Highlights
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Less frequent dosing maintains efficacy: 2–4 doses in the first 6 months is comparable to monthly dosing for preventing SREs.
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Strict monthly dosing increases ONJ risk: Patients receiving strict monthly injections had a significantly higher incidence of osteonecrosis of the jaw (12%) compared to those on a less frequent schedule (3%).
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Optimizing the therapeutic window: A tailored dosing strategy (2–––4 doses in 6 months) effectively balances the clinical benefits of SRE prevention with a minimized risk of medication-related complications.
Keywords: Bone metastasis, Denosumab, Zoledronic acid, Osteonecrosis of the Jaw, Skeletal-related event
Abstract
Background
Metastatic bone disease presents significant global challenges, necessitating effective strategy to prevent skeletal-related events (SREs) such as fractures and spinal cord compression. Denosumab and zoledronic acid have emerged as promising therapeutic options. However, the optimal dosing intervals remain to be defined.
Methods
This retrospective study, utilizing the institutional integrative medical database from single medical center, involving 1,045 adults with metastatic bone disease who had underwent surgery or radiotherapy for SREs. The study aimed to investigate whether extended dosing intervals for denosumab or zoledronate are associated with increased need for subsequent local treatment for subsequent SREs and a decreased risk of osteonecrosis of the jaw (ONJ). Patients receiving less than two doses within the initial six months after local treatment for bone metastasis were defined as the rarely-used group. The patients having 2–4 doses were in the occasionally-used group and those with more doses were in the strictly-used group.
Results
The subsequent SRE incidences were 27%, 16%, and 18% for the rarely-used, occasionally-used, and strictly-used groups, respectively. The occasionally-used group demonstrated comparable risks of SREs to the strictly-used group, while the rarely-used group showed increased risks. The ONJ incidence was significantly higher in the strictly-used patients (12%) versus the occasionally-used (3%).
Conclusion
A less frequent dosing schedule (2–4 injections in the first six months) for denosumab or zoledronic acid was associated with a lower ONJ risk without a significant increase in subsequent SRE risk after local treatment for bone metastasis in our study. Strict monthly dosing was associated with a higher ONJ risk in our series. These outcomes should be interpreted cautiously due to the retrospective design and heterogeneity of the primary tumors.
1. Introduction
Metastatic bone disease, arising from the spread of cancer cells to the bone, significantly impacts millions worldwide [1], compromising patients' quality of life and posing substantial risks to their overall survival. A crucial aspect of managing metastatic bone disease is the prevention of newly developed skeletal-related events (SREs), such as pathologic fractures, the need for radiotherapy, the need for surgery, and spinal cord compression [2], [3]. Denosumab (120 mg, subcutaneous injection, Xgeva) and zoledronic acid (4 mg, intravenous infusion, Zometa) show promise in reducing SREs and enhancing overall bone health [4], [5].
Denosumab, a monoclonal antibody, inhibits the formation, function, and survival of osteoclasts by targeting the receptor activator of nuclear factor-kappa B ligand (RANKL) [6]. Zoledronic acid, a bisphosphonate, suppresses the growth of osteoclasts and triggers osteoclast apoptotic cell death. Both drugs effectively reduce bone resorption, which accounts for their potency in managing bone metastases and related skeletal events. Although current guidelines recommend fixed four-week intervals for administration [7], [8], [9], optimal dosing intervals remain unclear, prompting exploration of alternative schedules for efficacy and patient convenience [10], [11], especially in those already treated with surgery or radiotherapy.
Investigating the dosing intervals of denosumab and zoledronic acid in patients with bone metastatic disease is crucial as it may mitigate the risk of adverse events, such as hypocalcemia and osteonecrosis of the jaw (ONJ) [12], [13], associated with long-term use of these drugs. A tailored dosing approach could potentially minimize these risks while maintaining drug efficacy in preventing SREs. Additionally, more flexible dosing schedules could enhance patient adherence to treatment regimens [14], [15], [16], as patients may find receiving the drugs at longer intervals more convenient, thereby improving their overall quality of life. Recent evidence suggests that alternative dosing schedules of zoledronic acid offer comparable efficacy while minimizing potential side effects and improving patient convenience [10], [11], [17]. Studies investigating alternative dosing schedules for denosumab have not yet been published. However, to our knowledge, previous studies have yet to specifically focus on patients who already received local treatment for an SRE. In response, we aimed to address this knowledge gap by retrospectively analyzing patients already treated for SREs with surgery or radiotherapy. A retrospective cohort design is suitable for addressing this question, as it allows for the evaluation of real-world outcomes and the tracking of rare adverse events, such as ONJ, across a large, heterogeneous population reflective of routine clinical practice.
In this study, we aimed to determine (1) whether patients receiving denosumab or zoledronic acid with a longer dosing interval for their metastatic bone disease had a higher probability of receiving subsequent local treatment for a newly developed SRE, and (2) whether this longer dosing interval is correlated with a lower risk of ONJ.
2. Guidelines
This study adhered to the Strengthening the reporting of cohort studies in surgery[18] (STROCCS 2025) guidelines. The institutional review board of National Taiwan University Hospital approved the study protocol (202205108RINA), and informed consent was waived due to its retrospective nature.
3. Methods
3.1. Participants
Adults (≥18 years) diagnosed with female breast cancer, prostate cancer, or lung cancer with metastatic bone disease, who had previously undergone surgery or radiotherapy for a skeletal-related event (SRE) at National Taiwan University Hospital between January 2010 and December 2019, were eligible for inclusion. The rationale behind selecting these specific cancer types is their alignment with the national insurance policy, which restricts reimbursement of two key antiresorptive agents exclusively to patients with these cancers. A minimum follow-up of six months after the initial local treatment, whether radiotherapy, surgery, or both, was required, ensuring adequate time for assessing treatment response and potential adverse events. This criterion resulted in 1,108 eligible subjects. Patients who received their first treatment for osseous metastasis at other institutions (n = 34) and those with multiple documented cancers with unascertainable tumor histology (n = 29) were excluded, leaving 1,045 patients for analysis. Based on institutional protocols and insurance reimbursement guidelines, patients were considered naive to oncologic doses of antiresorptive agents prior to the initial SRE. Data extraction from the The National Taiwan University Hospital-integrative Medical Database (NTUH-iMD) was independently performed and cross-validated by two institutional data engineers to ensure consistency. The extracted structured data were then systematically consolidated using data science methods for final biostatistical analysis.
3.2. Outcomes
The primary outcome was the incidence of subsequent SREs requiring further treatment within the first 24 months following the initial SRE treatment. A subsequent SRE had to meet two criteria [19], [20] (1) the subsequent metastatic site had to differ from the initial SRE site, as treatments at a previously treated location were considered revision or rescue treatments and did not align with the study design, and (2) the subsequent treatment for SRE must have occurred at least 12 weeks after the initial treatment, ensuring that no “planned” subsequent treatments were included in the analysis. The secondary outcome was the incidence of osteonecrosis of the jaw (ONJ) within the same 24-month period. Institutional dental specialists routinely performed pre-medication dental screening. Post-medication ONJ was diagnosed based on the 2022 guidelines from the American Association of Oral and Maxillofacial Surgeons (AAOMS)[21], which require a history of antiresorptive therapy alone or in combination with immune modulators or antiangiogenic medications, exposed bone persisting for more than 8 weeks, and no history of radiation therapy to the jaws or metastatic disease to the jaws. Patients presenting with symptoms suggestive of ONJ were routinely referred to a specialist in our hospital, who had an experience of surgically treating more than 1,500 patients, for diagnosis and further management. In general, conservative treatment would be administered for those with mild ONJ, while surgical debridement or resection would be administered for more severe cases.
3.3. Exploratory variables and Missing Items
Baseline demographic and clinical characteristics, including age, sex, primary tumor type (lung, breast, or prostate), date of initial SRE treatment, initial SRE location (spine, extremity, or pelvis), initial SRE treatment type (surgery or radiotherapy), Charlson comorbidities excluding metastatic cancer, Eastern Cooperative Oncology Group (ECOG) performance status (0–2 vs 3–4), concomitant medications, and 10 different preoperative laboratory tests, were collected. Except for alkaline phosphatase and albumin, for which the most recent values within 90 days before the index treatment were used, we retrieved the most recent laboratory value within 30 days before the index treatment for all laboratory values [22]. The dosing frequency of denosumab or zoledronic acid within the first six months was classified into three groups, rarely-used (0–1 injections), occasionally-used (2–4 injections), and strictly-used (5–6 injections). Missing proportion of each variable was less than 30% (Table 1).
Table 1.
Patient characteristics.
| Variables | Median (IQR) | %(N) | p-value | Missing (%) | |||
|---|---|---|---|---|---|---|
| All patient (N = 1045) |
Rarely used (N = 807) |
Occasionally used (N = 127) | Strictly used (N = 111) | |||
| Demographic factors | ||||||
| Age (years) | 63.1 (16.4) | 63.4 (15.6) | 62.1 (15.3) | 61.7 (21.1) | 0.204 | 0 |
| Male sex | 45.4 (474/1045) | 47.1 (380/807) | 34.6 (44/127) | 45 (50/111) | 0.033 | 0 |
| Body mass index | 23.0 (4.7) | 23.1 (4.73) | 23.1 (4.7) | 22.4 (3.8) | 0.212 | 1.2% |
| Oncological factors | ||||||
| Primary tumor | <0.01 | |||||
| Breast | 21.3 (223/1045) | 16.4 (133/807) | 38.6 (49/127) | 36.9 (41/111) | 0 | |
| Prostate | 18.2 (190/1045) | 18.1 (146/807) | 15 (19/127) | 22.5 (25/111) | 0 | |
| Lung | 60.5 (632/1045) | 65.4 (528/807) | 46.5 (59/127) | 40.5 (45/111) | 0 | |
| Spine metastasis | 60.5 (632/1045) | 58.6 (473/807) | 65.4 (83/127) | 68.4 (76/111) | 0.067 | 0 |
| Extremity metastasis | 17.4 (182/1045) | 16 (129/807) | 22 (28/127) | 22.5 (25/111) | 0.08 | 0 |
| Pelvis metastasis | 24.0 (251/1045) | 23.2 (187/807) | 25.2 (32/127) | 28.8 (32/111) | 0.067 | 0 |
| Visceral metastasis | 30.8 (322/1045) | 29.6 (239/807) | 39.3 (50/127) | 29.7 (33/111) | 0.084 | 0 |
| Brain metastasis | 14.8 (155/1045) | 15.4 (124/807) | 10.2 (13/127) | 16.2 (18/111) | 0.291 | 0 |
| Previous systemic therapy | 85.6 (895/1045) | 84.3 (680/807) | 90.6 (115/127) | 90 (100/111) | 0.06 | 0 |
| Previous chemotherapy | 46.6 (487/1045) | 45.7 (369/807) | 52 (66/127) | 46.8 (52/111) | 0.42 | 0 |
| Previous target therapy | 41.0 (428/1045) | 42.8 (345/807) | 35.4 (45/127) | 34.2 (38/111) | 0.09 | 0 |
| Previous hormone therapy | 34.0 (355/1045) | 49.1 (396/807) | 63.8 (81/127) | 62.2 (69/111) | <0.01 | 0 |
| Type of initial local management | 0.181 | |||||
| Surgery and/or radiotherapy | 17 (178/1045) | 17.8 (144/807) | 17.3 (22/127) | 10.8 (12/111) | 0 | |
| Radiotherapy alone | 83 (867/1045) | 82.2 (663/807) | 82.7 (105/127) | 8932 (99/111) | 0 | |
| Clinical factors | ||||||
| ECOG PS 0–2 | 97 (906/934) | 97 (692/714) | 97 (116/119) | 97 (98/101) | 0.831 | 10.6% |
| Other Charlson comorbidities | 37.0 (387/1045) | 36 (290/807) | 41 (52/127) | 40.5 (45/111) | 0.399 | 0 |
| Laboratory values | ||||||
| Hemoglobin | 12.1 (2.3) | 12.2 (2.3) | 11.6 (2.6) | 11.8 (2.3) | 0.03 | 7.3% |
| Creatinine | 0.7 (0.3) | 0.8 (0.3) | 0.7 (0.2) | 0.7 (0.3) | 0.24 | 17.7% |
| Outcomes | ||||||
| Subsequent skeletal-relate events | 24.3 (254/1045) | 27 (218/807) | 15.7 (20/127) | 14.4 (16/111) | <0.01 | 0 |
| Type of subsequent local management | <0.01 | |||||
| Surgery and/or radiotherapy | 16.1 (41/254) | 17.4 (38/218) | 5 (1/20) | 12.5 (2/16) | 0 | |
| Radiotherapy alone | 83.9 (213/254) | 82.6 (180/218) | 95 (19/20) | 87.5 (14/16) | 0 | |
| Osteonecrosis of jaw | 1.6 (17/1045) | 0 (0/807) | 2.4 (3/127) | 12.6 (14/111) | <0.01 | 0 |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status.
Boldp-values are < 0.05.
3.4. Statistical analysis
Descriptive statistics summarized the baseline characteristics of the study population. Categorical variables were presented as frequencies and percentages, while continuous variables were reported as medians and interquartile ranges (IQRs). The categorical variables, such as incidence of subsequent SREs and ONJ, among the three dosing frequency groups were compared using the chi-square tests, as appropriate.
Multivariable logistic regression models were fitted to evaluate the association between dosing frequency and subsequent SREs within the first 24 months, while adjusting for potential confounders. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated. Due to the overall low incidence of ONJ, the incidence was not compared between the occasionally-used and strictly-used groups using logistic regression models. The decision not to apply Cox proportional-hazard models was made because the artificial intervals we set, such as a minimum 6-month follow-up or a minimum interval of 12 weeks between the two SREs, would violate the models' basic assumptions. Multiple imputation with the MissForest technique was used to impute the missing proportion. All statistical analyses were conducted using a two-sided significance level of 0.05, and R version 4.0.4 was employed for the statistical analyses.
4. Results
Patient characteristics.
The median age of the patients was 63.1 years (IQR, 16.4; Table 1), with a sex distribution of 45.4% male (474 of 1045). The median BMI was 23.0 (IQR, 47.0). In terms of primary tumor types, lung cancer was the most prevalent at 60.5% (632 of 1045), followed by breast cancer at 21.3% (223 of 1045) and prostate cancer at 18.2% (190 of 1045). Among the patients, 60.5% had spine metastasis (632 of 1045), while 17.4% had extremity metastasis (182 of 1045) and 24.0% had pelvis metastasis (251 of 1045). Multiple SREs at different bones were observed in 17.3% of the patients (181 of 1045), with 30.8% experiencing visceral metastasis (322 of 1045) and 14.8% having brain metastasis (155 of 1045). A majority of the patients (85.7%) have undergone previous systemic therapy (895 of 1045), with 46.6% receiving chemotherapy (487 of 1045), 41.0% undergoing targeted therapy (428 of 1045), and 34.0% using hormone therapy (355 of 1045). As for antiresorptive agents, 77.2% of the patients rarely used them (807 of 1045), while 12.2% occasionally used them (127 of 1045) and 10.6% strictly used them (111 of 1045). Radiotherapy alone was the most common initial local management at 83% (867 of 1045). In clinical factors, 97% of patients had an ECOG PS score of 0–2 (906 of 934). Laboratory values include hemoglobin of 12.1 (IQR, 2.3) and creatinine of 0.7 (IQR, 0.3).
4.1. Subsequent SRE across dosing-frequency groups
A total of 24.3% of patients (254 of 1054) experienced subsequent SREs, with 83.9% (213 of 254) receiving radiotherapy alone and 16.1% (41 of 254) undergoing surgery and/or radiotherapy for local management (Table 1). In patients who rarely used antiresorptive agents, the incidence of subsequent SREs was 27.0% (218 of 807, Table 2). It was higher compared to those who occasionally (15.7%; 20 of 127; p value = 0.007) and strictly (14.4%; 16 of 111; p value = 0.04) used the agents. No significant difference in SRE risk was observed between occasionally-used and strictly-used groups (p value = 0.64). After adjusting for demographic, oncological, and clinical factors, patients who occasionally used the agents demonstrated similar risks of subsequent SREs (OR, 1.09; 95% CI, 0.51–1.31) compared to those who strictly used them, while patients who rarely used the agents exhibited increased risks (OR, 1.70; 95% CI, 1.01–2.97). Notably, patients with multiple bone metastases (OR, 5.45; 95% CI, 2.51–12.32) and those who received surgery with or without radiotherapy for the initial SRE (OR, 2.66; 95% CI, 1.68–4.22) were at a higher risk of experiencing subsequent SREs (Table 3). We also found that patients receiving initial local treatment to the pelvis carried a higher risk for having subsequent SREs in comparison with spine and extremity.
Table 2.
Incidence of subsequent SREs and ONJs in different dosing-interval groups.
| Rarely used (N = 807) |
Occasionally used(N = 127) | Strictly used(N = 111) | p-value | |||
| Rarely vs occasionally used | Rarely vs strictly used | Occasionally vs strictly used | ||||
| Subsequent SRE | 27.0% (218/807) | 15.7% (20/127) | 14.4% (16/111) | 0.007 | 0.04 | 0.64 |
| ONJ | 0% (0/807) | 2.4% (3/127) | 12.6% (14/111) | N/A | N/A | 0.01 |
| Breast cancer | 0% (0/133) | 0% (0/49) | 7.3% (3/41) | N/A | N/A | N/A |
| Lung cancer | 0% (0/528) | 1.7% (1/59) | 8.9% (4/45) | N/A | N/A | 0.09 |
| Prostate cancer | 0% (0/146) | 10.5% (2/19) | 28% (7/25) | N/A | N/A | 0.15 |
N/A: not available due to zero event in rarely used group.
Boldp-values are < 0.05.
Table 3.
Adjusted odds ratio for the development of subsequent SRE.
| Unadjusted OR | 95% CI | Adjusted OR | 95% CI | |
|---|---|---|---|---|
| Age | 0.99 | 0.97–1.00 | 0.99 | 0.97–1.00 |
| Sex (Male vs Female) | 1.00 | 0.75–1.32 | 0.87 | 0.61–1.25 |
| BMI | 1.01 | 0.96–1.05 | 1.01 | 0.96–1.05 |
| Primary tumor | ||||
| Lung vs Breast | 3.56 | 2.33–5.65 | 3.89 | 2.31–6.76 |
| Prostate vs Breast | 1.20 | 0.67–2.16 | 1.81 | 0.84–3.94 |
| Initial SRE location | ||||
| Spine vs Pelvis | 0.85 | 0.64–1.13 | 0.61 | 0.41–0.91 |
| Extremity vs Pelvis | 1.07 | 0.73–1.53 | 0.61 | 0.37–0.99 |
| Brain metastasis | 1.49 | 1.02–2.16 | 1.02 | 0.66–1.55 |
| Visceral metastasis | 1.29 | 0.96–1.74 | 1.23 | 0.87–1.72 |
| Multiple bone metastasis | 1.23 | 0.85–1.76 | 5.45 | 2.51–12.32 |
| Initial treatment (surgery ± RT vs RT alone) | 1.65 | 1.16–2.34 | 2.66 | 1.68–4.22 |
| Previous systemic treatment | 0.83 | 0.57–1.24 | 1.45 | 0.90–2.41 |
| Other Charlson comorbidities | 0.93 | 0.69–1.25 | 1.03 | 0.74–1.43 |
| ECOG PS (0–2 vs 3–4) | 0.47 | 0.14–1.24 | 0.56 | 0.16–1.53 |
| Antiresorptive agents dosing interval | ||||
| Rarely-used vs strictly used | 1.98 | 1.22–3.36 | 1.70 | 1.01–2.97 |
| Occasionally-used vs strictly used | 1.10 | 0.51–2.31 |
The variables considered significant by multivariate regression analysis are shown in bold text.
4.2. Subsequent ONJs across dosing-frequency groups
ONJ occurred in 1.6% of patients (17 of 1045). Among those who occasionally used denosumab or zoledronic acid, the incidence was 2.4% (3 of 127), while a higher incidence of 12.6% (14 of 111; p value = 0.01) was observed in patients who strictly used the agents. Among breast cancer patients, ONJ occurred in 0% (0 of 49) of the occasionally used groups and 7.3% (3 of 41) of the strictly used group. For lung cancer patients, ONJ occurred in 1.7% (1 of 59) of the occasionally used, and 8.9% (4 of 45) of strictly used groups, respectively. In prostate cancer patients, ONJ incidence was 10.5% (2 of 19) in the occasionally used group, and 28% (7 of 25) in the strictly used group. (Table 2).
5. Discussion
Denosumab and zoledronic acid have emerged as promising therapeutic options for patients with metastatic bone disease. When administered monthly, these agents can effectively prevent SREs, such as pathologic fractures, the need for radiotherapy, the need for surgery, and spinal cord compression. Our findings indicate that administering 2–4 injections within the first six months, rather than 5–6 injections, may reduce the incidence of ONJ without significantly increasing the risk of subsequent SREs.
Our patients in the strictly-used group appeared to have a higher risk for ONJ in comparison with patients recruited in international trials with short follow-up [23] but consistent with findings of recent studies involving Asian population and with longer follow-up [24], [25]. Consequently, our observational findings suggest that caution may be warranted when considering the strict monthly administration of denosumab or zoledronic acid for extended periods. The balance between clinical benefits and potential harm merits careful evaluation in future prospective studies. Future prospective, ideally randomized controlled trials, are needed to validate these findings and to establish the optimal dosing schedule for maximizing therapeutic outcomes while minimizing adverse events.
5.1. Limitations
This study presents several limitations that warrant consideration. First, the retrospective nature of the study precludes the systematic analysis of specific clinical conditions leading to different dosing frequencies and drug selection between denosumab or zoledronic acid. However, this should be a minor limitation, as our institutional philosophy was generally based on factors such as the number of bone metastases, the severity of bone metastasis, history of systemic therapy, dental condition, and patient preferences. By controlling for the first three factors, we found that the strict use of antiresorptive agents did not yield additional clinical benefits compared to occasional use. The institutional protocol dictated that if dental conditions were unsuitable or patients did not consent, antiresorptive agents would not be administered, thereby not influencing the incidence difference between subsequent SREs and ONJs in the occasionally-used and strictly-used groups. Second, the study population was drawn from different branches at different regions of an identical hospital system, which might limit the generalizability of our findings to broader populations. However, previous studies have yet to observe significant international prognostic differences, suggesting that our institutional protocol, therapeutic philosophy, and treatment efficacy were up-to-date. Third, we were unable to identify patients who were too frail to receive subsequent treatments for SREs despite the minimal invasiveness of radiotherapy and its generalizability. Furthermore, the overall low ONJ event rate and the relatively small number of patients in the occasionally-used and strictly-used groups significantly limit our statistical power. This low event rate restricts our ability to draw definitive comparative conclusions regarding ONJ risk between these specific dosing intervals, increasing the risk of type II errors and highlighting the need for cautious interpretation. Fourth, we acknowledge our cohort is highly heterogeneous. Although we used multivariable logistic regression to adjust for known confounders, unmeasured confounding by indication remains a concern, and the absence of propensity-based methods limits definitive causal inference. Fifth, exact overall survival and median follow-up times were not extracted from the database, as our analysis focused on a fixed 24-month observation window. Consequently, we cannot rule out the presence of a competing risk of death; differing survival times among the dosing-interval groups could inherently influence the cumulative opportunity for patients to develop subsequent SREs or ONJ. Additionally, we did not differentiate between denosumab and zoledronic acid in our analysis, and the combination of a limited sample size and pooled drug analysis may have obscured drug-specific effects, thereby reducing our ability to detect potential differences in their respective efficacy or safety profiles.. Finally, our database lacked granular data on specific established ONJ risk factors, including history of dental extractions, pre-treatment dental visits, concurrent use of antiangiogenic drugs or high-dose steroids, and the exact cumulative dose of prior antiresorptive agents. Consequently, these variables could not be included in our multivariable analysis, leaving the potential for residual confounding regarding ONJ development. Future larger-scale, international, prospective trials are needed to address these limitations. Despite these shortcomings, our study offers valuable insights into the impact of different dosing-frequency groups on subsequent SREs and ONJs in patients with initial SREs.
5.2. Subsequent SRE across dosing-frequency groups
The increasing survival of patients with metastatic bone disease raises concerns about the growing incidence of subsequent skeletal-related events (SREs). In one of our recent studies, 20% of patients from a modern cohort experienced a subsequent SRE, necessitating local management with surgery and/or radiotherapy [20]. As SREs can be debilitating and life-threatening, their prevention and management are crucial. Our study demonstrated a higher incidence of subsequent SREs in patients who rarely used antiresorptive agents compared to those who occasionally and strictly used them. The risk of subsequent SREs was similar between the occasionally-used and the strictly-used groups. This finding aligns with a previous study, which reported a non-statistically significant risk of subsequent SREs in patients (Hazard ratio, 1.14; 95% CI, 0.90–1.44), with only 17% having received surgery and/or radiotherapy for the initial SRE [26]. These results suggest that a less frequent dosing schedule might be sufficient to maintain the efficacy of denosumab or zoledronic acid in preventing SREs in patients with lower risks. Conversely, high-frequency antiresorptive agents should be administered in patients at high risk for subsequent SREs (such as those with multiple bone metastases or those who received surgery and/or radiotherapy for the initial SRE), even with cautiousness for the risk of ONJ. A tailored approach and careful monitoring of disease progression are necessary in these cases.
5.3. Subsequent ONJ across dosing-frequency groups
ONJ is a severe adverse event associated with long-term use of antiresorptive agents, such as denosumab and zoledronic acid, as it is characterized by the progressive destruction and death of bone tissue in the jaw, leading to significant pain, infection, and impaired oral function, a negative impact on patients' quality of life [23], [24]. Although the incidence of ONJ is reported to be low in patients receiving antiresorptive agents for osteoporosis, especially in cancers with short survival time [27], it can reach higher than 10% in Asian populations with bone metastatic diseases [24], [25]. This increased incidence emphasizes the importance of optimizing dosing schedules to balance drug efficacy and safety. Recent studies also suggest that individual risk assessment for ONJ should be conducted for patients undergoing antiresorptive treatment, and preventive measures should be taken.[16] In our study, we found a significantly higher incidence of ONJ among patients who strictly used denosumab or zoledronic acid compared to those who occasionally used the agents. This result supports the hypothesis that a more flexible dosing schedule could potentially mitigate the risk of ONJ while maintaining the efficacy of these drugs in preventing SREs. The difference in risk between dosing-frequency groups underscores the importance of optimizing dosing schedules to balance drug efficacy and safety, as well as considering individual patient factors and risk profiles when determining the most appropriate treatment approach.
6. Conclusion
In conclusion, although administering denosumab or zoledronic acid once per month is at the moment recommended to prevent SREs, our study suggests that at longer dosing intervals might provide similar efficacy in patients treated for SREs with surgery or radiotherapy. Besides, a strict use of these agents may be associated with a higher risk of ONJ, especially in the Asian population. Consequently, our findings we hypothesize that a less strict administration schedule (e.g., 2–4 doses in 6 months) may maintain a favorable balance between clinical benefits and the risk of adverse events. However, due to the inherent uncertainty of our retrospective design, these findings are purely hypothesis-generating. Further prospective, ideally randomized, trials are needed to confirm these findings and establish optimal dosing schedules for this patient population.
Ethics Statement.
This study was approved by the institutional review board (202205108RINA).
Funding.
The study was funded by institutional projects (112-HCH036). The funders of the study had no role in the study design, analysis, or drafting.
Presentation
Preliminary data was not previously presented.
CRediT authorship contribution statement
Ching-Wei Lin: Writing – review & editing, Writing – original draft, Investigation, Formal analysis, Data curation, Conceptualization. Han-Ying Wang: Writing – original draft, Methodology, Formal analysis, Conceptualization. Cheng-En Yu: Writing – original draft, Investigation, Formal analysis, Data curation. Hung-Kuan Yen: Writing – review & editing, Writing – original draft, Software, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Wei-Hsin Lin: Writing – review & editing, Validation, Supervision, Resources, Conceptualization. Shau-Huai Fu: Writing – review & editing, Supervision, Conceptualization. Jen-Chang Ko: Writing – review & editing, Supervision, Conceptualization. Chih-Wei Chen: Writing – review & editing, Writing – original draft, Validation, Methodology, Formal analysis, Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
Assistance with the study: We would like to thank all healthcare professionals from various departments of National Taiwan University Hospital for their contribution in supplying multidisciplinary care for our patients and the Department of Medical Research staff for gathering data from the institutional integrative medical database. The authors are also grateful to the staff of Department of Medical Research for gathering and providing clinical data from National Taiwan University Hospital-integrative Medical Database (NTUH-iMD) and to the staff of National Taiwan University Hospital-Statistical Consulting Unit (NTUH-SCU) for statistical consultation and analyses.
Contributor Information
Ching-Wei Lin, Email: linchingwei1112@gmail.com.
Han-Ying Wang, Email: Henry410167@gmail.com.
Cheng-En Yu, Email: lishin50416@gmail.com.
Hung-Kuan Yen, Email: b04401122@ntu.edu.tw.
Wei-Hsin Lin, Email: oweihsin@gmail.com, ethanlin@ntuh.gov.tw.
Shau-Huai Fu, Email: b90401045@gmail.com, Y03900@ms1.ylh.gov.tw.
Jen-Chang Ko, Email: e1205470@ms22.hinet.net.
Chih-Wei Chen, Email: ohw0701@gmail.com.
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