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PPI Use and Fracture Risk
Abstract & Commentary
By Barbara A. Phillips, MD, MSPH, Professor of Medicine, University of Kentucky; Director, Sleep Disorders Center, Samaritan Hospital, Lexington. Dr. Phillips is a consultant for Cephalon, and serves on the speakers bureaus for Resmed and Respironics.
Source: Gray SL, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: Results from the Women's Health Initiative. Arch Intern Med 2010;170:765-771.
Synopsis: Women who used proton pump inhibitors had a modestly increased risk of spine, forearm or wrist, and total fractures, but not hip fractures.
The authors undertook this analysis because several large epidemiological studies have suggested that proton pump inhibitor (PPI) use is associated with increased osteoporotic fracture risk, but not necessarily with hip fracture risk. This prospective study used data from the Women's Health Initiative (WHI), which included an ethnically and racially diverse population of postmenopausal women. The goals of the study were to prospectively examine associations of PPI use with fracture risk and changes in bone mineral density (BMD).
In brief, the women in this study were recruited from 40 centers in the United States over a 5-year period in the 1990s, when they were 50-79 years old and postmenopausal. This analysis included only women who had no prior hip fracture. Follow-up for this report was for an average duration of almost 8 years. The fracture outcomes for this analysis included hip, spine, forearm/wrist, and total fractures. Total fractures were defined as all reported clinical fractures other than those of the ribs, sternum, skull or face, fingers, toes, and cervical vertebrae, collected by self-report. Hip fractures were confirmed by radiology reports, but not all nonhip fractures were confirmed. The BMD was measured at baseline at some of the clinical centers.
Participants were asked to bring all current prescription medications to the baseline and 3-year visit, and women reported duration of use for each medication. Drugs considered to be PPIs for this study included esomeprazole magnesium, lansoprazole, omeprazole magnesium, pantoprazole sodium, and rabeprazole. In actuality, only omeprazole (Prilosec®) and lansoprazole (Prevacid®) were used, in 85% and 15% of individuals, respectively. Participants using both a PPI and a histamine2-receptor antagonist (H2RA) were classified as PPI users because this medication has stronger acid-suppressive effects.
The investigators had access to a large amount of self-reported data at baseline, including race or ethnicity, history of fracture, current and past smoking, self-report of several physician-diagnosed conditions, the Medical Outcomes Study scale, body mass index (BMI), physical activity, use of psychoactive medication, corticoster-oids, hormone therapy, and bisphosphonates. Dietary intake of calcium and vitamin D was assessed by a food questionnaire.
Among the 161,806 women in the total cohort at baseline, 2.1% were currently using a PPI medication, and 6.2% were using an H2RA only. Those who used PPIs were more likely than non-users to be obese, have osteoporosis, diabetes, or several other health conditions, and to use psychoactive medications. They were also more likely to have a history of fractures and have poorer physical function and poor/fair self-reported health.
During follow-up, 1500 hip fractures, 4881 forearm/wrist fractures, 2315 spine fractures, and 21,247 total fractures occurred. After adjustment, PPI use was not related to risk for hip fractures, but was related to increased risk of all other fractures, including total fractures. Specifically, those using PPIs had a 47% increased risk for spine fracture, a 26% increased risk for forearm/wrist fractures, and a 25% increased risk for total fractures. Duration of PPI use at baseline was not associated with fracture risk. The increased risk for total fractures with PPI use was limited to those younger than 70 years and to those with no previous history of fracture. The increased risk for total fractures with PPI use was not mitigated by use of high calcium supplementation. There was a very small increase in the total fracture risk in those who used H2RAs, but no increase in any specific fracture type.
With regard to BMD, women using PPIs had similar BMD compared with non-users at baseline, and it did not vary significantly with duration of PPI use. BMD changes were assessed over only a 3-year period, unlike fracture risk, which was assessed over nearly 8 years. After adjusting for supplemental vitamins or hormones, there was a reduced (74%) BMD at the hip in PPI users. The authors concluded that use of PPIs is modestly associated with clinical spine, forearm/wrist, and total fractures, but not hip fractures. They concluded, "it is prudent for clinicians to periodically reevaluate the need for long-term PPI therapy. For those older adults who do require long-term PPI therapy, it is reasonable to focus on using the lowest effective dose, ensuring adequate dietary calcium intake and adding calcium supplements when necessary."
This study confirms and extends findings of several large studies,1-4 which indicate that PPI use is a risk for fracture, but not for hip fracture. The changes in BMD with PPI use documented here were not impressive, and previous studies have failed to demonstrate bone loss in 2 cohorts of men and women with PPI use.4 But the jury is still out on PPIs and hip fractures. Several previous reports have found an association with PPI use and hip fracture. For example, in a Canadian study, 7 or more years of PPI use was associated with a 92% increase in risk for any fracture, and 5 or more years of use was associated with a 62% increase for hip fracture.3 In the current study, few women had durations of PPI use that exceeded 3 years, so increased hip fracture with PPI use might be increased for longer durations of use.
In this study, PPI use presented greatest risk for fracture in those younger than 70 years and those who had not had previous fractures. This could be because age and other risk factors for fractures are more important risk factors than PPI use, and "wash out" the effects of use of PPIs. However, not all studies of this issue have reported the same findings; others reported that PPI use did not increase the risk of hip fractures in a sample of women without known risk factors.5
The biological basis by which PPI use may increase fractures may be its profound acid-suppressive effects, which may reduce intestinal calcium absorption. However, calcium absorption is highly variable and actual data about the effect of PPI use on calcium absorption remain inconclusive.
It is notable that the women in this study who used PPIs were generally unhealthier than their non-using cohort members. It is possible that individuals who chose to take a medicine rather than address lifestyle may be at increased risk for fracture because of other, unmeasured unhealthy behaviors. It is also possible that heartburn itself predisposes or is a marker for increased fracture risk.
However, there are other risks associated with use of PPIs. In the same issue of the Archives of Internal Medicine, two large hospital-based studies demonstrated that patients who took PPIs while in the hospital had increased risk for Clostridium difficile infection.6,7
The bottom line is that PPIs are not a risk-free approach to reflux symptoms or GI bleed prophylaxis. Use with caution!
1. Vestergaard P, et al. Fracture risk associated with use of nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and acetaminophen and the effects of rheumatoid arthritis and osteoarthritis. Calcif Tissue Int 2006;79:84-94.
2. Yang YX, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006;296: 2947-2953.
3. Targownik LE, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008;179:319-326.
4. Yu EW, et al. Acid-suppressive medications and risk of bone loss and fracture in older adults. Calcif Tissue Int 2008;83:251-259.
5. Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 2008;28:951-959.
6. Linsky A, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010;170:772-778.
7. Howell MD, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010;170:784-790.