Parathyroid hormone (PTH) is a potential medicine for osteoporosis, and subcutaneous (s.c.) PTH treatment enhances bone mass; however, continuous infusion of PTH elicits bone resorption and induces bone loss. To clarify this contradictory phenomenon, we examined bone markers and bone mass in rats to assess the optimal duration of PTH(1-34) infusion. Continuous infusion of PTH at 1 µg/kg/h (C ss , steady-state concentration ca. 300 pg/mL) for 1-4 h clearly stimulated the expression both of bone formation-related genes (c-fos, Wnt4, EphrinB2) and of bone resorption-related genes (tnfsf11, tnfsf11b, encoding receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG)), but s.c. treatment stimulated these genes only 1-h after the injection. Rats were treated with 1-, 2-, or 4-h infusions of PTH daily using a totally implanted catheter system, and the femoral bone mineral density (BMD) was measured at 4 weeks. The 1-h infusion of PTH significantly stimulated serum bone formation markers (procollagen I N-terminal propeptide (PINP) and osteocalcin) on day 14 and femoral BMD at 2 and 4 weeks, but the 4-h infusion of PTH did not enhance BMD. Since the 4-h infusion increased the levels of both the bone formation markers and a bone resorption marker (urinary C-terminal telopeptide of type 1 collagen (CTx)), the increased bone resorption may predominate over bone formation. The intermittent elevation of plasma PTH to 300 pg/mL for 1-h each day is optimal for increasing bone mass in rats. In osteoporosis therapy in human, using the optimal duration for the clinical dose of PTH may selectively stimulate bone formation.Key words parathyroid hormone; bone mineral density; infusion; bone formation; bone marker; rat Intermittent administration of parathyroid hormone (PTH) is known to enhance bone mass in rats, while continuous infusion of PTH decreases bone mineral density (BMD) by increasing bone resorption.1) The contradictory phenomenon of PTH(1-34) action is caused by the dual effects of PTH on bone resorption and bone formation. To analyze the PTH action in bone, previous studies used an alzet infusion pump for programmed administrations or various dosing regimens of PTH(1-34) in rats, 2,3) but with this system it was difficult to identify the optimal duration of PTH treatment for anabolic and catabolic effects on bone.In previous studies, dosing rats with PTH(1-34) at 80 µg/kg elevated the serum level of PTH to 3800-18000 pg/mL, which is higher than the serum level of PTH (C max 160-360 pg/ mL) induced by therapeutic doses of PTH (0.3-0.4 µg/kg) in human.2-5) Furthermore, the pharmacokinetic profiles after intermittent subcutaneous (s.c.) administrations of PTH(1-34) in rats were shorter than those in human (T max and T 1/2 in rats: 15 min and 30 min; T max and T 1/2 in human: 30 min and 1 h).
4-6)These difficulties in establishing a relevant study mean that the optimal duration of PTH(1-34) to selectively exhibit anabolic effects on bone tissue has not been fully understood in either animals or humans...