Does alendronate therapy affect bone and cartilage remodeling in a murine post-traumatic OA model?

Objectives Bisphosphonates (BPs) are a class of anti-resorptive drugs classically used to treat osteoporosis by inhibiting osteoclast (OC) activity and increasing OC apoptosis thus reducing bone degradation. The use of BPs has been evaluated in osteoarthritis (OA) with conflicting results. Here, we analyzed the impact of alendronate (ALN) treatment on subchondral bone structure and expression of serum markers associated with bone remodeling processes in a murine destabilization-induced OA model.

Methods OA was induced in C57Bl/6J (WT) mice by surgical destabilization of the medial meniscus (DMM). ALN was applied by subcutaneous injection of 1mg/kg bodyweight bi-weekly over the time course of the experiment. Cartilage degradation was analyzed in SafraninO-stained sections of knee joints according to the OARSI guidelines. Alterations in the subchondral bone of the medial tibia were assessed by µCT. Serum samples were analyzed for bone remodeling markers and subchondral OC numbers were counted in tartrate resistant acid phosphatase (TRAP)-stained knee joint sections.

Results and Conclusion Both, WT control and ALN-treated WT mice showed mild OA-induced cartilage degradation compared to Sham groups after 12 weeks. ALN induced higher bone volume to total volume ratio (BV/TV) in DMM and Sham mice compared to respective WT control mice after 4 weeks. OA-related bone changes preceded cartilage alterations as DMM had induced a higher BV/TV in ALN-treated mice compared to ALN Sham mice already at 8 weeks after surgery. Though not significant, WT control mice showed a similar subchondral bone sclerosis of the medial tibia. Bone changes could not be associated with altered subchondral OC numbers, as OA induction did not affect OC numbers in the medial and lateral compartments of the tibia.

Generally, ALN treatment by trend induced higher numbers of OC. Furthermore, OA induction and ALN treatment did not affect serum concentrations for the osteoclast activity marker TRAcP5b. By trend, serum concentrations of the bone turnover marker CTX-I were reduced in WT control DMM mice after 12 weeks. In contrast, CTX-I concentrations were by trend increased in ALN-treated DMM mice compared to Sham mice. Dickkopf-1, an inhibitor of the Wnt signaling pathway that is involved in osteoblast activity regulation, was by trend increased after ALN treatment but the effect was stronger in the Sham mice. Similarly, serum concentrations of osteoprotegerin, an inhibitor of osteoclast formation, were tendentially increased in both, DMM and Sham, ALN-treated mice. Again, the effect was by trend stronger in Sham ALN mice.

ALN treatment had no beneficial effects on delaying cartilage degradation and instead even accelerated bone sclerotic changes. Compensatory mechanisms might induce higher OC numbers but not OC activity. Interestingly, ALN treatment also affected expression of serum markers associated with osteoblasts and osteocytes (DKK-1, OPG) in a non-favorable way suggesting

off-target effects in these cell populations.

Stichwörter osteoarthritis, destabilized medial meniscus, bisphosphonate, alendronate, bone, serum marker

Publication History

Article published online:
15 October 2020