Raloxifene, Estrogen, and Alendronate Affect the Processes of Fracture Repair Differently in Ovariectomized Rats

Abstract

We investigated the effects of inhibitors of bone resorption (estrogen, raloxifene, and alendronate) on the processes of fracture repair in ovariectomized (OVX) rats. One hundred forty female Sprague-Dawley rats at 3 months of age were either OVX or sham-operated and divided into five groups: sham control, OVX control, estrogen (17␣-ethynyl estradiol [EE2], 0.1 mg/kg), raloxifene (Rlx, 1.0 mg/kg), and alendronate (Aln, 0.01 mg/kg) groups. Treatment began immediately after the surgery. Four weeks postovariectomy, prefracture controls were killed and bilateral osteotomies were performed on the femoral midshafts and fixed with intramedullary wires. Treatment was continued and fracture calluses were excised at 6 weeks and 16 weeks postfracture for evaluation by X-ray radiography, quantitative computed tomography (QCT,) biomechanical testing, and histomorphometry. At 6 weeks postfracture, Aln and OVX had larger calluses than other groups. Sham and OVX had higher ultimate load than EE2 and Rlx, with Aln not different from either control. Aln calluses also contained more mineral (bone mineral content [BMC]) than all other groups. By 16 weeks postfracture, OVX calluses were smaller than at 6 weeks and the dimensions for Aln had not changed. Aln had higher BMC and ultimate load than OVX, EE2, and Rlx. EE2 and Rlx had similar biomechanical properties, which were similar to sham. Interestingly, OVX and Aln animals were heavier than other groups at all time points; therefore, ultimate load was normalized by body weight to show no significant differences in strength of the whole callus between groups at either 6 weeks or 16 weeks postfracture. However, Aln strongly suppressed remodeling of the callus, resulting in the highest content of woven bone, persistent visibility of the original fracture line, and lowest content of lamellar bone, compared with other groups. Therefore, the larger Aln callus appeared to be a remarkable, morphological adaptation to secure the fracture with inferior material. In conclusion, OVX-stimulated bone turnover resulted in the fastest progression of fracture repair that was most delayed with Aln treatment, consistent with marked suppression of bone resorption and formation activity. Estrogen and Rlx had similar effects that were generally similar to sham, indicating that mild suppression of bone turnover with these agents has insignificant effects on the progression of fracture repair. (J Bone Miner Res 2002;17:2237-2246)

The effect of alendronate sodium on trabecular bone structure in an osteoporotic rat model

“…Similar positive effects of alendronate have been also reported in the literature. [9][10][11][12][13][14][15][16][17] In addition, plasma calcium levels decreased in the Ovx group, compared to the Shm and alendronate groups with no difference between the Shm and alendronate groups. Iwamoto et al [14] reported decreased plasma osteocalcin and urine deoxypyridinoline levels with increased plasma calcium levels in the Ovx rats.…”

Effect of early administration of alendronate after surgery for distal radial fragility fracture on radiological fracture healing time

“…The lack of difference in radiological fracture healing time in our two groups might be partly related to a reduction in hard callus formation, even in the ALN group, compared with that observed in animal studies. 11,[14][15][16] The distal radius was fixed using a locking plate and screws, which provides very stable fixation with angular stability even in osteopenic bone. 37 The amount of callus formation partly depends on the stability of the fracture fragments, 38 with greater callus formation in unstable situations.…”

“…9 However, as bisphosphonate is a potent anti-resorptive agent, concerns remain regarding its possible adverse effects on the healing process of fractures. 10,11 Animal experiments consistently demonstrate that bisphosphonate inhibits the remodelling of hard callus to mature lamellar bone, 12,13 although most studies showed no adverse effect on radiologically assessed bony union or the material properties of the already fractured bone. [14][15][16] Human studies on the effect of bisphosphonate administration on the healing of acute fractures have yielded inconsistent results.…”

Osteoporosis increases chondrocyte proliferation without a change in apoptosis during fracture healing in an ovariectomized rat model

“…However, only a few have placed emphasis on the study of fracture healing, a complex cascade of cellular events. Skeletal conditions affect fracture treatment and healing initially but the effects of osteoporosis on this complex process remain unclear, with studies presenting contradictory results (2)(3)(4)(5)(6).…”