Women's musculoskeletal health: insights from the 2024 National Academies of Sciences, Engineering, and Medicine report on chronic conditions

After reviewing the NASEM report from an MSK-centric perspective, the ASBMR Women’s Musculoskeletal Health Working Group identified several opportunities for research, education, clinical care, and advocacy to improve MSK health in women with chronic health conditions. These are outlined briefly below ( Table 3 ). A recommended agenda to advance and improve the health of women with chronic conditions. Sex differences in biology, social stresses, and access to care all contribute to differences in disease presentation, timely diagnosis, differences in treatment responses, and co-morbidities between women and men. Many historical and structural issues around research funding, study design, and systemic biases have led to gaps in our knowledge on how specific diseases affect women. The National Academies of Science, Engineering, and Medicine (NASEM) report on “Advancing Research on Chronic Conditions in Women” provides a useful guide to better understand what we know and what we do not know about differences in chronic disease impacts in men vs women. The NASEM report identifies osteoporosis as a clear example of how sex affects the presentation and course of a chronic MSK condition. However, as outlined in the NASEM report, many chronic conditions affecting women have unexplored effects on MSK health. In this perspective, we provide a brief summary of the NASEM report and underscore potential issues for new or continuing research in areas of interest to the ASBMR. In addition, we identify gaps in which the critical role of MSK health was overlooked in the report or in the metrics used to calculate the impacts of chronic disease. The lack of discussion of osteoarthritis is a glaring example, especially given recent literature suggesting clear sex differences in its presentation and response to therapy. 10 , 14 , 18 , 19 , 34 Despite the greater incidence and/or severity of osteoporosis and other MSK diseases in women and their profound impact on quality of life, MSK health is clearly underreported and underappreciated in many studies examining the impact of chronic conditions in general, not just in women’s health. This omission underscores that the ASBMR and its membership need to continue efforts to advocate for inclusion of MSK endpoints into policy, economic, and basic and clinical research endeavors. Combined with efforts to promote focused research on women’s MSK health, this broad-based advocacy for inclusion of MSK outcomes will be instrumental to improving women’s health.

Recognizing the disproportionate impact of common, chronic MSK conditions on women, 18–21 a Working Group on Women’s Musculoskeletal Health was established by the American Society of Bone and Mineral Research (ASBMR) in Fall 2024. The committee was tasked with reviewing the NASEM report and educating society members about its findings. Musculoskeletal conditions encompass a wide variety of processes affecting bone, muscle, joints, ligaments, and tendons. Our goal was not to independently review the impact of MSK conditions on women’s health but rather to summarize the main findings of the NASEM report with an eye toward communicating research gaps, priorities, and opportunities for our field, and for advocating for MSK health more broadly. Table 2 summarizes overall findings of the report that provide a rationale for additional research on women’s musculoskeletal health. Below, we focus our analysis of the report around three main questions: (1) What are the research gaps and priorities for women’s musculoskeletal health that are relevant to the chronic conditions discussed in the NASEM report? (2) What perspectives and complexities were identified in the NASEM report that are important for ASBMR investigators to consider in order to improve women’s musculoskeletal health? (3) What research gaps in the field of women’s musculoskeletal health are missing from the NASEM report? Findings from NASEM report that provide rationale for additional research on women’s musculoskeletal health. We have divided our perspective into the following sections based on the organization of the NASEM report.

Although the reasons are not fully understood, women experience a higher prevalence of many chronic conditions compared to men, including osteoporosis. 8 , 14 , 15 , 22 In addition, as noted in the following section, other chronic conditions that are more common in women, such as Alzheimer’s disease (AD) and depression, also increase the risk for MSK complications. 23 , 24 These chronic conditions have a large impact on women’s quality of life, affecting physical, emotional, and social well-being. 25 The NASEM report emphasized that gaps exist in both data specific to women for chronic conditions in general and data specific to chronic conditions that only or disproportionally affect women. 12 The historical practice of clinical studies excluding women has contributed to an evidence gap for the prevention, diagnosis, and treatment of chronic conditions in half of the population. 2 , 26 Additionally, the co-occurrence of many of these chronic conditions with musculoskeletal health has rarely been considered. Broadly, there is a lack of understanding of how social factors affecting women contribute to increased susceptibility to chronic conditions. These data will need to be integrated with biological determinants of sex in longitudinal studies to provide insights across the lifespan of women with chronic conditions. Biological factors, such as genetics and hormonal variables, need to be intentionally considered in studies, assessed across groups, and correlated with physiology and disease. Basic science and pre-clinical research are also needed to provide a critical perspective on biological variables and molecular mechanisms that influence women and men differently. 27 , 28 Finally, when considered at all, musculoskeletal health is often considered in the context of a disparate set of different tissues rather than as an integrated physiological system, such as the cardiovascular, neurologic, or reproductive systems. Longitudinal studies are needed that assess impacts on the musculoskeletal health of women with chronic diseases, as well as the systemic effects of chronic musculoskeletal conditions in women. For researchers planning to tackle these studies, many methodological factors must be considered when planning studies of chronic conditions in women or female animals. Furthermore, given that some sex differences in disease presentation may relate to sex chromosomes, attention must be given to sex-specific differences between cell lines. 22 , 27–31

Literature suggests that women are more likely to have MCCs (defined as 2 or more co-occurring chronic physical or mental health conditions) than men, 79 although the overall differences are modest and depend on specific patterns of disease co-occurrence. Unfortunately, comorbidity indices (eg, Charlson comorbidity index [CCI]) do not generally include fractures, osteoporosis, or MSK health. 80 Thus, contributions of MSK conditions to overall MCC are likely substantially underestimated and specific associations of MSK conditions with other chronic diseases may be underrecognized. Comorbidity indices should adopt metrics on MSK health status to be more representative of the population. Many ongoing questions relate to MCCs. At the basic-science level, better preclinical models of MCC are needed, including for MSK conditions. The role of sex steroids (especially estrogen) pre- and post-menopause in other aging related chronic conditions in women needs to be ascertained, including frailty/sarcopenia, cardiovascular disease, dementia, and diabetes, as all these conditions also alter fracture risk. At the clinical level, the impact of menopause in accelerating biological clocks must be further investigated. 81 The literature suggests that menopause and E2 withdrawal accelerate cellular epigenetic aging and senescence as well as metabolic dysfunction. 81–83 Additionally, the role of inflammatory biomarkers in age-related MSK conditions should be evaluated. Studies also are needed to evaluate the benefits vs risks of targeting senescent cells to treat MCCs, including osteoporosis and frailty. 84 Finally, there is an opportunity for collaboration between psychology/psychiatry and MSK clinicians, as little is known about the role of adverse childhood experiences or gender-related chronic stressors on MSK conditions later in life.

The NASEM report highlights a series of chronic conditions that impact or affect women differently compared to men. 12 While these conditions affect both sexes, the NASEM report highlights disease-specific research gaps relative to their presentation in women vs men, as well as opportunities to improve the understanding of sex differences in their pathophysiology more broadly. Overall, our knowledge of how sex differences influence the manifestation of most diseases should be expanded. Research on sex differences in disease has traditionally focused on gonadal hormones; complementary studies on other forms of sex differences such as sex chromosomes and differentially expressed genes (eg, due to epigenetic differences) should be incorporated into grants and experimental designs. The ASBMR working group searched for potential links between these 21 conditions and found that 9 of these chronic conditions have potential effects on musculoskeletal physiology that might lead to new research opportunities. Our goal here is not to extensively review the literature about MSK health and these conditions but rather to point out potential connections and highlight possible research opportunities. Therefore, in this section, we will briefly summarize some diseases listed in the NASEM report that affect women disproportionally and also have links to MSK health. Depression is more common in women and is also a risk factor for osteoporosis. 49 , 50 Links have been made between mechanisms of depression and bone health. The Gamma-Aminobutryric Acid (GABA) and serotonin systems regulate bone and mood, and SSRIs used to treat depression can cause bone loss. 24 , 51–53 We should better understand sex differences in brain and bone crosstalk as well as with central serotonin and GABA systems. Additionally, research is needed to assess changes in bone and brain related to fluctuations in cortisol and estrogen with menstrual cycles and at the crucial time points of menarche, pregnancy, lactation, and menopause. 54 Substance use disorder can occur with multiple substances, and progression to dependence happens faster in women. 55 This disorder can affect menstrual cycles and cause bone loss. A research opportunity exists here to understand better the interactions between substance use, reproductive hormones, and bone health pre-menopause. 56 HIV is associated with higher rates of age-related conditions in women than men, including osteoporosis. 57 Within the HIV field, a research opportunity is to better describe the onset, course, and fracture incidence of post-menopausal women with longstanding disease. Migraine headaches are more common in women and can be triggered by fluctuations in estrogen. 58 Clinical associations also have been made between migraine and increased incidence of osteoporosis. 59 There is a need to better understand why the incidence of migraines is higher in women with osteoporosis and to assess the impact of estrogen administration in women with both conditions. Multiple sclerosis (MS) is associated with a high incidence of osteoporosis in both men and women. Estradiol levels have complex interactions with both MS progression and bone loss, and both worsen with menopause. 60 , 61 Some evidence suggests that anti-resorptive treatment in mice can affect the disease course of MS. 62 Research opportunities may include understanding how bone loss develops in MS patients, interrogating if bone turnover affects the activity or course of MS, and assessing if the immune reaction to myelin directly or indirectly affects bone cell innervation and activity. Fibromyalgia has associations with vitamin D levels and osteoporosis. 63 However, the literature is not clear regarding the role of vitamin D deficiency in fibromyalgia and the effectiveness of vitamin D supplementation. There is an opportunity for research to better understand the associations of fibromyalgia with osteoporosis and assess the primary or secondary effect of vitamin D levels. Alzheimer’s disease also has association with osteoporosis, and a diagnosis of osteoporosis is one of the best predictors of those who progress to an AD diagnosis in women but not in men. 64 , 65 ApoE4 variants increase risk for both diseases, and ApoE has effects on bone cell health and activity. 66 Opportunities are plentiful for research to elucidate the biological basis of observed pathophysiological links between osteoporosis and AD, including interrogating central brain regulation of bone turnover and vice versa. Additionally, studies should assess whether osteoporosis treatment regimens affect incidence or progression of AD. Sarcopenia has well known associations with osteoporosis, frailty, fall risk, and bone fractures. 67 Crosstalk between muscle and bone cells has been established, and the role of mechanical forces on the skeleton and sarcopenia are intertwined. 68 The NASEM report suggests that sarcopenia affects women disproportionally although it also clearly affects men. Opportunities here include further investigations of sex differences in the impact of sarcopenia and aging as well as continuing to expand research on muscle–bone cross talk, examining the early onset of sarcopenia and related bone loss, and interrogating the role of systemic factors, such as aging or cell senescence, and their combined effects on muscle and bone health. Finally, education can be expanded on the integrated nature of the musculoskeletal system and critical aspects of health in aging of women after menopause. Osteoporosis (OP) is a major bone metabolic disease that impacts women more than men. 14 , 22 , 69 , 70 The NASEM report highlights many research opportunities to improve our understanding and treatment of this chronic disease, including in the realm of basic science, clinical assessment, treatment, and education. Our field is well versed in the issues and opportunities for research and improved care for osteoporosis. In the context of this summary of the NASEM report, we will briefly summarize points made by this group. The NASEM report underscores the need to better understand the mechanisms responsible for sex differences in bone biology and how they offer risk or resilience to aging or chronic disease. Which of these mechanisms arise from cell-intrinsic sex-differences and which are due to changes in sex hormones? The NASEM report also identified the need to better define other sex-specific factors beyond estrogen (eg, inhibins, FSH, and others) in mediating bone loss after menopause. 71 How these factors influence other organ systems to indirectly impact the skeleton and/or joint health also would be useful information. The report emphasized the need to expand treatment options for osteoporosis. We must determine why bone formation wanes over time with all anabolic agents, and why we have been unable to “cure” osteoporosis. 72 The optimal timing and sequencing of treatment regimens also remains a topic of great interest. 72 , 73 In the clinic, better tools are needed for diagnostics. Genetic factors for bone strength and bone disease risk have potential to develop genetic screening tools for fracture risk. 74 Better methods are needed to identify increased fracture risk, particularly among those who do not have bone mineral density values in the clinically established osteoporotic range. Tools to assess bone material properties and other aspects of bone “quality” are also needed. Better education about osteoporosis and fracture risk is needed. Although reliable information on osteoporosis and fracture risk for patient use is available in multiple languages through the International Osteoporosis Foundation and the BHOF, less than 1/3 of women over 65 have a DXA scan. 59 How can we maximize patient awareness and improve screening efforts? Also, should DXA guidelines differ for early vs late post-menopausal patients? How do we support adoption of validated, non-DXA approaches to diagnose poor bone health? In addition to screening, 90% of women with fractures are not treated for at least one year after fracture. 75 Improved outreach, advocacy and expansion of fracture liaison and other post-fracture case-finding methods are sorely needed. Continuing controversies regarding the roles of calcium and vitamin D supplementation in bone health need to be resolved—there is considerable confusion among patients and primary care providers. 76–78 The field needs to meet public desire for “wellness” with clear, effective, data-driven diet, and exercise strategies to develop, protect, or restore skeletal health.

Women’s health is often focused on reproductive and gynecologic health, but the NASEM report stressed that there is also a need to focus on how sex and female reproductive cycles affect other physiologic systems and health variation across the lifespan. 12 In addition, research needs to consider the influence of gender in the social and psychological determinants of health and disease. Lack of research and inadequate prioritization of female-specific physiology and pathophysiology has led to knowledge gaps that impede advances toward individualizing prevention and treatment in women or men. Identified structural reasons for the dearth of scientific understanding into female-specific disease knowledge include more limited funding opportunities (both federal and non-federal) for women’s health and the tendency for research studies focused on female physiology or disease to be published in field-specific journals rather than high impact journals, which may result in fewer scientists focusing their research careers on female-specific health discovery. 2 , 12 , 39 On the clinical side, structural issues that were identified included lack of training to be attentive to sex-specific presentation of diseases and traditional gender stereotyping of symptoms. For example, pain during menstruation can be dismissed as “normal,” delaying diagnoses and contributing to co-morbidities. As a result, women with endometriosis often have a delay in diagnosis and face 3-4 times greater risk of chronic opioid use/dependence and overdose. 40 Many noticeable knowledge gaps exist in the study of menstruation and menopause. Variations in menstrual and menopausal symptoms need to be better understood, as does whether these symptoms correlate with risk for acute injuries or chronic conditions. Perimenopause often coincides with other midlife stressors and role transitions. Research is needed to dissect how factors like chronic stress or mental health can impact hormone status, and directly or indirectly influence chronic disease incidence in women. For example, what is the basis of sex differences in manifestations of musculoskeletal pain disorders, such as temporomandibular joint, lower back, and neck pain? Recent work has called attention to a constellation of MSK symptoms, termed the “musculoskeletal syndrome of menopause,” which has been suggested to affect up to 70% of women during perimenopause and the early post-menopausal period. 41 , 42 This constellation of symptoms includes arthralgia, myalgia, muscle weakness, and worsening joint pain associated with OA, in addition to the well-recognized bone loss and vasomotor symptoms that accompany this transition. The field also needs additional studies to assess the risks and benefits of menopausal hormone therapy (MHT) on overall health as well as bone, joint, and muscle health, including the prevention of osteoporosis, osteoarthritis, and traumatic joint injury. Questions remain on the timing of treatment. 43 For example, when should MHT be initiated? Should MHT be limited to the first 10 yr post-menopause as currently recommended 44 , 45 or are longer treatment durations beneficial, at least in a subset of women? What is the impact of MHT on the bone anabolic effects of resistance exercise? Also, can/should MHT be used after anabolic therapy for osteoporosis, or after joint replacements? These clinical questions (and others) are all important within our field and require more research. Finally, additional effort should be focused on the connection between common gynecological conditions and MSK health. Very little is known about the impacts of conditions, such as endometriosis, dysmenorrhea, menstrual pain, or chronic pelvic pain, on musculoskeletal health. Endometriosis is estimated to impact 5%-10% of reproductive aged women, 46 and appears to have an inflammatory/autoimmune component, genetic risk variants, and a greater risk of other morbidities. We need to better understand whether there are musculoskeletal comorbidities to these relatively common gynecological conditions. For example, the NASEM report notes that studies have shown a 40%-100% increased risk of RA in people with endometriosis. 47 Autoimmune disorders such as RA share features of immunologic and hormonal abnormalities with endometriosis and can be associated with bone deficits. 47 , 48 We need to better understand links among endometriosis, autoimmune arthritis, and other aspects of MSK health.

Engaging patients and communities about chronic conditions improves relevance and outcomes. Women’s health outcomes can be improved through patient-centered, community-engaged, and policy-driven approaches. 85 The NASEM report identified key barriers that can be targeted by professional societies, clinicians, and advocacy groups. These include: (1) a lack of knowledge about chronic conditions; (2) continued stigma and biases around chronic conditions, especially in women; and (3) considerable challenges with accessing affordable care. Ongoing challenges in the field of chronic conditions in women are limited research models, an overall underrepresentation of women in clinical trials, and a lack of data disaggregation by sex in large scale and meta-analyses. 86 Successful strategies that can be more widely implemented include patient engagement, community-based participation, health services research, and optimizing care through learning health systems. Additionally, telehealth opportunities can be increased to improve access to care, especially for underserved women. 87

Research in women’s health has historically been underrepresented but, increasingly, is an important part of the national scientific conversation. Over the years, various reports and task forces have been convened by scientific societies and national academies to compile information on current knowledge, key findings, and recommendations for the field. 1–4 A major prior outcome from these task forces was to include “sex as a biological variable” in research protocols as well as all grant submissions to the National Institutes of Health (NIH). This has resulted in a growing recognition of sex- and gender-based biological and psychosocial differences in the physiology, presentation, course and treatment of cardiovascular, metabolic and immune conditions, cancer, and musculoskeletal (MSK)-related diseases, such as arthritis and osteoporosis. 5–11 Most recently, the National Academies of Science, Engineering, and Medicine (NASEM) released a report on “Advancing Research on Chronic Conditions in Women” (2024). 12 The conditions included in the report were selected to cover a broad array of topics (see Table 1 ). The report covered female-specific and gynecological conditions, conditions predominantly affecting women or affecting women differently than men, as well as the presence of multiple chronic conditions (MCCs) in individual patients. Importantly, the focus on chronic conditions was motivated by a World Economic Forum Report in 2024 reporting that, although, on average, women live longer than men, women suffer approximately 9 more years from chronic health conditions that limit their ability to contribute to their family, communities, and workforce. 12 In general, the NASEM report found that NIH spending is misaligned with respect to the impact of chronic conditions experienced by women. The NIH Office of Research on Women’s Health provides a framework for defining chronic debilitating conditions in women, 24 of which have a known metric of research dollars spent per disability-adjusted life years (DALYs). 13 Despite their burden, especially in women, musculoskeletal conditions have a disproportionally low investment of research dollars. In fact, lower back pain and osteoarthritis were conditions with 2 of the 3 lowest DALYs, and, surprisingly, no DALY was assigned to osteoporosis. Nevertheless, other recent studies have demonstrated that osteoporosis is associated with a significant increase in DALYs for post-menopausal women. 14–17 The Bone Health and Osteoporosis Foundation (BHOF) reports that osteoporosis will cost the US Health Care System over 25 billion dollars in 2025, rising to $95 billion in 2040. Despite this, in 2024, the NIH allocation to “osteoporosis” was 143 million dollars (0.57 cents for research per dollar healthcare cost), a 20% decline relative to 2008 (not adjusted for inflation). In comparison, in 2024, the NIH spent 2.8 billion dollars on research for cardiovascular disease (40% increase compared to 2008), which cost the US health system 233 billion dollars (1.2 cents for research per dollar healthcare cost). Spending on cardiovascular disease is, thus, slightly more than twice as much as for osteoporosis, corrected for the relative cost to the US healthcare system. Clearly, research spending on osteoporosis does not offset the relatively low investment of research dollars per DALY as noted for other MSK diseases disproportionally affecting women. Chronic conditions reviewed in the 2024 NASEM report.

As noted in the Introduction, it has become increasingly clear that many disease processes can present and/or progress differently in men vs women. The NASEM report underscored the fact that the effects of chronic conditions cannot therefore be routinely generalized across both sexes. In both clinical and preclinical studies, outcomes should be investigated and reported separately for males and females. Only if there are no significant differences between the sexes, should results be pooled and analyzed together. In human trials, each sex should be further stratified to consider other biological and social determinants of health, such as race and ethnicity. Many examples exist where this approach has not been the case. 32 , 33 However, going forward, these guidelines should be followed, especially in clinical studies. Additionally, the timing of sampling and data collection from women should be standardized, or at least noted, with respect to menstrual cycle, pregnancy, and menopause. Analysis of results using appropriate statistical models should be able to adjust for these factors if the data points are collected and annotated accurately. The NASEM report also noted that studies of chronic conditions in women often failed to enroll participants fully representative of the populations affected by these diseases. 12 Variability in disease prevalence and severity across biological and social variables can lead to errors in estimates of disease burden in some groups due to inaccurate reflection or consideration of population heterogeneity. More representative longitudinal data on the incidence, burden, and outcomes of chronic conditions, including musculoskeletal disease, need to be collected. Unfortunately, no consensus exists on how to most accurately measure the impact of chronic conditions in women vs men, as the tools to do so have not been established. For instance, women may experience different symptoms and perceive pain differently than men. 6 , 10 Thus, a notable topic missing from the report was guidance on how clinical investigators might tailor their research procedures to account for potential differences in disease impacts between women and men.