Proton Pump Inhibitors Over Years Increase Osteoporotic Fracture Risks

By Crystal Phend
WINNIPEG, Manitoba, 13 aug 2008-- Chronic use of proton pump inhibitors over years for gastroesophageal acid reflux is associated with osteoporotic fractures but short-term use seems to be safe, researchers here found.
Proton pump inhibitors used for at least seven years was associated with an almost doubled risk of osteoporotic fracture (P=0.04) whereas shorter-term use did not significantly raise risk, reported William D. Leslie, of St. Boniface Hospital here, and colleagues in the Aug. 12 issue of the Canadian Medical Association Journal.
In a large observational study, long-term proton pump inhibitors use was associated with an even greater, nearly five-fold increased risk of hip fracture (P=0.002).
These findings reinforce increased fracture risk seen in two other large retrospective studies but not the early effects seen after one year of exposure in one of the studies (odds ratio 1.44, 95% confidence interval 1.3 to 1.59). (See: Proton Pump Inhibitors Linked to Fracture Risk)
In an accompanying editorial, J. Brent Richards, M.D., and David Goltzman, M.D., both of McGill University in Montreal, said the discrepancy may simply be an issue of statistical power, although it wouldn't be surprising if skeletal effects required years of exposure.
The researchers suggested, "clinicians must be increasingly vigilant in ensuring that proton pump inhibitors are used sparingly and only when absolutely indicated."
But despite confirmation of bone effects in several large studies, the editorialists stopped short of recommending that physicians change practice.
The risk-benefit equilibrium "should be reconsidered with knowledge of the mounting, yet incomplete, evidence suggesting that proton pump inhibitors increase the risk of fracture," they wrote.
Guidance from randomized, controlled trials or even prospective cohort studies is needed for cases where a PPI would be prescribed appropriately for a non-life-threatening indication over the long term, Drs. Richards and Goltzman said.
The association seems biologically compelling since the acidic environment of the stomach and proximal duodenum appear necessary for absorption of dietary calcium, but further proof is needed of this mechanism as well, they said.
Dr. Leslie's group used the administrative claims database covering all residents of Manitoba to determine whether long-term use of a PPI was associated with fracture risk.
The analysis included 15,792 adults ages 50 and older treated for fracture of the hip, vertebra, or wrist between April 1996 and March 2004 who were not on osteoprotective medications or in long-term care facilities.
Each of these cases was matched for age, sex, and comorbidities with three controls who had never had a hip, vertebral, or wrist fracture.
The association between PPI exposure and fractures strengthened over time, but became significant for osteoporosis-related fractures overall only after seven years of continuous exposure (adjusted OR 1.92, 95% CI 1.16 to 3.18). The adjusted odds ratios for shorter duration use were:
0.99 for use of one year or longer (95% CI 0.90 to 1.11).
0.94 for use of two years or longer (95% CI 0.82 to 1.07).
0.92 for use of three or more years (95% CI 0.78 to 1.07).
1.05 for use of four years or longer (95% CI 0.86 to 1.27).
1.16 for use of five or more years (95% CI 0.91 to 1.46).
1.28 for use of six year or longer (95% CI 0.93 to 1.77).
The associations were stronger for hip fracture specifically, with significantly elevated risk starting at five or more years of exposure (adjusted OR 1.62, 95% CI 1.02 to 2.58). This risk increased over time to an adjusted odds ratio of 2.49 after six years (95% CI 1.33 to 4.67) and to 4.55 after at least seven years of continuous exposure (95% CI 1.68 to 12.29).
The researchers noted that although many of the odds ratios suggested a modestly elevated risk of fracture similar in magnitude to other risk factors like smoking, osteoporotic fractures are common and lead to substantial morbidity and mortality.
"Therefore, relatively small increases in the relative risk of a fracture may have pertinent effects on the absolute risk of events and their associated costs to the individual and society," Dr. Leslie's group said.
For patients who require long-term therapy, it's possible that pharmacologic strategies, such as calcium supplementation or bisphosphonates, could mitigate fracture risk, they said. Further study of this option is needed, they noted.
The researchers also cautioned that the study was limited by inability to control for potential confounding by factors such as use of over-the-counter calcium supplements, vitamin D supplements, tobacco, and alcohol, which were not included in the database.
The study was funded by a grant from the Canadian Institutes of Health Research.
Dr. Leslie reported receiving speaker's fees and research support from Merck Frosst Canada and honoraria and unrestricted educational grants from sanofi-aventis, Procter and Gamble Pharmaceuticals Canada, Amgen Pharmaceuticals and Genzyme Canada.
A co-author reported receiving research funds from Janssen-Ortho Canada and from Astra-Zeneca Canada and having served on advisory boards for Janssen-Ortho Canada and for the Canadian Agency for Drugs and Technology in Healthcare to develop guidelines for PPI use in Canada.
Drs. Richards and Goltzman reported no conflicts of interest.
Additional source: Canadian Medical Association JournalSource reference: Targownik LE, et al "Use of proton pump inhibitors and risk of osteoporosis-related fractures" CMAJ 2008; 179: 319-26. Additional source: Canadian Medical Association JournalSource reference: Richards JB, Goltzman D "Proton pump inhibitors: balancing the benefits and potential fracture risks" CMAJ 2008; 179: 306-7.