From Bone Health to Lifespan: Pleiotropic Effects of Antiresorptive Agents

Abstract

Osteoporotic fractures are a major contributor to morbidity and excess mortality, particularly among older adults. Antiresorptive agents, including selective estrogen receptor modulators (SERMs), bisphosphonates (BPs), and denosumab, are widely used to prevent fractures, with robust support from clinical evidence. Beyond reducing fracture risk, emerging data indicate that these therapies may provide survival benefits through mechanisms that extend beyond skeletal protection. This review summarizes current evidence on the association between antiresorptive therapy and all-cause mortality, integrating findings from randomized controlled trials and large-scale observational cohorts. Intravenous and nitrogen-containing BPs, as well as denosumab, demonstrate the most consistent mortality reduction, especially in older or post-fracture populations. SERMs may provide modest benefits in selected women with increased cardiovascular or oncologic risk. The observed mortality reduction may be mediated not only by fracture prevention but also by pleiotropic effects, such as vascular protection, immune modulation, metabolic regulation, and anti-cancer actions. These findings underscore the importance of recognizing osteoporosis as a systemic disease and support early, sustained antiresorptive treatment to improve both skeletal and survival outcomes. Further studies are needed to clarify the underlying mechanisms and to guide individualized treatment strategies across diverse patient populations.

INTRODUCTION

Osteoporosis remains a global health challenge, accounting for more than 8.9 million fragility fractures each year—equivalent to one fracture every 3 seconds [1,2]. Osteoporotic fractures have a profound impact on mobility and quality of life and are associated with excess mortality [3]. These clinical consequences drive increasing healthcare expenditures and impose significant societal costs, highlighting the urgent need for effective interventions [1,4]. Antiresorptive therapies—including selective estrogen receptor modulators (SERMs), bisphosphonates (BPs), and denosumab—were initially developed to lower fracture risk [5,6]. The potential for these agents to extend survival was first demonstrated in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial, where a single annual infusion of zoledronic acid led to a 28% reduction in all-cause mortality among patients with recent hip fracture [7].

Following this pivotal discovery, an expanding body of observational research has suggested that antiresorptive agents may reduce mortality through pleiotropic effects that extend beyond skeletal protection [8-12]. Notably, these antiresorptive agents are frequently used in older, frail populations with high baseline mortality risk and are supported by extensive real-world datasets, enabling robust analyses of mortality outcomes [13-15]. In contrast, anabolic agents, including teriparatide, abaloparatide, and romosozumab, are prescribed less frequently, often limited to patients with lower cardiovascular risk and adequate ability for self-injection [13,15]. Additional safety concerns further restrict the use of anabolic agents in frail populations at elevated mortality risk. As a result, studies examining mortality outcomes with anabolic agents remain limited, and observational comparisons are more difficult to conduct.

With broader clinical use of these agents, their greater applicability in frail populations, and the availability of more extensive real-world data, this review focuses on antiresorptive agents. We examine their potential pleiotropic effects on mortality, assess the consistency of survival benefits across drug classes, and highlight key areas for future research.

FRACTURE-ASSOCIATED MORTALITY AS THE PRINCIPAL TARGET OF ANTIRESORPTIVE THERAPY

Osteoporotic fractures are sentinel events that are closely linked to excess mortality [16]. Antiresorptive therapies have been shown to reduce the incidence of these fractures, and fracture prevention remains the primary mechanism by which they are thought to improve survival [12,17]. The following sections address mortality outcomes, with an emphasis on the influence of fracture-mediated pathways.

Vertebral fractures and mortality

Vertebral fractures are strongly associated with excess mortality, independent of age, sex, or comorbidity [18,19]. In the Dubbo Osteoporosis Epidemiology Study, 10-year standardized mortality ratios (SMRs) were 1.8 in women and 2.1 in men, exceeding 4.0 in men aged 60 to 74 [20]. Korean national data revealed 1-year mortality rates of 9.0% in men and 4.0% in women aged ≥50, with a sharp increase observed beyond age 80 [21]. Despite these elevated risks, only 52% of Korean patients with vertebral fractures initiated anti-osteoporotic medication within 12 months, with a substantially lower percentage in men (29%) than in women (59%) [22]. A United States multiple-cause-of-death study identified over 40,000 deaths attributed to osteoporosis with pathological fractures, the majority being vertebral [23]. Although women accounted for most cases in absolute numbers due to higher fracture prevalence, men consistently exhibited higher age-adjusted mortality rates, particularly among those aged ≥75 years. Cardiovascular disease, respiratory illnesses, and neurodegenerative disorders such as dementia were the most common underlying causes of death, suggesting that vertebral fractures frequently coexist with or precipitate multisystem decline. These findings highlight vertebral fractures as early markers of systemic vulnerability and emphasize the urgency of prompt diagnosis and intervention, especially in older men.

Nonvertebral fractures and mortality

Hip fractures are the most devastating type of osteoporotic fracture, often leading to hospitalization, surgery, immobility, and irreversible functional decline [24,25]. The Dubbo Osteoporosis Epidemiology Study reported 10-year SMRs of 3.5 in men and 2.4 in women, with more than 80% of deaths in men and 66% in women occurring within 5 years after fracture [20]. Experiencing a second fracture increased mortality risk up to threefold in men, indicating cumulative vulnerability. Korean national data also show that 1-year mortality rates after hip fracture are 21.0% in men and 15.0% in women aged ≥50, with mortality rising sharply in men aged ≥90 [26]. Despite this substantial mortality burden, only 27% of hip fracture patients in South Korea initiated anti-osteoporotic medication within 12 months, with a particularly low rate in men (8%) compared to women (34%) [22]. This underscores a significant treatment gap in the population at greatest risk for adverse outcomes. In the United States, national mortality data indicate that more than half of early deaths following hip fracture are attributed to trauma-related complications, while cardiovascular disease becomes the predominant cause in later phases [27]. Taken together, these findings support the recognition of hip fractures as sentinel health events that accelerate systemic deterioration, especially in older men.

Mortality reduction via fracture prevention with antiresorptive therapy

The observed survival benefit of antiresorptive therapy is largely attributable to its ability to prevent osteoporotic fractures—particularly vertebral and hip fractures, both of which are independently linked to increased short- and long-term mortality. Fractures often trigger a cascade of immobility, hospitalizations, infections, and loss of functional independence, all of which contribute to elevated mortality risk, especially among frail older adults [27].

A network meta-analysis of 69 trials involving more than 80,000 postmenopausal women demonstrated that BPs significantly reduced the odds of clinical fractures (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.70 to 0.89) and hip fractures (OR, 0.80; 95% CI, 0.67 to 0.96) compared to placebo [28]. In the HORIZON Recurrent Fracture Trial, annual administration of zoledronic acid reduced the incidence of new clinical fractures and was associated with a 28% reduction in all-cause mortality over 1.9 years following hip fracture [7]. Similarly, a meta-analysis of trials involving more than 33,000 participants found an 11% relative reduction in mortality with antiresorptive therapy—an effect most pronounced in frailer populations at highest risk of death [29].

These findings reinforce the essential role of antiresorptive therapy not only in reducing fracture incidence but also in improving survival by preventing the downstream consequences of major osteoporotic fractures. Early and sustained treatment after a fragility fracture is critical to achieving both skeletal and survival benefits.

DRUG-SPECIFIC MORTALITY EFFECTS OF ANTIRESORPTIVE AGENTS: BEYOND FRACTURE PREVENTION

While fracture prevention remains the principal mechanism by which osteoporosis treatments reduce all-cause mortality, accumulating evidence indicates that certain antiresorptive agents may offer survival benefits that extend beyond skeletal protection. This section critically examines the association between antiresorptive therapies and mortality, focusing on three major classes—SERMs, BPs, and denosumab—drawing from randomized controlled trials (RCTs) and large-scale cohort studies. Emerging data also suggest that pleiotropic effects—including anti-inflammatory, cardiovascular, immunologic, and antineoplastic actions—may underlie additional survival benefits beyond fracture prevention [30]. The current evidence is synthesized to delineate the mortality impact of each agent class and to assess the relative contributions of fracture-mediated and systemic pathways.

Selective estrogen receptor modulators

SERMs, such as raloxifene and bazedoxifene, are primarily vertebral fractures in postmenopausal women [31,32]. However, emerging evidence suggests a modest but potentially meaningful association between SERM use and reduced all-cause mortality, potentially mediated by mechanisms beyond skeletal protection. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene did not significantly reduce cardiovascular events in the overall cohort of women with osteoporosis [32]. However, among women with elevated baseline cardiovascular risk (defined as ≥4 risk points), raloxifene was associated with a 40% reduction in major cardiovascular events over 4 years (relative risk, 0.60; 95% CI, 0.38 to 0.95) [33]. Notably, this benefit emerged after the first year of treatment and was most apparent in women with established coronary heart disease or multiple risk factors. A follow-up analysis further reported a 10% reduction in all-cause mortality with raloxifene, though statistical significance varied according to study design and population characteristics [34].

Several mechanisms have been proposed to account for these potential benefits. Raloxifene has been shown to favorably modulate cardiometabolic profiles, lowering total cholesterol and low-density lipoprotein cholesterol while maintaining high-density lipoprotein cholesterol [35]. It also enhances endothelial function and reduces levels of homocysteine and lipoprotein(a), both of which contribute to atherosclerosis and vascular aging. Unlike hormone replacement therapy, raloxifene does not increase C-reactive protein and may instead exert anti-inflammatory and antioxidant effects that help stabilize atherosclerotic plaques [36,37]. Additionally, both the MORE and Raloxifene Use for The Heart (RUTH) trials demonstrated significant reductions in the incidence of invasive estrogen receptor-positive breast cancer, which could partially explain improved long-term survival in SERM-treated women [38]. While SERM therapy has been linked to an increased risk of venous thromboembolism, this association is not consistently observed across all studies [39-41]. Importantly, no clear increase in arterial events such as myocardial infarction or stroke has been demonstrated, even among high-risk individuals.

Collectively, these findings suggest that SERMs may provide a modest survival advantage in select populations, particularly postmenopausal women with elevated cardiovascular or oncologic risk profiles (Table 1).

Table 1.

Summary of Mortality and Fracture Outcomes Associated with SERMs

Outcome	Findings	Supporting studies
Vertebral fracture reduction	Approximately 30%–50% risk reduction	MORE, RUTH trials
Nonvertebral fracture reduction	No significant reduction	MORE, RUTH trials
All-cause mortality reduction	Approximately 10% reduction in pooled analysis, mainly via ↓ non-CVD/non-cancer deaths; but inconsistent across studies
Mechanisms	Lipid-lowering: ↓ LDL-C, ↑ HDL-C
	Vascular/endothelial: ↓ vascular calcification, ↑ endothelial function, ↓ oxidative stress, ↓ inflammatory cytokines (IL-7, MCP-1)
	Anti-cancer: ↓ ER⁺ breast cancer via estrogen antagonism
	Bone quality: ↓ homocysteine, ↓ AGEs → improved collagen cross-linking
Influencing factors	Greater benefit in women with high estrogen receptor–positive breast cancer risk or those with low cardiovascular risk

SERM, selective estrogen receptor modulator; MORE, Multiple Outcomes of Raloxifene Evaluation; RUTH, Raloxifene Use for The Heart; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; IL-7, interleukin-7; MCP-1, monocyte chemoattractant protein-1; ER, estrogen receptor; AGE, advanced glycation end-products.

Bisphosphonates

Beyond their established role in skeletal health, BPs—especially nitrogen-containing and intravenous formulations—have demonstrated potential survival benefits through systemic mechanisms [42]. Multiple studies have reported reductions in all-cause mortality among BP users, independent of fracture incidence.

In the HORIZON Recurrent Fracture Trial, intravenous zoledronic acid was associated with a 28% reduction in all-cause mortality (hazard ratio [HR], 0.72; 95% CI, 0.56 to 0.93) among older adults [7]. While the original trial emphasized fracture outcomes, subsequent analyses highlighted mortality benefits potentially mediated by anti-inflammatory, cardiovascular, and metabolic effects [42]. In a large Swedish cohort of over 49,000 hip fracture patients, BP use was linked to a 15% lower risk of all-cause mortality (HR, 0.85; 95% CI, 0.79 to 0.91), with the protective effect evident within days of treatment initiation—suggesting early systemic action [43]. Another extensive Australian cohort study reported a 69% reduction in mortality among women on oral BPs (adjusted HR, 0.31; 95% CI, 0.17 to 0.59), even after accounting for comorbidities and functional status [44]. Similarly, a nationwide study of more than 31,000 postmenopausal women receiving antiresorptive therapy, most of whom were BP users, found a 57% reduction in all-cause mortality (HR 0.43; 95% CI, 0.34 to 0.54), including a marked reduction in cardiovascular mortality (HR, 0.48) [12]. Notably, a clear dose–response relationship emerged: the adjusted HR for all-cause mortality decreased further to 0.37 among patients with ≥3 years of antiresorptive therapy, underscoring the importance of sustained treatment.

Multiple mechanisms have been proposed to explain these survival benefits. BPs may reduce vascular calcification by binding to hydroxyapatite in atherosclerotic plaques and inhibiting the osteogenic differentiation of vascular smooth muscle cells via the mevalonate pathway [45,46]. They also attenuate inflammation by modulating cytokine production. Zoledronate, in particular, has been linked to reductions in arrhythmia- and infection-related mortality, possibly through effects on ion channels and immune function [47]. By suppressing bone turnover, BPs may also decrease systemic release of proinflammatory cytokines and bone-derived signaling factors, potentially mitigating cardiovascular and neurocognitive morbidity [48].

The magnitude of survival benefit appears to depend on the formulation used. Intravenous and nitrogen-containing BPs—such as alendronate, risedronate, ibandronate, and zoledronate—are more strongly associated with reduced mortality, whereas early-generation agents like etidronate show little or no effect [49]. Differences in drug potency, bioavailability, and pleiotropic properties likely account for these variations [50].

In summary, BPs—particularly in intravenous or nitrogen-containing forms—are associated with reductions in both all-cause and cardiovascular mortality. These effects are likely mediated through systemic, pleiotropic mechanisms beyond skeletal endpoints, with longer treatment duration and specific agent class further enhancing the magnitude of benefit (Table 2).

Table 2.

Summary of Mortality and Fracture Outcomes Associated with Bisphosphonates

Outcome	Findings	Supporting studies
Vertebral fracture reduction	40%–70% relative risk reduction	VERT, FIT, HORIZON trials
Nonvertebral fracture reduction	Approximately 20%–30% reduction overall; stronger in older and frail patients	VERT, HORIZON
All-cause mortality reduction	28% relative reduction in HORIZON (RCT, post-hip fracture); Approximately 10%–30% in RWE studies; Approximately 10% in RCT meta-analysis (borderline significant)
Mechanisms	Fracture-related: ↓ fractures → ↓ complications, ↓ immobility
	Vascular/endothelial: ↓ arterial calcification, ↑ endothelial NO, ↓ atherosclerosis
	Anti-inflammatory: ↓ TNF-α, ↓ IL-6, γδ T-cell modulation
	Anti-cancer: ↓ bone metastasis, ↑ apoptosis
	Senescence: ↓ DNA damage, ↓ cellular aging, ↑ physiological resilience
Influencing factors	Greatest effect seen in post-hip fracture patients
	Nitrogen-containing BPs (e.g., alendronate, risedronate) superior to non-n-BPs (etidronate)
	IV zoledronic acid more effective than oral
	Greater benefit in older adults (≥75 years)
	Mortality benefit observed beyond fracture risk reduction

VERT, Vertebral Efficacy with Risedronate Therapy; FIT, Fracture Intervention Trial; HORIZON, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly; RCT, randomized controlled trial; RWE, real-world evidence; NO, nitric oxide; TNF, tumor necrosis factor; IL-6, interleukin-6; γδ, gamma delta; BP, bisphosphonate; IV, intravenous.

Denosumab and mortality

Denosumab, a monoclonal antibody targeting receptor activator of nuclear factor kappa-B ligand (RANKL), has shown promise in reducing all-cause mortality in specific populations, potentially via mechanisms that extend beyond fracture prevention [51]. Its distinct pharmacologic profile, differing from that of BPs, positions denosumab as a candidate for systemic survival benefits, particularly in postmenopausal women.

In a large Australian real-world cohort, post-fracture denosumab use was associated with a 48% reduction in all-cause mortality among women compared to untreated controls (HR, 0.52; 95% CI, 0.36 to 0.72); however, no significant mortality reduction was observed in men [51]. A similar trend was reported in a nationwide Taiwanese study, where denosumab demonstrated the greatest reduction in mortality (HR, 0.64; 95% CI, 0.60 to 0.68), outperforming BPs and SERMs in multivariate analyses [52].

Mechanistically, denosumab’s potential mortality benefits are thought to arise from its modulation of the RANKL/receptor activator of nuclear factor kappa-B (RANK)/osteoprotegerin (OPG) axis, which has roles in vascular, metabolic, and immune regulation [53]. Preclinical studies suggest that RANKL inhibition may reduce vascular calcification and enhance β-cell proliferation, leading to improved glycemic control via increased glucagon-like peptide-1 (GLP-1) secretion [54]. Denosumab also suppresses osteoclast-derived dipeptidyl peptidase-4, a GLP-1 inhibitor, further reinforcing the connection between bone and energy metabolism [55]. Additionally, early clinical studies indicate possible reductions in fat mass and cardiometabolic markers during denosumab therapy, particularly in patients undergoing estrogen suppression [56]. Although these findings are preliminary, they support the possibility of cardiometabolic benefits, especially in estrogen-deficient or frail populations. Consistently, a large cohort study of older adults with hip or vertebral fractures demonstrated significantly lower cause-specific mortality from both cancer and cardiovascular disease among those treated with denosumab, strengthening the case for its pleiotropic benefit [52].

By contrast, in populations without prior fractures, denosumab has not consistently demonstrated superior survival benefits compared to BPs. In a large real-world study, denosumab users without prior fractures had significantly higher mortality than matched oral BP users (HR, 1.49 in women and 2.74 in men), indicating possible residual confounding by indication or underlying disease severity despite propensity score adjustment [51].

Furthermore, the discontinuation of denosumab has been linked to rebound bone turnover and increased risk of vertebral fractures, raising concerns regarding the durability of its long-term systemic benefits [57].

In summary, denosumab may confer fracture-independent mortality reduction, particularly in high-risk, post-fracture women, as supported by studies demonstrating reduced cancer-and cardiovascular-related deaths in adherent users (Table 3).

Table 3.

Summary of Mortality and Fracture Outcomes Associated with Denosumab

Outcome	Findings	Supporting studies
Vertebral fracture reduction	Approximately 68% relative risk reduction	FREEDOM trial
Nonvertebral fracture reduction	Approximately 20% reduction overall; hip fracture risk ↓40%	FREEDOM trial; meta-analysis
All-cause mortality reduction	Approximately 22%–36% reduction in RWE (vs. no treatment or SERMs); lower than BPs in some studies, similar to Zol in others
Mechanisms	Fracture-related: ↓ fractures, ↑ recovery reserve
	Vascular/endothelial: ↓ vascular calcification via RANKL-RANK-OPG pathway, ↓ inflammation
	Anti-cancer: ↓ bone metastasis; potential benefit via immune modulation
	Anti-aging/resilience: ↑ physiological reserve, ↓ frailty
Influencing factors	Greater benefit in older adults and women with renal dysfunction (estimated glomerular filtration mate <60 mL/min/1.73 m2)
	Mortality benefit more evident with good adherence (≥60% PDC)
	Superiority over SERMs in all-cause mortality and ischemic stroke risk

FREEDOM, Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months; RWE, real-world evidence; SERM, selective estrogen receptor modulator; BP, bisphosphonate; Zol, zoledronic acid; RANKL, receptor activator of nuclear factor kappa-B ligand; RANK, receptor activator of nuclear factor kappa-B; OPG, osteoprotegerin; PDC, proportion of days covered.

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

Antiresorptive therapies reduce all-cause mortality through both fracture-dependent and fracture-independent mechanisms [29]. While prevention of vertebral and hip fractures remains the most established pathway to improved survival, a growing body of evidence supports pleiotropic effects, especially for BPs and denosumab, that may extend beyond skeletal protection [17].

Among the agents reviewed, intravenous and nitrogen-containing BPs, as well as denosumab, appear to confer the most consistent mortality benefits, particularly in older adults and high-risk, post-fracture populations. SERMs may provide modest benefit in select women with elevated cardiovascular or oncologic risk profiles.

However, current evidence is constrained by the absence of head-to-head RCTs with mortality as a primary endpoint, as well as by potential confounding in observational studies [58]. Future research should focus on clarifying the causal pathways that link antiresorptive therapy to mortality reduction, defining the duration and sustainability of benefit, and determining the clinical implications of treatment discontinuation.

A comprehensive understanding of the full spectrum of effects for each drug class will help inform more tailored therapeutic strategies for managing osteoporosis and its systemic consequences.

CONCLUSIONS

Osteoporosis is increasingly recognized as a systemic disorder with implications that extend well beyond skeletal fragility [4]. While fracture prevention—particularly of hip and vertebral fractures—remains the primary established mechanism by which antiresorptive agents reduce mortality, a growing body of evidence supports additional survival benefits mediated by pleiotropic pathways [30]. These pathways include cardiovascular protection, immune modulation, metabolic regulation, and reduced cancer risk.

Of the agents reviewed, intravenous and nitrogen-containing BPs and denosumab demonstrate the most consistent associations with reduced all-cause mortality, particularly in older adults and high-risk post-fracture populations. SERMs may provide modest benefits in selected individuals with elevated cardiovascular or oncologic risk.

As summarized in our integrated framework (Fig. 1), both fracture-dependent and fracture-independent effects contribute to the overall mortality benefit observed with antiresorptive therapy. This mechanism underscores the importance of timely initiation and sustained use of these agents—not only for fracture prevention, but also for addressing broader systemic risks in vulnerable populations [6].

Fig. 1.

Schematic summary of mortality risk reduction mechanisms by antiresorptive agents. Antiresorptive drugs, including selective estrogen receptor modulators (SERMs), bisphosphonates (BPs), and denosumab (DMAB)—may reduce mortality via both direct and indirect pathways. Indirect effects are mediated primarily by vertebral and nonvertebral fracture prevention, especially hip fractures. Direct effects include pleiotropic mechanisms such as cardiovascular protection, anti-cancer, anti-inflammatory benefits, and vascular and hormonal effects. CVD, cardiovascular disease.

Further research is warranted to clarify causality, define the optimal duration of therapy, and guide personalized treatment strategies that maximize both skeletal and survival outcomes.