Do Proton Pump Inhibitors Increase the Risk for Hip Fractures - Research Proposal Example

Do Proton Pump Inhibitors Increase the risk for Hip Fractures particularly in the elderly population? Aims and objectives The aim of this study is to identify the relation between proton pump inhibitors and hip fracture and assess the amount of risk involved in exposure to these drugs. The study also aims to study the mechanism of hip fracture following proton pump inhibitors and what duration of exposure leads to increased risk of hip fracture. Introduction Hip fracture is one of the low-trauma complications of senile osteoporosis. It has devastating consequences. Senile osteoporosis is mainly seen in those above 65 years of age. It occurs due to low calcium intake, calcium malabsorption and many other causes. Currently there is lot of research pointing to the development of osteoporosis following long term proton pump inhibitors (PPI). PPI are modern drugs for the treatment of certain acid-related diseases like gastroesophageal reflux and infact, they have revolutionized acid-related therapy. There are millions of people on these drugs either on a continuous regime or a long-term regime. The devastating nature of hip fracture can be ascertained by the fact that the mortality rate is 20% (Cumming et al, 1997, qtd. in Yang et al, 2006) and atleast 1 in 5 patients land up in nursing home care (Chrischilles et al, 1991; qtd. in Yang et al, 2006). Materials and methods Pertinent literature regarding the role of proton pump inhibitors in hip fractures was retrieved from various databases, Blackwell-Synergy, CINAHL, CMJA, Cochrane, EMBASE, Health Reference Center Academic, Internures, MD Consult, Mosby’s Nursing Consult, Proquest5000 and ScienceDirect. In order to further analyze manageable number of the quality and acceptability of the research articles, inclusion criteria were conducted in the following search strategy. The applicable key terms were combined with using thesaurus, truncation, Boolean operators and other limit, such as a language, subject fields of journal and years of publication in the search strategy. For example, "PPIs" "proton pump inhibitors" "omeprazole" combined with “hip fracture" "osteoporosis" as title and text words were utilized in the search strategy. Also, it includes studies published from 1990 to 2009, health, medicine and nursing fields and English language articles. Thus, 30 relevant citations were identified by the search strategy. From these about 10 articles concentrated on the risk of increased hip fracture after exposure to PPI. These articles were studied and the following literature was produced. Literature review Osteoporosis is a chronic progressive metabolic disease of the bone. It is a systemic skeletal disease and can affect all the bones of the body. The main characteristics of this condition are low bone mass and microarchitectural deterioration of the tissue of the bones, thus causing increase in bone fragility. The reduction in skeletal mass occurs due to an imbalance between bone resorption and bone formation. The 2 most important factors contributing to the development of osteoporosis are ageing and loss of gonadal function. Hence this condition is more common in post menopausal women. The clinical picture is insidious and the disease becomes apparent when a fracture occurs. Other clinical symptoms include pain, disability and decreased quality of life. The fracture with worst consequence is hip fracture. There are many causes attributable to the etiology of osteoporosis. As the age of a person increases, the chances of acquiring osteoporosis also increase (Serota and Lane, 2006). Osteoporosis affects 16% of women and 7% of men above 50 years of age (Tenenhouse et al, qtd. in Targownik, Lix and Metge, 2008). Osteoporosis is the single most risk factor for development of fractures like fracture of hip, spinal vertebra, fore arm and proximal femur. The main problem with osteoporosis related fractures is that the fractures can end up in long term disability and the quality of life may be decreased. Major risk factors for the development of fractures in osteoporosis are low body mass index, ethnic back ground, female sex and physical inactivity (Targownik, 2008). Many medicines have been linked with increased risk of osteoporosis. They are corticosteroids and serotonin selective reuptake inhibitor. PPIs affect bone mineral metabolism (Targownik, 2008). Proton pump inhibitors or PPI are a class of drugs which cause long-lasting and pronounced reduction of gastric acid production. This category of drugs has superseded all other anti-acid drugs and they are the most wide selling anti-acid drugs in the market because of the efficacy and also safety. Most of the drugs which fall into this category are benximadole derivatives. The clinically used PPIs are omeprazole, pantoprazole, lansoprazole, rabeprazole, dexlansoprazole and esomeprazole. PPI act by irreversible blockage of H+/K+ ATPase which is also known as the proton pump. This enzyme is the lat stage of gastric acid secretion. PPI decrease absorption of insoluble calcium Elderly population have significant hypochlorhydria mainly due to increased prevalence of Helicopylori infection. Hypochlorhydria decreases PPI clearance thus giving more time to prevent calcium absorpton. PPI decrease absorption of insoluble calcium. Elderly populations have significant hypochlorhydria mainly due to increased prevalence of Helicopylori infection. Hypochlorhydria decreases PPI clearance thus giving more time to prevent calcium absorpton. In vitro studies and studies in humans have demonstrated decreased bone resorption by omeprazole by inhibiting vacuolar H-K -ATPase (Mizunashi et al, 1993). Researchers have proposed that these opposing effects of PPI on calcium metabolism probably increase the risk for hip fracture. Yang et al (2006) conducted a case-control trial to study the risk of hip fractures in those on PPI therapy. The purpose of the study was to determine if the opposing effects of PPI on calcium metabolism contributed to increased risk of hip fracture. The researchers found an association between hip fracture and long-term use of high-dose PPI. An important necessity for absorption of calcium is solubility. Calcium is consumed as insoluble salts. The acidic environment in the gut releases ionized calcium which is easily absorbable. Even a mild acidic environment is enough to dissolve considerable amounts of calcium salts. Long term PPI therapy grossly reduces the acid content in the gut and thus decreases calcium ion release and its absorption. Studies in rat show that omeprazole therapy and gastrectomy decrease calcium phosphate absorption and cause impairment of bone mineral density (Chonan et al, 1996). Human studies have shown that pernicious anemia and gastrectomy, both of which cause hypochlorhydria lead to decreased absorption of calcium (Goerss, 1992). However, in these 2 conditions acid suppression is much more when compared to acid suppression by PPI therapy. Hence they cannot be readily extrapolated to PPI therapy. One surprising aspect about PPI therapy and decreased calcium absorption is that full-dose omeprazole therapy does not reduce calcium absorption in young healthy individuals. This was proved by the study by Serfaty-Lacrosniere (1995; qtd. in Yang et al, 2006). However, O'Connell et al (2005) conducted a study to look into the effects of PPI on calcium carbonate absorption in elderly women beyond 65 years of age and reported that there was significant association between PPI therapy and decreased calcium absorption. As discussed previously, only a mild acidic environment is enough to absorb sufficient amounts of calcium. In short course PPI therapy, acid suppression is not much and hence the environment must be suitable for calcium absorption. However, in elderly patients there is high prevalence of Helicobacter pylori infection leading to achlorhydria and PPI therapy further suppresses acid content. Thus in elderly population even intermittent PPI therapy can lead to decreased calcium absorption and osteoporosis. The proton pump inhibition action of the PPIs is irreversible and actually site-specific. This is because of the fact that all the PPIs need 2 sequential protonation steps for activation of a pKa for the second step of less than one. Proton pump inhibition occurs in the secretory canaliculi of the gastric parietal cells and also osteoclastic vacuole. Actually osteoclastic proton inhibition is a protective effect for osteoporosis. Yang et al (2006) opine that when PPIs are taken in small doses, the protective effect of osteoclastic proton inhibition neutralizes the negative effects of acid suppression. This neutralization is not possible in higher doses of PPI therapy. In the study by Yang et al (2006), the researchers observed that the risk of hip fracture was modest with regular dose PPT treatment and the risk was profound with high-dose treatment. According to a study by Vestergaard et al (2006), drugs which decrease acid milieu in the gut tend to increase the risk of fractures. The highest risk is with PPI, followed by H-2 receptor antagonists and then antacids. The authors described the risk as clinically insignificant when the medications were taken over one year period. Many case control studies have hinted at increased risk of hip fractures with omeprazole use. Roux et al (2009) conducted an elaborate study on the incidence of vertebral fractures in those post menopausal women taking omeprazole. The age-adjusted vertebral fracture rates in users of omeprazole were 1.89 per 100 person- years and 0.6 for non-users. What duration of exposure to PPIs increases the risk of fractures is a debatable topic. While Yang et al (2006) reported that exposure to PPI for a even a year increases the risk for hip fracture. Targownik et al (2008) found that continuous exposure to these drugs for 5 years increased the risk of hip fracture and after 7 years of exposure, there was increased risk of any fracture. The mechanisms of association between hip fracture and PPI intake are not clear. However, scientists are of the opinion that the physiological consequences of PPI therapy influence bone metabolism and increase the risk for fracture Yang, 2008). Other than prevention of calcium absorption, secondary hypergastrinemia which can occur due to PPI therapy induces parathyroid gland hyperplasia and thus enhances bone resorption and osteoporosis (Yang, 2008). Implications of this literature review PPIs are good anti-acid drugs and because they are efficient and safe, physicians tend to prescribe them for long duration of time. Patients also take them over the counter and this leads to abuse of the medication. Based on the facts discussed in this review, doctors, nurses and other health professionals must avoid prescribing this category of drugs for a long duration of time. Caution must be exerted while prescribing them to elderly people and post-menopausal women. Patients must be advised not to consume these drugs without proper indication. Conclusion Hip fracture is a devastating complication of osteoporosis which can lead to significant morbidity, mortality and decreased quality of life. This condition predominantly occurs in old age and in post menopausal women, a time when there is increased necessity to take other drugs for maintenance of good health. PPIs are the most commonly used anti-acid drugs. These drugs cause osteoporosis due to decreased calcium absorption. The osteoporosis increases the risk of hip fracture. This complication is seen mainly in the elderly and when on long-term therapy. References Chonan, O., Takahashi, R., Yasui, H., Watanuki, M. (1998). Effect of L-lactic acid on calcium absorption in rats fed omeprazole. J Nutr Sci Vitaminol (Tokyo), 44, 473-481. Goerss, J.B., Kim, C.H., Atkinson, E.J., Eastell, R., O'Fallon, W.M., Melton, L.J. III. (1992). Risk of fractures in patients with pernicious anemia. J Bone Miner Res., 7, 573-579. O’Connell, M.B., Madden, D.M., Murray, A.M., Heaney, R.P., Kerzner, L.J. (2005). Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med., 118, 778-781. Roux, C., Briot, K., and Gossec, L. (2009). Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcified Tissue International, 84(1), 13-9. Serota, A.C. and Lane, J.M. (2006). Osteoporosis (Secondary). Emedicine from WebMD. Retrieved on 6th March, 2009 from http://emedicine.medscape.com/article/311449-overview Targownik, L.E., Lix, L.M., Metge, C.J. (2008). Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ, 179(4), 319-326. Vestergaard, P., Rejnmark, L. and Mosekilde, L. (2006). Proton Pump Inhibitors, Histamine H2 Receptor Antagonists, and Other Antacid Medications and the Risk of Fracture. Calcified Tissue International, 79(2), 76- 83. Yang, Y., Lewis, J.D., Epstein, S., and Metz, D.C. (2006). Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture. JAMA, 296, 2947- 2953. Yang, Y.X. (2008). Proton pump inhibitor therapy and osteoporosis. Curr Drug Saf., 3(3), 204-9. Read More