By Nancy Walsh, Staff Writer, MedPage Today
Postmenopausal women who use proton pump inhibitors (PPIs) regularly are at increased risk for hip fracture, particularly if they have ever smoked, a prospective cohort study has confirmed.
The risk of hip fracture was increased by 35% among women who used these drugs for at least two years compared with women who never used them (age-adjusted HR 1.35, 95% CI 1.12 to 1.62, P<0.01 for trend), according to Andrew T. Chan, MD, from Harvard Medical School in Boston, and colleagues.
Moreover, the risk for fracture rose by more than 50% among women with a history of smoking (multivariate HR 1.51, 95% CI 1.20 to 1.91), the researchers reported online in BMJ.
Some earlier investigations found a possible link between PPIs and fractures among older women, and two years ago the FDA warned of the potential connection, calling for more data.
Chan and colleagues turned to the Nurses’ Health Study, analyzing data from 79,899 postmenopausal women who had responded to biennial questionnaires about health and lifestyle.
From 2000 to 2008, there was a sharp increase of PPI use among participants, from 6.7% to 18.9%.
During almost 600,000 person-years of follow up, there were 893 new hip fractures.
The absolute risk was 2.02 per 1,000 person-years for women who reported regular use, while risk was 1.51 per 1,000 person-years among those who reported never having used PPIs.
The risk appeared to be limited to present or past smokers, because the adjusted hazard ratio among women who had never smoked was a nonsignificant 1.06 (95% CI 0.77 to 1.46).
The link with smoking could be explained by effects on calcium, according to the researchers.
“Smoking and PPIs may have a synergistic effect on fracture risk, mediated by impaired calcium absorption. In addition, experimental studies have postulated that both PPIs and smoking influence osteoclast function, perhaps suggesting a shared negative effect on bone remodeling,” they explained.
The increased risk for hip fracture with PPI use remained after adjustment for multiple factors including body mass index (HR 1.45, 95% CI 1.21 to 1.73), calcium intake (HR 1.35, 95% CI 1.12 to 1.62), or the use of hormone replacement or corticosteroids (HR 1.36, 95% CI 1.13 to 1.63).
Risk also rose with longer duration of PPI use:
Two years, HR 1.36 (95% CI 1.12 to 1.65)
Four years, HR 1.42 (95% CI 1.05 to 1.93)
Six to eight years, HR 1.55 (95% CI 1.03 to 2.32)
However, two years after stopping use, the fracture risk was no longer significant (HR 1.10, 95% CI 0.63 to 1.92).
The risk did not differ depending on whether the reason for PPI use was peptic ulcer, heartburn, or acid reflux.
The authors said they did not observe any change in risk after adjusting for concomitant use of drugs known to affect the risk of fracture, such as hormone replacement therapy, bisphosphonates, corticosteroids, and thiazide diuretics (fully adjusted multivariate HR 1.36, 95% CI 1.13 to 1.63).
The researchers also pooled their results with ten earlier studies, and found an overall odds ratio of 1.28 (95% CI 1.19 to 1.37) for hip fracture.
Strengths of the study included the prospective data collection and adjustment for numerous potential confounders, thereby closely pinpointing the effect of PPIs.
Limitations included self-report of hip fracture and a lack of information on the specific types of PPIs and doses.
The researchers concluded that their findings “provide compelling evidence” of fracture risk among women who use PPIs and support the FDA’s decision to warn about this risk.
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