Skeletal loading in animals

A number of in vivo skeletal loading models have been developed to test specific hypotheses addressing the key mechanical and biochemical signals involved in bone’s adaptive response to loading. Exercise protocols, osteotomy procedures, loading of surgically implanted pins, and force application through the soft tissues are common approaches to alter the mechanical environment of a bone. Although each animal overload model has a number of assets and limitations, models employing extrinsic forces allow greater control of the mechanical environment. Sham controls, for both surgical intervention (when performed) and loading, are required to unequivocally demonstrate that responses to loading are mechanically adaptive. Collectively, extrinsic loading models have fostered a greater understanding of the mechanical signals important for stimulating bone cells, and highlighted the roles of key signaling molecules in the adaptive response

Parathyroid Hormone Enhances Mechanically Induced Bone Formation, Possibly Involving L-Type Voltage- Sensitive Calcium Channels

PTH and mechanical loading might act synergistically on bone formation. We tested the in vivo effect of the L-type voltage-sensitive calcium channel (VSCC) blocker, verapamil, on bone formation induced by human PTH-(1–34) (PTH) injection with or without mechanical loading. Adult rats were divided into eight groups: vehicle, verapamil, PTH, or verapamil plus PTH with or without mechanical loading. Verapamil (100 mg/kg) was given orally 90 min before loading. PTH (80 μg/kg) was injected sc 30 min before loading. Loading applied to tibia and ulna for 3 min significantly increased the bone formation rate on both the endocortical surface of tibia and the periosteal surface of ulna (P < 0.0001). Treatment with PTH enhanced load-induced bone formation by 53% and 76% (P < 0.001) on the endocortical and periosteal surfaces, respectively. Treatment with verapamil suppressed load-induced bone formation rate by 77% and 59% (P < 0.01). Furthermore, verapamil suppressed bone formation in rats subjected to PTH plus loading by 74% and 68% (P < 0.0001) at the tibia and ulna, respectively. In the groups without loading, neither verapamil nor PTH treatment significantly changed any bone formation parameter. This study indicates that L-type VSCCs mediate load-induced bone formation in vivo. Furthermore, PTH enhances load-induced bone adaptation through involvement of L-type VSCCs

Heritability of Lumbar Trabecular Bone Mechanical Properties in Baboons

Genetic effects on mechanical properties have been demonstrated in rodents, but not confirmed in primates. Our aim was to quantify the proportion of variation in vertebral trabecular bone mechanical properties that is due to the effects of genes. L3 vertebrae were collected from 110 females and 46 male baboons (6–32 years old) from a single extended pedigree. Cranio-caudally oriented trabecular bone cores were scanned with microCT then tested in monotonic compression to determine apparent ultimate stress, modulus, and toughness. Age and sex effects and heritability (h2) were assessed using maximum likelihood-based variance components methods. Additive effects of genes on residual trait variance were significant for ultimate stress (h2 = 0.58), toughness (h2 = 0.64), and BV/TV (h2 = 0.55). When BV/TV was accounted for, the residual variance in ultimate stress accounted for by the additive effects of genes was no longer significant. Toughness, however, showed evidence of a non-BV/TV-related genetic effect. Overall, maximum stress and modulus show strong genetic effects that are nearly entirely due to bone volume. Toughness shows strong genetic effects related to bone volume and shows additional genetic effects (accounting for 10% of the total trait variance) that are independent of bone volume. These results support continued use of bone volume as a focal trait to identify genes related to skeletal fragility, but also show that other focal traits related to toughness and variation in the organic component of bone matrix will enhance our ability to find additional genes that are particularly relevant to fatigue-related fractures

Safety and efficacy of subcutaneous tanezumab in patients with knee or hip osteoarthritis

Background/objective: The objective of this study was to investigate the safety and efficacy of subcutaneous (SC) and intravenous (IV) tanezumab administration in osteoarthritis (OA) patients. Materials and methods: Study 1027 (NCT01089725), a placebo-controlled trial, evaluated the efficacy of SC tanezumab (ie, 2.5, 5, and 10 mg) and the therapeutic equivalence of 10 mg tanezumab given subcutaneously versus intravenously every 8 weeks in the symptomatic treatment of OA. Coprimary endpoints were: change from baseline in Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) Pain and Physical Function indices, and Patient\u27s Global Assessment (PGA) of OA. Study 1043 (NCT00994890) was a long-term, noncontrolled safety study of tanezumab (ie, 2.5, 5, and 10 mg) subcutaneously administered every 8 weeks. Both studies were discontinued prematurely due to a US Food and Drug Administration partial clinical hold. Results: Due to the clinical hold, Study 1027 was underpowered, and no statistical analyses were performed. Mean (standard error [SE]) change from baseline to week 8 in WOMAC Pain in tanezumab groups ranged from -3.59 (0.26) to -3.89 (0.32), versus -2.74 (0.25) with placebo. Mean (SE) change from baseline to week 8 in WOMAC Physical Function ranged from -3.13 (0.25) to -3.51 (0.28) with tanezumab and was -2.26 (0.24) with placebo. PGA mean (SE) change from baseline to week 8 ranged from -0.90 (0.11) to -1.08 (0.12) with tanezumab and was -0.78 (0.10) with placebo. Similar effectiveness was associated with tanezumab in Study 1043. Few patients in either study (1.4%-5.2%) discontinued due to adverse events. Five patients required total joint replacements in Study 1027 (placebo, n=2 [2.8%]; tanezumab 2.5 mg, n=3 [4.1%]) and 34 patients in Study 1043 (tanezumab 2.5 mg, n=11 [4.8%]; tanezumab 5 mg, n=8 [3.6%]; tanezumab 10 mg, n=15 [6.6%]). Conclusion: Preliminary results show similar efficacy and safety for both SC and IV administration of tanezumab based on the direct comparisons reported here and indirect comparisons with published results, confirming pharmacokinetic/pharmacodynamic modeling predictions

An epigenome-wide association study in whole blood of measures of adiposity among Ghanaians: the RODAM study.

BACKGROUND: Epigenome-wide association studies (EWAS) have identified DNA methylation loci involved in adiposity. However, EWAS on adiposity in sub-Saharan Africans are lacking despite the high burden of adiposity among African populations. We undertook an EWAS for anthropometric indices of adiposity among Ghanaians aiming to identify DNA methylation loci that are significantly associated. METHODS: The Illumina 450k DNA methylation array was used to profile DNA methylation in whole blood samples of 547 Ghanaians from the Research on Obesity and Diabetes among African Migrants (RODAM) study. Differentially methylated positions (DMPs) and differentially methylation regions (DMRs) were identified for BMI and obesity (BMI ≥ 30 kg/m2), as well as for waist circumference (WC) and abdominal obesity (WC ≥ 102 cm in men, ≥88 cm in women). All analyses were adjusted for age, sex, blood cell distribution estimates, technical covariates, recruitment site and population stratification. We also did a replication study of previously reported EWAS loci for anthropometric indices in other populations. RESULTS: We identified 18 DMPs for BMI and 23 for WC. For obesity and abdominal obesity, we identified three and one DMP, respectively. Fourteen DMPs overlapped between BMI and WC. DMP cg00574958 annotated to gene CPT1A was the only DMP associated with all outcomes analysed, attributing to 6.1 and 5.6% of variance in obesity and abdominal obesity, respectively. DMP cg07839457 (NLRC5) and cg20399616 (BCAT1) were significantly associated with BMI, obesity and with WC and had not been reported by previous EWAS on adiposity. CONCLUSIONS: This first EWAS for adiposity in Africans identified three epigenome-wide significant loci (CPT1A, NLRC5 and BCAT1) for both general adiposity and abdominal adiposity. The findings are a first step in understanding the role of DNA methylation in adiposity among sub-Saharan Africans. Studies on other sub-Saharan African populations as well as translational studies are needed to determine the role of these DNA methylation variants in the high burden of adiposity among sub-Saharan Africans