Sept. 2, 2005 — Women receiving estrogen-depleting treatments may develop "menopausal arthritis," according to a review article published in the September issue of Arthritis & Rheumatism. The authors suggest that the symptoms are usually transient and resolve with estrogen therapy or when aromatase inhibitors are discontinued.

"Effective new treatments for breast cancer, aromatase (estrogen synthetase) inhibitors, powerfully block the conversion of androgen precursors into estrogens, which thus lowers plasma estradiol levels to close to or below the detection limit of current assays and lowers levels of estrogen in peripheral tissues," write David T. Felson, MD, from Boston University in Massachusetts, and Steven R. Cummings, MD, from the University of California, San Francisco. "Because aromatase inhibitors reduce the rates of recurrence in women treated for early-stage postmenopausal breast cancer, these agents are becoming widely used in breast cancer treatment and are being explored as a treatment to prevent disease in women at high risk. Thus, their use is likely to increase."

The authors review trial data showing that women treated with aromatase inhibitors often develop musculoskeletal and joint pain or aching sometimes leading to treatment discontinuation. They also review biologic mechanisms linking estrogen deprivation with joint pain, both in natural menopause and in pharmacologic estrogen deprivation.

Although estrogen is not known to specifically affect articular structures in a manner that would cause joint pain, it influences inflammation and neural processing of nociceptive input via tissue-specific effects on inflammatory cytokines and direct effects on opioid pain fibers in the central nervous system (CNS).

Less is known about the specific effects of aromatase-containing cells on nociceptive fibers. The best evidence that decreased estrogen production may cause arthralgias comes from trials of aromatase inhibitors for the treatment or prevention of breast cancer. Compared with women receiving placebo or tamoxifen, those receiving aromatase inhibitors have greater frequency of arthralgia.

"Although arthralgias, diffuse pain, and myalgias have all been described, the particular range of syndromes induced by aromatase inhibitors and leuprolide is not clear," the authors write. "It is possible that the syndromes described as 'menopausal arthritis' and those produced by estrogen deprivation are different and that some are associated with pain outside joints, including generalized pain syndromes and prominent myalgias. More study is needed to better define these syndromes."

In the estrogen and progesterone group of the Women's Health Initiative (WHI), women receiving hormone therapy had significantly reduced "bodily pain," but other studies had conflicting results. Estrogen deprivation may cause arthralgias, but estrogen replacement may not necessarily treat musculoskeletal pain effectively because the synthetic hormone may deliver a supraphysiologic estrogen dose.

When objective findings accompany arthralgias, this may result in an erroneous diagnosis of osteoarthritis or rheumatoid arthritis in women who might not otherwise be diagnosed.

"The 'menopausal arthritis' described in several historic case series and reports of menopausal arthralgias from Asia may be related in pathogenesis to the symptoms induced by pharmacologic agents, especially aromatase inhibitors, agents that deplete estrogen," the authors conclude. "A small but significant proportion of women receiving estrogen-depleting treatments develop this musculoskeletal syndrome, a syndrome that has not been widely appreciated. It is important to recognize that the symptoms are usually transient and resolve with estrogen therapy or when these agents are discontinued."

The National Institutes of Health supported both authors, and Dr. Cummings' work was also supported by an unrestricted educational grant from Eikon Medical Communications.

Arthritis Rheum. 2005;52:2594-2598