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Does Sex Matter in Musculoskeletal Health? the Influence of Sex and Gender on Musculoskeletal Health*

Posted on: Saturday, 23 July 2005, 03:00 CDT

An AAOS/NIH Workshop Report

Disease prevalence rates differ for men and women; this comes as news neither to physicians nor to laypersons. Likewise, women's life expectancies differ from those of men. Among some populations, this difference is dramatic. For example, the National Center for Health Statistics reports that, in 2001, the life expectancy of a black American woman was 75.5 years and that of a black American man was just 68.6 years1. Worldwide, women live, on the average, between four and ten years longer than men do.

Historically, studies that have examined differences in men's and women's health have assumed that women were "little men,"2 and were limited to topics associated with the reproductive system, e.g., breast cancer and menopause, and that sex differences outside the reproductive system could be explained by variations in height, weight, body fat percentage, etc. Until the past decade, it was not possible to explore the basis of the differences in disease prevalence and morbidity and mortality between men and women at the genetic and cellular levels. Today, however, emerging information from such studies provides a compelling case for the existence of innate, and heretofore unexamined, differences between men and women. Medical researchers in virtually every discipline are now beginning to realize that every organ in the body, not just those related to reproduction, is capable of responding differently on the basis of sex, and that these different responses result from chromosomes as well as hormones. In the Institute of Medicine report3, Exploring the Biological Contributions to Human Health: Does Sex Matter?, "sex" is defined 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" is defined 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. 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. However, it remains to be seen to what extent sex differences impact health, disease, and medical conditions.

Musculoskeletal medicine is one of the areas in health care in which the effects of sex and gender (as defined above) most influence treatment and outcome. Musculoskeletal problems, such as osteoarthritis, osteoporosis, spinal disorders, and fractures, comprise an extremely large proportion of visits to primary care and orthopaedic physicians; all have a higher prevalence in women (Table I). Yet most clinicians are unaware that the sexual differences associated with these problems are the result of 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 cannot be explained simply by hormone levels. Responses to therapy (e.g., surgery, anesthesia, pain medication, pharmaceuticals, and rehabilitation) also differ with sex. What these differences are due to and how they might impact health-care delivery are not well understood. Similarly, numerous studies have shown that chronic musculoskeletal disorders are greater in females than in males, yet little is known about why this is the case. 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 most cases, therapeutic modalities, based on preclinical assessments with use of animal models, have been optimized for males. Only rarely have sex-specific differences been considered when defining how best to provide clinical care.

TABLE I Prevalence of Musculoskeletal Diseases in Men and Women

To explore the advances that have been made in understanding how male and female biological and physiological characteristics affect musculoskeletal health for the orthopaedic community, the American Academy of Orthopaedic Surgeons (AAOS), the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the Office of Research in Women's Health at the National Institutes of Health (NIH), organized a four-day workshop. Basic scientists, engineers, and clinicians from a broad spectrum of fields that treat and investigate musculoskeletal conditions at all stages of disease assembled at Hunt Valley, Maryland (see Appendix). The workshop sought to prioritize areas of research related to sex and gender in musculoskeletal health.

Fig. 1

X-chromosome inactivation in female somatic cells. This drawing shows that there is random inactivation early in the development in the maternal X chromosome. Females are therefore epigenetic mosaics. The distribution of the cells that express the mutated allele is variable. The phenotype observed in females heterozygous for X- chromosome-linked traits varies in severity depending on the proportion of cells expressing the mutant allele. This therefore produces variation in disease severity. (Modified, from: Wizeman TM, Pardue ML, editors; Institute of Medicine (US) Committee on Understanding the Biology of Sex and Gender Differences. Exploring the biological contribution to human health: does sex matter? Washington, DC: National Academy Press; 2001. Reprinted with permission.)

Initiated by the AAOS Women's Health Issues Committee and cosponsored by the AAOS Committee on Research, the workshop took its lead from the landmark report issued in 2001 by the Institute of Medicine entitled Exploring the Biological Contributions to Human Health: Does Sex Matter?3 That report emphasized four themes: every cell has a sex, sex begins in the womb, sex affects behaviors and perception, and sex affects health. These themes served as a framework for workshop participants as we sought to explore the impact of sex differences on musculoskeletal conditions.

Molecular, Cellular, and Matrix Biology

Every female cell is different from every male cell-different chromosomes, different mitochondrial properties, different mosaicism. Men and women are intrinsically different. It is a surprise when they are similar!

-Michael D. Lockshin

The Institute of Medicine study highlighted two mechanisms that help to explain how sex differences arise. In the traditional view, hormone-responsive genes are influenced by the hormonal milieux of the male and female differently throughout their life spans. The second mechanism posits that genes located on the X and Y sex chromosomes encode proteins that result in variations in biochemical and physiological pathways. These mechanisms are not mutually exclusive, and both, acting separately or in concert, may lead to differences at the molecular, cellular, and tissue levels.

Molecular Biology

The case for the second mechanism comes from several recent findings. It is now known that the Y chromosome contains more information than that required for the development of the male gonadal phenotype. Genes located on the Y chromosome participate in basic cellular functions that are expressed in many different tissues. Because these genes have no counterpart on the X chromosome, the expression of these genes is limited to males4. For example, recently, the variation in male height has been associated with polymorphism in an unidentified gene on the Y chromosome CYP19(5). This observation is of interest to the musculoskeletal scientist because the epiphyseal plates close later in males than they do in females, and males tend to grow to a greater height.

TABLE II Examples of Proteins Expressed on X or Y Chromosomes That Influence Musculoskeletal Growth and Development*

The X-chromosome genes are expressed differently in females in part because there is a double copy of the gene4. In addition, there are differences in meiotic effects, X-chromosome inactivation, and genetic imprinting. The inheritance of either a male or a female genotype is further influenced by whether the X chromosome comes from the mother or the father6. For example, in progressive diaphyseal dysplasia, males show more severe symptoms if they inherit the mutant gene from their father rather than their mother7.

Females are functionally genetic mosaics8 because the majority of genes on one of the two X chromosomes are silenced in every cell (Fig. 1). In contrast, males have only a single copy of the X chromosome and, as a result, none of the genes on this chromosome are silenced. The mosaicism in X-chromosome genes in females may be responsible for variations in the severity of recessive X- chromosome-linked diseases. Duchenne muscular dystrophy is an excellent example of this. A mutation in the dystrophin gene is responsible for the Duchenne muscular dystrophy phenotype9. This gene is expressed on the X chromosome and, for this reason, all males inheriting the gene from a female carrier have the disease, whereas only a very small fraction of the women express enough of the abnormal allele to dem\onstrate any disease whatsoever10,11.

It makes a difference whether the active X chromosome is inherited from the mother or the father, and which of the X chromosomes on the female is silenced12. Inheritance of imprinted genes is an example of nonmendelian genetics, in which only one member of the gene pair is expressed and expression is determined by the parent of origin. Examples of classic human disorders related to genomic imprinting are Beckwith-Wiedemann syndrome (chromosome 11), Prader-Willi or Angelman syndromes (chromosome 15), Russell-Silver syndrome (chromosome 7), and Albright hereditary osteodystrophy (chromosome 20)13. The Prader-Willi syndrome (loss of paternal expression) and the Angelman syndrome (loss of maternal expression) are complex developmental disorders14. The X-linked biglycan gene deficiency in Turner syndrome (X/O) results in a more masculine phenotype if the affected female gets the X from the father15. Table II provides other examples of X and Y-related proteins that are known to affect musculoskeletal development.

Cellular Biology

Both the genes expressed by the cells and the cell behavior itself show sexual dimorphism. Cells derived from females respond differently to estrogen, test-osterone, and other steroid hormones than do cells derived from males. Differences in response to estrogen and testosterone have been shown for male and female chondrocytes16, osteoblasts17, myoblasts18, colon cells19, and neuronal cells20,21. (Sex-dependent differences in osteocytes and osteoclasts have not yet been described.) We now recognize that cells in males and females have more than one form of estrogen receptor as well as androgen receptors, and the relative abundance of these receptors varies with sex and with the type of tissue22,23. Thus, one possible explanation for the difference in male and female mesenchymal cell response to estrogen may be related to differences in estrogen receptors24. Another possible explanation is the difference in the ability of males and females to convert testosterone into 17β-estradiol and 5α- dihydroxytestosterone locally25-27.

In addition to local factors produced by cells as autocrine and paracrine mediators, other cell components are influenced by the person's sex in ways that we do not yet understand. Autoimmune diseases, for example, appear to be influenced by the fact that women carry their babies' cells for decades. Abnormal numbers of these cells are found in patients with scleroderma, primary biliary cirrhosis, Sjgren syndrome, autoimmune thyroid disease, and thyroid nodules28. This is a rich opportunity for investigation.

Matrix Biology

Dimorphism of the musculoskeletal system is not defined solely by cellular responses; the structure and functions of bone, muscle, tendon, and ligament also exhibit sexual dimorphism. Specific muscles throughout the body are sexually dimorphic. For example, in the rabbit masseter muscle, equal proportions of fibers expressing slow and fast phenotypes are found in adult females and young adults of either sex, but, in adult males, >75% of the fibers contain fast contractile protein isoforms. These differences in fiber phenotype proportions are reflected in the contractile properties of the muscle fibers: the masseter muscle in females produces smaller forces than that in males. It is important to note that these sex differences in masseter muscles develop under the influence of testosterone in the male. Once initiated, androgenic changes in muscle fibers are retained for very long periods, even with non- detectable levels of serum testosterone, and the effects cannot be reversed by estradiol29. Less dramatic sex-dependent differences are found in other muscles. Androgen treatment also results in an increase in the firing rates of trigeminal motoneurons innervating the masticatory muscles. These changes in the motoneuron firing rate are induced by testosterone prior to any change in contractile protein gene transcription in their target muscles. This is compatible with a model of androgenic regulation of muscle fiber properties that includes both the muscle fibers themselves and the motoneurons that innervate them. These observations may be important to the orthopaedic surgeon when treating athletes who are either currently taking steroid hormones to enhance performance or those who have taken them previously.

A critical concern for the orthopaedist is the sex differences in the inheritance of peak bone mass and bone fragility. Traditionally, the divergence in skeletal phenotypes between men and women has been attributed to sex steroid action. However, new research in mice has indicated that the inheritance of mechanically relevant bone traits, such as strength and toughness, also depends on sex, the genotype of the parental strains, and maternal effects. Although males and females inherit skeletal traits differently30, the structure- function relationships are still dependent on the same underlying factors, including geometry and material properties consisting of mineral content and matrix quality31. Mineral properties are influenced by extracellular matrix proteins32, some of which are expressed on the X and Y chromosomes (Table II). These proteins affect mineral content, the extent of secondary mineralization, and crystallite size, which in turn impact the tissue mechanical properties such as strength and the ability to withstand load.

Growth and Development

Sexual dimorphism occurs in musculoskeletal size, shape, and strength. It has long been known that, during fetal development and early maturation, there are sex-dependent responses to estrogen by mesenchymal cells33-35. Furthermore, during postfetal growth and development, there are also differences in the response of growth plate chondrocytes and osteoblasts to estrogen36-41. The response to mechanical loading in osteoblasts42 and their response to bone morphogenetic proteins43 are dimorphic as well.

Sexual dimorphism is particularly marked in both developing and aging bone, and there are sexual differences in shape, size, and architecture. During development, bone enlarges by depositing new tissue on the periosteal surface while resorption occurs on the endosteal surface in both males and females. For most bones, particularly long bones, this expansion is superimposed upon cortical drift such that there is apposition and resorption occurring on both the periosteal and endosteal surfaces simultaneously44.

Prepubertal growth is associated with marked periosteal apposition, which is greater than net endocortical resorption. The net effect is that the cortex increases in thickness as long bones increase in length and diameter. After puberty, with closure of the epiphyses, no further increase in long bone length can occur but periosteal apposition continues in both sexes, very slowly enlarging the diameter of the long bone. As periosteal apposition is less than net endocortical resorption, the cortical thickness begins to decrease. This cortical thinning occurs in males and females but is less in males because periosteal apposition is probably greater while endocortical resorption is probably slightly less in males than females45-53. Not all of the data are consistent. For example, the amount of bone loss on the endocortical and trabecular surfaces of the vertebra during aging, measured with use of quantitative computed tomography, is comparable for both men and women54. Trabecular bone loss at the iliac crest, measured with use of quantitative histomorphometry, is also similar in men and women55. A great deal remains to be learned about the timing and extent of periosteal apposition during aging in both sexes.

This phenomenon has been studied in detail in animals. In growing rats, for example, cortical thickening increases during development in males by the acquisition of bone on the outer periosteal surface. However, one study has shown that, in females, predominant cortical thickening occurs on the inner surface56. In that study, males had greater bone width and greater breaking strength at eight months than did females. Gonadectomy reduced sex differences in bone width and strength; periosteal bone formation in males was halved, but in estrogen-deficient females it was doubled, indicating that testosterone stimulates periosteal bone formation while estrogen suppresses it. In growing mice, targeted overexpression of the androgen receptor in the osteoblast lineage substantially affected the morphology and quality of both cortical and trabecular tissues in males but had little effect on females57. In humans, similarly, during adulthood there are distinct sex differences in femoral remodeling. From about the third to the seventh decade, men show a fairly uniform increase in subperiosteal area, polar moment of inertia, and medullary area53. Women during this time-period do not have an increase in the subperiosteal areas, although they do have an increase in the medullary area. Furthermore, in the thirty to seventy-year age-range, osteoclasts produce greater numbers of resorption cavities in women than in men and they are smaller in size, but these differences are not noted after the age of seventy years58.

Dimorphism in the Mechanical Function of Bone, Tendon, and Ligament and in Muscle Injury

Bone Remodeling and Its Consequences

Bone modeling during development and remodeling throughout life determines bone strength, and both processes are dependent upon factors that regulate the number and activity of bone-forming osteoblasts and bone-resorbing osteoclasts. How cells and tissues respond to mechanical signals is a critical part of this picture. There is substantial evidence that estrogen modulates the ability of the skeleton to respond to biomechanical load. One possible mechanism by which estrogen affects the cellular response to loading may be through differences in cell-signaling. For example, nitric oxide, a fr\ee radical with multiple effects on bone-cell function59,60, is increased in response to exercise in women but not in men.

There is a difference in the prevalence of fracture between men and women52, and falls are a major contributor to fracture61. Injury severity in men and women is related to the height of the fall, fall direction, configuration of the body during impact, lack of protective responses, and low bone strength61-63. Fall-related determinants, such as fall direction, are comparable in men and women62. Factors related to the initiation of a fall, such as the ability to recover balance after a perturbation, do differ between men and women64-66. Bone strength is determined by the morphology (shape and size) and the quality (material properties) of the bones31; the genes that control these traits may be different for men and women67,68.

The pathogenesis of bone fragility in old age is likely to be heterogeneous. Reduced bone size in females may be the result of reduced periosteal apposition during growth or aging, or both, and the reduced volumetric bone-mineral density may be the result of reduced peak mineral accrual, age-related bone loss, or reduced periosteal apposition or several of these processes. Men and women have similar peak volumetric bone-mineral densities in young adulthood, but men have larger bones. Although the loads on the vertebral body are greater, the load per unit area (stress) does not differ by sex48.

Sexual dimorphism in the prevalence of vertebral fractures (men have fewer fractures than women) may be more the result of sex differences in age-related bone gain than in age-related bone loss. Duan et al.52 reported that the decrease in peak vertebral body bone- mineral content from young adulthood to old age, as determined with use of bone densitometry, was less in men than in women because of greater periosteal apposition in men. Periosteal bone formation also increased vertebral body cross-sectional area threefold more in men than in women. This resulted in the distribution of load onto a larger area, so that the load imposed per unit area was less in men. In men and women with spine fractures, cross-sectional area and volumetric bone-mineral density were reduced relative to age- matched controls. Thus, large amounts of bone are resorbed in both men and women, accounting for the age-related increase in spine fractures in both sexes. Compared with women, fewer men are at risk for fracture, largely because fewer men develop deficits in the structural determinants of bone strength below a level at which loads can exceed the ability of the bone to tolerate them52,69.

Studies in women with vertebral and hip fractures53,70 and their daughters have provided interesting insights into the growth- related and age-related origins of bone fragility. Women with hip fractures had increased periosteal and endocortical diameters in the femoral neck relative to women without fractures, but the cortical thickness and volumetric bone-mineral density were reduced. Theoretically, a daughter could resemble her mother by 50% because she shares, on the average, one-half of her mother's genes. The daughters of the women with hip fractures had a femoral neck diameter that was increased, on the average, by about one-half that of their mothers', while the endocortical diameter was increased by an average of one-third; the cortical thickness and volumetric bone- mineral density were not reduced in the daughters. Thus, the larger size of the femoral neck in women with hip fractures is likely to be growth-related; the wider endocortical cavity and thinner cortex probably result from excessive age-related endocortical bone resorption producing a thin cortex in a larger bone and subsequently predisposing it to structural failure. Theoretically, a daughter will resemble her mother (in the relative position of a trait in the normal age-specific distribution) by 50% because she shares, on the average, one-half of her mother's genes. Vertebral volumetric bone- mineral density in the mothers was reduced twice as much as that in the daughters. Study results were similar when daughters were compared with mothers both with and without fracture. Women with vertebral fractures had reduced vertebral volume and volumetric bone- mineral density, whereas their daughters had reduced vertebral volumetric bone-mineral density by half the deficit in the mothers but normal vertebraL volume, suggesting that the deficit in size in the mother was age-related, not growth-related.

Muscle, Tendon, and Ligament Injury

Although the literature has primarily focused on the increased risk for anterior cruciate ligament injuries in females compared with equivalently trained males, there is, in fact, sexual dimorphism in a broad range of soft-tissue injuries. Women have a higher prevalence of ankle sprains, certain spine injuries, and frozen shoulder. Here, too, development likely plays a critical role. For example, prior to puberty, girls and boys have similar jumping and landing strategies, but, during puberty, the strategies change. These findings have been demonstrated in studies that measured knee valgus on landing, i.e., stepping off a box and then jumping, in males and females before and after puberty70,71. Prior to puberty, males and females land similarly, with knees wide apart, and after puberty males land with knees wide apart, but females land with the lower extremities in valgus.

Several contributing factors have been proposed to explain the increased prevalence of anterior cruciate ligament injury in female athletes72, including sex differences in biomechanical73, neuromuscular71,74, anatomic75,76, and hormonal77,78 influences. It seems likely that all of these factors play some role in the increased susceptibility of females to anterior cruciate ligament injury. The possible interplay among these several factors can be summarized as follows: anterior cruciate ligament injury is determined by just two variables, the applied load on the ligament and the intrinsic load that the ligament can withstand. Simply stated, when the applied load to the anterior cruciate ligament is greater than the intrinsic ability of the anterior cruciate ligament to withstand the load, failure occurs. Factors that control the position of the knee, such as an individual's anatomy and neuromuscular control of the lower extremities and/or pelvis, ultimately determine the load transmitted to the anterior cruciate ligament. Certain lower extremity positions, such as valgus alignment of the knee, increase loads upon the anterior cruciate ligament79.

The size, shape, and internal composition of the anterior cruciate ligament determine the intrinsic ability of the ligament to withstand loading. Because the size of the anterior cruciate ligament is generally smaller in females than in males80, the loads at failure will be lower, assuming that there are no sex differences in the internal structure of the anterior cruciate ligament. Several factors, most notably the remodeling process, may result in the smaller ligament size. The anterior cruciate ligament, similar to other collagen-containing tissues, responds to load and injury by remodeling81. Remodeling modifies the size, shape, and structure of the anterior cruciate ligament as well as other static (capsular) and dynamic (contractile) soft tissues. Remodeling of other soft tissues around the knee determines the stiffness of the supporting knee structures and how much load is directly applied to the anterior cruciate ligament. Finally, sex hormones play a large role in determining the size and shape of soft tissues as evidenced by the changes that occur during puberty. Neuromuscular changes that occur at puberty also reflect the importance of sex hormones in the prevalence of anterior cruciate ligament injury. Therefore, sex hormones, neuromuscular control, anatomy, ligament structure, and size all affect the susceptibility to anterior cruciate ligament injury.

Musculoskeletal stability describes the capacity of a multisegment limb to maintain and control dynamic alignment under functional load in order to avoid strain injury to the passive tissues of the included joints82. Functional stability is maintained by means of muscle recruitment and neural reflex response. The critical components of stabilizing control include the recruitment patterns of voluntary muscles, intrinsic biomechanical impedance (stiffness) of actively contracting muscles, sensory proprioception, and reflex response. Sex differences have been identified in each component of stability control offering a possible explanation for the sexual variation in musculoskeletal injuries.

Active muscle recruitment is one of the primary control factors in joint stability83. Sex differences in muscle recruitment and coactivation have been observed in functional tasks84, indicating differences in musculoskeletal stability. Appropriate muscle recruitment is necessary for stabilizing control of the active stiffness of a joint during functional activities. Controlled measurements of joint dynamics have revealed major differences in active stiffness between males and females85; such differences are primarily attributed to sex differences in anthropometry. Sex differences in dynamic joint stiffness have also been observed in functional tasks86 and can likely be attributed to the combined effects of anthropometry and muscle recruitment87.

Reflex response also plays an important role in the dynamic alignment and stability of the musculoskeletal structure and includes components such as sensory proprioception and reflex gain. Ligaments contribute to sensory proprioception wherein a ligamentomuscular reflex arc exists from the mechanoreceptors in the ligaments to the muscles, which on activation develop forces to stabilize the knee, shoulder, elbow, ankle, and spine. Hence, gender- specific ligamentous laxity influences thereflex arc, e.g., anterior cruciate ligament deficiency has been linked to proprioceptive degradation88 and spinal ligament laxity has been associated with reduced sensory response and delayed reflex onset89. Sex differences in ligament laxity are well established90 and partially attributed to hormonal differences91, and they may explain the reported differences in passive tissue laxity and reflex response following prolonged and/or cyclic joint loading92.

Despite the increased prevalence of noncontact injuries of the anterior cruciate ligament in female athletes compared with that in male athletes92,93, the basis for the sex differences in ligament laxity remains controversial. Arendt et al.94 found a positive correlation between the occurrence of a non-contact injury of the anterior cruciate ligament and the female collegiate athlete's menstrual cycle regardless of the status with respect to oral contraceptive use, and Wojtys et al.78 demonstrated an effect of menstrual cycle phase on anterior cruciate ligament injury. Slauterbeck et al.95 observed a negative effect of high-dose estrogen on rabbit ligament laxity, while Strickland et al.96 reported no difference in an ovine model. Sex differences in tissue mechanics may explain reported differences in passive tissue laxity82 and reflex response92 following prolonged and/or cyclic joint loading or fatiguing activity, respectively.

Men and women have different patterns of athletic injuries97 as well as altered gait and motion patterns79. Biomechanical responses to muscle stiffness exhibit sex differences. The role of exercise in preventing injury has also become an exciting research field. Physical exercise is a physiologically relevant Stressor that exhibits sexual dimorphism. Males and females differ in their response to exercise with regard to fuel utilization patterns98, temperature control99, neuroendocrine regulation100, immune response, and muscle damage101. Exercise can activate the stress response and induce the synthesis of several heat shock proteins in both cardiac and skeletal muscle. Heat shock protein 70 has been directly linked to exercise-induced cardioprotection102 and inhibition of muscle damage103. Sexual dimorphism occurs in the accumulation of heat shock proteins in response to exercise and in the protective effects thereby gained102,104. Compared with females, males demonstrate a substantial increase in muscle heat shock protein 70, with subsequent enhanced cardioprotection following a single bout of exercise. These observations may have important implications with regard to the efficacy of exercise and exercise- training across the life span in both men and women.

Injury and Trauma

Profound suppression of immune and cardiovascular functions is known to occur in the setting of soft-tissue or bone injury along with major blood loss. Recent studies have demonstrated that proestrus female mice have sustained or enhanced immune responses following trauma/hemorrhage, whereas male mice have decreased immune responses105,106. Moreover, mortality rates following the induction of sepsis were considerably higher in males compared with proestrus females. The advantage that the proestrus females have in tolerating the effects of trauma/hemorrhage, however, is lost following ovariectomy or aging107,108. Castration of male mice two weeks prior to trauma/ hemorrhage prevents the occurrence of subsequent immunosuppression106. The administration of sex steroids or their metabolic precursors restores depressed immune function and increases the survival rate of animals subjected to trauma/ hemorrhage or sepsis109. This research suggests that there may be a rationale for the use of 17β-estradiol, flutamide, or metoclopramide (which are readily available clinically) as adjuncts in the treatment of trauma. These agents do not produce adverse hemodynamic effects, and they appear to be safe and novel immunomodulating agents for the treatment of immunodepression following severe blood loss in males and females, respectively. The protective effect identified in women following trauma/hemorrhage and sepsis has not been found in brain injury110, suggesting that site-specific differences may exist.

Stroke, the third leading cause of death in the United States, must be of concern to the musculoskeletal surgeon when dealing with elderly patients. Clinical ischemic stroke is increasingly recognized as a sexually dimorphic disease. Most international databases have consistently demonstrated that the prevalence of stroke is lower in women than in men until advanced age111-114. This native neuroprotection is lost within ten years after menopause, an observation attributed to age-related estrogen loss. Because of the epidemiological data suggesting that estrogen was protective against vascular disease and stroke, it became one of the commonest medications prescribed in the United States over the past several decades. However, the results from randomized clinical trials performed in the last three years have led to questions on the use of estrogen for either the primary or secondary prevention of vascular disease. In the Women's Estrogen for Stroke Trial115, women with established vascular disease who had experienced a recent transient ischemic attack or nondisabling stroke (within ninety days) were randomized to either a large dose of estrogen or a placebo. Women treated with estrogen not only had more strokes but had more fatal strokes. The recent releases of the results of the Women's Health Initiative progestin and estrogen arm in 2003(116) and estrogen-alone arm in 2004(117) also demonstrated that estrogen is unlikely to prevent strokes or heart disease in healthy postmenopausal women with normal vasculature. An increase in the prevalence of strokes was found in women in both treatment arms (twelve additional strokes per 10,000 person-years) compared with placebo, while there was a marked decrease in hip fracture rates (six fewer hip fractures per 10,000 person-years). It is now recommended that women with postmenopausal symptoms be treated with hormone replacement therapy at the lowest effective dose for the shortest possible time-period. It is important to note that the absolute risk of stroke to an individual woman is extremely small. In addition, numerous positive effects of estrogens (reduced hip fracture rate and a surprising reduction in breast cancer in the estrogen treatment arm) require further evaluation.

Despite these new clinical research findings, basic research continues to demonstrate that estrogen is neuroprotective in a variety of in vitro as well as animal injury models118. Estrogen treatment at physiologically relevant concentrations reduces infarction after stroke in ovariectomized or aged, reproductively senescent female animals, as well as in males118-120. In addition, hormonal effects do not fully account for the sexual dimorphism seen after cerebral ischemia. Emerging data have suggested that neuronal death may follow differing mechanistic paths depending on sex121. In vivo data have demonstrated differences in the sensitivity of sex- specific neuronal cultures as well as peripheral cells (splenocytes) to a variety of cytotoxic insults122. Male neurons are more sensitive to nitric oxide toxicity, whereas female cells are more sensitive to apoptosis122. The understanding of sex differences in cerebral ischemia is a critical starting point for the development of effective neuroprotective strategies. Using gender stratification to treat stroke may improve our ability to salvage the ischemic brain.

Malignant hyperthermia and exertional heat illness, important issues for sports medicine physicians, may be related syndromes. Malignant hyperthermia is an autosomal dominant, inherited, genetically heterogeneous myopathy characterized by dysregulation of intracellular calcium homeostasis in skeletal muscle. Exertional heat illness is a hyperthermic state in which heat is produced by muscular work that exceeds the body's capacity to dissipate it. Genetic susceptibility to malignant hyperthermia is associated with a markedly increased risk of exertional heat illness. The increased risk for these conditions in boys and men is likely due to gender discrepancies of increased exercise123-126.

Pain and Inflammation

Females are more sensitive to, less tolerant of, and more able to discriminate pain127, yet painful disorders are more prevalent in females than in males128. Evidence is rapidly emerging that these differences may be present because the sexes differ qualitatively in their neural processing of pain and analgesia129. That is, different neural circuits, transmitters, receptors, and genes may be relevant to pain modulation in males and females.

Differences in the efficacy of analgesics in men and women have also been described130. This is of particular importance for the orthopaedic surgeon because there are gender differences in response to and use of mu-receptor opiates131,132, kappa-acting opiates133, and anti-inflammatory medications134 in animals and humans. The expression of inflammatory mediators also is different in males and females, at least in the case of multiple sclerosis135.

Nonsteroidal anti-inflammatory drugs and selective cyclooxygenase- 2 (COX-2) inhibitors are some of the most commonly prescribed medications worldwide136. These drugs are used to treat painful inflammatory conditions, such as arthritis, traumatic injuries, back pain, and dysmenorrhea, and are becoming part of comprehensive pain management. While these drugs alter fracture-healing in animal models137-139, there are no data on whether the use of nonsteroidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors affects fracture-healing and bone ingrowth differently in men and women. This may have important clinical implications as young women are encouraged to use these drugs for both sports injuries and the management of mens\trual symptoms. Dose and time-response experiments have suggested that these agents must be present in sufficient doses for extended time-periods (especially during the early stages) to decrease bone healing140.

The nonsteroidal anti-inflammatory agents are widely used in the treatment of osteoarthritis141, while newer immunosuppressive drugs are more commonly used in autoimmune diseases such as rheumatoid arthritis. Many of these autoimmune diseases show a female predilection (Table 1). Although the dimorphic prevalence of autoimmune diseases has traditionally been attributed to sex hormones, and in vitro assays do demonstrate sex-hormone control of some measures of adaptive and innate immunity, if men and women have different immune responses, one would expect to find differences in disease severity as well as differences in responses to vaccines and infection-handling. Yet there is little difference between men and women in terms of these behaviors. In addition, not all autoimmune diseases are female predominant. Some thyroid, rheumatic, and hepatic diseases have very high female-to-male ratios, but the ratio is 1:1 for many autoimmune diseases and less than 1:1 for others. Inconsistent definitions and classifications of autoimmune diseases further confuse conclusions about female-to-male ratios. It is also interesting that these sex differences are consistent across populations.

The epidemiology of the sex-discrepant autoimmune diseases-i.e., variance of presentation of related diseases-suggests that an explanation for sex discrepancy lies in differential exposure, vulnerable periods, or thresholds rather than in intrinsic differences of immunomodulation142. Dissimilar exposures, susceptibilities, and responses to disease-initiating agents may result in variable biological responses and the initiation and manifestation of disease. Thus, the autoimmune disorders may be a group of disorders in which the concept "every cell has a sex" particularly pertains. Sex differences caused by X-inactivation, imprinting, X or Y-chromosome genetic modulators, and intrauterine influences provide an alternate, and as yet theoretical, explanation for sex differences in the prevalence of human disease. Behavioral differences can also contribute to differences in musculoskeletal disease in males and females. A classic example of this is the higher prevalence of Lyme disease in boys who spend more time in the woods where the disease-carrying tics in the environment are the causative agent.

TABLE III Influence of Sex and Gender on Musculoskeletal Health Conference Recommendation*

TABLE III Influence of Sex and Gender on Musculoskeletal Health Conference Recommendation*

Cancer

Sexual dimorphism in musculoskeletal oncology has received little analysis despite differences in all aspects of the etiology and treatment of neoplasms. From a public policy and research funding perspective, the predominant sex influences the research initiatives and treatment strategies. Unfortunately, the results from most protocols lump both sexes together.

Males experience disproportionately more primary bone tumors than females do, and females have more bone metastases than males do (Table I). Males have 60% more primary musculoskeletal tumors than females. Giant-cell tumor, surface osteosarcoma, and soft-tissue desmoid tumors are the rare exceptions to this rule. The female predominance with respect to desmoid tumors may be due to sex differences in the beta-catenin pathway143. Similarly, ring chromosomes are almost universally found in surface osteosarcomas, suggesting that females are more disposed to the development of ring chromosomes.

Skeletal development may be important in explaining the dimorphism. For example, osteogenic sarcoma develops, on the average, two years earlier in girls than in boys144. Females have a prognosis that is generally 15% better than that for males. The reasons are not considered in any of the national studies. Effective procedures such as rotationplasty are neither offered to nor accepted by girls and their parents as often as they are for boys (1:4). The response to chemotherapy is better in girls than in boys (60% compared with 53%). This translates into superior outcomes for girls (51% compared with 48% probability of ten-year event-free survival). Similar results have been reported for soft-tissue sarcomas.

The skeleton is the third most common site of metastatic cancer after the liver and the lung, and one-third to one-half of all patients with cancer have metastasis to bone144. Morbidity from bone metastases includes partial paralysis, hypercalcemia, pathologic fractures, and bone pain145. There are few treatments known for treating skeletal metastases, and none are curative. Current research is focusing on the tendency of prostate and breast cancer to metastasize to bone, the mechanism by which cancer cells adhere to and migrate into bone, and the interplay between metastatic cancer cells and the bone microenvironment.

Although cancer patients are living longer, skeletal metastases continue to be a feared complication since fractures can occur at the sites of bone involvement after minimal trauma. It has been hypothesized that a change in bone structural properties as a result of tumor-induced osteolysis determines the fracture risk in patients with skeletal metastases146. Metastatic cancer can affect the material properties of bone tissue directly by either stimulating bone resorption (e.g., breast cancer) or bone formation (e.g., prostate cancer) or changing the overall bone geometry by remodeling large regions of bone infiltrated by metastatic cancer cells.

Toxicity to chemotherapeutics differs by sex and estrus status147,148. Ironically, there may be a simultaneous increase in drug effectiveness and complications such as those seen with methotrexate, doxorubicin, and other drugs149. The severity of toxicity may also be influenced by sex150. There is greater toxicity in females who undergo isolated-limb perfusion for soft-tissue sarcoma than in males (22% compared with 7%)151. Genetic and HLA (human leukocyte antigen) tissue type and metabolic differences are known to cause a differential response and toxicity152. Occasionally, certain drugs such as parathyroid hormone and its analogues contribute to sex differences in cancer development153. Females have higher infertility rates154,155.

Female patients with breast cancer dominate paradigms on the treatment of pathologic fractures156, yet the outcome measures are made with use of instruments developed for primary cancers in men. Furthermore, the outcome measures may not be applied in an equally balanced fashion, and physicians have a more negative perception of prognosis in women than in men157. These aberrations influence the management of the most common orthopaedic oncologic conditions.

New Technologies for Musculoskeletal Management

One of the newest areas of research in the musculoskeletal field is tissue engineering for the repair and regeneration of musculoskeletal tissues. While it is generally known in the liver transplantation field that the sex of the donor and that of the recipient are critical components of the success of these procedures158,159, little attention has been paid to the sex of the donors and recipients of bone and tendon. The lower success rates of liver transplantations from male donors into female hosts were ascribed to differences in organ size; however, this is not the case in the musculoskeletal system. The data presented at this workshop indicate that the donor's sex, age, and hormone status also must be considered carefully in the development of tissue-engineered constructs with use of human cells for the treatment of musculoskeletal conditions.

The number of colony-forming osteogenic precursor cells harvested from patients decreases with age in women, but not in men160. This indicates that attempts to harvest such cells for bone-grafting and other tissue-engineering applications will differ depending on the sex of the patient. Muscle progenitor stem cells from females, however, are more effective in several tissue-engineered constructs compared with cells from males. Because females are more able to manage foreign bodies (which may be related to pregnancy) and not reject them161, the application of tissue-engineered products may face fewer rejection complications in women than in men. Additional research is needed to address this question.

An Agenda for Musculoskeletal Health

As the research analyzed in the present report demonstrates, the scientific investigation of sex differences in health and disease has progressed substantially during the past two decades. The recognition that it is essential to include women in clinical studies reflects a sharp reversal of the thinking that emerged from the medical horrors of World War II. While the Nuremberg Code (1949) and the Declaration of Helsinki (1964) protected human subjects in medical research experiments, the tragedies linked to the use of diethylstilbestrol and thalidomide in pregnant women in the 1950s and 1960s resulted in the classification of women and unborn children as "vulnerable populations." Consequently, in 1977, the United States Food and Drug Administration established a policy excluding pregnant women and potentially pregnant women from phase- I clinical studies until animal teratology and fetal toxicity studies could be completed and analyzed162.

Little in the science of the era challenged this presupposition because of the general belief that, in most situations, men and women did not differ significantly in their response to treatment. Moreover, female hormonal cycles introduced an unwanted set of variables in experimental research, decreasing the homogeneity of study populations and further complicating study design and data analysis. Ironically, the attention given to the female hormonal cycle did not lead researche\rs to investigate whether females could be appropriately treated with medications tested solely on males, and males continued to be studied as representative of the species. Male responses subtly came to be seen as the "norm" and female responses as "deviant or problematic."

However, in 1985, just eight years after the Food and Drug Administration established its guidelines, a report from the United States Public Health Service Task Force on Women's Health Issues163 concluded that women's health care was compromised by lack of research on women's health issues. In 1986, the National Institutes of Health responded to this report and issued new guidelines encouraging, but not requiring, the inclusion of women in federally funded clinical research projects164. Then, in response to criticism in 1990 by the General Accounting Office that the new guidelines were not regularly enforced, Congress passed the NIH Revitalization Act of 1993, which established the Office of Research on Women's Health and mandated the inclusion of women and minorities in clinical trials. In the same year, the Food and Drug Administration rescinded its policy of excluding women of childbearing age from early-phase trials165.

In 1994, Mastroianni et al., in a monograph for the Institute of Medicine, focused additional attention on sex disparities in research166. The report identified two forms of bias in the design of clinical studies: male bias, which is observer error biased by the adoption of a male perspective and habit of thought, and the male norm, which is the tendency to use men as the standard, even in studies of diseases that affect both sexes166. Recognizing this discrepancy, the Food and Drug Administration, in 1998, announced that it would refuse to file any new drug application that did not include enough women to assess safety and efficacy on the basis of sex167.

Ironically, most of the calls to action to study the effects of sexual dimorphism have focused on classic "women's diseases," such as autoimmune disorders, breast cancer, and depression. Likewise, the Institute of Medicine in its 2001 report3, for example, did not include any musculoskeletal health issues. This workshop, therefore, sought to answer the question: Are there sex-based differences that are important to orthopaedics?

This workshop unambiguously concluded that there are indeed sexbased differences in cell biology, tissue function, and disease presentation and management with the potential to affect how orthopaedic surgeons manage their patients. Furthermore, basic- science data indicate that while estrogens and androgens are important determinants of musculoskeletal sexual dimorphism, they are not the only ones. The conference agreed with the 1999 Task Force on Research on Women's Health of the Office of Research on Women's Health that urged multidisciplinary investigations across the life span168. It identified substantial research gaps, noting among other things that recent advances in molecular biology and genetics had not been uniformly integrated into all areas.

To accomplish this integration in musculoskeletal health, our workshop recast the recommendations of the 2001 Institute of Medicine report to make them germane to the challenges faced in orthopaedics and identified six critical priorities for future musculoskeletal research (described in detail in Table III).

1. Monitor sex differences and similarities for all musculoskeletal diseases and conditions, including diagnosis and treatment, which affect both sexes.

2. Longitudinal and cross-sectional studies of musculoskeletal diseases and conditions should be conducted and designed so that results can be analyzed by sex.

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

4. Mine cross-species information and develop relevant in vivo and in vitro models that incorporate the biological clock. Stratify both human and animal studies of musculoskeletal diseases and conditions based on sex.

5. Expand research on sex differences in neural organization and function, pain, and analgesia with respect to musculoskeletal diseases and conditions.

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

In the orthopaedic practice of the future, sex differences in the physiology and pathogenesis of disease will determine how each patient is treated. Every attendee of this workshop returned to the office or the laboratory determined to meet the challenge of the six recommendations by revising current investigations so that sexual dimorphism is properly considered. Only with concerted effort will the orthopaedic community understand how sex differences affect musculoskeletal health, disease, and treatment protocols.

* A Workshop Report based on a meeting of the American Academy of Orthopaedic Surgeons and the National Institutes of Health, Hunt Valley, Maryland, April 22 through 25, 2004.

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Source: Journal of Bone and Joint Surgery; American volume

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