Previously, we have shown alendronate to be effective in preventing or delaying the resorption of a bone graft [
17]In the present study we show that zoledronate, a more potent bisphosphonate is equally effective in weekly injections as the three times a week alendronate treatment. The bone chamber model is a stress-shielded model where the resorptive stimulus is high. Normally, all graft and new formed bone is resorbed as the remodelling is finished and an anticatabolic drug such as a bisphosphonate is probably more effective than in a mechanically loaded environment. In our experiments, we use subcutaneous injections, which could mean that less bisphosphonate is entering the systemic circulation. With higher doses or intravenous administration, this could hypothetically constitute a negative influence on bone formation. Further, a prolonged effect of the drug with slow-release effects could be the effect of a subcutaneous deposition compared to an intravenous administration.
Allografts were used as a model for necrotic, autologous bone. The strain of Sprague-Dawley rats used for this study is, however, inbred to such an extent that no differences can be detected in the incorporation of auto- versus allografts in this model [
20]. Theoretically, it could be assumed that also after freezing and thawing, allografts are more immunogenic than autologous bone and if so, allografts would stimulate bone resorption even more than an autograft. Since we wanted to study whether it is possible to reduce bone resorption during revascularization, such an increased tendency to resorption would necessitate an even greater protective effect of zoledronate in this model.
Table 1
Bone volume in the remodelled area and ingrowth distance of new bone into the graft. Bone volume fraction in the remodelled bone measured with Merz grid and expressed in percent of total tissue volume. Bone and vasculature ingrowth distance from living tissue into the graft.
New-formed bone (%) | 22 | 7 | 14 | 9 | 0.03 |
Remaining graft bone (%) | 13 | 6 | 5 | 5 | 0.008 |
Total Bone (%) | 35 | 0.12 | 19 | 0.13 | 0.01 |
Bone ingrowth distance into graft (mm) | 2,65 | 0.48 | 2,12 | 0.63 | 0.052 ns |
Vasculature ingrowth distance (mm) | 4.2 | 0.90 | 3.90 | 1.01 | Ns |
Lately, a number of new indications have been proposed for orthopaedic applications of bisphosphonates, relating to the ability of the substance to decrease the resorption of necrotic bone during revascularization and remodelling after an avascular necrosis. It appears that bone under remodelling can retain its form better if the remodelling is slowed down by for example a bisphosphonate [
4‐
6]. Still, there are concerns that bisphosphonates might interfere with the normal fracture and bone healing [
21]. Theoretically, the bone stock can be negatively influenced, both in the long run, by decreasing the ability to maintain and repair microfractures over years, but also in the short term by interfering with the bone formation. Osteoclasts are necessary for bone formation by the osteoblasts. Regarding the concern for long time complications, long time follow-up data regarding alendronate does not show an increased fracture rate in patients on osteoporosis prophylaxis treatment for up to 10 year [
22]. Zoledronate, however, is more potent than alendronate and could hypothetically interfere more, but no corresponding long time data exist. Regarding the fear to use a bisphosphonate for the short term influence on fracture healing, the results of the present and other recent experiments, using bone chambers as a model for remodelling of a graft or necrotic bone show, not only a decreased resorption as expected, but also an increased amount of new bone in the remodelled area. Although non-significant, a tendency towards an increased bone ingrowth distance or speed was noticed. One could interpret these results as if bisphosphonates would be not be merely an anticatabolic, but also function as an anabolic substance as hypothesized in some in vitro [
23,
24] and in vivo studies [
25]. Bisphosphonates are for example found to have an antiapoptotic effect in osteocytes and osteoblasts [
26], but several other explanations to the findings of an increased amount of newly formed bone can, however, be discussed. In contrast to cortical bone, remodelling in cancellous bone does not require cutting cones to make space for new bone. In cancellous bone there is sufficient space for new bone to form and often the new bone formation appears as appositional growth, covering the dead bone graft, which is not resorbed because it is bisphosphonate treated. In consequence, a larger surface area exists to lay down new forming bone onto (Fig
3). The fact that we find an increased amount of newly formed bone does not necessarily mean that more bone has formed or that zoledronate by any means is anabolic. New-formed bone might simply just prevail for a longer period if bone resorption is reduced. With the bisphosphonates, most of the calcified tissue that was present or has formed since the remodelling of the graft started will remain, both the old graft bone as well as the newly formed bone growing into the graft.
Regardless of reason, bone formation during bone graft remodelling was not decreased when treated with bisphosphonate in our study. On the contrary, more bone was found within the remodelled graft, both old graft and newly formed. Bisphosphonate treatment might, however, erroneously mimic an increased new bone formation, due to the absent resorption of the new formed bone.