Current Treatment Options in Gastroenterology (2014) 12:414–423 DOI 10.1007/s11938-014-0030-y
Stomach (C Howden, Section Editor)
Proton Pump Inhibitors and Risk of Bone Fractures Grigorios I. Leontiadis, MD PhD* Paul Moayyedi, BSc MB ChB PhD MPH FRCP FRCPC AGAF FACG Address * Division of Gastroenterology, Department of Medicine, McMaster University, 1280 Main Street West, Health Sciences Center, area 3V3, Hamilton, Ontario L8S 4K1, Canada Email: [email protected]
Published online: 11 September 2014 * Springer Science+Business Media, LLC 2014
Keywords Proton pump inhibitors I Bone fractures I Confounding
Opinion Statement There are 34 studies in almost 2 million participants that have reported on the association between proton pump inhibitor (PPI) therapy and risk of fracture. There is substantial variation between the results of each study but systematic reviews of the data suggest overall there is an association between PPI therapy and risk of fracture. The magnitude of the association is modest and is most likely due to confounding factors as patients prescribed PPI therapy tend to be more frail with more risk factors for fractures than those not given these drugs. There is no clear dose–response relationship and there is no association between PPI therapy and risk of fracture in those at highest risk. Finally, there is no clear mechanism through which PPI therapy increases the risk of fracture, as recent randomized trials show no impact of PPI therapy on calcium absorption and there is no association between PPI therapy and risk of osteoporosis. We therefore feel there is insufficient evidence to change PPI prescribing habits based on risk of fracture. Similarly, we do not recommend bone mineral density investigations for patients taking PPI therapy other than would be normally indicated. There is no evidence to support prescription of calcium and/or vitamin D in patients simply because they are taking PPI therapy. As with all medications, we only recommend prescribing PPI therapy when there is a clear indication that benefit will outweigh risk and at the lowest effective dose. Patients should be regularly assessed as to whether acid suppression is still required.
Introduction Proton pump inhibitors (PPIs) are effective in treating gastro-esophageal reflux disease [1]. This is a common disorder and a survey suggested that 9 % of general medical ambulatory care consultations resulted in a
prescription for a PPI [2]. These drugs are being increasingly used for disorders other than gastro-esophageal reflux and are associated with a significant cost [3]. This is compounded by the advent of generic PPI therapy and
PPIs and Fractures the availability of these drugs over the counter in the USA where there is evidence that inappropriate use becomes more prevalent [4]. This places a significant economic burden on healthcare communities [3] but there is also an emerging concern that these drugs may be associated with serious adverse consequences [5••]. PPI therapy has been associated with an increased risk of fractures, Clostridium difficile infection, pneumonia, and also cardiovascular events in patients taking clopidogrel [5••, 6–9]. This has led regulatory agencies to place “black-box” warnings on PPI therapies [10].
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These adverse events have received considerable press coverage and it is important that patients are not exposed to harm as PPI therapy becomes cheaper and available over the counter. One of the major concerns relates to risk of fracture. We have therefore conducted a literature search (fracture* OR osteoporosis OR “bone density”) AND (PPI* or “proton pump inhibitor*” OR “protonpump inhibitor*” OR “proton-pump inhibitor*” OR omeprazole OR esomeprazole OR lansoprazole OR pantoprazole OR rabeprazole) to evaluate primary studies and systematic reviews that have addressed this issue.
What is Already Known? The first studies on PPI use and fracture risk were two case–control studies that were published in 2006 [11, 12]. Both found a statistically significant association, although one study felt this association was not causal and probably related to confounding factors [11]. A systematic review [13] was conducted in 2007 to inform the 2008 Position Statement from the Canadian Association of Gastroenterology (CAG) [14], which concluded that “there is no persuasive evidence that the association is causal although this can never be excluded as a possibility”. Several publications followed in rapid succession and in turn triggered the publication of a large number of systematic reviews and metaanalyses that peaked in 2011. Five systematic reviews and meta-analyses were published in 2011 within a period of a few months [15–19]. All of them had conducted their literature search in 2010; the number of included studies varied from 7 to 11, depending on the inclusion criteria used; all five systematic reviews and meta-analyses found a statistically significant association between PPI use and fractures. However, all five systematic reviews and meta-analyses commented on the possibility that this finding was due to residual confounding, and three out of five emphasized this in the abstract conclusion. The most recent systematic review and meta-analysis was performed for the 2013 update of the CAG Position statement on hip fracture and PPI therapy [20••]. The literature search that was performed in May 2013 identified 25 relevant observational studies. A meta-analysis of the 13 case–control studies [11, 12, 21–31] that comprised 1,105,595 participants showed that PPI treatment was associated with hip fracture; the pooled odds ratio (OR) was 1.21; 95 % confidence interval (CI) 1.07– 1.38, with substantial heterogeneity that could not be explained by subgroup analyses. A meta-analysis of the 12 cohort studies [32–43] that included 834,442 participants (3,712,891 patient-years of follow up) also showed a statistically significant association between PPI treatment and hip fracture; the pooled relative risk [RR] was 1.30; 95 % CI 1.13–1.49, again, with substantial, unexplained heterogeneity. A previous systematic review and meta-analysis had found similar results for hip
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Stomach (C Howden, Section Editor) fractures, and also found associations between PPI use and vertebral fractures (OR 1.50 (95 % CI=1.32–1.72) and wrist/forearm fractures (OR 1.09 (95 % CI 0.95–1.24) [7].
What is New Since the Last Systematic Review and Metaanalysis? Since May 2013, eight additional observational studies (three cohort studies [44–46] and five case–control studies [47, 48, 49•, 50•, 51]) and one randomized controlled trial (RCT) [52•] have been published. All of the recent observational studies reported a statistically significant association of PPI use with fractures. Given the magnitude and precision of these results, it is unlikely that the point estimate for the OR and RR for the association would change substantially if these results were pooled with the results of the previous 25 observational studies that were included our recent meta-analysis [20••]; an updated meta-analysis would produce slightly tighter 95 % CIs, but would still have substantial heterogeneity. There are, however, additional interesting findings from these studies. Lewis et al. [47] in a cohort study of older Australian women found that PPI use was also associated with increased falls as well as impaired falls-associated metrics (both questionnaire-assessed metrics such as limiting outdoor activity and indoor activity due to fear of falling, dizziness, and numbness of feet and objective clinical measurements such as Timed Up and Go test and Romberg eyes closed tests), while no association of long-term PPI therapy with bone structure was observed. Lewis et al. [47] therefore concluded that the increased fracture risk among PPI users was more likely to be mediated by increased risk of falls rather than impaired bone structure. Three studies assessed the data for manifestations of a dose–response relationship. Of these, Cea Soriano et al. [50•] looked for but observed no duration response (current PPI use ≤1 month compared with PPI use ≥5 years). Two other research groups [49•, 51] implied that evidence of dose response was found, but these claims were not justified. Ding et al. [51] found that the point estimates for the hazard ratio (HR) for fracture increased nominally as the level of adherence to PPI treatment increased, but these differences were not statistically significant (the 95 % CIs for the HR for the three adherence levels overlapped widely). Similarly, the fact that the HR was statistically significant only for the highest adherence level and not for the other two adherence levels, cannot be used as proof of dose response, when this could have resulted from the low power of the analysis for the other two adherence levels. Adams et al. [49•] observed that high adherence, longest duration of use, and most recent use of PPIs were significantly associated with hip fracture, whereas the association was not statistically significant for the complementary categories (lower adherence, shorter duration, less recent use). Again, in each analysis, the 95 % CIs overlapped widely and the postulated dose response was not statistically significant. The association between PPI use and factures among patients on bisphosphonates is particularly interesting. A study of a cohort of bisphosphonate users [46] showed that PPIs were associated with increased risk of hip fractures, and a case–control study found that the magnitude of the association
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between PPIs and hip fractures was higher among bisphosphonate users compared with participants who were not taking bisphosphonates [47]. In both studies, the associations persisted after adjustment for confounders. However, these results were not supported by a recent RCT [52•], which is the only published RCT on the effect of PPIs on bone-related outcomes. Itoh et al. [52•] randomized 180 women with low bone mineral density (BMD) to risedronate plus rabeprazole or risedronate alone for 9 months. Fractures per group were reported, but the events were too few for any meaningful analysis, as the study was not powered for this outcome. The main outcomes of the study were changes in BMD and physical functioning (evaluated with the SF-36v2TM Health Survey) before and after treatment, and all these outcomes were significantly larger in the combined risedronate-PPI group vs. the risedronate-alone group. The RCT could not shed any light on the mechanism by which PPIs improved BMD among risedronate users, but it was speculated to have resulted from increased enteric absorption of risedronate due to decreased gastric acidity [52•].
Is There Residual Confounding? Modest associations between a risk factor and a disease for observational studies are more likely to be due to bias or confounding rather than a causal effect. The 34 observational studies that have assessed the risk of fracture in PPI users are not at high risk of serious bias, but are at very high risk of residual confounding, despite the fact that most of the researchers have adjusted for several known confounders. As we showed in a previous review, if for each study we tabulate the raw (unadjusted) results against the adjusted results, we can see that the magnitude of the PPI-fracture association is consistently lowered after adjustment for confounders [5••]. We have shown that for hip fracture but also other adverse events associated with PPIs such as pneumonia there is clear evidence that sicker patients are prescribed PPIs [5••]. It is therefore possible that the association with PPI and risk of fracture simply relates to frailer patients being prescribed these drugs and these patients are at higher risk of fractures for a number of reasons. Indeed, our concerns for residual confounding in the body of evidence on the association between PPI use and fractures are further strengthened when the primary studies are evaluated in more depth. A large number of comorbid diseases and an equally long list of medications act as confounders to the PPIfracture association, individually as well as through their contribution to the overall fragility or comorbidity burden of the participants. The association of these factors with fracture risk has been well documented; the comorbid diseases include not only skeletal diseases (osteoarthritis, rheumatoid arthritis) but also all cardiovascular diseases and a large number of non-cardiovascular disease categories (including infectious diseases, nutritional, and metabolic diseases, mental disorders, diseases of the nervous system and sense organs, and respiratory diseases), while the medications include corticosteroids, nonsteroidal anti-inflammatory drugs, thiazide diuretics, benzodiazepines, opioids, antipsychotics, and anticonvulsants [53, 54]. Overall, frailty and old age have also been recognized as risk factors for fractures [55, 56].
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Stomach (C Howden, Section Editor) As we hypothesized in a previous review [5••], PPI users are more likely to be older and sicker than individuals who are not taking PPIs. This has been consistently seen in the table of baseline characteristics of every single one of the 34 observational studies that assessed the association between PPIs and fractures: almost every disease and most of the medications that have been evaluated had been significantly more frequent among PPI users compared with non-users. In fact, PPI users have consistently been sicker and frailer even in observational studies that assessed the association between PPIs and other adverse outcomes, such as cardiovascular events among clopidogrel users, pneumonia, or C. difficile infection [5••, 57]. Many other studies from several countries have also confirmed that old age, frailty, and comorbidities are risk factors for being on long-term PPI treatment [40, 58, 59]. It is possible that physicians are more likely to initiate and maintain PPI treatment in frail patients, based on the physician’s subjective global assessment of the patient’s frailty, as it has been well documented that a large proportion of these old and frail PPI users do not have a clear indication for long-term PPI treatment [40, 58, 59]. Regardless of the reasons explaining the association of PPI use with frailty and comorbidities, unless adequate adjustment or matching at least for known confounders is performed, it is possible that the association of PPI use with fractures is simply a manifestation of residual confounding. That is, doctors are more likely to prescribe PPIs for frail older people who are already at high risk for fractures, irrespective of the use of PPIs. All 34 studies have attempted some statistical adjustment for confounders or matching, but even the best adjusted or matched studies have measured most of the confounders as dichotomous variables. Obviously, a model that adjusts for the confounding effect of a disease (such as dementia or osteoarthritis) by simply counting the presence or absence of this disease is an oversimplification. Ideally, the severity of each of the confounding factors/diseases should be measured as continuous or at least as ordinal outcomes, but such granularity of information cannot possibly be obtained in studies conducted on large administrative or research databases. One might expect that a more granular hypothetical adjustment model would have reduced the association even further. Therefore, it is very likely that most, if not all, of the modest association that remained after adjustment, is due to residual confounding. This is the most likely explanation of the discordant results of two nested case–control studies that each extracted data from the UK General Practice Research Database [12, 22]. The study that used a standard logistic regression model to adjust for known confounders showed a positive statistically significant association between PPI use and fractures [12], while the study that used propensity matching (which can achieve the best correction for both known and unknown confounders) found no statistically significant association [22].
What is the Quality of Evidence? Taking into account the above appraisal of the evidence, according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach [60], the quality of evidence for the association of PPI use with fractures is classified as very low. Evidence from observational studies starts as
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low quality but can be upgraded or downgraded according to specific criteria. In the case of the association between PPIs and fractures, none of the upgrading criteria can be applied (large effect; dose response; all possible confounding and biases would have reduced the demonstrated effect), while at least two downgrading criteria are fulfilled (study limitations due to inadequate adjustment for confounders; inconsistency as indicated by the substantial unexplained heterogeneity). Of note, the “very low” quality of evidence refers to the trustworthiness of the estimate of the association of PPI use with fractures. The quality (trustworthiness) of evidence for causation of fractures by PPIs is obviously even lower, because observational studies cannot prove causation.
Is There Biological Plausibility? The possibility that the association between PPI use and fractures is causal is further diminished as no plausible mechanism has been demonstrated through which PPIs can increase fracture risk. It has been postulated that as PPIs reduce gastric acidity the absorption of ingested calcium is reduced and this in turn leads to osteoporosis, which increases the risk of fractures. However, neither impaired calcium absorption nor osteoporosis has been confirmed in patients taking PPIs. Earlier studies had shown that calcium absorption is reduced in patients with pernicious anemia [61] and post-gastrectomy [62]. An RCT in postmenopausal women found that a 7-day course of a PPI can significantly reduce the absorption of calcium carbonate supplements when these are taken without meals [63]. However, two more recent RCTs that assessed the absorption of ingested calcium under usual physiologic conditions (with meals) and used better measurement techniques did not find any reduction of calcium absorption when PPIs were administered for 3 days in healthy male and female volunteers [64] and for 30 days in postmenopausal women [65]. Finally, a matched controlled (not randomized) trial in male individuals with heartburn found no measurable effect of a 12-week course of PPIs on calcium and bone metabolism (total serum calcium, ionized calcium, phosphorus, albumin, parathormone, 25-OH-vitamin D, C-terminal cross-linked telopeptides of type I collagen, and osteocalcin) [66]. There is also no evidence of an association between PPI use and osteoporosis. Of the nine observational studies that assessed this association, two case– control studies [67, 68] and four cohort studies (reported in three publications) [21, 32, 36] did not show significant results. One cohort study found that PPI users had lower BMD than non-users at baseline, but the authors commented that this was probably the result of residual confounding from unmeasured comorbidity, as PPI use over 10 years was not associated with further BMD loss [69••]. One case–control study found that trabecular BMD, one of five assessed osteoporosis parameters, was significantly lower among PPI users compared with non-users. However, PPI users did not differ significantly from non-users in the other four osteoporosis parameters (overall BMD, cortical BMD, cortical cross-sectional area, trabecular cross-sectional area) [70]. Observational-type data derived from a subgroup analysis of an RCT [71] showed significant posttreatment BMD reductions for most measurements, with small differences
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Stomach (C Howden, Section Editor) among the three PPI groups. Finally, the only true RCT quality data on the effect of PPI treatment on BMD come from the study by Itoh et al. [52•] that was mentioned earlier. Women with low BMD were randomized to risedronate plus rabeprazole or risedronate alone for 9 months; BMD was significantly higher in the group that received the PPI along with risedronate compared with the group that was on risedronate alone.
Conclusions There is a large body of observational evidence involving nearly 2 million participants that demonstrates there is an association between PPI therapy and risk of fracture. An epidemiologist would always emphasize that, when studies show an association between a drug and an outcome that is either beneficial or harmful, this does not imply causation. Rigorous evaluation of the data on fracture and PPI therapy provides a good example of this as the likely reason for this association is confounding factors and it is probable that PPI therapy is not a risk factor for fracture. Indeed, there is emerging evidence that residual confounding is the explanation for some other “harmful” effects of PPI therapy [72]. There is therefore little evidence that clinicians should change their behavior regarding PPI prescribing based on concerns regarding fracture risk. This does not mean that PPIs are safe. There are other possible harms that have not been evaluated in this review and clinicians should always be aware that there could be unknown risks with any medication they prescribe. Clinicians should only prescribe PPI therapy where it is clearly indicated and at the lowest dose that controls patients’ symptoms.
Compliance with Ethics Guidelines Conflict of Interest Grigorios I. Leontiadis declares no conflict of interest. Paul Moayyedi has received speaker’s fees from AstraZeneca and his chair is partly funded by an unrestricted donation from AstraZenca to McMaster University. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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Sharara AI, El-Halabi MM, Ghaith OA, Habib RH, Mansour NM, Malli A, et al. Proton pump inhibitors have no measurable effect on calcium and bone metabolism in healthy young males: a prospective matched controlled study. Metabolism. 2013;62:518– 26. 67. Targownik LE, Lix LM, Leung S, Leslie WD. Protonpump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology. 2010;138:896–904. 68. Lin SC, Koo M, Tsai KW. Association between Helicobacter pylori infection and risk of osteoporosis in elderly Taiwanese women with upper gastrointestinal diseases: a retrospective patient record review. Gastroenterol Res Pract. 2014;2014:814756. 69.•• Targownik LE, Leslie WD, Davidson KS, Goltzman D, Jamal SA, et al. The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based study from the Canadian Multicentre Osteoporosis Study (CaMos). Am J Gastroenterol. 2012;107:1361–9. An excellent study of 8,340 subjects undergoing bone mineral density testing that showed proton pump inhibitor therapy was associated with lower bone mineral density at baseline but was not associated with accelerated bone mineral loss at either 5-or 10-year follow-up 70. Maggio M, Lauretani F, Ceda GP, De Vita F, Bondi G, Corsonello A, et al. Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals. Bone. 2013;57:437–42. 71. Ozdil K, Kahraman R, Sahin A, Calhan T, Gozden EH, Akyuz U, et al. Bone density in proton pump inhibitors users: a prospective study. Rheumatol Int. 2013;33:2255–60. 72. Brophy S, Jones KH, Rahman MA, Zhou SM, John A, Atkinson MD, et al. Incidence of Campylobacter and Salmonella infections following first prescription for PPI: a cohort study using routine data. Am J Gastroenterol. 2013;108:1094–100.
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Proton Pump Inhibitors and Risk of Bone Fractures Grigorios I. Leontiadis, MD PhD* Paul Moayyedi, BSc MB ChB PhD MPH FRCP FRCPC AGAF FACG Address * Division of Gastroenterology, Department of Medicine, McMaster University, 1280 Main Street West, Health Sciences Center, area 3V3, Hamilton, Ontario L8S 4K1, Canada Email: [email protected]
Published online: 11 September 2014 * Springer Science+Business Media, LLC 2014
Keywords Proton pump inhibitors I Bone fractures I Confounding
Opinion Statement There are 34 studies in almost 2 million participants that have reported on the association between proton pump inhibitor (PPI) therapy and risk of fracture. There is substantial variation between the results of each study but systematic reviews of the data suggest overall there is an association between PPI therapy and risk of fracture. The magnitude of the association is modest and is most likely due to confounding factors as patients prescribed PPI therapy tend to be more frail with more risk factors for fractures than those not given these drugs. There is no clear dose–response relationship and there is no association between PPI therapy and risk of fracture in those at highest risk. Finally, there is no clear mechanism through which PPI therapy increases the risk of fracture, as recent randomized trials show no impact of PPI therapy on calcium absorption and there is no association between PPI therapy and risk of osteoporosis. We therefore feel there is insufficient evidence to change PPI prescribing habits based on risk of fracture. Similarly, we do not recommend bone mineral density investigations for patients taking PPI therapy other than would be normally indicated. There is no evidence to support prescription of calcium and/or vitamin D in patients simply because they are taking PPI therapy. As with all medications, we only recommend prescribing PPI therapy when there is a clear indication that benefit will outweigh risk and at the lowest effective dose. Patients should be regularly assessed as to whether acid suppression is still required.
Introduction Proton pump inhibitors (PPIs) are effective in treating gastro-esophageal reflux disease [1]. This is a common disorder and a survey suggested that 9 % of general medical ambulatory care consultations resulted in a
prescription for a PPI [2]. These drugs are being increasingly used for disorders other than gastro-esophageal reflux and are associated with a significant cost [3]. This is compounded by the advent of generic PPI therapy and
PPIs and Fractures the availability of these drugs over the counter in the USA where there is evidence that inappropriate use becomes more prevalent [4]. This places a significant economic burden on healthcare communities [3] but there is also an emerging concern that these drugs may be associated with serious adverse consequences [5••]. PPI therapy has been associated with an increased risk of fractures, Clostridium difficile infection, pneumonia, and also cardiovascular events in patients taking clopidogrel [5••, 6–9]. This has led regulatory agencies to place “black-box” warnings on PPI therapies [10].
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These adverse events have received considerable press coverage and it is important that patients are not exposed to harm as PPI therapy becomes cheaper and available over the counter. One of the major concerns relates to risk of fracture. We have therefore conducted a literature search (fracture* OR osteoporosis OR “bone density”) AND (PPI* or “proton pump inhibitor*” OR “protonpump inhibitor*” OR “proton-pump inhibitor*” OR omeprazole OR esomeprazole OR lansoprazole OR pantoprazole OR rabeprazole) to evaluate primary studies and systematic reviews that have addressed this issue.
What is Already Known? The first studies on PPI use and fracture risk were two case–control studies that were published in 2006 [11, 12]. Both found a statistically significant association, although one study felt this association was not causal and probably related to confounding factors [11]. A systematic review [13] was conducted in 2007 to inform the 2008 Position Statement from the Canadian Association of Gastroenterology (CAG) [14], which concluded that “there is no persuasive evidence that the association is causal although this can never be excluded as a possibility”. Several publications followed in rapid succession and in turn triggered the publication of a large number of systematic reviews and metaanalyses that peaked in 2011. Five systematic reviews and meta-analyses were published in 2011 within a period of a few months [15–19]. All of them had conducted their literature search in 2010; the number of included studies varied from 7 to 11, depending on the inclusion criteria used; all five systematic reviews and meta-analyses found a statistically significant association between PPI use and fractures. However, all five systematic reviews and meta-analyses commented on the possibility that this finding was due to residual confounding, and three out of five emphasized this in the abstract conclusion. The most recent systematic review and meta-analysis was performed for the 2013 update of the CAG Position statement on hip fracture and PPI therapy [20••]. The literature search that was performed in May 2013 identified 25 relevant observational studies. A meta-analysis of the 13 case–control studies [11, 12, 21–31] that comprised 1,105,595 participants showed that PPI treatment was associated with hip fracture; the pooled odds ratio (OR) was 1.21; 95 % confidence interval (CI) 1.07– 1.38, with substantial heterogeneity that could not be explained by subgroup analyses. A meta-analysis of the 12 cohort studies [32–43] that included 834,442 participants (3,712,891 patient-years of follow up) also showed a statistically significant association between PPI treatment and hip fracture; the pooled relative risk [RR] was 1.30; 95 % CI 1.13–1.49, again, with substantial, unexplained heterogeneity. A previous systematic review and meta-analysis had found similar results for hip
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Stomach (C Howden, Section Editor) fractures, and also found associations between PPI use and vertebral fractures (OR 1.50 (95 % CI=1.32–1.72) and wrist/forearm fractures (OR 1.09 (95 % CI 0.95–1.24) [7].
What is New Since the Last Systematic Review and Metaanalysis? Since May 2013, eight additional observational studies (three cohort studies [44–46] and five case–control studies [47, 48, 49•, 50•, 51]) and one randomized controlled trial (RCT) [52•] have been published. All of the recent observational studies reported a statistically significant association of PPI use with fractures. Given the magnitude and precision of these results, it is unlikely that the point estimate for the OR and RR for the association would change substantially if these results were pooled with the results of the previous 25 observational studies that were included our recent meta-analysis [20••]; an updated meta-analysis would produce slightly tighter 95 % CIs, but would still have substantial heterogeneity. There are, however, additional interesting findings from these studies. Lewis et al. [47] in a cohort study of older Australian women found that PPI use was also associated with increased falls as well as impaired falls-associated metrics (both questionnaire-assessed metrics such as limiting outdoor activity and indoor activity due to fear of falling, dizziness, and numbness of feet and objective clinical measurements such as Timed Up and Go test and Romberg eyes closed tests), while no association of long-term PPI therapy with bone structure was observed. Lewis et al. [47] therefore concluded that the increased fracture risk among PPI users was more likely to be mediated by increased risk of falls rather than impaired bone structure. Three studies assessed the data for manifestations of a dose–response relationship. Of these, Cea Soriano et al. [50•] looked for but observed no duration response (current PPI use ≤1 month compared with PPI use ≥5 years). Two other research groups [49•, 51] implied that evidence of dose response was found, but these claims were not justified. Ding et al. [51] found that the point estimates for the hazard ratio (HR) for fracture increased nominally as the level of adherence to PPI treatment increased, but these differences were not statistically significant (the 95 % CIs for the HR for the three adherence levels overlapped widely). Similarly, the fact that the HR was statistically significant only for the highest adherence level and not for the other two adherence levels, cannot be used as proof of dose response, when this could have resulted from the low power of the analysis for the other two adherence levels. Adams et al. [49•] observed that high adherence, longest duration of use, and most recent use of PPIs were significantly associated with hip fracture, whereas the association was not statistically significant for the complementary categories (lower adherence, shorter duration, less recent use). Again, in each analysis, the 95 % CIs overlapped widely and the postulated dose response was not statistically significant. The association between PPI use and factures among patients on bisphosphonates is particularly interesting. A study of a cohort of bisphosphonate users [46] showed that PPIs were associated with increased risk of hip fractures, and a case–control study found that the magnitude of the association
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between PPIs and hip fractures was higher among bisphosphonate users compared with participants who were not taking bisphosphonates [47]. In both studies, the associations persisted after adjustment for confounders. However, these results were not supported by a recent RCT [52•], which is the only published RCT on the effect of PPIs on bone-related outcomes. Itoh et al. [52•] randomized 180 women with low bone mineral density (BMD) to risedronate plus rabeprazole or risedronate alone for 9 months. Fractures per group were reported, but the events were too few for any meaningful analysis, as the study was not powered for this outcome. The main outcomes of the study were changes in BMD and physical functioning (evaluated with the SF-36v2TM Health Survey) before and after treatment, and all these outcomes were significantly larger in the combined risedronate-PPI group vs. the risedronate-alone group. The RCT could not shed any light on the mechanism by which PPIs improved BMD among risedronate users, but it was speculated to have resulted from increased enteric absorption of risedronate due to decreased gastric acidity [52•].
Is There Residual Confounding? Modest associations between a risk factor and a disease for observational studies are more likely to be due to bias or confounding rather than a causal effect. The 34 observational studies that have assessed the risk of fracture in PPI users are not at high risk of serious bias, but are at very high risk of residual confounding, despite the fact that most of the researchers have adjusted for several known confounders. As we showed in a previous review, if for each study we tabulate the raw (unadjusted) results against the adjusted results, we can see that the magnitude of the PPI-fracture association is consistently lowered after adjustment for confounders [5••]. We have shown that for hip fracture but also other adverse events associated with PPIs such as pneumonia there is clear evidence that sicker patients are prescribed PPIs [5••]. It is therefore possible that the association with PPI and risk of fracture simply relates to frailer patients being prescribed these drugs and these patients are at higher risk of fractures for a number of reasons. Indeed, our concerns for residual confounding in the body of evidence on the association between PPI use and fractures are further strengthened when the primary studies are evaluated in more depth. A large number of comorbid diseases and an equally long list of medications act as confounders to the PPIfracture association, individually as well as through their contribution to the overall fragility or comorbidity burden of the participants. The association of these factors with fracture risk has been well documented; the comorbid diseases include not only skeletal diseases (osteoarthritis, rheumatoid arthritis) but also all cardiovascular diseases and a large number of non-cardiovascular disease categories (including infectious diseases, nutritional, and metabolic diseases, mental disorders, diseases of the nervous system and sense organs, and respiratory diseases), while the medications include corticosteroids, nonsteroidal anti-inflammatory drugs, thiazide diuretics, benzodiazepines, opioids, antipsychotics, and anticonvulsants [53, 54]. Overall, frailty and old age have also been recognized as risk factors for fractures [55, 56].
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Stomach (C Howden, Section Editor) As we hypothesized in a previous review [5••], PPI users are more likely to be older and sicker than individuals who are not taking PPIs. This has been consistently seen in the table of baseline characteristics of every single one of the 34 observational studies that assessed the association between PPIs and fractures: almost every disease and most of the medications that have been evaluated had been significantly more frequent among PPI users compared with non-users. In fact, PPI users have consistently been sicker and frailer even in observational studies that assessed the association between PPIs and other adverse outcomes, such as cardiovascular events among clopidogrel users, pneumonia, or C. difficile infection [5••, 57]. Many other studies from several countries have also confirmed that old age, frailty, and comorbidities are risk factors for being on long-term PPI treatment [40, 58, 59]. It is possible that physicians are more likely to initiate and maintain PPI treatment in frail patients, based on the physician’s subjective global assessment of the patient’s frailty, as it has been well documented that a large proportion of these old and frail PPI users do not have a clear indication for long-term PPI treatment [40, 58, 59]. Regardless of the reasons explaining the association of PPI use with frailty and comorbidities, unless adequate adjustment or matching at least for known confounders is performed, it is possible that the association of PPI use with fractures is simply a manifestation of residual confounding. That is, doctors are more likely to prescribe PPIs for frail older people who are already at high risk for fractures, irrespective of the use of PPIs. All 34 studies have attempted some statistical adjustment for confounders or matching, but even the best adjusted or matched studies have measured most of the confounders as dichotomous variables. Obviously, a model that adjusts for the confounding effect of a disease (such as dementia or osteoarthritis) by simply counting the presence or absence of this disease is an oversimplification. Ideally, the severity of each of the confounding factors/diseases should be measured as continuous or at least as ordinal outcomes, but such granularity of information cannot possibly be obtained in studies conducted on large administrative or research databases. One might expect that a more granular hypothetical adjustment model would have reduced the association even further. Therefore, it is very likely that most, if not all, of the modest association that remained after adjustment, is due to residual confounding. This is the most likely explanation of the discordant results of two nested case–control studies that each extracted data from the UK General Practice Research Database [12, 22]. The study that used a standard logistic regression model to adjust for known confounders showed a positive statistically significant association between PPI use and fractures [12], while the study that used propensity matching (which can achieve the best correction for both known and unknown confounders) found no statistically significant association [22].
What is the Quality of Evidence? Taking into account the above appraisal of the evidence, according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach [60], the quality of evidence for the association of PPI use with fractures is classified as very low. Evidence from observational studies starts as
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low quality but can be upgraded or downgraded according to specific criteria. In the case of the association between PPIs and fractures, none of the upgrading criteria can be applied (large effect; dose response; all possible confounding and biases would have reduced the demonstrated effect), while at least two downgrading criteria are fulfilled (study limitations due to inadequate adjustment for confounders; inconsistency as indicated by the substantial unexplained heterogeneity). Of note, the “very low” quality of evidence refers to the trustworthiness of the estimate of the association of PPI use with fractures. The quality (trustworthiness) of evidence for causation of fractures by PPIs is obviously even lower, because observational studies cannot prove causation.
Is There Biological Plausibility? The possibility that the association between PPI use and fractures is causal is further diminished as no plausible mechanism has been demonstrated through which PPIs can increase fracture risk. It has been postulated that as PPIs reduce gastric acidity the absorption of ingested calcium is reduced and this in turn leads to osteoporosis, which increases the risk of fractures. However, neither impaired calcium absorption nor osteoporosis has been confirmed in patients taking PPIs. Earlier studies had shown that calcium absorption is reduced in patients with pernicious anemia [61] and post-gastrectomy [62]. An RCT in postmenopausal women found that a 7-day course of a PPI can significantly reduce the absorption of calcium carbonate supplements when these are taken without meals [63]. However, two more recent RCTs that assessed the absorption of ingested calcium under usual physiologic conditions (with meals) and used better measurement techniques did not find any reduction of calcium absorption when PPIs were administered for 3 days in healthy male and female volunteers [64] and for 30 days in postmenopausal women [65]. Finally, a matched controlled (not randomized) trial in male individuals with heartburn found no measurable effect of a 12-week course of PPIs on calcium and bone metabolism (total serum calcium, ionized calcium, phosphorus, albumin, parathormone, 25-OH-vitamin D, C-terminal cross-linked telopeptides of type I collagen, and osteocalcin) [66]. There is also no evidence of an association between PPI use and osteoporosis. Of the nine observational studies that assessed this association, two case– control studies [67, 68] and four cohort studies (reported in three publications) [21, 32, 36] did not show significant results. One cohort study found that PPI users had lower BMD than non-users at baseline, but the authors commented that this was probably the result of residual confounding from unmeasured comorbidity, as PPI use over 10 years was not associated with further BMD loss [69••]. One case–control study found that trabecular BMD, one of five assessed osteoporosis parameters, was significantly lower among PPI users compared with non-users. However, PPI users did not differ significantly from non-users in the other four osteoporosis parameters (overall BMD, cortical BMD, cortical cross-sectional area, trabecular cross-sectional area) [70]. Observational-type data derived from a subgroup analysis of an RCT [71] showed significant posttreatment BMD reductions for most measurements, with small differences
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Stomach (C Howden, Section Editor) among the three PPI groups. Finally, the only true RCT quality data on the effect of PPI treatment on BMD come from the study by Itoh et al. [52•] that was mentioned earlier. Women with low BMD were randomized to risedronate plus rabeprazole or risedronate alone for 9 months; BMD was significantly higher in the group that received the PPI along with risedronate compared with the group that was on risedronate alone.
Conclusions There is a large body of observational evidence involving nearly 2 million participants that demonstrates there is an association between PPI therapy and risk of fracture. An epidemiologist would always emphasize that, when studies show an association between a drug and an outcome that is either beneficial or harmful, this does not imply causation. Rigorous evaluation of the data on fracture and PPI therapy provides a good example of this as the likely reason for this association is confounding factors and it is probable that PPI therapy is not a risk factor for fracture. Indeed, there is emerging evidence that residual confounding is the explanation for some other “harmful” effects of PPI therapy [72]. There is therefore little evidence that clinicians should change their behavior regarding PPI prescribing based on concerns regarding fracture risk. This does not mean that PPIs are safe. There are other possible harms that have not been evaluated in this review and clinicians should always be aware that there could be unknown risks with any medication they prescribe. Clinicians should only prescribe PPI therapy where it is clearly indicated and at the lowest dose that controls patients’ symptoms.
Compliance with Ethics Guidelines Conflict of Interest Grigorios I. Leontiadis declares no conflict of interest. Paul Moayyedi has received speaker’s fees from AstraZeneca and his chair is partly funded by an unrestricted donation from AstraZenca to McMaster University. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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