Uncovering the "riddle of femininity" in osteoarthritis: a systematic review and meta-analysis of menopausal animal models and mathematical modeling of estrogen treatment

Abstract

Objective: Post-menopausal women are disproportionately affected by osteoarthritis (OA). As such, the purpose of this study was to (1) summarize the state-of-the-science aimed at understanding the effects of menopause on OA in animal models and (2) investigate how dosage and timing of initiation of estrogen treatment affect cartilage degeneration.

Design: A systematic review identified articles studying menopausal effects on cartilage in preclinical models. A meta-analysis was performed using overlapping cartilage outcomes in conjunction with a rigor and reproducibility analysis. Ordinary differential equation models were used to determine if a relationship exists between cartilage degeneration and the timing of initiation or dosage of estrogen treatment.

Results: Thirty-eight manuscripts were eligible for inclusion. The most common menopause model used was ovariectomy (92%), and most animals were young at the time of menopause induction (86%). Most studies did not report inclusion criteria, animal monitoring, protocol registration, or data accessibility. Cartilage outcomes were worse in post-menopausal animals compared to age-matched, non-menopausal animals, as evidenced by cartilage histological scoring [0.75, 1.72], cartilage thickness [-4.96, -0.96], type II collagen [-4.87, -0.56], and c-terminal cross-linked telopeptide of type II collagen (CTX-II) [2.43, 5.79] (95% CI of Effect Size (+greater in menopause, -greater in non-menopause)). Moreover, modeling suggests that cartilage health may be improved with early initiation and higher doses of estrogen treatment.

Conclusions: To improve translatability, animal models that consider aging and natural menopause should be utilized, and more attention to rigor and reproducibility is needed. Timing of initiation and dosage may be important factors modulating therapeutic effects of estrogen on cartilage.

Keywords: Estrogen; Menopause; Meta-analysis; Osteoarthritis; Ovariectomy; Timing hypothesis.