The Influence of Sex and Gender on Musculoskeletal Health:Symposium Report

Oral presentation: Section A

Historically, studies that looked at differences in men's and women's health assumed that women were "little men" and were limited to topics associated with the reproductive system (breast cancer and menopause, prostate cancer). Today, medical researchers in virtually every discipline are beginning to realize that every organ in the body, not just those related to reproduction, has the capability to respond differently on the basis of sex (see Endnote), and that these different responses are determined genetically as well as hormonally. In other words, a male cell is not the same as a female cell, and sex chromosome-linked genes can be expressed in both germ-line and somatic cells. It remains to be seen, however, just how sex and gender differences impact health, disease, and medical conditions.

Musculoskeletal medicine is one of the areas in healthcare in which appreciation of the effects of sex and gender most influences treatment and outcome. Musculoskeletal complaints such as osteoarthritis, osteoporosis, spinal disorders, and fractures, comprise an extremely large proportion of visits to primary care and orthopaedic physicians and all have a higher prevalence in women. Yet most clinicians are unaware of the sexual differences associated with these problems.

In the last five years, there has been an increased awareness that differences in the incidence of musculoskeletal diseases, conditions, and sport injuries between males and females are based on inherent differences in biology at the cellular and molecular level. There is a biologic basis for the differences in injury mechanism, pain sensation, drug handling, and healing response that go far beyond estrogen and testosterone levels. Responses to therapy (e.g., surgery, anesthesia, pain medication, pharmaceuticals, rehabilitation, etc.) also differ with sex. What these differences are due to and how they might impact health care delivery are not well understood. This is in part because the mechanisms involved have not been well described, nor have they been correlated with clinical observations or disseminated to clinical audiences. In many cases, therapeutic modalities have been optimized for males, based on preclinical assessments using male animal models. Only in limited instances have these sex-specific differences been considered in defining how clinical care should be provided. Numerous studies show that chronic musculoskeletal pathology is greater in females than in males, yet little is known about why this is the case.

The American Academy of Orthopaedic Surgeons (AAOS) Symposia (formerly the AAOS Workshops) are now in their 17^th year. Throughout their history, the AAOS Symposia have served to define gaps in knowledge concerning skeletal biology and to explore new directions for basic research in orthopaedics. The purpose of this particular symposium was to bring to the orthopaedic field the advances that have been made in the understanding of how male and female biology and physiology impact on musculoskeletal health by bringing basic scientists and engineers together with clinicians who treat the musculoskeletal patient at all stages of their care. In addition, the symposium sought to identify new areas of research related to sex and gender issues in musculoskeletal health.

The specific aims of the symposium were to:

1. Define the current state of knowledge concerning sex-specific differences in musculoskeletal biology, physiology and related sciences (including anesthesia, analgesia, and rehabilitation).

2. Review and discuss current clinical studies and clinical trials related to musculoskeletal diseases and conditions that affect females to a greater degree than males.

3. Identify areas of need for new basic and clinical research.

4. Define needs and opportunities for applications of advanced research to clinical practice.

5. Identify future needs that will arise when translating research to the clinical setting.

6. Stimulate the research agenda and provide education to the musculoskeletal community and practicing physician in the form of an immediate publication via the Internet.

7. Publish summary articles in journals read by the musculoskeletal community and practicing clinician.

8. Provide on-going clinical studies and trials information updates to the musculoskeletal community and the practicing physician via the Internet.

Speakers were selected based on their expertise in the field. Some speakers were selected for their expertise in sex and gender biology in fields outside of orthopaedics and dentistry in order to enhance opportunities for cross-fertilization of research approaches. Each speaker wrote a brief paper, which included recommendations for future research directions.

Throughout the presentations it was apparent that there are sex and gender based differences in cell biology, tissue function, and disease presentation and management that affect how orthopaedic surgeons should manage their patients. Additionally, every attendee indicated that they planned to go back to their offices and laboratories and determine whether they were seeing sexual dimorphism in their studies. Furthermore, basic science data indicated that while estrogen and testosterone were important determinants of musculoskeletal sexual dimorphism, they were not the only ones. It was also pointed out that earlier studies pointing to differences in male and female bone properties and bone cell behavior should be revisited. Thus the meeting served as a reminder and a stimulus to all investigators to consider the possibility that sex is playing a role when interpreting their data.

The overarching recommendations of the symposium mirrored many of the conclusions of the recent Institute of Medicine report Exploring the Biological Contributions to Human Health: Does Sex Matter?. The symposium emphasized the need to:

1. Monitor sex differences and similarities in incidence, diagnosis, prognosis, and treatment for all musculoskeletal diseases that affect both sexes.

2. Conduct longitudinal and cross-sectional studies that can be analyzed by gender.

3. Make sex-specific data in musculoskeletal diseases and disorders more readily available.

4. Mine cross-species information and develop relevant in vivo and in vitro models that incorporate the biological clock.

5. Expand research on sex differences in neural organization and function, pain, and analgesia.

6. Promote research on sex at the molecular, cellular, and tissue levels with specific emphasis on musculoskeletal diseases.

Endnote

Based on the Institute of Medicine report Exploring the Biological Contributions to Human Health: Does Sex Matter?, "sex" was defined in this program as "the classification of living things, generally as male or female according to their reproductive organs and functions assigned by the chromosomal complement," and gender as "a person's self-representation as male or female, or how that person is responded to by social institutions on the basis of the individual's gender presentation." While both the biologic (sex) and environmental (gender) differences are important to the researcher and clinician dealing with musculoskeletal problems, the emphasis of this conference was on the differences between males and females.

Acknowledgements

Co-sponsored by American Academy of Orthopaedic Surgeons, National Institute of Arthritis and Musculoskeletal and Skin Diseases and Office of Research on Women's Health, National Institutes of Health. In addition, the Orthopaedic Education and Research Foundation provided an educational grant in support of the symposium. Other sponsors included Kyphon, Inc., OrthoLogic Corp., Pfizer, Inc., EBI, LP, and the Orthopaedic Research Society.

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