Does Inflammation Increase Fracture Risk?
Aging is associated with chronic, low-grade, systemic inflammation characterized by an increase in circulating levels of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1 (IL-1).
This pro-inflammatory response has been linked to a wide range of chronic conditions associated with aging, including cardiovascular disease,1diabetes,2 and dementia.3 There’s mounting evidence implicating chronic systemic inflammation in osteoporosis and fracture risk in adults.
Most studies in older white women
At least 10 observational studies have examined the association of inflammatory markers with bone loss and fracture risk in humans. Most included only older women, and most of these subjects were white, says Centers for Disease Control and Prevention epidemiologist and researcher Kamil Barbour, PhD, MPH, who led 3 of the studies examining inflammation and osteoporosis-related fractures while at the University of Pittsburgh. But despite this limitation, he says, the studies offer compelling evidence that inflammation could be a significant risk factor for bone loss and fracture in aging.
The trials conducted by the University of Pittsburgh research team showed a 1.5-fold to 2.5-fold greater risk for fracture in older women with the highest levels of inflammation compared to those with the lowest levels.
“Two of our studies looked at hip fractures and 1 examined nontraumatic fractures, and we did find very strong associations,” Dr. Barbour said. “In 2 of the 3 studies there was a 2.5-fold greater risk for hip fractures in women with high levels of inflammation.”
2014 study examines hip fracture risk
The most recent study by Dr. Barbour and his colleagues, published in the Journal of Bone and Mineral Research in April, examined inflammatory markers and the risk of hip fractures in older white women.4 The researchers used a case-cohort design nested in a cohort of 4709 participants in the Study of Osteoporotic Fractures. From this group, 1171 women were randomly selected as the subcohort (mean age 80.1 ±4.1 years). Also selected were the first 300 women with incident hip fractures during follow-up (146 neck fractures and 150 intertrochanteric fractures). The latter group included 77 cases from the random subcohort of 1171 women.
Follow-up for hip fractures occurred every 4 months, with more than 95% of follow-up contact completed. Cytokines IL-6 and soluble receptors (SR) of IL-6 (IL-6 SR) and TNF (TNF SR1 and TNF SR2) were measured, and the participants were followed for a median of 6.3 years.
In multivariate models, the hazard ratio (HR) of hip fracture for women in the highest quartile inflammatory marker level was 1.64 (95% CI 1.09-2.48; P=.03) for IL-6 and 2.05 (95% CI 1.35-3.12; P<.01) for TNF SR1 when compared with women in the lowest levels.4 Among the other findings:
- Women who had 2 and 3 to 4 inflammatory markers in the highest quartile had a HR of 1.51 (95% CI 1.07-2.14) and 1.42 (95% CI 0.87-2.31), respectively, for fracture compared to women with 1 marker or fewer in the highest quartile (P=.03).4
- Sensitivity analysis limited to inflammatory markers individually associated with hip fracture showed a 73% increase in this risk among women with the highest versus lowest inflammatory burden.4
- After adjusting for 7 potential mediators, 2 of them—renal function biomarker cystatin C and bone mineral density—were found to attenuate hazard ratios among women with the highest inflammatory burden, by 20% and 15%, respectively.4
Kidney function, inflammation, fracture risk related
In addition, Dr. Barbour noted that renal function appeared to be a significant mediating factor in the inflammation, hip fracture pathway. In both the 2014 study and a 2012 trial that included data from the Women’s Health Initiative (WHI), controlling for cystatin C led to the largest attenuation of hip fracture risk among women with the highest inflammatory burden: decreases of 19% and 15%, respectively.4
“It appears that poor kidney function leads to greater inflammation and bone loss, while greater inflammation leads to kidney damage and bone loss,” Dr. Barbour says. “We need to understand this possible bidirectional association better when we explore possible interventions.”
IL-6 shows strongest association
Dr. Barbour’s 2012 study also involved a nested case-control study design.5 The researchers selected 400 cases of incident hip fractures from the WHI data and 400 controls matched for age, race, and date of blood draw from 39,795 postmenopausal women without previous hip fractures. Median follow-up was 7 years.
Subjects with the highest levels of inflammatory burden for 3 markers examined (IL-6 SR, TNF SR1, and TNF SR2) had an almost threefold (2.76; 95% CI 1.22-6.25) increase in hip fracture risk compared to those with the lowest burden.5
One of the first studies to examine the possible impact of inflammation on bone status in humans is also one of the only studies to include men. In 2008, researchers in Australia reported the results of their longitudinal study, which was the first to show an association between baseline inflammatory markers, change in these markers, and bone loss and resorption in older adults.6
The most consistent associations were for IL-6 in both sexes, with less consistency for high-sensitivity C-reactive protein (hs-CRP) and TNF-α.6 Several recent studies, all using prospective cohort designs, have explored the association between hs-CRP and incident fracture risk.
hs-CRP Predicts Incident Fracture Risk
In 2006, JAMA published a study involving 1494 elderly white women followed for a median of 5.5 years.7 Researchers reported that for each standard deviation increase in hs-CRP, there was an independent 25% to 32% increase in fracture risk, depending on fracture site.
Similarly, a study published in 2011 that compared elderly Japanese women with Caucasian women found hs-CRP to be a significant predictor of osteoporotic fracture in elderly Asian women who had significantly lower hs-CRP levels than Caucasian women.8
A study published in the summer of 2013 included data from the Study of Women’s Health Across the Nation (SWAN) trial.9 During 9 years of follow-up, 10.4% of the women experienced fractures. The findings suggested that fracture risk increases with increasing CRP, but only above the threshold of 3 mg/L. Unlike bone mineral density, composite strength indices were inversely related to hs-CRP levels, and partially explained the increased fracture risk associated with inflammation.9
More study needed
While the majority of the studies suggest a causal role for inflammation in age-related bone loss and fracture risk, Dr. Barbour says more research is needed to strengthen the association, especially in men.
“I know a lot of people will remain skeptical and say inflammation is just a marker for frailty or something else,” he says. “But in our studies we controlled for frailty, and this did not change our results.”
- Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the risk of coronary heart disease in men and women. N Engl J Med. 2004;351:2599-2610.
- Hu FB, Meigs JB, Li TY, et al. Inflammatory markers and risk of developing type 2 diabetes in women.Diabetes. 2004;53:693-700.
- Weaver JD, Huang MH, Albert M, et al. Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology. 2002;59:371-378.
- Barbour KE, Lui LY, Ensrud KE, et al. Inflammatory markers and risk of hip fracture in older white women: The Study of Osteoporotic Fractures. J Bone Miner Res. 2014 Apr 9. [Epub ahead of print]
- Barbour KE, Boudreau R, Danielson ME, et al. Inflammatory markers and the risk of hip fracture: the Women’s Health Initiative. J Bone Miner Res. 2012;27:1167-1176.
- Ding C, Parameswaran V, Udayan R, et al. Circulating levels of inflammatory markers predict change in bone mineral density and resorption in older adults: a longitudinal study. J Clin Endocrinol Metab.2008;93:1952-1958.
- Pasco JA, Kotowicz MA, Henry MJ, et al. High-sensitivity C-reactive protein and fracture risk in elderly women. JAMA. 2006;296:1353-1355.
- Nakamura K, Saito T, Kobayashi R, et al. C-reactive protein predicts incident fracture in community-dwelling elderly Japanese women: the Muramatsu study. Osteoporos Int. 2011;22:2145-2150.
- Ishii S, Cauley JA, Greendale GA, et al. C-reactive protein, bone strength, and nine-year fracture risk: data from the Study of Women’s Health Across the Nation (SWAN). J Bone Miner Res. 2013;28:1688-1698.