MrOS continues to shed light on osteoporosis, fractures in men

Issue: November 2016

The NIH-sponsored Osteoporotic Fractures in Men study initially set out to examine bone loss and fracture risk factors in older men. Almost 20 years later, hundreds of studies have used data and insights generated from this large community-based cohort study to change how fractures are understood, measured and prevented.

Endocrine Today talked with 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 and one of the original researchers, about the important findings and influences of the Osteoporotic Fractures in Men (MrOS) study.

Why focus on men and osteoporosis?

Orwoll: We hear often that diseases are less studied in women than in men. This seems to be the opposite.

The initial NIH grant for MrOS was written in 1998. At that time, and frankly, today, 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. Ultimately, the reason MrOS was founded and continued is to address that gap in knowledge and the gap in clinical care.

It’s undoubtedly true that osteoporosis is more prevalent in women. Quite a while ago, I think that the fact that osteoporosis does occur more often in women led to an appropriate, but exaggerated, focus on it as a postmenopausal women’s disease. I think the osteoporosis in women and in men issue is analogous, but flipped, to the heart attack in men and women issue. For a long time, we believed that heart attacks were a man’s disease, and that’s clearly not true.

What have been the main findings of the MrOS studies so far?

Orwoll: There are many hundreds of publications now from MrOS, and I group them into a number of major areas. One of the major aims of the MrOS study was to understand what causes fracture and the nature of fracture in men, and there have been a lot of contributions in that area. For instance, MrOS has contributed to understanding how bone density and other risk factors come together to increase the likelihood of fracture in a man. As one example, a recent publication about hip fracture synthesized all that and made us understand better the fact that men with low bone density and other risk factors are at the highest risk for bone fracture — as more and more risk factors are added to low bone density, the likelihood that a man is going to have a bone fracture goes way up. Understanding that process has clear indications for how we detect and manage men who might be at risk for fracture.

In another example, it’s become clear from MrOS recently that men and women probably have different pathways to fracture in that women with osteoporosis much more frequently have fractures as a result of minor trauma, whereas men, potentially because of differences in kinds of activity, more often have fractures because of major trauma. Bone density and osteoporosis are still at the root of it, but the incident that causes the fracture differs. That’s also important for understanding how we can detect and prevent fractures in men — both long bone fractures, like hip fracture or arm fracture, but also vertebral fractures.

MrOS has contributed substantially to our understanding of how low bone density translates into fracture risk. This was the first study to explore, in men or women, newer kinds of assessing bone strength using CT, basically using biomechanical models of bone strength and how they contribute to fracture risk. These models have been catalytic to the field. MrOS researchers have reported that men lose bone at an accelerating rate with age, and that’s very different from what we previously understood. Still, the common perception is that bone loss is a linear phenomenon with men. In fact, it is not, it accelerates with age; and that means the risk factor correspondingly accelerates with age. Men who lose bone the most are men who fracture the most.

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Another really important area that MrOS has contributed to in a major way is the relationship between sex steroids and fracture risk and bone loss. For a long time, the field believed that testosterone was important in bone health in men, and it probably is, but one of the MrOS studies clearly has shown that estradiol is the most important sex steroid in terms of bone loss and fracture risk, and that sex hormone-binding globulin also apparently plays an important role in determining the rate of fracture and the rate of bone loss. These findings have been revelatory.

Similarly, MrOS has been instrumental in defining the relationship of vitamin D to bone loss and fracture in men overall. We’ve demonstrated the levels of vitamin D that are important for maintaining bone and preventing fracture, and those findings have been very important in developing the public health recommendations for vitamin D requirements.

The final thing I would mention is genetics. Obviously, genetics is very important for bone strength and fracture risk. MrOS, along with a variety of other studies, has contributed in a major way to understanding those genetic factors that are important for skeletal health.

How have MrOS findings influenced practice?

Orwoll: MrOS has been instrumental in defining the non-bone determinants of fracture risk; in other words, what causes falls and what the predictors of falls are in older men. To an extent at least as great as bone strength, falls are important for determining fracture risk. Basically, men who fall more, fracture more. It comes down primarily to weakness and balance, and muscle comes into this in a very important way. The fact that muscle is so important has transformed the field of osteoporosis so that many of the societies — the American Society for Bone and Mineral Research (ASBMR), the National Osteoporosis Foundation, the International Osteoporosis Foundation — now list sarcopenia as one of their key targets going forward. For men, MrOS has been at the heart of that.

Balance, in which muscle strength plays a role, also is important, and MrOS has identified some key clinical measures, such as walking speed or how easy it is for a man to stand up from a chair or simple muscle strength. Some of those tests are predictive of how likely it is for a man to fall.

A study presented at ASBMR this year by Nicholas Harvey, MA, MB, BChir, MRCP, PhD, professor of rheumatology and clinical epidemiology in the MRC Lifecourse Epidemiology Unit at the University of Southampton, uses fall information from MrOS to show that adding that information to the fracture risk assessment (FRAX) algorithm aids in predicting 10-year fracture risk. I think that will lead to the incorporation of some questions about fall history into the FRAX algorithm. So this is an example of how MrOS is contributing to the practice of osteoporosis care.

Finally, I would mention the vitamin D findings that I highlighted before because we’ve learned a lot for MrOS and other studies on how to interpret vitamin D measurements and what to shoot for in terms of vitamin D supplementation. One of the early studies that used MrOS data evaluated the cost-effectiveness of drug therapies in men with osteoporosis. That kind of information is very important for practitioners who have to decide what medications to use for osteoporosis and when to use them. How to use low bone density in men is obviously key for the practice of osteoporosis in men.

Where do we need to go from here?

Orwoll: Osteoporosis care in men still lags substantially that in women. Men with osteoporosis are detected and treated much less frequently than are women, so the whole field of treatment of osteoporosis in men is lagging. There continue to be no studies of the effectiveness of therapy for reducing fracture risk in men, at least no studies of things like hip fracture or other clinical fractures. We clearly need a better understanding of what generates fall risk and fracture risk in men so that we can go on to develop preventive approaches and treatments tailored for men. I mentioned that falls and fractures probably share causation in men and women but are probably different in men and women. For instance, what causes falls for men and women, I believe, are different. We need to better understand those things and go on to come up with practical recommendations tailored for men that practitioners can build into their practices. There are some basic issues that again overlap with woman: What’s the basic biology of bone loss and bone strength in men? Bone loss happens at a different rate in men and women. There are probably different genes that govern this in men and women. The sarcopenia field is probably driven by different biological factors in men and women, and we need to understand in both sexes what makes these things happen, but to understand the differences that are driven by sex specifically, and by doing so we’ll get at clinical issues like developing treatments and preventive measures. – compiled by Jill Rollet

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References:
Black DM, et al. J Bone Miner Res. 2008;23:1326-1333.
Cauley JA, et al. J Bone Min Res. 2016;doi:10.1002/jbmr.2836.
Cawthon P, et al. J Bone Miner Res. 2009; doi:10.1359/jbmr.090419.
Harvey N, et al. Abstract 1078. Presented at: ASBMR 2016; Sept. 16-19, 2016; Atlanta.
Kanis JA, et al. Osteoporos Int. 2005;16:6-14.
Mackey D, et al. JAMA. 2007;298:2381-2388.
Orwoll E, et al. J Clin Endocrinol Metab. 2009;doi: 10.1210/jc.2008-1784.
Wang X, et al. J Bone Miner Res. 2012;doi:10.1002/jbmr.1539.

Disclosure: Orwoll reports receiving research funding from Eli Lilly and Merck.