A single systemic dose of pamidronate improves bone mineral content and accelerates restoration of strength in a rat model of fracture repair

Abstract

Complications in fracture repair that lead to a delay in union remain clinically problematic. We believe that unwanted pre-mature catabolism of the healing callus, for example, in stress shielded situations, diminishes the rate at which strength is restored in bone repair and possibly leads to delayed union. We hypothesized that a single systemic dose of a nitrogen-containing bisphosphonate (N-BP) would increase bone mineral content (BMC), volume, and mechanical strength of union in fracture repair. We also set out to investigate local delivery to assess whether systemic exposure could be eliminated, due to concerns of bisphosphonate dosing of nontarget organs. After an open osteotomy fixed with a K wire, 40 12-week old Wistar male rats were divided into four groups of 10: saline control, bolus systemic subcutaneous injection of pamidronate (3 mg/kg), local low dose of pamidronate (0.1 mg), and a local high dose of pamidronate (1.0 mg). Rats were sacrificed 6 weeks post-operatively. Operated and non-operated femora underwent radiographic evaluation, quantitative computer tomography, and biomechanical testing in torsion. The growth plates and metaphyses of the tibia of the non-operated side were assessed for evidence of systemic exposure in the local groups. Significant increases in callus BMC and volume of the bolus systemic dose group were found compared to the saline control (p < 0.05). Further, the strength of the systemic dose callus was increased by 60% from 0.35 Nm (f0.11) for the saline control callus to 0.56 Nm (f0.25) for the systemic group (p = 0.05). Local treatment did not result in increased strength. The contralateral tibia1 growth plates of the local groups showed evidence of systemic exposure by the presence of retained primary spongiosa. This study confirms that a single perioperative systemic dose of pamidronate leads to significant increases in the BMC, volume, and strength of healing fractures in rats, making single dose N-BP therapy an appealing candidate for further examination in fracture repair.

Bisphosphonate treatment delays stress fracture remodeling in the rat ulna

“…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.…”

Efeito do ácido zoledrônico em tíbias de ratas ooforectomizadas: estudo prospectivo e randomizado

“…O ácido zoledrônico, um novo e poderoso bisfosfonato, age inibindo a ação osteoclástica e, conseqüente-mente, diminuindo a reabsorção óssea (10,11) . O osso do tipo trabecular é o principal sítio de ação da droga, mantendo a espessura e a densidade das conexões ósseas e aumentando sua resistência às fraturas (12)(13)(14) .…”

“…Os representantes mais acreditados da classe dos inibidores da reabsorção óssea são os bisfosfonatos, que, bloqueando a atividade osteoclástica, são especialmente úteis nas doenças que se manifestam por rápida remodelação óssea (10,11) . Dentre os medicamentos desta classe terapêutica, os chamados amino-bisfosfonatos, ou bisfosfonatos de 3ª geração, são até 10 mil vezes mais potentes que os bisfosfonatos mais conhecidas (12)(13)(14) .…”

Manipulating the anabolic and catabolic response in bone graft remodeling: Synergism by a combination of local BMP‐7 and a single systemic dosis of zoledronate

“…5 In other situations with few cells at hand, like in a critical defect or using an allograft, an anabolic drug can be used to increase the recruitment and/or the differentiation of mesenchymal osteoprogenitor cells. 11 In some fractures, an anabolic deficiency, such as a genetic defect like congenital pseudartrosis of the tibia or a necrosis of the bone ends, is combined with increased or premature catabolism, due to stress shielding or instability, and the combination of both an anabolic and an anticatabolic compound seems attractive.…”

“…4 In fractures, postponing the catabolic response and in consequence the resorption of the new-forming callus, leads to a stronger callus. 5 Bone morphogenic proteins (BMPs) bind to specific cell receptors, starting a signaling cascade that leads to both recruitment and differentiation of mesenchymal progenitor cells into osteoblasts. However, resorption can also be increased.…”