Effect of Sequential Treatment with Bisphosphonates After Teriparatide in Ovariectomized Rats: A Direct Comparison Between Risedronate and Alendronate

Abstract

Teriparatide (TPTD), a recombinant human parathyroid hormone N-terminal fragment (1-34), is a widely used bone anabolic drug for osteoporosis. Sequential treatment with antiresorptives such as bisphosphonates after TPTD discontinuation is generally recommended. However, relative effects of bisphosphonates have not been determined. In the present study, we directly compared effects of risedronate (RIS) and alendronate (ALN) on bone mineral density (BMD), bone turnover, structural property and strength in ovariectomized (OVX) rats, when administered after TPTD. Female Sprague Dawley rats were divided into one sham-operated and eight ovariectomized groups. TPTD, RIS, and ALN were given subcutaneously twice per week for 4 or 8 weeks after 4 week treatment with TPTD. TPTD significantly increased BMD (+9.6%) in OVX rats after 4 weeks of treatment. 8 weeks after TPTD withdrawal, vehicle-treated group showed a blunted BMD increase of +8.4% from the baseline. In contrast, 8 weeks of treatment with RIS and ALN significantly increased BMD to 17.4 and 21.8%, respectively. While ALN caused a consistently larger increase in BMD, sequential treatment with RIS resulted in lower Tb.Sp compared to ALN in the fourth lumbar vertebra as well as in greater stiffness in compression test. In conclusion, the present study demonstrated that sequential therapy with ALN and RIS after TPTD both improved bone mass and structure. Our results further suggest that RIS may have a greater effect on improving bone quality and stiffness than ALN despite less prominent effect on BMD. Further studies are necessary to determine clinical relevance of these findings to fracture rate.

Keywords: Alendronate; Bone architecture; Bone quality; Risedronate; Teriparatide.

Fig. 1

Study timeline. Treatment was started from the next day after surgery. Animals were treated with vehicle or teriparatide (TPTD) twice a week for 4 weeks. After TPTD withdrawal, vehicle, risedronate (RIS), or alendronate (ALN) were given subcutaneously for 4 or 8 weeks. BMD, bone architecture, and bone strength was measured at 4, 8, or 12 weeks after surgery

Fig. 2

Effect of sequential treatment with bisphosphonates after teriparatide on lumber vertebral BMD (L2-L5). Sham-operated rats are shown in open circles. Ovariectomized rats treated with vehicle for 4 weeks are shown in open squares. The other rats were first treated with teriparatide for 4 weeks, and then with vehicle (closed circles), risedronate (closed triangles), or alendronate (closed rhombuses) for up to 8 weeks. Percent increases from the baseline in lumber vertebral BMD (L2-L5), measured by in vivo DEXA are shown in mean ± SD. At 4 weeks, sham and vehicle: n = 8 and TPTD: n = 56. At 8 weeks, sham: n = 8 and TPTD→vehicle, TPTD→RIS, and TPTD→ALN: n = 16. At 12 weeks, sham, TPTD→vehicle, TPTD→RIS, and TPTD→ALN: n = 8. ^*** p < 0.001 and ^**** p < 0.0001 compared with the vehicle-treated group at the same time point

Fig. 3

Effect of sequential treatment with bisphosphonates after teriparatide on lumbar vertebral BMD (L4). After ovariectomy, rats were treated with vehicle or teriparatide for 4 weeks. After teriparatide withdrawal, risedronate or alendronate was given for another 4 or 8 weeks. Lumber vertebrae were harvested from the rats at 4, 8, or 12 weeks for ex vivo BMD measurements by pDEXA. Values of lumbar vertebral BMD (L4) are shown in mean ± SD. n = 8. **p < 0.01 and ****p < 0.0001 compared with the vehicle-treated group at same time point. c p < 0.001 significant difference between risedronate and alendronate

Fig. 4

Effect of sequential treatment with bisphosphonates after teriparatide on a stiffness and b maximum load of lumber vertebra (L5). After ovariectomy, rats were treated with vehicle or teriparatide for 4 weeks. After teriparatide withdrawal, risedronate or alendronate was given for another 4 or 8 weeks. Lumber vertebrae (L5) were harvested from the rats at 4, 8, or 12 weeks and subjected to compression tests. Data are mean ± SD. n = 8. ^* p < 0.05 significant difference between risedronate and alendronate