Key Risk Factors of Non-Healing Bone Fractures Identified Interview with:

R. Grant Steen, PhD Medical Affairs, Bioventus LLC Durham, North Carolina

Dr. R. Grant Steen

R. Grant Steen, PhD
Medical Affairs,
Bioventus LLC
Durham, North Carolina What is the background for this study? What are the main findings?

Response: When we started this research, it was really only guesswork as to how big a problem fracture nonunion really is. What we’ve done is to work with an enormous database of patient health claims, with two goals.

First, we wanted to characterize how common fracture nonunion is among patients across a wide age range.
Second, we wanted to identify risk factors that make a patient more likely to have problems healing.

We’ve now succeeded in both aims. We know that roughly 5% of fracture patients will go to nonunion, and we know a whole host of risk factors that predispose them to do so.
Most of the risk factors that we’ve identified—with a few exceptions—would not be a surprise to physicians who treat fracture patients. However, what we’ve done is to put all of these risk factors in a broader context, so that we know which risk factors are most important and which are less so.

For example, it has been known for a long time that smoking is a risk factor for nonunion. What we’ve shown is that, in the scheme of things, it’s not all that important. Let me be more precise here, because this is an important point. If all you know about a patient is that they smoke, we’ve shown that smoking is associated with a 62% increase in risk of nonunion. That’s a lot. But, as you learn more about that patient and can factor that new knowledge into a risk prediction, it turns out that smoking, all by itself, increases the risk of nonunion by only about 20%. However, smoking is a surrogate marker for a range of other risk factors that also increase risk, including male gender, cardiovascular disease, obesity, vitamin D deficiency, alcoholism, and so on. Once you factor these separate risk factors into your new nonunion prediction, you have a much more nuanced—and probably much more accurate—prediction of nonunion risk.

Some of the risk factors we’ve identified will likely be a surprise. For example, we’ve shown that use of certain medications is associated with an increased risk of nonunion. Many physicians suspected that analgesics are a problem, but relatively few would have guessed that both anticonvulsants and anticoagulants are also a problem. Furthermore, having osteoarthritis or rheumatoid arthritis increases the risk of nonunion for certain patients. These are all surprises.

Another thing that may be a surprise is that different bones have very different risk factors. We’ve discussed smoking as a risk factor, but it turns out that smoking increases nonunion risk by about 30% in fibula and especially femur (P < 0.01). But smoking has no significant impact on nonunion risk in metatarsal, metacarpal, tarsal, humerus, scaphoid, and patella. The fact that the risk of smoking is so variable and counter-intuitive could explain why it has taken so long to understand fracture nonunion. What should readers take away from your report?

Response: Bone fractures are far more common than most people realize; according to recent research (not ours!), the lifetime risk of any fracture at age 50 years is 53% among women and 21% among men (van Staa et al. Bone. 2001;29(6):517). Of all fractures, we know that roughly 5% will fail to heal, which means that millions of people in the United States will experience a nonunion. Treatment of nonunion is often surgical, and such surgery is difficult, risky, painful, and expensive. We have identified key risk factors that put patients at risk of nonunion. If physicians consider these risk factors carefully, it should be possible to alter treatment for patients at risk, to minimize that risk going forward. What recommendations do you have for future research as a result of this study?

Response: We are now characterizing the relationship between patient medications and risk of nonunion. Important questions for the future include: Which pain medications actually increase risk of nonunion? Are there any pain medications that can be taken safely? Does it matter whether pain medications are given after fracture, or is it possible that risk only accrues when pain medications are taken prior to the fracture? Is there anything else you would like to add?

Response: We continue to work on predicting which patients are at greatest risk of nonunion. We focus on helping physicians to recognize patients at risk, so that these patients can be counseled on how best to reduce the risk of nonunion. We hope, in the near future, to have available to physicians a computer program that will run as an app on a handheld device and that will enable physicians to identify patients most at risk of nonunion. Thank you for your contribution to the community.


Robert Zura, Ze Xiong, Thomas Einhorn, J. Tracy Watson, Robert F. Ostrum, Michael J. Prayson, Gregory J. Della Rocca, Samir Mehta, Todd McKinley, Zhe Wang, R. Grant Steen.
Epidemiology of Fracture Nonunion in 18 Human Bones.
JAMA Surgery, 2016; e162775 DOI:10.1001/jamasurg.2016.2775

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on September 12, 2016 by Marie Benz MD FAAD