizability of these associations in 3664 perimenopausal women (age 47.9 [4.4] years) from a UK family cohort. We confirmed a positive, albeit lower magnitude, association between β‐CTX and citrate (adjusted βwomen = 0.020 [0.013, 0.026], P = 1.95 × 10−9) and an inverse association of similar magnitude between β‐CTX and triglycerides (β = −0.354 [−0.471, −0.237], P = 3.03 × 10−9). Conclusions: Bone resorption is positively related to circulating citrate and inversely related to triglycerides. Further studies are justified to determine whether plasma citrate or triglyceride concentrations are altered by factors known to modulate bone resorption, such as bisphosphonates. [ABSTRACT FROM AUTHOR]

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA‐binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z‐scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome‐wide and gene‐based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10−16; PGENE = 8 × 10−17). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone–derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)‐dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss‐of‐function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Background: High impact physical activity (PA) is thought to improve skeletal health, but its relation to other health outcomes are unclear. We investigated associations between PA impact magnitude and body mass index (BMI) in older adults.Methods: Data were taken from the Cohort for Skeletal Health in Bristol and Avon (COSHIBA), Hertfordshire Cohort Study, and MRC National Survey of Health and Development. Vertical acceleration peaks from 7-day hip-worn accelerometer recordings were used to classify PA as low (0.5 < g < 1.0g), medium (1 < g < 1.5g), or higher (≥1.5g) impact. Cohort-specific associations of low, medium, and higher impact PA with BMI were examined using linear regressions and estimates combined using random-effects meta-analysis.Results: A total of 1182 participants (mean age = 72.7 years, 68% female) were included. Low, medium, and higher impact PA were inversely related to BMI in initial models. After adjustment for confounders and other impacts, low, but not medium or higher, impacts were inversely related to BMI (-0.31, p < .001: overall combined standard deviation change in BMI per doubling in the number of low impacts). In adjusted analyses of body composition measured by dual-energy X-ray absorptiometry in COSHIBA, low, but not medium or higher, impacts were inversely related to total body fat mass (-0.19, p < .001) and android:gynoid fat mass ratio (-0.16, p = .01), whereas high impact PA was weakly and positively associated with lean mass (0.05, p = .06).Conclusions: Greater exposure to PA producing low magnitude vertical impacts was associated with lower BMI and fat mass at older age. Low impact PA may help reduce obesity risk in older adults. [ABSTRACT FROM AUTHOR]

Background: Individuals who have experienced a stroke, or transient ischemic attack, face a heightened risk of future cardiovascular events. Identification of genetic and molecular risk factors for subsequent cardiovascular outcomes may identify effective therapeutic targets to improve prognosis after an incident stroke., Methods: We performed genome-wide association studies (GWAS) for subsequent major adverse cardiovascular events (MACE) (N cases =51,929, N cntrl =39,980) and subsequent arterial ischemic stroke (AIS) N cases =45,120, N cntrl =46,789) after first incident stroke within the Million Veteran Program and UK Biobank. We then used genetic variants associated with proteins (pQTLs) to determine the effect of 1,463 plasma protein abundances on subsequent MACE using Mendelian randomization (MR)., Results: Two variants were significantly associated with subsequent cardiovascular events: rs76472767 (OR=0.75, 95% CI = 0.64-0.85, p= 3.69×10 -08 ) with subsequent AIS and rs13294166 (OR=1.52, 95% CI = 1.37-1.67, p=3.77×10 -08 ) with subsequent MACE. Using MR, we identified 2 proteins with an effect on subsequent MACE after a stroke: CCL27 (effect OR= 0.77, 95% CI = 0.66-0.88, adj. p=0.05), and TNFRSF14 (effect OR=1.42, 95% CI = 1.24-1.60, adj. p=0.006). These proteins are not associated with incident AIS and are implicated to have a role in inflammation., Conclusions: We found evidence that two proteins with little effect on incident stroke appear to influence subsequent MACE after incident AIS. These associations suggest that inflammation is a contributing factor to subsequent MACE outcomes after incident AIS and highlights potential novel targets.