Intermittent Ibandronate Maintains Bone Mass, Bone Structure, and Biomechanical Strength of Trabecular and Cortical Bone After Discontinuation of Parathyroid Hormone Treatment in Ovariectomized Rats.

Although parathyroid hormone (PTH) expresses an anabolic effect on bone mass, the increased bone mass disappears once PTH treatment is withdrawn. Therefore, sequential treatment with anti-bone-resorptive agents is required to maintain bone mass after PTH treatment. We examined the effect of sequential treatment with ibandronate (IBN), a nitrogen-containing bisphosphonate, following PTH in ovariectomized (OVX) rats. Wistar-Imamichi rats (27 weeks old) were ovariectomized and treated with PTH (10 µg/kg, s.c.; 5 times/week; PTH group) for 8 weeks from 8 weeks after OVX. Thereafter, PTH was withdrawn and rats were administered IBN (10 µg/kg, s.c.; every 4 weeks; PTH-IBN group) or vehicle (PTH-Veh group) for another 8 weeks. PTH increased bone mineral density (BMD) measured by dual-energy X-ray absorptiometry and biomechanical strength in the lumbar spine and femur as compared to the disease control rats. BMD and biomechanical strength in the PTH-Veh group were lower than in the PTH group, whereas in the PTH-IBN group they were maintained at the level of the PTH group. Microstructure of the trabecular and cortical bone in the PTH-IBN group was not significantly different from that in the PTH group. In histomorphometric analysis of the lumbar vertebra, eroded surface and osteoclast surface in the PTH-Veh group were no different from those in the PTH group, whereas they were lower in the PTH-IBN group. Osteoid surface, osteoblast surface, and mineralize surface decreased in both PTH-IBN and PTH-Veh groups compared to the PTH group, and these parameters in the PTH-IBN group were lower than in the PTH-Veh group. These results indicated that intermittent IBN after PTH treatment suppressed bone turnover and maintained BMD, biomechanical strength, and microstructure in the lumbar spine and femur of OVX rats.

[Pharmacological action and clinical effects of falecalcitriol, a highly potent derivative of active vitamin D3].

Much effort has been made to create highly potentiated active vitamin D for better clinical applications and falecalcitriol was successfully synthesized as one of such candidates with highly potent and long-lasting effects. Its chemical structure has a calcitriol side chain modification in which both methyls at positions C-26 and C-27 are substituted by tri-fluoromethyls. The mechanism for its strong and long-lasting effects is probably due to altered side chain metabolism and decreased inactivation. Although C-24 position hydroxylation catalyzed by Cyp24 inactivates calcitriol, falecarcitriol is metabolized to C-23S hydroxylated metabolite by the same enzyme Cyp24 and this metabolite still has strong activity. Stronger action of falecalcitriol has been shown in target organs or cells of active vitamin D such as bone, parathyroid cells, and keratinocytes, when compared with calcitriol, the endogenous active form of vitamin D. Daily oral administration of falecalcitriol at doses lower than those required for calcitriol has been shown to have clinical effects for the treatment of diseases such as hyperparathyroidism due to chronic renal failure (2 degrees HPT), rickets, osteomalacia and hypoparathyroidism. The comparative study with alfacalcidol showed its specific action on parathyroid hormone suppression and better improvement of bone metabolism markers in 2 degrees HPT patients.