Exogenous PTH and Endogenous 1,25-Dihydroxyvitamin D Are Complementary in Inducing an Anabolic Effect on Bone

Abstract

PTH and 1,25(OH) 2 D each exert dual anabolic and catabolic skeletal effects. We assessed the potential interaction of PTH and 1,25(OH) 2 D in promoting skeletal anabolism by comparing the capacity of exogenous, intermittently injected PTH(1-34) to produce bone accrual in mice homozygous for the 1␣(OH)ase-null allele [1␣(OH)ase −/− mice] and in wildtype mice. In initial studies, 3-mo-old wildtype mice were either injected once daily (40 g/kg) or infused continuously (120 g/kg/d) with PTH(1-34) for up to 1 mo. Infused PTH reduced BMD, increased the bone resorption marker TRACP-5b, and raised serum calcium but did not increase serum 1,25(OH) 2 D. Injected PTH increased serum 1,25(OH) 2 D and BMD, raised the bone formation marker osteocalcin more than did infused PTH, and did not produce sustained hypercalcemia as did PTH infusion. In subsequent studies, 3-mo-old 1␣(OH)ase −/− mice, raised on a rescue diet, and wildtype littermates were injected with PTH(1-34) (40 g/kg) either once daily or three times daily for 1 mo. In 1␣(OH)ase −/− mice, baseline bone volume (BV/TV) and bone formation (BFR/BS) were lower than in wildtype mice. PTH administered intermittently increased BV/TV and BFR/BS in a dose-dependent manner, but the increases were always less than in wildtype mice. These studies show that exogenous PTH administered continuously resorbs bone without raising endogenous 1,25(OH) 2 D. Intermittently administered PTH can increase bone accrual in the absence of 1,25(OH) 2 D, but 1,25(OH) 2 D complements this PTH action. An increase in endogenous 1,25(OH) 2 D may therefore facilitate an optimal skeletal anabolic response to PTH and may be relevant to the development of improved therapeutics for enhancing skeletal anabolism.

Short-term intermittent PTH 1-34 administration enhances bone formation in SCID/Beige mice

“…Together, these data suggest inTo our knowledge, the skeleton of SCID/Beige mice has not been previously characterized regarding its response to exogenous intermittent PTH 1-34. However, the SCID/Beige mouse was developed on a C57BL/6J background [31]; arguably the most widely employed mouse strain in studies of PTH action on bone [12,13,17,19,32,33]. Our observations of increased serum osteocalcin, number of osteoblasts, and trabecular thickness are consistent with reports describing PTH 1-34 induced bone remodeling in C57BL/6J mice [12,32].…”

Age‐related decline in osteoblastogenesis and 1α‐hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone

“…These data indicate that PTH1-34 “restored” hMSCs from old subjects with responsiveness to 25OHD 3 by upregulation of CYP27B1 expression and enzymatic activity. Samadfam et al recently showed that intermittently administered PTH increased bone density in 1α-hydroxylase −/− mice, but that there was a greater effect in mice with an active 1,25(OH) 2 D-synthesizing system (Samadfam et al 2008). They concluded that PTH and vitamin D may interact to potentiate osteoblast differentiation.…”

The calcium-sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice

“…Mice homozygous for the CaSR-null mutation (Casr (13,19,38,42). The pumps were implanted subcutaneously into the back of the necks of mice under anesthesia (100 mg/kg ketamine and 3 mg/kg xylazine), and the incision was closed according to the manufacturer's instructions.…”