Is relaxin the reason?

Osteoarthritis (OA) of the hand joints represents the second most common site of osteoarthritis overall, and the economic and work-related costs are high. Arthritis of the basilar joint of the thumb, or the trapeziometacarpal (TMC) joint, can be functionally debilitating, and patients may be unable to turn a doorknob or remove a jar top.

A large sex difference is found in the presentation of symptomatic TMC arthritis, with women noting basilar thumb pain more frequently than men. In the Framingham population study, for example, women older than age 70 had a higher prevalence of symptomatic arthritis in nearly every hand joint, with an odds ratio of 3:1 compared to men. In census studies, women have shown a prevalence rate of 24.3 percent for basal thumb arthritis, which is significantly higher than the prevalence rate among men (10.3 percent).

Joint laxity
The reasons for the higher prevalence of osteoarthritis in general and basal thumb joint arthritis in particular among women are not known. Hormonal differences between the sexes have been proposed as one explanation for this phenomenon. Joint laxity, which is known to be greater in women than men, is another theory.

In studies of knee OA, varus-valgus laxity is associated with loss of joint space and decreased function, with women showing higher laxity values than men. A study in cadavers demonstrated greater axial rotation of female knees with loading, suggesting that abnormal loading due to increased laxity may predispose to osteoarthritis.

Generalized joint laxity, defined as greater than average motion, is seen more frequently in younger persons and in women. A more pathologic form, hypermobility syndrome, is also seen more frequently in women and is associated with more frequent joint sprains and injuries, as well as more prolonged recovery and therapy.

In a more extreme form of joint laxity, among 24 patients (average age, 16 years) with Ehlers–Danlos syndrome, 66 percent had subluxation of the TMC joint and 16 percent had radiographic OA. This indicates that abnormal degrees of joint laxity may lead to asymmetric joint loading with subsequent arthritic wear over time.

Is relaxin responsible?
Relaxin has been proposed as a hormonal target responsible for joint laxity in females. Relaxin, a member of the insulin superfamily of peptides, is produced in women primarily by the corpus luteum during pregnancy, to modulate softening of the cervix and pubic symphyseal ligaments in preparation for giving birth.

Relaxin has also been characterized in the reproductive tract of males, specifically in the prostate and vas deferens. Relaxin’s effect on the extracellular matrix occurs through the induction of matrix metalloproteases (MMPs), specifically MMP-1 (collagenase) and MMP-3 (stromelysin), and through downregulation of the tissue inhibitor of matrix metalloprotease-1 (TIMP-1).

Relaxin upregulates an enzyme that has been directly linked to OA and may represent another pathway in TMC arthritis. MMPs have been shown to have an active role in joint destruction in osteoarthritis. MMP-1 plays a primary role in cartilage and bone destruction by degradation of type I and II collagen, and MMP-3 mediates destruction of the extracellular matrix.

Relaxin receptors are present in the anterior oblique ligament in the TMC joint complex, as immunohistochemical binding has demonstrated. In a study of 8 ligament samples obtained from women undergoing surgery for thumb TMC arthritis, immunohistochemical binding of antibody to relaxin receptors was found. However, the presence of receptors does not indicate when or how they are activated.

Relaxin as a potential explanation for the increased prevalence of osteoarthritis in women may have two mechanisms of action. First, by increasing basal thumb laxity early in life, relaxin may predispose the joint to later OA degeneration. If the expression of relaxin and the number of receptors at the anterior oblique ligament are higher in women than in men, relaxin’s effect on the ligament would be increased in women during the years of childbearing potential, leading to increased laxity of this joint and abnormal biomechanical loading with use. Uneven loading of the joint would then cause OA over time. In addition, upregulation of MMPs and downregulation of TIMP-1 by relaxin as a direct effect could add to this process, setting off a destructive cascade of cartilage and bone loss and leading to arthritis.

With the aging of the U.S. workforce and the growth in the elderly population, the effect of painful arthritis of the hand can be devastating in terms of lost work and inability to perform normal daily functions such as fine pinch and manipulation of small objects. More research on this problem is clearly needed if we are to help keep seniors active and independent. If relaxin levels are identified as a risk factor in women, potential preventive strategies might include modification of thumb use, splinting, or intra-articular blockade of relaxin’s effect on the carpometacarpal joint of the thumb.

Until more research is available, when a middle-aged patient—male or female—complains of hand pain, basilar thumb arthritis should always be ruled out. Orthopaedists should perform an examination for generalized joint laxity, as well as tenderness at the base of the thumb, and take a radiograph to confirm findings of arthrosis of the basilar thumb joint.

Jennifer Wolf, MD, is an associate professor of orthopaedic surgery at the University of Connecticut Health Center; she can be reached at jmwhand@hotmail.com

Karen B. King, PhD, is an associate professor in orthopaedic surgery at the University of Colorado-Denver. Allison E. Williams is the associate chief of nursing (research) at the Denver VAMC.

Putting sex in your orthopaedic practice
This quarterly column from the AAOS Women’s Health Issues Advisory Board and the Ruth Jackson Orthopaedic Society provides important information for your practice about issues related to sex (determined by our chromosomes) and gender (how we present ourselves as male or female, which can be influenced by environment, families and peers, and social institutions). It is our mission to promote the philosophy that male and female patients experience and react to musculoskeletal conditions differently; when it comes to patient care, surgeons should not have a one-size-fits-all mentality.