Effect of Dosing Interval Duration of Intermittent Ibandronate Treatment on the Healing Process of Femoral Osteotomy in a Rat Fracture Model

Abstract

The effects of bisphosphonate treatment schedule on fracture healing have not previously been tested. We evaluated the effect of ibandronate dosing interval duration on healing following surgical “fracture” (osteotomy) using a rat femoral fracture model. Six-week-old rats (n = 160) underwent osteotomy and were then allocated into vehicle control (CNT) or an ibandronate treatment group: 5 μg/kg daily (DAY, 5 days/week), 75 μg/kg once every 3 weeks (I-3), 150 μg/kg once every 6 weeks (I-6), resulting in the same total ibandronate dose over the study. Rats were killed after 6 or 18 weeks. At 18 weeks, all fracture lines had disappeared in the CNT and I-6 groups; approximately 10% of fracture lines remained in the DAY and I-3 groups. Ibandronate-treated groups showed large callus areas around the fractures, which shrank between 6 and 18 weeks after surgery; the extent of shrinkage decreased with shorter dosing interval. In histomorphometry, callus remodeling was suppressed by ibandronate; this became more apparent at shorter dose intervals. The structural properties of osteotomized femora were increased in the DAY group compared with CNT, but intrinsic material properties reduced inversely and became closer to those of CNT in response to increased dosing interval. Ibandronate induced formation of large calluses around osteotomies but delayed woven bone remodeling into lamellar bone and reduced intrinsic material properties in a rat fracture model. Extending the dosing interval of intermittent ibandronate treatment appeared to reduce the suppression of callus remodeling caused by ibandronate, which would have delayed healing after osteotomy.

Effect of Alendronate on the Healing Time of Distal Radial Fractures Treated Conservatively: An Observational Study

“…Bisphosphonates are effective therapeutic agents for an array of diseases related to the bone as they are good inhibitors of bone resorption [7]. Due to their effectiveness in reducing the incidence of fragility structures, they are highly favored as therapeutic agents for osteoporosis [7].…”

“…Due to their effectiveness in reducing the incidence of fragility structures, they are highly favored as therapeutic agents for osteoporosis [7]. They are categorized into nitrogen-containing and non-nitrogen-containing bisphosphonates based on their mechanism of action.…”

“…Nitrogen-containing bisphosphonates have the property of persisting for a considerable amount of time on the surface of the bone. This has, in turn, resulted in an increased use of these agents in clinical practice through dosing intermittently [7]. Alendronate is a bisphosphonate which contains nitrogen which is administered orally and the above-stated reasons have led to it being given at a daily and weekly dosage of almost 7 times that of the standard daily dose [7].…”

“…Tests have been performed on both animals as well as humans in different studies to understand the interaction between bisphosphonates and the fracture healing process. Animal studies have indicated that inhibition of the hard callus remodeling to mature lamella bone occurs as a consequence of bisphosphonates [7,8]. However, studies on humans, in the same manner, have not led to definitive results [9].…”

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

“…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.…”