Bisphosphonates as disease-modifying drugs in osteoarthritis preclinical studies: a systematic review from 2000 to 2020

Abstract

Bisphosphonates have been proposed as possible disease-modifying drugs in osteoarthritis. However, the evidence of their efficacy is poor and their outcomes presented a great heterogeneity. Therefore, the aim of this study is to systematically review the main effects of bisphosphonate use on synovial joint tissues and biochemical markers in preclinical studies over the past two decades (2000–2020). Three databases (Pubmed, Scopus, and Web of Science) were searched, and after screening, twenty-six studies with five different types of bisphosphonates were included in the review. The animal model selected, the type of bisphosphonate used, the therapy duration, and the main effects of individual drugs on synovial tissues were evaluated. Additionally, the quality and risk of bias assessments were performed using the Animals in Research Reporting In Vivo Experiments guidelines and the Systematic Review Centre for Laboratory animal Experimentation tool. Studies showed high variability in experimental designs. Consequently, the comparison of the findings in order to draw specific conclusions about the effectiveness of the drugs is complicated. However, the results of this systematic review suggested that bisphosphonates seemed to reduce the osteoarthritic changes in a dose-dependent manner showing better chondroprotective effects at high doses. Besides, a time-dependent efficacy was also detected in terms of cartilage status. One can conclude that the disease stage of the time-point of treatment initiation may constitute a key factor in the antiresorptive drug efficacy. Generally, we noted that bisphosphonate administration seemed to show positive subchondral bone conservation and fewer biomarker alterations. However, they did not appear to suppress the osteophyte development and their chondroprotective effect is highly variable among the studies. Bisphosphonates appeared to show a positive anti-inflammatory effect on the synovial membrane. However, only a few included publications were focused on their investigation. Regarding the therapy duration, there is a significant lack of evidence on evaluating their effectiveness in preclinical long-term studies and further experimental studies may be needed to examine the pharmacological response in these circumstances. This systematic review might help to clarify the efficacy of bisphosphonates and their function as disease-modifying treatments in osteoarthritis.

The Development of Disease-Modifying Therapies for Osteoarthritis (DMOADs): The Evidence to Date

“… 17 , 104 In a recent systematic review including preclinical studies (n=26) over the past two decades (2000–2020), these drugs showed better chondroprotective effects at high doses with a dose-dependent manner as well as depending on the timing of treatment initiation in relation to OA stage (time-dependency). 105 Therefore, these agents may still be of potential benefits in certain OA endotypes with high rates of subchondral bone turnover. This phenotype-dependency has been demonstrated in pre-clinical research, where bisphosphonates are differentially effective in reducing pain and not only bone but also cartilage pathology in OA models with high versus low bone turnover.…”

Osteoarthritis of the knee - biochemical aspect of applied therapies (review)

“…Subchondral bone lesions are visible in magnetic resonance imaging (MRI) in many patients with OA [ 68 ]. BPs delay and reverse pathological changes occurred in the bone and cartilage, and have a pain-relieving effect in animal model [ 69 ]. They can inhibit MMPs expression [ 70 ].…”

Is the Use of Bisphosphonates Putting Horses at Risk? An Osteoclast Perspective

“…In addition to their main antiresorptive properties, BPs are believed to have antiinflammatory and analgesic effects [4,[44][45][46][47][48], which make them an attractive potential treatment for multiple diseases, including osteoarthritis (OA). Meta-analyses and systematic reviews have concluded that BP studies have controversial results, and BP effects may be more related to pain relief than disease modification [48][49][50]. These pain-relieving effects could be beneficial for some individuals, but in human or animal athletes, masking pain could also be dangerous and lead to further deterioration of joint conditions.…”