The Final Word on Proton Pump Inhibitors and Osteoporosis? - editorial
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Full text of original study follows editorial
Gastroenterology March 2013
Editorial: "Compared with non-PPI users, PPI users had lower baseline BMD at the hip and femoral neck but not the lumbar spine........After adjustment for confounding factors, regression models did not show association between use of PPI and rate of change of BMD at any measurements"...Authors of original study concluded: "PPI users had lower BMD at baseline than PPI non-users, but PPI use over 10 years did not appear to be associated with accelerated BMD loss. These findings provide support for the view that PPI use does not have a significant effect on bone mineral loss, and that the increase in PPI-associated fracture risk described in other studies may be due to residual confounding, or alternatively, a BMD-independent cause for fracture. Further studies to better delineate or rule out potential mechanisms through which PPIs may affect bone strength or fracture risk are needed to provide additional evidence about whether PPIs truly have a clinically meaningful, direct relationship with bone health. The reasons for discordant findings between PPI use at baseline and during follow-up require further study......While there are no obvious reasons why low BMD should directly promote higher rates of PPI use, low BMD may be a marker for other comorbidities that may predispose participants to PPI use. Previous studies have suggested that PPI use is much more common among subjects with indicators of frailty, including the use of multiple distinct medications, higher levels of overall comorbidity, and poor mobility. These markers of frailty may also be associated with low BMD and increased fracture. If individuals with low BMD, who are also presumably at higher fracture risk, are more likely to be started on PPIs, then this may conceivably explain the findings of other studies that report an association between PPI use and fracture. As is suggested in Table 2, PPI users were significantly more likely to use other medications known to negatively influence BMD, and were also more likely to have rheumatoid arthritis, COPD, thyroid disease, chronic renal disease, or inflammatory bowel disease......only 0.9% of the sample used PPIs continuously over the 10 years of the study, we may not have had sufficient power to detect a clinically significant change in BMD associated with PPI use. However, even in the y5-y10 analysis, during which time 4.3% of subjects were continuous PPI users, our findings do not support a clinically significant effect of PPI use on the rate of BMD change (e.g., mean femoral neck loss -0.3% over 5 years with the lower limit of the 95% confidence interval -1.4%). Another possible explanation is that the majority of any negative effect on BMD occurs relatively soon after initiation of PPI therapy, and thus the failure to detect further changes in the BMD over time among those who continued to use PPIs was due to a ceiling effect. Some of the prior research studying the relationship between PPI use and fractures detected an increase in fracture risk early in the course of therapy with no further increases over time, while others have shown greater increases in risk with longer durations of use"
Targownik LE, Leslie WD, Davison KS, et al; CaMos Research Group. The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based from the Canadian Multicentre Osteoporosis Study (CaMos). Am J Gastroenterol 2012;107:1361-1369.
Osteoporosis is a common disease that is characterized by low bone mass and remains asymptomatic until patients develop a vertebral or other fracture (J Bone Miner Res 1994;9:1137-1141). The prevalence in adults over the age of 50 is approximately 20% for women and 7% for men. For adults who develop hip fractures, the estimated 1-year mortality rates range between 12% and 37% (JAMA 2009;302:1573-1579). Risk factors for osteoporosis include female gender, sedentary lifestyle, tobacco consumption, low body mass index, inflammatory bowel disease, hyperparathyroidism, and use of medications including corticosteroids, antiepileptics, thiazides, and antidepressants including selective serotonin reuptake inhibitor therapy.
Gastroesophageal reflux disease (GERD) is a common disorder affecting approximately 10% of Americans on a daily basis, and 40% of Americans monthly (Clin Gastroenterol Hepatol 2005;3:543-552; Gut 2005;54:710-717). In September 2012, the US Food and Drug Administration issued a warning regarding use of proton pump inhibitors (PPIs) and osteoporosis stating that "several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose PPI, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated."
In the current study by Targownik et al from the University of Manitoba (Canadian Multicentre Osteoporosis Study [CaMos]), the authors used a random population sample from 1995 to 1997 that included subjects over the age of 25. In-person, interviewer-administered questionnaires (IAQ) were administered to all subjects including medical history, intake of calcium and vitamin D, and bone mineral density (BMD) assessment using dual energy x-ray absorptiometry (DXA) on all enrolled subjects at L1-L4, the femoral neck, and total hip. Repeat questionnaire and BMD assessments occurred at years 5 and 10.
The authors subsequently analyzed the relationship between PPI use and change in BMD at each site between years 0-5, 0-10, and 5-10. They performed multivariate linear regression analysis to control for confounders including age, gender, body mass index, history of fracture, rheumatoid arthritis, inflammatory bowel disease, chronic liver, kidney thyroid disease, tobacco, alcohol, history of falls, and multiple predisposing medications including steroids, thiazides, ß-blockers, nitrates, selective serotonin reuptake inhibitors, and tamoxifen. Data regarding adequate consumption of calcium and vitamin D (≥1200 mg calcium and/or ≥400 IU of vitamin D) was recorded.
There were a total of 9423 subjects enrolled in the study, of whom 8340 (88.5%) completed initial IAQ and BMD assessments. At 5 years, 6458 (77%) patients underwent repeat assessments of IAQ and BMD, and a total of 4512 (55%) completed the 10-year survey. Two hundred twenty-eight (3%) subjects used PPI at baseline, 8% at year 5, and 11.5 % at year 10. Continuous PPI use was only reported by 0.9% of the cohort.
Compared with non-PPI users, PPI users had lower baseline BMD at the hip and femoral neck but not the lumbar spine. In general, PPI users tended to be older with higher body mass index (P < .001), greater intakes of vitamin D and calcium, higher rates of prior nontrauma fractures (P = .015) and comorbidities, and users of multiple medications (P < .001 for use of steroids, thiazide diuretics, and selective serotonin reuptake inhibitors). After adjustment for confounding factors, regression models did not show association between use of PPI and rate of change of BMD at any measurements. In addition, use of bisphosphonates and hormone replacement therapy was associated with increases in BMD.
The presence of gastric acid and an acidic proximal duodenum are required to free ingested calcium from foodstuffs for absorption to occur in the small intestine. Lack of sufficient amounts of gastric acid can lead to secondary hyperparathyroidism, increased rates of osteoclastic bone resorption, and skeletal turnover, and subsequent reduction in bone mass.
Although short-term studies have suggested that PPI use can decrease calcium absorption, consequences of this effect have not been demonstrated in long-term outcomes analyses. Early published studies in small numbers of subjects where omeprazole 20 mg was administered to healthy subjects or patients undergoing dialysis, suggested that omeprazole resulted in decreased calcium absorption after short exposures to the drug ranging from 3 days to 20 months (Nephrol Dial Transplant 1995;10:1376-1380; Nephron 2002;91:474-479; Artif Organs 1998;22:569-573; Am J Med 2005;118:778). However, a randomized, controlled trial in healthy subjects measuring calcium absorption using gastrointestinal lavage after omeprazole 40 mg was administered for 17 days did not show any change in intestinal calcium absorption (J Am Coll Nutr 1995;14:364-368).
Subsequent case-control studies assessing potential associations between dose and duration of PPI therapy and hip fractures showed mixed results. The first study by Vestergard et al (Calcif Tissue Int 2006;79:76-83) performed in Denmark examined 124,655 case with hip fracture compared with 373,962 controls matched for age and gender. The study found that the odds ratio for hip fracture in PPI users was 1.18 (95% confidence interval [CI], 1.12-1.43) for users <1 year ago and was 1.01 (95% CI, 0.96-1.06) for patients who used the drug >1 year ago. The odds ratio did not change depending on the PPI dosage. A subsequent study by Yang et al (JAMA 2006;296:2947-2953) compared 2722 cases of hip fractures in patients taking PPIs for >1 year and 10,834 hip fractures in patients not taking PPIs with 135,386 matched controls and found an odds ratio (OR) for PPIs of 1.44 (95% CI, 1.30-1.59) with the risk being 1.4 for ≤1.75 average daily doses and 2.65 when the average daily dose exceeded 1.75. The OR was 1.22 after 1 year of use and increased to 1.59 after 4 years. The third study by Targownik et al from Canada (CMAJ 2008;179:319-326) matched 15,792 cases with either vertebral, wrist, or hip fractures with 47,289 controls and reported ORs by PPI duration of use. Although at >1 year of PPI use the odds ratio was 0.99, it increased to 1.16 at 5 years of use, and to 1.92 after 7 years. A cause-and-effect relationship between PPI use and fractures was unable to be established based on a low magnitude of associations, probable bias based on the retrospective nature, and inconsistency between studies in demonstration of effect (Am J Gastroenterol 2009;104[Suppl 2]:S21-S26).
Subsequent studies assessed BMD based on DXA scans and again showed inconsistent results. A study by Yu et al in 2008 (Calcif Tissue Int 2008;83:251-259) did not show differences in rate of total hip BMD decline between PPI users and nonusers. Gray et al (Arch Intern Med 2010;170:765-771) showed that both users and nonusers had increases in BMD of the hip from baseline to year 3 of the study. However, increases in BMD were lower among PPI users than nonusers. Targownik et al (Gastroenterology 2010;138:896-904) subsequently were unable to demonstrate a relationship between BMD of the lumbar spine or hip and PPI exposure during the 5 years before BMD testing. In this study, use of PPIs was not associated with more rapid rates of BMD decline.
To add to the existing literature, a case-control study published in 2010 (Gastroenterology 2010;139:93-101) demonstrated that the excess hip fracture risk among PPI users was only present in persons with ≥1 other risk factor for fracture. In this study, patients with hip fractures were more likely than controls to have previously received >2-year supply of PPIs (OR, 1.30). Higher dosages were associated with increased risk (OR, 1.41 for dosages >1.5 pills per day).
Multiple meta-analyses assessing the risk of PPI use and fractures were published in 2011 (Eur J Gastroenterol Hepatol 2011;23:794-800; Am J Med 2011;124:519-526; Ann Fam Med 2011;9:257-267; Am J Gastroenterol 2011;106:1209-1218; Bone 2011;48:768-776). The majority of the studies concluded that the risk of hip fracture increased moderately among PPI users (relative risk, 1.2-1.30) in addition to spine fractures (relative risk, 1.6). However, the studies were limited by significantly heterogeneity, and when studies were adjusted for other risk factors for fracture, PPIs were no longer causal. H2-receptor antagonists did not seem to be associated risk with fractures.
Based on these studies, it appears that low BMD may be a marker for other comorbid conditions that predispose subjects to use PPI and other medical therapy rather than a direct sequelae of PPI therapy. A study published in 2011 that calculated a "refractory GERD score" determined that higher use PPI was associated with female gender, higher comorbidity scores, and greater overall costs (Aliment Pharmacol Ther 2011;34:555-567).
Should every GERD patient in our gastroenterology practices be started on vitamin D and calcium therapy with their PPI prescriptions and referred for BMD testing? Based on the recent study from Targownik et al and the prior literature, I would make the argument that the typical GERD patient without significant comorbidities or risk for fractures not be referred to the bone density clinic for testing and treatment. However, gastroenterologists should discuss this issue with GERD patients who do have other risk factors for hip fracture so that testing can be performed if indicated. Certainly in GERD patients with established osteoporosis, PPI therapy should be continued if indicated because there is no evidence that it worsens this preexisting condition. In patients with milder heartburn symptoms, step-down therapy to H2-receptor antagonists can be considered if patients have adequately controlled symptoms and are able to demonstrate healing of erosive esophagitis.
Certainly, in patients with GERD symptoms that are not relieved by PPI therapy, diagnostic testing should occur with ambulatory pH monitoring, esophageal manometry, and other testing as indicate to demonstrate that long-term PPI therapy is warranted.
Am J Gastroenterol 2012; 107:1361-1369; doi:10.1038/ajg.2012.200; published online 10 July 2012
The Relationship Between Proton Pump Inhibitor Use and Longitudinal Change in Bone Mineral Density: A Population-Based From the Canadian Multicentre Osteoporosis Study (CaMos)
Laura E Targownik MD, MSHS1, William D Leslie MD, MSc1, K Shawn Davison PhD2, David Goltzman MD3, Sophie A Jamal MD, PhD4, Nancy Kreiger MPH, PhD4, Robert G Josse MBBS4, Stephanie M Kaiser MD5, Christopher S Kovacs MD6, Jerilynn C Prior MD7, Wei Zhou MSc3 and the CaMos Research Group8
1. 1University of Manitoba, Winnipeg, Manitoba, Canada
2. 2University of Saskatchewan, Saskatoon, Saskatchewan, Canada
3. 3McGill University, Montreal, Quebec, Canada
4. 4University of Toronto, Toronto, Ontario, Canada
5. 5Dalhousie University, Halifax, Nova Scotia, Canada
6. 6Memorial University of Newfoundland, St John's, Newfoundland, Canada
7. 7University of British Columbia, Vancouver, British Columbia, Canada
Proton pump inhibitor (PPI) use has been identified as a risk factor for hip and vertebral fractures. Evidence supporting a relationship between PPI use and osteoporosis remains scant. Demonstrating that PPIs are associated with accelerated bone mineral density (BMD) loss would provide supportive evidence for a mechanism through which PPIs could increase fracture risk.
We used the Canadian Multicentre Osteoporosis Study data set, which enrolled a population-based sample of Canadians who underwent BMD testing of the femoral neck, total hip, and lumbar spine (L1-L4) at baseline, and then again at 5 and 10 years. Participants also reported drug use and exposure to risk factors for osteoporosis and fracture. Multivariate linear regression was used to determine the independent association of PPI exposure and baseline BMD, and on change in BMD at 5 and 10 years.
In all, 8,340 subjects were included in the baseline analysis, with 4,512 (55%) undergoing year 10 BMD testing. After adjusting for potential confounders, PPI use was associated with significantly lower baseline BMD at the femoral neck and total hip. PPI use was not associated with a significant acceleration in covariate-adjusted BMD loss at any measurement site after 5 and 10 years of follow-up.
PPI users had lower BMD at baseline than PPI non-users, but PPI use over 10 years did not appear to be associated with accelerated BMD loss. The reasons for discordant findings between PPI use at baseline and during follow-up require further study.
Proton pump inhibitors, or PPIs, are among the most frequently prescribed medications in clinical practice, with 147 million prescriptions for PPIs being dispensed in the United States in 2010 (1). Part of the reason for the widespread use of PPIs has been both their high efficacy for the treatment and prevention of gastroesophageal reflux disease and peptic ulcer disease (2,3,4), as well as their reputation for being well tolerated and unlikely to lead to long-term complications.
However, over the past decade, there have been an increasing number of studies that have linked the use of PPIs to increases in the risk for a variety of serious adverse events (5,6,7). Among the associations of highest concern has been the possible link between the long-term use of PPIs and the development of osteoporosis-related fractures, particularly those of the hip (8,9,10,11,12,13,14,15). This association has been primarily detected through the retrospective analysis of pre-existing data, and the strengths of the associations have ranged considerably from study to study. To date, there are no studies using data that were prospectively collected to evaluate the association between PPI use and fracture. Furthermore, the mechanism through which PPI use could increase the risk of fracture has yet to be elucidated (16,17). In spite of these limitations, the US Food and Drug Administration has issued a black-box warning advising that PPI use may increase the risk of subsequent fracture (18).
If the association between PPIs and fracture is indeed causal, then one would expect to also see an effect of PPIs on the intermediate pathways that predispose to fracture. In particular, determining that PPI use is associated with the development of low bone mineral density (BMD) from which the diagnosis of osteoporosis could be made, or with accelerated loss of longitudinally assessed BMD, would provide tangible support for the causality of the PPI-fracture association. Previous studies, which have analyzed the association between PPI use and BMD, have yielded conflicting results (8,19,20); and thus, the true relationship between PPIs and changes in BMD remains poorly characterized. Therefore, we sought to use a large population-based cohort to determine the relationships between prior PPI use and BMD at the time of enrollment and, using longitudinal assessments of BMD, to determine whether those with chronic PPI use have a different rate of BMD change than non-PPI-treated people.
Overall, 9,423 subjects were enrolled in the original CaMos cohort, of whom 8,340 completed the initial IAQ and underwent initial BMD assessments. In all, 6,458 participants (77%) underwent repeat assessments of the full IAQ and measurement of BMD at 5 years, and 4,512 (55%) completed the full 10 years of follow-up. Description of the participants included in the baseline analyses and in the longitudinal analyses is summarized in Table 1. In the baseline cross-sectional analyses, 228 (2.7%) subjects reported using PPIs. PPI use increased to 7.6% at year 5 and 11.5% at year 10. Continuous use of PPI at all time points was limited to 0.9% of the cohort.
Baseline comparisons of PPI users and non-users are shown in Figure 1 and Table 2. Users of PPIs had significantly lower unadjusted BMD at each of the measurement sites. PPI users were also significantly older, had a higher mean BMI, greater intakes of calcium and Vitamin D, and reported a slightly higher rate of prior fracture than non-PPI users. PPI users were also much more likely to have many of the concurrent medical conditions, and were more likely to be using many of the medications, including bisphosphonates, glucocorticoids, selective serotonin receptor inhibitors, thiazides, nitrates, and ß-blockers.
After adjusting for multiple confounders, PPI use was associated with lower baseline BMD at both the total hip (-0.019±0.008 g/cm2, P=0.028) and the femoral neck (-0.022±0.007 g/cm2, P=0.002), but not at the lumbar spine (-0.014±0.011 g/cm2, P=0.179) (Table 3). When users of osteoprotective medications and glucocorticoids were excluded, PPI use was again associated with lower adjusted baseline BMD at the femoral neck (-0.026±0.008 g/cm2, P=0.002) and total hip (-0.026±0.010 g/cm2, P=0.008). Limiting the analysis to subjects over the age of 50 years did not significantly affect the parameter estimates for PPI use (total hip: -0.021±0.010 g/cm2, P=0.028, femoral neck: -0.025±0.008 g/cm2, P=0.002).
After adjustment for potential confounders, the regression models did not demonstrate a significant association between continuous PPI use and the rate of change in BMD at any of the measurement sites between y0 and y5, between y0 and y10, or between y5 and y10 (Table 4). The lack of an association between PPI use and change in BMD remained when PPI use was defined as being current at the time of the most recent BMD assessment. There were also no significant changes in BMD attributable to PPI use in analyses restricted to subjects over age 50 years and to those not using glucocorticoids or osteoprotective medications. The use of bisphosphonates and menopausal hormone therapy was uniformly associated with increasing BMD. BMD gains of lower magnitude were also associated with the use of thiazide diuretics, whereas glucocorticoid use was often predictive of BMD loss. Interactions between PPI and bisphosphonate use were not detected in any of the longitudinal analyses.