Globally, the use of proton pump inhibitors is extremely widespread, and many patients are treated for prolonged periods . In accordance with being one of the most widely prescribed drugs worldwide, there is a growing concern that this treatment is overprescribed and that this may have individual and societal consequences . One of the strongest concerns, as discussed below, is the potential for skeletal harm in the form of osteoporosis and fractures.
The increasing use of PPIs in the elderly takes place against a background of osteoporotic fractures being an increasing economic burden to society [3,4] in addition to the harm to the individual patient in terms of morbidity and mortality. Though PPIs have been linked to development of osteoporosis and to osteoporotic fractures in a number of studies [5,6], the magnitude of effect has in the past been viewed as fairly modest and possibly inflated by or even explained by confounding. This is illustrated by earlier studies, which concluded that hip fractures were only associated with PPI use when at least one other risk factor was present  and by a large case-control study  showing only a transient effect that disappeared on longer term use. Rodent data suggested that a direct effect of PPIs on bone was reduction of bone resorption, resulting in prevention of bone loss, which could be one potential mechanism contributing to attenuation of fracture risk over time . The multiple mechanisms by which PPIs could influence skeletal health are reviewed in detail below.
Given the demographic of PPI users, there is likely to be overrepresentation of patients with preexisting risk factors for osteoporosis and fractures because of comorbid conditions, comedications, and lifestyle factors . However, as several large studies [11▪▪,12,13] linked PPI use to fractures, the FDA issued a warning in 2010 about potential fracture risk (http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm). There have been concerns that this warning may have been ill judged as separate studies conducted on the same UK database had reached conflicting results and as more recent Dutch data, as mentioned above, indicated that the risk of fractures was, if anything, attenuated upon long-term PPI use as opposed to short-term use . But in this respect, too, studies had yielded inconsistent results as a Canadian case-control study  in 2008 found the opposite, that is, that PPI use was only associated with an increased risk of fractures, when continuous use exceeded 5 years. A subsequent large meta-analysis in 2011 confirmed an overall association between PPI use and fractures, an association that was not present for H2 antagonists though used at the same indication, but could not exclude the possibility of residual confounding .
Taken together, these studies left clinicians with the message that while users of PPIs are clearly at an increased risk of osteoporotic fractures, and hence a group that should perhaps be monitored for development of osteoporosis, there was doubt as to whether cessation of PPI treatment would in fact reduce the risk of fractures. This would of course be the case if PPIs caused osteoporosis but not if PPI use just served as an indicator of a fracture prone combination of health and lifestyle factors.
As discussed below, several mechanisms of action were proposed and studied, including both direct and indirect effects on bone and on calcium absorption, though confounders such as vitamin B12 deficiency, Helicobacter infections, smoking, and lifestyle factors may also play a major role [17,18].
The purpose of this review is to update readers on the most recent developments in regard to the association between PPIs and osteoporosis and discuss how the field has advanced. This work focuses on papers published in the past 12 to 18 months, which we will discuss in the context of prior meta-analyses and guidance. Particularly noteworthy studies are flagged in the list of references. We shall address Bone mass density (BMD) and fracture studies separately.
PPI USE AND BMD
Over the course of the last 18 months there have been only a couple of new studies specifically aiming at unmasking possible deleterious effects on BMD by PPIs.
Decreases in BMD among PPI users, taken in combination with NSAIDs were addressed in a 12-month prospective open-label comparative study, where 216 PPI users were divided into five groups (four different PPI groups and one control group). Treatment was accompanied by overall reductions in femoral neck and hip BMD though this was significantly attributable only to esomeprazole , not to the other PPIs studied.
By contrast, a longitudinal observational cohort study of American women across the menopause transition, which included annual evaluation and repeated BMD assessments found no difference in the rate of bone loss when incident PPI users (N = 207) were compared with incident users of H2RA(N = 185) or with women who used neither drug (N = 1676). This study [20▪▪] is particularly reassuring in terms of BMD effects because the menopausal transition is a time of accelerated bone loss where the BMD signal would be expected to be particularly strong and the authors verified the robustness of their study design by demonstrating the expected increase in BMD on hormone therapy. However, as the mechanism by which PPIs could influence fracture risk remains unknown, it is possible that effects could differ among the elderly, where bone loss rates are lower but calcium intake and calcium absorption more likely to be compromised as discussed below. Taken together, a direct association between reductions in BMD and PPI use remains somewhat doubtful even after inclusion of recent data.
PROTON PUMP INHIBITORS USE AND INCREASED RISK OF FRACTURES
Please refer to Table 1[21▪▪–23▪▪,24▪,25▪,26▪▪,27] for structured summaries of the studies. A case-control study [21▪▪] of 124 799 patients (aged 4–29) using PPIs showed that there was a risk of fracture among young adults (18–29 years old) odds ratio (OR) 1.39 (95% CI 1.26–1.53) using PPIs, but not in children (<18 years) OR 1.13 (95% CI 0.92–1.39).
Over a 10-year period 6774 matched control groups consisting of men older than 45 years were followed, the end point being hip fractures related to PPIs (omeprazole and pantoprazole). Omeprazole was associated with an increased risk of hip fracture OR 1.13 (95% CI 1.01–1.27), whereas this was short of significance – though of similar effect size – in the case of pantoprazole [OR 1.10 (95% CI 0.97–1.24)] in a comparison of ever-users vs never-users. Potential causality was supported by the finding of the risk being particularly high in recent users (first tertile of recency of use) [22▪▪].
A prospective cohort study [23▪▪] in 4432 elderly Australian women followed for 10 years showed that women who initiated PPIs were at increased risk of subsequent fracture SHR 1.29 (95%CI 1.08–1.55).
A smaller observational study [24▪] of 1604 PPI users matched with a control group of 23 672 also revealed an increased risk of fractures, as well as an increased risk related to adherence and dependent on doses.
A Swedish prospective study included 6414 postmenopausal women (The WHILA project) in 1995–2000. During the follow-up period the risk of fracture was doubled in women using PPIs, [OR 2.53 (95% CI 1.28–4.99)]. This study revealed an unexpected statistical interaction between hormone therapy and PPI use on fracture outcomes. Hence, PPI use was strongly associated with risk for fracture in hormone therapy users [OR 3.31 (95% CI 1.96–5.80)] but not in women who did not use [hormone therapy1.13 (95% CI 0.57–2.24)] [25▪]. The authors concluded that PPI use negated the bone protective effect of hormone therapy but did not provide any robust explanation why there was no effect of PPIs on fracture risk in nonhormone therapy users, given a similar prevalence of exposure. Though not addressed in the study, it is possible that hormone therapy users were at higher base risk of fractures or that women who took both PPI and hormone therapy were frailer or more likely to be multimedicated.
A modestly increased risk for hip fractures [OR 1.09 (95% CI 1.01–1.17)] among patients on PPIs was found in a UK primary practice nested case-control study consisting of 10 958 patients with incident hip fractures and 20 000 nonfracture control patients. The study [26▪▪] provided additional evidence of dose dependency (medium or high dose) but no association with duration of use.
In accordance with the criticisms previously voiced about the FDA warnings of fracture risk with PPI , a recent review intended for gastroenterologists concluded that the association between PPI and risk of fracture was likely modest, and possibly explained by confounding factors. It was felt that there was insufficient evidence to change PPI prescribing habits, nor did they find it relevant to perform BMD measurements, or support the treatment of PPIs with calcium and/or vitamin D . As we hinted at in the introduction, though well intentioned this interpretation may make for a missed opportunity to identify and treat osteoporosis in this patient group even if their increased likelihood of fractures is not caused directly by exposure to PPIs but by other equally modifiable risk factors.
Another practical issue is whether PPI coadministration may blunt the effect of oral bisphosphonates as these drugs are commonly prescribed to the same patients and as bisphosphonates may elicit upper GI adverse events that could trigger PPI use, either over the counter or as a prescription. The question of interaction remains unclear and may indeed differ from bisphosphonate to bisphosphonate [29,30].
A recent prescription database study for the SIDIAP database for Catalonia, Spain, determined that PPI use was a predictor of major osteoporotic fracture SHR 1.41 (95% CI 1.22–1.65) among patients treated with oral bisphosphonates. Also noteworthy was the fact that no less than 60% of the patients taking bisphosphonates also used PPIs .
Taken together, these data suggest that physicians should probably avoid combining PPIs and oral bisphosphonates, though should the need arise then there are better data to advocate the use of risedronate than alendronate in these circumstances. The optimum approach may be to change to a parenteral antiresorptive drug such as zoledronic acid or denosumab in patients who develop upper GI issues with oral bisphosphonates.
THE SEARCH FOR THE BIOLOGICAL MECHANISM
Though a link between PPIs and fractures has been found many times over, there is a lack of conclusive evidence for causality. Such evidence would need to include not only a dose-response relationship – found in some studies and refuted in others – but also a coherent and persuasive mechanism of action. Indeed, for any physician posed with a possible drug side-effect, the determination of the mode of action is important because it confirms causality and may offer pathways for prevention.
Researchers have previously hypothesized that the effect might be because of reduced intestinal absorption of either calcium, magnesium – as hypomagnesaemia is a known side-effect of PPI use in some patients – or both. However, studies have reached conflicting results regarding fractional calcium absorption during PPI use and there is a possibility that the effect may be more pronounced with increasing age [32–34].
Interestingly, a recent 8-week intention-to-treat study  on bone metabolism consisting of 13 patients on an 8-week PPI treatment for gastric ulcers actually showed signs of increased bone resorption as urine levels of deoxypyridinoline, a first generation marker of bone resorption, increased. This was accompanied by a slight decrease in PTH, which was short of statistical significance and an increase in serum calcium, suggesting that effects were not secondary to compromised calcium absorption but that PPIs act directly or indirectly to stimulate bone resorption.
The hypothesis that pantoprazole might have a direct effect on bone metabolism was tested in vitro by Prause et al. who carried out two 7-day in-vitro studies on osteoclasts and osteoblasts, respectively. Cell viability was evaluated when directly stimulated with pantoprazole. Conversely to what might have been expected, this revealed that direct stimulation resulted in an increased mitochondrial activity, gene expression, and protein synthesis in the osteoblasts. Direct stimulation of osteoclasts resulted in an inhibition in degredation and absorption of bone matrix. On the basis of these two studies [36,37], they concluded that the pathophysiological mechanism probably is not on the cellular level.
Hinson et al. found that mild hyperparathyroidism was a feature of chronic PPI use PTH 65.5 vs 30.3 pg/ml (P = 0.001). This was regardless of concurrent use of oral bisphosphonates.
As studies have failed to reveal conclusive evidence that PPI use links to reduced BMD, despite circumstantial evidence that bone resorption may increase on initiation of PPIs, it is of course relevant to consider other mechanisms by which patients could be at increased risk of fractures. Interestingly, an increased risk of falling has also been related to PPI use . In this study, a significantly lower level of vitamin B12 was found in PPI users, when compared with nonusers. This led the authors to discuss if the increased risk of falling could be mediated by B12 deficiency causing gait disturbances, muscle weakness, visual disturbances, and cognitive decline. They do emphasize that, as their study was observational, a causation could not be determined.
The increased risk of falling was confirmed in an Austrian cross-sectional study  consisting of 700 women, where use of PPIs showed an increased risk of fall OR 1.92 (95% CI = 1.05–3.50) and risk of fractures as well OR 2.15 (95% CI 1.10–4.21).
PRESCRIBING PPIS APPROPRIATELY
Initiating and furthering drug treatment should always be based on the correct indication.
In a study of 212 cases of acid suppression therapy, it was found that in 75.5% of the patients acid suppressants where given as prophylaxis. Of these, 58.1% where given without an appropriate indication and 75% of the acid suppressants were PPIs .
When PPIs are given on weak clinical grounds or even on the wrong indication, it is understandable why they have become one of the most prescribed drugs globally, and it underscores the importance of careful prescribing.
In the setting of rheumatology, PPIs are often used as cotherapy in combination with NSAIDs as ulcer prophylaxis, and for example, as long-term treatment in systemic sclerosis patients with oesophageal involvement. It is important that the treating physician and the patient are aware of these potential drawbacks to PPIs, whether prescribed or purchased as over the counter medications.
There is a clear association between PPI use and fracture. The risk is modest and seems to be dependent on dose ; the risk may not be lower with short-term use [6,14] though the studies have not uniformly agreed on this [22▪▪]. The underlying mechanism remains unclear and there is no evidence that supplements with calcium and vitamin D decrease the risk posed by PPI use.
PPIs should only be used in so far as the indication is clear. This appears to be particularly important in postmenopausal women.
In the patients being treated with PPI, the dose and duration should be reevaluated by the treating physician, to avoid unnecessary continuation and inappropriately high doses. Some patients may be managed on older antacids such as H2RA, which have been found to be quite safe skeletally. Additional work is needed to further explore the nature of the changes in bone metabolism that appear to occur in patients on PPIs and whether these changes may be short lived  or whether they persist. Directions for future research would include long-term assessment of state-of-the-art bone turnover markers before, during, and after PPI initiation, ideally coupled with calcium kinetics, dynamic bone biopsy and advanced bone imaging with HR-pQCT.
The association between use of PPIs and the risk of osteoporosis and fractures is if anything further strengthened by recent studies. Though the overall increased risk is, for the most part, modest we should bear in mind that use of PPIs should perhaps flag out the patient for additional attention to risk factors for osteoporosis, which may be modifiable, and strengthen the case for referring patients to DXA. More importantly, because a causal link cannot be ruled out, overuse of PPIs should be avoided partly because of the apparent increase in fracture risk but also because of the risk of other adverse events.
Financial support and sponsorship
This work did not receive financial support.
Conflicts of interest
B.N.A.: none. P.B.J. reports speaker's fees from Eli Lilly and prior institutional research contracts with Roche, Pfizer and Merck. B.A. reports current institutional research grants and contracts with Novartis and UCB, past institutional research contracts with Amgen and NPS Pharmaceuticals and past payment for membership of advisory boards from Nycomed, Merck and Amgen.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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Large and elegant clinical cohort study with longitudinal BMD information, showing positive influence of hormone therapy but no apparent adverse BMD outcome in incident PPI users.
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Large case-control study originating from Kaiser California, addressing type of PPI, duration, dose, and level of recent use.
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Important cohort study linking Australian Longitudinal Study on Women's Health to healthcare dataset on national prescriptions and hospital contacts from four Australian states.
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Important data from Pennsylvania's Pharmaceutical Assistance Contract for the Elderly program demonstrating link between adherence to PPIs and risk of fractures.
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Prospective study in postmenopausal women showing surprising interaction between hormone therapy and PPI use in terms of fracture outcomes.
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Important observational study of risk of hip fractures with PPI use, nested case-control study using a large primary care research database in the United Kingdom.
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