Do Proton Pump Inhibitors Increases the Risk of Osteoporosis - Research Paper Example

Micro-Scale Meta-Analysis Suggests that Chronic Treatment with Proton Pump Inhibitors May Increase Risk of Fracture Resulting from Osteoporosis Abstract Contemporary studies of chronic usage of Proton Pump Inhibiting drugs (PPIs) suggest a link to calcium metabolism and the occurrence of osteoporosis related fractures. Though some research groups suggest that PPI does not directly contribute to bone degradation, there is an undeniable statistical link between chronic PPI use and fracture caused by osteoporosis, begging further inquiry on the mechanism of this correlation. This report further explores the relationship of treatment with PPIs for extended periods greater than one year in a wide subset of individuals taken from four clinical trials without regard to the duration of exposure or the dosage of the PPI drug. Based on this micro-scale meta-analysis, there is a clear indication those that have taken PPI drugs for longer than two years consecutively are only a marginal higher risk for fracture resulting from osteoporosis. This supports the theory that PPI drugs do in fact contribute to the calcium metabolic activities that result in loss of bone mass, particularly in individuals exhibiting preexisting risk factors for osteoporosis; however, the contribution of PPI drugs alone is so marginal that it is likely that an individual patient will not develop osteoporosis without other contributing factors. Introduction Proton Pump Inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. Because these drugs are often prescribed for chronic conditions, some studies argue that the occurrence of osteoporosis is increased as the drugs affect bone mineral metabolism. The most serious clinical consequence of osteoporosis is hip fracture, which increases in incidence exponentially with age and incurs high morbidity, mortality and healthcare expenditure. Other common fractures occur at the spine, forearm and shoulder.16 There are several mechanisms by which PPIs may achieve their experimentally observed correlation with osteoporosis related fracture. Proton pump inhibitors (PPIs) have become one of the most commonly prescribed classes of medications in the primary care setting.14 Their ability to enable practitioners to simply and effectively treat a variety of acid-peptic diseases with minimal side-effects has placed PPIs among the major advancements in dealing with gastric conditions and disorders. Omeprazole (Prilosec) was introduced to the United Stated market in the year 1989, and its rapid success and longevity have led to several other PPI drug becoming readily available by prescription in the United States. The intravenous form of pantoprazole (Protonix I.V.) is now available, and the U.S. Food and Drug Administration (FDA) approved one of the the newest PPI, esomeprazole (Nexium), in 2001.14 Osteoporosis is a common condition throughout the developed world, affecting up to 16% of women and 7% of men aged 50 years and older. The condition is of primary concern because of the increased incidence of fractures caused by bone degredation.1 The normal amount and variety of proteins and minerals in the bone is altered in cases of osteoporosis, and the standard the bone mineral density (BMD) is reduced, disrupting the bone microarchitecture itself and contributing to its structural failure. The World Health Organization (WHO) defines the condition of osteoporosis in women as a bone mineral density 2.5 standard deviations below peak bone mass (represented by the twenty-year old healthy female average bone mass) as measured by DXA. Osteoporosis is a gradual condition that may develop to different extents in different areas of the body and often affect bones that move or are put under constant stress more than stationary and flat bones.15 ‘Established osteoporosis’ refers to cases of osteoporosis in which fragility fractures exist.15 A fragility fracture is a traumatological term for a bone fracture that occurs as a result of a fall from standing height or less. The three fracture sites said to be typical of fragility fractures are vertebral fractures, fractures of the neck of the femur and Colles fracture of the wrist. This definition arises because a healthy indivudal human being ought to be able to fall from standing height without breaking any bones.16 In the case of osteoporosis, fragility fractures become increasingly common and require smaller impact events to trigger because of the change in bone structure. There is much debate over how and even if PPI use may be linked to osteoporosis related fractures; however, numerous experimental studies suggest that there is a link, though it may not be a direct one. It is theorized that in long-term usage of PPIs the cause of the increased risk of fracture is that the reduction of stomach acid reduces the amount of calcium dissolved in the stomach. Another theory suggest that PPIs may actually interfere with the breakdown and rebuilding of bone by interfering with the acid production of osteoclasts.7 Other research groups argue that experimental evidence shows that PPI drug use, even over elongated periods of time, does not contribute directly to osteoporosis or accelerated bone mineral density (BMD).3 Still other group offer proof of PPIs role in interfering with calcium absorption using radio-labeled calcium.9 Statistical evidence from multiple contemporary studies, including the sampling contained in this report, suggest that there is a statistical link between chronic PPI usage and fracture; however, the mechanism of that connection is beyond the scope of this paper and will be discussed only as a review of research that pertains to the general linkage between PPI usage and the condition. Overview of Mechanism and Action As suggested by the name Proton Pump Inhibitors, PPI drugs have been shown to function by long term inhibition of gastric acid secretion by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system of the parietal cell.14 Though the blockage on the individual pump is irreversible, the overall after on the gastric system remains reversible when the drug is no longer administered. The terminal stage of gastric acid secretion is characterized by the action of the proton pump, which is directly responsible for the secretion of hydrogen cations into the gastric lumen. Because the process of the proton pump is critical to gastric acid secretion, it provides an ideal target for reducing these secretions. 14 By targeting the terminal step in acid production irreversibly, PPI drugs are capable of dramatically reducing gastric acid secretion by up to 99% far more quickly and more effectively than H2 antagonist drugs which have long been used to treat similar conditions. The lack of acid in the stomach causes a dramatic increase in pH, which is conducive to healing of stomach injuries or ulcers. It also results in a state of hypochlorydria, where lack of sufficient hydrochloric acid (HCl) results in poorer breakdown of proteins, reducing the availability of vitamins and nutrients for absorption in the intestines. When stomach acid is removed either by neutralizing it or by blocking it's production, the body experiences a gradual health decline due to malabsorption of nutrients. Insufficient absorption of vitamin B12 and Calcium have particularly been noted, and other nutrients that are malabsorbed due to low stomach acid levels include: iron, magnesium, selenium, zinc, folic acid, vitamins A, thiamin (B1), riboflavin (B6), riboflavin (B6), and E.24 Some researchers implicate this in the link between osteoporosis and long-term PPI drug use.13 The PPI drug itself is distributed in an inactive form that is a neutrally charged, lipophillic molecule that easily crosses the membrane of parietal cells in the stomach to reach the gastric pump mechanism site. The drug enters the intracellular compartments, such as the parietal cell canaliculus, that have acidic environments, where it is converted to its active form where it will covalently bind with the gastric pump mechanism, irreversibly deactivating it.13 Most PPI drugs are from a class called of benzimidazole derivatives; however, some contemporary research shows major advancement in use of certain classes of imidazopyridine derivatives that may ultimately provide a more effective means of treatment with less significant risks.12 Though a variety of PPI drugs are now commercially available, they all share this same basic method of action. Documented Adverse Affects of PPI Drugs Because debate still remains on Proton Pump Inhibitors’ role in calcium metabolism, though some correlation between fractures and PPI use clearly exists, it becomes increasingly important to look at the numerous other documented effects that PPI have been show to exhibit for clues. Exploring the linkage between the two may result in a clearer understanding of not only PPI drugs and there action, but also the role of gastric secretions in metabolism, particularly the metabolism of bone. As researchers, we must interpret clinical data on PPIs to provide better methods of providing clinical treatment.23 PPIs have become a first-choice management for laryngopharyngeal reflux, which generally involves long-term treatment with the drug. Though the long-term effects of PPIs are poorly documented, several analyses demonstrate epidemiological links between PPI and conditions such as altered mineral and vitamin absorption, orthopedic injury, acute coronary syndromes (ACS), and infectious risks.8 This class of drugs works by raising the gastrointestinal pH, which some researchers speculate would leave the gastrointestinal tract much more prone to bacterial pathogens and spores.8 Observation has shown that Clostridium difficile-associated diarrhea (CDAD), which is prominent when antimicrobial agents are used, is slightly more common in chronic PPI users that are hospitalized.10 Similarly, increased risk of community acquired pneumonia (CAP) is seen in chronic PPI users. The proposed mechanism of occurrence for this phenomenon is the same as that seen for CDAD above, only it is now the upper aerodigestive tract that is being colonized by harmful pathogens because of less gastric acid suppression.8 Despite these known adverse effects there is little evidence to suggest that practitioners should be concerned with the long-term administration of PPI drugs to their patients, as most side effect are not severe and the drug classes’ usefulness. PPI drugs, like many contemporary drugs are often prescribed by physicians for conditions outside of those for which they are approved and recommended, including for treatment of children and pregnant women, where no long-term studies of their effects have been made.21 Many physicians may also not be informed of the latest FDA recommendation concerning PPI drugs.22 The formulation may be administered in a manner or dosage outside of its intent, which can result in additional clinical complications.18 With PPIs, several modern researchers have expressed that overuse and abuse may be major problems that are developing with the drug, and ones that should merit greater concern from practitioners and clinicians prescribing these drugs. A 2009 report in Gastroenterology suggests that PPIs may cause dependency by increasing gastric symptoms if they are discontinued.19 Multiple studies have not only isolated and confirmed overuse of these agents in inpatient settings, but also numerous cases of outpatient abuse and overuse as well. In general, approximately 50% to 60% of prescriptions of acid-suppressive medications used in hospitalized patients are found to be without appropriate indications and are often prescribed without proper analysis of the long-term risks associated with these drugs. Often, behavioral intervention shows equal or better results that the use of PPI for numerous gastric conditions.25 It is possible that PPI overuse or use outside of the conditions it was intended to treat also plays a role in adverse events that may be linked, including occurrence of osteoporosis related fracture. Perspectives on PPI Correlation with Osteoporosis by Various Research Groups Researchers remain divided as to whether PPI drug use is actually causative in the development of osteoporosis related fracture. One researcher reports, based on a study of 1,005,126 people that upon following up for several years after their PPI use, 1,500 hip fractures, 4881 forearm or wrist fractures, 2,315 clinical spine fractures, and 21,247 total fractures occurred. Though the incidence of fractures was slightly higher than expected, the measured Bone Mass Density (BMD) measurements did not vary between PPI users and nonusers at the baseline of the study. PPI drug use was associated with only a marginal effect on 3-year BMD change at the hip (P=.05) but not at other sites. As such, PPI could not be implicated in a dramatic change in BMD over the trial period, suggesting that use of PPI drugs was not influential in causing osteoporosis.6 A second researcher makes the statement that PPI use was not associated with having osteoporosis at either the hip (OR, 0.84; 95% CI, 0.55–1.34) or the lumbar spine (OR, 0.79; 95% CI, 0.59 –1.06) for PPI use of less than 1500 doses over the previous 5 years. This research group goes on to show that no significant decrease was observed in BMD at either site attributable to PPI use.3 As with the study above, this study seems to suggest that the obvious effect on calcium metabolism that was thought to perhaps be causative in osteoporosis may not be as significant in causing the condition as originally thought. The primary logic behind linking PPI use to osteoporosis related fractures, and thus osteoporosis itself seems to be the experimental research data showing that long-term PPI users exhibit a higher instance of osteoporosis related fractures across numerous pieces of published researcher. In order to make an informed statement about the linkage between PPI drug use and osteoporosis, consideration of the group of patients that commonly use PPI drugs must be made. Unfortunately, data on the demographic of PPI users is not readily available, though many researchers have thought to adjust their data on the basis of a number of qualifying factors including but not limited to age, race, and p re-existent medical conditions. Selection of Studies Selection of studies was done by manual search of the available literature using the PubMed database and searching for the terms “proton” and “osteoporosis” resulting in 15 preliminary articles. These 15 were narrowed down to 4 articles containing relevant clinical studies meeting the following criteria. Not that this micro-scale meta-analysis provides a generalization based on the results of these studies with not adjustment for bias. Studies were eligible for inclusion in the meta-analysis if they met all of the following criteria: (i) PPI was given to patients greater than one year; (ii) the study consisted of a meaningfully large sampling of subjects; (iii) instance of fracture as a symptom of osteoporosis is exhibited; (iv) H2-receptor antagonists were not administered to patients greater than one year at any point. Determination of PPI exposure is based on total cumulative exposure lengths recorded in each individual study, as influence on calcium metabolism is likely to only be affected over chronic use.3 This study does not seek to differentiate between different effects on calcium metabolism associated with varying length of chronic use, but instead seeks to show that there is a trend of effect on calcium metabolism resulting in increased chance of fracture at any point over two years of chronic PPI use. This study is not intended to provide useful data as to the mechanism of linkage between osteoporosis and long-term PPI use, thought discussion of this mechanism in pertinent research will be included in analyzing results in order to make results more meaningful to application in hospitals, primary care, and other clinical settings. Recommendations are made based on the research studies used as a basis for this micro-scale meta-analysis and do not reflect adjustment for any bias. Broad sampling and research compilation would be necessary in order to assure that these finding are correct across all areas of bias. The studies used in this work are the ones that contained the most relevant and extractible data to provide a useful and meaningful correlation of the link between osteoporosis and long-term PPI use as determined by the author. Treatment of Preliminary Study Data No attempt was made to account for publication bias in this study or to correct any specific or general geographic, national, or private bias expressed in the research groups that complete3d the investigations used in this report. As such this study is intended to represent a fixed effect model of the increased risk for osteoporosis relative to the publications presented in Table 1.2 Additionally, data in this report has not been adjusted for age, gender, ethnicity, PPI dosage, income, region of residence, diagnoses (short- or long-term diabetes, epilepsy, ischemic heart disease, myocardial infarction, hypertension, arthritis, solid organ transplant, chronic obstructive pulmonary disease, substance use, depression, schizophrenia, dementia), home care use and/or multiple medications. Data in this report was taken as a sum of the all lengths of PPI administration reported in included studies that exceeded two years. Original data from reports used is seen in Table 1. Case and control data represents the sum of studies of different subjects at varying lengths of administration from two to eight years. This data has been combined in order to generalize results, providing analysis indicative only of PPI’s linkage in osteoporosis. It is important to note that this analysis may not provide meaningful data pertaining to the length of PPI dosage that results in increased chance of osteoporosis. The data used in this report has been compiled in order to generate useful quantitative and qualitative data to assist in the developing analysis of where PPI drug use over extended periods can be implicated in osteoporosis related fracture. Table 1. Four study arms on which the meta-analysis was carried out. Length of PPI administration and study are listed along with the case (incidence of osteoporosis as determined by fracture occurrence) and control (no fracture incidence). Author Case Control Span of PPI Administration Targownik[3] 38 095 114 030 2 to 7 years Corley[4] 33 752 130 471 ≥2 years Yang[5] 732 4 478 1 to 4 years Gray[6] 584 3 396 ≥2 years Quantitative Data Synthesis All statistical analyses were conducted with the Comprehensive Meta Analysis Software Version 2.2.050 released November 10, 2009 and available through Meta-Anlysis.com. The random effect was used to calculate summary statistics and the high resolution visual output feature was used to create Figure 1. Results Table 2 shows the Event Rate, the Logit Event Rate, and the Std Error for each study, respectively. The corresponding meta-analysis is shown in Figure 1. Table 2.  Results Author Event Rate Logit Event Rate Std Error Targownik[3] 0.250419063305091 -1.09637853174429 0.006 Corley[4] 0.250419063305091 -1.09637853174429 0.006 Yang[5] 0.250419063305091 -1.09637853174429 0.040 Gray[6] 0.250419063305091 -1.09637853174429 0.045 Figure 1. Meta-Analysis Side B corresponds to an increased risk of fracture over side A. Discussion Proton Pump Inhibitors are useful drugs commonly prescribed in many contemporary clinical practices for long-term use. Though some risks exist with any drug that drastically modifies gastric secretions, and thus dramatically effects metabolism, this study shows that risks associated with long-term use are minimal. The extremely low P values and moderate shift in event rate suggest that some correlation exists between PPI drug long-time users and those that develop osteoporosis related factures. Because this correlation is minimal, it is likely that other factors, such as pre-existing conditions and other risk factors play a necessary role in the onset and development of osteoporosis, though long-term PPI drug use may contribute for those already at risk by reducing calcium absorption during use. The conditions of the study and preconceptions of the researcher may provide room for misinterpretation of data, as the adjustment the researcher groups make based on the experimental PPI user group may vary greatly and are somewhat difficult to quantify objectively. Conclusion More than 113 million prescriptions are written every year in the United States alone for proton pump inhibitors Proton Pump Inhibitors, and as such it is the responsibility of the medical community to determine if a link exists between long-term use of PPI drugs and osteoporosis.20 Based on the micro-scale meta-analysis of four prominent studies expressing varying viewpoints on this linkage, it appears that the long-term use of PPI drugs provide only a small, if any, contribution towards development of osteoporosis and osteoporosis related fractures. This likely occurs through the mechanism of interference with calcium uptake in the gastrointestinal tract, as results are similar to those of minor long-term calcium deficiency, though additional study would be required to pinpoint the exact mechanism of linkage between PPI drugs and osteoporosis development. In practice, physicians are encouraged to note that long-term administration of PPI drugs, though PPI drugs alone will not cause osteoporosis, may increase the risk to patients already at risk for osteoporosis or osteoporosis related fractures. REFERENCES 1. Tenenhouse A, Joseph L, Kreiger N, et al. Estimation of the prevalence of low bone density in Canadian women and men using a population-specific DXA reference standard: the Canadian Multicentre Osteoporosis Study (CaMos). Osteoporos Int 2000;11:897-904. 2. Supercourse: Epidemoligy, the Internet and Global Health. WHO Collaborating Center. University of Pittsburgh. Accessed 6 August, 2009. 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