Proton-Pump Inhibitors Versus H2-Receptor Antagonists on the Risk of Major Osteoporotic Fractures: A Global Propensity-Score-Matched Cohort Study

Proton-Pump Inhibitors Versus H2-Receptor Antagonists on the Risk of Major Osteoporotic Fractures: A Global Propensity-Score-Matched Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Proton-Pump Inhibitors Versus H2-Receptor Antagonists on the Risk of Major Osteoporotic Fractures: A Global Propensity-Score-Matched Cohort Study Danling Jiang, Xi Li, WenPin Cheng, Bei Li, Guoqing Lv, Yue Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7725160/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Long-term suppression of gastric acid is crucial for various conditions; however, proton-pump inhibitors (PPIs) may negatively impact skeletal health more than histamine-2 receptor antagonists (H2RAs). There is limited head-to-head data, particularly within Asian communities that have unique calcium consumption and drug metabolism patterns. Methods We conducted a retrospective cohort study that matched participants using propensity scores, utilizing the TriNetX integrated claims and electronic health-record database. Adults aged between 18 and 80 years who had at least 12 prescriptions for either a sole PPI or H2RA therapy from 2015 to 2025 were included. Following a 1:1 nearest-neighbor matching (caliper = 0.1), 131,698 individuals remained in each cohort. The outcomes measured included major osteoporotic fracture (MOF; primary), hip repair/arthroplasty, vertebral compression fracture, newly diagnosed osteoporosis, and malignant melanoma (negative control). The application of Cox proportional-hazards models allowed for the assessment of hazard ratios (HRs) and their linked 95% confidence intervals (CIs). Results Over a span of more than two million person-years, PPIs were linked to a higher incidence of MOF compared to H2RAs (HR 1.23, 95% CI 1.18–1.28; p < 0.0001). Significant dangers were pointed out regarding hip repair/arthroplasty (HR 1.46, 1.35–1.58) and vertebral compression fractures (HR 1.16, 1.09–1.23), while newly diagnosed osteoporosis showed no notable changes (HR 1.01, 0.98–1.03). The negative-control outcome indicated no correlation. In the Asia-Pacific subgroup, the risk of MOF increased by 77% (HR 1.77, 1.56–2.01). Consistent findings emerged from subgroup and sensitivity analyses. The increased fracture risk remained despite comparable demographics, comorbidities, and consistent acid suppression, suggesting that there may be drug-class-specific skeletal toxicity—potentially due to impaired mineral absorption, elevated gastrin levels, and increased bone turnover. The more pronounced effect in East-Asian populations highlights the interaction between dietary and genetic influences. Conclusions Ongoing PPI treatment, in contrast to H2RA therapy, leads to significant increases in the risk of fragility fractures. These findings advocate for a reduction in PPI usage duration, favoring H2RAs for patients at greater fracture risk, and call for proactive measures to safeguard bone health while future studies explore causality and effective strategies for mitigation. Health sciences/Diseases Health sciences/Medical research Health sciences/Risk factors Proton Pump Inhibitors Histamine H2 Antagonists Fractures Osteoporotic Hip Fractures Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction To effectively manage gastro-esophageal reflux disease, acid-suppressive drugs are vital, although their different pharmacodynamic traits could influence bone health differently. Proton-pump inhibitors (PPIs) are effective in significantly diminishing the production of gastric acid, thus limiting calcium absorption within the intestines, increasing gastrin levels, and ultimately resulting in greater bone resorption by osteoclasts [ 1 ]. On the other hand, histamine-2 receptor blockers (H2RAs) merely partially limit acid secretion and show little influence on how minerals dissolve, hinting at a perhaps diminished chance of fractures. Epidemiological studies largely corroborate this mechanistic distinction. Through a detailed case-control study with more than 160,000 participants in the US, it was found that extended high-dose PPI use was tied to a 2.6-fold increase in hip fracture risk, while a comparable duration of H2RA exposure did not present this correlation [ 2 ]. A following meta-analysis, comprising eleven global cohorts (over 700,000 individuals), confirmed that PPIs consistently raised the likelihood of hip, spine, and overall fractures, while H2RAs did not have a meaningful impact [ 3 ]. Additionally, prospective imaging studies indicate that women on PPI therapy for a year or more exhibit reduced cortical bone thickness and a higher likelihood of falls—factors that could contribute to increased bone fragility independently of bone mineral density [ 4 ]. A recent British study focusing on frail elderly adults found elevated rates of fragility fractures among long-term PPI users, highlighting the clinical significance in at-risk populations [ 5 ]. However, many previous studies either compared PPIs against non-users or included predominantly white participants, causing uncertainty about whether the increased risk is due to specific properties of the drug class or simply reflects the severity of acid suppression. Furthermore, H2RAs—often considered second-line treatments—have rarely been tested as an active comparator due to their distinct mechanisms. These issues are particularly relevant in East-Asian populations, where lower dietary calcium levels and rapid CYP2C19 metabolism might lessen the effectiveness of PPIs. Our upcoming multinational study, focusing on new users, will directly compare chronic use of PPIs and H2RAs across more than two million person-years globally and in APAC region, examining the incidence of major osteoporotic fractures (MOF), lab value diagnosed osteoporosis, surgically treated hip fractures, and vertebral compression fractures. By utilizing detailed claims data and comprehensive subgroup analyses, we aim to determine whether PPIs pose additional fracture risks beyond what is associated with general acid suppression and to establish safer long-term prescribing practices. Ethics Statement Exemption was secured from the Shih Kong Wu Ho-Su Memorial Hospital Institutional Review Board for this investigation (IRB number: 20250803R), eliminating the requirement for participant consent. The analysis employed healthcare data obtained through TriNetX, a federated global research platform that facilitates scientific inquiry using de-identified patient records. TriNetX adheres to the Health Insurance Portability and Accountability Act (HIPAA), which establishes the regulatory framework for medical data privacy and security within the United States. The platform has obtained ISO 27001:2013 accreditation and utilizes an Information Security Management System (ISMS) to ensure compliance with HIPAA Security Rule requirements for healthcare data protection. Patient data within the TriNetX environment, whether presented as aggregate metrics or individual records, undergo comprehensive de-identification in accordance with Section 164.514(a) of the HIPAA Privacy Rule. An independent expert has certified the de-identification protocols pursuant to Section 164.514(b)(1) standards, with the most recent attestation issued in December 2020. This certification replaces the need for the previously obtained Western Institutional Review Board waiver. Medical institutions contributing to the TriNetX database execute Business Associate Agreements (BAAs) that establish appropriate legal frameworks, confirm institutional permissions, and verify authorization for data utilization in research contexts. These contractual arrangements maintain institutional anonymity while enabling scientific investigation. The system employs sophisticated data anonymization procedures that prevent attribution of patient records to specific healthcare facilities, thereby protecting organizational identity while facilitating collaborative research initiatives. Data availability statement The data that support the findings of this study were obtained from the TriNetX research network (TriNetX, LLC, Cambridge, MA, USA). The data are not publicly available due to institutional data use agreements and patient privacy regulations. Access to the TriNetX platform is available to participating institutions under license, and data can be requested directly from TriNetX ( https://trinetx.com ) subject to appropriate approvals. Material and Method Data Source and Study Design This retrospective cohort analysis utilized the TriNetX Global Collaborative Network, a federated research platform that, at the time of the query (6 July 2025), included de-identified electronic health records from 147 healthcare organizations (HCOs) across North America, Europe, the Middle East, and Asia-Pacific. The database captures longitudinal information on demographics, diagnoses, procedures, medications, and laboratory findings. Data contributions are fully de-identified in accordance with HIPAA 45 CFR § 164.514, and research activities performed on the network are granted a waiver of informed consent by the privacy board of each participating institution. Cohort Construction The study included adult patients aged 18–80 years whose records indicated long-term acid-suppressive treatment, defined a priori as having ≥ 12 distinct prescriptions within a single drug class between 1 January 2015 and 1 January 2025. Two mutually exclusive exposure cohorts were established: Exclusive long-term PPI users:12 dispensations of proton-pump inhibitors (ATC A02BC) with no exposure to H2-receptor antagonists (H2RA) at any time; initial unmatched N = 783,003. Exclusive long-term H2RA users:12 dispensations of H2RAs (ATC A02BA) with no PPI exposure; initial unmatched N = 132,615. The index date was identified as the first prescription meeting the ≥ 12-instance criteria. To reduce the risk of reverse causality, follow-up commenced 180 days post-index and continued until the last recorded encounter; patients with outcomes before this timeframe were automatically excluded by the TriNetX “exclude prior outcome” feature. Outcome Definitions Skeletal events were the primary outcomes, operationalized using validated ICD-10-CM, procedure, medication, and LOINC codes available within the TriNetX interface (comprehensive code lists in Supplementary 1). The endpoints included major osteoporotic fracture, osteoporosis, hip-fracture repair/arthroplasty, vertebral compression fracture, and malignant melanoma (negative control). Covariates and Propensity-Score Matching (PSM) Baseline covariates assessed before the index date included: age, sex, self-reported race (White, Black/African American, Asian), and the presence (yes/no) of nine ICD-10 chapter-level comorbidity groupings—diabetes mellitus (E08-E13), endocrine/nutritional/metabolic disorders (E00-E89), hypertensive diseases (I10-I1A), respiratory diseases (J00-J99), musculoskeletal disorders (M00-M99), genitourinary diseases (N00-N99), infectious and parasitic diseases (A00-B99), injuries/poisonings (S00-T88), and factors influencing health status (Z00-Z99). The calculation of propensity scores involved employing multivariable logistic regression techniques. A greedy nearest-neighbor 1:1 matching without replacement and a caliper of 0.1 pooled SD of the logit generated two balanced cohorts (N = 131,698 each) with all absolute standardized mean differences < 0.10. Statistical Analyses Utilizing Kaplan–Meier estimators in time-to-event analyses, two-sided log-rank tests were performed; we extracted hazard ratios (HRs) alongside 95% confidence intervals (CIs) from Cox proportional-hazards models to gauge relative hazards. Continuous or count outcomes were compared with Welch’s two-sample t-tests. Proportional-hazards assumptions were evaluated using Schoenfeld residuals provided by the platform. The analyses were all two-tailed, and a P value under 0.05 was recognized as having statistical significance. Analyses were conducted within TriNetX Analytics (Cambridge, MA, build 07-2025). By presenting an exhaustive account of the study design, patient population, interventions, outcome measures, data collection methods, and staistical analysis, this Material and Methods section ensures the reproducibility and validation of the conclusions drawn from this research paper. Results A total of 915,618 adult patients fulfilled the predefined inclusion criteria, comprising 783,003 exclusive long-term proton-pump inhibitor (PPI) users and 132,615 exclusive long-term H2-receptor antagonist (H2RA) users. Following greedy nearest-neighbor 1:1 propensity-score matching without replacement (caliper = 0.1 pooled standard deviation of the logit), 131,698 patients remained in each cohort, yielding two balanced groups of 263,396 participants in the final analytic sample. (Fig. 1 ) The demographic characteristics of the participants, such as age, gender, and race, were comparable between the groups. Furthermore, baseline major clinical characteristics were similar among the groups (Table 1 ). Table 1 baseline characteristics of the cohort (before and after the Propensity Score Matching) Before matching After matching Clinical Characteristics PPI group (n = 768,530) H2RA group (n = 131,721) Std diff PPI group (n = 131,698) H2RA group (n = 131,698) Std diff Age at index Mean ± SD 55.9 ± 13.9 52.9 ± 15.8 0.2028 53 ± 15.6 52.9 ± 15.8 0.006 Gender Female 371,790 (48.38%) 70,544 (53.56%) 0.1037 70,422 (53.47%) 70,523 (53.55%) 0.0015 Male 396,740 (51.62%) 61,177 (46.44%) 0.1037 61,276 (46.53%) 61,175 (46.45%) 0.0015 Race White 440,675 (57.34%) 75,056 (56.98%) 0.0073 76,616 (58.18%) 75,056 (56.99%) 0.024 Black or African American 64,255 (8.36%) 16,742 (12.71%) 0.142 16,692 (12.67%) 16,742 (12.71%) 0.0011 Asian 33,844 (4.40%) 11,417 (8.67%) 0.1732 10,434 (7.92%) 11,394 (8.65%) 0.0264 Comorbidities Factors influencing health status and contact with health services 351,145 (45.69%) 73,794 (56.02%) 0.2078 75,464 (57.30%) 73,771 (56.02%) 0.0259 Endocrine, nutritional and metabolic diseases 332,416 (43.25%) 63,312 (48.07%) 0.0967 64,499 (48.98%) 63,300 (48.07%) 0.0182 Diseases of the musculoskeletal system and connective tissue 299,646 (38.99%) 54,592(41.45%) 0.0501 54,393 (41.30%) 54,588 (41.45%) 0.003 Disease of the genitourinary system 242,645 (31.57%) 49,826 (37.83%) 0.1317 50,221 (38.13%) 49,807 (37.82%) 0.0065 Disease of the respiratory system 262,518 (34.16%) 48,360(36.71%) 0.0534 48,480 (36.81%) 48,358 (36.72%) 0.0019 Hypertensive diseases 244,512 (31.82%) 43,537 (33.05%) 0.0264 44,135 (33.51%) 43,535 (33.06%) 0.0097 Injury, poisoning and certain other consequences of external causes 208,112 (27.08%) 40,964 (31.10%) 0.0886 41,000 (31.13%) 40,957 (31.10%) 0.0007 Certain infectious and parasitic diseases 167,430 (21.79%) 31,211 (23.70%) 0.0456 30,900 (23.46%) 31,208 (23.70%) 0.0055 Diabetes mellitus 123,272 (16.04%) 22,128 (16.80%) 0.0205 22,353 (16.97%) 22,127 (16.80%) 0.0046 In the primary global cohort, long-term proton pump inhibitor (PPI) therapy was associated with a significantly higher risk of major osteoporotic fracture (MOF) than histamine-2 receptor antagonist (H2RA) therapy (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.18–1.28; p < 0.0001). Elevated risks were likewise observed for hip repair/arthroplasty (HR 1.46, 95% CI 1.35–1.58; p < 0.0001) and vertebral compression fracture (HR 1.16, 95% CI 1.09–1.23; p < 0.0001), whereas incident osteoporosis was not significantly different between groups (HR 1.01, 95% CI 0.98–1.03; p = 0.62). The negative-control outcome of melanoma showed no association (HR 1.10, 95% CI 0.95–1.27). (Fig. 2 ) Geographic stratification revealed a stronger signal in the Asia–Pacific (APAC) region, where PPI use conferred a 77% increase in MOF risk (HR 1.77, 95% CI 1.56–2.01; p < 0.0001) and a 39% increase in vertebral compression fracture (HR 1.40, 95% CI 1.16–1.68; p = 0.0004); the hip repair/arthroplasty endpoint was not significant in APAC (HR 1.01, 95% CI 0.68–1.51; p = 0.95). (Fig. 3 ) Prespecified subgroup analyses showed broadly consistent excess hazard ratios for MOF across sex (men: HR 1.17, 95% CI 1.10–1.25; women: HR 1.28, 95% CI 1.21–1.35), chronic kidney disease status (CKD+: HR 1.31, 95% CI 1.20–1.43; CKD–: HR 1.20, 95% CI 1.15–1.25), systemic corticosteroid use (HR 1.33, 95% CI 1.27–1.39), Helicobacter pylori infection (HR 1.16, 95% CI 1.02–1.31), and body-mass-index strata (BMI ≥ 30 kg/m²: HR 1.16, 95% CI 1.07–1.26; BMI reference range: HR 1.08, 95% CI 0.98–1.19). (Supplementary Fig. 1–8) Sensitivity analyses confirmed the robustness of these findings: the association persisted when propensity-score matching was restricted to demographic covariates alone (model 1, HR 1.23, 95% CI 1.18–1.28) and when matching was based solely on comorbidities (model 2, HR 1.36, 95% CI 1.30–1.41). (Fig. 4 , 5 ) Discussion In this study, our aim was to assess the long-term skeletal safety of proton pump inhibitor (PPI) treatment in comparison to histamine-2 receptor antagonist (H2RA) treatment in adults undergoing chronic acid suppression. Our results show that prolonged PPI usage was linked to a notably greater risk of the primary outcome, major osteoporotic fractures, and similarly posed heightened risks for the secondary outcomes of hip repair/arthroplasty and vertebral compression fractures. Long-term suppression of gastric acid is increasingly acknowledged as a risk factor for skeletal health, as sufficient acidity in the gastrointestinal tract is crucial for the ionization and transportation of calcium and magnesium. The considerable decrease in stomach acid from proton-pump inhibitors (PPIs) obstructs mineral uptake, induces secondary hyperparathyroidism, and quickens the resorption of bone via osteoclasts [ 6 – 9 ]. Furthermore, PPIs promote chronic hypergastrinemia, which enhances histamine-dependent osteoclast activity, lowers osteoprotegerin levels, and raises bone turnover rates [ 10 , 11 ]. When hypomagnesemia occurs alongside other conditions, it adversely affects parathyroid hormone release and the formation of 1,25-dihydroxy-vitamin-D, worsening structural fragility [ 12 , 13 ]. In contrast, histamine-2-receptor antagonists (H2RAs) result in milder and shorter acid suppression with minimal influence on calcium solubilization or gastrin release, thus presenting a biologically reasonable lower risk of fractures [ 14 , 15 ]. These contrasting mechanisms warrant direct epidemiological comparisons, particularly concerning significant clinical events such as major osteoporotic fractures (MOF), surgically treated hip fractures, and vertebral compression fractures (VCF), all of which contribute to mortality, disability, and healthcare costs in aging populations [ 16 – 18 ]. Prominent cohorts from the United Kingdom General Practice Research Database and Canadian administrative claims, each involving over 150,000 participants, were the first to reveal a 1.5- to 1.9-fold increase in hip and spine fractures among chronic PPI users compared to non-users [ 19 – 23 ]. Further observational research from the Nurses’ Health Study (n ≈ 80,000) and the Women’s Health Initiative (n ≈ 130,000) reinforced dose-response links and observed some alleviation tied to proper calcium intake [ 9 , 24 , 25 ]. Meta-analyses encompassing more than two million individuals estimate relative increases in fracture risk of 20–35% for any fracture and 30–60% for hip or spine fractures linked with PPIs, whereas H2RAs appear largely neutral [ 26 – 30 ]. Randomized controlled trials are limited and often underpowered (< 1,000 participants, ≤ 12 months), highlighting the need for extensive real-world datasets to identify infrequent but serious skeletal outcomes [ 30 , 31 ]. Emerging evidence from Asian populations has only recently begun to surface. In a study by Park et al., they evaluated more than 1 million person-years involving senior Korean women and identified a 32% greater probability of osteoporotic fractures associated with PPIs as opposed to H2RAs [ 32 ]. In Taiwan, Chou et al. tracked 398,885 patients with type 2 diabetes and found a 41% increased risk of hip fractures in long-term PPI users compared to non-users, although they did not make a direct comparison with H2RAs [ 33 ]. A nationwide case-control study in Korea involving 21,754 fracture cases similarly established a population-wide association between PPIs and fractures but did not include an active comparator group [ 34 ]. While these studies are substantial, they did not comprehensively address acid-suppression classes, specific fracture types, and Asian-specific factors such as lower calcium intake and a higher prevalence of CYP2C19 rapid metabolizers. Utilizing a multinational claims database encompassing more than 250,000 individuals and over two million person-years of follow-up, our research offers the most comprehensive head-to-head analysis of PPIs versus H2RAs within global and Asian population to date. We have uncovered statistically meaningful heightened dangers for significant osteoporotic fractures, hip-fracture surgery/arthroplasty, and vertebral compression fractures linked to PPIs when compared to H2RAs, with findings consistently observed across different subgroups categorized by gender, age, chronic kidney issues, corticosteroid treatment, helicobacter pylori infection, and high body mass index. Importantly, there was no substantial disparity in the rates of physician-confirmed osteoporosis between the two groups, which suggests that the skeletal vulnerability linked to PPIs is fundamentally demonstrated through fractures occurring from minor trauma rather than through initial imaging evidence of bone depletion. The hazard ratios we observed align with the higher ranges of previous meta-analyses [ 28 , 29 ] while refining these estimates by illustrating that the increased risk continues even when both groups are under acid suppression treatment. Our active-comparator approach reduces the potential for confounding by indication, and the inclusion of East-Asian patients—who possess different dietary calcium intake, genetic variations, and baseline bone-mineral density than Western individuals—improves the external applicability of our findings in a region undergoing significant population aging. Together, the insights gathered advocate for a measured approach to the extended use of PPIs, recommending H2RAs for those at a higher risk of fractures, and stressing the need for proactive strategies aimed at improving bone health—these include calcium and vitamin D supplementation, engaging in weight-bearing activities, and regular dual-energy X-ray absorptiometry for chronic PPI users. However, our research has several limitations due to its retrospective nature involving the TriNetX federated claims and electronic health-record network. First, although extensive propensity-score adjustments were made, we cannot rule out residual and unmeasured confounding factors—such as the use of over-the-counter acid-suppressive medications, smoking and alcohol consumption, levels of physical activity, and intake of dietary calcium or vitamin D. Second, medication exposure was determined based on prescription or dispensing records instead of confirmed ingestion; variations in dosage, formulation, and non-prescription PPI use were not consistently recorded, which could result in misclassification of exposure. Third, fracture outcomes were identified using diagnostic and procedure codes without systematic confirmation through radiographic imaging, increasing the risk of coding errors or under-reporting, especially for asymptomatic vertebral fractures. Fourth, essential covariates related to bone health, including baseline bone-mineral density, serum vitamin D levels, inflammatory markers, and menopausal status, were not available in the aggregated dataset. Fifth, variations in coding practices, data completeness, and follow-up duration among the participating health-care organizations may introduce variability at the site level that we cannot control for. Finally, since TriNetX primarily collects data from tertiary-care centers that are willing to contribute to the network, our cohort may not adequately represent patients treated in community settings or low-resource areas, which could limit the generalizability of these results. Future prospective, randomized studies with direct measurement of bone parameters are needed to establish causality and enhance risk-mitigation strategies. Prospective cohort studies with granular lifestyle data and randomized controlled trials comparing step-down strategies from PPIs to H2RAs, coupled with serial DXA and high-resolution peripheral quantitative CT, are needed to delineate causality, quantify dose–response gradients, and test targeted bone-protection protocols, particularly in aging Asian populations with escalating acid-related disease burdens. Conclusion Ultimately, our broad international analysis points out that the sustained use of proton pump inhibitors (PPIs)—in contrast to histamine-2 receptor antagonists (H2RAs)—is tied to a considerably heightened risk of major osteoporotic fractures, hip surgeries or joint replacements, and vertebral compression fractures. These links persist uniformly across multiple factors like gender, age, kidney performance, the application of systemic corticosteroids, Helicobacter pylori infection, and distinct body mass index classifications. While the occurrence of newly diagnosed osteoporosis by physicians did not vary between the two treatment groups, the increased fracture risk implies that the fragility of bones under prolonged PPI treatment is largely reflected in fracture incidents rather than early signs of bone loss on imaging. These results emphasize the need for careful, time-restricted use of PPIs, a more favorable consideration of H2RAs for patients at higher risk of fractures, and a proactive approach to bone health. Future research should seek to establish causality, define dose-response relationships, and evaluate targeted strategies for bone protection and tapering off treatments to reduce skeletal injury while ensuring effective acid suppression. Declarations Author Contributions Dr. Danling Jiang established the investigational framework, devised the methodological protocol, and executed terminal academic scrutiny before manuscript validation. Dr. Xi Li orchestrated data collection methodologies, implemented statistical analytical procedures, and generated the preliminary research document. Dr. WenPin Cheng coordinated clinical information synthesis and performed autonomous confirmation of computational results. Dr. Bei Li helped with data collection. Dr. Guoqing Lv furnished clinical expertise, enhanced interpretative evaluation of research findings, and engaged in iterative manuscript optimization. Dr. Yue Li provided investigational supervision and conducted systematic methodological review across sequential manuscript versions to ensure scientific validity and maintain adherence to rigorous academic standards. Conflict of Interest and Funding The authors have disclosed no conflicts of interest for this work. The study proceeded without external funding, and all authors were engaged in both the research process and the manuscript’s composition. Data Availability The data that support the findings of this study were obtained from the TriNetX research network (TriNetX, LLC, Cambridge, MA, USA). The data are not publicly available due to institutional data use agreements and patient privacy regulations. Access to the TriNetX platform is available to participating institutions under license, and data can be requested directly from TriNetX (https://trinetx.com) subject to appropriate approvals. References Leontiadis GI, Moayyedi P. Proton pump inhibitors and risk of bone fractures. Curr Treat Options Gastroenterol. 2014;12(4):414-423. doi:10.1007/s11938-014-0030-y Corley DA, Kubo A, Zhao W, Quesenberry CP. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology. 2010;139(1):93-101. doi:10.1053/j.gastro.2010.03.055 Yu EW, Bauer SR, Bain PA, Bauer DC. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. 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2","display":"","copyAsset":false,"role":"figure","size":40020,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the outcomes in the Global setting\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7725160/v1/aefd2ca375975f53ba0201bf.png"},{"id":95499727,"identity":"53b39499-e083-48bf-9f91-d29a5dcea1c9","added_by":"auto","created_at":"2025-11-10 05:16:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":39220,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the outcomes in the Asia-Pacific (APAC) region\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7725160/v1/6a699f09e936e33cf054e4e4.png"},{"id":95499757,"identity":"bea0147d-74a0-4e5b-b45d-d6c2a3acbadc","added_by":"auto","created_at":"2025-11-10 05:16:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":37975,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the sensitivity test over the PSM covariate restricted to demographic characters\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7725160/v1/fa922f8656932b26aa758784.png"},{"id":95499729,"identity":"de37bce4-ff3a-48aa-8988-187bfd55d656","added_by":"auto","created_at":"2025-11-10 05:16:47","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":37415,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of the sensitivity test over the PSM covariate restricted to comorbidities\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7725160/v1/442663d6161506fb6bd83e44.png"},{"id":101881726,"identity":"4577f448-46ec-4cd5-9323-c7592d72107d","added_by":"auto","created_at":"2026-02-04 15:15:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":723328,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7725160/v1/70c82170-2722-4657-9e60-aa8c68b684dc.pdf"},{"id":95529198,"identity":"cc621fc3-5308-4d64-91ac-478e1ca955f4","added_by":"auto","created_at":"2025-11-10 10:16:53","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":875465,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryI.docx","url":"https://assets-eu.researchsquare.com/files/rs-7725160/v1/0c93976ee25cb7632ebef836.docx"},{"id":95529112,"identity":"0938475f-f98a-48e5-a390-81bfb6ee31f2","added_by":"auto","created_at":"2025-11-10 10:16:46","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":354975,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryFigure.docx","url":"https://assets-eu.researchsquare.com/files/rs-7725160/v1/f2103d61b610015756fef31a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Proton-Pump Inhibitors Versus H2-Receptor Antagonists on the Risk of Major Osteoporotic Fractures: A Global Propensity-Score-Matched Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTo effectively manage gastro-esophageal reflux disease, acid-suppressive drugs are vital, although their different pharmacodynamic traits could influence bone health differently. Proton-pump inhibitors (PPIs) are effective in significantly diminishing the production of gastric acid, thus limiting calcium absorption within the intestines, increasing gastrin levels, and ultimately resulting in greater bone resorption by osteoclasts [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. On the other hand, histamine-2 receptor blockers (H2RAs) merely partially limit acid secretion and show little influence on how minerals dissolve, hinting at a perhaps diminished chance of fractures.\u003c/p\u003e\u003cp\u003eEpidemiological studies largely corroborate this mechanistic distinction. Through a detailed case-control study with more than 160,000 participants in the US, it was found that extended high-dose PPI use was tied to a 2.6-fold increase in hip fracture risk, while a comparable duration of H2RA exposure did not present this correlation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A following meta-analysis, comprising eleven global cohorts (over 700,000 individuals), confirmed that PPIs consistently raised the likelihood of hip, spine, and overall fractures, while H2RAs did not have a meaningful impact [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Additionally, prospective imaging studies indicate that women on PPI therapy for a year or more exhibit reduced cortical bone thickness and a higher likelihood of falls\u0026mdash;factors that could contribute to increased bone fragility independently of bone mineral density [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A recent British study focusing on frail elderly adults found elevated rates of fragility fractures among long-term PPI users, highlighting the clinical significance in at-risk populations [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eHowever, many previous studies either compared PPIs against non-users or included predominantly white participants, causing uncertainty about whether the increased risk is due to specific properties of the drug class or simply reflects the severity of acid suppression. Furthermore, H2RAs\u0026mdash;often considered second-line treatments\u0026mdash;have rarely been tested as an active comparator due to their distinct mechanisms. These issues are particularly relevant in East-Asian populations, where lower dietary calcium levels and rapid CYP2C19 metabolism might lessen the effectiveness of PPIs. Our upcoming multinational study, focusing on new users, will directly compare chronic use of PPIs and H2RAs across more than two million person-years globally and in APAC region, examining the incidence of major osteoporotic fractures (MOF), lab value diagnosed osteoporosis, surgically treated hip fractures, and vertebral compression fractures. By utilizing detailed claims data and comprehensive subgroup analyses, we aim to determine whether PPIs pose additional fracture risks beyond what is associated with general acid suppression and to establish safer long-term prescribing practices.\u003c/p\u003e\n\u003ch3\u003eEthics Statement\u003c/h3\u003e\n\u003cp\u003eExemption was secured from the Shih Kong Wu Ho-Su Memorial Hospital Institutional Review Board for this investigation (IRB number: 20250803R), eliminating the requirement for participant consent. The analysis employed healthcare data obtained through TriNetX, a federated global research platform that facilitates scientific inquiry using de-identified patient records.\u003c/p\u003e\u003cp\u003eTriNetX adheres to the Health Insurance Portability and Accountability Act (HIPAA), which establishes the regulatory framework for medical data privacy and security within the United States. The platform has obtained ISO 27001:2013 accreditation and utilizes an Information Security Management System (ISMS) to ensure compliance with HIPAA Security Rule requirements for healthcare data protection.\u003c/p\u003e\u003cp\u003ePatient data within the TriNetX environment, whether presented as aggregate metrics or individual records, undergo comprehensive de-identification in accordance with Section 164.514(a) of the HIPAA Privacy Rule. An independent expert has certified the de-identification protocols pursuant to Section 164.514(b)(1) standards, with the most recent attestation issued in December 2020. This certification replaces the need for the previously obtained Western Institutional Review Board waiver.\u003c/p\u003e\u003cp\u003eMedical institutions contributing to the TriNetX database execute Business Associate Agreements (BAAs) that establish appropriate legal frameworks, confirm institutional permissions, and verify authorization for data utilization in research contexts. These contractual arrangements maintain institutional anonymity while enabling scientific investigation. The system employs sophisticated data anonymization procedures that prevent attribution of patient records to specific healthcare facilities, thereby protecting organizational identity while facilitating collaborative research initiatives.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eData availability statement\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study were obtained from the TriNetX research network (TriNetX, LLC, Cambridge, MA, USA). The data are not publicly available due to institutional data use agreements and patient privacy regulations. Access to the TriNetX platform is available to participating institutions under license, and data can be requested directly from TriNetX (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://trinetx.com\u003c/span\u003e\u003cspan address=\"https://trinetx.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) subject to appropriate approvals.\u003c/p\u003e\u003c/div\u003e"},{"header":"Material and Method","content":"\u003cp\u003eData Source and Study Design\u003c/p\u003e\u003cp\u003eThis retrospective cohort analysis utilized the TriNetX Global Collaborative Network, a federated research platform that, at the time of the query (6 July 2025), included de-identified electronic health records from 147 healthcare organizations (HCOs) across North America, Europe, the Middle East, and Asia-Pacific. The database captures longitudinal information on demographics, diagnoses, procedures, medications, and laboratory findings. Data contributions are fully de-identified in accordance with HIPAA 45 CFR \u0026sect;\u0026nbsp;164.514, and research activities performed on the network are granted a waiver of informed consent by the privacy board of each participating institution.\u003c/p\u003e\u003cp\u003eCohort Construction\u003c/p\u003e\u003cp\u003eThe study included adult patients aged 18\u0026ndash;80 years whose records indicated long-term acid-suppressive treatment, defined a priori as having\u0026thinsp;\u0026ge;\u0026thinsp;12 distinct prescriptions within a single drug class between 1 January 2015 and 1 January 2025. Two mutually exclusive exposure cohorts were established:\u003c/p\u003e\u003cp\u003eExclusive long-term PPI users:12 dispensations of proton-pump inhibitors (ATC A02BC) with no exposure to H2-receptor antagonists (H2RA) at any time; initial unmatched N\u0026thinsp;=\u0026thinsp;783,003.\u003c/p\u003e\u003cp\u003eExclusive long-term H2RA users:12 dispensations of H2RAs (ATC A02BA) with no PPI exposure; initial unmatched N\u0026thinsp;=\u0026thinsp;132,615.\u003c/p\u003e\u003cp\u003eThe index date was identified as the first prescription meeting the \u0026ge;\u0026thinsp;12-instance criteria. To reduce the risk of reverse causality, follow-up commenced 180 days post-index and continued until the last recorded encounter; patients with outcomes before this timeframe were automatically excluded by the TriNetX \u0026ldquo;exclude prior outcome\u0026rdquo; feature.\u003c/p\u003e\u003cp\u003eOutcome Definitions\u003c/p\u003e\u003cp\u003eSkeletal events were the primary outcomes, operationalized using validated ICD-10-CM, procedure, medication, and LOINC codes available within the TriNetX interface (comprehensive code lists in Supplementary 1). The endpoints included major osteoporotic fracture, osteoporosis, hip-fracture repair/arthroplasty, vertebral compression fracture, and malignant melanoma (negative control).\u003c/p\u003e\u003cp\u003eCovariates and Propensity-Score Matching (PSM)\u003c/p\u003e\u003cp\u003eBaseline covariates assessed before the index date included: age, sex, self-reported race (White, Black/African American, Asian), and the presence (yes/no) of nine ICD-10 chapter-level comorbidity groupings\u0026mdash;diabetes mellitus (E08-E13), endocrine/nutritional/metabolic disorders (E00-E89), hypertensive diseases (I10-I1A), respiratory diseases (J00-J99), musculoskeletal disorders (M00-M99), genitourinary diseases (N00-N99), infectious and parasitic diseases (A00-B99), injuries/poisonings (S00-T88), and factors influencing health status (Z00-Z99). The calculation of propensity scores involved employing multivariable logistic regression techniques. A greedy nearest-neighbor 1:1 matching without replacement and a caliper of 0.1 pooled SD of the logit generated two balanced cohorts (N\u0026thinsp;=\u0026thinsp;131,698 each) with all absolute standardized mean differences\u0026thinsp;\u0026lt;\u0026thinsp;0.10.\u003c/p\u003e\u003cp\u003eStatistical Analyses\u003c/p\u003e\u003cp\u003e Utilizing Kaplan\u0026ndash;Meier estimators in time-to-event analyses, two-sided log-rank tests were performed; we extracted hazard ratios (HRs) alongside 95% confidence intervals (CIs) from Cox proportional-hazards models to gauge relative hazards. Continuous or count outcomes were compared with Welch\u0026rsquo;s two-sample t-tests. Proportional-hazards assumptions were evaluated using Schoenfeld residuals provided by the platform. The analyses were all two-tailed, and a P value under 0.05 was recognized as having statistical significance. Analyses were conducted within TriNetX Analytics (Cambridge, MA, build 07-2025).\u003c/p\u003e\u003cp\u003eBy presenting an exhaustive account of the study design, patient population, interventions, outcome measures, data collection methods, and staistical analysis, this Material and Methods section ensures the reproducibility and validation of the conclusions drawn from this research paper.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 915,618 adult patients fulfilled the predefined inclusion criteria, comprising 783,003 exclusive long-term proton-pump inhibitor (PPI) users and 132,615 exclusive long-term H2-receptor antagonist (H2RA) users. Following greedy nearest-neighbor 1:1 propensity-score matching without replacement (caliper\u0026thinsp;=\u0026thinsp;0.1 pooled standard deviation of the logit), 131,698 patients remained in each cohort, yielding two balanced groups of 263,396 participants in the final analytic sample. (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e) The demographic characteristics of the participants, such as age, gender, and race, were comparable between the groups. Furthermore, baseline major clinical characteristics were similar among the groups (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ebaseline characteristics of the cohort (before and after the Propensity Score Matching)\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eBefore matching\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eAfter matching\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eClinical Characteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePPI group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;768,530)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH2RA group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;131,721)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStd diff\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePPI group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;131,698)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH2RA group\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;131,698)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStd diff\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003eAge at index\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55.9\u0026thinsp;\u0026plusmn;\u0026thinsp;13.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.9\u0026thinsp;\u0026plusmn;\u0026thinsp;15.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52.9\u0026thinsp;\u0026plusmn;\u0026thinsp;15.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e371,790 (48.38%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70,544 (53.56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.1037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70,422\u003c/p\u003e\n \u003cp\u003e(53.47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70,523\u003c/p\u003e\n \u003cp\u003e(53.55%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e396,740 (51.62%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61,177 (46.44%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.1037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61,276\u003c/p\u003e\n \u003cp\u003e(46.53%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61,175\u003c/p\u003e\n \u003cp\u003e(46.45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0015\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003eRace\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWhite\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e440,675 (57.34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75,056 (56.98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0073\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76,616\u003c/p\u003e\n \u003cp\u003e(58.18%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75,056\u003c/p\u003e\n \u003cp\u003e(56.99%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBlack or African American\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64,255\u003c/p\u003e\n \u003cp\u003e(8.36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16,742\u003c/p\u003e\n \u003cp\u003e(12.71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.142\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16,692\u003c/p\u003e\n \u003cp\u003e(12.67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16,742\u003c/p\u003e\n \u003cp\u003e(12.71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAsian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33,844\u003c/p\u003e\n \u003cp\u003e(4.40%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11,417\u003c/p\u003e\n \u003cp\u003e(8.67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.1732\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10,434\u003c/p\u003e\n \u003cp\u003e(7.92%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11,394\u003c/p\u003e\n \u003cp\u003e(8.65%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0264\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"7\"\u003e\n \u003cp\u003eComorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFactors influencing health status and contact with health services\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e351,145\u003c/p\u003e\n \u003cp\u003e(45.69%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73,794\u003c/p\u003e\n \u003cp\u003e(56.02%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.2078\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e75,464\u003c/p\u003e\n \u003cp\u003e(57.30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e73,771\u003c/p\u003e\n \u003cp\u003e(56.02%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0259\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEndocrine, nutritional and metabolic diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e332,416\u003c/p\u003e\n \u003cp\u003e(43.25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63,312\u003c/p\u003e\n \u003cp\u003e(48.07%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0967\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e64,499\u003c/p\u003e\n \u003cp\u003e(48.98%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63,300\u003c/p\u003e\n \u003cp\u003e(48.07%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0182\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiseases of the musculoskeletal system and connective tissue\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e299,646\u003c/p\u003e\n \u003cp\u003e(38.99%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54,592(41.45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0501\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54,393\u003c/p\u003e\n \u003cp\u003e(41.30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54,588\u003c/p\u003e\n \u003cp\u003e(41.45%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease of the genitourinary system\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e242,645\u003c/p\u003e\n \u003cp\u003e(31.57%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49,826\u003c/p\u003e\n \u003cp\u003e(37.83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.1317\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50,221\u003c/p\u003e\n \u003cp\u003e(38.13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49,807\u003c/p\u003e\n \u003cp\u003e(37.82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0065\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease of the respiratory system\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e262,518\u003c/p\u003e\n \u003cp\u003e(34.16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48,360(36.71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0534\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48,480\u003c/p\u003e\n \u003cp\u003e(36.81%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48,358\u003c/p\u003e\n \u003cp\u003e(36.72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0019\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHypertensive diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e244,512\u003c/p\u003e\n \u003cp\u003e(31.82%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43,537\u003c/p\u003e\n \u003cp\u003e(33.05%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0264\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e44,135\u003c/p\u003e\n \u003cp\u003e(33.51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43,535\u003c/p\u003e\n \u003cp\u003e(33.06%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0097\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInjury, poisoning and certain other consequences of external causes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e208,112\u003c/p\u003e\n \u003cp\u003e(27.08%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40,964\u003c/p\u003e\n \u003cp\u003e(31.10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0886\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41,000\u003c/p\u003e\n \u003cp\u003e(31.13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40,957\u003c/p\u003e\n \u003cp\u003e(31.10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCertain infectious and parasitic diseases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e167,430\u003c/p\u003e\n \u003cp\u003e(21.79%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31,211\u003c/p\u003e\n \u003cp\u003e(23.70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0456\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30,900\u003c/p\u003e\n \u003cp\u003e(23.46%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31,208\u003c/p\u003e\n \u003cp\u003e(23.70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0055\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDiabetes mellitus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e123,272\u003c/p\u003e\n \u003cp\u003e(16.04%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22,128\u003c/p\u003e\n \u003cp\u003e(16.80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0205\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22,353\u003c/p\u003e\n \u003cp\u003e(16.97%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22,127\u003c/p\u003e\n \u003cp\u003e(16.80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.0046\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eIn the primary global cohort, long-term proton pump inhibitor (PPI) therapy was associated with a significantly higher risk of major osteoporotic fracture (MOF) than histamine-2 receptor antagonist (H2RA) therapy (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.18\u0026ndash;1.28; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Elevated risks were likewise observed for hip repair/arthroplasty (HR 1.46, 95% CI 1.35\u0026ndash;1.58; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and vertebral compression fracture (HR 1.16, 95% CI 1.09\u0026ndash;1.23; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), whereas incident osteoporosis was not significantly different between groups (HR 1.01, 95% CI 0.98\u0026ndash;1.03; p\u0026thinsp;=\u0026thinsp;0.62). The negative-control outcome of melanoma showed no association (HR 1.10, 95% CI 0.95\u0026ndash;1.27). (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003eGeographic stratification revealed a stronger signal in the Asia\u0026ndash;Pacific (APAC) region, where PPI use conferred a 77% increase in MOF risk (HR 1.77, 95% CI 1.56\u0026ndash;2.01; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and a 39% increase in vertebral compression fracture (HR 1.40, 95% CI 1.16\u0026ndash;1.68; p\u0026thinsp;=\u0026thinsp;0.0004); the hip repair/arthroplasty endpoint was not significant in APAC (HR 1.01, 95% CI 0.68\u0026ndash;1.51; p\u0026thinsp;=\u0026thinsp;0.95). (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\n\u003cp\u003ePrespecified subgroup analyses showed broadly consistent excess hazard ratios for MOF across sex (men: HR 1.17, 95% CI 1.10\u0026ndash;1.25; women: HR 1.28, 95% CI 1.21\u0026ndash;1.35), chronic kidney disease status (CKD+: HR 1.31, 95% CI 1.20\u0026ndash;1.43; CKD\u0026ndash;: HR 1.20, 95% CI 1.15\u0026ndash;1.25), systemic corticosteroid use (HR 1.33, 95% CI 1.27\u0026ndash;1.39), Helicobacter pylori infection (HR 1.16, 95% CI 1.02\u0026ndash;1.31), and body-mass-index strata (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30 kg/m\u0026sup2;: HR 1.16, 95% CI 1.07\u0026ndash;1.26; BMI reference range: HR 1.08, 95% CI 0.98\u0026ndash;1.19). (Supplementary Fig.\u0026nbsp;1\u0026ndash;8)\u003c/p\u003e\n\u003cp\u003eSensitivity analyses confirmed the robustness of these findings: the association persisted when propensity-score matching was restricted to demographic covariates alone (model 1, HR 1.23, 95% CI 1.18\u0026ndash;1.28) and when matching was based solely on comorbidities (model 2, HR 1.36, 95% CI 1.30\u0026ndash;1.41). (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e,\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, our aim was to assess the long-term skeletal safety of proton pump inhibitor (PPI) treatment in comparison to histamine-2 receptor antagonist (H2RA) treatment in adults undergoing chronic acid suppression. Our results show that prolonged PPI usage was linked to a notably greater risk of the primary outcome, major osteoporotic fractures, and similarly posed heightened risks for the secondary outcomes of hip repair/arthroplasty and vertebral compression fractures.\u003c/p\u003e\u003cp\u003eLong-term suppression of gastric acid is increasingly acknowledged as a risk factor for skeletal health, as sufficient acidity in the gastrointestinal tract is crucial for the ionization and transportation of calcium and magnesium. The considerable decrease in stomach acid from proton-pump inhibitors (PPIs) obstructs mineral uptake, induces secondary hyperparathyroidism, and quickens the resorption of bone via osteoclasts [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Furthermore, PPIs promote chronic hypergastrinemia, which enhances histamine-dependent osteoclast activity, lowers osteoprotegerin levels, and raises bone turnover rates [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. When hypomagnesemia occurs alongside other conditions, it adversely affects parathyroid hormone release and the formation of 1,25-dihydroxy-vitamin-D, worsening structural fragility [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In contrast, histamine-2-receptor antagonists (H2RAs) result in milder and shorter acid suppression with minimal influence on calcium solubilization or gastrin release, thus presenting a biologically reasonable lower risk of fractures [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. These contrasting mechanisms warrant direct epidemiological comparisons, particularly concerning significant clinical events such as major osteoporotic fractures (MOF), surgically treated hip fractures, and vertebral compression fractures (VCF), all of which contribute to mortality, disability, and healthcare costs in aging populations [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eProminent cohorts from the United Kingdom General Practice Research Database and Canadian administrative claims, each involving over 150,000 participants, were the first to reveal a 1.5- to 1.9-fold increase in hip and spine fractures among chronic PPI users compared to non-users [\u003cspan additionalcitationids=\"CR20 CR21 CR22\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Further observational research from the Nurses\u0026rsquo; Health Study (n\u0026thinsp;\u0026asymp;\u0026thinsp;80,000) and the Women\u0026rsquo;s Health Initiative (n\u0026thinsp;\u0026asymp;\u0026thinsp;130,000) reinforced dose-response links and observed some alleviation tied to proper calcium intake [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Meta-analyses encompassing more than two million individuals estimate relative increases in fracture risk of 20\u0026ndash;35% for any fracture and 30\u0026ndash;60% for hip or spine fractures linked with PPIs, whereas H2RAs appear largely neutral [\u003cspan additionalcitationids=\"CR27 CR28 CR29\" citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Randomized controlled trials are limited and often underpowered (\u0026lt;\u0026thinsp;1,000 participants, \u0026le; 12 months), highlighting the need for extensive real-world datasets to identify infrequent but serious skeletal outcomes [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEmerging evidence from Asian populations has only recently begun to surface. In a study by Park et al., they evaluated more than 1\u0026nbsp;million person-years involving senior Korean women and identified a 32% greater probability of osteoporotic fractures associated with PPIs as opposed to H2RAs [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In Taiwan, Chou et al. tracked 398,885 patients with type 2 diabetes and found a 41% increased risk of hip fractures in long-term PPI users compared to non-users, although they did not make a direct comparison with H2RAs [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. A nationwide case-control study in Korea involving 21,754 fracture cases similarly established a population-wide association between PPIs and fractures but did not include an active comparator group [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. While these studies are substantial, they did not comprehensively address acid-suppression classes, specific fracture types, and Asian-specific factors such as lower calcium intake and a higher prevalence of CYP2C19 rapid metabolizers.\u003c/p\u003e\u003cp\u003eUtilizing a multinational claims database encompassing more than 250,000 individuals and over two million person-years of follow-up, our research offers the most comprehensive head-to-head analysis of PPIs versus H2RAs within global and Asian population to date. We have uncovered statistically meaningful heightened dangers for significant osteoporotic fractures, hip-fracture surgery/arthroplasty, and vertebral compression fractures linked to PPIs when compared to H2RAs, with findings consistently observed across different subgroups categorized by gender, age, chronic kidney issues, corticosteroid treatment, helicobacter pylori infection, and high body mass index. Importantly, there was no substantial disparity in the rates of physician-confirmed osteoporosis between the two groups, which suggests that the skeletal vulnerability linked to PPIs is fundamentally demonstrated through fractures occurring from minor trauma rather than through initial imaging evidence of bone depletion. The hazard ratios we observed align with the higher ranges of previous meta-analyses [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] while refining these estimates by illustrating that the increased risk continues even when both groups are under acid suppression treatment. Our active-comparator approach reduces the potential for confounding by indication, and the inclusion of East-Asian patients\u0026mdash;who possess different dietary calcium intake, genetic variations, and baseline bone-mineral density than Western individuals\u0026mdash;improves the external applicability of our findings in a region undergoing significant population aging. Together, the insights gathered advocate for a measured approach to the extended use of PPIs, recommending H2RAs for those at a higher risk of fractures, and stressing the need for proactive strategies aimed at improving bone health\u0026mdash;these include calcium and vitamin D supplementation, engaging in weight-bearing activities, and regular dual-energy X-ray absorptiometry for chronic PPI users.\u003c/p\u003e\u003cp\u003eHowever, our research has several limitations due to its retrospective nature involving the TriNetX federated claims and electronic health-record network. First, although extensive propensity-score adjustments were made, we cannot rule out residual and unmeasured confounding factors\u0026mdash;such as the use of over-the-counter acid-suppressive medications, smoking and alcohol consumption, levels of physical activity, and intake of dietary calcium or vitamin D. Second, medication exposure was determined based on prescription or dispensing records instead of confirmed ingestion; variations in dosage, formulation, and non-prescription PPI use were not consistently recorded, which could result in misclassification of exposure. Third, fracture outcomes were identified using diagnostic and procedure codes without systematic confirmation through radiographic imaging, increasing the risk of coding errors or under-reporting, especially for asymptomatic vertebral fractures. Fourth, essential covariates related to bone health, including baseline bone-mineral density, serum vitamin D levels, inflammatory markers, and menopausal status, were not available in the aggregated dataset. Fifth, variations in coding practices, data completeness, and follow-up duration among the participating health-care organizations may introduce variability at the site level that we cannot control for. Finally, since TriNetX primarily collects data from tertiary-care centers that are willing to contribute to the network, our cohort may not adequately represent patients treated in community settings or low-resource areas, which could limit the generalizability of these results. Future prospective, randomized studies with direct measurement of bone parameters are needed to establish causality and enhance risk-mitigation strategies.\u003c/p\u003e\u003cp\u003eProspective cohort studies with granular lifestyle data and randomized controlled trials comparing step-down strategies from PPIs to H2RAs, coupled with serial DXA and high-resolution peripheral quantitative CT, are needed to delineate causality, quantify dose\u0026ndash;response gradients, and test targeted bone-protection protocols, particularly in aging Asian populations with escalating acid-related disease burdens.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eUltimately, our broad international analysis points out that the sustained use of proton pump inhibitors (PPIs)\u0026mdash;in contrast to histamine-2 receptor antagonists (H2RAs)\u0026mdash;is tied to a considerably heightened risk of major osteoporotic fractures, hip surgeries or joint replacements, and vertebral compression fractures. These links persist uniformly across multiple factors like gender, age, kidney performance, the application of systemic corticosteroids, Helicobacter pylori infection, and distinct body mass index classifications. While the occurrence of newly diagnosed osteoporosis by physicians did not vary between the two treatment groups, the increased fracture risk implies that the fragility of bones under prolonged PPI treatment is largely reflected in fracture incidents rather than early signs of bone loss on imaging. These results emphasize the need for careful, time-restricted use of PPIs, a more favorable consideration of H2RAs for patients at higher risk of fractures, and a proactive approach to bone health. Future research should seek to establish causality, define dose-response relationships, and evaluate targeted strategies for bone protection and tapering off treatments to reduce skeletal injury while ensuring effective acid suppression.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Danling Jiang established the investigational framework, devised the methodological protocol, and executed terminal academic scrutiny before manuscript validation. Dr. Xi Li\u0026nbsp;orchestrated data collection methodologies, implemented statistical analytical procedures, and generated the preliminary research document. Dr. WenPin Cheng coordinated clinical information synthesis and performed autonomous confirmation of computational results.\u0026nbsp;Dr.\u0026nbsp;Bei Li\u0026nbsp;helped with data collection.\u0026nbsp;Dr. Guoqing Lv\u0026nbsp;furnished clinical expertise, enhanced interpretative evaluation of research findings, and engaged in iterative manuscript optimization. Dr. Yue Li\u0026nbsp;provided investigational supervision and conducted systematic methodological review across sequential manuscript versions to ensure scientific validity and maintain adherence to rigorous academic standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest and Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have disclosed no conflicts of interest for this work. The study proceeded without external funding, and all authors were engaged in both the research process and the manuscript’s composition.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data that support the findings of this study were obtained from the TriNetX research network (TriNetX, LLC, Cambridge, MA, USA). The data are not publicly available due to institutional data use agreements and patient privacy regulations. Access to the TriNetX platform is available to participating institutions under license, and data can be requested directly from TriNetX (https://trinetx.com) subject to appropriate approvals.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLeontiadis GI, Moayyedi P. Proton pump inhibitors and risk of bone fractures. Curr Treat Options Gastroenterol. 2014;12(4):414-423. doi:10.1007/s11938-014-0030-y\u003c/li\u003e\n\u003cli\u003eCorley DA, Kubo A, Zhao W, Quesenberry CP. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology. 2010;139(1):93-101. doi:10.1053/j.gastro.2010.03.055\u003c/li\u003e\n\u003cli\u003eYu EW, Bauer SR, Bain PA, Bauer DC. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med. 2011;124(6):519-526. doi:10.1016/j.amjmed.2011.01.007\u003c/li\u003e\n\u003cli\u003eLewis JR, Barre D, Zhu K, Ivey KL, Lim EM, Hughes J, et al. Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. J Bone Miner Res. 2014;29(11):2489-2497. doi:10.1002/jbmr.2279\u003c/li\u003e\n\u003cli\u003eZirk-Sadowski J, Masoli JA, Strain WD, Delgado J, Henley W, Hamilton W, et al. Proton-pump inhibitors and fragility fractures in vulnerable older patients. Am J Gastroenterol. 2017;112(3):520-523. doi:10.1038/ajg.2016.584\u003c/li\u003e\n\u003cli\u003eYang YX, Lewis JD, Epstein S, Metz DC, Wan J, Ferrentino JA, et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296(24):2947-2953. doi:10.1001/jama.296.24.2947\u003c/li\u003e\n\u003cli\u003eVestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H₂ receptor antagonists and risk of fracture. Calcif Tissue Int. 2006;79(3):127-134. doi:10.1007/s00223-006-0055-9\u003c/li\u003e\n\u003cli\u003eTargownik LE, Lix LM, Metge CJ, Leslie WD, Prior H, Shearer B, et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179(4):319-326. doi:10.1503/cmaj.071330\u003c/li\u003e\n\u003cli\u003eGray SL, LaCroix AZ, Larson JC, Manson JE, Cauley JA, McTiernan A, et al. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women. Arch Intern Med. 2010;170(9):765-771. doi:10.1001/archinternmed.2010.94\u003c/li\u003e\n\u003cli\u003eAdams AL, Black MH, Zhang JL, Shi JM, Jacobsen SJ. Proton-pump inhibitor use and hip fractures in men: a population-based case-control study. Ann Epidemiol. 2014;24(4):286-290. doi:10.1016/j.annepidem.2014.01.004\u003c/li\u003e\n\u003cli\u003eMaes ML, Fixen DR, Linnebur SA. Adverse effects of proton pump inhibitor use in older adults: a review. Ther Adv Drug Saf. 2017;8(9):273-297. doi:10.1177/2042098617715381\u003c/li\u003e\n\u003cli\u003eEom CS, Park SM, Myung SK, Yun JM, Ahn JS. Use of acid-suppressive drugs and risk of fracture: a meta-analysis. Ann Fam Med. 2011;9(3):257-267. doi:10.1370/afm.1234\u003c/li\u003e\n\u003cli\u003eLenihan CR, Sukumaran Nair S, Vangala C, Ramanathan V, Montez-Rath ME, Winkelmayer WC. Proton pump inhibitor use and risk of hip fracture in kidney transplant recipients. Am J Kidney Dis. 2017;69(5):595-601. doi:10.1053/j.ajkd.2016.09.019\u003c/li\u003e\n\u003cli\u003eLin SM, Yang SH, Liang CC, Huang HK. Proton pump inhibitor use and the risk of osteoporosis and fracture in stroke patients: a population-based cohort study. Osteoporos Int. 2018;29(1):153-162. doi:10.1007/s00198-017-4262-2\u003c/li\u003e\n\u003cli\u003ePouwels S, Lalmohamed A, Souverein PC, Cooper C, Veldt BJ, Leufkens HG, et al. Use of proton pump inhibitors and risk of hip/femur fracture: a case-control study. Osteoporos Int. 2011;22(3):903-910. doi:10.1007/s00198-010-1437-1\u003c/li\u003e\n\u003cli\u003eKaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy. 2008 Aug;28(8):951-9. doi: 10.1592/phco.28.8.951. PMID: 18657011.\u003c/li\u003e\n\u003cli\u003eHussain S, Siddiqui AN, Habib A, Hussain MS, Najmi AK. Proton pump inhibitors\u0026rsquo; use and risk of hip fracture: a systematic review and meta-analysis. Rheumatol Int. 2018;38(11):1999-2014. doi:10.1007/s00296-018-4142-x\u003c/li\u003e\n\u003cli\u003ePark DH, Seo SI, Lee KJ, Kim J, Kim Y, Seo WW, et al. Long-term proton pump inhibitor use and risk of osteoporosis and hip fractures: a nationwide population-based and multicenter cohort study using a common data model. J Gastroenterol Hepatol. 2022;37(8):1534-1543. doi:10.1111/jgh.15879\u003c/li\u003e\n\u003cli\u003eFraser LA, Leslie WD, Targownik LE, Papaioannou A, Adachi JD; CaMos Research Group. The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study. Osteoporos Int. 2013 Apr;24(4):1161-8. doi: 10.1007/s00198-012-2112-9. Epub 2012 Aug 14. PMID: 22890365; PMCID: PMC5096922.\u003c/li\u003e\n\u003cli\u003eKhalili H, Huang ES, Jacobson BC, Camargo CA, Feskanich D, Chan AT, et al. Proton pump inhibitor use and risk of hip fracture in relation to diet. BMJ. 2012;344:e372. doi:10.1136/bmj.e372\u003c/li\u003e\n\u003cli\u003eFreedberg DE, Haynes K, Denburg MR, Zemel BS, Leonard MB, Abrams JA, et al. Use of proton pump inhibitors is associated with fractures in young adults: a population-based study. Osteoporos Int. 2015;26(10):2501-2507. doi:10.1007/s00198-015-3168-0\u003c/li\u003e\n\u003cli\u003eNgamruengphong S, Leontiadis GI, Radhi S, Dentino A, Nugent K. Proton pump inhibitors and risk of fracture: a systematic review. Am J Gastroenterol. 2011;106(7):1209-1218. doi:10.1038/ajg.2011.123\u003c/li\u003e\n\u003cli\u003ePoly TN, Islam MM, Yang HC, Wu CC, Li YJ. Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int. 2019 Jan;30(1):103-114. doi: 10.1007/s00198-018-4788-y. Epub 2018 Dec 12. PMID: 30539272.\u003c/li\u003e\n\u003cli\u003eYu EW, Blackwell T, Ensrud KE, Hillier TA, Lane NE, Orwoll ES, et al. Acid-suppressive medications and risk of bone loss and fracture. Calcif Tissue Int. 2008;83(4):251-259. doi:10.1007/s00223-008-9150-9\u003c/li\u003e\n\u003cli\u003eMin YW, Lee YC, Kim K, Ryu S, Hong KS, Jeon HH, Kim YS, Park JH, Son HJ, Rhee PL. Proton pump inhibitor use is associated with hip fracture development: a nationwide population-based cohort study. Korean J Intern Med. 2020 Sep;35(5):1084-1093. doi: 10.3904/kjim.2018.331. Epub 2019 Nov 4. PMID: 31671930; PMCID: PMC7487306.\u003c/li\u003e\n\u003cli\u003eKwok CS, Yeong JK, Loke YK. Meta-analysis: risk of fractures with acid-suppressing medication. Bone. 2011 Apr 1;48(4):768-76. doi: 10.1016/j.bone.2010.12.015. Epub 2010 Dec 23. PMID: 21185417.\u003c/li\u003e\n\u003cli\u003eNassar Y, Richter S. Proton-pump Inhibitor Use and Fracture Risk: An Updated Systematic Review and Meta-analysis. J Bone Metab. 2018 Aug;25(3):141-151. doi: 10.11005/jbm.2018.25.3.141. Epub 2018 Aug 31. PMID: 30237993; PMCID: PMC6135649.\u003c/li\u003e\n\u003cli\u003eZhou B, Huang Y, Li H, Sun W, Liu J, Zhang Y, et al. Proton-pump inhibitors and risk of fractures: an updated meta-analysis. Osteoporos Int. 2016;27(1):339-347. doi:10.1007/s00198-015-3262-7\u003c/li\u003e\n\u003cli\u003eWei J, Chan AT, Zeng C, Bai X, Lu N, Lei G, Zhang Y. Association between proton pump inhibitors use and risk of hip fracture: A general population-based cohort study. Bone. 2020 Oct;139:115502. doi: 10.1016/j.bone.2020.115502. Epub 2020 Jun 25. PMID: 32593677.\u003c/li\u003e\n\u003cli\u003eThong BKS, Ima-Nirwana S, Chin KY. Proton Pump Inhibitors and Fracture Risk: A Review of Current Evidence and Mechanisms Involved. Int J Environ Res Public Health. 2019 May 5;16(9):1571. doi: 10.3390/ijerph16091571. PMID: 31060319; PMCID: PMC6540255.\u003c/li\u003e\n\u003cli\u003eOh DJ, Nam JH, Lee HS, Moon YR, Lim YJ. The combined use of anti-peptic agents is associated with an increased risk of osteoporotic fracture: a nationwide case-control study. Korean J Intern Med. 2024;39(2):228-237. doi:10.3904/kjim.2023.326\u003c/li\u003e\n\u003cli\u003ePark JH, Song YM, Jung JH, Han K. Comparative analysis of the risk of osteoporotic fractures with proton pump inhibitor use and histamine-2 receptor antagonist therapy in elderly women: A nationwide population-based nested case-control study. Bone. 2020 Jun;135:115306. doi: 10.1016/j.bone.2020.115306. Epub 2020 Feb 29. PMID: 32126312.\u003c/li\u003e\n\u003cli\u003eChou YS, Jiang HJ, Chen CH, Ho PS, Lee TC. Proton pump inhibitor use and hip fracture in Taiwanese patients with type 2 diabetes. Sci Rep. 2020;10:14081. doi:10.1038/s41598-020-70712-9\u003c/li\u003e\n\u003cli\u003eKim JJ, Jang EJ, Park J, Sohn HS. Association between proton pump inhibitor use and risk of fracture: a Korean case-control study. PLoS One. 2020;15(7):e0235163. doi:10.1371/journal.pone.0235163\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Proton Pump Inhibitors, Histamine H2 Antagonists, Fractures, Osteoporotic, Hip Fractures","lastPublishedDoi":"10.21203/rs.3.rs-7725160/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7725160/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e\u003cp\u003eLong-term suppression of gastric acid is crucial for various conditions; however, proton-pump inhibitors (PPIs) may negatively impact skeletal health more than histamine-2 receptor antagonists (H2RAs). There is limited head-to-head data, particularly within Asian communities that have unique calcium consumption and drug metabolism patterns.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003e We conducted a retrospective cohort study that matched participants using propensity scores, utilizing the TriNetX integrated claims and electronic health-record database. Adults aged between 18 and 80 years who had at least 12 prescriptions for either a sole PPI or H2RA therapy from 2015 to 2025 were included. Following a 1:1 nearest-neighbor matching (caliper\u0026thinsp;=\u0026thinsp;0.1), 131,698 individuals remained in each cohort. The outcomes measured included major osteoporotic fracture (MOF; primary), hip repair/arthroplasty, vertebral compression fracture, newly diagnosed osteoporosis, and malignant melanoma (negative control). The application of Cox proportional-hazards models allowed for the assessment of hazard ratios (HRs) and their linked 95% confidence intervals (CIs).\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOver a span of more than two million person-years, PPIs were linked to a higher incidence of MOF compared to H2RAs (HR 1.23, 95% CI 1.18\u0026ndash;1.28; p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Significant dangers were pointed out regarding hip repair/arthroplasty (HR 1.46, 1.35\u0026ndash;1.58) and vertebral compression fractures (HR 1.16, 1.09\u0026ndash;1.23), while newly diagnosed osteoporosis showed no notable changes (HR 1.01, 0.98\u0026ndash;1.03). The negative-control outcome indicated no correlation. In the Asia-Pacific subgroup, the risk of MOF increased by 77% (HR 1.77, 1.56\u0026ndash;2.01). Consistent findings emerged from subgroup and sensitivity analyses. The increased fracture risk remained despite comparable demographics, comorbidities, and consistent acid suppression, suggesting that there may be drug-class-specific skeletal toxicity\u0026mdash;potentially due to impaired mineral absorption, elevated gastrin levels, and increased bone turnover. The more pronounced effect in East-Asian populations highlights the interaction between dietary and genetic influences.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOngoing PPI treatment, in contrast to H2RA therapy, leads to significant increases in the risk of fragility fractures. These findings advocate for a reduction in PPI usage duration, favoring H2RAs for patients at greater fracture risk, and call for proactive measures to safeguard bone health while future studies explore causality and effective strategies for mitigation.\u003c/p\u003e","manuscriptTitle":"Proton-Pump Inhibitors Versus H2-Receptor Antagonists on the Risk of Major Osteoporotic Fractures: A Global Propensity-Score-Matched Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-10 05:16:42","doi":"10.21203/rs.3.rs-7725160/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"00804548-97f4-44ec-ae8f-e96610fb1ee2","owner":[],"postedDate":"November 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":57414145,"name":"Health sciences/Diseases"},{"id":57414147,"name":"Health sciences/Medical research"},{"id":57414149,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2026-02-04T07:43:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-10 05:16:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7725160","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7725160","identity":"rs-7725160","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}