Impact of Alendronate on Biomaterial Resorption, Bone Formation, and Strength in Humoral Critical-Sized Defects in Dogs

Introduction:

Osteoporosis has a large impact on healthcare systems. Local approaches to treat osteoporotic bone loss are being explored including a minimally-invasive local osteo-enhancement procedure (LOEP) leveraging a resorbable, tri-phasic calcium-based implant material (AGN1). The impact of systemic antiresorptive therapy on calcium-based implant material resorption and bone formation has not been clearly defined. The study evaluated the long-term impact of alendronate treatment on resorption and bone formation following implantation of AGN1 in critical-sized bone defects in dogs.

Methods:

Sixty skeletally mature adult hounds were equally assigned to alendronate (0.2 mg/kg/day) or vehicle treatment. Unilateral proximal humeral axial defects, 13 × 50 mm, were filled with AGN1. Intact contralateral humeri served as controls. At 13, 26, and 52 wks, radiographs were taken of the explanted bones. Serial sections were obtained for contact radiographs and histological sections, which were embedded in methylmethacrylate and stained with fuchsin and toluidine blue and scored for bone area and residual AGN1. An 8 mm diameter by 20 mm long section was obtained for µCT analysis and biomechanical testing (Fig 1). Statistical analysis used Spearman correlations (resorption) and Friedman Tests (BV).

Fig. 1: MicroCT microarchitecture analysis showing increased mineral volume, trabecular number, and degree of connectivity, regardless of alendronate treatment.

Results:

AGN1 resorption increased over time (rs = 0.524, p ≤0.01) with 98.7% resorbed at 52 wks; the remaining 1.3% was incorporated into trabeculae. No significant difference in AGN1 resorption was observed (p > 0.05). Significant neovascularization and macrophage activity were noted during resorption. When measured in histology sections, significantly more bone was found in defects treated with AGN1 at 13 wks regardless of alendronate treatment. In assessing the core volume, percent mineral in the defects was significantly greater than contralateral controls with alendronate at all time points and at 13 and 26 wks without alendronate (Figure 1). In alendronate-treated dogs trabecular number and connectivity were significantly higher than controls at all time points and higher than controls at 13 and 26 wks in dogs not receiving alendronate (p ≤0.02). At all-time points, ultimate compressive strength was not significantly different than the unoperated contralateral control. No difference in elastic modulus was observed between AGN1 treated and unoperated controls at 13 or 52 wks.

Discussion:

The injectable calcium sulfate/calcium phosphate graft was compatible with alendronate as the material resorbed and regenerated bone that restored biomechanical strength as early as 13 wks. The regenerated bone remodeled towards normal bone over the course of 52 wks. The triphasic implant material is an excellent candidate for local enhancement of bone at high risk of fracture, such as osteoporotic bone in the proximal femur or vertebrae.