Abstract
Background
Lung cancer with progressive bone metastases usually leads to skeletal-related events (SREs) and a reduced quality of life. Denosumab delays the onset of SREs and is associated with improved overall survival. However, other factors associated with overall survival in patients with lung cancer and bone metastases remain unclear. This study aimed to evaluate the survival benefit of denosumab use in patients with lung cancer and bone metastases and how other factors affect overall survival in these patients.
Methods
This retrospective cohort study included 622 patients with lung cancer treated at a southern Taiwan Medical Center between 2018 and 2022. The overall survival of patients with lung cancer and bone metastases treated with denosumab (n=90) was compared with that of patients who did not receive denosumab (n=212). Kaplan-Meier survival analysis and Cox proportional hazards models were used to evaluate the factors associated with the overall survival of these patients.
Results
Denosumab use was associated with improved overall survival among patients with lung cancer and bone metastases compared with untreated patients (HR 0.61, 95% CI 0.47 to 0.80, p<0.001, overall survival 455 days vs 172 days), particularly in patients who had received more than five cycles of treatment (HR 0.31, 95% CI 0.19 to 0.50, p<0.001). Systemic cancer treatments, such as tyrosine kinase inhibitors, chemotherapy and immunotherapy, were also associated with improved overall survival in these patients.
Conclusions
Denosumab usage, especially good compliance, for over five cycles in patients with lung cancer and bone metastases was associated with improved overall survival. Future studies should focus on strategies to improve adherence to denosumab treatment and maximise its clinical benefits.
Keywords: Lung Cancer, Compliance
WHAT IS ALREADY KNOWN ON THIS TOPIC
Denosumab, a bone-targeted therapy, is known to delay skeletal-related events and might improve survival in patients with lung cancer with bone metastasis.
WHAT THIS STUDY ADDS
This retrospective cohort study confirms that denosumab with high treatment compliance (receiving more than five doses) is associated with longer overall survival in patients with lung cancer and bone metastases.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
These findings highlight the critical importance of treatment adherence. Clinicians should encourage lung cancer patients with bone metastasis to receive denosumab regularly and systemic cancer treatments for improving survival.
Introduction
Lung cancer is a leading cause of cancer-related mortality, accounting for over 25% of all cancer deaths.1 Bone metastases occur in approximately 35%–60% of patients with lung cancer, contributing to skeletal-related events (SREs), pain and reduced quality of life.2 These metastases complicate management and increase the disease’s socioeconomic burden. Conventional management of lung cancer bone metastases often involves bisphosphonates (eg, zoledronic acid),3 which inhibit osteoclast-mediated bone resorption.4 However, bisphosphonates can cause renal toxicity and a risk of osteonecrosis of the jaw (ONJ).
Denosumab, a monoclonal antibody against RANKL, offers an alternative by preventing osteoclast activation and reducing bone resorption.5 Denosumab has also been associated with better overall survival (OS) in lung cancer patients with bone metastases compared with zoledronic acid.6 7 Despite these benefits, the factors contributing to improved survival in patients with lung cancers with bone metastases remain unclear. Most evidence for denosumab’s efficacy comes from studies including multiple cancer types,8 9 and few have examined the impact of treatment compliance on OS. Real-world data suggest both denosumab and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) can improve survival in lung cancer with bone metastases,10 11 but the relative benefits of different EGFR-TKIs are inconclusive.
This retrospective cohort study aimed to evaluate whether denosumab use is associated with improved OS in patients with lung cancer and bone metastases, and to identify other factors influencing OS in this population.
Methods
Participants
This retrospective cohort study included patients with stage IV lung cancer treated at a medical centre in southern Taiwan from January 2018 to December 2022. Eligible patients were adults (≥18 years) diagnosed with stage IV lung cancer (The American Joint Committee on Cancer eighth edition) with confirmed bone metastasis by imaging (CT, bone scan or positron emission tomography) during the study period.
All eligible patients were included (sample size determined by patient availability rather than a formal calculation). Patients were excluded if they had an SRE at the time of lung cancer diagnosis, incomplete medical records or <6 months of follow-up (unless they died within 6 months). Therefore, all included patients had complete data for the variables analysed, and no data imputation was required. Patients were grouped into three categories: (1) stage IV lung cancer without bone metastasis; (2) bone metastasis without denosumab treatment and (3) bone metastasis with denosumab treatment. We collected baseline data including age, sex, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, lung cancer histology, EGFR mutation status (exon 19 deletion, L858R or other mutations) and treatments (chemotherapy, immunotherapy and TKIs). OS and SREs (pathological fractures, spinal cord compression or surgical/radiotherapy interventions for bone complications) were recorded.
We also documented denosumab use, including the number of treatment cycles, persistence and compliance. Persistence was defined as denosumab administration at ≤35 days intervals over 1 year,12 and compliance was defined as receiving ≥12 doses per year.13 14 Because the median number of denosumab doses in our cohort was five, patients who received more than five doses were considered to have ‘good compliance’ (noting that ≥4 doses is a common efficacy threshold for bone metastasis treatment).
Statistical analyses
All statistical analyses were conducted using SPSS V.28.0. Descriptive statistics were used to summarise the baseline characteristics of the study groups. Continuous variables were expressed as medians with IQRs, and categorical variables were presented as frequencies and percentages. Differences between the groups were assessed using Fisher’s exact test for categorical variables. A p<0.05 was considered statistically significant.
Survival analysis was performed using Kaplan-Meier survival curves to estimate OS, and comparisons between groups were conducted using the log-rank test. Separate survival curves were generated for the subgroups based on age, TKI use, denosumab cycles, compliance and persistence.
Cox proportional hazards regression models were used to identify factors associated with OS. Univariate analysis was conducted to examine the association between each variable and the survival outcomes. Significant variables from the univariate analysis were included in the multivariate Cox regression models to adjust for potential confounders. HRs and adjusted HRs (aHR) with 95% CIs were reported for each factor. The variables included in the multivariate model were age, sex, smoking status, lung cancer subtype, mutation type, ECOG performance score, TKI use, chemotherapy, immunotherapy, number of bone metastases and denosumab treatment.
Patient and public involvement
Patients or public were not involved in the design of this study.
Results
Clinical characteristics
Table 1 shows the baseline characteristics of the study groups. The study included 622 patients with stage IV lung cancer categorised as follows: patients with lung cancer without bone metastasis (N=320), patients with lung cancer bone metastasis without denosumab (N=212) and patients with lung cancer bone metastasis with denosumab (N=90). The median patient age was 67 years, and 72% of the patients were male. Most patients had adenocarcinoma, followed by squamous cell carcinoma and other cancer types.
Table 1. Baseline characteristics of the overall group of patients with lung cancer (N=622), patients with lung cancer without bone metastases (N=320), patients with lung cancer bone metastases without denosumab treatment (N=212) and patients with lung cancer bone metastases with denosumab treatment (N=90).
| Characteristic | Overall, (N=622)* |
No bone metastasis (N=320)* |
Bone metastasis No Denosumab (N=212)* |
Bone metastasis Denosumab (N=90)* |
P value† |
|---|---|---|---|---|---|
| Age (years) | 67 (60, 77) | 67 (60, 76) | 68 (60, 78) | 65 (61, 73) | 0.10 |
| Gender | 0.2 | ||||
| Female | 176 (28%) | 82 (26%) | 63 (30%) | 31 (34%) | |
| Male | 446 (72%) | 238 (74%) | 149 (70%) | 59 (66%) | |
| Smoking | 308 (50%) | 147 (46%) | 120 (57%) | 41 (46%) | 0.031 |
| Lung cancer type | <0.001 | ||||
| Adenocarcinoma | 461 (74%) | 221 (69%) | 159 (75%) | 81 (91%) | |
| Squamous cell carcinoma | 59 (9.5%) | 35 (11%) | 21 (9.9%) | 3 (3.3%) | |
| Others | 102 (16.4%) | 64 (20%) | 32 (15.1%) | 6 (6.7%) | |
| Mutation | <0.001 | ||||
| None | 327 (53%) | 202 (63%) | 99 (47%) | 26 (29%) | |
| EGFR-L858R | 116 (19%) | 51 (16%) | 38 (18%) | 27 (30%) | |
| EGFR-Ex19Del | 108 (17%) | 37 (12%) | 45 (21%) | 26 (29%) | |
| Other mutations | 71 (11%) | 30 (9.4%) | 30 (14%) | 11 (12%) | |
| ECOG | <0.001 | ||||
| 0–1 | 466 (75%) | 271 (85%) | 121 (57%) | 74 (82%) | |
| 2–4 | 156 (25%) | 49 (15%) | 91 (43%) | 16 (18%) | |
| TKI | <0.001 | ||||
| None | 356 (57%) | 212 (66%) | 114 (54%) | 30 (33%) | |
| Afatinib | 112 (18%) | 41 (13%) | 38 (18%) | 33 (37%) | |
| Erlotinib/gefitinib | 96 (15%) | 44 (14%) | 36 (17%) | 16 (18%) | |
| Osimertinib | 29 (4.7%) | 7 (2.2%) | 16 (7.5%) | 6 (6.7%) | |
| Others | 29 (4.7%) | 16 (5.0%) | 8 (3.8%) | 5 (5.6%) | |
| Chemotherapy | 215 (35%) | 125 (39%) | 66 (31%) | 24 (27%) | 0.039 |
| Immunotherapy | 35 (5.6%) | 18 (5.6%) | 10 (4.7%) | 7 (7.8%) | 0.6 |
| Other metastasis | 490 (79%) | 320 (100%) | 115 (54%) | 55 (61%) | <0.001 |
| Pathological fracture | 27 (8.9%) | – | 17 (8.0%) | 10 (11%) | 0.4 |
| Spinal compression | 17 (5.6%) | – | 11 (5.2%) | 6 (6.7%) | 0.6 |
| Radiotherapy or operation | 83 (28%) | – | 45 (21%) | 38 (42%) | <0.001 |
| Denosumab cycles (No.) | 5 (2, 16) | – | – | 5 (2, 16) | |
| Compliance to denosumab | 30 (33%) | – | – | 30 (33%) | |
| Persistence to denosumab | 50 (56%) | – | – | 50 (56%) |
Median (IQR); n (%).
Fisher’s exact test for count data with simulated p value (based on 2000 replicates).
ECOG, Eastern Cooperative Oncology Group; TKI, tyrosine kinase inhibitor.
The median age across the three groups was similar, ranging from 65 to 68 years (p=0.1), suggesting no significant difference in age distribution across the groups. The distribution of males and females did not significantly differ between the groups (p=0.2). The proportion of males was higher than females in all groups, with 74% in the no bone metastasis, 70% in the bone metastasis without denosumab treatment, and 66% in the bone metastasis with denosumab treatment groups.
A significant difference in smoking rate was observed between the groups (p=0.031). The bone metastasis without denosumab treatment group had the highest proportion of smokers compared with the no bone metastasis and denosumab-treated groups.
Significant differences were observed in the histological types of lung cancer between the groups (p<0.001). The adenocarcinoma subtype was more prevalent in the denosumab-treated group than in the bone metastasis without denosumab treatment and no bone metastasis groups. Significant differences were also observed in mutation status (p<0.001). The proportion of patients with EGFR mutations (EGFR-L858R and EGFR-Ex19Del) was higher in the denosumab-treated group than in the other groups.
A significant difference in ECOG performance status across the groups (p<0.001) showed a higher proportion of patients with a good performance status (ECOG 0–1) in the denosumab group (82%) than in the bone metastasis without denosumab treatment group (57%). Significant differences in TKI use were also observed (p<0.001). Patients in the denosumab group were more likely to be treated with afatinib than those who did not receive denosumab. Osimertinib use was higher in the bone metastasis without denosumab treatment group than in the other groups. Chemotherapy usage differed significantly (p=0.039), with a lower percentage in the denosumab group than in the bone metastasis without denosumab treatment and no bone metastasis groups. No significant differences were observed in immunotherapy use across the groups (p=0.6). Regarding SREs, 28% of patients (n=83) underwent radiotherapy (n=72), surgery (n=18) and both (n=7) for bone complications. A key finding was that patients receiving denosumab had a significantly higher rate of these interventions than untreated patients (42% vs 21%, p<0.001).
Survival outcomes and Kaplan-Meier curves
The Kaplan-Meier curves (figure 1) showed significant differences in OS among the three groups. Patients with bone metastases treated with denosumab had better survival outcomes than those who were not treated with denosumab (HR=0.61, p<0.001). The median OS was 455 days in the denosumab-treated group, 172 days in the non-denosumab-treated group, and 234 days in the no bone metastasis group. The effect of TKIs on OS in patients with lung cancer and bone metastases is shown in figure 2. The use of TKIs was associated with improved OS compared with no TKI use (p<0.001, HR=0.47 in the afatinib group; p<0.001, HR=0.40 in the gefitinib/erlotinib group; p<0.001, HR=0.18 in the osimertinib group and p<0.001, HR=0.23 in the other TKI group). The median OS was longer in patients treated with osimertinib than in those treated with gefitinib/erlotinib or afatinib. Specifically, the median OS was 425 days in the afatinib group and 530 days in the gefitinib/erlotinib group. In the osimertinib group, the median OS had not yet been reached. Figure 3 highlights the effect of the number of denosumab cycles on OS. Patients receiving five or more cycles had better survival outcomes than those who received fewer cycles (HR=0.31, p<0.001). Onlinesupplemental figure 1AB shows the Kaplan-Meier curves for compliance and persistence with denosumab treatment, respectively. No significant differences were observed when compliance and persistence were used as factors for OS analysis (compliance HR=1.12, p=0.6; persistence HR=1.07, p=0.8).
Figure 1. Kaplan-Meier overall survival curves among patients with lung cancer without bone metastases, bone metastases with denosumab treatment and bone metastases without denosumab treatment.
Figure 2. Kaplan-Meier overall survival curves among patients with lung cancer bone metastases according to tyrosine kinase inhibitors (TKIs) received.
Figure 3. Kaplan-Meier overall survival curves among denosumab-treated patients with lung cancer according to the number of denosumab treatment cycles.
Multivariate Cox regression analysis for factors associated with increased OS for patients with lung cancer and bone metastases
Online supplemental table 1 shows the Cox regression models for the factors affecting OS among lung cancer patients with bone metastases. The univariate analysis of patients with bone metastases showed that several factors significantly affected OS. Patients over 65 years of age had a significantly higher risk of death compared with those 65 years and below (HR=1.44, p=0.004). Ever-smokers had a significantly higher risk of death than non-smokers (HR=1.52, p<0.001). Patients with squamous cell carcinoma (HR=2.37, p<0.001) and other lung cancer types (HR=1.79, p=0.002) had significantly lower survival rates than patients with adenocarcinoma. Patients with EGFR-L858R (HR=0.43, p<0.001), EGFR-Ex19Del (HR=0.28, p<0.001) and other mutations (HR=0.34, p<0.001) had a significantly reduced risk of death compared with patients with lung cancer without mutations. Patients with ECOG scores of 2–4 had a much higher risk of death than those with scores of 0–1 (HR=2.60, p<0.001). TKI usage such as afatinib (HR=0.47, p<0.001), erlotinib/gefitinib (HR=0.40, p<0.001), osimertinib (HR=0.18, p<0.001) and others (HR=0.18, p<0.001) were associated with a significantly lower risk of death than those not treated with TKIs. Patients who received chemotherapy had an increased risk of death (HR=1.42, p=0.009), whereas those who received immunotherapy had a significantly decreased risk of death (HR=0.52, p=0.034). Patients treated with denosumab had a significantly lower risk of death than those not treated with denosumab (HR 0.60, 95% CI 0.46 to 0.79, p<0.001).
Furthermore, patients with an ECOG score of 2–4 had a significantly higher risk of death than those with lower scores (aHR=2.17, p<0.001). Afatinib (aHR=0.24, p=0.004), erlotinib/gefitinib (aHR=0.16, p<0.001) and osimertinib (aHR=0.05, p<0.001) usage significantly reduced the risk of death. Chemotherapy (aHR=0.32, p<0.001) and immunotherapy (aHR=0.32, p<0.001) were also associated with improved survival. Among patients with bone metastasis, those treated with denosumab had a significantly lower risk of death than those not treated with denosumab (aHR=0.67, p=0.010). However, whether the patient had multiple bone metastases or weight-bearing bone metastases did not significantly affect the multivariate analysis. Additionally, patients with other metastases showed a significantly increased risk of death in multivariate analysis (aHR=1.44, p=0.008).
Online supplemental table 2 shows the Cox regression models for the factors affecting survival among all patients with lung cancer. The univariate analysis indicated that several factors significantly affected patient survival. Patients over 65 years of age (HR=1.40, p<0.001), male patients (HR=1.50, p<0.001), smokers (HR=1.45, p<0.001), ECOG scoring 2–4 (HR=2.44, p<0.001), patients with squamous cell carcinoma (HR=2.31, p<0.001), or other types of lung cancer (HR=1.65, p<0.001) had a significantly higher risk of death. Patients with the EGFR-L858R mutation (HR=0.39, p<0.001), EGFR-Ex19Del mutation (HR=0.27, p<0.001), patients treated with afatinib (HR=0.40, p<0.001), erlotinib/gefitinib (HR=0.39, p<0.001), osimertinib (HR=0.18, p<0.001), immunotherapy (HR=0.58, 95% p= 0.008) or denosumab (HR 0.58, p=0.008) had a significantly lower risk of death than untreated patients.
In the multivariate analysis, sex remained an important predictor, with male patients having a higher risk of death than females (aHR=1.28, p=0.040). Patients with ECOG scores of 2–4 had a significantly higher risk of death than those with scores of 0–1 (aHR=1.72, p<0.001). Patients treated with afatinib (aHR=0.29, p=0.002), erlotinib/gefitinib (aHR=0.25, p<0.001) and osimertinib (aHR=0.10, p<0.001), and immunotherapy (aHR=0.35, p<0.001) also showed significant protective effects in the multivariate analysis. Patients not treated with denosumab had a significantly higher risk of death than those treated with denosumab (aHR=1.38, p=0.007). Furthermore, patients with other metastases had a significantly higher risk of death than those without (aHR=1.48, p=0.003).
Online supplemental table 3 shows the Cox regression models for the factors affecting survival among denosumab-treated patients with lung cancer. The univariate analysis of patients with bone metastases treated with denosumab showed that several factors significantly influenced survival. The lung cancer type significantly affected patient survival. Patients with squamous cell carcinoma had a significantly higher risk of death than those with adenocarcinoma (HR=4.00, p=0.023); patients with other types of lung cancer also had a significantly higher risk of death (HR=2.75, p=0.035). Genetic mutations showed an apparent protective effect in the univariate analysis. Patients with the EGFR-L858R mutation had a significantly lower risk of death than those who did not (HR=0.35, p<0.001), as did patients with the EGFR-Ex19Del mutation (HR=0.19, p<0.001). Other mutation types were also associated with a significantly lower risk of death (HR=0.16, p<0.001). The ECOG performance status scores showed some effect in the univariate analysis, with patients scoring 2–4 having a higher risk of death than those with scores of 0–1 (HR=1.64, p=0.091), with no statistical significance. Patients treated with afatinib (HR=0.46, p=0.005), erlotinib/gefitinib (HR=0.42, p=0.013) or osimertinib (HR=0.25, p=0.024) showed a significantly lower risk of death than those not treated with TKIs. Patients who received chemotherapy had a significantly higher risk of death (HR=2.34, p=0.001), whereas patients who received immunotherapy had a lower risk of death (HR=0.52, p=0.2), although this was not significant.
In the multivariate analysis, genetic mutations, TKIs, chemotherapy and immunotherapy were not significantly associated with survival. Patients with other metastases had a significantly increased risk of death (aHR=2.87, p=0.001). Patients who received five or more cycles of denosumab still had a significantly reduced risk of death compared with patients receiving less than five cycles (aHR=0.19, p<0.001). This finding is consistent with a protective association of long-term denosumab treatment.
Discussion
Our study demonstrates that denosumab treatment is associated with improved OS in patients with lung cancer and bone metastases, particularly for those who received more than five doses (‘good compliance’). This finding is consistent with previous reports suggesting denosumab can prolong survival in this population.7 10 We also observed that EGFR-TKI therapy significantly improved OS in patients with bone metastases, reflecting the known efficacy of targeted therapy in EGFR-mutated non–small cell lung cancer (NSCLC) . Similarly, studies in breast and prostate cancer with bone metastases have shown better outcomes with denosumab treatment.8 9 Prior research on denosumab in lung cancer has yielded mixed results. One study found a survival benefit from denosumab only in patients who had already experienced SREs10 (our study excluded patients with pre-existing SREs). Another report showed an OS benefit only when denosumab was combined with an EGFR-TKI and anti-VEGF therapy11; however, that analysis included only EGFR-mutant patients, whereas our study included patients regardless of mutation status. An open-label phase III trial in 2020 found no OS benefit from adding denosumab to chemotherapy in advanced lung cancer,15 highlighting variability in outcomes. A possible explanation for our positive findings is that denosumab reduces SRE incidence, which is associated with poor prognosis.16 Thus, better adherence to denosumab (leading to fewer SREs) may indirectly contribute to improved survival.
EGFR mutations are prevalent in patients with NSCLC, especially in Asian populations, and are associated with increased responsiveness to EGFR-TKIs.10 11 EGFR-TKIs have revolutionised the treatment of EGFR-mutated NSCLC, leading to significant improvements in progression-free survival (PFS) and OS.17 This study highlights the survival benefit of targeted therapy, especially EGFR-TKIs, in patients with lung cancer and bone metastases. Similarly, Ko et al10 reported that EGFR-TKIs, especially afatinib, are associated with improved survival among patients with EGFR-mutated lung cancer and bone metastasis. Another retrospective study suggested the benefits of afatinib in terms of PFS and good performance status in terms of OS.18 However, the findings of this study differ from those of previous studies. All EGFR-TKIs, including afatinib, erlotinib/gefitinib and osimertinib, were associated with survival. Unlike the study by Ko et al,10 which did not include osimertinib in their analysis, the results of this study demonstrated that osimertinib may be associated with even greater survival benefits than other EGFR-TKIs. This observation is consistent with the findings of Chen et al,11 who also reported the superior efficacy of osimertinib in EGFR-mutated populations. Interestingly, the data showed that the use of EGFR-TKIs did not significantly influence survival outcomes in the denosumab-treated group. This result suggests that the survival advantage associated with denosumab may be independent of EGFR-TKI treatment or may reflect the relatively small patient sample size, limiting the ability to detect differences.
Although relatively few patients in our cohort received immune checkpoint inhibitors (ICIs), ICI use was associated with improved OS in patients with bone metastases, consistent with the substantial survival benefits ICIs provide in advanced lung cancer.19 Retrospective data suggest that combining denosumab with immunotherapy is safe and may improve response rates, median PFS and SRE outcomes in NSCLC with bone metastases, although statistical significance was not reached.20 A real-world study also found that adding bone-targeted therapy (denosumab or similar agents) to pembrolizumab significantly improved PFS and OS,20 indicating that bone-targeted adjuncts might enhance immunotherapy efficacy.
Chemotherapy remains an important treatment modality for advanced lung cancer with bone metastases, as it can reduce overall tumour burden and potentially alleviate bone pain.21 In our study, chemotherapy use was independently associated with better OS after adjusting for other factors, which aligns with the findings of Peters et al.15 However, another trial reported no OS improvement from the addition of denosumab to chemotherapy, except in the squamous cell carcinoma subset.22
Persistence and compliance are crucial components of effective denosumab treatment in patients with lung cancer and bone metastases. Understanding these concepts is essential for optimising patient outcomes, as they significantly influence the therapeutic efficacy of denosumab and improve OS. This study also revealed that patients receiving more than five cycles of denosumab had improved OS compared with those receiving fewer cycles. This finding suggests a potential dose-response relationship in which prolonged denosumab therapy confers greater benefits. The median number of denosumab cycles administered is seven.8 9 23 During this treatment period, the drug has been reported to be associated with fewer bone complications, such as fractures or spinal cord compression, and maintains a favourable safety profile. Long-term denosumab use has been associated with continued suppression of bone turnover markers and a reduced risk of SREs.11 12 However, extended use also raises concerns regarding adverse effects such as ONJ and hypocalcaemia.24 25 ONJ is one of the most significant adverse events associated with denosumab treatment, with varying incidence rates across studies.24 25 Studies suggest that optimising oral health and eliminating any sources of infection before starting denosumab significantly lowers the risk of ONJ.26 Furthermore, during denosumab therapy, meticulous oral hygiene and regular dental check-ups were strongly recommended to maintain oral health and allow for the early identification of any lesions.26 27 Comparative analyses have shown that the risk of ONJ is similar for denosumab and zoledronic acid.26 28 However, in this study, ONJ did not occur in the patients who were treated with denosumab, possibly because of the short duration of denosumab treatment. Moreover, the cost-effectiveness of denosumab in the USA has led to an increase in denosumab prescriptions, reflecting its acceptance in clinical practice.13 Denosumab has also been shown to be cost-effective when adherence is high, due to its efficacy in preventing costly SREs,29 30 and its favourable profile has increased its adoption in practice.13 Nonetheless, achieving high adherence is challenging. Patient-related factors (eg, understanding of disease and medication, beliefs), medication-related factors (side effects, dosing frequency) and healthcare system factors (accessibility, patient–provider relationship) all influence compliance.31 Future strategies should address these factors to improve long-term adherence to denosumab.
Limitations
Despite these promising results, this study had several limitations. The retrospective design and reliance on clinical records from a single institution may have reduced the generalisability of the findings. Moreover, causality cannot be established in an observational study. As with any retrospective study, our analysis is vulnerable to survival-related biases, such as immortal-time and survivorship bias. This is particularly relevant to our ‘≥5 cycles’ categorisation. In our setting, denosumab is administered approximately every 4 weeks, meaning five administrations are typically completed within 112 days. A key concern is that the ‘≥5 cycles’ category may simply be selecting for patients who survived long enough to receive this many doses (ie, survivorship bias). However, the median OS in our study exceeded this 112-day window in both groups (455 days for denosumab recipients vs 172 days for non-recipients). By definition, at least half of the patients in each cohort survived beyond the time required to reach five doses. While this consideration reduces this bias, it does not eliminate it. We frame ‘≥5 cycles’ as a marker of sustained exposure early in follow-up. We thus interpret the observed association cautiously, acknowledging that time-varying or landmark designs would more robustly address any residual bias. Confounding by indication is another important concern. To mitigate this, we prespecified multivariable adjustment for key prognostic covariates. Furthermore, denosumab was administered as part of routine care and was not allocated or restricted based on ECOG performance status or other baseline characteristics. In Taiwan, patients with lung cancer and bone metastases are generally eligible for denosumab, given its favourable adverse-event profile. Our standardised protocol, which required a pretreatment dental evaluation and ongoing oral hygiene reinforcement to minimise ONJ risk, reflects this routine approach. Despite these adjustments, we acknowledge that residual confounding cannot be fully excluded. Additionally, the study did not investigate the reasons for non-compliance or non-persistence, which could offer valuable insights into targeted interventions to improve adherence.
Conclusions
This study demonstrated that denosumab and systemic cancer treatments such as TKIs, chemotherapy or immunotherapy were associated with improved OS in patients with lung cancer and bone metastasis. Good compliance with denosumab therapy, along with the completion of at least five treatment cycles, appears to be important and was associated with more favourable outcomes. However, future prospective and multicentre trials are necessary to confirm these findings, assess the long-term effects of denosumab treatment in diverse populations, investigate the mechanisms underlying the antitumour effects of denosumab, and determine the optimal treatment duration and combination strategies. Moderate compliance and persistence rates also highlight the need for further research to improve adherence to denosumab therapy. Additionally, incorporating patient-reported outcomes and economic analyses will provide valuable insights for clinicians and policy-makers to optimise the care of patients with lung cancer and bone metastases.
Supplementary material
The funder (E‑Da Hospital; grant EDAH107024) had no role in the study design; data collection, analysis or interpretation; writing of the manuscript; or the decision to submit/publish this article.
Footnotes
Funding: This work was supported by E‑Da Hospital (grant EDAH107024).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Ethics approval: This study was approved by the Institutional Review Board (IRB) committee of the E-DA Healthcare Group (EMRP-113-132). All methods we used were carried out following the principles of the Declaration of Helsinki.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Presented at: This abstract of this paper was presented at the TSPCCM 2024 Congress meeting as a poster presentation with interim findings.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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Data Availability Statement
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