Why are older women predisposed to osteoarthritis?

A drop in estradiol and progesterone may explain the increased risk of osteoarthritis after menopause, a mouse study suggests.

• Menopause is one risk factor for osteoarthritis.
• One recent study in mice uncovered that menopause led to a drop in 17beta-estradiol and progesterone, which increased cartilage aging, degeneration, and disassembly of the extracellular matrix.
• This research opens up the door for developing certain treatments for osteoarthritis.

Osteoarthritis is a condition that can affect joint mobility and cause joint pain. Experts are interested in understanding the relationship between experiencing menopause and the risk for osteoarthritis.

A study recently published in Nature AgingTrusted Source used mouse models and human cells to explore this relationship.

Researchers found that loss of 17beta-estradiol and progesterone in mice with chemically induced menopause affected cartilage degeneration.

Similarly, treatment with 17beta-estradiol and progesterone protected against cartilage degeneration in mice and appeared to improve human cartilage cells, too.

Why does osteoarthritis risk increase at postmenopause?

According to the Centers for Disease Control and Prevention (CDC)Trusted Source, women over 50 are at a higher risk for osteoarthritis. This age is around the time that menopause happensTrusted Source.

The current study’s authors wanted to explore how menopause affects joint function. They note that knee osteoarthritis is twice as common in postmenopausal females than in males, but research remains lacking.

This research used female mice. Researchers chemically induced menopause in the mice and looked at blood samples to examine sex hormone levels.

They found that 17beta-estradiol and progesterone levels dropped post-menopause while follicle-stimulated hormone (FSH) increased. Researchers also observed that the menopausal mice gained weight.

Researchers then looked at how these hormonal changes affected joint tissue. In the knee joints, they observed an increased cartilage degeneration in the menopausal group. The group also had worse synovitisTrusted Source, which is inflammation of the synovium, a critical component of joints.

Since the researchers observed synovial changes in both groups, they believe that menopause may make these changes worse.

When looking at the mice’s bones, they found that the menopausal mice had components like lower bone mineral density in a certain area of the tibia called the metaphysis.

However, outcomes were similar when looking at the end of the mice’s tibias in both groups. Researchers think this may mean that only certain regions of subchondral bone may be more affected by menopause.

Estradiol and progesterone treatment may improve cartilage health

The study authors were able to examine cartilage samples at various points in the menopause transition. They identified various increased and decreased proteins in the samples and found that cellular signaling changes happened before changes to the extracellular matrix of the cartilage.

They also observed decreases in certain types of collagen and an increase in another type common in diseased cartilage. These and other findings suggested that menopause increases the likelihood of collagen degrading.

Researchers then wanted to see the effect of giving mice 17beta-estradiol and progesterone after induction of menopause. Some mice received 17beta-estradiol, others received progesterone, and others received both.

These results were compared to results in mice that received the medication dasatinib and no intervention. Mice received these interventions at the halfway point of irregular cycles, mid-perimenopause, through to the start of menopause.

They found that mice that received either 17beta-estradiol alone or 17beta-estradiol and progesterone experienced improved cartilage integrity and return of gait to pre-menopausal parameters. However, no treatments impacted the subchondral bone or synovium.

Researchers also gathered data from human chondrocyte cellsTrusted Source, which are cartilage cells. The samples were from women over 60 who underwent a total knee replacement.

They looked at how various levels of sex hormones impacted the chondrocytes. Their observations suggest that progesterone blunts the aging of the menopausal chondrocytes, and combined 17beta-estradiol and progesterone best improves chondrocyte health.

Samples treated with 17beta-estradiol and progesterone saw an increase in cartilage formation markers.

Study author Fabrisia Ambrosio, PhD, MPT, the Atlantic Charter Director at the Discovery Center for Musculoskeletal Recovery, Schoen Adams Research Institute, Spaulding Rehabilitation Hospital, explained the highlights of the research to Medical News Today:

“Our study addresses a critical gap in our understanding of how menopause impacts cartilage health and why postmenopausal women face a much higher risk and severity of osteoarthritis compared to age-matched men. To explore this disparity, we employed a laboratory model using mice to mimic the hormonal changes that occur during menopause in humans. We discovered that the loss of two key sex hormones, 17beta-estradiol and progesterone, after menopause significantly increases cartilage vulnerability with aging.”

Future research to confirm findings in humans

Since this study was conducted primarily in mice, this raises the question to what extent its findings actually apply in people.

Moreover, since menopause was chemically induced in the mice, there may have been other systemic changes at play, and researchers did not examine these. Researchers also did not examine pain behaviors, a major component of osteoarthritis.

Kecia Gaither, MD, MPH, MS, MBA, FACOG, double board-certified in obstetrics and gynecology and maternal fetal medicine, who was not involved in this study, told MNT that: “Murine models of research, while enlightening, don’t fully replicate the human body. [The findings] thought-provoking as to potential therapeutics, but certainly more research need be done.”

The study authors also acknowledge that there could have been an interaction between the mice’s weight and menopausal status. This could be helpful to examine with future research.

Furthermore, here may have been confounding regarding the results for quantified bone loss. This is because the type of mice the researchers used all experience bone loss starting at around 6 to 8 months old.

Also, when looking at the intervention of taking 17beta-estradiol and progesterone, researchers only gave these until the start of menopause, which could have impacted the results.

The authors note that future research can explore how hormonal interventions affect the synovium and subchondral bone, as this research did not observe a change in these structures following the hormonal intervention.

Additionally, some mice in the groups that received only 17beta-estradiol or only progesterone experienced neoplasms and hyperplasia in the intestines. Thus, it may also be important to look into the adverse effects of hormones moving forward.

Aside from gait changes, the observed activity of the mice was similar across groups. The gait changes were different from previous research in mice with post-traumatic osteoarthritis.

Researchers also assumed that the women they collected tissue samples from were postmenopausal, as all women were over 60.

Finally, the research focused on knee osteoarthritis, and examining additional joints may be helpful in future research.

Future research can confirm the mechanisms at play and whether it matches the data found in this study.

Speaking of future research, Ambrosio noted:

“Building on the insights from this study, future research aims to develop targeted therapeutics not only for osteoarthritis but also for other menopause-associated musculoskeletal disorders, such as back pain. By exploring these broader implications, we hope to advance comprehensive treatments that address multiple facets of musculoskeletal health during aging.”

Can hormone therapy treat osteoarthritis?

This study paves the way for additional research into more effective osteoarthritis treatments. According to Ambrosio, “these findings provide valuable insights into the underlying mechanisms of osteoarthritis and offer a foundation for bridging the gap between lab-based discoveries and real-world solutions for individuals living with this condition.”

“Understanding why postmenopausal women are disproportionately affected by osteoarthritis is a critical step toward designing effective interventions,” she pointed out. “Our findings lay the groundwork for strategies we hope will eventually slow, mitigate, or even prevent the onset of this debilitating disease, improving the quality of life for millions of individuals.”

There should also be caution and more research when it comes to the use of hormone replacement therapy.

Fiona Watt, MBBS, BMedSci, PhD, a consultant rheumatologist and senior researcher at Imperial College London, in the United Kingdom, who was not involved in the study, noted: “The study suggests that hormone replacement reduced markers of senescence and promoted chondrogenic markers suggesting potential for regeneration. I think this is entirely conceivable but not yet proven in humans and these results should increase research activity in the fields of endocrinology, women’s health and [osteoarthritis] to understand these relationships better in translational human studies.”

“The question arises of whether we should consider use of hormone replacement therapy, either to prevent osteoarthritis or try to treat it if it occurs in post menopausal populations. This would be outside of its existing licenses. We lack evidence in humans to support this currently and fully powered human randomised clinical trials in populations at risk of or with osteoarthritis are needed to better understand whether [hormone replacement therapy] or similar agents would be efficacious.”– Fiona Watt, MBBS, BMedSci, PhD

https://www.medicalnewstoday.com/articles/why-are-older-women-predisposed-to-osteoarthritis