Effect of Sequential Therapy with Incadronate after Withdrawal of Recombinant Human Parathyroid Hormone (1-84) on Bone Quantity and Quality in Ovariectomized Rats

Abstract

Background: Human parathyroid hormone (hPTH) is a promising anabolic agent. However, since hPTH (1-34) is available only via injection, and has a critical side effect of causing bone tumors during life-long administration in the rat, it would be practical to use PTH for the shortest possible duration to obtain the maximal effect. In addition, acquired bone mass due to hPTH tend to decrease after drug cessation. To determine the effectiveness of the osteoporosis-reversing concept of lose, restore, and maintain (LRM), recombinant human PTH(1-84) [rhPTH(1-84)] and the respective anti-resorptive agents were sequentially studied. Methods: Thirty six, 20-week-old, Sprague-Dawley rats were used in this study. Treatment was started on the 25th week after an ovariectomy, which had been performed at 20 weeks of age, with 5w eeks of rhPTH (1-84) 100 (μg/kg/d), 5 days/wk, followed by the respective sequential therapies for 5 weeks as follows: 1) Ovariectomized rats (OVX, n=6), 2) Sham operated rats (SHAM, n=6), 3) OVX rats with PTH maintenance (PTH-M, n=6), 4) OVX rats treated with PTH then withdrawn (PTH-W, n=6), 5) PTH-treated OVX rats then treated with 17β-estradiol (PTH-E, 10 μg/d, SQ, 5 days/wk, n=6), 6) PTH-treated OVX rats then treated with incadronate (PTH-I, 3 mg/kg, per os 5 days/wk, n=6). The bone mineral density (BMD) of the right femurs was measured using dual χ-ray absorptiometry (DXA). Microcomputed tomography (μCT) was used to measure the structural parameters of the 2nd lumbar vertebrae. A three-point bending test of the femur and compressive tests of vertebrae were also performed. Results: Bone quantity data showed that the femoral BMD was significantly higher in the PTH-M and PTH-I groups than in the OVX and PTH-W groups (P < 0.05). Measurement of the cortical thickness revealed that only the PTH-M group had a significant increase (P = 0.001). The ultimate force (Fu) at the midshaft of the femur was stronger in the PTH-M group than in the OVX group (P < 0.001). However, no significant difference was found among the treated groups. Conclusion: PTH withdrawal resulted in the loss of the acquired BMD, but sequential therapy with the anti-resorptive, incadronate, prevented further bone loss. The use of incadronate after rhPTH(1-84), as a sequential regimen, was significantly effective on the maintenance in the bone mass, but further clarification in the improvement in the bone quality is needed (J Kor Soc Endocrinol 20:334～343, 2005).