These results are similar to another case-control study published last year by Vestergaard et al. reporting an increased risk of hip fracture with PPI use (adjusted OR 1.45 [95% CI 1.28–1.65]) and spine fracture (OR 1.60 [95% CI 1.25–2.04]).1 That study did not find a dose-response to PPI use, but its methodology was different in determination of cases (all individuals with a fracture in Denmark during 2000), and they examined all individuals receiving a PPI as opposed to long-term use, which may account for the differences between the studies.
There are limitations to this study, as in all case-control studies. Not all confounders may have been measured or assessed. Exposure assessment status is always subject to bias, although, given the method of prescription capture in the GPRD and that omeprazole was not over-the-counter until 2004, this is probably minimal. Calcium supplementation could not be assessed and may be an important mediator.
This is a well done study linking PPI use with an increased risk of hip fracture that supports similar findings from earlier case-control studies. We recognize that patients who have undergone gastrectomy or are afflicted with pernicious anemia, and thus have achlorohydria, are at increased risk of osteoporosis and fracture. The animal and limited human data from patients with achlorohydria suggest that a potential mechanism may be reduced absorption of insoluble calcium salts in a non-acidic environment. This mechanism fits with the observation of a dose-response relationship in the current study. Certainly, this study raises many more questions, and I anxiously await further epidemiologic studies looking at associations of vertebral and other fracture risks, as well as animal data clarifying the effect of PPI use on calcium absorption.
At this time, I will not change my use of PPIs in my patient population, particularly since many of them have esophageal motility abnormalities. However, this study is enough to make me pause and educate my patients on the importance of twice-daily calcium supplementation with soluble calcium salts (such as calcium carbonate or calcium citrate) taken with a meal and an acidic beverage to try and increase absorption.
Reference
Stopping Alendronate at Five Years Not a Fracture Risk
By Eric S. Schned, MD
Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after five years of treatment—the Fracture Intervention Trial Long-Term Extension (FLEX): a randomized trial. JAMA. 2006;296(24):2927-2938.
Abstract
Context: The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. Objective: To compare the effects of discontinuing alendronate treatment after five years versus continuing for 10 years. Design and setting: Randomized, double-blind trial conducted at 10 U.S. clinical centers that participated in the Fracture Intervention Trial (FIT). Participants: One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of five years of prior alendronate treatment. Intervention: Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for five years (1998–2003). Main outcome measures: The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. Results: Compared with continuing alendronate, switching to placebo for five years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1-collagen, 59.5% (P < .001) for serum n=propeptide of type-1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after five years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After five years, the cumulative risk of nonvertebral fractures (relative risk [RR], 1.00; 95% CI, 0.76–1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24–0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60–1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. Conclusions: Women who discontinued alendronate after five years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to five years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond five years.
Commentary
Most rheumatologists are comfortable treating patients with postmenopausal osteoporosis with oral bisphosphonates for up to five years. We’re used to seeing significant increases in BMD, and we are confident that we are preventing vertebral and nonvertebral fractures.
