Published in Post Reproductive Health

Abstract
Arthralgia is a common complaint around the time of menopause in many women. It is estimated that over 50% of women experience arthralgia or arthritis at the time of menopause. The complex of symptoms has been linked to the joint and tendon response to the decline in sex hormones as well as sarcopenia, or loss of muscle volume associated with aging. The diagnosis of “arthritis of menopause” has been identified since 1925, but treatments have been symptomatic at best.1,2 Joint synovium and cartilage interaction with estrogen is well documented. This article reviews the literature regarding the current approaches to treatment of arthralgia of menopause.

Keywords
Postmenopause, menopause, alternative therapies

Methods
Acomprehensive review of the literature written on this topic was conducted from November 2022 to March 2023, including the search terms “arthritis of menopause,” “sarcopenia,” “climacteric arthritis,” “soy isoflavones” the compounds “puerain, daidzin, anddaidzein.” Data collection included articles written in the past 100 years obtained through PubMed, Medline, Google Scholar, and OVID. Articles included include in this review were primarily from the past 10 years and had large numbers of participants.

Menopause is defined as a physical period of transition that signifies the end of a woman’s reproductive years. Typical symptoms of menopause attributed to the reduction in circulating levels of estrogen and progesterone are hot flashes, night sweats, urogenital symptoms, disturbed sleep, mood and memory changes and sexual dysfunction.3 Little is written about the condition known as “arthralgia of menopause,” even though it has been described since 1925. Cecil and Archer wrote in their landmark 1926 article; “‘Arthritis of the menopause’, a subset of degenerative arthritis affecting women around age 52. Interestingly some of its clinical features such as early knee involvement, lumbar pain, Heberden’s nodes, and association with obesity resemble those of OA.”4 The effects of decreasing estrogen on the joint synovium and cartilage are often misdiagnosed as rheumatoid arthritis (RA), degenerative osteoarthritis, or fibromyalgia. Morning stiffness and swelling of the distal interphalangeal joints and proximal interphalangeal joints in peri- and post-menopausal women often mimic rheumatoid arthritis (RA) and osteoarthritis (OA). One article indicated that close to one half of the diagnosed cases of RA are misdiagnosed, and the correct diagnosis was menopausal arthralgia or menopausal OA.5
The condition of menopausal arthralgia is often confounded by sarcopenia, or the accelerated loss of muscle mass and strength, and replacement of muscle volume with fat, that occurs around the time of menopause for women. The definition of sarcopenia is clinically defined as “2 standard deviations below the mean appendicular muscle mass of young healthy adults.” For women, this occurs typically in the fifth to sixth decade with functional impairments are seen such as difficulty maintaining balance, difficulty rising from a chair, decreased walking speed, and difficulty climbing stairs. The mechanism of action is primarily due to an imbalance in muscle protein synthesis and breakdown, as well as the increase in catabolic factors such as inflammation and oxidative stress.

A growing body of evidence is supporting that the post-climacteric decline in muscle mass may be linked to the loss of estrogen that accompany the menopause. Sarcopenia can also be related to the decrease in physical activity that often accompanies aging, as well as a decrease in protein status, and weight gain with increase in visceral fat content. During this process, there is replacement of muscle tissue with fat, the combination of events making the diagnosis difficult to isolate to only one cause. It is estimated, however, that postmenopausal women have a decline of 0.6% of muscle mass per year if sarcopenia is left untreated.

Several mechanisms of action for interarticular changes in postmenopausal woman have been proposed. Estrogen binding sites are present in synoviocytes and CD8+ memory T-cells. Estrogens modulate macrophage maturation. The medication class called “aromatase inhibitors” (AI), used for the treatment of postmenopausal breast cancer, chemically decreases estrogens. The side effects of AI’s are well known and include joint pain and arthralgia. In addition, cartilage metabolism is affected by the loss of estrogen, and estrogen receptors (ER) have been demonstrated on chondrocytes. 3 Radiographic studies of the rate of cartilage loss in the knee demonstrate women’s cartilage deteriorates at a faster rate than men, and the difference becomes more prominent after age 50.7 Estradiol loss has also been linked to autoimmunity through the suppression of NF-kappa B, and transient activation of T and B lymphocytes as well as production of inflammatory cytokines IL-6 and TNF alpha, all hallmarks of chronic inflammation.

Medication treatment of estrogen-related arthralgia have largely been symptomatic, and the use of estrogens in postmenopausal women should be balanced against its known risks.11 Estradiol is known to increase skeletal muscle mass though stimulating satellite cell production; however, the role of estradiol to specifically treat or prevent sarcopenia is contradictory. Human studies on Selective Estrogen Receptor Modulators (SERMS) have demonstrated beneficial effects on cartilage metabolism and bone biomarkers in women, but are also not without side effects.12 Traditionally, anti-inflammatory medications are used, which interrupt the inflammation but do nothing to address the estrogen receptor influence on the joint itself. Drugs in this class may disrupt the inflammatory cascade of cytokines to control pain, but may miss the root cause of the arthralgia. The increaseinIL-6 and TNF alpha that occurs during this time has been associated with physical disability and decline in function, but prior to this occurrence falling estrogen levels affect the function of the joint tendon and cartilage.

The hormone dehydroepiandosterone (DHEA) is a precursor to sex steroids and a pro-hormone that has been associated with increased lean muscle mass. Studies are mixed on effectiveness in postmenopausal women.DHEA is known to increase lean muscle mass and decrease fat mass, as well as improve glucose and insulin levels. Circulating levels of DHEA decline with age, and this effect is especially prominent after menopause in women. Declining levels of DHEA have been associated with decrease in physical performance, but studies do not agree on the “off-label” use of DHEA for pre-sarcopenia and sarcopenia treatment.

Alternative and complementary options to medical management of arthralgia of menopause focus on soy isoflavone supplementation and controlling inflammation through diet and weight loss. Isoflavones can be found in soy beans, legumes and soybean products. One study on obese sarcopenic postmenopausal women found that 70 mg/ day of soy isoflavone supplementation over 24 weeks significantly increased lean muscle mass. Another less known isoflavone is an herb commonly used in traditional Chinese medicine called Kudzu root or Gen Ge. It has shown promise in the treatment of postmenopausal arthralgia. Use of Kudzu root extract originates in China, and is known to contain isoflavones that possess phytoestrogenic effects similar to the class of medications known as SERMs. SERMs are medications used for the treatment of osteoporosis in women, but have not been evaluated for the use of arthritis of menopause. Kudzu root has been used in traditional Chinese medicine for over 1200 years. The compounds found in Kudzu root extract, puerain, daidzin, and daidzein, have been compared to hormone replacement in some studies.

In a randomized trial of 50 women (age 54.2 years, SD 2.9) using kudzu root extract over a 28 day period, there was a statistically significant improvement in biomarkers for bone resorption and cartilage degradation. During the trial, no adverse effects were seen in blood parameters, blood pressure, or heart rate. The study used a maximum daily dose of 338 mg of puerarin, but separated participants into varied dosing schedules.

In the same study, biomarkers of bone resorption and cartilage degradation showed statistically significant improvement with 4 weeks of two capsules three times a day of 28 G puerain.
A second study using the kudzu flower with the addition of mandarin peel involving 84 women at the time of menopause, found statistically significant improvement on bone markers with high tolerability and few side effects.

Animal studies using ovariectomized rats dosed with Kudzu root extract demonstrate similar statistically significant effects on increased bone mineral density and reduction of cartilage degradation.

Other approaches to addressing arthralgia of menopause and attenuated age-related muscle loss utilize strength through resistance training to improve muscle mass, balance, and pain of menopausal arthalgia.14 In one study comparing different types of resistance training, blood flow restricted low load resistance training was particularly effective for the treatment and prevention of sarcopenia in the elderly.

Conclusion
Arthralgia of menopause is a common complaint affecting close to 50% of all women at the time of menopause.Blumer 97 Decreasing levels of estrogen affect the joint synovium and cartilage, and may play a role in sarcopenia found in older adults. The condition of arthralgia of menopause is commonly misdiagnosed as age related OA, fibromyalgia, or RA. Pharmacological options for treatment focus on HRT supplementation or decreasing inflammation and pain. Nonpharmalogical approaches include weight loss and exercise, isoflavone supplementation, such as soy, legumes, and Kudzu root or puerain. The pre-hormone DHEA may also have protective effects on lean muscle mass in patients with sarcopenia, but more studies are needed. Finally, resistance training has been proven as effective in age related sarcopenia and provides benefit to the effects of arthralgia of menopause. More studies are needed on the most effective combination and frequency of interventions for both treatment and prevention of these conditions. Awareness of the impact of decreasing estradiol on bone, cartilage, and muscle health is also crucial for physicians to be able to recommend a treatment plan specific to the cause, not the effect, of age-related muscle and bone loss.

Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD
Janice Blumer https://orcid.org/0000-0001-6352-6235