Sex differences in risk for MSK dysfunction can arise during fetal development. An example of this category is hip dysplasia in babies when they are born. Many studies have indicated that the incidence of neonatal hip dysplasia is greater in females than males, with an Odds Ratio for F/M of 3.8-4 commonly reported (de Hundt et al., 2012; de Oliveira Barbosa and Albernaz, 2019). Within this population there are some features that have been raised and risk factors identified including family history and genetics (Shaw et al., 2016; Swarup et al., 2018; Harsanyi et al., 2020; Zhang et al., 2020). The incidence of unilateral hip dysplasia is greater on the left side than the right, and only a small subset (∼10%) of patients exhibit bilateral hip dysplasia (Mousavibaygei et al., 2022).

When detected this condition can often be corrected by non-invasive procedures using braces or a Pavlik harness (Vafaeian et al., 2019) to maintain the ball of the hip within the socket. Failure to correct the condition early after birth leads to an inability to treat conservatively and development of early OA, often requiring arthroplasty at an early age (Shaw et al., 2016). Thus, to maintain proper biomechanics for the hip during subsequent growth and maturation requires proper placement of the two parts of the joint. Interestingly, whether excessive hip laxity develops in this population after puberty, when sex hormone levels rise and cycle during the menstrual cycle, could not be found in the literature. If tissues of individuals experiencing developmental hip dysplasia had some intrinsic unique responsiveness to sex hormones, one might expect a possible resurgence of the hip laxity leading to altered biomechanics and risk for early OA.

Mechanistically, the basis for sex-dependent differences in development of hip dysplasia is not well defined. As the non-invasive treatment of the condition is usually a temporary and short-term intervention to keep the hip in the hip socket, the hip dysplasia is not a permanent developmental problem and once removed from the intrauterine environment, the neonate can “correct” the deficiency. As ligaments support the stability of the head of the femur in the hip socket, it was once thought that the ligamentum teres was relevant to the developmental problem. However, the gross characteristics of this ligament were not found to be significantly different in patients and controls (Walker, 1980). Such studies did not characterize the functioning of such ligaments so perhaps the laxity of connective tissues contributing to the integrity of hip development were unduly affected by maternal hormones, a situation that self corrected after birth under conditions counteracting the pre-birth structural influence. Of note and potentially relevant to this point, elevated levels of estrogen receptors have been detected in hip tissues from babies with developmental dysplasia of the hip (Desteli et al., 2013), as well as higher levels of receptors for relaxin (an IGF-1 related protein) elevated late in pregnancy and in milk in some species (Steinmetz et al., 1987; Goldsmith et al., 1994) including humans (Schauberger et al., 1996), and in hip tissues from babies with this dysplasia (Ayanoglu et al., 2021). However, this interpretation would not however explain any left-right hip differences! As the hip dysplasia can vary in extent (i.e., severity), there must also be factors other than hormone levels involved, possibly at the level of cells within the tissues, at the level of sex-hormone receptors, or possibly genetic factors (Harsanyi et al., 2020). Thus, any left-right differences within a sex may have other variables involved in the outcomes. This conclusion would also be supported by results from pregnant humans where joint laxity occurs but does not correlate with serum relaxin levels (Schauberger et al., 1996).

Of note, there has been continual improvement in the detection of hip dysplasia using imaging modalities (Barrera et al., 2019; Ghasseminia et al., 2021; Kilsdonk et al., 2021) so detection of cases has experienced increased sensitivity (Zonobi et al., 2018). Such approaches may also shed light on sex differences in patients with borderline dysplasia (Saks et al., 2021). Further improvements may be possible with enhanced technology using machine learning and artificial intelligence approaches and improved training (Ghasseminia et al., 2022). Further, some reports also indicate it may be possible to detect the condition in the prenatal period (Komut and Zehir, 2021). These will be important advances to continue as even the more subtle variants of hip dysplasia could have impact for development of hip osteoarthritis later in life and potentially explain the female preponderance of osteoarthritis in the post-menopausal phase of the lifespan (Hart et al., 2021). This is relevant as even if detected in childhood and treated, many patients still exhibit altered gait patterns (Lee et al., 2022a).

Interesting, the concept of ligament laxity playing a role in developmental hip dysplasia perhaps should not be dismissed as ligament laxity may also play a role in risk for knee injuries during adolescence and beyond as discussed below. It is also of interest to determine whether females with neonatal hip dysfunction would also predispose for development of hip issues following pregnancies where laxity again occurs and could again impact the integrity of the hip biomechanics (discussed below).

Some individuals, mainly females again, are diagnosed with acetabular dysplasia as adolescents or adults (Lee et al., 2013a). Such dysplasia also shows a left hip susceptibility and can lead to osteoarthritis. While very young babies with hip instability can have acetabular dysplasia (Wenger et al., 2013), some authors suggest that acetabular dysplasia is a separate disease from development dysplasia (Lee et al., 2013a). Such suggestions will require further investigation as to the underlying mechanisms, but both conditions appear to exhibit some sex differences.

Juvenile idiopathic arthritis (JIA) can develop in very young children through to skeletal maturity. Thus, this autoimmune disease affecting the joints of growing individuals can occur prior to onset of puberty as well as after puberty (Barnes et al., 2010; Hollenbach et al., 2010; Ahmed et al., 2014; Cattalini et al., 2019). JIA exhibits a sex bias of F/M = 3-6.6/1 (Cattalini et al., 2019) although this ratio may be dependent on race and ethnicity variables (Ringold et al., 2013; Ahmed et al., 2014). In addition, the sex bias cannot be explained by sex hormones alone (Chiaroni-Clarke et al., 2016). Some JIA patients also develop psoriatic arthritis (∼5%) (Brunello et al., 2022), while others develop uveitis (inflammation of the anterior chamber of the eye) which can lead to blindness if not treated (Rosenberg, 1987; Rosenberg, 2002; Quartier, 2021). A subset of females with JIA are at particular risk to develop uveitis (Haasnoot et al., 2019; Lee et al., 2019). Interestingly HLA-B27 is reported to be a predictor of some disease characteristics in boys (Berntson et al., 2008). Therefore, JIA is likely an umbrella term for a heterogeneous disease with different variables influencing the sex differences in the disease and its sequalae.

While much of the research on JIA has focused on immune aspects of the disease or characterization of clinical presentation differences (Hinks et al., 2018; Eng et al., 2019; Gohar et al., 2019; Nigrovic et al., 2021; Onel et al., 2021), details regarding why certain joints are involved in the disease process and not others, why the eye is involved in some patients, and how the sex differences are manifested in pre-puberty versus post-puberty cases remains to be elucidated. As reported by Kuntze et al. (2020), the presence of JIA affecting the knees can impact gait during growth and development which may have long-lasting implications. While in a preclinical model, it has been reported by Kydd et al. (2007) that induction of an inflammatory arthritis in the female rabbit knee can lead to molecular changes in the eye. Additional unpublished results indicate that induction of unilateral knee arthritis in this model leads to changes in the cornea and vitreous humor of both eyes [Kydd, Hewitt and Hart, unpublished observations]. This led to the concept that there may be a “knee-eye-brain axis” of regulation that is mediated either by humoral factors or neural mechanisms, and this may be relevant to the JIA-uveitis link (Hart, 2018). However, such an axis would not explain the relative rarity of uveitis in adult rheumatoid arthritis patients, but the relatively common occurrence of non-infectious uveitis in adults with spondyloarthritis, as mainly unilateral uveitis (Seve et al., 2015).

Following attainment of skeletal maturity, many females still experience changes in knee joint laxity during the menstrual cycle and this again was proposed to be associated with increased risk for ACL rupture (Lee et al., 2013b; Herzberg et al., 2017; Shagawa et al., 2021). Again, it was also determined that there was heterogeneity in such cycle-associated laxity with some individuals labeled “responders” and others “non-responders” (Schmitz and Shultz, 2013) similar to what had been shown by Park et al. (2009).

Phase of the menstrual cycle was also reported to influence the stability of the thumb, and lead to risk for degeneration of the trapeziometacarpal joint (Parker et al., 2022). The authors attributed this laxity and subsequent degeneration to serum relaxin level changes during the menstrual cycle (Parker et al., 2022). At the time of arthroplasty of this joint, it was shown that there was elevated relaxin binding activity in tissues around the joint from females but not males. In contrast, laxity of the cervical spine was reported to not to be influenced by the menstrual cycle changes (Weis et al., 2016; Parker et al., 2022).

Shultz et al. (2012) reported that serum levels for IGF-1 and markers of collagen turnover were associated with menstrual cycle-associated changes in knee laxity and potential risk for knee injury. The timing, direction of the changes and extent of the changes were influenced by whether the individuals were or were not taking oral contraceptives (Shultz et al., 2012). The authors reported that lower serum collagen production fragments and greater IGF-1 concentrations predicted greater anterior knee laxity. A limitation of such studies is that serum levels reflect total body changes in those parameters and not just those associated with the knee and therefore the correlation may not be relevant to the knee specifically. In addition, given that collagen is an essential structural component of most connective tissues of the knee (ligaments, menisci, cartilage, capsule) it may be a risky strategy to modify collagen cyclically every ∼28 days from the onset of puberty to menopause. Interestingly, in an in vitro generated, tissue engineered artificial ligament made with ACL cells, culturing the tissue with estrogen in vitro led to alterations in mechanical function without loss of collagen (Lee et al., 2015). These authors reported that exposure to estrogen led to decreases in the activity of lysyl oxidase, the enzyme that catalyzes formation of covalent collagen crosslinks. Presently, this is a correlation and details regarding how such a mechanism could work in vivo during multiple menstrual cycles remains to be elucidated.

An alternative hypothesis might be that the menstrual cycle-associated changes in joint laxity is regulated by changes in water content. Increases and decreases in ligament water content can influence laxity (Wallace et al., 2002). As many females appear to retain water during parts of the menstrual cycle (Bunt et al., 1989; Ramsay, 1989; Kosar et al., 2022), and skin thickness is increased in specific phases of the menstrual cycle and during pregnancy, reversible changes in water content could be responsible. The skin changes were speculated to be associated with hormone-mediated water retention (Eisenbeiss et al., 1998). In some pregnant females, pregnancy-associated changes in cornea thickness have been reported, presumably due to water retention that is reversed postpartum (Taradaj et al., 2018). As changes in water content would be a readily reversible strategy to influence the properties of a connective tissue, it would be preferred over one that involved the degradation and synthesis of an essential structural component such as collagen. Thus, over ∼30 years of menstrual cycles, the water content strategy would not be prone to risk for loss of the integrity of the tissues involved via altering the integrity of the main structural molecules, the collagens.

During pregnancy many women develop joint laxity including in the spine as well as low back pain (Daneau et al., 2021; Chatprem et al., 2022; Wakkar and Pati, 2022). These complications can be at higher risk in those with hypermobility syndromes (VanderJagt and Butler, 2019; Ahlqvist et al., 2020; Pezaro et al., 2020; Robinson et al., 2022). While many women recover after pregnancy, some reports indicate that persistent post-pregnancy changes in the sacroiliac joint may contribute to the long-term postural deformities (Bailey et al., 2020) and sacroiliac joint dysfunction (Fiani et al., 2021). Sex differences in sacroiliac joint and lumbar spine degeneration have been noted and may occur via different process (Muellner et al., 2022). However, whether there is a subset of females whose pregnancy-associated back pain and sacroiliac involvement are causal of degenerative disease later in life remains to be confirmed by large studies.

The term spondyloarthritis covers a heterogeneous set of conditions that can involve a variety of tissue (Sharip and Kunz, 2020) including joints and the spine, specifically the sacroiliac joints (Brown et al., 2020; Xiong et al., 2022). These inflammatory immune-mediated conditions can affect spinal tissues especially support tissues such as ligaments and their entheses of the axial skeleton (Alber et al., 2022; Li et al., 2022). Long considered mainly a disease of men, particularly ankylosing spondylitis, has more recently been reported to also affect a subset of females (Masi, 1992; Wright et al., 2020; Cunha et al., 2022; Marzo-Ortega et al., 2022; Stovall et al., 2022). Sex differences in disease presentation characteristics (Chimenti et al., 2021), as well as disease activity compared to males have been reported, with females exhibiting higher disease activity than males and exhibiting different response patterns to clinical interventions (Mease et al., 2021; Stovall et al., 2022; van der Horst-Bruinsma et al., 2022).

The onset and progression of the axial spondyloarthritis spectrum of diseases clearly has a genetic basis (Brown et al., 2020), with association with HLA B27 (Masi, 1992; Diaconu et al., 2022). Recent attempts to identify biomarkers of disease subtypes has progressed (Akhtari et al., 2020; Alber et al., 2022), as well as insights into inflammatory mechanisms (Lee et al., 2022b). In addition, recent information has revealed that the gut microbiome of patients is different from a healthy control population, but no sex differences were noted (Wang et al., 2022). Additional study of intestinal tissue and fecal samples have identified potential alterations in the tryptophan metabolizing pathways that could be involved in microbiome contributions to the disease progression (Berlinberg et al., 2021).

Thus, the sex differences in spondyloarthritis are somewhat different from many of the other diseases discussed previously in that the majority of patients are males rather than females, even though this set of diseases is believed to have an autoimmune basis. Therefore, the females with spondyloarthritis-related conditions are likely a unique subpopulation of individuals. The molecular and cellular basis for these differences has not yet been delineated, but this area is the focus of considerable investigation so hopefully, some insights will emerge in the near future to clarify these issues.

Osteoporosis (OP), or loss of bone integrity and increased risk for low-energy fractures (Vandenput et al., 2022), is often thought of as a disease of post-menopausal females. However, OP affects only a subset of post-menopausal females, and the ratio of females/males with OP is ∼3/1 [discussed in 21]. The treatment of males with OP is understudied (Rinonapoli et al., 2021; Vescini et al., 2021). There are also sex-differences in when fractures occur in males and females, with males suffering from fractures ∼10 years later in life than females (Vescini et al., 2021). The extent of bone loss is quite variable between individuals of either sex, so the underlying mechanisms must be complex and influenced by several factors. While there are reported sex differences in skeletal growth (Nieves, 2017), any correlations between bone growth early in life and rate of bone loss with aging and onset of menopause have not been established.

OP in females was effectively treated with hormone replacement therapy (HRT) for many years until a variety of risk factors were identified (i.e., cardiovascular disease, breast cancer, venous thromboembolism, endometrial cancer) which led to a reluctance to support such treatment (Booyens et al., 2022; Davis and Baber, 2022; Pan et al., 2022). However, this treatment option is now being revisited. In light of such reluctance regarding use of HRT, a number of other options have been developed including bisphosphonates, monoclonal antibodies against proteins involved in bone cell function, vitamin D, and anabolic peptides such as parathyroid hormone fragment and calcitonin (Zhou et al., 2014; Mulder et al., 2016; Chandran, 2022; Lim, 2022; Zhu and March 2022). Such interventions vary in effectiveness and side-effects, and thus, many patients are now using those with lower risks. However, in both men and women, OP is often the “silent disease” until a fracture occurs, so many individuals with OP are not treated, and this is especially true for men as the condition is generally viewed as a female disease. The molecular basis for why this particular subset of females is affected by OP following loss of sex hormones at menopause remains undefined. Similarly, the molecular or genetic basis for why a subset of males develop OP also remains largely unknown. Furthermore, it also remains to be determined if similar or very different mechanisms are involved. However, males do respond to bisphosphonates and other treatments (Adler, 2018; Johnston and Dagar, 2020) so there may be some commonalities.

Osteoarthritis (OA) is a degenerative disease of joints such as the knee, hip, shoulder and also fingers of the hand. For many years it was presented as a disease of articular cartilage as that tissue was the one most affected. However, it is now thought of more as a disease of the whole joint, considering the joint as an organ system (Radin et al., 1991; Frank et al., 2004). As reviewed recently by Hart (Hart, 2022b), OA is now considered an inflammatory disease and there appear to be sex differences in some inflammatory markers in OA (Perruccio et al., 2019).

In the years prior to the onset of menopause, the ratio of females to males with OA is ∼1/1, but after menopause, the ratio become >2/1 [discussed in 21,22,200]. Thus, after menopause, there is an increase in the number of females with the condition compared to males. It has been proposed that this subset of post-menopausal females developing primarily knee and hip OA represent a unique and separate subtype of OA (Hart et al., 2021; Hart, 2022a; Hart, 2022b). Presently, conservative treatment options such as exercise, pain medications, and bracing are not sex specific. However, in the future some options could be sex-specific to address the potentially unique mechanisms involved in OA arising in post-menopausal females as suggested by Hart (Hart, 2022a) and Hart et al. (Hart et al., 2021). Therefore, there has been slow progress in the conservative treatment realm for OA, and for many patients this leads to a total joint replacement for the condition.

Thus, in a subset of post-menopausal females the loss of sex hormones leads to alterations in joint regulatory mechanisms leading to OA. What is uniquely different in this subset and how sex hormone loss contributes to the OA development, remains to be elucidated for the most part.

Sarcopenia is the age-related loss of muscle structure and function (i.e., muscle mass and strength) and can occur in both males and females, but there are some sex-associated differences in the onset and progression of such muscle loss (Du et al., 2019; Buckinx and Aubertin-Leheudre, 2022; McMillian et al., 2022). Sarcopenia can also be influenced by associated obesity in some patients (Jia et al., 2022; Muollo et al., 2022). Sarcopenia and sarcopenic obesity in older individuals can influence other age- and sex-related conditions such as osteoporosis (Edwards et al., 2015), cardiovascular fitness (Billingsley et al., 2022), osteoarthritis (Godziuk et al., 2020), and cognitive performance (Cavazzotto et al., 2022), all affecting different subsets of post-menopausal females compared to age-matched males.

Therefore, sarcopenia as an age-related loss of muscle integrity would appear to interface with other post-menopause conditions to impact disease activity and progression. As some post-menopausal females also gain weight after menopause, likely due to loss of estrogen’s effect on energy balance (De Jesus and Henry, 2022; Mahboobfard et al., 2022), sarcopenic obesity is also very prevalent in this population, a finding that may enhance the impact of the other conditions discussed above.

Estrogen is believed to play a role in intravertebral disc (IVD) degeneration (Wang and Griffith, 2010; Jin et al., 2020). In the post-menopausal state, the presenting symptom is usually pain (Wang, 2016). The IVD degeneration types include adult-onset lumbar scoliosis (Aebi, 2005; Rumancik et al., 2005; Urrutia et al., 2011a; Urrutia et al., 2011b) or spondylolisthesis (Jacobsen et al., 2007; Cholewicki et al., 2017). The causes for the development of such conditions in post-menopausal women is mainly unknown, but some associations with parity have been made (Cevik et al., 2020), and risk factors for pregnancy-related pelvic girdle pain investigated (Wuytack et al., 2020), as well as a focus on pregnancy-associated changes in motor control of the spine (Desgagnes et al., 2022). Some evidence that exercise can help prevent development of low back pain has appeared, but it is not compelling as yet (Santos et al., 2022). In addition, some evidence for the role of HRT in preventing developing of some post-menopausal spondylolisthesis has been generated (Marty-Poumarat et al., 2012), potentially implicating the loss of estrogen in develop of the condition rather than a consequence of pregnancy-associated factors alone.

In summary, a number of MSK conditions arise in subsets of post-menopausal females at rates higher than age-matched males, or associated with conditions uniquely associated with females (i.e., pregnancy). Some of these can be linked more directly to loss of sex hormones than others, but clearly there are significant sex differences that have been noted. Of interest is the differences between adolescent idiopathic scoliosis which appears to arise in the thoracic spine post-puberty and onset of increased levels of sex hormones, and adult scoliosis which is associated with the lumbar spine and arises in the post-menopausal state following loss of sex hormones. The development of adult scoliosis can be a “re-activation” of somewhat quiescent AIF or not but does appear to occur rapidly in the post-menopausal state in a subset of patients (Urrutia et al., 2011a; Marty-Poumarat et al., 2012). Why it occurs in a particular subset is currently unknown. In a recent Clinical Case Series with 187 patients having Adult Symptomatic Lumbar Scoliosis (ASLS), >90% were female (Carreon et al., 2020). Therefore, there is a majority of patients with ASLS that are post-menopausal females (mean age >58 years) (Carreon et al., 2020). Details regarding the characteristics of the males with ASLS could not be found.

At the surface, these differences may be difficult to reconcile, but it is also clear that many epigenetic changes occur at the time of puberty (Hart, 2022a) and also from life experiences, so the loss of sex hormones following menopause likely does not return females to the pre-puberty state. Thus, the basis for the development of post-menopausal conditions is likely complex and multifactorial.