Effect of Bisphosphonate (Incadronate) on Fracture Healing of Long Bones in Rats

Abstract

This study was designed to test whether bisphosphonates disturb the process of fracture healing. Female SpragueDawley rats were injected with either two doses of bisphosphonate (incadronate) (10 µg/kg and 100 µg/kg) or vehicle three times a week for 2 weeks. Right femora were then fractured and fixed with intramedullary wires. Incadronate treatment was stopped in pretreatment groups (P-10 and P-100 groups), while the treatment was continued in continuous treatment groups (C-10 and C-100 groups). Animals were sacrificed at 6 and 16 weeks after surgery. Soft X-ray of all fractured femora was taken. After mechanical testing, fractured femora were stained in Villanueva bone stain and embedded in methyl methacrylate. Cross-sections near fracture line were analyzed by microradiography and histomorphometry. Radiographic study showed that bony callus was present in all the fractures and incadronate treatment led to a larger callus, especially in C-100 group at both 6 and 16 weeks. Histologic study showed that the process of fracture healing in pretreatment groups was delayed at 6 weeks, but reached control level thereafter and showed same characteristics as in control at 16 weeks. Woven bony callus could still be seen in continuous treatment groups at 16 weeks. Mechanical study indicated that the ultimate load of C-100 group was slightly higher than the other treatment groups and control. The results suggest that pretreatment with incadronate did not affect fracture healing at 16 weeks after fracture. However, continuous incadronate treatment could lead to larger callus, but it delayed remodeling process during fracture healing, especially with high-dose treatment. (J Bone Miner Res 1999;14:969-979)

Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

“…In complete fractures in rats, bisphosphonate treatment does not alter the rate of bone union and consistently results in a larger callus. 12,13,36 Similar results were observed in models using dogs and sheep. 37,38 In these studies, mechanical properties of the callus were improved 3,12,13,36 or not significantly changed by treatment with bisphosphonates.…”

“…In experimental studies of complete fracture in rats, treatment with bisphosphonates consistently increased the hard callus volume, strength and mineral content. 3,12,13 In animal models, stress fractures heal by direct remodeling along the fracture line. 14,15 Treatment with bisphosphonates may therefore have a negative effect on stress fracture healing when compared to complete fractures.…”

Effects of receptor activator of NFκB (RANK) signaling blockade on fracture healing

“…As observed with bisphosphonate therapy, withdrawal of the agent restores osteoclast numbers and activity during the remodeling phase of fracture healing [24,25,29]. We also found that RANK signaling is not required for the early phase of fracture healing as evidenced by the repair (callus formation) observed in RANK 4-mice.…”

Calcium phosphate drug delivery system: influence of local zoledronate release on bone implant osteointegration

“…The drug at too high concentrations could then have detrimental effects on the fixation of the implant over longer periods of time. Indeed, conflicting studies have reported that the use of bisphosphonate can interact with the repair of cracks and fractures, while other studies were unable to demonstrate this phenomena [17,[21][22][23]. Specifically for the zoledronate, it has been shown that aminobisphosphonate (like zoledronate), due to the lower dosing, will not impair with the fractures and cracks repair [4].…”