Osteoporosis Research in Men: Rethinking Standards and Reference Models

The Challenge

Men account for nearly a third of osteoporosis-related hip fractures in Europe and the U.S. (Dhanwal et al., 2010). Nonetheless, osteoporosis is considered primarily a disease of postmenopausal women, and men are rarely evaluated or treated for it (Szulc et al., 2012).

Method: Rethinking Standards and Reference Models

Research in many fields—for example, heart disease—has relied on reference models that treat men as the norm. Women are often studied as deviations from that norm. In the case of osteoporosis, however, diagnostic models have been developed for women using bone mineral density (BMD) norms of healthy young white women, and criteria to identify risk in men are not well established. Researchers are improving these reference models and opening new areas of research by considering disease progression in both women and men, and by evaluating risk using sex-specific reference models.

Gendered Innovations:

1. Establishing Male Reference Populations By 1997, evaluation of men's bone quality was based on BMD norms of healthy young men rather than healthy young women (Looker, 1997). More work needs to be done to redefine diagnostic cutoffs for both women and men (Binkley et al., 2010).
2. Creating New Diagnostics Based on Secondary Contributors to Osteoporosis and Metabolic Bone Disorders (SECOBs) Researchers have identified medical conditions (such as hypogonadism and hypercalciuria) and treatments (such as chemotherapeutics and anticonvulsants) that correlate with osteoporotic fracture, especially in men. New diagnostics take SECOBs into account—along with variables such as BMD, sex, and lifestyle. Accounting for these factors improves diagnosis in both women and men.

The Challenge
Method: Rethinking Concepts
Gendered Innovation 1: Male Reference Populations
Method: Rethinking Standards and Reference Models
Is the T≤ -2.5 Cutoff Appropriate for Male Patients?
The Male Reference Model and Osteoporosis Intervention
Method: Analyzing Factors Intersecting with Sex and Gender—Environment and Geographical Location (Differences among Men)
Ancestry, Ethnicity, and Geography
Method: Analyzing Gender - Physical Activity (Differences among Women)
Gendered Innovation 2: New Diagnostics Based on Secondary Contributors to Osteoporosis and Metabolic Bone Disorders (SECOBs)
Conclusions
Next Steps

The Challenge

Osteoporosis has been considered primarily a disease of postmenopausal women, an assumption that has shaped its screening, practice, diagnosis, and treatment (Klinge, 2010). This perception may exist because osteoporosis manifests about 10 years earlier in women than in men (see chart at right) and because women of all ages have higher risks of fracture than age-matched men (see chart below).

Although women have a higher fracture risk at a given age, medical outcomes of fractures are worse in men. A low-trauma ("fragility") fracture is associated with approximately twice the risk of a future fracture for a woman, but more than three times the risk for a man. As a result, the absolute risk of a subsequent fracture (per 100 patient-years) is similar in men (5.7%) and women (6.2%) (Center et al., 2007). In addition, a fragility fracture is associated with a twofold increase in mortality for a woman but a threefold increase for a man (Bliuc et al., 2009). These findings have led researchers to redefine osteoporosis as a disease affecting both women and men (see Method).

Method 1: Rethinking Concepts

Osteoporosis has traditionally been defined as a disease of white, postmenopausal women. Men, however, account for nearly a third of osteoporosis-related hip fractures in Europe and the U.S., and it is becoming clear that they have been underdiagnosed because of the limited scope of diagnostic definitions (Amin, 2010). In 2002, the U.S. Centers for Disease Control and Prevention (CDC) noted that, because of the lack of data, "there is no consensus at this time concerning the definition of low bone density in groups other than white women; however, it is clear that osteoporosis is not solely a disease of white women" (CDC, 2002). Redefining osteoporosis to include men as well as at-risk minority groups has led to new research and clinical practices that consider osteoporosis in broader populations.

View General Method

Gendered Innovation 1: Male Reference Populations

Low bone mineral density (BMD) has long been recognized as an important predictor of fracture risk. Diagnostic criteria for osteoporosis were initially based on how many standard deviations a patient's BMD drops from the mean BMD of a female reference group, specifically young (aged 20-29 years) white women (CDC, 2002). The T-score is the standard deviation from the mean for this reference group. Negative T-scores indicate bone loss. Based on studies of women, a T-score of -2.5 (i.e., 2.5 S.D. below the mean for the reference group) has been defined as the diagnostic cutoff for osteoporosis (World Health Organization, 2003).

Between 1988 and 1994, the U.S. CDC collected BMD data from more than 14,000 U.S. women and men (National Center for Health Statistics, 1994). In 1997, a reference population of young men was used to calculate T-scores for male patients on the basis of healthy male (rather than healthy female) BMD values (Looker, 1997).

Calculating men's T-scores based on a male reference population greatly alters diagnosis rates. The prevalence of osteoporosis in men was estimated as 1%-4% using a female reference population; it has been estimated to be 3%-6% using a male reference population(Looker, 1997; Cummings, 2002). This practice marks an important gendered innovation (see Method).

Method : Rethinking Standards and Reference Models

When establishing reference models, researchers must consider:

1. The Reference Population: To what group of young, healthy people should a given patient be compared? Is it important that the patient be matched to a reference population of the same sex? The same ethnicity? Lifestyle? Geographic location?
2. The Diagnostic Cutoff: How many standard deviations below the mean of the reference population best diagnose osteoporosis?

In spite of these advances, problems persist. Diagnostic models based on BMD alone do not reliably predict who will suffer an osteoporotic fracture (Kanis et al., 2008a).

View General Method

Is the T ≤ -2.5 Cutoff Appropriate for Male Patients?

The T ≤ -2.5 cutoff (using a male reference population) is a common diagnostic for osteoporosis in men, although this is a matter of debate (Szulc et al., 2012). In a recent study of more than 7,000 men and women age 55 and older, 56% of non-vertebral fractures in women and 79% of non-vertebral fractures in men occurred in participants who were not diagnosed with osteoporosis according to the T ≤ -2.5 cutoff (Schuit et al., 2004). Moreover, there are concerns about the usefulness of T-scores in predicting fracture risk, especially in premenopausal women and men under age 50 (Leslie et al., 2006; Cummings, 2006).

Multiple international models for diagnosing osteoporosis have been established. The Canadian Medical Association, the United Kingdom's National Osteoporosis Guideline Group (NOGG) and Royal College of Physicians, and the German Dachverband Osteologie e.V. (DVO) each endorse different protocols for osteoporosis diagnosis (Papaioannou et al., 2010; Compston et al., 2008; Baum et al., 2008).

The Male Reference Model and Osteoporosis Intervention

Developing a male reference population represented a gendered innovation that led, in turn, to further clinical research—see Designing Health & Biomedical Research. These include:

1. Considering Bone Health as an Integral Part of Men's Health Research is underway on possible lifestyle strategies for preventing osteoporosis in men, such as a healthy diet, physical activity, and not smoking tobacco (Pinheiro et al., 2009)—see Method.
2. Testing Pharmaceutical Treatments in Men Bisphosphonates, a class of anti-osteoporotic drugs, were evaluated two decades ago in postmenopausal women, but only recently in men (Francis, 2007). Including men in osteoporosis drug research may be important. Recent studies in postmenopausal women have called into question the benefits of long-term (beyond 3-5 years) bisphosphonate therapy, and the FDA now recommends that "all patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis" (Whitaker et al., 2012). More research is needed to understand the risks and benefits of specific dosing regimens in men and in pre-menopausal women (Giusti et al., 2010).

Method: Analyzing Factors Intersecting with Sex and Gender—Environment and Geographical Location (Differences among Men)

Significant differences exist between individuals of the same sex and, ostensibly, the same race. For example, widely used BMD reference values for white U.S. men have proven inappropriate for white Danish men (Høiberg et al., 2007).

An important step toward more comprehensive diagnostic criteria is the U.S. National Institutes of Health (NIH) Study of Osteoporotic Fractures in Men ("Mr. OS"), which began enrolling a cohort of 6,000 U.S. men 65 years and older in 2000 and was extended to include large cohorts of men in China and in Sweden. In addition to examining the relation between BMD and fracture risk in men, Mr. OS examines factors—exercise level, diet, body composition, tobacco use, and alcohol—that often correlate with sex, race, and ethnicity (Bennett, 2004; Cauley et al., 2005).

View General Method

Ancestry, Ethnicity, and Geography

For patients of a given sex, factors such as ancestry and ethnicity should also be considered in establishing reference populations. In the U. S., significant differences are seen in fracture risk between women of different self-reported races. Although African American women have lower fracture rates than white women (48% lower risk), black women have higher mortality after hip fracture than do white women. Reasons may include socioeconomic disparities, unequal access to treatment, and prevalence of other diseases (Thomas, 2007)—see Method.

Method: Analyzing Gender—Physical Activity (Differences among Women)

Biologist Anne Fausto-Sterling has described how environment and experience can "shape the very bones that support us." Osteoporosis is a complex disease that emerges over the lifecycle as a response to "specific lived lives" (Fausto-Sterling, 2008). Gender roles interact with sex in determining bone strength: In Europe and the U.S., adolescent girls may exercise less than boys. Along with biological factors, these gendered behaviors result in girls laying down less bone than boys in their teens. In addition, occupational divisions of labor mean that men are more likely than women to do heavy physical work, such as construction (Fausto-Sterling, 2005). And older women are generally less physically active than their male counterparts; inactivity may contribute to bone loss and increase fracture risk.

View General Method

Gendered Innovation 2: New Diagnostics Based on Secondary Contributors to Osteoporosis and Metabolic Bone Disorders (SECOBs)

Researchers studying differences both between and within groups of women and men have identified secondary contributors to osteoporosis and metabolic bone disorders (SECOBs), medical conditions, and treatments that increase the risk of osteoporotic fracture. Understanding SECOBs is especially important in estimating men's fracture risk; men with fragility fractures are more likely than women to have previously diagnosed SECOBs, and when patients are screened after a fracture, new SECOBs are more often found in men (50%) than in women (32%) (Ryan et al., 2011; Tannenbaum et al., 2002). New diagnostics include the following:

In addition to the above, other systems of fracture risk estimation exist; Gimeno et al. describe nine different systems as "most commonly used" (2010).Clinicians continue to debate the relative advantages and disadvantages of the FRAX, GFRC, and QFracture systems, all of which can be used to estimate a patient's risk of osteoporotic fracture over the next ten years (Bolland et al., 2011; Bennett et al., 2010).

Conclusions

Osteoporosis has been reconceptualized as affecting both women and men. This gendered innovation led to the development of male reference populations, allowing for better evaluation of fracture risk in men. BMD alone, however, is not a good predictor of fracture in women or men. New diagnostics, such as FRAX, GFRC, and QFracture, may predict a patient's fracture risk more accurately than BMD alone by analyzing factors intersecting with sex and gender.

Next Steps

1. Use gender analysis to optimize osteoporosis prevention. Many risk factors and protective factors are gendered. A prevention campaign might focus on increasing physical activity and on smoking cessation, recognizing that women are more likely to be physically inactive and men are more likely to smoke tobacco.
2. Develop reference models focused on how fracture risk is influenced by biological sex and gendered behaviors. The U.S. Preventive Services Task Force has concluded that "evidence is lacking, of poor quality, or conflicting" regarding osteoporosis screening for men (USPSTF, 2011). Current European guidelines for the diagnosis and management of osteoporosis recommend evaluating men's fracture risk according to diagnostic thresholds developed to predict fracture risk in postmenopausal women (Kanis et al., 2008b).
3. Work to educate the public about the true incidence of the disease and to promote bone-healthy lifestyles in women and men (NIH, 2010). The NIH has determined through surveys that a majority of American men view osteoporosis as a "woman's disease". Correcting this inaccurate view is important. The gendered beliefs of physicians may also contribute to the perception that osteoporosis is a woman's disease, resulting in osteoporosis in men being "substantially underdiagnosed, undertreated, and underreported" (Qaseem et al., 2008; Geusens et al., 2007).

Osteoporosis has long been defined as a disease primarily of post-menopausal women—an assumption that has shaped its screening, diagnosis, and treatment. Why is this a problem? Men account for a third of osteoporosis-related hip fractures after age 75—and when they break their hips, they die more often than women. We don't know why.

Despite the relatively high number of men who suffer from osteoporosis, the basic diagnostics for the disease were developed using young, white women (aged 20-29 years).

Gendered Innovation:

The breakthrough came in 1997 when a reference population of young men was established to diagnose osteoporosis in men. Although we now have reference populations for men, men are still diagnosed using the female diagnostic cut-off rate—this has not yet been revised for men.

Work continues to diagnose osteoporosis in different populations of women and men. Osteoporosis is a disease with both sex and gender components: bones are formed by biology and also by culture, such as exercise rates, nutrition, and general lifestyle. These differences in lifestyle may explain differences in osteoporosis rates across ethnic groups. Current studies are analyzing cohorts of men from China and Sweden, for example, to understand these types of differences. The goal is to maintain healthy bones in diverse populations.