The regulation of bone remodeling by an adipocyte-derived hormone implies that bone may exert a feedback control of energy homeostasis. To test this hypothesis we looked for genes expressed in osteoblasts, encoding signaling molecules and affecting energy metabolism. We show here that mice lacking the protein tyrosine phosphatase OST-PTP are hypoglycemic and are protected from obesity and glucose intolerance because of an increase in beta-cell proliferation, insulin secretion, and insulin sensitivity. In contrast, mice lacking the osteoblast-secreted molecule osteocalcin display decreased beta-cell proliferation, glucose intolerance, and insulin resistance. Removing one Osteocalcin allele from OST-PTP-deficient mice corrects their metabolic phenotype. Ex vivo, osteocalcin can stimulate CyclinD1 and Insulin expression in beta-cells and Adiponectin, an insulin-sensitizing adipokine, in adipocytes; in vivo osteocalcin can improve glucose tolerance. By revealing that the skeleton exerts an endocrine regulation of sugar homeostasis this study expands the biological importance of this organ and our understanding of energy metabolism.

The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (Nf1(ob)(-/-) mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in Nf1(ob)(-/-) mice, thereby increasing Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in Nf1(ob)(-/-) mice without affecting other organ weight, while a high-protein diet overcame Atf4(-/-) and Rsk2(-/-) mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development.

Many clinical studies have shown that osteoporosis is associated with atherosclerosis and cardiovascular death. Although both high plasma levels of low density lipoprotein cholesterol (LDL-C) and low plasma levels of high density lipoprotein cholesterol (HDL-C) are known to be risk factors for atherosclerosis, it is unclear whether such lipid derangements are also associated with the pathogenesis of osteoporosis. In this study, we evaluated the relationships between plasma levels of total C, LDL-C, HDL-C, or triglyceride (TG) versus bone mineral density (BMD) at the lumbar spine, femoral neck, radius, or total body as well as the presence of vertebral fractures in 214 Japanese postmenopausal women (age range, 47-86 years, mean 62.7). Multiple regression analysis was performed between BMD at each skeletal site versus each lipid level adjusted for age, years after menopause, body mass index (BMI), and %fat. Plasma LDL-C levels were significantly and inversely correlated with the absolute values of both one-third radial (1/3R) and distal radial (UDR) BMD (p<0.01), and tended to be inversely correlated with the absolute values of L-BMD (p=0.051). In contrast, plasma HDL-C levels were significantly and positively correlated with the absolute values of L, 1/3R and UDR BMD (p<0.05). On the other hand, plasma TG levels were significantly lower in women with vertebral fractures than in those without fractures (97.0+/-36.5 vs. 126.4+/-65.8 mg/dl, mean+/-SD, p<0.05). When multivariate logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and each lipid level adjusted for age, years after menopause, BMI, and %fat as independent variables, TG alone was selected as an index affecting the presence of vertebral fractures (odds ratio: 0.51, 95% confidential interval: 0.29-0.89 per SD increase, p<0.05). Our study showed that plasma LDL-C and HDL-C levels were inversely and positively correlated with both R- and L-BMD values, respectively, while low plasma TG levels were associated with the presence of vertebral fractures in postmenopausal women. Thus, plasma lipids might be related to bone mass and bone fragility, and might be the common factor underlying both osteoporosis and atherosclerosis.

Sclerostin, a SOST protein secreted by osteocytes, negatively regulates formation of mineralized bone matrix and bone mass. We report the results of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial of blosozumab, a humanized monoclonal antibody targeted against sclerostin, in postmenopausal women with low bone mineral density (BMD). Postmenopausal women with a lumbar spine T-score -2.0 to -3.5, inclusive, were randomized to subcutaneous blosozumab 180 mg every 4 weeks (Q4W), 180 mg every 2 weeks (Q2W), 270 mg Q2W, or matching placebo for 1 year, with calcium and vitamin D. Serial measurements of spine and hip BMD and biochemical markers of bone turnover were performed. Overall, 120 women were enrolled in the study (mean age 65.8 years, mean lumbar spine T-score -2.8). Blosozumab treatment resulted in statistically significant dose-related increases in spine, femoral neck, and total hip BMD as compared with placebo. In the highest dose group, BMD increases from baseline reached 17.7% at the spine, and 6.2% at the total hip. Biochemical markers of bone formation increased rapidly during blosozumab treatment, and trended toward pretreatment levels by study end. However, bone specific alkaline phosphatase remained higher than placebo at study end in the highest-dose group. CTx, a biochemical marker of bone resorption, decreased early in blosozumab treatment to a concentration less than that of the placebo group by 2 weeks, and remained reduced throughout blosozumab treatment. Mild injection site reactions were reported more frequently with blosozumab than placebo. In conclusion, treatment of postmenopausal women with an antibody targeted against sclerostin resulted in substantial increases in spine and hip BMD. These results support further study of blosozumab as a potential anabolic therapy for osteoporosis.