Inflammation, Osteoporosis, and Fracture Risk

By Jamie Santa Cruz

Individuals with the highest levels of inflammatory markers are much more likely to experience fractures.

Systemic inflammation has been correlated with an increased risk of a variety of chronic conditions associated with aging, including cardiovascular disease, diabetes, dementia, and cancer, among others.1-4 Now, increasingly, chronic inflammation is also being associated with osteoporosis and fracture risk. Indeed, three studies on the topic from the University of Pittsburgh have found that individuals with the highest levels of inflammatory markers are up to three times more likely to experience fractures, including hip fractures in particular.5-7

According to Kamil Barbour, PhD, epidemiologist at Centers for Disease Control and Prevention and lead author of the two most recent studies, the connection between inflammation and bone loss has been well established for some time through in vitro and animal research, but epidemiological research is a more recent phenomenon. To date, there are only half a dozen such studies examining inflammation and the risk of fracture.

The first few of these epidemiological studies focused on C-reactive protein (CRP) as the key marker of inflammation, and all found CRP to be a significant predictor of fracture risk.8-10 But while earlier research focused on CRP, the research from the team at the University of Pittsburgh has been the first to focus on cytokines. The team's initial study, published in Journal of Bone and Mineral Research in 2007, examined nontraumatic, nonvertebral fractures in the Health Aging and Body Composition cohort, consisting of 2,985 black and white men and women between the ages of 70 and 79. The study revealed a very strong association between inflammation and fracture, with the risk being almost three times greater for subjects with the greatest number of inflammatory markers.5

Though this first study lacked the statistical power to look at hip fractures in particular, a subsequent study, led by Barbour and published in 2012, was able to focus specifically on hip fracture. This study, a nested case-control design, focused on the Women's Health Initiative cohort, which consisted exclusively of older postmenopausal women, but the results were similar to those in the previous study: subjects with high levels of cytokines again showed close to a threefold increased risk of hip fracture.6

In their most recent study, which appeared in September 2014 in Journal of Bone and Mineral Research, Barbour and his colleagues sought to replicate their previous findings and confirm the results in an even older cohort (mean age of 80.1). Again, this study, which had a stronger longitudinal design than the previous two studies, found an association between elevated levels of cytokines and increased risk of hip fracture, though the association was not as pronounced as in the previous cohorts—those with higher inflammatory markers had only a 1.5-fold increased risk.7 This weaker association came as a slight surprise, says Barbour, yet he notes that the finding isn't entirely without explanation. Older individuals typically have a greater number of chronic conditions, which makes it more difficult in general to find strong associations.

Mechanisms
As for the mechanism by which inflammation leads to osteoporosis and fracture, current research has identified two possibilities. The first, according to Mike Lewiecki, MD, osteoporosis director at the New Mexico Clinical Research & Osteoporosis Center, involves the RANK ligand pathway. The presence of inflammatory cytokines causes osteoblasts, the bone-forming cells, to produce RANK ligand, which in turn stimulates osteoclast differentiation activity and survival that results in increased bone absorption and bone loss. According to Lewiecki, this explains why rheumatoid arthritis (RA), the prototypical chronic inflammatory disease, is associated with localized bone erosions (and why RA is considered a risk factor for fracture risk). While RA is associated with localized bone loss, systemic cytokines can cause generalized bone loss, ultimately resulting in osteoporosis.

A second possible mechanism focuses on estrogen levels. According to Barbour, estrogen deficiency may augment cytokine-mediated osteoclast activation, again resulting in increased bone resorption.

Mediating Factors: Kidney Function and Frailty
A key finding in the most recent study conducted by Barbour and his colleagues is the association between inflammation and renal function. In the study cohort, higher levels of inflammation were linked with poorer kidney function as marked by cystatin-C. "When you look at the literature," says Barbour, "there is a lot […] that shows that inflammation may reduce kidney function, and you also see that poor kidney function may increase inflammation in adults. So there's this bidirectional association between inflammation and kidney function. When you account for it in the analysis, it explains a lot of the association between inflammation and hip fracture." According to Barbour, the association suggests that intervention on both inflammation and kidney function may be useful ways to reduce the risk of hip fracture, though that possibility remains to be explored in future research.

A second mediating factor in the connection between inflammation and fracture risk is frailty. According to Jane Cauley, DrPH, a professor of epidemiology at the University of Pittsburgh Graduate School of Public Health, who has been involved in all three studies from the University of Pittsburgh, previous research has shown that inflammation is associated with increased frailty, which is in turn associated with greater risk of fracture. Thus, although inflammation appears to drive bone resorption directly and therefore has a direct impact on fracture risk, some of the association between inflammation and fracture risk also appears to be indirect.

Additional Research, Anti-inflammatory Interventions
To date, most research on inflammation and fracture risk has focused on women—specifically older white women. The cohort for the first study conducted by the University of Pittsburgh team included both genders, and a Swedish study in 2014 also focused on men, with the latter showing that elderly men with the highest levels of inflammation as measured by CRP were 48% more likely to break a bone.11 However, few other studies have included men, and the research on fracture risk in males is "still ongoing," according to Barbour.

A second issue that has not yet been explored is the question of whether decreasing inflammation will actually decrease fracture risk. A few studies have suggested that anti-inflammatory interventions are effective in treating other chronic age-related diseases, such as cardiovascular disease, and this suggests that such interventions may also be useful in treating osteoporosis and preventing fractures.12 However, evidence from clinical trials about the efficacy of anti-inflammatory interventions is limited, and there have been no trials to date focusing specifically on how such interventions might affect osteoporosis and fracture risk.

Further, even if anti-inflammatory interventions prove effective, it is unclear what the clinical cutoffs should be for treatment. "There is a clinical cutoff for CRP," says Cauley. "If it's above a certain level, it's important in terms of cardiovascular disease. But there are no such levels [yet] for all these other cytokines."

Clinician Takeaways
If anti-inflammatory interventions prove successful in future clinical trials, the obvious implication for clinicians will be to target inflammation as a means of preventing fracture. And indeed, Barbour believes that anti-inflammatory therapies may be justified now, even in the absence of clinical trials, given that reduction of inflammation is key in preventing a large number of chronic diseases. "You always want to reduce inflammation," he says.

Cauley, however, is more cautious. Given the lack of evidence about whether treating inflammation would be effective in preventing fracture, she argues that the main emphasis for clinicians at this point should be simply awareness that there is a connection between inflammation and fracture.

Lewiecki agrees about the importance of awareness, noting that osteoporosis in general is a disease that is both underdiagnosed and undertreated, with many patients who meet the standard guidelines for having a bone density test failing to receive one. "Physicians […] need to be aware that chronic inflammation is a risk factor for fracture and be vigilant in evaluating these patients," says Lewiecki. Many such patients will need a bone density test to get a better idea of fracture risk. In addition to ensuring adequate intake of calcium and vitamin D, he recommends considering pharmacological therapy to reduce fracture risk if appropriate.

Vigilance is especially important for patients with chronic inflammatory diseases who are being treated with glucocorticoids, given that glucocorticoids themselves cause bone loss. "These patients have a double whammy," says Lewiecki. "The disease itself can cause osteoporosis and increase fracture risk, and the drugs used to treat the disease can do the same things." He stresses that patients treated with glucocorticoids such as prednisone may have a rapid increase in fracture risk even before the glucocorticoids result in a measurable bone loss; thus, going off of bone density alone may underestimate fracture risk.

"Awareness that these are risk factors, particular attention to thorough skeletal evaluation of these patients, and then consideration of using medications that are approved for osteoporosis would be a big help," says Lewiecki.

— Jamie Santa Cruz is a freelance writer based in Englewood, Colorado.

References
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