Denosumab Plus Immune Checkpoint Inhibitors in Bone Metastases From Solid Tumors

Abstract

Bone metastases are a common and devastating complication of advanced solid tumors, significantly impairing patients’ quality of life and prognosis. Immune checkpoint inhibitor (ICI) plus bone-targeted therapies have emerged as a promising strategy to improve outcomes in patients with bone metastases. Denosumab, a fully human mAb targeting RANKL, can inhibit osteoclast-mediated bone resorption and prevent skeletal-related events. Beyond its direct bone remodeling activity, denosumab can also modulate the immune microenvironment, enhance anti-tumor immunity by reducing the release of immunosuppressive factors into the bone milieu, and improve vascular integrity within previously damaged bone tissue to facilitate immune cell infiltration into the metastatic niches. ICIs restore T-cell activity by overcoming tumor-induced immune suppression, thereby enabling more effective anti-tumor responses. Emerging evidence have suggested a potential synergy of denosumab plus ICIs, mechanistically by reinvigorating T-cell function and promoting maturation and antigen-presenting capacity of dendritic cells to further amplify adaptive immune response against metastatic bone tumors. The present narrative review summarizes the preclinical and clinical findings on this combination and discusses potential biomarkers and current challenges for the optimization of patient selection and therapeutic paradigm. Besides, we briefly overview current ongoing studies that investigate the potential antitumor synergy with denosumab plus ICIs in bone metastases.

Plain Language Summary

Bone metastases are a frequent and serious complication in patients with advanced solid cancers, often causing pain, fractures, and reduced quality of life. Combining immune checkpoint inhibitors (ICIs) with bone-targeted therapies has emerged as a potential approach to improve outcomes for these patients. Denosumab, an antibody that blocks RANKL, can prevent bone loss and skeletal-related events by reducing the activity of bone-resorbing cells. Beyond protecting bone, denosumab may also help the immune system fight cancer by improving the bone environment, reducing immunosuppressive factors, and supporting immune cell infiltration into metastatic sites. ICIs work by restoring the activity of T cells, helping the body mount stronger anti-tumor responses. Emerging evidence suggested that combining denosumab with ICIs could enhance the immune attack on cancer in the bone, potentially by boosting Tcell function and improving how immune cells recognize and respond to tumor antigens. This review summarizes the current preclinical and clinical evidence on this combination, discusses potential biomarkers and challenges, and ongoing studies aimed at optimizing treatment strategies in bone metastases.

Keywords

denosumab immune checkpoint inhibitors bone metastases solid tumors

Introduction

Bone metastases represent a common and severe complication in patients with advanced solid tumors, exhibiting a high incidence, especially in patients with breast cancer, prostate cancer, and lung cancer.¹ The metastatic disease to the bone significantly impacts the patient’s quality of life and prognosis. Under the substantial burden, current treatment strategies for bone metastases are multidisciplinary and tailored to address both tumor progression and skeletal complications.²

The treatment of bone metastasis can be categorized into therapies targeting the tumors and those addressing tumor-induced bone diseases.³ As for the tumor-targeting treatment, ICI has been approved as a standard treatment for various malignancies; however, its effectiveness in individuals with bone metastasis was limited by the unique microenvironment characteristics of bone metastases.⁴ In the bone microenvironment, osteoblasts, osteoclasts, and tumor cells interact closely: osteoblasts can interact with tumor cells to activate the Wnt signaling pathway, abnormally promoting bone formation, while also producing factors such as IGF-1 and TGF-β to modulate local immunity (Figure 1).^5,6 Tumor cells release factors including RANKL and M-CSF, which activate osteoclasts and induce osteolytic lesions.⁷ In addition, the bone marrow is enriched with immunosuppressive cells, including Tregs (which preferentially migrate to bone marrow and have been proven as an important source of RANKL), myeloid-derived suppressor cells (MDSCs, which inhibit T cell activation and enhance Treg activity), tumor-associated macrophages (TAMs), and Th17 cells, collectively maintaining local immunosuppression.⁶ Then, hypoxia in the bone marrow can also induce upregulation of PD-1/PD-L1, further regulating the immune suppression.^8,9 These features together constitute the immunosuppressive microenvironment of bone metastases, which makes ICI monotherapy of limited efficacy.

Figure 1.

Mechanism of denosumab and immune checkpoint inhibitor combination in the bone tumor microenvironment

As for the latter, the approaches to alleviate tumor-induced bone diseases mainly focus on anti-resorptive drugs. Among them, with advances in research on the role of the RANK-RANKL axis in the pathogenesis of bone metastasis, the anti-RANKL monoclonal antibody denosumab has been widely used in clinical practice to reduce the frequency of SREs in patients with advanced solid tumors and to increase their quality-adjusted life years.¹⁰ In addition to its bone-protective effects, denosumab can also act as a key coordinator between bone biology and tumor immunology.¹⁰ Specifically, in the bone metastasis tumor microenvironment, activated T cells—especially CD8⁺ T cells—can express RANKL and interact with dendritic cells (DCs), prolonging T-DC contact and thereby activating additional T cells. At the same time, this leads to elevated RANKL levels in the microenvironment, which act on osteoclasts and RANK⁺ myeloid cells, such as MDSCs, further exacerbating bone destruction and reinforcing immunosuppression.¹¹ Denosumab, by blocking the RANKL-RANK signaling axis, alleviates immunosuppressive states; additionally, RANKL inhibition can downregulate PD-1 expression on CD8⁺ T cells, further enhancing T-cell activity and antitumor effects.¹² By improving the immunosuppressive state of the bone metastatic microenvironment, denosumab provides more favorable conditions for ICIs to exert their effects, potentially enhancing overall antitumor efficacy. Overall, the combination of denosumab with ICIs may be an effective comprehensive treatment strategy for patients with bone metastasis, capable of treating the primary tumor, inhibiting bone destruction, and delaying the occurrence of SREs, finally improving prognosis and patients’ quality of life. The present narrative review focused on the preclinical advances and clinical evidence of potential synergistic effects with denosumab plus ICIs in bone metastases from solid tumors. Additionally, we also discussed key challenges and future directions in optimizing this therapeutic approach, providing insights into its potential application in clinical practice. This review is guided by the Scale for the Assessment of Narrative Review Articles SANRA.¹³

Methods

A comprehensive literature search was conducted in PubMed, Web of Science, and Google Scholar to identify relevant studies on denosumab combined with ICIs in bone metastases from solid tumors. The search covered articles published from the database inception to June 2024. Keywords included “denosumab”, “immune checkpoint inhibitors”, “bone metastases”, and “RANKL” were used alone or in combination. Preclinical studies, prospective and retrospective clinical studies, relevant review articles, and conference abstracts reporting clinical or translational data were considered. Reference lists of included articles were also manually screened to identify additional relevant studies.

Treatments of Bone Metastases

Overview of Clinical Studies With Denosumab Plus ICIs in Bone Metastases From Solid Tumors Denosumab

Clinically, denosumab in combination with ICIs has mainly been explored for the treatment of bone metastases in melanoma and non-small cell lung cancer (NSCLC). Evidence from these studies generally indicates potential benefits of the combination therapy; however, improvements were not consistently statistically significant across all cohorts.

In retrospective studies of metastatic melanoma, denosumab combined with ICIs has demonstrated promising efficacy. For example, Angela et al. observed that patients receiving denosumab combined with PD-1 inhibitors (dual therapy) or nivolumab plus ipilimumab (triple therapy) achieved encouraging objective response rates (ORR, 50-54%) and progression-free survival (PFS, 6 months).¹⁴ Similarly, Afzal et al. reported comparable efficacy, with patients receiving denosumab plus ICIs achieving an ORR of 54.5% and a median PFS of 4.2 months.¹⁵ However, results from prospective studies have been highly heterogeneous. Gerhardt et al. conducted a prospective, multicenter clinical study involving 16 patients with unresectable stage IV melanoma and found that denosumab plus dual ICIs resulted in modest tumor responses and survival outcomes (ORR, 17.6%; PFS, 2.9 months).¹⁶ In contrast, Moschos et al. observed an ORR of 48%, with a median PFS of 18.1 months and overall survival (OS) of 31.7 months.¹⁷ This discrepancy may be attributable to differences in treatment sequencing, as Moschos et al. administered denosumab alone first and added ICIs on day 21 to form the combination regimen. Interestingly, Mabrut et al. observed in a retrospective study in patients with solid tumors that initiating ICIs prior to bone-targeted therapy was associated with numerically more favorable clinical outcomes compared with bone-targeted therapy prior to ICIs (PFS, 10.9 vs 9.1 months).¹⁸ These findings suggest that the optimal treatment sequence remains to be further investigated.

In NSCLC patients, denosumab combined with ICIs may improve survival outcomes. Although prospective studies have reported relatively modest benefits (PFS, 1.7 months; OS, 8.3 months),¹⁹ most retrospective studies have demonstrated longer OS. For example, in two retrospective studies by Manglaviti et al., the median OS for patients receiving combination therapy was 15.1 and 15.2 months, respectively.^19,20 The authors further noted that, in the era of immunotherapy, a high bone tumor burden (HBTB) could identify patients who derive survival benefits from bone-targeted agents (BTA), particularly in the context of denosumab-ICI combination therapy. Future trials evaluating BTA-ICI combinations in NSCLC patients with bone metastases should consider HBTB as a stratification factor. Similarly, two retrospective studies by Asano et al. reported median OS of 14.2 and 16 months.^20,21 However, it’s important to note that although multiple retrospective studies have reported outcomes, much of the available data come from only a few centers, which may limit the generalizability of the observed benefits of combination therapy. In addition, a study in renal cell carcinoma has reported preliminary therapeutic benefits (PFS, 7.5 months). However, these trials are still ongoing, and survival outcomes may be updated as the studies progress, warranting continued attention. In addition, studies have also been conducted in renal cell carcinoma, with one study reporting preliminary PFS data (7.5 months), suggesting potential therapeutic benefit. As the studies are still ongoing, survival outcomes may be updated, warranting continued attention. The main characteristics and outcomes of these studies are summarized in Table 1.

Table 1.

Clinical Studies With Denosumab Plus ICIs in Bone Metastases From Solid Tumors

Study	Phase	Patient number	Bone metastases, %	Publication	Intervention	Cancer type	ORR, %	DCR, %	PFS, months	OS, months	Status
Bongiovanni et al.²² ^a	Retrospective	111	100	2021	ICI±BTT	NSCLC	7.6/64.6	53.8/91.5	3.9/15.9/2.7	15.8/21.8	Completed
Cao et al.²³	Retrospective	69	100	2021	ICI+deno	NSCLC	18.8	40.6	2.8	6.3	Completed
Angela et al.¹⁴	Retrospective	29	100	2019	Ipili+Nivo+deno/PD-1i+deno	Melanoma	54/50	77/75	6/6	NR/NR	Completed
Afzal et al.¹⁵	Retrospective	11	100	2018	ICI+deno	Melanoma	54.5	63.6	4.2	57	Completed
Mabrut et al.¹⁸	Retrospective	268	100	2024	ICI alone/ICI+deno	Solid tumors	-	-	2.7/2.8	7.2/9.1	Completed
Asano et al.²⁰	Retrospective	47	100	2024	ICI+deno	NSCLC	40.4	67.3	7.4	14.2	Completed
Asano et al.²¹	Retrospective	20	100	2022	ICI+deno	NSCLC	15.0	30.0	-	16	Completed
Li et al.²⁴	Retrospective	40	100	2022	ICI+deno	NSCLC	47.5	95	378 days	-	Completed
Manglaviti et al.²⁵	Retrospective	16	100	2021	ICI+deno	NSCLC	-	-	2.6	15.1	Completed
Manglaviti et al.²⁶	Retrospective	51	100	2023	ICI+deno	NSCLC	-	-	-	15.2	Completed
Gontier et al.²⁷	Retrospective	48	100	2022	ICI-based (ICI+deno, n=11)	Solid tumors	23	69	6	17	Completed
POPCORN	Phase 1b/2	30	-	-	Nivo+deno	NSCLC	-	-	-	-	Recruiting
CHARLI²⁸	Phase 1b/2	52	Unknown	2023	Nivo+deno/Ipili+Nivo+deno	Melanoma	56/71	-	NR/NR	-	Completed
KEYPAD	Phase 2	70	Unknown	2023	Pembro+deno	ccRCC	30	-	7.5	-	Recruiting
Moschos et al.¹⁷	Phase 2	25	Unknown	2024	ICI+deno	Melanoma	48	-	18.1	31.7	Completed
DENIVOS¹⁹	Phase 2	82	100	2022	Nivo+deno	NSCLC	14.6	42.7	1.7	8.3	Completed
Gerhardt et al.¹⁶	Phase 2	16	100	2024	ICI+deno	Melanoma	17.6	42.6	2.9	-	Completed
NIVOREN	Phase 2	31	100	2023	Nivo+deno	RCC	-	-	-	-	Completed

Abbreviations: deno, denosumab; Nivo, nivolumab; Ipili, Ipilimumab; Pembro, pembrolizumab; BTT, bone-targeted therapy; ICI, immune checkpoint inhibitors; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; NSCLC, non-small cell lung cancer; NR, not reached; CR, complete response; ccRCC, clear cell renal cell carcinoma; RCC, renal cell carcinoma.

^aThe ORR/DCR/OS data are reported with ICI alone, followed by ICI plus zoledronate/denosumab. The PFS outcomes are reported in the following order: ICI alone, ICI plus denosumab, and ICI plus zoledronate.

Overall, these studies provide signals suggestive of a potential synergistic effect between denosumab and ICIs, indicating that combination therapy may offer clinical benefits for patients with bone metastases. However, both retrospective and prospective studies have notable limitations, including small sample sizes, patient heterogeneity, differences in ICI regimens and treatment duration, and the lack of control groups in most studies. Therefore, these findings should be considered hypothesis-generating, and the current evidence is of moderate-to-low quality. The causal relationship of the potential synergy between denosumab and ICIs remains uncertain and requires validation in prospective, large-scale studies. In addition, the impact of treatment sequencing on the synergistic effect warrants further investigation. It is also unclear whether the observed benefits are primarily due to direct anti-tumor effects or mediated through the bone microenvironment. Finally, the question of whether denosumab is used as a concomitant therapy or one of the main therapeutic components should also be further answered in the future.

Challenges and Prospects

The combination of ICIs and denosumab offers a theoretical benefit and shows promise for the treatment of bone metastases, but faces challenges and uncertainties that require further investigation. These issues include resistance mechanisms arising from the unique characteristics of the bone microenvironment and the irAEs requiring careful consideration and management in clinical practice.

Toxicity Management of irAEs

Patients who received ICIs often experienced irAEs accompanied by the regression of the primary tumors. These irAEs are typically caused by inflammation and the expansion of immune cells and include common manifestations with dermatologic, gastrointestinal, pulmonary, and endocrine toxicities. Despite the broad spectrum of these toxicities, most issues can be managed with close monitoring and symptomatic treatment without necessitating discontinuation of ICI therapy.⁴ Recent studies indicated that patients who have previously or concurrently received denosumab treatment alongside anti-PD-1 therapy experience a numerically higher rate of grade 3 or higher irAEs compared to those receiving PD-1 inhibitors alone (21.4% vs. 11.6%).²⁹ Mechanistically, preclinical studies in mouse models have supported a potential role of anti-RANKL therapy in enhancing ICI-induced immune toxicity, including increased endocrine irAEs and modulation of Treg populations.²⁹ Additionally, recent case reports have revealed several uncommon irAEs during combination, such as multi-organ toxicities and granulomatous reactions. Although investigators primarily attribute these irAEs to immunotherapy, the complex interactions between the ICIs and denosumab make it difficult to entirely rule out contributions from bone-targeted therapy. Clinicians often prescribed bone-targeted agents as concomitant therapy to prevent SREs; however, denosumab was associated with hypocalcemia, and the inflammatory response induced by immunotherapy may exacerbate this condition.¹⁴ Therefore, careful monitoring of calcium levels and proactive management of hypocalcemia are critical components of care for these patients.

Beyond the commonly observed ICI-induced toxicities, patients may also develop rheumatic and musculoskeletal adverse events (AEs), including arthritis and rheumatoid arthritis.^30,31 Moreover, there is a significant increase in bone loss and skeletal complications following ICI therapy, including vertebral compression fractures, femoral neck fractures, vertebral and thoracic fractures, as well as pathological and osteoporotic fractures. A multidisciplinary approach—incorporating oncologists, endocrinologists, and pain management specialists—is essential for effectively managing such toxicities while minimizing their impacts on bone health.

Recently, osteonecrosis of the jaw (ONJ), a well-known and serious AE initially associated with bone-targeted therapies, has been identified as a new irAE in patients receiving ICIs, with or without bone-targeted agents such as denosumab. Patients typically present with recurrent jaw infections, accompanied by soft tissue swelling and pain, which can progress to jaw necrosis and bone exposure, and pathological fractures in severe cases. Moreover, these complications often necessitate the discontinuation or modification of immunotherapy, potentially compromising treatment efficacy and negatively impacting prognosis.^14,18,32 This underscores the need for heightened vigilance regarding ONJ as an unforeseen irAE. A comprehensive oral examination is recommended both before and during treatment to facilitate early diagnosis and optimal patient management.

In addition to the aforementioned AEs, case reports have also identified systemic bone loss and/or focal bone lesions in patients receiving α-PD-1 or α-PD-1/α-CTLA-4 therapy. Although the underlying mechanisms remain poorly understood, these effects may be linked to disrupted bone remodeling in a pro-inflammatory state, because all reported cases demonstrated elevated levels of the bone resorption marker CTX.³⁰

Additionally, Álvaro et al. reported that denosumab might induce transient but severe neuropsychiatric symptoms, potentially through mechanisms involving RANKL blockade and subsequent immune-inflammatory alterations.³³ Therefore, caution and close monitoring are recommended, particularly in patients with preexisting neurobiological vulnerabilities, to ensure early detection and appropriate management of potential AEs.

An overview of clinically reported irAEs associated with denosumab and ICIs in bone metastases is provided in Table 2.

Table 2.

Clinically Reported IrAEs Associated With Denosumab and ICIs in Bone Metastases

IrAEs	Proposed mechanisms	Specific irAE/Symptom	Management strategies
Common irAEs^a
Cutaneous toxicities	ICI-induced disruption of peripheral T-cell tolerance, leading to activation of autoreactive T cells, inflammation, and tissue damage in the skin organs that heavily rely on immune homeostasis.	Rash	Grade 3: Interrupt treatment
Cutaneous toxicities		Inflammatory dermatitis	Grade 4: Supportive care
Gastrointestinal toxicities	Immune activation leads to an increase in autoreactive T cells in the intestine, which attack intestinal epithelial cells and intestinal microbiota, and the proinflammatory microenvironment leads to intestinal mucosal injury.	Pneumonitis	Grade 2-3: Interrupt treatment+Supportive care
Gastrointestinal toxicities		Nausea	Grade 4: Permanently discontinue treatment
Lung toxicities	Excessive immune activation and inflammatory cytokines lead to Immune-mediated pulmonary injury.	Pneumonia	Grade 1-2: Interrupt treatment+Supportive care
Lung toxicities		Pneumonia	Grade 4: Permanently discontinue treatment
Endocrine toxicities	Autoreactive T cells lead to endocrine gland autoimmunity, while T cells can also directly attack glandular tissue.	Hypothyroidism	Grade 1-2: Close monitoring
Endocrine toxicities		Hypothyroidism	Grade 3: Interrupt treatment+Supportive care
Musculoskeletal toxicities	Inflammatory T-cell responses and cytokines lead to immune-mediated inflammation of joints and muscles.	Myasthenic syndrome	For Arthalgia:
		Myasthenic syndrome	Grade 3: Interrupt reatment+Supportive care
		Arthalgia	For myasthenic syndrome:
			Supportive care should be considered at all grades
			Grade 3: Permanently discontinue treatment
Nervous system toxicities	T cells in the central nervous system or peripheral nerves mediate an autoimmune response leading to nerve damage.	Encephalitis	Grade 2: Supportive care
Rare irAEs^b
Skeletal-related	A pro-inflammatory state disrupts bone remodeling by increasing osteoclast activity and bone resorption, leading to elevated levels of markers such as CTX.	Osteoporotic fractures	Discontinuation of ICIs
		Resorptive bone lesions	Discontinuation of ICIs
	Systemic activation of T cells leads to an osteoprotegerin ligand‐mediated increase in osteoclastogenesis and bone loss.	Osteonecrosis of the jaw	Discontinuation of ICIs
		Osteonecrosis of the jaw	Interruption of denosumab
Neuropsychiatric-related	RANKL blockade exacerbates immune-inflammatory alterations.	Delirium	Discontinuation of denosumab
		Depressive worsening	Discontinuation of denosumab
		Depressive worsening	Use anxiolytics

Abbreviations: irAEs, immune-related adverse events; ICIs, immune checkpoint inhibitors; CTX, C-telopeptide levels.

^aSummarizes the irAEs reported so far in patients receiving denosumab plus ICIs; management strategies are based on ASCO guidelines.³⁴

^bRare irAEs’ management strategies were the specific interventions applied to each patient.

Overcome Resistance

Resistant Mechanism of ICIs in Bone Metastases

One of the primary mechanisms of immune evasion in bone metastases was the ability of tumor cells to manipulate the bone microenvironment, creating an immunosuppressive milieu that inhibited effective immune responses. Currently, commonly used PD-1/PD-L1/CTLA-4 inhibitors function by blocking immune checkpoints, thereby activating T lymphocytes and promoting an anti-tumor immune response. However, the presence of MDSCs in the bone marrow has been shown to inhibit T cell activation and facilitate tumor progression.⁶ In parallel, Tregs within the bone marrow further exacerbated this immunosuppressive environment by inhibiting immune cell function and contributing to poor therapeutic responses.³⁵ Persistent hypoxia in bone marrow metastases further enhanced immunosuppression by upregulating PD-L1 expression in tumor cells, dendritic cells, macrophages, and MDSCs, which not only restricted T cell activity but also increased the prevalence of immunosuppressive Tregs and TAMs, ultimately limiting the host’s immune response to tumor growth.^4,35 Preclinical studies have explored the use of nanoparticles to alleviate hypoxia in bone metastases, reducing Treg levels and improving survival rates in mice models of established bone metastases.³⁵

Moreover, the inherent heterogeneity of bone metastases may also influence the immune landscape within the bone, leading to cancer-type-specific responses and resistance patterns to ICIs.³⁶ For instance, in osteoblastic lesions, immune cells were enriched with phosphorylated STAT3, components of the JAK-STAT pathway, and key immune checkpoints such as PD-L1, B7-H4, OX40L, and IDO-1, offering potential therapeutic targets for patients with bone metastases. By contrast, osteolytic lesions exhibited an increased presence of immune cells (including cytotoxic cells, macrophages, exhausted CD8⁺ T cells, CD45⁺ immune cells, neutrophils, and mast cells) rich in phosphorylated AKT and components of the PI3K-AKT pathway, which were associated with reduced bone mass.³⁶ Overall, these emerging insights into resistance mechanisms provide a foundation for future clinical studies aimed at improving the efficacy of immunotherapy in bone metastases.

Theoretical Breakthrough Points for the Combination Therapy

From a mechanistic perspective, denosumab targets and blocks the RANK-RANKL axis, disrupting the immunosuppressive network established within the bone metastatic microenvironment, thereby alleviating myeloid cell-mediated inhibition of anti-tumor immunity and partially reversing ICIs resistance associated with bone metastases. Preclinical studies have demonstrated that denosumab combined with ICIs can markedly increase the infiltration of CD8⁺ and CD4⁺ T cells within tumor tissues and enhance anti-tumor immune responses.^11,12 Clinically, in melanoma patients receiving dual ICIs plus denosumab, an increase in circulating CD8⁺ T cells and elevated levels of pro-inflammatory cytokines in the serum were observed, consistent with the trends seen in preclinical studies.¹⁶ Moreover, although direct evidence remains limited, the addition of denosumab may favorably remodel the bone metastatic microenvironment. For example, it may inhibit osteoclast activity via RANKL blockade, potentially normalizing the vascular network and alleviating hypoxia at metastatic sites; since the RANK-RANKL axis can promote the activity or accumulation of immunosuppressive myeloid cells within the bone marrow, denosumab may reduce the enrichment of these cells. These potential effects, however, require further investigation for confirmation.

Based on the ability of denosumab to improve the bone metastatic microenvironment and partially reverse resistance to ICIs, the sequence of administering denosumab before ICIs could theoretically provide greater clinical benefit. However, as discussed above, current evidence does not establish which treatment sequence is optimal, and this question remains to be further investigated.

Potential Biomarkers for Predicting the Efficacy of ICI With or Without Denosumab in Bone Metastases From Solid Tumors

A key focus is the identification of specific biomarkers that can predict responses to immunotherapy, thereby optimizing patient selection. Previous studies have highlighted the potential of various biomarkers, including protein expression profiles of primary tumors—such as the combined expression of macrophage capping protein and GIPC PDZ domain-containing protein—as well as gene expression signatures and circulating tumor cells.³⁷ However, research on predictive biomarkers for ICIs in the treatment of bone metastases remains ongoing, and further studies are needed to establish reliable indicators for therapeutic response. Alberto et al. demonstrated that a pre-treatment neutrophil-to-lymphocyte ratio (NLR) ≤5 was associated with a favorable OS in NSCLC patients with bone metastases receiving ICIs, with or without bone-targeted therapy.²² Asano et al. developed two novel predictive scoring systems—one incorporating dynamic changes in serum inflammatory markers of NLR and C-reactive protein (CRP) levels, and another (IMMUNO-SCORE) incorporating serum inflammatory and nutritional markers such as CRP, NLR, albumin, and the prognostic nutritional index, which both revealed significant correlations with clinical outcomes during ICI treatment in NSCLC with bone metastases.³⁸ Some retrospective studies have identified potential predictive factors, such as HBTB, PD-L1 tumor proportion score, and an ICI plus denosumab treatment duration of more than three months.^23,26 Overall, the current evidence regarding predictive biomarkers for ICI combined with or without denosumab in bone metastases remains low-level. Further research is needed to refine patient stratification based on the likelihood of benefiting from immunotherapy, ultimately advancing toward a more personalized treatment approach.

Strengths and Limitations

This review has summarized the current state of bone metastases from multiple perspectives, including epidemiology, disease diagnosis, clinical characteristics, pathogenesis, and the clinical application of ICI therapy combined with denosumab. As a narrative review, it provides an overview and synthesis of the existing evidence, with an emphasis on integrating clinical and mechanistic findings. However, several limitations should be acknowledged. First, the literature search was conducted using PubMed, Web of Science, and Google Scholar, while other databases were not systematically searched, which may have resulted in the omission of relevant studies. Nevertheless, as a narrative review, study selection was performed in a thoughtful and purposive manner, with explicit and transparent justification for inclusion, aiming to provide a balanced and comprehensive overview of the available evidence. Then, no quantitative synthesis or meta-analysis was performed, and publication bias cannot be excluded.

Conclusion

Bone remains one of the most common metastatic sites, particularly in breast cancer, prostate cancer, and lung cancer. Although ICIs have demonstrated remarkable success in treating primary tumors and certain distant metastases, and denosumab has shown promising bone-protective effects, existing clinical evidence preliminarily suggests that their combination may improve survival outcomes in patients with bone metastases; however, the therapeutic effect has not yet reached the expected level. It must be emphasized that the synergistic efficacy of this combination in bone metastases remains in the preliminary exploration stage. Most available evidence originates from retrospective studies, which are inherently subject to bias and heterogeneity, while prospective studies remain limited, often involving small sample sizes or single-arm designs. Therefore, the synergistic effect must be confirmed through high-quality prospective trials before being incorporated into clinical implementation.

Significant knowledge gaps remain regarding the combined use of ICIs and denosumab, highlighting the urgent need for randomized controlled trials in baseline-balanced populations and for clarifying whether denosumab primarily functions as a bone-protective agent or an immune modulator in exerting synergistic effects. Future research should prioritize: (i) designing rigorous prospective randomized controlled trials to determine the efficacy of the combination therapy and to explore the optimal sequencing of administration; (ii) exploring bone metastasis-specific predictive biomarkers for patient stratification; (iii) establishing expert consensus on toxicity management for combination regimens; and (iv) further elucidating the molecular and immunological mechanisms underlying the combined effects to inform optimized therapeutic strategies. Until such high-level evidence becomes available, this combination strategy must be approached with caution. In current clinical practice, denosumab may be used in patients receiving ICIs according to standard indications for SRE prevention, but it should not yet be considered a routine immune-enhancing agent. Clinicians should carefully balance patient survival, disease status, and economic factors while ensuring the best possible quality of life for patients.

Footnotes

ORCID iD

Na Wang

Ethical Considerations

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the 1. Gansu Science and Technology Project (24JRRA314). 2. Excellent Young Talents Project from Gansu Provincial Department of Health (GSWSQN2024-10). 3. Chronic Disease Management Research Project of National Health Commission Capacity Building and Continuing Education Center (GWJJMB202510022031).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Appendix

References

Huang

Shen

, et al. Incidence of patients with bone metastases at diagnosis of solid tumors in adults: a large population-based study. Ann Transl Med. 2020;8(7):482. doi:10.21037/atm.2020.03.55.

Coleman

Hadji

Body

, et al. Bone health in cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2020;31(12):1650-1663. doi:10.1016/j.annonc.2020.07.019.

Costelloe

Lin

Chuang

, et al. Bone Metastases: Mechanisms of the Metastatic Process, Imaging and Therapy. Semin Ultrasound CT MR. 2021;42(2):164-183. doi:10.1053/j.sult.2020.08.016.

Joseph

Johnson

. Immune checkpoint inhibitors in bone metastasis: Clinical challenges, toxicities, and mechanisms. J Bone Oncol. 2023;43:100505. doi:10.1016/j.jbo.2023.100505.

Hall

Bafico

Dai

Aaronson

Keller

. Prostate cancer cells promote osteoblastic bone metastases through Wnts. Cancer Res. 2005;65(17):7554-7560. doi:10.1158/0008-5472.Can-05-1317.

Xiang

Gilkes

. The Contribution of the Immune System in Bone Metastasis Pathogenesis. Int J Mol Sci. 2019;20(4):999. doi:10.3390/ijms20040999.

Yiang

, et al. Molecular Regulation of Bone Metastasis Pathogenesis. Cell Physiol Biochem. 2018;46(4):1423-1438. doi:10.1159/000489184.

Noman

Desantis

Janji

, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781-790. doi:10.1084/jem.20131916.

Mortezaee

Majidpoor

Kharazinejad

. The impact of hypoxia on tumor-mediated bypassing anti-PD-(L)1 therapy. Biomed Pharmacother. 2023;162:114646. doi:10.1016/j.biopha.2023.114646.

10.

Gül

Sendur

Aksoy

Sever

Altundag

. A comprehensive review of denosumab for bone metastasis in patients with solid tumors. Curr Med Res Opin. 2016;32(1):133-145. doi:10.1185/03007995.2015.1105795.

11.

Ahern

Harjunpää

Barkauskas

, et al. Co-administration of RANKL and CTLA4 Antibodies Enhances Lymphocyte-Mediated Antitumor Immunity in Mice. Clin Cancer Res. 2017;23(19):5789-5801. doi:10.1158/1078-0432.Ccr-17-0606.

12.

Ahern

Harjunpää

O'Donnell

, et al. RANKL blockade improves efficacy of PD1-PD-L1 blockade or dual PD1-PD-L1 and CTLA4 blockade in mouse models of cancer. Oncoimmunology. 2018;7(6):e1431088. doi:10.1080/2162402x.2018.1431088.

13.

Baethge

Goldbeck-Wood

Mertens

. SANRA-a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019;4:5. doi:10.1186/s41073-019-0064-8.

14.

Angela

Haferkamp

Weishaupt

, et al. Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases. Cancer Immunol Immunother. 2019;68(7):1187-1194. doi:10.1007/s00262-019-02353-5.

15.

Afzal

Shirai

. Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with anti-RANKL denosumuab in malignant melanoma: a retrospective analysis at a tertiary care center. Melanoma Res. 2018;28(4):341-347. doi:10.1097/cmr.0000000000000459.

16.

Schaper-Gerhardt

Gutzmer

Angela

, et al. The RANKL inhibitor denosumab in combination with dual checkpoint inhibition is associated with increased CXCL-13 serum concentrations. European Journal of Cancer. 2024;202:202. doi:10.1016/j.ejca.2024.113984.

17.

Moschos

Ollila

Googe

, et al. 1465 Denosumab improves clinical benefit of PD1 inhibitors in metastatic melanoma (MM) presumably via a suppressive effect on immunoregulatory myeloid cell populations. Journal for immunotherapy of cancer. 2024;12(Suppl 3):A1696. doi:10.1136/jitc-2024-SITC2024.1465.

18.

Mabrut

Mainbourg

Peron

, et al. Synergistic effect between denosumab and immune checkpoint inhibitors (ICI)? A retrospective study of 268 patients with ICI and bone metastases. J Bone Oncol. 2024;48:100634. doi:10.1016/j.jbo.2024.100634.

19.

Decroisette

Monnet

Ricordel

, et al. 1035P A phase II trial of nivolumab and denosumab association as second-line treatment for stage IV non-small-cell lung cancer (NSCLC) with bone metastases: DENIVOS study (GFPC 06-2017). Annals of Oncology. 2022;33:S1028-S1029. doi:10.1016/j.annonc.2022.07.1161.

20.

Asano

Yamamoto

Demura

, et al. Combination therapy with immune checkpoint inhibitors and denosumab improves clinical outcomes in non-small cell lung cancer with bone metastases. Lung Cancer. 2024;193:107858. doi:10.1016/j.lungcan.2024.107858.

21.

Asano

Yamamoto

Demura

, et al. The Therapeutic Effect and Clinical Outcome of Immune Checkpoint Inhibitors on Bone Metastasis in Advanced Non-Small-Cell Lung Cancer. Front Oncol. 2022;12:871675. doi:10.3389/fonc.2022.871675.

22.

Bongiovanni

Foca

Menis

, et al. Immune Checkpoint Inhibitors With or Without Bone-Targeted Therapy in NSCLC Patients With Bone Metastases and Prognostic Significance of Neutrophil-to-Lymphocyte Ratio. Front Immunol. 2021;12:697298. doi:10.3389/fimmu.2021.697298.

23.

Cao

Afzal

Shirai

. Does denosumab offer survival benefits? -Our experience with denosumab in metastatic non-small cell lung cancer patients treated with immune-checkpoint inhibitors. J Thorac Dis. 2021;13(8):4668-4677. doi:10.21037/jtd-21-150.

24.

Lei

, et al. Efficacy and safety of concomitant immunotherapy and denosumab in patients with advanced non-small cell lung cancer carrying bone metastases: A retrospective chart review. Front Immunol. 2022;13:908436. doi:10.3389/fimmu.2022.908436.

25.

Manglaviti

Galli

Bini

, et al. 184P Bone-targeted agents (BTA) improve survival in advanced non-small cell lung cancer (aNSCLC) patients (pts) with high bone tumor burden (HBTB) treated with PD-(L)-1 inhibitors (ICIs). Journal of Thoracic Oncology. 2021;16(4):S797. doi:10.1016/S1556-0864(21)02026-8.

26.

Manglaviti

Bini

Apollonio

, et al. High bone tumor burden to identify advanced non-small cell lung cancer patients with survival benefit upon bone targeted agents and immune checkpoint inhibitors. Lung Cancer. 2023;186:107417. doi:10.1016/j.lungcan.2023.107417.

27.

Gefard-Gontier

Markich

Zysman

, et al. Evolution of bone metastases in patients receiving at least three months of checkpoint inhibitors. Cancer Immunol Immunother. 2022;71(11):2609-2618. doi:10.1007/s00262-022-03180-x.

28.

Lau

PKH

Harris

Eastgate

, et al. CHARLI: A phase Ib/II trial of ipilimumab-nivolumab-denosumab or nivolumab-denosumab in patients with unresectable stage III and IV melanoma. Journal of Clinical Oncology. 2023;41(16_suppl):9525. doi:10.1200/JCO.2023.41.16_suppl.9525.

29.

Peluso

Ortega

Huang

, et al. 1176 Anti-RANKL bone resorptive therapy increases immune related adverse events (irAEs) during checkpoint inhibitor therapy. Journal for immunotherapy of cancer. 2024;12(Suppl 2):A1305. doi:10.1136/jitc-2024-SITC2024.1176.

30.

Moseley

Naidoo

Bingham

, et al. Immune-related adverse events with immune checkpoint inhibitors affecting the skeleton: a seminal case series. Journal for immunotherapy of cancer. 2018;6(1):104. doi:10.1186/s40425-018-0417-8.

31.

Filippini

Gatti

Di Martino

, et al. Bone fracture as a novel immune-related adverse event with immune checkpoint inhibitors: Case series and large-scale pharmacovigilance analysis. Int J Cancer. 2021;149(3):675-683. doi:10.1002/ijc.33592.

32.

Khan

Morrison

Kendler

, et al. Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ. J Clin Densitom. 2017;20(1):8-24. doi:10.1016/j.jocd.2016.09.005.

33.

Oteo-Álvaro

García

Sánchez

Santamaria

de Diego-Adeliño

. Neuropsychiatric adverse reactions in patients treated with denosumab: two case reports and a review of data from the FDA Adverse Event Reporting System (FAERS). Osteoporos Int. 2023;34(10):1799-1804. doi:10.1007/s00198-023-06838-z.

34.

Schneider

Naidoo

Santomasso

, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. Journal of Clinical Oncology. 2021;39(36):4073-4126. doi:10.1200/JCO.21.01440.

35.

Murphy

Osteicochea

Atkins

Sannes

McClarnon

Adjei

. Optimizing Oxygen-Production Kinetics of Manganese Dioxide Nanoparticles Improves Hypoxia Reversal and Survival in Mice with Bone Metastases. Mol Pharm. 2024;21(3):1125-1136. doi:10.1021/acs.molpharmaceut.3c00671.

36.

Ihle

Provera

Straign

, et al. Distinct tumor microenvironments of lytic and blastic bone metastases in prostate cancer patients. Journal for immunotherapy of cancer. 2019;7(1):293. doi:10.1186/s40425-019-0753-3.

37.

Iuliani

Simonetti

Ribelli

, et al. Current and Emerging Biomarkers Predicting Bone Metastasis Development. Front Oncol. 2020;10:789. doi:10.3389/fonc.2020.00789.

38.

Asano

Hayashi

Takeuchi

, et al. Combining dynamics of serum inflammatory and nutritional indicators as novel biomarkers in immune checkpoint inhibitor treatment of non-small-cell lung cancer with bone metastases. Int Immunopharmacol. 2024;136:112276. doi:10.1016/j.intimp.2024.112276.