Getting to the 'Why' of Increased Osteoarthritis Risk in Postmenopausal Women

A study led by researchers at Spaulding Rehabilitation, a member of the Mass General Brigham healthcare system, provides critical insights into the relationship between menopause and osteoarthritis. 

Women comprise 80% of the estimated 10 million osteoarthritis cases in the United States, and postmenopausal women are disproportionately affected. The hormonal changes associated with menopause have long been known to accelerate the development and progression of osteoarthritis. However, a deeper understanding of the biological mechanisms underlying this correlation is necessary for developing effective treatments.

"Osteoarthritis represents a huge burden for postmenopausal women, significantly decreasing mobility, functional abilities, and the ability to participate in activities that patients love," says senior study author Fabrisia Ambrosio, PhD, MPT, director of the Discovery Center for Musculoskeletal Recovery of the Schoen Adams Research Institute at Spaulding Rehabilitation. "It's a huge problem, and yet one for which we have no effective interventions in the clinic."

After chemically inducing menopause in mice, the researchers discovered that menopause accelerated cartilage degeneration. Furthermore, they detected a drop in two key sex hormones, 17β-estradiol and progesterone, that increased cartilage vulnerability with aging. The findings could pave the way for novel strategies that slow or prevent osteoarthritis progression in postmenopausal women. 

The study was published in Nature Aging in January 2025. 

Developing a Mouse Model of Menopause

Osteoarthritis is characterized by degradation of the cartilage tissue in joints. Cartilage comprises two major components, the extracellular matrix (the surrounding proteins that provide structure) and chondrocytes (the resident cell population). In osteoarthritis, the health of both these cartilage components, in addition to structures surrounding the joint, is compromised, preventing smooth articulation between bones. 

A key hurdle in studying the role of menopause in osteoarthritis, Dr. Ambrosio notes, is the lack of reliable animal models of menopause. In response, the researchers developed a model that used a chemical to slowly degenerate the ovaries of middle-aged mice, thus inducing menopause over time. 

"Most studies to date have used a surgical model of menopause applied to younger mice. That's a problem because it fails to capture the aged microenvironment that characterizes older women going through menopause," Dr. Ambrosio says. "And since we induced a gradual transition into menopause through chemical depletion of the ovaries, our model includes a perimenopausal phase to replicate more closely what human females actually experience." 

Following the induction of menopause, the researchers examined blood samples to track sex hormone levels over time. Network medicine analyses revealed that the combination of 17β-estradiol/progesterone loss with menopause drives extracellular matrix degradation and chondrocyte deterioration, which directly contributes to cartilage degeneration and then osteoarthritis. 

"We see the onset of cellular senescence, in which the chondrocytes enter into a period of growth arrest and can no longer function effectively," Dr. Ambrosio says. "This leads to the drastic remodeling of the cartilage tissue, which gets more fibrotic and degrades—key hallmarks of osteoarthritis."

The researchers also studied the effect of giving mice 17β-estradiol and progesterone after inducing menopause. They found that subsequently restoring these hormones to pre-menopausal levels protected against cartilage degeneration.

A First Step Toward Disease-Modifying Therapies?

Dr. Ambrosio hopes that by clarifying what's happening in the cartilage of postmenopausal women, the study eventually will spur the development of disease-modifying therapies. 

"Maybe that's not directly hormone therapies, but instead, downstream targets of the hormones and their action on cartilage. That's where we might be able to find some unique and novel treatment interventions," she says. 

As for future research, Dr. Ambrosio is interested in exploring ways to counteract cellular senescence in chondrocytes—including through restoration of a healthy extracellular matrix, which could then revive cartilage after the loss of integrity and onset of osteoarthritis. 

"The bottom line," she says, "is that we have a lot of work to do to really understand what's happening in some of the disease pathogenesis here."