As women enter perimenopause and menopause, a majority will experience musculoskeletal symptoms associated with estrogen loss that has been collectively described as the “ musculoskeletal syndrome of menopause,” referring to arthralgia, loss of bone density and muscle mass, and progression of osteoarthritis (OA).

“New-onset arthralgias in perimenopause and postmenopause are considered common,” according to Jaime Vondenberg, DO, a rheumatologist at Cleveland Clinic in Cleveland. “Roughly 70% of women experience musculoskeletal symptoms in perimenopause.”

But whether the typical signs and symptoms of “musculoskeletal syndrome of menopause” may reflect other underlying pathology calls for close evaluation, according to experts who spoke with Medscape Medical News.

A handful of studies over the past few years reinforce earlier findings that document the rise in risk for muscle or joint pain experienced by perimenopausal and postmenopausal women compared with premenopausal women. This rise in risk coincides with recent study data indicating that postmenopausal women have 35% higher likelihood of developing rheumatoid arthritis (RA) than do premenopausal women, which rises to threefold higher odds for women with early-onset vs later menopause. There is also evidence that postmenopausal women with clinically suspect arthralgia have nearly threefold higher risk of developing anti-citrullinated protein autoantibody (ACPA)-negative inflammatory arthritis. This risk for ACPA-negative inflammatory arthritis is 11 times higher in women with early-onset menopause at or before the age of 45.

Possible Mechanisms

Several proposed mechanisms may contribute to the elevated rates of arthritis and arthralgia reported in perimenopausal and postmenopausal women.

“Estrogen deficiency is thought to play a central role by reducing protective estrogen receptor signaling in bone, cartilage, tendon, and muscle, leading to cartilage thinning, bone loss, and accelerated joint degeneration,” said Micaela Bayard, MD, a rheumatologist and associate professor of medicine at The Icahn School of Medicine at Mount Sinai in New York City. “Declining estrogen and progesterone also promote immune dysregulation, shifting the immune system toward a more proinflammatory state that may facilitate inflammatory arthritis in susceptible individuals.”

In OA specifically, Aysegul Atasoy-Zeybek, PhD, assistant professor of physical medicine and rehabilitation at Mayo Clinic in Rochester, Minnesota, conceptualizes menopause as a biologic amplifier of susceptibility rather than an independent cause.

“The increase in OA after menopause occurs in parallel with chronological aging, accumulated joint injury, changes in body composition, muscle loss, and cardiometabolic risk,” she explained. In a recent review, she and her colleagues “proposed that the most useful framework is the intersection between loss of ovarian hormones and age-related failure of joint homeostasis, particularly cellular senescence, chronic low-grade inflammation, and extracellular-matrix degradation.”

Estrogen is likely not the only hormone involved in musculoskeletal morbidity in menopause, Atasoy-Zeybek said. “Menopause also involves loss of progesterone, changes in androgens, and marked increases in gonadotropins such as follicle-stimulating hormone.”

In a recent study in which investigators chemically induced menopause in middle-aged female mice, the findings indicate loss of both estrogen and progesterone as possible mechanisms driving cartilage degeneration in an OA model.

“Notably, combined treatment of estrogen and progesterone at the perimenopausal stage reduced cartilage degeneration in mice,” said study co-author Fabrisia Ambrosio, PhD, professor of physical medicine and rehabilitation at Harvard Medical School in Boston. “We are now focused on understanding how we can translate these mechanistic findings into more effective interventions for patients.”

Finally, Vondenberg pointed to sleep disruption and changes in body composition, including loss of muscle mass, as indirect mechanisms that may influence the risk for musculoskeletal morbidity in menopause.

Screening, Evaluation, and Referral

For primary care physicians (PCPs) evaluating perimenopausal and postmenopausal women with new-onset musculoskeletal symptoms, the “priority is distinguishing common menopausal arthralgia from true inflammatory arthritis,” Bayard said. New clinically detectable synovitis, prolonged morning stiffness, constitutional symptoms, or progressive functional impairment should prompt evaluation with complete blood count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and anti-cyclic citrullinated peptide (CCP) antibodies.

The presence of objective synovitis or high-titer anti-CCP positivity warrants immediate referral to rheumatology, Bayard advised. However, menopause-associated RA is often seronegative, so negative serologies should not preclude a rheumatology referral for patients with persistent inflammatory symptoms.

Plain films of symptomatic joints can help to further distinguish OA pain from inflammatory arthritis, Vondenberg noted.

For rheumatologists, evaluation of patients with menopausal arthralgia should include a detailed reproductive history, including age at menopause, surgical vs natural menopause, and use of hormone therapy or aromatase inhibitor, all of which influence arthritis risk and symptom interpretation, according to Bayard. “The differential diagnosis should also include polymyalgia rheumatica, crystal arthritis, RS3PE [remitting seronegative symmetrical synovitis with pitting edema], and when clinically indicated, occult malignancy.”

Comprehensive screening for musculoskeletal problems in perimenopausal and postmenopausal women should include bone density and muscle/strength assessment alongside the joint evaluation, Atasoy-Zeybek added.

“When middle-aged women present with new joint pain, it is important to determine where they are in the menopausal transition” to guide appropriate education and management strategies, said Heidi Prather, DO, attending physician at Hospital for Special Surgery (HSS) and founder and medical director of the HSS Lifestyle Medicine Program in New York City. “Women may not offer the information without being asked, as they may be unaware of the links between hormone changes and soft tissue and joint pain.”

Treatment Considerations

For some women, the chronic systemic inflammation associated with estrogen loss can be well managed with lifestyle and conventional medical interventions including hormone replacement therapy (HRT), Prather explained. “For others, things can seem out of control, and usual care is not as effective.”

“Treatment of new-onset arthritis or arthralgia during the menopausal transition should be guided by the underlying diagnosis,” Bayard said. “If inflammatory arthritis is strongly suspected and rheumatology evaluation will be delayed, PCPs may initiate a conventional DMARD [disease-modifying antirheumatic drug], most commonly methotrexate.”

Treatment with glucocorticoids should be minimized due to increased risk for osteoporosis, infection, diabetes, and cardiovascular disease with long-term use, she cautioned.

Given the high prevalence of menopausal arthralgia, many of these referrals will not have inflammatory arthritis, Vondenberg noted. “As such, a multidisciplinary approach should be taken in the setting of perimenopausal arthralgias to address sleep, weight changes, mood and vasomotor symptoms.”

Additionally, “HRT can be considered for musculoskeletal complaints, always aiming to utilize the lowest effective dose for the shortest duration and through the guidance of a woman’s health professional familiar with prescribing HRT,” Vondenberg said.

Limited evidence showed a modest improvement in joint pain and a significant reduction in the incidence of new-onset musculoskeletal symptoms in postmenopausal women receiving HRT vs placebo. However, there have been no large randomized controlled trials focused on HRT as a treatment for menopausal joint pain.

“HRT should be avoided in women with contraindications such as prior breast cancer, venous thromboembolism, stroke, coronary heart disease, or active liver disease, and abrupt discontinuation should be avoided because it may precipitate or worsen arthralgia,” according to Bayard.

For OA, the most appropriate comprehensive strategy is “careful differential diagnosis, evidence-based management, optimization of muscle and bone health, and individualized HRT decisions based on established menopausal indications and the patient’s overall benefit-risk profile,” Atasoy-Zeybek said.

Remaining Needs

Along with randomized controlled trials exploring HRT specifically for menopause-associated arthritis, Vondenberg cited the need for longitudinal studies that would follow women from perimenopause through postmenopause with standardized musculoskeletal outcomes.

Prather pointed to the need for studies assessing “modifiable and nonmodifiable factors to best arm women with the information they need to manage and improve their health” across the menopause transition and beyond.

“The menopause experience is a continuum, not an endpoint destination,” she said. “Our education and interventions should reflect this.”

Ambrosio, Atasoy-Zeybek, and Vondenberg reported having no relevant disclosures. Bayard reported having a paid partnership with Biogen’s lupus advocacy project and serving on the BlueCross and BlueShield Pharmacy and Medical Policy Committee. Prather reported receiving honoraria from Varian Medical Systems.