Long-Term Efficacy and Safety of Denosumab: Insights beyond 10 Years of Use
Article information
, Youn-Ju Lee2,3, Jinyoung Kim4, Chaiho Jeong5, Yejee Lim6, Jeongmin Lee7, Ki-Hyun Baek,4, on Behalf of the Catholic Medical Center Bone Research GroupAbstract
Osteoporosis management in post-menopausal women focuses on fracture prevention, with denosumab as a key therapeutic option. Despite its proven efficacy in reducing fracture risk and increasing bone mineral density (BMD) over 10 years, its long-term impact remains uncertain. We evaluated the literature on its efficacy and safety beyond the initial decade. Clinical trials and real-world studies confirm denosumab’s sustained efficacy, especially in lumbar spine BMD, with hip BMD stabilizing. Concerns about adverse events (AEs) like hypocalcemia and osteonecrosis of the jaw necessitate vigilant monitoring. Risks of atypical femoral fractures and malignancies also require attention, despite unclear links to treatment duration. Clinical guidelines for denosumab beyond 10 years are limited, emphasizing the need for careful monitoring. In certain scenarios, such as advanced chronic kidney disease, prolonged denosumab may be required to balance AE risks with fracture prevention benefits. Denosumab shows potential for long-term efficacy in augmenting BMD; however, monitoring for AEs is crucial to guide clinical decision-making effectively.
INTRODUCTION
Osteoporosis, characterized by decreased bone mineral density (BMD) and microarchitectural deterioration, poses a significant global health burden, predisposing individuals to an increased fracture risk and associated morbidity and mortality [1]. Thus, preventing fractures is imperative in managing osteoporosis, especially post-menopause; various medications have been developed to achieve this goal [2-4]. Denosumab, a fully human monoclonal antibody targeting the receptor activator of nuclear factor kappa-B ligand (RANKL), was developed. By effectively inhibiting RANKL-mediated osteoclastogenesis and bone resorption, denosumab helps mitigate bone loss and decreases fracture incidence [1,5], offering a potent treatment option for patients with increased fracture risk [6-8]. Clinical trials and real-world studies have validated the efficacy and safety of denosumab in enhancing BMD and mitigating fracture risk [5,9-14]. Consequently, denosumab has been incorporated into clinical guidelines and is globally adopted by healthcare practitioners for osteoporosis management [7,15-19].
Patients with osteoporosis often require long-term, sometimes indefinite, medication to maintain skeletal health and prevent fractures. However, denosumab use is associated with a risk of rebound phenomenon [20,21]. Therefore, monitoring the long-term effectiveness and safety of this treatment is essential for as long as the high fracture risk persists.
Although data up to a decade confirmed sustained BMD gains with denosumab, unlike other anti-resorptive agents, which typically plateau, the efficacy, safety, and continuation of these benefits beyond this timeframe remain unexplored [9]. Moreover, the evolving demographics of osteoporosis, characterized by an aging population and increased prevalence of long-term denosumab users, highlight the need to elucidate the long-term implications of this treatment approach. Therefore, in this narrative review, we aimed to comprehensively evaluate the existing evidence on the efficacy and safety profile of denosumab treatment and to estimate its probable long-term efficacy and safety benefits. By synthesizing clinical data, we addressed critical issues such as the prolonged effects of denosumab on BMD after the initial decade of treatment, the temporal association between denosumab use and the occurrence of adverse events (AEs), and the clinical contexts and implications for denosumab dosing, often required for over 10 years. Furthermore, we examined how current guidelines address the use of denosumab for over 10 years. Despite limited reporting on the efficacy and safety of denosumab administration beyond a decade, we aimed to analyze available literature and make predictions about the effects and safety of prolonged denosumab use to assist clinicians in guiding patient care.
LONG-TERM EFFICACY PREDICTIONS FOR DENOSUMAB
Over the past decade, denosumab has been established as the key treatment option in managing osteoporosis, owing to its considerable efficacy in reducing fracture risk and enhancing BMD [1]. Notably, denosumab has shown promise across diverse population groups, from women post-menopause to men with osteoporosis. Long-term studies spanning up to 10 years have consistently confirmed its ability to sustain these benefits, providing compelling evidence of its enduring impact on fracture prevention and bone health maintenance [9]. Bone et al. [9] revealed that a decade of denosumab treatment resulted in a 21.7% and 9.2% increase in spine and hip BMD, respectively. Extended therapy demonstrated low fracture rates, with the estimated relative risk (RR) for new vertebral and non-vertebral fractures at 0.62 (95% confidence interval [CI], 0.47 to 0.80) and 0.54 (95% CI, 0.43 to 0.68), respectively, compared with that in the placebo arm [9]. Ferrari et al. [22] compared the incidence of non-vertebral fractures during the initial 1 to 3 years of denosumab usage with those occurring over an extended treatment period of up to 10 years and observed that continuing treatment beyond year 3 significantly lowered fracture rates, with the decreased risk becoming evident by year 4. This reduced risk persisted throughout the 10-year treatment period, albeit without a further progressive decline [23]. Hence, while the efficacy of denosumab for up to 10 years is well-established, its long-term effectiveness beyond this period requires further investigation.
BONE DENSITY CHANGES AFTER A DECADE OF DENOSUMAB USE
The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension trial indicated continuous enhancement in BMD at the lumbar spine, total hip, and femoral neck throughout a decade of denosumab therapy [9]. To predict changes in BMD over 10 years, we utilized a multiscale indirect response model based on pharmacology research [24,25]. This method provides a relevant approach to understanding the integrated dynamic influence of anti-resorptive agents on the longitudinal change in BMD [24,25]. In the nonlinear model used to analyze BMD changes in the lumbar spine with long-term denosumab administration, time was transformed into a quadratic polynomial to incorporate nonlinear patterns. A logistic growth model was used to predict long-term changes in total hip BMD, as total hip BMD in the FREEDOM extension trial showed an initial increase followed by a gradually reduced growth [26]. We reported that BMD at the lumbar spine increased by 21.7% at 10 years, i.e., the end of the FREEDOM extension trial, and then continued to increase slowly, with a predicted final BMD gain of 27.9% (Fig. 1) [27]. Total hip BMD was predicted to show a final increase of 9.2% at the end of the FREEDOM extension trial at year 10, with a plateau through year 20, and a 9.8% increase in bone density from baseline at year 20 (Fig. 2) [27]. While lumbar spine BMD exhibited a sustained upward trajectory over another 10-year period, hip BMD demonstrated a stable pattern in our prediction model [27]. In our predictive model, with denosumab administration beyond 10 years, the rate of increase in BMD at the spine decreases over time, though continued gains in BMD are still observed. At the hip, BMD appears to be maintained at the increased levels. Therefore, for patients with low BMD after 10 years of treatment, extending denosumab therapy beyond this period may be worth considering. However, the potential clinical benefits and risks of prolonged administration should be carefully evaluated. Caution must be exercised while interpreting these results, as they are from predictive model analyses based on existing research and do not account for all possible effects of denosumab on bone physiology. Changes in BMD post-10 years must be validated using well-designed real-world data.
FRACTURE PREVENTION AFTER A DECADE OF DENOSUMAB USE
A 3-year administration of denosumab reduced the risk of new vertebral fractures, hip fractures, and nonvertebral fractures by 68%, 40%, and 20%, respectively [5]. Additionally, in a 10-year extension study, the risk of fractures remained low [9]. It is difficult to predict how effective more than 10 years of denosumab administration is in preventing fractures. Unlike the prediction of changes in bone density after 10 years, this issue is very complex to approach statistically. There have been studies that predicted the occurrence of fractures after denosumab administration. Ferrari et al. [22] reported on the effects of 10 years of denosumab administration on fractures and significant adverse effects using a virtual-twin analysis. In this study, the virtual twin method estimated that denosumab treatment significantly reduced the fracture rate compared to the virtual placebo group [22]. More specifically, in the placebo group and the denosumab group, clinical fractures per 100,000 subject-years were 3,180 versus 1,777, major osteoporotic fractures were 2,699 versus 1,525, vertebral fractures were 1,879 versus 901, and non-vertebral fractures were 2,924 versus 1,528, respectively [22]. Thus, in the virtual model, the risk of fractures in all areas was reduced over 10 years in the denosumab treatment group [22]. Predicting fractures is challenging, but fracture prevention can be anticipated through changes in BMD. In the analysis by Eastell et al. [28], bone density was validated as a surrogate marker for reduced fracture risk. Therefore, improvements in BMD are expected to lower the risk of fractures.
PREDICTING GENERAL SIDE EFFECTS AFTER EXTENDED DENOSUMAB TREATMENT
Current evidence confirms that RANKL inhibition by denosumab is generally safe and well-tolerated for up to 10 years of use [10]. In the FREEDOM trial, which confirmed the efficacy and safety of denosumab over 3 years, no significant AEs were observed between the denosumab and placebo groups, and the number of serious AEs or discontinuations owing to AEs did not significantly differ [5]. The incidence of clinically significant hypocalcemia did not vary between the groups. However, the frequency of eczema and cellulitis at the injection site was increased in the denosumab group [5]. Subsequent analysis indicated a slight increase in infection-related AEs in the denosumab group; however, the occurrences were minimal and not linked to the timing or duration of the injection [29]. No significant change in the pattern of these AE reports occurred during the FREEDOM extension trial. The yearly incidence of AEs of interest, including hypocalcemia, pancreatitis, severe cellulitis, or erythema, remained similar throughout the extension period [9]. Furthermore, no association was observed between the duration of denosumab treatment and the occurrence of these AEs, suggesting these events, despite their occurrence, were idiosyncratic regardless of treatment duration. Therefore, predictions that the incidence of these AEs would increase proportionally with ≥10 years of denosumab use may not be valid. Nonetheless, recognizing that these AEs can occur at any time post-denosumab treatment is vital.
The occurrence of hypocalcemia following denosumab administration warrants attention [30]. The risk of hypocalcemia after denosumab is increased in patients with reduced renal function [31-34]. As of January 19, 2024, the U.S. Food and Drug Administration included a boxed warning indicating a heightened risk of severe hypocalcemia among individuals with chronic kidney disease (CKD). Current evidence suggests prolonged denosumab use does not increase the risk of hypocalcemia; conversely, calcium levels decrease less with subsequent denosumab doses [35]. Hypocalcemia may occur in patients with predisposing conditions such as low baseline calcium levels, renal dysfunction, or malabsorption. Thus, clinicians should assess the risk of developing hypocalcemia each time before administering denosumab and ensure adequate calcium supplementation and periodic monitoring of calcium levels during treatment [36,37].
INCIDENCE OF OSTEONECROSIS OF THE JAW WITH EXTENDED DENOSUMAB TREATMENT
Osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF) are major side effects associated with denosumab administration. Most denosumab-induced ONJ cases are associated with high doses used in treating bone metastasis or bone involvement of malignancy (120 mg every 4 weeks; 1% to 15%) [38-40], whereas the incidence of ONJ remains low for doses used in routine osteoporosis treatment (60 mg every 6 months) in the absence of risk factors such as dental extraction, poor oral hygiene, use of removable dental appliances, and chemotherapy [38,41-46]. De Cicco et al. [45] demonstrated that anti-mouse RANKL antibodies inhibited alveolar bone destruction in model mice with periodontitis. The FREEDOM trial reported no cases of ONJ, whereas the FREEDOM extension trial documented 13 adjudicated cases of ONJ—seven in the long-term group and six in the cross-over group—resulting in 5.2 cases per 10,000 person-years of medication exposure [9]. Notably, invasive oral procedures were reported in nine of these 13 ONJ cases [9].
In patients with cancer, the duration of anti-resorptive therapy is a risk factor for ONJ development; however, this association is less defined in patients with osteoporosis [46]. Ng et al. [47] conducted a systematic review and identified a 1.9% and 6.9% risk of ONJ in patients with cancer treated with denosumab for <24 and >24 months, respectively; however, this trend is less pronounced in osteoporosis treatments. Data from a large prospective, randomized, placebo-controlled clinical trial with zoledronic acid revealed no significant increase in ONJ in patients treated for up to 9 years [48-50]. European prescribing data indicates a gradual increase in ONJ incidence from 0.04% at 3 years to 0.06% at 5 years, reaching 0.44% at 10 years [51]. European prescribing information suggests that ONJ incidence increases with prolonged denosumab treatment [51]. However, since most reports have not yet clearly established a temporal association between denosumab administration and the occurrence of ONJ [46], caution is advised in drawing definitive conclusions regarding this association until more concrete evidence becomes available.
Until more definitive evidence is collected on the long-term use of denosumab and ONJ incidence, clinicians should take necessary precautions to mitigate ONJ risk. Patients should be encouraged to address any pre-existing dental issues, practice good oral hygiene, seek prompt treatment for new dental issues, and regularly visit their dentist, especially in cases where long-term denosumab use is necessary.
ASSESSING ATYPICAL FEMORAL FRACTURE RISKS IN EXTENDED DENOSUMAB THERAPY
In the FREEDOM study trial, no AFF cases were recorded, whereas, in the FREEDOM extension trial, two AFF cases were observed; this resulted in an incidence rate of 0.8 per 10,000 person-years [9]. A recent systemic review by the European Calcified Tissue Society, analyzing two clinical trials and 14 case reports, identified 31 AFF cases in 22 patients [52]; only 11 received routine osteoporosis doses, whereas others received higher doses for cancer treatment [52]. Given the limited evidence, establishing a definitive relationship between denosumab duration and AFF development is challenging; consequently, predictions on the impact of long-term use on AFF development remain uncertain. Nevertheless, the incidence of AFF is likely to remain low with extended denosumab treatment, and the fracture-preventive effect is expected to outweigh the risk of AFF. In the FREEDOM extension trial, the virtual twin method was used to determine a skeletal benefit/risk ratio of 281 for AFF [22].
While some risk factors for AFF with bisphosphonates are well-established [53-55], the risk factors that may influence the development of denosumab-induced AFF are not well understood. We recommend that clinicians should promptly recognize AFF, particularly in patients previously treated with bisphosphonates [56], by monitoring for lateral femur tenderness and using dual-energy X-ray absorptiometry for the early identification of incomplete atypical AFF [57,58]. Alternatively, bilateral full-length femoral imaging should be considered to detect AFF spectrum abnormalities, as recommended by the International Society for Clinical Densitometry [59].
MALIGNANCY RISKS WITH PROLONGED DENOSUMAB USE
As denosumab inhibits RANKL, it might also reduce the immunomodulatory role of RANKL and increase the risk of malignancy [60]. Counterintuitively, the incidence of malignancies between the denosumab arm and controls in the 3-year FREEDOM study or the subsequent 7-year extension study did not significantly differ [5,9]. Moreover, Zhou et al. [61] conducted a meta-analysis and observed no increased risk of neoplasms in the denosumab group compared with that in the placebo- or bisphosphonate-treated groups (RR, 1.14; 95% CI, 0.95 to 1.37; P=0.16). Rosenberg et al. [62] also conducted a meta-analysis of 25 randomized controlled trials with denosumab and found no associated risk of malignancy (RR, 1.08; 95% CI, 0.94 to 1.24; P=0.30). However, these analyses are limited because denosumab exposure was only up to 48 months, and results might differ with longer exposure periods. Thus, long-term observations are essential to ascertain the impact of extended denosumab administration (>over 10 years) on the development of malignancies.
CLINICAL SCENARIOS FOR EXTENDED DENOSUMAB ADMINISTRATION
Under certain clinical conditions, particularly in patients with reduced renal function, prolonged administration of denosumab may be necessary. As denosumab is cleared by the reticuloendothelial system, it can be administered without dose adjustment to patients with CKD. The effectiveness and safety of denosumab for osteoporosis in patients with reduced renal function were reported in the FREEDOM trial [30,63]. In a subgroup of patients across various CKD stages, denosumab effectively reduced the risk of fractures and was not associated with increased AEs in those with impaired renal function [30,63]. However, advanced CKD (CKD stage 3b and below) often involves CKD-mineral and bone disorder relative to its incidence in patients with mild to moderate CKD (CKD stage 1–3a); this complicates the understanding of bone metabolism. Although the FREEDOM trial included some patients with advanced CKD stages 4–5, evidence of the efficacy of denosumab in these patients remains insufficient. Moreover, the efficacy and safety of denosumab in patients with end-stage kidney disease must be further elucidated. After monitoring 48 patients who underwent dialysis, Iseri et al. [64] reported that 12 months of denosumab treatment reduced bone turnover and increased BMD; however, they did not report on fracture prevention. When initiating denosumab in patients with reduced renal function, the duration of treatment is crucial. The rebound phenomenon, characterized by a sudden increase in fracture risk and decrease in BMD upon denosumab discontinuation, is well-documented and should be managed by transitioning to bisphosphonate therapy to prevent this effect in cases where denosumab discontinuation is necessary [20,21,65]. In mild to moderate CKD, patients can transition to bisphosphonates post-denosumab according to guidelines; however, in advanced CKD, bisphosphonate options are limited. Therefore, continuous denosumab therapy without interruption might extend beyond 10 years for these patients. Currently, robust evidence is lacking on the long-term safety and effectiveness of denosumab in advanced CKD. Nonetheless, uninterrupted treatment may be essential, particularly where discontinuation may result in AEs and no viable alternatives are available. There may be questions regarding whether denosumab should be administered indefinitely in this patient group. However, currently, there is insufficient evidence to make a clear recommendation. Therefore, clinical judgment is required to carefully weigh the potential AEs of discontinuing denosumab against the benefits of continuing its administration.
Osteoporosis treatment is primarily aimed at preventing fractures. Although denosumab administration may result in side effects, it remains effective in preventing fractures [22]. As fractures are a major socioeconomic burden, the economic impact of fracture prevention must also be considered [66-69]. We analyzed the cost-effectiveness of denosumab in Korea in a cost-consequence analysis using a Markov model, comparing the group treated only <T-score of –2.5, the diagnostic threshold for osteoporosis, with the group treated continuously until a T-score of ≥–2.0 [67]. The results indicated that maintaining a T-score of ≥–2.0 led to superior fracture prevention and corresponding economic benefits [66]. While we assumed lifelong osteoporosis treatment, the findings suggest that continuing denosumab treatment beyond 10 years may be cost-effective for patients at high risk of fracture. Prolonged administration of denosumab may be indicated in clinical situations where the adverse effects of discontinuation are evident, or when the skeletal benefits of treatment outweigh the side effects.
CLINICAL GUIDELINES FOR EXTENDED DENOSUMAB THERAPY
Since the Endocrine Society revised its postmenopausal osteoporosis management guidelines in 2019, many societies have updated their guidelines for osteoporosis treatment. Although the efficacy of denosumab in treating postmenopausal osteoporosis is well-supported, guidelines remain unclear on dosing beyond 10 years. Table 1 presents sections of the guideline addressing the use of denosumab for over 10 years. The Endocrine Society’s guideline indicates that patients at high risk for fracture after 5 to 10 years of denosumab use should continue the treatment or other osteoporosis therapies [8]. Although the quality of evidence was deemed insufficient owing to limited data, continuation of denosumab might help balance benefits and harms to the musculoskeletal system for patients at high risk after 10 years [8]. The American College of Physicians recommends further investigation into the long-term benefits and risks of denosumab, extending beyond 10 years; however, it does not provide specific guidance on prolonged use [17]. The Russian Association for Osteoporosis suggests that extended denosumab therapy may be appropriate for patients with severe osteoporosis [70]. Additionally, most guidelines issued in the past 5 years do not address denosumab dosing after 10 years [7,16,18,19,71-73]. Collectively, recent guidelines lack detailed directives on long-term denosumab dosing owing to insufficient long-term data; however, updates may be incorporated as more evidence becomes available.
Guidelines from Various Medical Organizations on the Effectiveness and Safety of Long-Term Denosumab Administration beyond 10 Years
CONCLUSIONS
Based on limited evidence and predictive models, we reviewed the long-term effects of denosumab treatment exceeding 10 years on BMD and the incidence of AEs. Although the benefits to BMD are expected to persist beyond 10 years, results may vary depending on the presence of secondary osteoporosis or patient compliance. AEs such as AFF and ONJ were considerably infrequent in the 10-year phase 3 study to establish a temporal relationship. While general use in osteoporosis treatment might increase ONJ risk, the overall risk is low, and definitive evidence on the association between treatment duration and ONJ development is lacking. ONJ incidence may increase with longer denosumab use; therefore, patients receiving treatment for over 10 years should be continually monitored for the occurrence of these events. The association between denosumab duration and ONJ development must be further explored. There are several unresolved issues regarding long-term denosumab administration that require further investigation. Research on the efficacy and safety of denosumab administration beyond 10 years in patients with advanced CKD is necessary. Furthermore, careful consideration should be given to the impact of discontinuing long-term denosumab treatment, particularly after 10 years, on the occurrence of rebound phenomenon and the appropriate clinical management of such cases.
Despite these concerns, the benefits of denosumab in preventing fractures, particularly in patients at high and very high risk, significantly outweigh the potential risks. In some cases, long-term use of denosumab may be necessary after the initial treatment period. However, with limited clinical data on denosumab use beyond 10 years, gathering further evidence on its long-term safety and efficacy is essential. More comprehensive data are needed to strengthen the clinical evidence base and confirm the long-term outcomes of denosumab therapy.
Notes
CONFLICTS OF INTEREST
Youn-Ju Lee, affiliated with Medical Excellence Inc., declares no conflicts of interest related to the findings of this study. The other authors report no potential conflicts of interest relevant to this article.
ACKNOWLEDGMENTS
The authors received financial support from the Catholic Medical Center Research Foundation in the program year of 2023.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00273406).