Concentration of Bisphosphonate (Incadronate) in Callus Area and Its Effects on Fracture Healing in Rats

Abstract

The aim of the present study was to investigate effects of incadronate on early stages of fracture healing and to detect its concentration in callus area (Ca.Ar). Rats were injected three times per week with either two doses of incadronate (10 g/kg and 100 g/kg) or vehicle for 2 weeks. Femora were then fractured and fixed and animals were divided into pretreatment (P-10 and P-100) and continuous treatment (C-10 and C-100) groups. Incadronate treatment was stopped in P-10 and P-100 groups but continued in C-10 and C-100 groups. Animals were killed at 2 weeks and 4 weeks after fracture. Results showed significantly large callus, compared with the control, only in C-100 group at 4 weeks but not at 2 weeks. Both linear labeled surface (LS) and eroded surface (ES) decreased significantly in C-10 and C-100 groups at 2 weeks and 4 weeks. Osteoclast number (N.Oc) decreased significantly in C-10 and C-100 groups at 2 weeks but increased slightly at 4 weeks. However, there was no significant difference in the above parameters in P-10 and P-100 groups at 4 weeks. Apoptotic osteoclasts were observed only in the C-100 group at 4 weeks. A time-course decrease in incadronate concentration was detected in P-10 and P-100 groups whereas an increase was observed in C-10 and C-100 groups. These findings suggest that larger callus under incadronate treatment may result from the inhibition of bone resorption, histological characteristics of callus may be correlated with incadronate concentration, and metabolism of incadronate in bone may be related to the rate of bone turnover.

Near-infrared fluorescent probe traces bisphosphonate delivery and retention in vivo

“…FRFP has been used to visualize osteogenic labeling in bone-defect models, with high fluorescence concentrating in areas of high osteoblastic activity. (24,26) These studies corroborate earlier studies using radiolabeled bisphosphonates to demonstrate high drug delivery to sites of active bone regeneration during fracture repair (66) and histologic studies demonstrating unremodeled cartilage retained in fracture callus treated with bisphosphonate. (67) Similarly, FRFP, when injected into mice with osteolytic lesions resulting from tumor xenograft injections, localizes under osteoclasts at the tumor-bone interface.…”

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].…”