gms | German Medical Science

Objectives: Bisphosphonates (BP) are considered as a treatment option for osteoarthritis (OA) due to their anti-catabolic effect preventing high bone turnover. Taking bisphosphonates can, on the one hand, inhibit microtrauma in the bone marrow caused by inflammatory processes in OA and stabilize the subchondral bone layer, and on the other hand, bisphosphonate usage may cause a reduction in pain symptoms associated with OA. On the other hand, bisphosphonates may trigger acute phase-like reactions leading to the release of proinflammatory cytokines such as IL-1, which are considered to be the driving force for the catabolic response of chondrocytes in OA.

Methods: In vivo, the effects of high-dose alendronate (ALN) treatment on subchondral bone and articular cartilage after destabilization of the medial meniscus (DMM) of male C57Bl6/J mice were analyzed. Histology was used to semi-quantitatively evaluate the degree of OA after ALN administration and/or DMM. Subsequently, the ratio of bone volume to total volume and to bone surface was determined by µCT, and epiphyseal trabecular morphology was analyzed by high-resolution nano-CT. This was supplemented by serum analysis of IL-1 and ADAMTS-5 concentration and markers of bone remodeling. In addition, semi-quantitative immunohistochemical detection of the neurokinin (NK) 1 receptor was performed to assess possible pain symptomatology in the animals.

Results and conclusion: Serum analysis of markers of bone resorption marker and IL-1 levels revealed no change upon ALN treatment or OA induction whereas ADAMTS-5 levels were reduced in all ALN treated mice groups over exp. time line. Histologic evaluation according to OARSI recommendations showed that ALN treatment accelerated cartilage destruction 2 weeks after OA induction but prevented further degradation during the course of the disease. In contrast, cartilage degradation in untreated DMM mice was initially slower but steadily increased over time. Micro-CT analysis of the medial epiphysis showed an increase in bone volume fraction (BV/TV) of the subchondral tibial bone 4 weeks after surgery in ALN-treated mice, accompanied by decreased bone surface density in the ALN group. This effect leveled off after 8 weeks, with only the DMM group (ALN and controls) showing significantly higher subchondral bone volume accompanied by decreased subchondral bone density.

Ultrahigh-resolution nano-CT analysis showed an increase in trabecular density and trabecular numbers in the ALN mice 8 weeks post-op. Bone mineral density (BMD) decreased compared with untreated mice. ALN reduced osteophyte formation and increased meniscal ossicles; these two structures also showed decreased mineralization.

As expected, the use of ALN to treat OA promoted bone preservation, possibly by modulating local macrophage and osteocyte metabolism. ALN administration slowed down cartilage degradation only in the later stages of the pathology. Therefore, the timing and dosage of ALN as treatment option in OA must be carefully considered.