Shin Takaoka

The Calcium-sensing Receptor (CaR) is involved in strontium ranelate-induced osteoblast differentiation and mineralization.

Strontium ranelate is known to reduce fracture risk in osteoporotic patients by stimulating bone formation and suppressing bone resorption. However, the mechanism by which strontium exerts this beneficial effect on bone is unclear. We examined whether or not the calcium-sensing receptor (CaR), which is activated by divalent cations including Sr (2+), is involved in this mechanism. Both strontium ranelate and strontium chloride dose-dependently stimulated phosphorylation of extracellular signal-regulated kinase (ERK) in Human Embryonic Kidney 293 cells transiently transfected with the human CaR. Strontium ranelate also dose- and time-dependently stimulated phosphorylation of ERK in mouse osteoblastic MC3T3-E1 cells expressing the CaR endogenously. Strontium ranelate increased mRNA expression of osteocalcin and bone morphogenetic protein-2 in MC3T3-E1 cells as well as mineralization and proliferation of the cells. Pretreatments of NPS2390, a CaR inhibitor, almost totally antagonized strontium ranelate-induced mineralization and proliferation of MC3T3-E1 cells. These findings indicate that strontium ranelate induces not only osteoblast proliferation but also its differentiation and mineralization by activating the CaR, and confirm that the therapeutic efficacy of strontium ranelate for osteoporosis may be partly mediated by the CaR.

Relationships between undercarboxylated osteocalcin and vitamin K intakes, bone turnover, and bone mineral density in healthy women

BACKGROUND & AIMS Low vitamin K intakes and high levels of undercarboxylated osteocalcin (ucOC) are risk factors for hip fractures. However, the relationship between ucOC and vitamin K intakes, bone mineral density (BMD) and bone biochemical markers is not clarified. METHODS We enrolled 221 healthy women, and examined BMD, urinary type-I collagen cross-linked-N-telopeptide (uNTX), and nutrient intakes. BMD was measured at the lumbar spine and femoral neck. RESULTS Vitamin K intakes were significantly and negatively correlated with ucOC after adjustment for age, height, and body weight (r=-0.305, p<0.0001). ucOC was negatively associated with lumbar BMD (r=-0.147, p<0.05), but not femoral neck BMD (r=-0.099, p=0.095) after adjustment for age, height, and body weight. In multiple regression analysis, even after adjustment for age, height, body weight, and vitamin K intake, a significant and positive correlation remained between ucOC and urinary NTX (r=0.493, p<0.0001). Moreover, in postmenopausal women, ucOC levels were positively correlated with urinary NTX, but not BMD. CONCLUSION Dietary vitamin K intakes influence serum levels of ucOC in healthy women. Furthermore, ucOC may be linked to bone biochemical markers.

Serum calcium is positively correlated with fasting plasma glucose and insulin resistance, independent of parathyroid hormone, in male patients with type 2 diabetes mellitus

Patients with primary hyperparathyroidism have impaired glucose tolerance more often than do controls, and parathyroid resection sometimes improves this derangement. However, it is unclear whether serum calcium (Ca) or parathyroid hormone (PTH) is more strongly related to impaired glucose metabolism in subjects without primary hyperparathyroidism. In this cross-sectional study, we examined patients with type 2 diabetes mellitus (DM) (271 men and 209 women) and analyzed the relationships between serum concentrations of Ca or intact PTH and DM-related variables. Simple regression analyses showed that the level of serum Ca was significantly and positively correlated with the levels of fasting plasma glucose, immunoreactive insulin, and homeostasis model assessment insulin resistance in men (P < .05), but not in women. In contrast, intact PTH was not significantly correlated with DM-related parameters in either sex. Multiple regression analyses showed that the significant and positive correlations between serum Ca vs fasting plasma glucose and homeostasis model assessment insulin resistance in men still remained after adjustment for intact PTH as well as age, body weight, height, creatinine, albumin, phosphate, bone metabolic markers, and estradiol (P < .05). Serum Ca level is positively associated with impaired glucose metabolism, independent of PTH or bone metabolism, in men with type 2 DM.