The Aging Athlete

THE AGING ATHLETE

Prakash Jayabalan

SEX DIFFERENCES IN THE AGING ATHLETE

Currently people over age 65 account for 12% to 13% of the total population, and by 2030 it is estimated that they will comprise 20% (1). With this aging population comes the increasing societal burden of musculoskeletal diseases. The majority of these degenerative disorders are characterized by patients presenting with increased pain, decreased range of motion, and functional deficits, which together can cause a significant reduction in quality of life. Age-associated decline in physical function and physiological decline lead to an increase in morbidity and mortality rates. Sex differences have been shown to potentially play a role in both etiology and treatment outcome for these diseases and this chapter outlines the differences seen. This chapter focuses on common issues related to sex-specific responses to training in the aging athlete and two of the most common disorders associated with aging: sarcopenia and osteoarthritis (OA). Osteoporosis, although a common problem in the aging athlete, is featured in Chapter 12 on bone health.

SEX SPECIFIC RESPONSES WITH AGING

Physiological Decline With Aging and Sedentary Behavior

Aging is associated with physiological declines in bone mineral density (BMD) and lean body mass with an increase in body fat and central adiposity. In women, the onset of menopause likely also augments this decline in activity. Wang et al. compared almost 400 women in the early postmenopausal period to women who were premenopausal and found higher levels of abdominal and total body fat in postmenopausal women (2). However, there was also correlation between age and fat distribution. They did note that a decrease in lean muscle mass after menopause appeared to be independent of age and could be more attributed to menopause. Douchi et al. compared body composition variables between pre- and postmenopausal women (3). They also demonstrated a significant increase in percentage of body fat, trunk fat mass, and trunk-leg fat ratio with aging. Baker et al. found that in addition to a decline in BMD in postmenopausal women compared to men of a similar age, these women also had a higher incidence of metabolic syndrome, with associated cardiovascular risk factors, including obesity, high levels of low density lipoprotein (LDL) cholesterol, hypertension, and high fasting blood glucose levels (4). These metabolic changes were attributed to both changes in body composition and decreased physical activity. A longitudinal study of 77,000 women aged 34 to 59 years, done over 24 years, found that lower levels of physical activity (less than 30 minutes a day of moderate-intensity to vigorous activity) was associated with a higher risk of cardiovascular disease and all-cause mortality (5). Furthermore, Sisson et al. found higher levels of sedentary behavior (more than 4 hours a day) associated with a 54% increased risk in development of cardiovascular disease (6).

Sex Differences in Fat Metabolism With Aging

Women in general have lower rates of resting fat oxidation compared with men (7,8). A lower rate of fat utilization has been shown to increase subsequent weight gain (8). This difference may explain the higher amount of adipose tissue in women compared to men. The fat oxidation that occurs during exercise is from adipose-derived free fatty acids through lipolysis. Lipolysis is regulated by the sympathetic nervous system through stimulation of alpha- and beta-adrenergic receptors (9). Differences in fat mobilization via the sympathetic nervous system activation have been postulated to explain variations in bodily fat content between men and women. In keeping with prior findings, Toth et al. showed that older men (over 65 years of age) oxidize fat more than women at rest (10). However the differences they observed in resting fat oxidation could not be explained by variations in noradrenergic activity, free fatty acid availability, body composition, or aerobic capacity. They also found that there was no difference in rate of lipolysis or fat oxidation during submaximal exercise. Furthermore, despite higher plasma noradrenaline concentrations, no sex differences in the rate of appearance of free fatty acids or fat oxidation were found during submaximal exercise.

Sex Differences in Response/Reaction Times

Reaction times are defined as the elapsed time between the presentation of a sensory stimulus and subsequent behavioral response. They are a vital part of an athlete’s performance and have been shown to vary with both age and gender. It has been shown that reaction times shorten from individuals in their late 20s and then increase slowly from individuals in their 50s into their 70s, with more variability with aging. Variability in reaction times in older adults has been associated with impaired recognition of stimuli and has been suggested to be a potential measure of neural integrity (11). Individuals over age 50 have been shown to be better at reacting to targets by visual distraction because they look for known features of the targets (12). Myerson et al. (13) found that older adults were as proficient as younger people at assimilating information. In general, the majority of studies have shown that in almost every age group, men have faster reaction times than women. The slower reaction times in women are not reduced by practice to the levels of their male counterparts. Spierer et al. reported that when male soccer players were compared to female lacrosse players, the men were able to respond faster to both visual and auditory stimuli (14). Botwinick and Thompson postulated that the difference between sexes was accounted for by the lag between the presentation of the stimulus and the start of muscle contraction (15). The duration of muscle contraction to perform the task was similar, however. Interestingly, a 2005 study found that gradual dehydration, with the average loss of 2.6% of body weight over a 7-day period, caused females to have lengthened choice reaction time (two stimuli with two potential responses), but males to have shortened choice reaction times (16). Barral and Debû tested men and women’s ability to aim at a target and found that men were faster than women initially in aiming; however, the women were more accurate (17). A study with rats found similar results: When rats were given a choice reaction task with distractions, males tended to make premature responses and female rats were more likely to miss the valid stimuli (18). Of note, it has been reported that the typical male advantage in visual reaction time is getting smaller, particularly outside the United States. A potential explanation could be that compared to these early studies, women now participate in fast-action sports that require faster reaction times (19).

SARCOPENIA

Sarcopenia has been commonly defined as the age-related loss of muscle mass. However, over recent years, this term has evolved to also include loss in strength and function. A consensus statement on sarcopenia proposed the inclusion of functional measures such as gait speed in the diagnostic evaluation of the condition (20).

Epidemiology of Sarcopenia

Sarcopenia has varying reported prevalence between men and women. Baumgartner et al. measured appendicular muscle mass in the New Mexico elderly study cohort (population based survey of 883 elderly Hispanic and non-Hispanic white men and women living in New Mexico from 1993–1995) (21). They reported that 15% of males and 24% of females aged 65 to 70 had sarcopenia measured by relative muscle mass (RMM) on dual-energy x-ray absorptiometry (DXA) scanning. They also found higher rates of disability in sarcopenic men (4.1 times higher) and women (3.6 times higher) compared with those with muscle mass in the normal range. The prevalence of sarcopenia was higher for men over age 75 (58%) than women (45%). Iannuzzi-Sucich et al., studying a community-dwelling cohort in Connecticut of 195 women and 142 men, reported a prevalence of sarcopenia of 53% in men and 31% in women in a sub-cohort aged greater than 80 (22). Using data from the third National Health and Nutrition Exam Survey (NHANES III), Janssen and colleagues reported 50% of men and 72% of women over the age of 80 met criteria for sarcopenia using the skeletal muscle index (23). Generally, the reported prevalence of sarcopenia has been lower for both sexes in non-U.S. populations. For example Tankó et al. reported a prevalence of 12% in a population of Danish women over age 70 who had sarcopenia, while in a Taiwanese population, Chien and colleagues found a prevalence of 20% in all subjects over 80 years of age (24,25).

Longitudinal observational studies have reported a progressive decline in skeletal muscle mass beginning in the third decade that becomes clinically significant in the fifth decade (26). For both sexes, the loss of muscle mass was greater in the lower body. Furthermore, Candow and Chilibeck reported that the loss of muscle strength with aging was greater in the lower body in men and women (27). This finding may reflect decreased activity or altered patterns of activity of the lower extremity muscles with aging.

Sex-Related Pathophysiology of Sarcopenia

Several interrelated factors have been postulated to cause the development and progression of sarcopenia. Nutritional, hormonal, metabolic, and immunological factors likely contribute in varying degrees to age-related losses of muscle mass, strength, muscle quality, and function. The loss of muscle mass appears to be the most important etiological process, with studies incorporating muscle biopsies showing diminished type II fiber size (20%–50% reduction), with type I fibers (1%–25%) being less affected (28). In addition to age, a number of demographic factors influence the progression of skeletal muscle decline seen in sarcopenia. The initial muscle mass represents a pivotal factor that determines the development of clinically evident sarcopenia and represents the hypothetical threshold that distinguishes a normal from an abnormal decline. This means that the larger the starting mass, the longer it will take for the threshold of clinically evident sarcopenia to develop (28). Therefore, men have a larger total muscle mass and strength compared to women that in part may explain some of the sex differences seen with sarcopenia.

Patterns of Skeletal Muscle Decline

The pattern of skeletal muscle loss varies between the sexes. Using a cross-sectional design Vandervoort and McComas examined young, middle-aged, and elderly men and women (29). Maximal voluntary and electrically evoked twitch forces were determined for the ankle plantar flexor and dorsiflexor muscles. Women generated lower forces than men at all ages, and significant declines in force were observed for both groups with progressive age. Strength losses were relatively similar for men and women, and decline rates were similar for evoked and voluntary contractions over time for both sexes. Over a 4-year period, Bassey and Harris reported a 3% loss of grip strength in men and 5% for women (30). The age-related decline in skeletal muscle may be greater in men compared to women and the differences in body composition could significantly affect muscle function in men and women. For example, low muscle mass is more strongly associated with poor muscle strength in men, whereas in women higher levels of adipose tissue may act to impair function (31). Sex-specific confounders such as different patterns of activity and hormonal differences were not investigated in these studies and could have a significant effect on the susceptibility to loss of muscle mass and strength.

Sex Differences in Muscle Quality With Aging

Muscle quality (MQ) refers to muscle strength per unit of cross-sectional area (CSA) and is suggested to be a more beneficial indicator of muscle function rather than strength alone. Sex differences in MQ have been demonstrated with aging. Lynch et al. examined differences in MQ between arm and leg muscles (32). They measured concentric and eccentric strength and determined muscle mass using whole body DXA scanning, with estimation of arm and leg muscle mass. Age-associated decline in MQ was greater for men than women, whereas leg muscle quality declined similarly between the sexes. It is important to note that arm MQ was higher than leg MQ for all age groups and both sexes. However in men, the decline in MQ was at the same rate for the arm and leg, whereas in women the decline in MQ was greater in leg musculature than arm MQ. These differing patterns of age-related changes in MQ were postulated by the authors to be related to increased connective tissue and changes in neural connections, though muscle biopsies were not performed. Frontera et al. tested whole muscle strength, whole muscle cross-sectional area (WMCSA), and contractile properties of segments from single fibers of the vastus lateralis in young men, older men, and women. Although age-related differences were eliminated after controlling for WMCSA, sex-related differences were not. Type I and type IIA fibers from older men were stronger than similar fibers from older women (28).

Hormones, Aging, and Sarcopenia

Sex hormones such as estrogen and testosterone have been shown to have anabolic effects on skeletal muscle. In rat models, gonadectomy causes a dramatic decline in spontaneous physical activity (33). The suppression of ovarian function in young women may trigger a decline in muscle mass and the withdrawal of estrogens in menopausal women appears to accelerate the loss of muscle mass (i.e., muscle quantity) and the decline in specific muscle force (i.e., muscle quality) (34). To date, the exact mechanisms by which hormones regulate skeletal muscle metabolism have not been fully elucidated. Furthermore, it is not clear whether age-related changes in gonadal function regulate physical activity in humans.

Estrogen

Gonadal function is a mediator of the sexual dimorphism that occurs in hypertrophy of skeletal muscles mass during puberty. It has been postulated that the loss of gonadal function with aging likely contributes to the development of sarcopenia in adults. Estrogen has been postulated to act against the development of sarcopenia by inhibiting the release of inflammatory procatabolic cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin (IL-1 and IL-6). IL-6 has been shown to have a biological link to the anabolic cytokine insulin-like growth factor 1 (IGF-1), levels of which have been found to be low in the postmenopausal period (35,36). Cappola et al. showed that women with IGF-1 levels in the lowest quartile or IL-6 levels in the highest quartile had a significantly greater limitation in walking and activities of daily living. IL-6 levels have also been shown to be a significant predictor of the development of sarcopenia (37).

The onset of menopause is associated with decreased levels of circulating 17-beta-estradiol concentrations in middle-aged and elderly women. Studies have shown that at menopause onset, women lose fat-free, lean muscle mass and instead gain fat mass such as adipose tissue (38). In addition, muscle strength also declines at this time; however, a major limitation in the literature is that few studies have correlated these findings to estrogen concentrations. The use of estrogen replacement therapy (ERT) has also not been shown to prevent the changes in body composition that occur with menopause such as loss of skeletal muscle mass (39). Kenny et al. showed that there was no significant difference in the rate of sarcopenia between nonobese, long-term ERT users and those not using ERT (40). In addition, ERT did not augment the increases in fat-free mass or leg strength in postmenopausal women age 60 to 72. However, a study of women in the early postmenopausal period who had ERT together with a prescribed resistance training program reported improvement in lower extremity muscle CSA and power compared to controls who did not receive ERT (41). This suggests that ERT may have a potentially beneficial effect on muscle mass early in the postmenopausal period when taken together with resistance exercise. Further studies are required to elucidate the role of ERT in maintaining muscle mass and function.

Testosterone

In males, serum levels of testosterone decreased approximately 1% a year with age. As women age, testosterone levels also decrease to a variable extent, particularly in the postmenopausal years. Epidemiological studies have suggested that there is a relationship between decline in muscle mass, strength, and function with decreasing testosterone levels (42). Testosterone replacement has been shown to increase muscle mass and strength in hypogonadal men (43) and women (42) and also increase muscle protein synthesis. In a randomized placebo-controlled trial, Ferrando et al. reported that following 6 months of testosterone replacement, male subjects had increased total lean body mass and leg and arm strength, which was associated with an increased expression of IGF-1 (44). Studies have also shown that low levels of testosterone are associated with increases in IL-6 concentration. Increased levels of IL-6 have been shown to decrease satellite cell density and proliferative capacity. Satellite cells have been described as myofiber stem cells that give rise to new myofibers. Importantly, they are activated and proliferate in response to muscle injury. They have been suggested to be a vital target for androgen-associated hypertrophy as they express androgen receptors (45). Benjamin and colleagues investigated myoblasts transfected with wild-type or mutant androgen receptors and showed that testosterone caused a variable rate of cellular differentiation and proliferation (46). Although testosterone replacement appears to be a potential future treatment option in hypogonadal aging individuals, further research is required to delineate the optimal dosing regimen for improving function and the risks of long-term use.

The steroid hormone dehydroepiandrosterone (DHEA) has been shown to decline with age in males and females, and exogenous administration of the hormone in elderly subjects has been shown to increase biologically active IGF-1 (47,48). Morales et al. gave elderly patients exogenous DHEA for 6 months, which led to reduced body fat mass and increased muscle strength at the knee and lumbar paraspinal musculature in men only, not in women (49).

Of note, levels of growth hormone and IGF-1 decline with increasing age, and increasing serum levels through exogenous administration has been postulated to be of therapeutic benefit for sarcopenia. In general it has been shown that growth hormone administration increases muscle mass but not strength. Yarasheski et al. showed that 1 month of growth hormone or IGF-1 increased nitrogen balance protein turnover and muscle protein synthesis, but in response to a 16-week resistance training program, growth hormone did not increase strength or protein synthesis compared to no hormone administration. At present there is insufficient evidence to recommend these treatments (50).

ATHLETIC TRAINING IN THE AGING ATHLETE

Sex Differences in Response to Aerobic Exercise

The American Heart Association currently suggests at least 150 minutes per week of moderate exercise or 75 minutes per week of vigorous exercise for general health (51). Multiple cross-sectional and interventional studies have reported that endurance-type training can have significant beneficial effects on cardiovascular (CV) risk factors, including blood pressure, lipid profiles, body fat, and insulin sensitivity (52,53). In addition, maximum oxygen consumption (VO_2max) typically decreases 5% to 15% on average per decade after the age of 25, and aerobic exercise has been shown to increase this parameter (54). These physiological responses to aerobic exercise result in a number of beneficial physiological changes that include increased mitochondrial density, capillary density, and myoglobin content, and decreased blood pressure and heart rate with improved ability to deliver glucose as well as oxygen to working muscles (55). A recent longitudinal study of 23,747 men and women attempted to investigate the level of activity that may protect against CV mortality (56). The subjects did not have a history of CV disease at baseline, and their level of physical activity was tracked over a period of 7 to 10 years. The investigators found that a minimum of two sessions of moderate to vigorous physical activity per week was associated with a reduced risk of CV disease and all-cause mortality in both men and women. Inactive individuals had an elevated risk of CV disease and all-cause mortality (hazard ratio [HR]: 1.50 versus active individuals with HR: 1.11). Multiple studies in older men and women have supported these findings, demonstrating that walking or jogging for 30 to 60 minutes 2 to 5 days per week can have beneficial effects on BMD, VO_2max, and body weight (57–59).

Ogawa et al. investigated the mechanisms by which aging, gender, and physical training affect CV responses to exercise (60). They quantified VO_2max, cardiac output, and heart rate during submaximal and maximal treadmill exercise in men and women of both young age (average 27 ± 3 years) and older individuals (age 63 ± 3 years) who were both sedentary and physically trained. They found that physically trained subjects who were in the older age group had a 25% to 32% higher VO_2max compared to sedentary individuals. For physically trained subjects, maximal cardiac output and stroke volume normalized to fat-free mass were greater in men than women. This difference appears to be related to the greater percentage of body fat in women than men.

Sex Differences in Response to Resistance Exercise/Strength Training

Resistance training (RT) has been shown to have benefits on body composition, mobility, and functional capacity. It has been shown that regular RT can help maintain or increase BMD and total body mineral content as patient’s age (61). Despite the benefits of RT being well documented, there remains some disparity in regard to ideal training volume for a patient in terms of the loads used, number of repetitions that should be performed, and comparative individualized regimens for men and women (62).

In one of the few sex comparative studies, Bamman et al. tested whether older men (n = 9, 69 ± 2 years) would experience greater resistance-training-induced myofiber hypertrophy than older women (n = 5, 66 ± 1 years) following knee extensor training 3 days per week at 65% to 80% of one-repetition maximum (1RM) for 26 weeks (63). Vastus lateralis biopsies were analyzed for myofiber areas, myosin heavy chain isoform distribution, and levels of messenger RNA (mRNA) for anabolic proteins such as IGF-1 and myogenin. For all three primary fiber types, there was enhanced 1RM strength gain in men compared to women. This was not found to be related to circulating IGF-1, myogenin, or expression of the myogenic transcripts they examined. Lemmer et al. examined a cohort of young (n = 18, 20–30 years old) and older (n = 23, 65–75) men and women for their 1RM and isokinetic strength before and after a 9-week unilateral knee extension strength training and detraining regimen (64). They found that changes in 1RM strength due to a strength training and detraining regimen were determined by age. Strength training induced increases in muscular strength that were maintained significantly above baseline for all groups except older women after 31 weeks of detraining. Studies that did not compare sexes and were performed singularly with older men or women have also suggested differences in the hypertrophic response to strength/resistance training. For example, hypertrophy of types I (34%) and II (28%) muscle fibers has been shown following resistance training, with greater increases after 12 weeks in sedentary males of varying ages. Older women, however, are potentially more resistant to myofiber hypertrophy in response to this type of training regimen (28). Charette et al. reported that CSA of type II muscle fibers increases 20% after 12 weeks of resistance training in older women with no change in type I fiber size (65). However, a year of resistance training in older women only causes modest increases in type I CSA (10%–28%) and no significant changes in type II CSA (66). Häkkinen et al. did show hypertrophy in all three primary myofiber types (22%–36%) following 21 weeks of resistance training in older women (67). The resistance training program used in this study was different in that it was spread across 21 weeks with higher loading volume during the final 8 weeks of the study, which may have influenced their results. In another elderly female cohort, low volume training (one set per exercise) compared to high volume training (three sets per exercise) performed twice a week for 13 weeks induced significant improvements in maximal dynamic strength for knee extensors and elbow flexion, muscular activation of the vastus medialis, biceps brachii, and muscle thickness for the knee extensors and elbow flexors. This suggests that during the initial months of training, elderly women can increase upper and lower body strength through low volume training. This level of activity may also improve adherence to exercise regimens prescribed.

OSTEOARTHRITIS

OA is the most common cause of disability in patients over age 65, and it is estimated that by 2030, 20% of the U.S. population will be at risk for the disease (1). In 2004, the estimated cost of treating patients with this condition was $849 billion, the equivalent of 7.7% of the gross domestic product (GDP). Patients with OA commonly present with pain, decreased range of motion, and functional deficits, which have a significant impact on quality of life. Men and women vary in the prevalence, location, and severity of OA. In large population-based studies, women in general have more multiple joint involvement of OA, particularly of the knees, ankles, and feet, whereas men have a greater prevalence of OA of the hips, wrist, and spine (1,68). More recent studies in non-Caucasian populations have further suggested that female sex is a major predisposing factor for knee OA, and that in general women have more severe clinical symptoms. A study using the NHANES III, a U.S.-based study cohort, in individuals with knee OA (radiographic definition of Kellgren-Lawrence [K-L] grade greater than or equal to 2) over 60 years of age were more likely to be female and African American (69). A study of Korean community residents (n = 660) who were age 65 to 91 found that women had more severe radiographic OA than men. Women also had worse Western Ontario and McMaster Universities Arthritis Index (WOMAC) and short form health survey (SF-36) scores (suggesting worse physical function and quality of life) compared to men for the same K-L grading of OA (70). In a similar epidemiologic study of Japanese patients age 60 to 69, the prevalence of knee OA on radiographs was 35% in men and 57% in women (68).

Sex-Related Structural Risk Factors for the Development of OA

Joint Alignment

Abnormal loading mechanics of the joint that can occur with changes in joint alignment can potentially increase the risk of developing cartilage damage. The majority of studies that have investigated sex differences in joint alignment and associations with the development of OA have been of the knee. Estimates of the contact stresses at the articular surface of the knee joint during a static standing position have been shown to predict the development of symptomatic and radiographic knee OA 15 months after a baseline evaluation (71). At the knee, varus alignment, for example, increases the stress on articular cartilage in the medial compartment and, conversely, valgus alignment increases the stress in the lateral compartment. Varus alignment has been commonly associated with knee OA, with the finding of an almost twofold increased risk of development of the disease compared to neutral or valgus alignment (72). However, the prevalence of varus alignment in this particular study was not influenced by the sex of the participants. When individuals have radiographic evidence of knee OA at baseline there is also evidence that both varus and valgus limb alignment increase the risk of progression of the disease (73). Although there is likely a role of limb alignment in the development and progression of knee OA in particular, there is limited evidence of sex differences influencing limb alignment and subsequently affecting the incidence of knee OA (74). The main issue from epidemiological studies is that there are a large number of etiological factors that also play a role in the development of OA. These include biomechanical and biochemical changes that occur during dynamic actions such as walking and changes that occur naturally with age irrespective of sex.

Studies have shown differences in the structure of the knee joint that may contribute to differences in the prevalence of OA. For example, the female femur has been shown to be narrower than the male femur. Women also have a thinner patella, with a larger quadriceps angle (Q angle), with a proportionately smaller lateral tibial condyle compared to the medial tibial condyle (75). The distal femur as a whole in women is smaller, with generally a proportionately narrower medial-lateral diameter compared to the anterior-posterior distance.

Cartilage Thickness

There are differences in the thickness of the knee articular cartilage between men and women. The cartilage of the distal femur is thinner both in adolescence and adulthood in females compared to males. Adult men also have significantly larger patellar and femoral cartilage volume than women, independent of body and bone size (76). Using three-dimensional MRI, Faber et al. demonstrated that women have smaller cartilage volumes than men with percentage differences ranging from 19.9% at the patella to 46.6% in the medial tibia (77). Sex differences of the cartilage thickness were smaller at the femoral trochlea (2.0% difference), medial tibia (13.3%), and medial femoral condyle (4.3%). Cartilage surface areas were on average lower in females by 21% at the femur and 33.4% at the lateral tibia. Sex differences in cartilage volume and surface area in men and women could contribute to the increased risk in women of developing OA, though this is yet to be elucidated. A longitudinal study of an Australian cohort (135 men, 190 women, aged 26–61, mean age 45 years) showed that women have a proportionately higher cartilage volume loss compared to men with time, with these changes seen as early as age 40 (78). Over an average of 2.3 years, women had a higher annual rate of cartilage volume loss compared to men in all knee compartments, but only tibial cartilage loss was statistically significant.

Kumar et al. evaluated the differences in cartilage MR relaxation times (which have been shown to predict future progression of OA) and static and dynamic measures of knee joint loading between men and women in three groups: young healthy (under age 35), middle-aged healthy (35 years or older), and OA populations (79). Of note, higher T_1ρ (MRI relaxation time) indicates worsened cartilage composition with lower proteoglycan content They showed that compared to men, middle-aged women with knee OA have higher MR relaxation times in the lateral and patellofemoral compartments and lower second peak adduction moment. The women also had lower static and dynamic varus in the middle-aged and OA groups and lower varus and more valgus alignment during walking in all groups. This suggests that the women with OA in this study had greater loading over the lateral compartment during walking. Women in the OA group had higher articular cartilage T_1ρ readings in the lateral compartment compared to men.

Muscle Strength and the Progression of OA

Cross-sectional studies have suggested that weakness of knee extensor muscles precedes the development of knee OA (80,81). The contribution of muscle function to the stresses experienced during joint loading has been investigated during dynamic patterns of movement such as walking (82). The Multicenter Osteoarthritis Study (MOST) is a large prospective study of risk factors for knee OA. A sub-cohort of participants (1,617) without radiographic knee OA were grouped into tertiles of quadriceps strength (82). The study found that subjects within the highest third of quadriceps strength had significantly less development of symptomatic knee OA at 30 months follow-up. Approximately 10% percent of the knees in women and 8% of those in men had incident symptomatic knee OA 30 months from baseline. Together with the previous findings, this large longitudinal study demonstrated that weak quadriceps strength was predictive of incident symptomatic but not radiographic OA progression in both sexes.

Resisted knee extension exercises are commonly incorporated in the rehabilitation regimen of patients diagnosed with knee OA. Although they have been shown to have a functional benefit for patients, improvement in knee extension strength has not been shown to have a significant effect on the structural progression of the disease at the tibiofemoral joint. Regardless of limb alignment, Amin et al. found that there was no association of quadriceps strength with tibiofemoral joint cartilage loss for either sex. They did, however, find that there was an association with decreased cartilage loss in the lateral aspect of the patellofemoral joint on MRI, but there were no differences between sexes (83).

During dynamic activities such as walking there are different patterns of muscle activity in OA between men and women. In a subgroup of the MOST study, 60 subjects from this cohort, who had an average age of 64.2 (33 women, 27 men) and had developed radiographic and symptomatic knee OA, were evaluated in terms of their muscle strength and gait characteristics while performing a 400-meter walk (84). The variability in walking speed for male subjects was explained to a mild extent by the power in the sagittal plane produced by muscles that span the hip and ankle joints when walking at a moderate speed (0.89 meters per second). In addition, the 400-meter walk times for men had a strong correlation with isokinetic strength of the knee flexors and extensors. In women, however, isokinetic strength for the knee and hip muscles was not associated with the 400-meter walk time. In contrast, their walk time had a significant correlation with the torque and power about the hip in the frontal plane and knee joint in the sagittal plane when walking at a moderate speed. Interestingly, in subjects with symptomatic knee OA, the speed of a 400-meter walk decreased with age for men, whereas with women, it decreased with self-reported pain score (the WOMAC pain score). In men, the torque and power produced around the knee during walking did not differ with the level of functional mobility and was similar to men without symptomatic knee OA. However, women who were higher functioning had larger hip and ankle muscle activity during walking than those that were less mobile. These findings suggest that men and women with knee OA and who are higher functioning rely more on an ankle strategy than a hip strategy when walking. Men with less mobility decrease the ankle strategy and women with less mobility decrease their hip strategy. A study that incorporated gait analysis in an Israeli population of patients with knee OA reported that both men and women walked at the same speed, cadence, and step length but found differences in the phases of the gait cycle. Women walked with a longer stance phase and double limb support but had a smaller swing and single limb support compared to men. They also had a smaller toe-out angle compared to men (85).

Hip Dysplasia as a Risk Factor for OA

It is well known that severe developmental dysplasia of the hip is a risk factor for the development of hip OA and has a preponderance toward women (86). Studies have attempted to compare the differences in risk for the development of OA in individuals with mild developmental dysplasia of the hip between the sexes. Using a prospective cohort design over 8 years, acetabula dysplasia was associated with only a small increased risk for incident hip OA in a study of elderly white women (87). In the Rotterdam study of adults aged 55 or older who had no radiographic evidence of OA at baseline, acetabula dysplasia was a strong determinant of the development of OA at a mean of 6.6 years follow-up (88). Although women with acetabula dysplasia developed joint space narrowing more often during the follow-up period, the overall association between dysplasia and OA was independent of age, gender, and body mass index (BMI). A similar study cohort, the Copenhagen Osteoarthritis Study, found that the risk for hip OA in men and women was influenced by hip dysplasia in men and hip dysplasia and age in women (89). A smaller study on Turkish men and women found that acetabula hip dysplasia was more common in men (13%) than in women (3.7%), though this was not a significant factor in the development of hip OA (90).

A number of issues still remain in examining the impact of structural factors of the joint that could influence sex differences seen in OA. Due to a lack of long-term longitudinal studies investigating the impact of rehabilitation regimens, it remains unknown whether strength training can significantly alter the structural progression of knee OA and whether there is a difference in response between the sexes. Also, during walking exercise, the differences in the loading magnitudes on articular cartilage between men and women require elucidation. This could allow the creation of more efficacious regimens that are individualized to patient’s sex and potentially limit structural progression of the disease.

SYSTEMIC RISK FACTORS FOR THE DEVELOPMENT OF OA

Inflammation and Obesity

Multiple observational studies have shown that obesity is a significant risk factor for the development of OA, with an increased risk in women. BMI is a known independent predictor of the onset and progression of knee OA, with a stronger effect in women than men (91,92) The Framingham study reported a relative risk of OA in overweight individuals was 2.07 times greater for women and 1.51 times greater for men compared to those individuals with the lowest body weights (91). The Genetics of Osteoarthritis and Lifestyle (GOAL) case-control study identified BMI as a factor that increased the likelihood of developing knee OA, the odds ratio (OR) being 2.68, with the risk for knee OA being greater for women (OR: 3.23) compared to men (OR: 2.20) (92). The waist-to-hip ratio, which is a measure of body shape and health, has been shown to be independently associated with an increased risk of hip and not knee OA in women, whereas there is no such association in men (93). In a study of 387 patients with meniscal tears, radial tears of the medial meniscus (which has been shown to cause a 25% increase in cartilage contact pressure) were associated with older age, female sex, and obesity (94). However, another study by Laberge et al. showed that in 137 obese individuals with OA aged 45 to 55, 64% had meniscal tear with a significantly higher prevalence in men (36%) compared to women (13%) (95).

Historically OA has been described as a “wear and tear” disease, with association of the disease with excessive joint loads. Obesity has often been thought to be an etiological factor for the development of OA due to the likely increased loads placed on the joint with increased body weight. However, recent epidemiological studies have revealed that the risk of OA in non-weight bearing joints such as the hand is twofold higher in obese individuals compared to those with a normal BMI (96). A potential reason for this is that obesity has been shown to be a chronic inflammatory state as evidenced by increased production of systemic cytokines and inflammatory mediators such as IL-6 and IL-8, and interferon-γ in these patients (97). Adipokines are cytokines specifically secreted by white adipose tissue and are involved in the inflammatory process and matrix degradation. Women have been shown to have higher concentrations of adipokines in their synovial fluid compared to men (98). This is likely due to differences in body fat content compared to men particularly in the postmenopausal period. In vitro studies have shown that these proteins upregulate matrix metalloproteinases (MMPs) and induce collagen release from cartilage by working in synergy with other procatabolic cytokines such as IL-1beta (99). Leptin is the most well investigated adipokines and patients with OA have been shown to have higher concentrations in their synovial fluid, which correlated strongly to BMI (100). For example, Hooshmand et al. found increased levels of leptin together with IGF-1 in knee joint synovial fluid in women with knee OA, but not in men (101). There are a lack of studies that have investigated whether the different levels of these inflammatory cytokines in men and women contribute to the differences in incidence of OA between genders.

Hormones and OA

Most epidemiological studies have shown that OA is more prevalent in men than women before the age of 50, but after menopause, the incidence in women increases significantly and is associated with a higher severity of symptoms (102,103). It has therefore been suggested that there is potentially a link between OA and concentrations of sex hormones, particularly serum estradiol. However, this hypothesis is controversial and is discussed in great detail in Chapter 1 on the influence of sex hormones on the musculoskeletal system.

CLINICAL PRESENTATION AND TREATMENT OF OA

There are limited studies reporting differences in the clinical presentation for OA between men and women. Women tend to report knee pain more frequently than men and seek care from physicians for hip and knee problems more often than men (104). A study using the Framingham cohort showed that 64% of older women and 52% of older men reported musculoskeletal pain (105). The factors associated with the pain in women were BMI, systolic blood pressure, and depressive symptoms and not radiographic OA. In men the pain was associated with polyarticular radiographic OA. A study using a Swedish population registry of people aged 55 to 74 found that women had significantly more knee-related complaints on the Knee OA Outcome Score (KOOS), including pain, symptoms, and ability to perform activities of daily living compared to age-matched men. In men, worsened sports and recreation functioning was seen in the 75- to 84-year-old age group, but in women, this was observed in the 55- to 74-year-old age group.

The majority of studies pertaining to rehabilitation regimens have focused on resistance exercises on the quadriceps, with minimal differences in outcome between men and women. For end-stage OA, women tend to delay surgery and generally wait until their symptoms are more severe compared to men. In terms of surgical outcomes, the best outcomes occur in nonobese women over age 60 (implant survival was 99.4%,); whereas the worst results were in obese men less than 60 years (survival rate of 35.7%) (106). Overall this study found that men tended to have a higher surgical revision rate than women (10.2% and 8%, respectively). Similar trends were seen in a report on 134,799 primary total knee replacements from the Australian Joint Registry (107). A statistically significant difference was noted in the cumulative 5-year revision rate of the replacement, 4% for men and 3.3% for women. In contrast, a report from the Swedish Arthroplasty Registry (35,857 unicompartmental and total knee arthroplasties) did not find any differences between genders in revision rates (108). Of note, women are also less likely to undergo surgery, which explains their higher use of prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) (104). Conventionally, patients undergoing total knee replacement have been treated with the same prostheses irrespective of gender. However, as outlined previously, sex differences in the anatomy of the knees have led to the introduction of gender-specific prostheses in recent years. These include the NexGen Gender Solutions prostheses (Zimmer Biomet, Warsaw, Indiana) and the Triathlon Knee System (Stryker Orthopaedics, Mahwah, New Jersey). The NexGen gender-specific prosthesis, for example, was designed specifically for the female anatomy with a narrower medial to lateral dimension to prevent against overhang of the component and limiting potential soft-tissue irritation and pain. In addition, the thickness of the anterior flange is reduced to accommodate the reduced height of the femoral condyles in women and the angle of the trochlear groove is increased by 3° to match the larger Q angle in women. Theoretically these gender-specific prostheses are thought to result in a better anatomic fit, but there is little evidence of improved surgical outcomes including patient function or satisfaction (109–111). The majority of studies in this domain have examined total knee replacements.

Similar investigations in total hip replacements are inconsistent. For example, Röder et al. (112) reported that women had lower early acetabular cup failure than men independent of cup fixation. Conversely, Howard et al. (113) reported a protective association of male sex and the risk of cup revision. A study using a Scandinavian registry did not find significant sex differences in total hip arthroplasty (THA) revision rates. Potential reasons for the conflicting findings between these studies could be attributed to the different definitions of revision, follow-up times, statistical analyses, and different outcome measures used (112–114). Inacio et al. investigated the association between the risk of implant failure and sex in 35,140 THAs performed between 2001 and 2010. In their study women had a 29% higher risk of short-term implant failure, after considering for the specific surgeon, surgeon-volume, and implant-specific risk factors compared to men. Of note, these investigators also observed that among those who received smaller femoral head sizes, women continued to have a 19% higher risk of revision compared to men (115). The varying findings of studies investigating outcome of THA and the influence of patient sex have limited the need for development of gender-specific hip joint prostheses.

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