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

PTH and 1,25(OH)₂D each exert dual anabolic and catabolic skeletal effects. We assessed the potential interaction of PTH and 1,25(OH)₂D in promoting skeletal anabolism by comparing the capacity of exogenous, intermittently injected PTH(1‐34) to produce bone accrual in mice homozygous for the 1α(OH)ase‐null allele 1α(OH)ase^?/? mice] and in wildtype mice. In initial studies, 3‐mo‐old wildtype mice were either injected once daily (40 μg/kg) or infused continuously (120 μg/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)₂D. Injected PTH increased serum 1,25(OH)₂D 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 1α(OH)ase^?/? mice, raised on a rescue diet, and wildtype littermates were injected with PTH(1–34) (40 μg/kg) either once daily or three times daily for 1 mo. In 1α(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)₂D. Intermittently administered PTH can increase bone accrual in the absence of 1,25(OH)₂D, but 1,25(OH)₂D complements this PTH action. An increase in endogenous 1,25(OH)₂D may therefore facilitate an optimal skeletal anabolic response to PTH and may be relevant to the development of improved therapeutics for enhancing skeletal anabolism.