Proton Pump Inhibitors (PPIs) are among the most frequently prescribed medications worldwide for the management of acid-related gastrointestinal disorders, including gastroesophageal reflux disease (GERD), peptic ulcer disease, Zollinger–Ellison syndrome, and prevention of non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy. Commonly used PPIs include omeprazole, pantoprazole, rabeprazole, esomeprazole, and lansoprazole. These drugs exert their pharmacological action by irreversibly inhibiting the gastric H+/K+-ATPase enzyme system located on the secretory surface of gastric parietal cells, thereby producing profound and sustained suppression of gastric acid secretion. Due to their efficacy and favorable short-term safety profile, PPIs have become one of the most commonly utilized classes of drugs in clinical practice worldwide and in India.¹ The widespread use of PPIs has increased substantially over the last two decades, particularly in developing countries such as India, where they are frequently prescribed for both approved and off-label indications. Drug utilization studies conducted in Indian tertiary care hospitals have reported extensive use of pantoprazole and rabeprazole, often for prolonged durations without periodic reassessment of therapeutic necessity.² Long-term use of PPIs has therefore emerged as an important public health concern due to the growing evidence linking chronic acid suppression with various adverse effects, including nutrient malabsorption, hypomagnesemia, vitamin B12 deficiency, enteric infections, and disturbances in bone metabolism.³ Calcium plays a fundamental role in skeletal development and maintenance of bone integrity. Adequate calcium absorption depends on several physiological factors, including vitamin D status and gastric acidity. Gastric acid facilitates the dissolution and ionization of dietary calcium salts, making calcium available for absorption in the small intestine. Chronic suppression of gastric acid secretion by PPIs may impair this process, leading to reduced intestinal calcium absorption and subsequent alterations in calcium homeostasis.⁴ Reduced calcium availability may stimulate compensatory secretion of parathyroid hormone (PTH), resulting in increased bone resorption and progressive loss of bone mineral density (BMD).⁵ Several epidemiological studies have reported an association between prolonged PPI therapy and increased risk of osteoporosis-related fractures, particularly involving the hip, vertebrae, and wrist. Yang et al. demonstrated that long-term PPI use was associated with a significantly increased risk of hip fractures among older adults.⁶ Similarly, Targownik et al. observed reduced bone mineral density and increased fracture risk among chronic PPI users.⁷ Proposed mechanisms include impaired calcium absorption, secondary hyperparathyroidism, altered osteoclast function, hypomagnesemia, and vitamin D deficiency.⁸ The issue assumes particular significance in India, where osteoporosis and vitamin D deficiency are highly prevalent. Studies conducted by Malhotra and Mithal reported that osteoporosis has become a major public health problem affecting millions of Indians, particularly postmenopausal women and the elderly.⁹ Furthermore, Marwaha et al. demonstrated widespread vitamin D deficiency among healthy Indian individuals despite abundant sunlight exposure.¹⁰ Similar findings were reported by Khadgawat et al., who documented a high prevalence of hypovitaminosis D among healthy urban adults in northern India.¹¹ Such baseline nutritional deficiencies may potentiate the adverse skeletal effects associated with long-term PPI therapy. Bone health in the Indian population is influenced by multiple factors including inadequate dietary calcium intake, limited consumption of dairy products, sedentary lifestyle, socioeconomic disparities, and nutritional deficiencies. Aggarwal et al. reported a substantial burden of osteopenia and osteoporosis among peri- and postmenopausal Indian women.¹² Consequently, chronic PPI use in this vulnerable population may further compromise bone strength and increase susceptibility to fragility fractures. Despite growing international evidence regarding the relationship between prolonged PPI use and impaired bone health, limited data are available from Indian populations. Given the widespread prescription of PPIs and the high prevalence of osteoporosis-related risk factors in India, evaluation of the long-term effects of these drugs on calcium metabolism and skeletal health is of considerable clinical importance. Understanding these effects may help clinicians optimize therapy, identify high-risk patients, and implement preventive strategies such as calcium and vitamin D supplementation, lifestyle modification, and periodic bone health assessment. Therefore, the present study was undertaken to evaluate the long-term effects of Proton Pump Inhibitors on calcium metabolism and bone health among adult patients receiving prolonged PPI therapy. Aim To assess the long-term effects of Proton Pump Inhibitors on calcium metabolism and bone health among adult patients receiving prolonged therapy.

Study Design The present study was designed as a hospital-based, observational, comparative cross-sectional study to evaluate the long-term effects of Proton Pump Inhibitors (PPIs) on calcium metabolism and bone health among adult patients receiving prolonged PPI therapy. Study Setting The study was conducted in the Department of Pharmacology in collaboration with the Department of General Medicine at a tertiary care teaching hospital in India. Study Duration The study was carried out over a period of 12 months. Ethical Considerations Prior approval was obtained from the Institutional Ethics Committee (IEC) before initiation of the study. The study was conducted according to the ethical principles outlined in the Declaration of Helsinki and Indian Council of Medical Research (ICMR) guidelines for biomedical research involving human participants. Written informed consent was obtained from all participants prior to enrollment. Confidentiality of participant information was strictly maintained throughout the study. Study Population Patients attending the Medicine Outpatient Departments (OPD) and receiving long-term PPI therapy were screened for eligibility. Study Groups Participants were divided into two groups: Group A (PPI Users) Patients receiving any Proton Pump Inhibitor (Omeprazole, Pantoprazole, Rabeprazole, Esomeprazole, or Lansoprazole) continuously for a period of 12 months or longer. Group B (Control Group) Age- and sex-matched healthy individuals or patients not receiving Proton Pump Inhibitors and without known metabolic bone disorders. Sample Size A total of 100 participants were included in the study. • Group A (Long-term PPI Users): 50 participants • Group B (Controls): 50 participants The sample size was calculated based on previous studies evaluating the effects of chronic PPI therapy on bone mineral density and serum calcium levels, considering a confidence level of 95% and power of 80%. Inclusion Criteria For Group A 1. Patients aged between 30 and 70 years. 2. Continuous use of Proton Pump Inhibitors for ≥12 months. 3. Both male and female participants. 4. Willingness to provide written informed consent. For Group B 1. Age- and sex-matched healthy controls. 2. No history of long-term PPI use. 3. No known metabolic bone disease. 4. Willingness to participate in the study. Exclusion Criteria Participants meeting any of the following criteria were excluded: 1. Chronic Kidney Disease (CKD). 2. Chronic Liver Disease. 3. Hyperparathyroidism. 4. Thyroid disorders affecting bone metabolism. 5. Malabsorption syndromes.. Sampling Technique Eligible participants were recruited using consecutive sampling until the required sample size was achieved. Statistical Analysis Data were analyzed using Statistical Package for Social Sciences (SPSS) Version 25.0.

Table 2: Comparison of Biochemical Parameters Between Long-Term PPI Users and Controls Parameter Reference Range PPI Users (n=50) Mean ± SD Controls (n=50) Mean ± SD p-value Serum Calcium (mg/dL) 8.5–10.5 8.4 ± 0.5 9.2 ± 0.4 <0.001* Serum Phosphorus (mg/dL) 2.5–4.5 3.2 ± 0.4 3.5 ± 0.5 0.004* Serum Magnesium (mg/dL) 1.8–2.5 1.7 ± 0.2 2.0 ± 0.3 0.002* Serum Vitamin D [25(OH)D] (ng/mL) >30 19.6 ± 7.1 28.4 ± 8.2 <0.001* Serum Parathyroid Hormone (PTH) (pg/mL) 15–65 67.3 ± 14.2 45.8 ± 11.5 <0.001* Serum Alkaline Phosphatase (IU/L) 44–147 118.5 ± 28.6 92.3 ± 20.8 <0.001* Serum Albumin (g/dL) 3.5–5.0 4.1 ± 0.4 4.2 ± 0.3 0.18 *Statistically significant (p < 0.05) Table 1: Baseline Demographic and Clinical Characteristics of Study Participants Characteristics PPI Users (n=50) Mean ± SD / n (%) Controls (n=50) Mean ± SD / n (%) p-value Age (years) 54.3 ± 8.1 53.6 ± 7.9 0.72 Gender Male 28 (56%) 27 (54%) 0.84 Female 22 (44%) 23 (46%) 0.84 Residence Urban 31 (62%) 29 (58%) 0.68 Rural 19 (38%) 21 (42%) 0.68 Body Weight (kg) 67.5 ± 9.8 68.2 ± 8.9 0.71 Height (cm) 163.8 ± 7.5 164.6 ± 6.9 0.58 Body Mass Index (BMI, kg/m²) 25.1 ± 3.4 24.8 ± 3.1 0.65 Smoking Status Smokers 12 (24%) 10 (20%) 0.63 Non-Smokers 38 (76%) 40 (80%) 0.63 Alcohol Consumption Alcohol Users 9 (18%) 8 (16%) 0.79 Non-Alcohol Users 41 (82%) 42 (84%) 0.79 Physical Activity Level Sedentary 24 (48%) 22 (44%) 0.68 Moderately Active 19 (38%) 21 (42%) 0.67 Highly Active 7 (14%) 7 (14%) 1 Average Daily Calcium Intake (mg/day) 615 ± 135 640 ± 128 0.34 Average Sunlight Exposure (minutes/day) 24.5 ± 10.8 27.2 ± 11.3 0.23 Family History of Osteoporosis 8 (16%) 6 (12%) 0.56 History of Previous Fracture 5 (10%) 3 (6%) 0.46 Duration of PPI Therapy (years) 3.8 ± 1.5 NA — Duration Categories 1–2 Years 14 (28%) NA — 3–5 Years 24 (48%) NA — >5 Years 12 (24%) NA — Table 1 A: Distribution of Proton Pump Inhibitors Among PPI Users (n = 50) Type of PPI Number (%) Pantoprazole 22 (44%) Rabeprazole 14 (28%) Omeprazole 7 (14%) Esomeprazole 5 (10%) Lansoprazole 2 (4%) No statistically significant differences were observed between the two groups with respect to age, gender distribution, BMI, smoking status, alcohol intake, physical activity, dietary calcium intake, or sunlight exposure (p > 0.05). Therefore, both groups were comparable at baseline, minimizing potential confounding factors. The mean duration of PPI therapy among users was 3.8 ± 1.5 years, with pantoprazole being the most frequently prescribed PPI. Table 1 B: Indications for Long-Term PPI Therapy Indication Number (%) Gastroesophageal Reflux Disease (GERD) 21 (42%) Peptic Ulcer Disease 11 (22%) NSAID-induced Gastropathy 9 (18%) Dyspepsia 6 (12%) Zollinger–Ellison Syndrome 3 (6%) Long-term PPI users exhibited significantly lower serum calcium, phosphorus, magnesium, and vitamin D levels compared to controls. Mean serum PTH and alkaline phosphatase levels were significantly elevated among PPI users, indicating altered calcium homeostasis and increased bone turnover. No significant difference was observed in serum albumin levels between the two groups. Table 3: Comparison of Bone Mineral Density (BMD) Scores Between Long-Term PPI Users and Controls BMD Parameter PPI Users (n=50) Mean ± SD Controls (n=50) Mean ± SD Mean Difference p-value Lumbar Spine BMD (g/cm²) 0.892 ± 0.112 1.021 ± 0.098 -0.129 <0.001* Femoral Neck BMD (g/cm²) 0.781 ± 0.105 0.912 ± 0.087 -0.131 <0.001* Lumbar Spine T-score -1.8 ± 0.7 -0.8 ± 0.6 -1.0 <0.001* Femoral Neck T-score -1.6 ± 0.8 -0.7 ± 0.5 -0.9 <0.001* Lumbar Spine Z-score -1.2 ± 0.6 -0.5 ± 0.4 -0.7 <0.001* Femoral Neck Z-score -1.1 ± 0.5 -0.4 ± 0.3 -0.7 <0.001* *Statistically significant (p < 0.05) Bone Mineral Density assessment using Dual-Energy X-ray Absorptiometry (DEXA) revealed significantly lower BMD values among long-term PPI users compared with controls. The mean lumbar spine BMD and femoral neck BMD were markedly reduced in the PPI group. Similarly, lumbar spine and femoral neck T-scores were significantly lower among chronic PPI users, indicating greater bone loss and increased risk of osteopenia and osteoporosis. The observed differences were statistically significant (p < 0.001), suggesting a strong association between prolonged PPI therapy and reduced bone mineral density. Table 4: Prevalence of Bone Disorders Among Study Participants Bone Health Status (Based on WHO T-score Criteria) PPI Users (n=50) n (%) Controls (n=50) n (%) p-value Normal Bone Mineral Density 15 (30%) 34 (68%) <0.001* Osteopenia 24 (48%) 12 (24%) 0.012* Osteoporosis 11 (22%) 4 (8%) 0.046* Total Participants with Bone Disorders (Osteopenia + Osteoporosis) 35 (70%) 16 (32%) <0.001* *Statistically significant (p < 0.05) The prevalence of bone disorders was significantly higher among long-term Proton Pump Inhibitor (PPI) users compared to controls. Among the 50 participants receiving prolonged PPI therapy, only 30% had normal Bone Mineral Density (BMD), whereas 68% of controls demonstrated normal BMD. Osteopenia was the most common bone disorder observed in the PPI group, affecting 48% of participants compared with 24% in the control group. Furthermore, osteoporosis was identified in 22% of chronic PPI users, which was considerably higher than the 8% observed among controls. Overall, 70% of participants receiving long-term PPI therapy exhibited some degree of bone mineral loss (osteopenia or osteoporosis), compared with only 32% of individuals in the control group. The difference between the groups was statistically significant (p < 0.001). These findings suggest that prolonged PPI use is associated with an increased prevalence of reduced bone mineral density and may contribute to the development of osteopenia and osteoporosis. The observed reduction in bone health among chronic PPI users may be attributed to impaired calcium absorption, vitamin D deficiency, hypomagnesemia, and secondary hyperparathyroidism resulting from long-term gastric acid suppression. The results underscore the importance of periodic bone health assessment, particularly in patients receiving PPIs for extended durations, elderly individuals, postmenopausal women, and those with additional risk factors for osteoporosis.

The present study was designed to evaluate the long-term effects of Proton Pump Inhibitors (PPIs) on calcium metabolism and bone health among adult patients receiving therapy for ≥1 year. The findings demonstrate significant alterations in biochemical markers of bone metabolism along with reduced bone mineral density (BMD) and increased prevalence of osteopenia and osteoporosis in chronic PPI users compared to controls. The present study demonstrated that prolonged PPI therapy significantly affects calcium metabolism and bone health. Patients receiving PPIs for more than one year showed significantly lower serum calcium levels compared with controls. Gastric acid plays an important role in dissolving dietary calcium salts into absorbable ionic forms. Suppression of gastric acid secretion by PPIs can impair this process and reduce calcium bioavailability. A significant reduction in vitamin D levels was also observed among chronic PPI users. Similar findings have been reported in international studies conducted by Yang et al., Corley et al., and Fraser et al., which linked long-term acid suppression to impaired mineral metabolism and increased fracture risk. Elevated PTH concentrations among PPI users suggest development of secondary hyperparathyroidism as a compensatory response to reduced calcium absorption. Persistent elevation of PTH can accelerate bone resorption and contribute to bone loss. Bone Mineral Density measurements revealed significantly lower T-scores in both lumbar spine and femoral neck regions among PPI users. These findings are consistent with previous studies demonstrating increased incidence of osteopenia and osteoporosis in chronic PPI users. Indian studies by Khadgawat et al. and Marwaha et al. have documented widespread vitamin D deficiency among Indian adults. The coexistence of vitamin D deficiency and prolonged PPI therapy may synergistically worsen bone health outcomes in Indian populations. The prevalence of osteoporosis in the present study was markedly higher among PPI users (22%) compared with controls (8%). Similar associations have been reported in large population-based studies from North America and Europe. The findings highlight the importance of judicious prescribing of PPIs, particularly in elderly patients and postmenopausal women who already possess increased susceptibility to osteoporosis.

Long-term use of Proton Pump Inhibitors is associated with significant alterations in calcium metabolism, including reduced serum calcium and vitamin D levels, elevated parathyroid hormone concentrations, and decreased bone mineral density. Chronic PPI therapy may increase the risk of osteopenia, osteoporosis, and fragility fractures. Clinicians should periodically evaluate bone health and consider calcium and vitamin D supplementation in high-risk individuals receiving prolonged PPI treatment.

1. Tripathi KD. Essentials of Medical Pharmacology. 9th ed. New Delhi: Jaypee Brothers; 2023. 2. Sharma S, Tandon VR, Mahajan A. Drug utilization pattern of proton pump inhibitors in Indian tertiary care hospitals. Int J Basic Clin Pharmacol. 2018;7(4):746-752. 3. Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium. Curr Gastroenterol Rep. 2010;12(6):448-457. 4. O'Connell MB, Madden DM, Murray AM, et al. Effects of proton pump inhibitors on calcium carbonate absorption. Am J Med. 2005;118(7):778-781. 5. Wright MJ, Proctor DD, Insogna KL, Kerstetter JE. Proton pump inhibitor use and bone health. Nutr Rev. 2008;66(2):103-108. 6. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296(24):2947-2953. 7. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179(4):319-326. 8. Fraser LA, Leslie WD, Targownik LE, et al. The effect of proton pump inhibitors on fracture risk. Osteoporos Int. 2013;24(4):1161-1168. 9. Malhotra N, Mithal A. Osteoporosis in Indians. Indian J Med Res. 2008;127(3):263-268. 10. Marwaha RK, Tandon N, Reddy DRHK, et al. Vitamin D and bone mineral density status of healthy Indians. Am J Clin Nutr. 2005;82(2):477-482. 11. Khadgawat R, Brar KS, Gahlo M, et al. High prevalence of vitamin D deficiency in healthy urban adults in India. Osteoporos Int. 2004;15(1):56-60. 12. Aggarwal N, Raveendran A, Khandelwal N, et al. Prevalence and related risk factors of osteoporosis in peri- and postmenopausal Indian women. J Midlife Health. 2011;2(2):81-85. 13. Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures. Gastroenterology. 2010;139(1):93–101. 14. Katz PO, Gerson LB, Vela MF. Guidelines for diagnosis and management of GERD. Am J Gastroenterol. 2022;117(1):27–56. 15. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2022. 16. Katzung BG. Basic and Clinical Pharmacology. 16th ed. New York: McGraw-Hill; 2024.