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Osteoporosis as serious, but less understood in men than women
In 1998, researchers submitted the initial NIH grant for a large community-based cohort study, dubbed the Osteoporotic Fractures in Men study, or MrOS, designed to examine bone loss and fracture risk factors in older men. Despite hundreds of studies based on data and insights from that original study published during the last 20 years, much less is known about fractures and osteoporosis in men than in women.
These studies have contributed significantly to the understanding of how bone mineral density and other risk factors come together to increase the likelihood of fracture in a man.
Source: Sheila Orwoll. Printed with permission.
“Some of the main findings include a much better recognition of how bone density relates to fracture in men,” Eric S. Orwoll, MD, professor of medicine and attending physician in the bone and mineral section of the division of endocrinology, diabetes and clinical nutrition at Oregon Health & Science University in Portland, told Endocrine Today. “It’s clear as part of the work in the Osteoporotic Fractures in Men study, as well as in other studies, that it’s just as important in men as it is in women, and the relationships between bone density and fracture risks are very similar in men as they are in women.”
Orwoll said the lack of recognition of osteoporosis and fractures in men “often leads to ignoring the fact that a fracture is a wake-up call.”
“Osteoporosis in men is much less well understood than is osteoporosis in women, and the clinical care of osteoporosis in men is much less established in the medical community than is osteoporosis in women,” Orwoll said. “Ultimately, the reason MrOS was founded and continued is to address that gap in knowledge and the gap in clinical care.”
Micol Rothman, MD, associate professor of medicine in the division of endocrinology, metabolism and diabetes at the University of Colorado in Aurora, said one of the reasons osteoporosis may be considered a “woman’s disease” is because of the relationship between menopause and bone deterioration.
“Women certainly are at higher risk, but unfortunately, men do get neglected here, and when fractures do happen in men, the mortality risk is even higher than in women,” Rothman said.
Although osteoporosis is still considered a woman’s disease, a man aged 60 years has a 25% chance of experiencing a fracture in his lifetime, according to Jane A. Cauley, DrPH, distinguished professor in the department of epidemiology and associate dean for research in the Graduate School of Public Health at the University of Pittsburgh.
“We have to improve on the understanding that osteoporosis is a significant problem in older men,” Cauley told Endocrine Today. “The mortality after hip fracture is actually worse in men than in women. There’s a myth out there that osteoporosis is a woman’s problem, not a man’s problem, and that’s one of the most important messages we have to address.”
Endocrine Today spoke with several experts about the risks for fracture and osteoporosis in men, findings from MrOS, treatments and screening methods.
Similarities, differences between men and women
According to Robert D. Blank, MD, PhD, an Endocrine Today Editorial Board Member, a woman has about a 50% lifetime chance of sustaining a fracture under what could be considered a low-trauma circumstance.
“The risk for men is approximately half of what it is for women, maybe two-thirds,” said Blank, who is also chief of endocrinology and professor of medicine in the division of endocrinology, department of medicine at the Medical College of Wisconsin in Milwaukee. “The male skeleton and the female skeleton do not look the same. Male bones are much bigger, and as you know from pieces of wood, a big branch is harder to break than a smaller branch — it’s as simple as that, men have bigger bones so they aren’t as fragile.”
Orwoll said fractures in men occur more commonly as a result of trauma, whereas in older women, fractures are commonly low-trauma events.
“In older men, they’re much more often the result of more-impressive accidents or more-traumatic episodes, which is probably because activities are different in older men than they are in women. That probably teaches us something about how to prevent fracture,” he said.
Suzanne M. Jan De Beur, MD, associate professor of medicine at Johns Hopkins University School of Medicine, described fracture, whether in men or women, as a “skeletal heart attack.”
“It’s not something to be ignored, it’s not something you can just put a cast on, patch up and go on with life as usual,” Jan De Beur said. “That’s a harbinger of skeletal fragility.”
The NIH Osteoporosis and Related Bone Diseases National Resource Center recognizes two types of osteoporosis. Primary osteoporosis occurs primarily as age-related bone loss, whereas secondary osteoporosis has at least one underlying cause. These causes can include use of glucocorticoid medications and other immunosuppressive drugs, hypogonadism, excessive alcohol consumption, smoking, chronic obstructive pulmonary disease and asthma, cystic fibrosis, gastrointestinal disease, hypercalciuria, anticonvulsant medications, thyrotoxicosis, hyperparathyroidism, immobilization, homocystinuria, neoplastic disease, ankylosing spondylitis and rheumatoid arthritis and systemic mastocytosis.
“One thing that’s a bit different in men than women, is that about 50% of the time, there’s an identifiable underlying cause in men,” Jan De Beur said. “When I have a male patient, I make sure I do a very thorough secondary screening, meaning for secondary causes of osteoporosis. About 50% of the time men will either have hypogonadism, smoking, alcohol or glucocorticoid use, or some other secondary cause.”
In a 2016 study published in the Journal of Bone and Mineral Research, Cauley and colleagues evaluated data from MrOS on 5,876 men not prescribed osteoporosis medications at baseline and followed the cohort for incident hip fractures (regardless of trauma level) for a mean of 8.6 years; questionnaires were administered by telephone or mail every 3 years, and hip fractures were verified by physician adjudication of medical records.
During the follow-up period, 178 men (3%) experienced an incident hip fracture; age-adjusted incidence was 3.5 per 1,000 person-years. Men who sustained a hip fracture were more likely to be older than 75 years, have lower body weight and femoral neck BMD, and experience greater height loss since age 25 years. They also were more likely to smoke and to have had a previous fracture or fall after age 50 years. Self-reported history of myocardial infarction or angina, Parkinson’s disease, hyperthyroidism and poorer executive function were all related to an increased risk for hip fracture after multivariable adjustment.
“What we found was that the risk factors seemed to be the same as they were in women,” Cauley said. “The most important thing is it’s really a combination of low BMD as well as the number of risk factors. Men who had the lowest bone density, but had a greater number of risk factors, seemed to have a higher incidence of hip fracture compared with men who had zero risk factors and normal BMD. [Risk] seems to have to do with a cumulative number of risk factors.”
Effects of sex hormones
Hypogonadism in men presents a separate challenge for bone health.
“There are men who are frankly hypogonadal,” Orwoll said. “That is clearly detrimental to the skeleton and increases fracture risk, and that gets to be particularly important in some special situations.”
For men with hypogonadism characterized by low testosterone, sexual dysfunction and other characteristics of androgen deficiency, using testosterone supplementation to decrease the risk for bone loss is controversial.
“Testosterone is important. Obviously, you aren’t going to use testosterone in women, but in hypogonadal men, testosterone can be important and can be appropriate,” Orwoll said. “It’s been demonstrated that testosterone improves bone density in hypogonadal men.”
In the Testosterone Trials study published in JAMA Internal Medicine in 2017, researchers evaluated 211 men aged at least 65 years with two testosterone level measures averaging less than 275 ng/dL. Participants were assigned to testosterone or placebo gel for 1 year, adjusting testosterone gel to maintain levels correlated with the normal range for young men.
Compared with participants receiving placebo, those receiving testosterone showed greater increases in mean spine trabecular volumetric BMD (7.5% vs. 0.8%; P < .001), spine peripheral volumetric BMD, and hip trabecular and peripheral volumetric BMD. Significantly greater increases in mean estimated strength of spine trabecular bone, spine peripheral bone and hip trabecular and peripheral bone were also observed in the testosterone group vs. the placebo group.
Cauley said that although the findings were “dramatic,” the effects were not large enough to conclude that testosterone therapy would lead to a decrease in fractures.
In fact, no long-term large studies demonstrate that testosterone reduces fracture risk.
“We know that it is good for bone density, but in order to be really confident that testosterone is useful for osteoporosis in hypogonadal men, we’d like to have trials that demonstrate a reduction in fracture, and those are not available,” Orwoll said. “We don’t know enough yet about the adverse effects that may accompany testosterone therapy — cardiovascular events, prostate cancer — all of those are not very well-defined yet, so the role of testosterone therapy in preventing or treating osteoporosis in men is still controversial.”
Orwoll said men with prostate cancer also have an increased risk for bone loss because reducing testosterone and estradiol levels is used for treatment, and “in that situation, bone loss and increase in fracture is a very obvious downside of that therapy for prostate cancer.”
Prevention, treatment
In 2015, the National Osteoporosis Foundation updated its Clinician’s Guide to Prevention and Treatment of Osteoporosis. The guide recommends adequate calcium intake (1,000 mg per day for men aged 50-70 years; 1,200 per day for men aged at least 71 years), vitamin D intake, including supplements, (800-1,000 IU per day) in those aged at least 50 years when necessary, and regular weight-bearing and muscle-strengthening exercises. Further, clinicians should counsel patients to quit smoking and avoid excessive alcohol use.
“The usual prevention in men is similar to that in women — adequate calcium and vitamin D, nutrition, adequate exercise, avoiding risk factors, such as smoking and drinking, all of those are very important in men,” Orwoll said. “As in women, when a fracture occurs after the age of 50 years, that should prompt an evaluation and a bone density measurement in men.”
According to the National Osteoporosis Foundation guideline, BMD testing should be performed in men aged at least 70 years and in those aged 50 to 69 years with other risk factors. Vertebral imaging should be performed in men aged at least 80 years if T-score is –1 or less at the lumbar spine, total hip or femoral neck and in those aged at least 50 years with low-trauma fracture during adulthood, historical height loss of 4 cm or more, prospective height loss of 2 cm or more, and recent or ongoing long-term glucocorticoid treatment.
Two of the most commonly used tools for screening for osteoporosis and fractures are DXA and the Fracture Risk Assessment Tool, or FRAX.
In some states, Medicare does cover screening [with DXA] for men over the age of 70, according to Jan De Beur. “DXA is a good screening tool,” Jan De Beur said. “It’s not a perfect screening tool, but most screening tools aren’t perfect. I recommend screening in men, all men over the age of 70, but you might screen earlier in men with risk factors.”
Cauley said she also recommends DXA for men at risk for fracture.
“At age 70, it’s not going to hurt them to have a bone density test,” Cauley said. “It’s a noninvasive test; it predicts fracture better than cholesterol predicts the risk for a heart attack.”
Blank said FRAX is an “especially good” tool for people with histories of prior fractures, whether personal or familial, and for those with other common risk factors.
“Using a combination of FRAX and DXA, to me, is more powerful than using either of them alone because it takes the whole person into account,” Jan De Beur said. “It takes their family history, personal history, habits such as smoking and alcohol, their past and current glucocorticoid use. It’s helpful in taking a DXA score and putting it into context. All DXA scores aren’t created equal. I like to use FRAX in combination with DXA to help me really identify those men, and women, who are high risk and really should be aggressively treated vs. those that we can do lifestyle modifications and monitor for clinical fracture and change in DXA.”
The National Osteoporosis Foundation recommends pharmacologic treatment for adults with hip or vertebral fractures, those with T-score –2.5 or less at the femoral neck, total hip or lumbar spine by DXA, and those aged at least 50 years with low bone mass at the femoral neck, total hip or lumbar spine by DXA and 10-year hip fracture probability of at least 3% by FRAX. Pharmacologic treatments include bisphosphonates, calcitonin, hormone therapy, parathyroid hormone and receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors.
Guidelines published in 2012 by the Endocrine Society are similar to those from the National Osteoporosis Foundation and include the recommendations that DXA be used in men aged at least 70 years and in those aged 50 to 69 years with fracture risk factors; vitamin D supplementation be used to achieve levels of at least 30 ng/dL; pharmacologic treatment be used in men aged at least 50 years who have had spine or hip fractures and in those at high risk for fracture based on low BMD and/or clinical risk factors; BMD by DXA be monitored by clinicians at the spine and hip every 1 to 2 years; and those at risk for osteoporosis consume 1,000 mg to 1,200 mg of calcium daily.
Moving forward
Orwoll said part of the issue with the lower level of awareness of osteoporosis and fractures in men is that the information available is simply not as complete as that in women.
“Most of the studies that are available about diagnostic and therapeutic approaches in osteoporosis have been done in postmenopausal women, so there is much less information about effective diagnostic and treatment paradigms in men,” he said. “That, in turn, has led to some prominent official recommendations that don’t adequately emphasize the need to recognize the risk of osteoporosis in men and that fail to recognize the therapeutic options that are available.”
Orwoll said different biological factors exist in men and women, and there is a need to understand, in both sexes, what causes fractures and osteoporosis.
“By doing so, we’ll get at clinical issues like developing treatments and preventive measures,” he said.
According to Blank, more epidemiologic data about fractures in men are needed to match what is known about fractures in women.
“That’s the single most important thing, just bothering to look in the first place,” he said. – by Amber Cox
- References:
- Cauley JA, et al. J Bone Miner Res. 2016;doi:10.1002/jbmr.2836.
- Cosman F, et al. Osteoporos Int. 2014;doi:10.1007/s00198-014-2794-2.
- NIH. Osteoporosis in men. Available at: www.bones.nih.gov/health-info/bone/osteoporosis/men. Accessed Jan. 30, 2018.
- Snyder PJ, et al. JAMA Intern Med. 2017;doi:10.1001/jamainternmed.2016.9539.
- Watts NB, et al. J Clin Endocrinol Metab. 2012;doi:10.1210/jc.2011-3045.
- For more information:
- Robert D. Blank, MD, PhD, can be reached at Medical College of Wisconsin, Froedtert Specialty Clinics — Suite E4200, 9200 W. Wisconsin Ave., Milwaukee, WI 53226; email: roblank@mcw.edu.
- Jane A. Cauley, DrPH, can be reached at Graduate School of Public Health, 130 DeSoto Street, A510 Crabtree, Pittsburgh, PA 15261; email: jcauley@edc.pitt.edu.
- Suzanne M. Jan De Beur, MD, can be reached at 5200 Eastern AvenueEndocrinology MFL-Center Suite 4300, Baltimore, MD 21224; email: sjandebe@jhmi.edu.
- Eric S. Orwoll, MD, can be reached at 3181 SW Sam Jackson Park Rd, Portland, OR 97239; email: orwoll@ohsu.edu.
- Micol Rothman, MD, can be reached at 1635 Aurora Ct, 6th Floor, Aurora, CO 80045; email: micol.rothman@ucdenver.edu.
Disclosures: Blank reports he is a consultant for Amgen, Novo Nordisk, Radius Health and Ultragenyx. Orwoll reports he receives research support from Eli Lilly and Mereo and consulting fees for Bayer, Eli Lilly and Merck. Cauley, Jan De Beur and Rothman report no relevant financial disclosures.