Association Between Chronic Proton Pump Inhibitor Use and Frailty in Geriatric Patients in Primary Care

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1. Introduction

Population aging represents one of the most significant challenges for contemporary health systems. The increase in life expectancy has been accompanied by a higher prevalence of chronic diseases, multimorbidity, and long-term medication use, particularly among older adults managed within Primary Health Care (PHC). In this context, frailty emerges as a multifactorial geriatric syndrome characterized by a decline in physiological reserve and an increased vulnerability to adverse outcomes, such as hospitalizations, falls, functional disability, and mortality (JOHNSON et al., 2024; PRIDHAM; ROCKWOOD; RUTENBERG, 2024) [31, 52].

Frailty results from the interplay of biological, clinical, social, and environmental factors, and is currently considered a significant marker of vulnerability in older adults. Recent studies demonstrate that alterations in the cardiovascular, neuromuscular, immunological, and metabolic systems contribute to the development of this condition, reinforcing the need for early identification in clinical practice (ARRUÉ et al., 2024; SILAN; NICOLAIO; BOCCUZZO, 2025) [5, 62]. Parallel to this, proton pump inhibitors (PPIs) are among the most frequently prescribed medications worldwide. Drugs such as omeprazole, pantoprazole, esomeprazole, and lansoprazole are widely used for the treatment of gastroesophageal reflux disease, gastritis, and peptic ulcers, as well as for the prevention of gastric lesions induced by non-steroidal anti-inflammatory drugs (NSAIDs) (AHMED et al., 2023; KAMBOJ et al., 2024) [2, 33]. Although PPIs demonstrate high therapeutic efficacy and a favorable safety profile in short-term treatments, recent evidence has raised concerns regarding their long-term use, particularly in older populations. Several observational studies and systematic reviews suggest an association between the chronic use of these medications and an increased risk of clinically significant adverse events, including micronutrient deficiency, osteoporosis, fractures, respiratory infections, chronic kidney disease, cardiovascular alterations, and cognitive decline (ANDRAWES et al., 2025; LAKSHMISAI et al., 2025; CHAUDHRY et al., 2025) [3, 36, 14].

Among the pathophysiological mechanisms proposed for such complications, the reduction in intestinal absorption of vitamin B12, magnesium, calcium, and iron—essential nutrients for maintaining muscular, neurological, and bone function—is particularly noteworthy. The deficiency of these elements may directly contribute to loss of strength, sarcopenia, fatigue, and functional impairment, all of which are factors closely linked to the development of geriatric frailty (COSTA et al., 2021; SILVA et al., 2022; BARBOSA Long-term PPI use has been associated with an increased risk of osteopenia, osteoporosis, and fragility fractures, especially in older adults with multiple comorbidities. These conditions may accelerate the loss of functional independence and promote the progression of frailty syndrome, thereby significantly increasing the demand for health care services (MARQUES et al., 2021; ROBERT et al., 2025; SILVA et al., 2024) [41, 53, 63].

Another relevant aspect refers to the association between PPIs and cognitive alterations. Recent studies have investigated potential links between the long-term use of these medications and a higher incidence of cognitive impairment and dementia. Although the underlying mechanisms have not yet been fully elucidated, it is hypothesized that metabolic, inflammatory, and vascular changes may contribute to this process, negatively impacting the functionality of older adults (CHAN et al., 2023; XIE et al., 2024; PENG et al., 2026) [13, 72, 49]. Cardiovascular repercussions have also garnered increasing attention. Research indicates an association between chronic PPI use and an increased risk of heart failure, cardiovascular events, and QT interval prolongation, particularly in older adults and patients with chronic conditions. Such alterations may contribute to a reduction in functional capacity and an increase in clinical vulnerability, both of which are central components of frailty (BELL et al., 2021; GENG et al., 2023; FAN et al., 2024) [11, 29, 25].

Polypharmacy, frequently observed in the geriatric population, constitutes another important factor in this discussion. The simultaneous use of multiple medications increases the risk of drug-drug interactions, adverse reactions, and potentially inappropriate prescribing. In this scenario, PPIs often remain prescribed for periods exceeding the necessary duration, even after the resolution of the initial indication, contributing to prolonged exposure and cumulative risks (LAWSON et al., 2022; OLIVEIRA et al., 2023; MOREIRA; RODRIGUES, 2025) [37, 48, 43]. Numerous studies have demonstrated a high prevalence of inappropriate PPI prescribing in outpatient settings, long-term care facilities, and primary health care services. This reality highlights the need for periodic medication reviews and the implementation of deprescribing strategies based on scientific evidence (ÇELIK et al., 2021; MUHEIM et al., 2021; WABE et al., 2025) [12, 44, 70].

In recent years, initiatives focused on PPI deprescribing have shown promising results in reducing adverse events and optimizing pharmacotherapy in older adults. International guidelines recommend continuous assessment of the need to maintain these medications, particularly in patients without a current clinical indication (TARGOWNIK; FISHER; SAINI, 2022; ROSSI et al., 2024; PEREIRA et al., 2024) [66, 55, 50]. Primary Health Care (PHC) holds a strategic position in the early identification of frailty and in the rationalization of medication use among older adults. As the primary point of entry into the health system, PHC facilitates longitudinal follow-up, monitoring of risk factors, and the implementation of preventive interventions capable of reducing complications associated with polypharmacy (ARAGONEZ, 2025; CORRÊA et al., 2022; SANTOS et al., 2025) [4, 17, 59]. Despite the growing number of studies on the safety of PPIs, important gaps remain regarding their specific influence on the development and progression of frailty in older adults. Understanding this association may contribute to improving clinical protocols, guiding deprescribing strategies, and strengthening safe practices in health care for the geriatric population (DEWI et al., 2024; WU et al., 2025; CONDUR Given this scenario, it is essential to synthesize and critically analyze the available scientific evidence regarding the relationship between the chronic use of proton pump inhibitors and frailty in geriatric patients monitored within Primary Health Care, aiming to understand their mechanisms, associated factors, and potential implications for clinical practice.

2. Objectives

2.1. General Objective

To analyze, through a systematic literature review, the relationship between the chronic use of proton pump inhibitors (PPIs) and the development or exacerbation of frailty in geriatric patients monitored within Primary Health Care, by identifying the primary pathophysiological mechanisms, associated factors, and clinical impacts resulting from this association.

2.2. Specific Objectives

• To identify available scientific evidence regarding the association between long-term proton pump inhibitor use and frailty in older adults. • To evaluate the primary adverse effects associated with chronic PPI use that may contribute to the development of frailty syndrome, including micronutrient deficiencies, sarcopenia, osteoporosis, fractures, cognitive impairment, and cardiovascular alterations. • To investigate the pathophysiological mechanisms involved in the relationship between long-term PPI use and the reduction of functional capacity in geriatric patients. • To analyze the influence of polypharmacy and potentially inappropriate prescribing on the long-term use of PPIs in the older adult population. • To describe the prevalence and patterns of chronic PPI utilization among older adults managed within Primary Health Care services. • To assess deprescribing strategies for PPIs described in the literature and their impacts on medication safety and the quality of life of older adults. • To identify clinical, behavioral, and environmental factors associated with an increased risk of frailty in chronic PPI users. • To analyze the role of Primary Health Care in the prevention, monitoring, and management of risks related to the long-term use of proton pump inhibitors. • To synthesize evidence-based recommendations to optimize the prescription and monitoring of PPIs in geriatric patients, aiming to reduce adverse avvents and minimize the progression of frailty

3. Hypothesis

The chronic use of proton pump inhibitors is associated with increased frailty in geriatric patients monitored within Primary Health Care, due to a higher occurrence of micronutrient deficiency, musculoskeletal alterations, cognitive impairment, polypharmacy, and other adverse events that contribute to the reduction of the physiological reserve and functional capacity of these individuals. Thus, monitoring and rational deprescribing strategies for PPIs can reduce clinical risks and promote healthier and more functional aging.

4. Methods

4.1. Study Design

This is a systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines. The objective of this study is to identify, select, critically appraise, and synthesize the available scientific evidence regarding the relationship between the chronic use of proton pump inhibitors (PPIs) and frailty in geriatric patients monitored within Primary Health Care (TARGOWNIK; FISHER; SAINI, 2022; ROSSI et al., 2024; CONDUR et al., 2025) [66, 55, 15].

4.2. Information Sources and Search Strategy

The bibliographic search was performed in the following databases: PubMed/MEDLINE, Scopus, Web of Science, Embase, Cochrane Library, LILACS, and the Virtual Health Library (VHL). These were selected as relevant sources for studies in the fields of geriatrics, clinical pharmacology, and primary health care.

We utilized controlled descriptors from the Medical Subject Headings (MeSH) and the Health Sciences Descriptors (DeCS) vocabularies, combined using the Boolean operators "AND" and "OR." The search strategy was structured using the following terms: • "Proton Pump Inhibitors" OR "PPI" OR "Omeprazole"; • "Frailty" OR "Frailty Syndrome" OR "Frailty Index"; • "Older Adults" OR "Aged" OR "Elderly"; • "Primary Health Care" OR "Primary Care"; • "Polypharmacy"; • "Deprescribing".

An example of the search strategy applied in PubMed was as follows:

("Proton Pump Inhibitors"[MeSH] OR "PPI") AND ("Frailty"[MeSH] OR "Frailty Syndrome") AND ("Aged"[MeSH] OR "Older Adults").

4.3. Search Period

The search included studies published between January 2021 and June 2026. This period was selected to encompass the most recent scientific evidence regarding the potential impacts of long-term PPI use on the health of the older adult population.

4.4. Inclusion Criteria

Studies were considered eligible if they met the following criteria: • Study Design: Original articles, systematic reviews, meta-analyses, observational studies, and clinical trials. • Timeframe: Publications between January 2021 and June 2026. • Language: Publications available in Portuguese, English, or Spanish. • Population: Studies involving individuals aged 60 years or older. • Topic: Research addressing the long-term use of proton pump inhibitors (PPIs) and its relationship with frailty, functional capacity, sarcopenia, polypharmacy, or adverse events related to aging. • Setting: Studies conducted in outpatient settings, community-based settings, hospital settings, or Primary Health Care.

4.5. Exclusion Criteria

Studies were excluded if they met any of the following criteria: • Duplicates: Duplicate records across the searched databases.

• Non-original publications: Letters to the editor, editorials, expert opinions, and conference abstracts lacking full-text availability. • Population: Studies involving exclusively pediatric or young adult populations. • Scope: Research that did not directly address the relationship between proton pump inhibitor (PPI) use and frailty or related clinical outcomes. • Methodological limitations: Studies with poorly described methodologies or those for which the full text was not accessible.

4.6. Study Selection Process

The study selection process was conducted in three independent stages: • Stage 1: Screening of titles and abstracts identified across the databases. • Stage 2: Full-text reading of potentially eligible articles. • Stage 3: Application of eligibility criteria to define the final sample.

The entire selection process was conducted by two independent reviewers. Any discrepancies were resolved through consensus or by consultation with a third reviewer. The process of identification, screening, eligibility, and inclusion of studies is detailed in the PRISMA 2020 flow diagram.

4.7. Data Extraction

Data from the included studies were extracted using a standardized form, ensuring consistency in the synthesis of results. The following information was collected: • Study identification: Authors and year of publication. • Geographic context: Country of the study. • Methodology: Study design. • Population characteristics: Number of participants and age range. • Exposure parameters: Type and duration of PPI use. • Frailty assessment: Instruments used to measure frailty. • Clinical outcomes: Main endpoints evaluated. • Synthesis of findings: Results regarding the association between PPI use and frailty. • Study quality: Limitations identified by the authors.

4.8. Methodological Quality Assessment

The methodological quality of the included studies was assessed using specific instruments tailored to each study design: • Newcastle-Ottawa Scale (NOS): Used for observational studies. • AMSTAR-2: Used for systematic reviews. • RoB 2 (Risk of Bias Tool): Used for randomized clinical trials.

The studies were classified as having a low, moderate, or high risk of bias, according to the criteria established by each respective tool.

4.9. Data Synthesis and Analysis

The results were synthesized through a narrative and descriptive approach, accounting for the methodological heterogeneity of the included studies. The analysis focused on identifying the primary mechanisms through which long-term PPI use may contribute to the development or exacerbation of geriatric frailty, including nutritional alterations, musculoskeletal impairment, cognitive decline, cardiovascular events, polypharmacy, and reduced functional capacity.

Whenever possible, results were grouped into thematic categories to facilitate the interpretation of findings and the comparison across studies.

4.10. Ethical Aspects

As this study is a systematic review based exclusively on secondary data available in the scientific literature, without direct involvement of human subjects or access to individualized information, submission to a Research Ethics Committee was not required, in accordance with the guidelines of Resolution No. 466/2012 of the Brazilian National Health Council.

4.11. PRISMA Flow Diagram

The study selection process is presented in the PRISMA 2020 flow diagram (Figure 1), covering the identification, screening, eligibility, and inclusion stages of the articles, thereby ensuring the transparency and reproducibility of the methodological process.

Fig 1: PRISMA 2020 flow diagram illustrating the identification, selection, eligibility, and inclusion process of studies on the relationship between long-term proton pump inhibitor use and frailty in geriatric patients within Primary Health Care.

5. Results

The search strategy adopted enabled the identification of relevant studies published between 2021 and 2026, which addressed the chronic use of proton pump inhibitors (PPIs) and their potential impacts on the health of the elderly population. Following the application of the eligibility criteria established in this systematic review, evidence was selected from observational studies, systematic reviews, meta-analyses, clinical guidelines, and research conducted across various care settings, including Primary Health Care, outpatient services, long-term care institutions, and hospitals. The analyzed studies primarily investigated the association between long-term PPI use and outcomes related to geriatric frailty, such as micronutrient deficiencies, musculoskeletal impairment, osteoporosis, fractures, cognitive decline, cardiovascular events, polypharmacy, and reduced functional capacity.

Overall, the results demonstrated that long-term PPI use is frequently associated with factors that may contribute to the development or exacerbation of frailty in the elderly. The most commonly reported mechanisms involved impaired absorption of essential nutrients, particularly vitamin B12, magnesium, calcium, and iron, as well as increased susceptibility to adverse clinical events that compromise the autonomy and functionality of this population. Furthermore, several studies highlighted a high prevalence of long-term prescriptions without periodic reassessment of therapeutic necessity, underscoring the importance of monitoring strategies and deprescribing within the context of Primary Health Care (SHAHID et al., 2025; MUHEIM et al., 2021; TARGOWNIK; FISHER; SAINI, 2022) [61, 44, 66]. Table 1 presents a synthesis of the main studies included in this systematic review, highlighting authors, methodological design, study population, key findings, and the observed relationship between long-term proton pump inhibitor use and geriatric frailty. The collective analysis of the evidence allowed for the identification of multiple pathophysiological mechanisms involved in this association, as well as clinical and pharmacological factors capable of increasing vulnerability in the elderly (WU et al., 2025; DEWI et al., 2024; CONDUR et al., 2025) [71, 22, 15]. The selected studies underscore the relevance of periodic pharmacotherapy assessment and the implementation of safe deprescribing strategies, especially in patients monitored within Primary Health Care who are exposed to polypharmacy (ROSSI et al., 2024; PEREIRA et al., 2024; CORRÊA et al., 2022) [55, 50, 17].

Table 1: Summary of main studies on long-term proton pump inhibitor use, frailty, and clinical outcomes in geriatric patients. Authors/Year Study Design Population / Setting Main Findings Relationship with Frailty Wu et al., 2025 Observational study and Mendelian randomization Elderly PPI users Identified an association between PPI use and higher frailty index.

Suggests a possible link between chronic PPI exposure and increased functional vulnerability.

Dewi et al., 2024 Observational clinical study Elderly on long-term PPIs Linked long-term PPI use to frailty syndrome.

Points to PPIs as a potential factor associated with the development or worsening of frailty.

Condur et al., 2025 Clinical review Elderly with multiple chronic conditions Discussed clinical risks of PPI use in multimorbid elderly patients.

Multimorbidity and long-term PPI use may intensify the risk of functional decline.

Lakshmisai et al., 2025 Systematic review Patients on chronic PPI therapy Reported adverse events, including renal, bone, and nutritional alterations.

These effects may contribute to loss of physiological reserve and increased frailty.

Chaudhry et al., 2025 Systematic review Chronic PPI users Associated PPIs with kidney disease, fractures, and cognitive decline.

These outcomes are directly related to functional deterioration in older adults.

Robert et al., 2025 Systematic review and meta-analysis Elderly exposed to PPIs Demonstrated an association between PPIs and increased fracture risk.

Fracture-related disability can accelerate dependency and frailty.

Shahid et al., 2025 Systematic review Elderly in polypharmacy Linked long-term PPI use to micronutrient depletion.

Vitamin B12, magnesium, calcium, and iron deficiency may contribute to sarcopenia, fatigue, and frailty.

Barbosa et al., 2025 National review/study Chronic elderly PPI users Described the impact of PPIs on micronutrient absorption.

Nutritional malabsorption represents an important mechanism contributing to frailty.

Costa et al., 2021 Integrative review Elderly on long-term PPIs Reported vitamin B12 deficiency and hypomagnesemia associated with prolonged PPI use.

Metabolic alterations may impair muscle strength, cognition, and functional capacity.

Silva et al., 2022 National study/review Elderly PPI users Associated hypovitaminosis B12 with long-term PPI therapy.

B12 deficiency may contribute to neuropathy, anemia, fatigue, and functional decline.

Marques et al., 2021 National review Elderly PPI users Linked long-term PPI use with osteoporosis and fractures.

Bone loss increases falls, disability, and frailty risk.

Silva et al., 2024 National study/review Elderly PPI users Evaluated effects of PPIs on bone health.

Reinforces association between chronic PPI use, bone fragility, and fracture risk.

Chan et al., 2023 Observational study Older adults Investigated association between PPIs, incident dementia, and cognitive decline.

Cognitive impairment may increase dependency and frailty.

Xie et al., 2024 Review of observational evidence PPI users Updated evidence regarding PPIs and dementia risk.

Cognitive decline contributes to geriatric vulnerability and reduced autonomy.

Peng et al., 2026 Updated review Patients on PPIs Discussed association between PPIs and dementia.

Potential impact on cognition and functional independence.

Bell et al., 2021 Observational study PPI users Linked PPI use with increased cardiovascular disease and heart failure risk.

Cardiovascular disease may reduce functional capacity and increase frailty.

Geng et al., 2023 Observational study Patients with type 2 diabetes Associated PPI use with increased cardiovascular risk.

Cardiovascular vulnerability may worsen frailty in elderly diabetic patients.

Fan et al., 2024 Clinical study Elderly PPI users Reported QT interval prolongation associated with PPI use.

Cardiovascular alterations may increase adverse events and functional limitations.

Maret-Ouda et al., 2023 Observational study Elderly PPI users Investigated pneumonia risk associated with PPI use.

Respiratory infections may precipitate functional decline and frailty.

Oliveira et al., 2023 National study Elderly in Primary Health Care Evaluated polypharmacy and potentially inappropriate prescribing.

Polypharmacy is associated with frailty and inappropriate long-term PPI use.

Moreira and Rodrigues, 2025 National study Elderly in Primary Care Discussed potentially inappropriate medications in older adults.

Highlights medication review as a strategy to reduce frailty risk.

Santos et al., 2025 National study Community-Linked frailty, polypharmacy, and potentially inappropriate medications.

Demonstrates the importance of evaluating medication profiles in frailty assessment.

Çelik et al., 2021 Observational study Outpatients Demonstrated inappropriate PPI prescribing in outpatient settings.

Unnecessary prolonged PPI exposure may increase adverse events in elderly patients.

Muheim et al., 2021 Population study General population Identified potentially inappropriate PPI prescribing.

Supports screening and deprescribing among frail elderly individuals.

Dixon and Bolt, 2023 Outpatient study Geriatric patients Evaluated appropriateness of PPI therapy.

Highlights risks of unnecessary long-term PPI maintenance.

Wabe et al., 2025 Long-term care study Institutionalized elderly Identified inappropriate PPI use and underutilization.

Institutionalized elderly are at higher risk of frailty and polypharmacy.

Targownik, Fisher, and Saini, 2022 Clinical practice update Patients on PPIs Presented recommendations for PPI deprescribing.

Provides strategies to reduce medication-related risks associated with chronic PPI use.

Rossi et al., 2024 Systematic review Studies on deprescribing Evaluated clinical approaches for PPI deprescribing.

Deprescribing may reduce adverse events and improve medication safety.

Pereira et al., 2024 National review Elderly PPI users Discussed deprescribing strategies in geriatric populations.

Reinforces the role of Primary Health Care in safe PPI management.

Lai et al., 2021 Intervention study Family medicine Evaluated deprescribing of inappropriate PPIs in residency practice.

Demonstrated feasibility of reducing unnecessary PPI use in primary care.

Ayoub et al., 2021 Intervention study Community health center Evaluated opportunities for PPI de-escalation.

Shows potential for reducing chronic PPI exposure through primary care interventions. Source: Prepared by the authors (2026), based on studies included in the systematic review. The main studies analyzed indicate that the long-term use of proton pump inhibitors (PPIs) in geriatric patients may be associated with the development or exacerbation of frailty through multiple mechanisms, including micronutrient deficiency, bone alterations, increased risk of fractures, cognitive decline, cardiovascular events, infections, polypharmacy, and potentially inappropriate prescribing. In Primary Health Care, these findings underscore the importance of periodic pharmacotherapy review, early identification of frailty, and the implementation of safe deprescribing strategies, especially in elderly patients with multimorbidity and higher functional vulnerability (CONDUR et al., 2025; WU et al., 2025; ROSSI et al., 2024) [15, 71, 55]. Frailty represents a multifactorial clinical condition characterized by a decline in physiological reserve and a reduced capacity of the organism to respond adequately to stressors. This geriatric syndrome is associated with a higher risk of falls, hospitalizations, functional disability, institutionalization, and mortality, serving as a key marker of vulnerability in the elderly. In recent years, the growing aging population has expanded scientific interest in identifying potentially modifiable factors related to the development and progression of frailty (JOHNSON et al., 2024; PRIDHAM; ROCKWOOD; RUTENBERG, 2024; SILAN; NICOLAIO; BOCCUZZO, 2025) [31, 52, 62].

In this context, several studies have investigated the potential impact of chronic PPI use on the functional health of the elderly. Although these drugs are widely used and considered safe for short-term treatment, recent evidence suggests that prolonged use may be associated with metabolic, nutritional, and clinical alterations capable of promoting the onset or worsening of frailty. Among the most frequently described mechanisms are micronutrient deficiency, muscle mass loss, reduced bone mineral density, cognitive decline, and increased multimorbidity burden (ANDRAWES et al., 2025; LAKSHMISAI et al., 2025; SHAHID et al., 2025) [3, 36, 61]. Given this scenario, the assessment of frailty using specific indices has been widely employed to quantify the degree of vulnerability in the elderly and to understand the factors associated with its progression. Table 2 presents the main studies identified in this systematic review that investigated the association between long-term PPI use and geriatric frailty indicators, highlighting their key findings and clinical implications (WU et al., 2025; DEWI et al., 2024; ARRUÉ Table 2: Summary of main studies on frailty and frailty indices associated with long-term proton pump inhibitor use in geriatric patients. Authors/Year Study Design Population Frailty Assessment Main Results WU et al., 2025 Observational and Mendelian randomization Elderly PPI users Frailty Index (FI) Identified a significant association between long-term PPI use and increased frailty scores.

DEWI et al., 2024 Observational study Elderly in clinical follow-up Frailty Criteria Demonstrated a higher prevalence of frailty syndrome among chronic PPI users.

JOHNSON et al., 2024 Longitudinal study Community-Frailty Index Subdimensions Showed that multiple frailty dimensions are related to the accumulation of clinical deficits.

PRIDHAM; ROCKWOOD; RUTENBERG, 2024 Longitudinal study Geriatric population Frailty Index Demonstrated that the progressive increase in the frailty index is associated with worse clinical outcomes.

SILAN; NICOLAIO; BOCCUZZO, 2025 Population study Elderly in administrative databases Frailty Index Developed a simplified model for the early identification of frailty in the elderly. ARRUÉ et al., 2024 Clinical study Elderly with functional changes Multidimensional assessment Linked cardiovascular and motor alterations to increased frailty.

SANTOS et al., 2025 Observational study Community-Standardized geriatric instruments Demonstrated an association between frailty, polypharmacy, and potentially inappropriate medications.

CONDUR et al., 2025 Clinical review Multimorbid elderly Global functional assessment Identified that chronic PPI users are at higher risk for frailty-related events. LAWSON et al., 2022 Clinical review Elderly on polypharmacy Functional assessment Showed that multiple medication use significantly increases the risk of frailty. MOREIRA; RODRIGUES, 2025 Observational study Elderly in Primary Care Geriatric criteria Linked potentially inappropriate medications to increased clinical vulnerability.

OLIVEIRA et al., 2023 Cross-sectional study Primary Care users Multidimensional assessment Demonstrated an association between polypharmacy and functional impairment in the elderly.

WABE et al., 2025 Long-term care study Institutionalized elderly Vulnerability indices Identified a high prevalence of frailty associated with inappropriate medication use.

ARAGONEZ, 2025 Review Elderly in PHC Beers-Fick criteria Highlighted the role of potentially inappropriate medications in worsening frailty.

CORRÊA et al., 2022 Deprescribing study Elderly in Primary Care Comprehensive Geriatric Assessment Demonstrated the benefits of therapeutic review in reducing risks associated with frailty. Source: Prepared by the authors (2026), based on studies included in the systematic review.

The potential adverse effects associated with the long-term use of proton pump inhibitors (PPIs) have sparked growing interest in scientific literature, especially given their widespread use among elderly patients. Although these drugs are considered safe for short-term treatments, recent evidence suggests that their chronic use may interfere with the absorption of essential nutrients, compromising different organic systems and contributing to the development of conditions associated with geriatric frailty (ANDRAWES et al., 2025; KAMBOJ et al., 2024; LAKSHMISAI et al., 2025) [3, 33, 36]. Among the main pathophysiological mechanisms described, the reduced intestinal absorption of vitamin B12, magnesium, calcium, and iron stands out, as these are essential micronutrients for the maintenance of neurological, muscular, and bone function. Furthermore, studies have demonstrated an association between long-term PPI use and a higher risk of osteoporosis, fragility fractures, cognitive impairment, and the development of dementia. Such conditions can result in a progressive loss of functional autonomy, increased dependency, and greater clinical vulnerability in the elderly (COSTA et al., 2021; ROBERT et al., 2025; XIE et al., 2024) [19, 53, 72]. Table 3 presents the main studies identified in this systematic review that investigated the relationship between the long-term use of proton pump inhibitors and outcomes related to micronutrient deficiency, bone health, fracture risk, cognitive decline, and dementia, highlighting the mechanisms involved and their clinical repercussions in the geriatric population (SHAHID et al., 2025; CHAN et al., 2023; PENG et al., 2026) [61, 13, 49].

Table 3: Summary of main studies on micronutrient deficiency, bone health, fracture risk, cognitive decline, and dementia associated with long-term proton pump inhibitor use in geriatric patients. Authors/Year Outcome Evaluated Main Findings Potential Impact on Frailty COSTA et al., Vitamin B12 deficiency and hypomagnesemia Demonstrated an association between long-term PPI use and reduced serum levels of vitamin B12 and magnesium.

Favors fatigue, sarcopenia, neuropathies, and functional loss.

SILVA et al., 2022 Hypovitaminosis B12 Identified a higher frequency of vitamin B12 deficiency in chronic PPI users.

May contribute to neurological and cognitive impairment.

BARBOSA et al., 2025 Micronutrient absorption Evidenced impairment in the absorption of calcium, iron, magnesium, and vitamin B12.

Increases metabolic and functional vulnerability.

SHAHID et al., 2025 Micronutrient depletion Systematic review demonstrated a consistent association between PPIs and nutritional deficiency in the elderly.

Relates to increased risk of frailty and functional dependency.

SANTOS et al., 2025 Nutritional alterations Reported impaired micronutrient absorption due to PPI-induced hypochlorhydria.

Favors muscle loss and worsening physical performance.

MARQUES et al., 2021 Osteoporosis and fractures Demonstrated an association between long-term PPI use and increased risk of osteoporosis. Increases the occurrence of falls and fragility fractures.

SILVA et al., 2024 Bone health Evidenced the negative impact of PPIs on bone mineral density.

Contributes to functional disability and loss of independence.

ROBERT et al., 2025 Fractures Meta-analysis identified a higher risk of fractures in chronic PPI users.

Fractures are associated with institutionalization and mortality.

CHAUDHRY et al., 2025 Fractures and kidney disease Systematic review linked PPIs to osteoporotic fractures and renal alterations.

Potentiates the progression of geriatric frailty.

MAES et al. Adverse effects in the elderly Reported increased risk of bone impairment in long-term users.

Favors reduced mobility and functionality.

CHAN et al., 2023 Cognitive decline and dementia Demonstrated an association between PPI use and higher incidence of cognitive decline.

May accelerate dependency and functional impairment.

XIE et al., 2024 Dementia Observational review identified consistent evidence on the association between PPIs and dementia. Aggravates the clinical and social vulnerability of the elderly.

PENG et al., 2026 Dementia Updated evidence reinforced the possible relationship between long-term PPI use and cognitive impairment. Contributes to a worse functional prognosis.

KOUNDINYA et al., 2025 Cognitive decline Narrative review highlighted inflammatory and metabolic mechanisms associated with dementia. Relates to increased cognitive frailty.

EMAD et al., 2025 Dementia Umbrella review identified a moderate association between PPIs and risk of cognitive impairment. Potentiates loss of autonomy and independence.

SERENO et al., Vitamin B12 and nervous system Demonstrated the importance of vitamin B12 for the maintenance of neurological function.

PPI-induced deficiency may favor cognitive alterations.

LOUREDO et al., 2021 Metabolic changes in aging Evidenced the relevance of metabolic balance for the maintenance of geriatric functionality. Nutritional disorders may accelerate frailty. Source: Prepared by the authors (2026), based on studies included in the systematic review. Beyond the effects related to micronutrient deficiency, bone health, and cognitive impairment, recent evidence has demonstrated that long-term use of proton pump inhibitors may be associated with significant cardiovascular repercussions and increased therapeutic complexity in elderly patients. Considering that the geriatric population frequently presents with multiple chronic diseases and high medication consumption, it is essential to understand the impact of PPIs within the context of polypharmacy and the potential risks arising from the prolonged maintenance of these drugs (BELL et al., 2021; FORESTA et al., 2024; CONDUR et al., 2025) [11, 27, 15].

Observational studies and systematic reviews have reported an association between chronic PPI use and an increased risk of cardiovascular events, including heart failure, coronary artery disease, QT interval prolongation, and higher cardiovascular mortality. Although the underlying mechanisms are not yet fully elucidated, it is believed that endothelial, inflammatory, metabolic, and electrolyte alterations may contribute to these outcomes. Concurrently, several authors highlight that the unnecessary continuation of PPIs in geriatric therapeutic regimens represents one of the most frequent forms of potentially inappropriate prescribing observed in clinical practice (BELL et al., 2021; FAN et al., 2024; MUHEIM et al., 2021).

In this context, medication review and deprescribing strategies have been widely recommended by national and international guidelines as tools capable of reducing adverse events, optimizing pharmacotherapy, and minimizing factors associated with geriatric frailty. Table 4 presents the main studies related to cardiovascular events, polypharmacy, and PPI deprescribing strategies identified in this systematic review (TARGOWNIK; FISHER; SAINI, 2022; ROSSI et al., 2024; PEREIRA et al., 2024) [66, 55, 50].

Table 4: Summary of main studies on cardiovascular events, polypharmacy, and deprescribing strategies associated with long-term proton pump inhibitor use in geriatric patients. Author/Year Focus Area Main Findings Relevance to Geriatric Frailty BELL et al., 2021 Cardiovascular disease Identified an association between long-term PPI use and increased risk of cardiovascular disease and heart failure.

May reduce functional capacity and increase clinical vulnerability.

GENG et al., 2023 CV risk in T2DM Demonstrated an association between PPIs and increased cardiovascular risk in diabetic patients. Potentiates adverse outcomes in elderly patients with multimorbidity.

FAN et al., 2024 QT interval prolongation Evidenced an association between PPI use and electrocardiographic alterations.

Increases the risk of cardiovascular events and clinical complications.

FORESTA et al., Cardiovascular complications Reported a higher frequency of cardiovascular events in elderly PPI users.

Contributes to functional decline and progression of frailty.

SONG et al., 2023 Mortality Meta-analysis demonstrated increased mortality in long-term elderly PPI users.

Reflects greater clinical vulnerability and risk of adverse outcomes.

LAWSON et al., 2022 Polypharmacy Identified challenges related to the simultaneous use of multiple medications.

Polypharmacy is a recognized factor in the development of frailty.

OLIVEIRA et al., 2023 Inappropriate prescribing Demonstrated a high prevalence of potentially inappropriate medications in PHC.

Increases the risk of adverse events and functional impairment.

MOREIRA; RODRIGUES, 2025 Inappropriate medications Linked inappropriate prescriptions to increased geriatric vulnerability.

Favors functional decline and dependency.

SANTOS et al., 2025 Frailty and polypharmacy Evidenced an association between polypharmacy and higher frailty indices.

Reinforces the need for periodic therapeutic review.

FURTADO et al., 2021 Physiological impact Demonstrated the negative impact of excessive medication exposure in the elderly.

Relates to an increase in adverse events and frailty.

ROCHA et al., 2021 Medication interactions Highlighted pharmacodynamic and pharmacokinetic risks in the elderly.

Contributes to clinical instability and reduced functionality.

ARAGONEZ, 2025 Beers-Fick criteria Reinforced the importance of identifying potentially inappropriate medications.

Assists in preventing drug-related frailty.

TARGOWNIK; FISHER; SAINI, Deprescribing guidelines Presented recommendations for the safe discontinuation of PPIs without current indication. Reduces exposure to adverse events related to long-term use.

ROSSI et al., 2024 Deprescribing strategies Systematic review demonstrated the efficacy of deprescribing programs.

Contributes to greater therapeutic safety in the elderly.

PEREIRA et al., 2024 Deprescribing in PHC Evidenced clinical benefits of periodic re-evaluation of PPI use.

Favors the reduction of polypharmacy and frailty factors.

CORRÊA et al., 2022 Deprescribing screening Demonstrated the feasibility of identifying patients eligible for deprescribing.

Reduces risks associated with unnecessary medication use.

LAI et al., 2021 Family medicine intervention Demonstrated success in withdrawing inappropriately prescribed PPIs.

Improves the quality of geriatric pharmacotherapy.

AYOUB et al., 2021 Therapeutic de-escalation Evidenced opportunities for the safe reduction of PPI use.

Minimizes cumulative risks associated with long-term exposure.

WABE et al., 2025 Uso inadequado em instituições geriátricas Identificaram elevada prevalência de utilização inadequada de IBPs.

Reforça a necessidade de monitoramento contínuo da farmacoterapia. Source: Prepared by the authors (2026), based on studies included in the systematic review.

The integrated analysis of the studies included in this systematic review allowed not only for the identification of the association between chronic proton pump inhibitor (PPI) use and geriatric frailty, but also for an understanding of the underlying pathophysiological mechanisms, the factors that potentiate this relationship, and the possible intervention strategies applicable to clinical practice. Understanding these elements is fundamental to supporting preventive and therapeutic actions aimed at promoting healthy aging and reducing the impacts arising from frailty in the elderly population (WU et al., 2025; CONDUR et al., 2025; ROSSI The analyzed studies demonstrated that frailty associated with long-term PPI use does not result from a single isolated factor, but rather from the interaction between metabolic, nutritional, cardiovascular, musculoskeletal, and cognitive alterations that accumulate over time. Thus, identifying the primary mechanisms involved is essential to understanding how these medications can influence the reduction of physiological reserve and increase the clinical vulnerability of the elderly (SHAHID et al., 2025; KAMBOJ et al., 2024; DEWI et al., 2024) [61, 33, 22].

Beyond biological mechanisms, literature highlights the importance of clinical and sociodemographic factors capable of potentiating the risks related to long-term PPI use. Characteristics such as advanced age, multimorbidity, polypharmacy, institutionalization, and nutritional impairment were frequently associated with increased frailty, reinforcing the need for a multidimensional approach in the follow-up of geriatric patients (LAWSON et al., 2022; SANTOS et al., 2025; WABE et al., 2025) [37, 59, 70]. Finally, considering that Primary Health Care (PHC) constitutes the primary setting for the longitudinal follow-up of the elderly population, several studies emphasize the need to implement strategies aimed at periodic pharmacotherapy review, early frailty screening, and the promotion of the rational use of medications. In this context, the safe deprescribing of PPIs emerges as an important tool for minimizing adverse events and optimizing the quality of care provided to the elderly (TARGOWNIK; FISHER; SAINI, 2022; PEREIRA et al., 2024; AYUB et al., 2021) [66, 50, 7]. Table 5 presents the main pathophysiological mechanisms described in the literature that relate chronic PPI use to the development and exacerbation of geriatric frailty. Table 6 synthesizes the main risk factors identified in the selected studies, highlighting the clinical and epidemiological elements associated with the greater vulnerability of elderly PPI users. Lastly, Table 7 brings together the main recommendations for Primary Health Care, emphasizing monitoring, prevention, and deprescribing strategies that may contribute to reducing the risks associated with long-term PPI use and to preserving the functionality and autonomy of the geriatric population.

Table 5: Main pathophysiological mechanisms linking long-term PPI use to the development and exacerbation of geriatric frailty. Mechanism Evidence Found Potential Clinical Consequence Vitamin B12 deficiency Reduced gastric absorption Neuropathy, cognitive deficit Hypomagnesemia Long-term PPI use Muscle weakness, arrhythmias Reduced calcium absorption Chronic hypochlorhydria Osteoporosis and fractures Altered gut microbiota Continuous PPI use Systemic inflammation Renal impairment Interstitial nephritis and CKD Accelerated frailty Cardiovascular alterations Endothelial dysfunction Reduced functional capacity Source: Prepared by the authors (2026), based on studies included in the systematic review.

Table 6: Main risk factors identified for frailty in long-term PPI users. Risk Factor Frequency in Literature Impact Age ≥ 80 years Very frequent High Polypharmacy Very frequent High Multimorbidity Very frequent High PPI use > 1 year Frequent Moderate/High Low nutritional status Frequent High Physical inactivity Frequent Moderado Source: Prepared by the authors (2026), based on studies included in the systematic review.

Table 7: Recommendations for Primary Health Care (PHC): Monitoring, prevention, and deprescribing strategies. Strategy Objective Annual PPI review Identify use without clinical indication Application of the Frailty Index Early screening Nutritional assessment Detect micronutrient deficiencies Laboratory monitoring Monitor B12, magnesium, calcium, and iron levels Polypharmacy review Reduce drug-drug interactions Deprescribing protocols Reduce adverse events Health education Improve therapeutic adherence Source: Prepared by the authors (2026), based on studies included in the systematic review. With the objective of complementing the analysis of the results obtained in this systematic review, visual representations were developed to synthesize the main findings identified in scientific literature regarding the relationship between chronic proton pump inhibitor (PPI) use and frailty in geriatric patients. The use of visual resources enables a more comprehensive understanding of the mechanisms involved and the clinical outcomes most frequently associated with the long-term use of these medications.

Figure 2 presents the distribution of the main outcomes reported in the studies included in this review, highlighting the areas with the highest concentration of scientific evidence. Among the most frequently observed findings are alterations related to micronutrient deficiency, bone health, cognitive impairment, cardiovascular events, and polypharmacy. These outcomes represent critical factors in the reduction of functional capacity and the increase of clinical vulnerability in the elderly population (SHAHID et al., 2025; ROBERT et al., 2025; CHAN et al., 2023; BELL et al., 2021) [61, 53, 13, 11].

Additionally, Figure 3 illustrates the pathophysiological model proposed based on the analyzed studies, demonstrating the sequence of biological events potentially triggered by the long-term use of PPIs. The model highlights how the reduction of gastric acidity can interfere with the absorption of essential nutrients and contribute to metabolic, musculoskeletal, cardiovascular, and neurological alterations, culminating in the development or exacerbation of geriatric frailty (COSTA et al., 2021; SILVA et al., 2024; WU et al., 2025) [19, 63, 71].

Source: Prepared by the authors (2026), based on studies included in the systematic review. Fig 2: Distribution of the main adverse effects associated with chronic use of proton pump inhibitors in older adults.

Source: Prepared by the authors (2026), based on evidence synthesized from the studies included in the systematic review. Fig 3: Pathophysiological model illustrating the relationship between chronic proton pump inhibitor use and the development of geriatric frailty.

6. Discussion

The results of this systematic review evidenced a consistent association between chronic proton pump inhibitor (PPI) use and multiple factors related to the development and exacerbation of frailty in geriatric patients (WU et al., 2025; DEWI et al., 2024; CONDUR et al., 2025) [71, 22, 15]. Although PPIs remain among the most widely prescribed medications globally for the treatment of acid-peptic disorders, a growing body of evidence has demonstrated that their long-term use may trigger physiological alterations capable of compromising functional capacity and increasing clinical vulnerability in the elderly. In this context, our findings support the hypothesis that prolonged PPI exposure represents a potentially modifiable factor within the multifactorial process that characterizes frailty syndrome (KAMBOJ et al., 2024; LAKSHMISAI et al., 2025; SHAHID et al., 2025) [33, 36, 61].

Among the primary results, an association was identified between the chronic use of PPIs and increased frailty indices. Wu et al. (2025) identified that long-term users of these medications presented significantly higher scores on frailty assessment instruments, suggesting that the cumulative effects of the therapy may contribute to the progressive compromise of physiological reserve. Similar results were observed by Dewi et al. (2024), who demonstrated a higher prevalence of frailty syndrome in elderly patients undergoing long-term use of these drugs (WU et al., 2025; DEWI et al., 2024) [71, 22].

Frailty is recognized as a dynamic condition resulting from the accumulation of biological deficits throughout the aging process. In this regard, Johnson et al. (2024) and Pridham, Rockwood, and Rutenberg (2024) highlight that the progressive increase in frailty indices is directly related to functional impairment, a higher incidence of hospitalizations, and increased mortality. Thus, any pharmacological intervention capable of accelerating the accumulation of these deficits must be carefully monitored in the geriatric population (JOHNSON et al., 2024; PRIDHAM; ROCKWOOD; RUTENBERG, 2024) [31, 52].

Another aspect widely identified in the analyzed studies refers to nutritional alterations resulting from the long-term use of PPIs. Costa et al. (2021) and Silva et al. (2022) observed a significant association between the chronic use of these medications and vitamin B12 deficiency, whereas Barbosa et al. (2025) and Shahid et al. (2025) reported impaired absorption of calcium, iron, and magnesium. These alterations stem primarily from the reduction in gastric acidity promoted by PPIs, a condition that directly interferes with the bioavailability of several essential micronutrients (COSTA et al., 2021; SILVA et al., 2022; BARBOSA et al., 2025; SHAHID et al., 2025) [19, 64, 8, 61]. The clinical consequences of these nutritional deficiencies are particularly relevant to the elderly population. Vitamin B12 deficiency is associated with the onset of peripheral neuropathies, cognitive impairment, and reduced functional capacity, whereas hypomagnesemia may favor muscle weakness, cardiac arrhythmias, and clinical instability. Collectively, these factors contribute to the progressive loss of functional autonomy, constituting central elements in the pathophysiology of geriatric frailty (COSTA et al., 2021; SERENO et al., 2024) [19, 60].

The results of this review also demonstrated an important association between long-term PPI use and alterations in bone health. Marques et al. (2021) and Silva et al. (2024) reported that reduced calcium absorption secondary to hypochlorhydria may predispose to the development of osteopenia and osteoporosis. These findings are reinforced by the meta-analysis conducted by Robert et al. (2025), which identified a significant increase in fracture risk among chronic users of these medications (MARQUES et al., 2021; SILVA et al., 2024; ROBERT et al., 2025) [41, 63, 53]. Fractures represent one of the most impactful events in elderly health, frequently associated with the loss of independence, institutionalization, and increased mortality. Thus, the association between PPIs, bone fragility, and fractures reinforces the need for continuous clinical and laboratory monitoring, especially in elderly patients with additional risk factors for bone mass loss (ROBERT et al., 2025; SILVA et al., 2024) [53, 63].

Cognitive impairment constitutes another significant outcome identified in this review. Chan et al. (2023) demonstrated an association between long-term PPI use and a higher incidence of cognitive decline, while Xie et al. (2024) and Peng et al. (2026) reinforced the existence of consistent observational evidence linking these medications to an increased risk of dementia. Although causality has not yet been fully established, the results suggest that inflammatory, metabolic, and vascular mechanisms may play a role in this process (CHAN et al., 2023; XIE et al., 2024; PENG et al., 2026) [13, 72, 49].

According to Koundinya et al. (2025), micronutrient deficiency, especially of vitamin B12 and magnesium, may represent one of the mechanisms underlying the association between PPIs and cognitive impairment. Considering that cognition is a fundamental component for the maintenance of functional independence, such alterations may significantly contribute to the progression of geriatric frailty (KOUNDINYA et al., 2025; SHAHID et al., 2025) [34, 61]. Beyond the nutritional and neurological effects, the studies included in this review evidenced potential cardiovascular repercussions associated with the long-term use of PPIs. Bell et al. (2021) identified an increased risk of heart failure and cardiovascular disease in chronic users, while Geng et al. (2023) observed similar results in patients with type 2 diabetes mellitus. Additionally, Fan et al. (2024) demonstrated an association between the use of these medications and QT interval prolongation, a condition potentially related to an increased risk of arrhythmias (BELL et al., 2021; GENG et al., 2023; FAN et al., 2024) [11, 29, 25]. Foresta et al. (2024) highlight that cardiovascular alterations may directly contribute to the reduction of functional capacity and to the increase of clinical vulnerability in the elderly. Thus, although the individual absolute risk remains relatively low, the high prevalence of PPI utilization makes these findings particularly relevant in terms of public health (FORESTA et al., 2024) [27].

Another significant result identified in this review refers to polypharmacy. Oliveira et al. (2023), Moreira and Rodrigues (2025), and Santos et al. (2025) demonstrated that chronic PPI users frequently present with multiple comorbidities and high medication consumption, significantly increasing the risk of drug-drug interactions, adverse reactions, and potentially inappropriate prescribing. This condition is recognized as one of the primary factors associated with the development of geriatric frailty (OLIVEIRA et al., 2023; MOREIRA; RODRIGUES, 2025; SANTOS et al., 2025) [48, 43, 59].

Furtado et al. (2021) emphasize that polypharmacy promotes physiological and metabolic overload, favoring the occurrence of adverse events and compromising functional capacity in the elderly. Similarly, Rocha et al. (2021) highlight that age-related pharmacokinetic and pharmacodynamic changes potentiate the risks associated with the simultaneous use of multiple medications (FURTADO et al., 2021; ROCHA et al., 2021) [28, 54]. Given this scenario, deprescribing emerges as a critical strategy to reduce the risks associated with the long-term use of PPIs. Targownik, Fisher, and Saini (2022) published international recommendations advising the periodic reassessment of the clinical necessity for maintaining these medications, especially when used in the absence of a current clinical indication (TARGOWNIK; FISHER; SAINI, 2022) [66]. Similar results were observed by Rossi et al. (2024) and Pereira et al. (2024), who demonstrated clinical benefits resulting from the safe withdrawal of PPIs in eligible patients (ROSSI et al., 2024; PEREIRA et al., 2024) [55, 50]. Lai et al. (2021) and Ayoub et al. (2021) demonstrated that structured deprescribing programs can significantly reduce unnecessary PPI exposure without a significant increase in the recurrence of gastrointestinal symptoms. These findings reinforce the importance of interprofessional practice and longitudinal follow-up in Primary Health Care (LAI et al., 2021; AYOUB et al., 2021) [35, 7].

Primary Health Care plays a pivotal role in the early identification of frailty, monitoring of polypharmacy, and periodic review of prescriptions. Aragonez (2025) and Corrêa et al. (2022) highlight that systematic screening and therapeutic review strategies enable the identification of patients at higher risk of adverse events, favoring preventive interventions and contributing to the maintenance of functional capacity (ARAGONEZ, 2025; CORRÊA et al., 2022) [4, 17].

Despite the consistency of the findings observed, this review presents limitations inherent to the included studies, especially regarding the predominance of observational designs, which hinder the establishment of definitive causal relationships. Furthermore, the heterogeneity of the methods used for frailty assessment and the different populations analyzed may influence the comparability of the results. However, even considering these limitations, the compiled evidence suggests that the chronic use of proton pump inhibitors should be carefully monitored in geriatric patients, particularly in those with multiple comorbidities, polypharmacy, and early signs of frailty. The adoption of strategies for periodic assessment, nutritional monitoring, and deprescribing when clinically indicated may represent an important measure to minimize risks and promote healthier and more functional aging (TARGOWNIK; FISHER; SAINI, 2022; ROSSI et al., 2024; PEREIRA et al., 2024) [66, 55, 50].

7. Conclusion

This systematic review demonstrated that chronic use of proton pump inhibitors is associated with multiple factors potentially related to the development and exacerbation of frailty in geriatric patients followed up in Primary Health Care. The analyzed evidence demonstrated that the prolonged use of these medications may promote significant pathophysiological alterations, including micronutrient deficiency, compromised bone health, increased risk of fractures, cognitive decline, cardiovascular events, and greater exposure to polypharmacy.

The results indicated that deficiency in vitamin B12, magnesium, calcium, and iron constitutes one of the primary mechanisms involved in this association, contributing to reduced muscle strength, neurological impairment, loss of functional capacity, and increased clinical vulnerability. Concurrently, the higher incidence of osteoporosis, fractures, and cognitive alterations reinforces the influence of PPIs on different components of geriatric frailty. It was also observed that elderly patients who are chronic PPI users frequently present with multimorbidity and high medication consumption—factors that potentiate the risk of adverse events and accelerate functional decline. In this context, polypharmacy proved to be a significant element associated with the progression of frailty and the occurrence of potentially inappropriate prescribing. The evidence also demonstrated that strategies for periodic pharmacotherapy review and safe deprescribing of PPIs can contribute to reducing clinical risks and improving medication safety in the elderly population. Thus, Primary Health Care assumes a pivotal role in the early identification of vulnerable patients, in monitoring adverse effects related to the long-term use of these medications, and in implementing preventive interventions aimed at preserving functional capacity.

It is concluded that the chronic use of proton pump inhibitors should be carefully evaluated in geriatric patients, considering their potential impacts on frailty and quality of life. The adoption of evidence-based practices for monitoring, therapeutic reassessment, and deprescribing may represent a relevant strategy to promote healthier aging, reduce adverse events, and optimize comprehensive care for the elderly.