Osteoporosis is a systemic skeletal disease characterized by low bone mass, deterioration of bone microarchitecture, and compromised bone strength, ultimately leading to an increased risk of fragility fractures [1]. It is one of the most prevalent chronic musculoskeletal disorders worldwide and represents a major public health challenge due to its association with disability, reduced quality of life, increased mortality, and substantial healthcare costs [2]. The burden of osteoporosis continues to rise as populations age and life expectancy increases across both developed and developing countries. Fragility fractures, particularly those involving the hip, vertebrae, and wrist, are among the most serious consequences of osteoporosis and are associated with significant morbidity, prolonged hospitalization, loss of independence, and increased mortality among older adults [3].

Globally, osteoporosis affects hundreds of millions of individuals and contributes to millions of fractures annually [4]. The disease is particularly common among postmenopausal women because of estrogen deficiency, although men also experience substantial morbidity and mortality related to osteoporotic fractures [5]. As demographic transitions continue to increase the proportion of elderly individuals within populations, the incidence of osteoporosis-related fractures is expected to rise considerably over the coming decades [6]. Consequently, identifying modifiable risk factors for bone loss has become an important priority for clinicians, researchers, and public health authorities.

Bone is a dynamic tissue that undergoes continuous remodeling throughout life. This process involves a delicate balance between bone formation by osteoblasts and bone resorption by osteoclasts, coordinated by osteocytes and regulated through complex hormonal, mechanical, and biochemical signaling pathways [7]. Under physiological conditions, bone remodeling maintains skeletal integrity and mineral homeostasis. However, disturbances in this balance can result in excessive bone resorption, inadequate bone formation, or both, leading to progressive reductions in bone mineral density (BMD) and deterioration of bone quality [8]. Numerous endogenous and exogenous factors influence bone remodeling, including age, sex hormones, nutritional status, physical activity, chronic diseases, and medication exposure.

Traditionally, osteoporosis has been classified into primary and secondary forms. Primary osteoporosis includes postmenopausal osteoporosis and age-related osteoporosis, which account for the majority of cases encountered in clinical practice [9]. Secondary osteoporosis, in contrast, results from identifiable underlying conditions or exposures that adversely affect bone metabolism. Common causes include endocrine disorders, inflammatory diseases, gastrointestinal disorders, chronic kidney disease, malignancies, and the use of certain medications [10]. Recognition of secondary osteoporosis is particularly important because many contributing factors are potentially preventable or reversible when identified early.

Medication-induced osteoporosis represents a significant subset of secondary osteoporosis and has gained increasing attention in recent years [11]. Advances in medical care have improved survival and quality of life for patients with chronic diseases, resulting in greater long-term exposure to pharmacological therapies. While these medications often provide substantial therapeutic benefits, some may inadvertently compromise skeletal health through direct or indirect effects on bone metabolism [12]. The widespread use of these agents means that even modest adverse effects on bone can translate into a considerable population-level burden of osteoporosis and fractures.

Among medication-related causes of osteoporosis, glucocorticoid-induced osteoporosis is the most extensively studied and remains the prototype of drug-induced bone disease [13]. Long-term glucocorticoid therapy is known to suppress osteoblast function, increase osteocyte apoptosis, enhance bone resorption, and impair calcium metabolism, leading to rapid bone loss and increased fracture risk. As a result, clinical guidelines have been developed to facilitate screening, prevention, and treatment of glucocorticoid-induced osteoporosis [14]. However, growing evidence suggests that numerous non-corticosteroid medications may also adversely affect bone health, although awareness of these associations remains comparatively limited.

The recognition of non-corticosteroid drug-induced osteoporosis has expanded substantially over the past two decades [15]. Epidemiological studies, clinical trials, and mechanistic investigations have identified several commonly prescribed medications that may contribute to reductions in BMD and increased fracture risk. These medications are used across diverse medical specialties, including gastroenterology, psychiatry, oncology, endocrinology, infectious diseases, nephrology, neurology, and transplantation medicine. Consequently, medication-related bone disease has become a multidisciplinary concern requiring collaboration among healthcare providers involved in the management of chronic illnesses.

One of the most widely prescribed medication classes implicated in adverse skeletal outcomes is proton pump inhibitors (PPIs). These agents are commonly used for the treatment of gastroesophageal reflux disease, peptic ulcer disease, and other acid-related gastrointestinal disorders. Although generally considered safe, prolonged PPI use has been associated with an increased risk of fractures in several observational studies [16]. Proposed mechanisms include reduced gastric acidity leading to impaired calcium absorption, alterations in magnesium homeostasis, and potential effects on osteoclast function. Given the widespread and often prolonged use of PPIs, even a small increase in fracture risk may have important public health implications.

Antiepileptic drugs (AEDs) represent another important category of medications associated with skeletal complications [17]. Both older enzyme-inducing AEDs and some newer agents have been linked to reduced BMD, vitamin D deficiency, altered calcium metabolism, and increased fracture risk. Patients with epilepsy may be particularly vulnerable because they often require lifelong therapy and may already have additional fracture risk factors related to seizures, falls, and reduced physical activity.

Hormonal therapies used in cancer treatment have also emerged as major contributors to medication-induced osteoporosis. Aromatase inhibitors, which are widely used in hormone receptor-positive breast cancer, profoundly suppress estrogen production and accelerate bone loss in postmenopausal women [18]. Similarly, androgen deprivation therapy (ADT), a cornerstone of treatment for advanced prostate cancer, induces hypogonadism and is associated with significant reductions in BMD and increased fracture risk [19]. Because these therapies are often administered for prolonged periods, their skeletal consequences have become an important aspect of survivorship care in oncology.

Selective serotonin reuptake inhibitors (SSRIs), among the most commonly prescribed antidepressants worldwide, have also been implicated in adverse bone outcomes [20]. Serotonin plays a role in bone physiology, and alterations in serotonergic signaling may influence bone remodeling. Several observational studies have reported associations between SSRI use and increased fracture risk, although the precise mechanisms remain incompletely understood.

Thiazolidinediones (TZDs), used in the management of type 2 diabetes mellitus, have attracted considerable attention because of their effects on bone metabolism [21]. These agents activate peroxisome proliferator-activated receptor gamma (PPAR-γ), promoting adipocyte differentiation at the expense of osteoblast formation. As a result, TZD therapy has been associated with decreased bone formation, reduced BMD, and increased fracture risk, particularly among postmenopausal women. The recognition of these skeletal effects has influenced prescribing practices and highlighted the importance of considering bone health when selecting antidiabetic therapies.

Additional medication classes have also been associated with osteoporosis and fractures. Antiretroviral therapies used in the treatment of human immunodeficiency virus (HIV) infection have been linked to reductions in BMD through mechanisms involving chronic inflammation, altered vitamin D metabolism, and direct effects on bone cells [22]. Loop diuretics may increase urinary calcium excretion and contribute to negative calcium balance, while calcineurin inhibitors used in organ transplantation can adversely affect bone remodeling and mineral metabolism.

The mechanisms through which medications influence bone health are diverse and often multifactorial. Some drugs interfere with calcium absorption or vitamin D metabolism, leading to secondary hyperparathyroidism and increased bone resorption. Others alter endocrine pathways, resulting in deficiencies of estrogen, testosterone, or other hormones essential for skeletal maintenance. Certain medications exert direct effects on osteoblasts, osteoclasts, or osteocytes, thereby disrupting normal bone remodeling processes. In addition, some therapies increase the likelihood of falls through sedation, dizziness, muscle weakness, or impaired balance, indirectly contributing to fracture risk independent of changes in BMD [23].

Very serious health problems when medicines cause bone weakness in patients. Fragility fractures cause long-term pain, deformity, and loss of mobility, leading to dependence on others for daily activities. Hip fractures are surely among the most serious injuries in older adults, often demanding surgery and long months of recovery. Moreover, such fractures carry a well-known risk of death within the first year following the injury. Vertebral fractures surely cause long-term back pain and spinal deformity; moreover, they can seriously affect breathing and reduce the overall quality of life.

As per current understanding, there are several challenges regarding the proper evaluation of osteoporosis caused by medications. Many patients taking these medicines already have health conditions that can affect bones on their own, so it becomes very difficult to say whether the bone problem is coming from the drug or the disease itself. The differences in study design, exposure time, patient groups, and outcome measures are only making the findings vary so much across studies. Also, basically, fracture risk depends on many factors beyond BMD, age, sex, health conditions, nutrition, physical activity, and the same tendency to fall also plays a major role. Also, we are seeing that linking specific medicines to bone-related effects is not straightforward, and we must read the available evidence very carefully. Nevertheless, increasing recognition of medication-related bone disease has important implications for clinical practice. Identifying patients at elevated risk allows healthcare providers to implement preventive measures such as lifestyle modification, optimization of calcium and vitamin D intake, regular weight-bearing exercise, smoking cessation, limitation of alcohol consumption, and periodic assessment of BMD. In selected high-risk individuals, pharmacological interventions may also be warranted to preserve bone mass and reduce fracture risk.

Given the widespread use of non-corticosteroid medications with potential adverse effects on bone, a comprehensive synthesis of current evidence is essential. Understanding the mechanisms, magnitude of risk, and clinical implications associated with these therapies can facilitate informed decision-making and improve patient outcomes. Enhanced awareness among clinicians may promote earlier recognition of medication-induced osteoporosis and encourage the implementation of appropriate monitoring and preventive strategies.

Therefore, the objective of this systematic review is to critically evaluate and synthesize current evidence regarding the association between commonly prescribed non-corticosteroid medications and osteoporosis-related outcomes, including reductions in bone mineral density and increased fracture risk. By examining data from observational studies, randomized controlled trials, cohort studies, case-control investigations, and meta-analyses, this review aims to provide a comprehensive overview of medication-induced osteoporosis beyond corticosteroid exposure. Furthermore, it seeks to identify knowledge gaps, highlight populations at greatest risk, and support the development of evidence-based approaches for the prevention, monitoring, and management of drug-related skeletal complications.

Study Design and Reporting Standards This systematic review was conducted to evaluate the association between non-corticosteroid medications and osteoporosis-related outcomes, including reductions in bone mineral density (BMD), osteopenia, osteoporosis, and fragility fractures. The review methodology followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines to ensure transparency, reproducibility, and methodological rigor throughout the review process [24]. Literature Search Strategy A comprehensive literature search was performed using PubMed/MEDLINE, Scopus, Web of Science, Embase, Cochrane Library, and Google Scholar databases. Studies published between January 2000 and December 2025 were considered eligible for screening. Search strategies combined Medical Subject Headings (MeSH) and free-text keywords related to medication-induced osteoporosis and skeletal health. The primary search terms included: • “Drug-induced osteoporosis” • “Secondary osteoporosis” • “Bone mineral density” • “Fragility fracture” • “Proton pump inhibitors” • “Antiepileptic drugs” • “Aromatase inhibitors” • “Androgen deprivation therapy” • “Selective serotonin reuptake inhibitors” • “Thiazolidinediones” • “Antiretroviral therapy” • “Loop diuretics” • “Calcineurin inhibitors” Boolean operators (AND, OR) were applied to optimize search sensitivity and specificity. Manual screening of reference lists from relevant reviews and eligible studies was also conducted to identify additional records [25]. Eligibility Criteria Inclusion Criteria Studies were included if they: • Evaluated non-corticosteroid medications associated with bone loss or fracture risk. • Reported outcomes related to osteoporosis, osteopenia, bone mineral density, or fragility fractures. • Included adult participants (≥18 years). • Were observational studies, cohort studies, case-control studies, randomized controlled trials, systematic reviews, or meta-analyses. • Were published in peer-reviewed journals and available in English [26]. Exclusion Criteria Studies were excluded if they: • Focused exclusively on glucocorticoid-induced osteoporosis. • Included pediatric populations only. • Were editorials, conference abstracts, letters, or case reports. • Lacked clinically relevant skeletal outcomes. • Presented duplicate datasets or insufficient methodological information [27]. Study Selection Process All retrieved records were imported into a reference management system and screened for duplication. Following duplicate removal, titles and abstracts were independently assessed for relevance. Potentially eligible studies underwent full-text review according to predefined inclusion and exclusion criteria. Disagreements regarding study eligibility were resolved through discussion and consensus among reviewers [28]. Data Extraction A standardized data extraction form was used to collect information from eligible studies. The following variables were extracted: • Author and publication year • Country of study • Study design • Sample size • Drug class investigated • Duration of medication exposure • Bone mineral density outcomes • Osteoporosis prevalence • Fracture incidence • Major findings and conclusions [29] Quality Assessment and Risk of Bias Methodological quality was assessed using established appraisal tools according to study design. Observational studies were evaluated using the Newcastle–Ottawa Scale (NOS), while systematic reviews and meta-analyses were assessed using the AMSTAR-2 framework [30]. Risk of bias evaluation included participant selection, exposure assessment, outcome measurement, control of confounding variables, completeness of follow-up, and reporting quality. Studies were categorized as having low, moderate, or high risk of bias and were retained for qualitative synthesis regardless of quality score to preserve comprehensiveness [31]. Data Synthesis Given the heterogeneity in study populations, drug classes, outcome definitions, and follow-up durations, a qualitative synthesis approach was adopted. Evidence was grouped according to medication category, including proton pump inhibitors, antiepileptic drugs, aromatase inhibitors, androgen deprivation therapies, selective serotonin reuptake inhibitors, thiazolidinediones, antiretroviral agents, loop diuretics, and calcineurin inhibitors [32]. The primary outcomes of interest included: • Changes in bone mineral density • Osteoporosis prevalence • Fragility fracture incidence • Biological mechanisms of skeletal injury • Population-specific risk factors [33] PRISMA Study Selection The database search identified 1,462 records through electronic databases and manual reference screening. Following removal of 278 duplicate records, 1,184 studies remained for title and abstract screening. Of these, 902 records were excluded because they did not meet eligibility criteria or lacked relevant osteoporosis outcomes. A total of 282 full-text articles were assessed for eligibility. After detailed review, 204 studies were excluded because of inadequate outcome reporting, insufficient data, irrelevant exposure, or duplicate populations. Ultimately, 78 studies met all inclusion criteria and were included in the final qualitative synthesis [34]. Figure 1. PRISMA Flow Diagram

A total of 78 studies met the inclusion criteria and were included in the final qualitative synthesis. The included evidence comprised prospective and retrospective cohort studies, case-control studies, randomized controlled trials, cross-sectional investigations, systematic reviews, and meta-analyses evaluating the effects of non-corticosteroid medications on bone mineral density (BMD), osteoporosis development, and fracture risk. Collectively, the evidence demonstrated that several commonly prescribed drug classes are associated with adverse skeletal outcomes, although the magnitude of risk varied according to medication type, treatment duration, patient characteristics, and underlying comorbidities [35]. Among the evaluated drug classes, aromatase inhibitors, androgen deprivation therapies, antiepileptic drugs, and thiazolidinediones demonstrated the strongest and most consistent associations with osteoporosis and fractures, whereas evidence regarding proton pump inhibitors, selective serotonin reuptake inhibitors, antiretroviral therapies, and other agents was more heterogeneous.

Characteristics of Included Studies

The included studies were conducted across North America, Europe, Asia, Australia, and South America. Sample sizes ranged from fewer than 100 participants in mechanistic investigations to large population-based cohorts involving several hundred thousand individuals [36]. Most studies evaluated adults receiving long-term pharmacotherapy for chronic conditions such as gastroesophageal reflux disease, epilepsy, breast cancer, prostate cancer, depression, diabetes mellitus, HIV infection, organ transplantation, and cardiovascular disorders. Follow-up durations varied substantially, ranging from one year to more than ten years in longitudinal investigations.

The majority of studies assessed bone mineral density using dual-energy X-ray absorptiometry (DXA), while fracture outcomes were evaluated through hospital records, national databases, clinical registries, and self-reported events. Several meta-analyses pooled data from multiple observational studies and randomized trials to estimate overall fracture risk associated with specific drug classes [37].

Table 1. Characteristics of Major Drug Classes Associated with Osteoporosis

Proton Pump Inhibitors and Bone Health

Proton pump inhibitors (PPIs) were among the most extensively studied non-corticosteroid medications associated with osteoporosis-related outcomes. Multiple observational studies reported an association between prolonged PPI use and increased fracture risk, particularly involving the hip, vertebrae, and wrist [38]. Several large cohort studies demonstrated that chronic users exhibited higher rates of osteoporotic fractures compared with non-users, especially among elderly individuals and those receiving long-term therapy.

The proposed mechanisms primarily involved impaired calcium absorption resulting from chronic gastric acid suppression. Additional factors such as hypomagnesemia, vitamin B12 deficiency, and potential alterations in osteoclast function were also implicated [39]. However, findings regarding reductions in bone mineral density were inconsistent. While some studies reported modest declines in BMD among chronic users, others found little evidence of clinically significant bone loss after adjustment for confounding variables. Consequently, although fracture risk appears moderately increased, the precise contribution of PPIs to osteoporosis remains debated.

Antiepileptic Drugs and Osteoporosis

Antiepileptic drugs (AEDs) demonstrated one of the strongest associations with adverse skeletal outcomes. Both enzyme-inducing agents such as phenytoin, carbamazepine, and phenobarbital and certain newer agents were linked to reductions in bone mineral density and increased fracture risk [40]. Patients receiving long-term AED therapy frequently exhibited lower vitamin D levels, secondary hyperparathyroidism, and abnormalities in calcium metabolism.

Several studies reported significantly increased rates of osteopenia and osteoporosis among individuals treated with AEDs for prolonged periods. Fracture risk was further amplified by seizure-related falls and reduced physical activity. Meta-analyses consistently demonstrated that chronic AED exposure is associated with clinically meaningful skeletal deterioration, particularly among older adults and patients receiving lifelong therapy [41].

Aromatase Inhibitors and Bone Loss

Aromatase inhibitors (AIs) emerged as one of the most important medication-related causes of osteoporosis in oncology practice. Studies involving postmenopausal women with hormone receptor-positive breast cancer consistently demonstrated accelerated bone loss among patients receiving anastrozole, letrozole, and exemestane [42].

Suppression of estrogen production resulted in increased bone turnover, rapid declines in BMD, and elevated fracture risk. Several longitudinal studies reported annual reductions in bone density significantly exceeding those observed in untreated postmenopausal populations. Fracture incidence increased progressively with treatment duration, emphasizing the importance of routine bone health monitoring and preventive interventions in women undergoing AI therapy [43].

Androgen Deprivation Therapy

Androgen deprivation therapy (ADT), commonly used in advanced prostate cancer management, was also strongly associated with osteoporosis-related outcomes. Multiple studies demonstrated significant reductions in BMD within the first year of treatment, with continued bone loss observed during prolonged therapy [44].

The skeletal effects of ADT were primarily attributed to profound reductions in testosterone and estrogen levels, both of which are essential for maintaining bone integrity. Fracture risk increased substantially among men receiving long-term treatment, and several studies identified ADT as an independent predictor of osteoporosis and skeletal complications. These findings have led to increased emphasis on bone health assessment within prostate cancer survivorship programs [45].

Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) have attracted growing attention because of their potential effects on bone metabolism. Several observational studies reported increased fracture rates among SSRI users, particularly among older adults and postmenopausal women [46].

Although some studies demonstrated modest reductions in BMD among chronic users, findings were less consistent than those observed for aromatase inhibitors, ADT, or AEDs. Nevertheless, accumulating evidence suggests that prolonged SSRI exposure may contribute to skeletal vulnerability in susceptible populations [47].

Thiazolidinediones and Skeletal Outcomes

Thiazolidinediones (TZDs), particularly pioglitazone and rosiglitazone, demonstrated a consistent association with adverse bone health outcomes. Several studies reported increased fracture rates among women receiving TZD therapy for type 2 diabetes mellitus [48]. Mechanistic investigations indicated that activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) suppresses osteoblast differentiation while promoting adipocyte formation within bone marrow.

This shift in cellular differentiation contributes to reduced bone formation and progressive bone loss. Clinical studies consistently demonstrated increased fracture risk among long-term users, leading many experts to recommend caution when prescribing TZDs to patients at elevated risk for osteoporosis [49].

Antiretroviral Therapy, Loop Diuretics, and Calcineurin Inhibitors

Evidence regarding antiretroviral therapy (ART), loop diuretics, and calcineurin inhibitors was less extensive but generally supported an association with adverse skeletal outcomes. Several studies involving HIV-positive populations demonstrated reductions in BMD following initiation of tenofovir-containing regimens. Proposed mechanisms included chronic inflammation, altered vitamin D metabolism, and direct effects on bone cells.

Loop diuretics were associated with increased urinary calcium excretion and negative calcium balance, potentially contributing to bone loss during prolonged therapy. Similarly, calcineurin inhibitors used in organ transplantation were linked to disturbances in bone remodeling and increased osteoporosis prevalence. Although the magnitude of risk varied among studies, these findings suggest that skeletal monitoring may be beneficial in selected high-risk populations receiving these therapies [50].

Risk of Bias Assessment

Quality assessment revealed that most included studies were of moderate to high methodological quality. Cohort and case-control studies generally achieved favorable Newcastle Ottawa Scale scores, while systematic reviews satisfied major AMSTAR-2 criteria. Common methodological limitations included retrospective study design, residual confounding, variability in medication exposure assessment, and differences in fracture ascertainment methods. Despite these limitations, the consistency of findings across multiple study designs strengthened confidence in the observed associations between several non-corticosteroid medications and adverse skeletal outcomes.

The findings of this systematic review demonstrate that drug-induced osteoporosis extends well beyond the traditionally recognized effects of corticosteroids and represents an increasingly important contributor to secondary osteoporosis and fragility fractures. The included studies collectively indicate that several commonly prescribed non-corticosteroid medications are associated with adverse skeletal outcomes through diverse biological pathways affecting bone remodeling, mineral metabolism, hormonal regulation, and fracture susceptibility [51]. As the global prevalence of chronic diseases continues to rise and long-term pharmacotherapy becomes increasingly common, understanding the skeletal consequences of these medications has become a critical component of comprehensive patient care.

Historically, corticosteroids have dominated discussions surrounding medication-induced bone disease because of their profound and well-established effects on osteoblast function, osteocyte survival, calcium metabolism, and bone remodeling [52]. Consequently, clinical guidelines, screening recommendations, and preventive strategies have largely focused on glucocorticoid-induced osteoporosis. However, emerging evidence indicates that numerous non-corticosteroid medications may exert clinically meaningful effects on bone health that warrant similar attention.

One of the most significant observations emerging from this review is the variability in skeletal risk across different drug classes. Certain medications demonstrated strong and consistent associations with bone loss and fractures, whereas others exhibited more modest or heterogeneous effects. Among the evaluated agents, aromatase inhibitors, androgen deprivation therapies, antiepileptic drugs, and thiazolidinediones showed the most convincing evidence of clinically significant skeletal deterioration [53]. In contrast, evidence regarding proton pump inhibitors, selective serotonin reuptake inhibitors, antiretroviral therapies, and other medications remains less definitive, although accumulating data continue to suggest potentially important effects in susceptible populations.

Aromatase inhibitors emerged as one of the strongest contributors to medication-related osteoporosis. These agents profoundly suppress estrogen production and consequently accelerate bone turnover and bone loss in postmenopausal women undergoing treatment for hormone receptor-positive breast cancer [54]. Estrogen plays a fundamental role in maintaining skeletal integrity by inhibiting osteoclast-mediated bone resorption and preserving bone remodeling balance. Suppression of estrogen production therefore creates a physiological environment conducive to rapid skeletal deterioration.

Similarly, androgen deprivation therapy has become increasingly recognized as a major cause of osteoporosis among men receiving treatment for prostate cancer. Testosterone and estrogen both contribute substantially to male skeletal health, and suppression of gonadal hormone production leads to accelerated bone loss, impaired bone strength, and increased fracture risk [55].

Antiepileptic drugs also demonstrated strong associations with adverse bone outcomes. The mechanisms underlying antiepileptic drug-induced osteoporosis are multifactorial and involve alterations in vitamin D metabolism, secondary hyperparathyroidism, impaired calcium absorption, and direct effects on bone cells [56]. Patients with epilepsy often require lifelong therapy, resulting in prolonged exposure to medications capable of influencing skeletal health. Furthermore, seizure-related falls may further increase fracture risk independent of bone density changes. The combination of medication-related bone loss and increased fall propensity highlights the complex interaction between disease-related and treatment-related factors contributing to skeletal morbidity in this population.

Thiazolidinediones represent another important example of medication-induced skeletal injury. By activating peroxisome proliferator-activated receptor gamma (PPAR-γ), these agents alter mesenchymal stem cell differentiation in favor of adipocyte formation while suppressing osteoblast development [57]. This shift compromises bone formation and contributes to progressive skeletal deterioration. Several studies included in this review demonstrated increased fracture risk among patients receiving thiazolidinedione therapy, particularly among postmenopausal women. These findings have influenced prescribing practices and emphasize the importance of considering bone health when selecting pharmacological therapies for diabetes management.

The relationship between proton pump inhibitors and osteoporosis remains more controversial. Several large observational studies and meta-analyses have reported increased fracture risk among chronic users, particularly involving hip fractures [58]. Proposed mechanisms include impaired calcium absorption resulting from reduced gastric acidity, alterations in magnesium metabolism, vitamin B12 deficiency, and potential effects on osteoclast function. However, evidence regarding reductions in bone mineral density has been inconsistent, and some studies have suggested that observed associations may be partially explained by confounding factors such as age, comorbidities, smoking, and underlying health status.

Selective serotonin reuptake inhibitors have also generated increasing interest because of their potential influence on bone metabolism. Serotonin receptors are expressed in bone tissue, and alterations in serotonergic signaling may affect osteoblast and osteoclast activity [59]. Several observational studies have reported increased fracture rates among SSRI users, although distinguishing medication effects from the influence of underlying depression remains challenging. Depression itself has been associated with reduced physical activity, poorer nutrition, hormonal disturbances, and increased inflammatory activity, all of which may adversely affect bone health. Consequently, further research is required to clarify the independent contribution of SSRIs to osteoporosis risk.

Evidence regarding antiretroviral therapy further illustrates the complexity of medication-induced osteoporosis. HIV infection itself is associated with chronic inflammation, immune dysregulation, altered endocrine function, and increased fracture risk. Separating disease-related effects from medication-induced changes therefore presents a significant challenge [60]. Nevertheless, several studies have demonstrated reductions in bone mineral density following initiation of specific antiretroviral regimens, particularly those containing tenofovir. These findings suggest that both disease-related and treatment-related mechanisms contribute to skeletal deterioration in HIV-positive populations.

An important theme emerging from this review is the multifactorial nature of drug-induced osteoporosis. Unlike many primary bone diseases, medication-related skeletal complications rarely result from a single pathogenic mechanism. Instead, most drugs influence bone health through multiple interacting pathways involving mineral metabolism, endocrine regulation, cellular remodeling processes, inflammation, nutritional status, and fall risk [61].

The concept of cumulative skeletal burden is particularly relevant in contemporary clinical practice. Many patients receive multiple medications simultaneously, several of which may adversely affect bone health. Older adults frequently represent the most vulnerable population because they often experience polypharmacy, age-related bone loss, reduced physical activity, nutritional deficiencies, and multiple chronic diseases [62]. The additive or synergistic effects of multiple osteoporosis-associated medications remain insufficiently understood and warrant further investigation. Future research should focus not only on individual drugs but also on the cumulative impact of medication combinations commonly encountered in routine clinical care.

Another important observation concerns the limitations of relying exclusively on bone mineral density as an indicator of skeletal health. Several studies demonstrated increased fracture risk despite relatively modest changes in BMD [63]. These findings suggest that medication-induced alterations in bone quality, microarchitecture, collagen integrity, and fall risk may contribute substantially to fracture susceptibility. Consequently, comprehensive assessment of skeletal health should extend beyond traditional bone density measurements and incorporate broader evaluation of fracture risk factors.

The findings of this review have important implications for clinical practice. Recognition of medication-related osteoporosis allows healthcare providers to implement preventive strategies before substantial skeletal deterioration occurs [64]. Risk assessment should be incorporated into routine clinical decision-making when initiating long-term therapies known to affect bone health. Consideration of baseline osteoporosis risk factors, including age, sex, family history, previous fractures, smoking status, alcohol use, physical activity, nutritional status, and comorbid conditions, can facilitate individualized management strategies.

Routine monitoring of bone health may be particularly valuable among high-risk populations. Dual-energy X-ray absorptiometry remains the standard method for assessing bone mineral density and identifying patients who may benefit from preventive interventions [65]. Periodic assessment of vitamin D status, calcium intake, renal function, and other relevant metabolic parameters may further improve risk stratification. In selected patients, early initiation of anti-osteoporotic therapies may be appropriate to mitigate medication-related bone loss.

Lifestyle modification remains a cornerstone of osteoporosis prevention regardless of underlying cause. Adequate calcium and vitamin D intake, regular weight-bearing exercise, smoking cessation, moderation of alcohol consumption, and fall-prevention strategies can help preserve skeletal health among individuals receiving long-term pharmacotherapy [66]. These interventions are particularly important because many medication-related risk factors interact with modifiable lifestyle factors to influence overall fracture susceptibility.

Despite the growing body of evidence supporting medication-induced osteoporosis, several important challenges remain. The majority of available studies are observational, limiting the ability to establish definitive causal relationships. Confounding by indication, selection bias, exposure misclassification, and variability in outcome assessment may influence reported findings [67].

Limitations

This review has several limitations. Most included studies were observational in nature, restricting causal inference and increasing susceptibility to residual confounding. Considerable heterogeneity existed regarding medication exposure definitions, treatment duration, patient characteristics, and methods used to assess bone mineral density and fracture outcomes. Additionally, some drug classes were represented by relatively few studies, limiting the strength of conclusions that could be drawn. Publication bias and inconsistent reporting of skeletal outcomes may also have influenced the available evidence. Finally, relatively few studies evaluated bone quality and microarchitectural changes directly, leaving important mechanistic questions unresolved [68].

Drug-induced osteoporosis is an important and increasingly recognized cause of secondary osteoporosis that extends far beyond corticosteroid exposure. Evidence synthesized in this systematic review indicates that several commonly prescribed non-corticosteroid medications, including aromatase inhibitors, androgen deprivation therapies, antiepileptic drugs, thiazolidinediones, proton pump inhibitors, selective serotonin reuptake inhibitors, antiretroviral agents, loop diuretics, and calcineurin inhibitors, may adversely affect bone health through diverse mechanisms involving hormonal alterations, impaired mineral metabolism, disrupted bone remodeling, and increased fracture susceptibility. Among these drug classes, aromatase inhibitors, androgen deprivation therapies, antiepileptic drugs, and thiazolidinediones demonstrated the strongest and most consistent associations with bone loss and fragility fractures. These findings highlight the need for greater awareness of medication-related skeletal complications, particularly among older adults, postmenopausal women, cancer patients, and individuals receiving long-term pharmacotherapy. Routine assessment of bone health, early identification of high-risk patients, and implementation of preventive strategies are essential to reduce osteoporosis-related morbidity. Further prospective studies are required to clarify causal relationships, quantify long-term fracture risk, and develop evidence-based guidelines for the prevention and management of drug-induced osteoporosis beyond corticosteroid use.

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