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
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
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
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
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