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Review Article
Calcium & bone metabolism Long-Term Efficacy and Safety of Denosumab: Insights beyond 10 Years of Use
Jeonghoon Ha1orcid, Youn-Ju Lee2,3, Jinyoung Kim4, Chaiho Jeong5, Yejee Lim6, Jeongmin Lee7, Ki-Hyun Baek4orcid, on Behalf of the Catholic Medical Center Bone Research Group
Endocrinology and Metabolism 2025;40(1):47-56.
DOI: https://doi.org/10.3803/EnM.2024.2125
Published online: January 13, 2025

1Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

2Department of Biostatistics, Korea University College of Medicine, Seoul, Korea

3Medical Excellence Inc., Seoul, Korea

4Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

5Division of Endocrinology and Metabolism, Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea

6Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

7Division of Endocrinology and Metabolism, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea

Corresponding author: Ki-Hyun Baek. Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 10 63-ro, Yeongdeungpo-gu, Seoul 07345, Korea Tel: +82-2-379-1400, Fax: +82-2-780-3132, E-mail: drbkh@catholic.ac.kr
• Received: July 30, 2024   • Revised: September 24, 2024   • Accepted: October 10, 2024

Copyright © 2025 Korean Endocrine Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • 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.
  • Keywords: Osteoporosis; Denosumab; Bone density; Drug safety; Long-term care
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.
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.
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.
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.
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].
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.
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].
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.
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.
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.
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.

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).

Fig. 1.
Prediction of the duration of denosumab treatment and percentage change from baseline in lumbar spine bone mineral density. Adapted from Lee et al. [27]. FREEDOM, Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months.
enm-2024-2125f1.jpg
Fig. 2.
Prediction of the duration of denosumab treatment and percentage change from baseline in total hip bone mineral density. Adapted from Lee et al. [27]. FREEDOM, Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months.
enm-2024-2125f2.jpg
Table 1.
Guidelines from Various Medical Organizations on the Effectiveness and Safety of Long-Term Denosumab Administration beyond 10 Years
Medical organization Guideline
Endocrine Society For women with postmenopausal osteoporosis at high risk of fracture after 5–10 years of use, continue denosumab or switch to another osteoporosis treatment.
American Association of Clinical Endocrinologists No specific comments regarding denosumab use beyond 10 years.
American College of Physicians No specific comments regarding denosumab use beyond 10 years.
UK National Osteoporosis Guideline Group Benefits and risks of prolonged treatment durations with denosumab should be examined via well-designed, real-world evidence studies.
Canadian Medical Association No specific comments regarding denosumab use beyond 10 years.
Swiss Association against No specific comments regarding denosumab use beyond 10 years.
Osteoporosis Russian Association for Osteoporosis No specific comments regarding denosumab use beyond 10 years.
Taiwanese Osteoporosis Association Treatment with denosumab for up to and exceeding 10 years is justified in patients with severe osteoporosis.
Korean Society for Bone and Mineral Research No specific comments regarding denosumab use beyond 10 years.
African Society of Bone Health and Metabolic Diseases No specific comments regarding denosumab use beyond 10 years.
  • 1. Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med 1998;338:736–46.ArticlePubMed
  • 2. Brown JP. Long-term treatment of postmenopausal osteoporosis. Endocrinol Metab (Seoul) 2021;36:544–52.ArticlePubMedPMCPDF
  • 3. Reid IR, Billington EO. Drug therapy for osteoporosis in older adults. Lancet 2022;399:1080–92.ArticlePubMed
  • 4. Saltik H, Ozturk F, Emiroglu C, Hekimoglu B, Aypak C. Knowledge, attitude, and behavior levels of postmenopausal women about osteoporosis. J Bone Metab 2023;30:347–54.ArticlePubMedPMCPDF
  • 5. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65.PubMed
  • 6. Walker MD, Shane E. Postmenopausal osteoporosis. N Engl J Med 2023;389:1979–91.ArticlePubMed
  • 7. Camacho PM, Petak SM, Binkley N, Diab DL, Eldeiry LS, Farooki A, et al. American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the diagnosis and treatment of postmenopausal osteoporosis: 2020 update. Endocr Pract 2020;26(Suppl 1):1–46.Article
  • 8. Eastell R, Rosen CJ, Black DM, Cheung AM, Murad MH, Shoback D. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2019;104:1595–622.ArticlePubMedPDF
  • 9. Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, et al. 10 Years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 2017;5:513–23.PubMed
  • 10. Kendler DL, Cosman F, Stad RK, Ferrari S. Denosumab in the treatment of osteoporosis: 10 years later: a narrative review. Adv Ther 2022;39:58–74.ArticlePubMedPMCPDF
  • 11. Rhee Y, Chang DG, Ha J, Kim S, Lee Y, Jo E, et al. Real-world safety and effectiveness of denosumab in patients with osteoporosis: a prospective, observational study in South Korea. Endocrinol Metab (Seoul) 2022;37:497–505.ArticlePubMedPMCPDF
  • 12. Koh JM, Chung DJ, Chung YS, Kang MI, Kim IJ, Min YK, et al. Assessment of denosumab in Korean postmenopausal women with osteoporosis: randomized, double-blind, placebo-controlled trial with open-label extension. Yonsei Med J 2016;57:905–14.ArticlePubMedPMCPDF
  • 13. Lai EC, Lin TC, Lange JL, Chen L, Wong IC, Sing CW, et al. Effectiveness of denosumab for fracture prevention in real-world postmenopausal women with osteoporosis: a retrospective cohort study. Osteoporos Int 2022;33:1155–64.ArticlePubMedPMCPDF
  • 14. Yoon SH, Kim K, Kim KC. The effect of denosumab in elderly patients regarding bone density and fracture risk. J Bone Metab 2023;30:275–82.ArticlePubMedPMCPDF
  • 15. Shoback D, Rosen CJ, Black DM, Cheung AM, Murad MH, Eastell R. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society Guideline update. J Clin Endocrinol Metab 2020;105:dgaa048.ArticlePubMedPDF
  • 16. Morin SN, Feldman S, Funnell L, Giangregorio L, Kim S, McDonald-Blumer H, et al. Clinical practice guideline for management of osteoporosis and fracture prevention in Canada: 2023 update. CMAJ 2023;195:E1333–48.ArticlePubMedPMC
  • 17. Qaseem A, Hicks LA, Etxeandia-Ikobaltzeta I, Shamliyan T, Cooney TG; Clinical Guidelines Committee of the American College of Physicians, et al. Pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults: a living clinical guideline from the American College of Physicians. Ann Intern Med 2023;176:224–38.ArticlePubMedPMC
  • 18. Park SY, Kim SH, Lee YK, Shin JH, Ha YC, Chung HY. Position statement: postmenopausal osteoporosis treatment strategies in Korea. J Bone Metab 2023;30:289–95.ArticlePubMedPMCPDF
  • 19. Tai TW, Huang CF, Huang HK, Yang RS, Chen JF, Cheng TT, et al. Clinical practice guidelines for the prevention and treatment of osteoporosis in Taiwan: 2022 update. J Formos Med Assoc 2023;122 Suppl 1:S4–13.ArticlePubMed
  • 20. Tsourdi E, Zillikens MC, Meier C, Body JJ, Gonzalez Rodriguez E, Anastasilakis AD, et al. Fracture risk and management of discontinuation of denosumab therapy: a systematic review and position statement by ECTS. J Clin Endocrinol Metab 2020;106:264–81.ArticlePDF
  • 21. Tay WL, Tay D. Discontinuing denosumab: can it be done safely?: a review of the literature. Endocrinol Metab (Seoul) 2022;37:183–94.ArticlePubMedPMCPDF
  • 22. Ferrari S, Lewiecki EM, Butler PW, Kendler DL, Napoli N, Huang S, et al. Favorable skeletal benefit/risk of long-term denosumab therapy: a virtual-twin analysis of fractures prevented relative to skeletal safety events observed. Bone 2020;134:115287.ArticlePubMed
  • 23. Siris E, McDermott M, Pannacciulli N, Miller PD, Lewiecki EM, Chapurlat R, et al. Estimation of long-term efficacy of denosumab treatment in postmenopausal women with osteoporosis: a FRAX- and virtual twin-based post hoc analysis from the FREEDOM and FREEDOM Extension Trials. JBMR Plus 2020;4:e10348.PubMedPMC
  • 24. Peterson MC, Riggs MM. Predicting nonlinear changes in bone mineral density over time using a multiscale systems pharmacology model. CPT Pharmacometrics Syst Pharmacol 2012;1:e14.ArticlePubMedPMCPDF
  • 25. Hasegawa C, Duffull SB. Automated scale reduction of nonlinear QSP models with an illustrative application to a bone biology system. CPT Pharmacometrics Syst Pharmacol 2018;7:562–72.PubMedPMC
  • 26. Tsoularis A, Wallace J. Analysis of logistic growth models. Math Biosci 2002;179:21–55.ArticlePubMed
  • 27. Lee J, Lee YJ, Ha J. Denosumab in osteoporosis: predicting long-term efficacy beyond 10 years. J Bone Metab 2024;31:246–9.ArticlePubMedPMCPDF
  • 28. Eastell R, Vittinghoff E, Lui LY, McCulloch CE, Pavo I, Chines A, et al. Validation of the surrogate threshold effect for change in bone mineral density as a surrogate endpoint for fracture outcomes: the FNIH-ASBMR SABRE Project. J Bone Miner Res 2022;37:29–35.PubMed
  • 29. Watts NB, Roux C, Modlin JF, Brown JP, Daniels A, Jackson S, et al. Infections in postmenopausal women with osteoporosis treated with denosumab or placebo: coincidence or causal association? Osteoporos Int 2012;23:327–37.ArticlePubMedPMC
  • 30. Broadwell A, Chines A, Ebeling PR, Franek E, Huang S, Smith S, et al. Denosumab safety and efficacy among participants in the FREEDOM Extension Study with mild to moderate chronic kidney disease. J Clin Endocrinol Metab 2021;106:397–409.ArticlePubMedPMCPDF
  • 31. Bird ST, Smith ER, Gelperin K, Jung TH, Thompson A, Kambhampati R, et al. Severe hypocalcemia with denosumab among older female dialysis-dependent patients. JAMA 2024;331:491–9.ArticlePubMedPMC
  • 32. Cowan A, Jeyakumar N, McArthur E, Fleet JL, Kanagalingam T, Karp I, et al. Hypocalcemia risk of denosumab across the spectrum of kidney disease: a population-based cohort study. J Bone Miner Res 2023;38:650–8.PubMed
  • 33. Gopaul A, Kanagalingam T, Thain J, Khan T, Cowan A, Sultan N, et al. Denosumab in chronic kidney disease: a narrative review of treatment efficacy and safety. Arch Osteoporos 2021;16:116.ArticlePubMedPDF
  • 34. Dave V, Chiang CY, Booth J, Mount PF. Hypocalcemia post denosumab in patients with chronic kidney disease stage 4-5. Am J Nephrol 2015;41:129–37.ArticlePubMedPDF
  • 35. Festuccia F, Jafari MT, Moioli A, Fofi C, Barberi S, Amendola S, et al. Safety and efficacy of denosumab in osteoporotic hemodialysed patients. J Nephrol 2017;30:271–9.ArticlePubMedPDF
  • 36. Bover J, Bailone L, Lopez-Baez V, Benito S, Ciceri P, Galassi A, et al. Osteoporosis, bone mineral density and CKD-MBD: treatment considerations. J Nephrol 2017;30:677–87.ArticlePubMedPDF
  • 37. Tsvetov G, Amitai O, Shochat T, Shimon I, Akirov A, Diker-Cohen T. Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low? Osteoporos Int 2020;31:655–65.ArticlePubMedPDF
  • 38. Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015;30:3–23.PubMed
  • 39. Owosho AA, Blanchard A, Levi L, Kadempour A, Rosenberg H, Yom SK, et al. Osteonecrosis of the jaw in patients treated with denosumab for metastatic tumors to the bone: a series of thirteen patients. J Craniomaxillofac Surg 2016;44:265–70.ArticlePubMedPMC
  • 40. Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, et al. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol 2020;21:60–72.ArticlePubMed
  • 41. Everts-Graber J, Lehmann D, Burkard JP, Schaller B, Gahl B, Hauselmann H, et al. Risk of osteonecrosis of the jaw under denosumab compared to bisphosphonates in patients with osteoporosis. J Bone Miner Res 2022;37:340–8.ArticlePubMedPDF
  • 42. Boquete-Castro A, Gomez-Moreno G, Calvo-Guirado JL, Aguilar-Salvatierra A, Delgado-Ruiz RA. Denosumab and osteonecrosis of the jaw: a systematic analysis of events reported in clinical trials. Clin Oral Implants Res 2016;27:367–75.ArticlePubMed
  • 43. Papapoulos S, Chapurlat R, Libanati C, Brandi ML, Brown JP, Czerwinski E, et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: results from the first two years of the FREEDOM extension. J Bone Miner Res 2012;27:694–701.PubMed
  • 44. Rutkowski P, Gaston L, Borkowska A, Stacchiotti S, Gelderblom H, Baldi GG, et al. Denosumab treatment of inoperable or locally advanced giant cell tumor of bone: multicenter analysis outside clinical trial. Eur J Surg Oncol 2018;44:1384–90.ArticlePubMed
  • 45. De Cicco D, Boschetti CE, Santagata M, Colella G, Stagliano S, Gaggl A, et al. Medication-related osteonecrosis of the jaws: a comparison of SICMF-SIPMO and AAOMS Guidelines. Diagnostics (Basel) 2023;13:2137.ArticlePubMedPMC
  • 46. Ruggiero SL, Dodson TB, Aghaloo T, Carlson ER, Ward BB, Kademani D. American Association of Oral and Maxillofacial Surgeons’ Position Paper on medication-related osteonecrosis of the jaws: 2022 update. J Oral Maxillofac Surg 2022;80:920–43.ArticlePubMed
  • 47. Ng TL, Tu MM, Ibrahim MF, Basulaiman B, McGee SF, Srikanthan A, et al. Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review. Support Care Cancer 2021;29:925–43.ArticlePubMedPDF
  • 48. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809–22.PubMed
  • 49. Black DM, Reid IR, Boonen S, Bucci-Rechtweg C, Cauley JA, Cosman F, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2012;27:243–54.PubMed
  • 50. Black DM, Reid IR, Cauley JA, Cosman F, Leung PC, Lakatos P, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2015;30:934–44.ArticlePubMedPDF
  • 51. Noble JA, McKenna MJ, Crowley RK. Should denosumab treatment for osteoporosis be continued indefinitely? Ther Adv Endocrinol Metab 2021;12:20420188211010052.ArticlePubMedPMCPDF
  • 52. van de Laarschot DM, McKenna MJ, Abrahamsen B, Langdahl B, Cohen-Solal M, Guanabens N, et al. Medical management of patients after atypical femur fractures: a systematic review and recommendations from the European Calcified Tissue Society. J Clin Endocrinol Metab 2020;105:1682–99.ArticlePubMedPMCPDF
  • 53. Franceschetti P, Bondanelli M, Caruso G, Ambrosio MR, Lorusso V, Zatelli MC, et al. Risk factors for development of atypical femoral fractures in patients on long-term oral bisphosphonate therapy. Bone 2013;56:426–31.ArticlePubMed
  • 54. Dhanekula ND, Crouch G, Byth K, Lau SL, Kim A, Graham E, et al. Asian ethnicity and femoral geometry in atypical femur fractures: independent or interdependent risk factors? JBMR Plus 2022;6:e10607.ArticlePubMedPMCPDF
  • 55. Black DM, Abrahamsen B, Bouxsein ML, Einhorn T, Napoli N. Atypical femur fractures: review of epidemiology, relationship to bisphosphonates, prevention, and clinical management. Endocr Rev 2019;40:333–68.ArticlePubMed
  • 56. Everts-Graber J, Bonel H, Lehmann D, Gahl B, Hauselmann H, Studer U, et al. Incidence of atypical femoral fractures in patients on osteoporosis therapy: a registry-based cohort study. JBMR Plus 2022;6:e10681.PubMedPMC
  • 57. McKiernan FE. Atypical femoral diaphyseal fractures documented by serial DXA. J Clin Densitom 2010;13:102–3.ArticlePubMed
  • 58. McKenna MJ, van der Kamp S, Heffernan E, Hurson C. Incomplete atypical femoral fractures: assessing the diagnostic utility of DXA by extending femur length. J Clin Densitom 2013;16:579–83.ArticlePubMed
  • 59. Cheung AM, McKenna MJ, van de Laarschot DM, Zillikens MC, Peck V, Srighanthan J, et al. Detection of atypical femur fractures. J Clin Densitom 2019;22:506–16.ArticlePubMed
  • 60. Cheng ML, Fong L. Effects of RANKL-targeted therapy in immunity and cancer. Front Oncol 2014;3:329.ArticlePubMedPMC
  • 61. Zhou Z, Chen C, Zhang J, Ji X, Liu L, Zhang G, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol 2014;7:2113–22.PubMedPMC
  • 62. Rosenberg D, Avni T, Tsvetov G, Gafter-Gvili A, Diker-Cohen T. Denosumab is not associated with risk of malignancy: systematic review and meta-analysis of randomized controlled trials. Osteoporos Int 2021;32:413–24.ArticlePubMedPDF
  • 63. Jamal SA, Ljunggren O, Stehman-Breen C, Cummings SR, McClung MR, Goemaere S, et al. Effects of denosumab on fracture and bone mineral density by level of kidney function. J Bone Miner Res 2011;26:1829–35.ArticlePubMedPDF
  • 64. Iseri K, Watanabe M, Yoshikawa H, Mitsui H, Endo T, Yamamoto Y, et al. Effects of denosumab and alendronate on bone health and vascular function in hemodialysis patients: a randomized, controlled trial. J Bone Miner Res 2019;34:1014–24.ArticlePubMedPDF
  • 65. Anastasilakis AD, Makras P, Yavropoulou MP, Tabacco G, Naciu AM, Palermo A. Denosumab discontinuation and the rebound phenomenon: a narrative review. J Clin Med 2021;10:152.ArticlePubMedPMC
  • 66. Kang JY, Choi L, Johnson B, Yang H. Cost-effectiveness of denosumab for the treatment of postmenopausal osteoporosis in South Korea. J Bone Metab 2022;29:83–92.ArticlePubMedPMCPDF
  • 67. Cha S, Sohn M, Yang H, Yeh EJ, Baek KH, Ha J, et al. Cost-consequence analysis of continuous denosumab therapy for osteoporosis treatment in South Korea. BMC Musculoskelet Disord 2024;25:76.ArticlePubMedPMCPDF
  • 68. Wan Y, Zeng F, Tan H, Lu Y, Zhang Y, Zhao L, et al. Cost-effectiveness analyses of denosumab for osteoporosis: a systematic review. Osteoporos Int 2022;33:979–1015.ArticlePubMedPDF
  • 69. Li N, Cornelissen D, Silverman S, Pinto D, Si L, Kremer I, et al. An updated systematic review of cost-effectiveness analyses of drugs for osteoporosis. Pharmacoeconomics 2021;39:181–209.ArticlePubMedPMCPDF
  • 70. Belaya Z, Rozhinskaya L, Dedov I, Drapkina O, Fadeev V, Golounina O, et al. A summary of the Russian clinical guidelines on the diagnosis and treatment of osteoporosis. Osteoporos Int 2023;34:429–47.ArticlePubMedPDF
  • 71. Gregson CL, Armstrong DJ, Bowden J, Cooper C, Edwards J, Gittoes NJL, et al. UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos 2022;17:58.ArticlePubMedPMCPDF
  • 72. El Miedany Y, Paruk F, Kalla A, Adebajo A, El Gaafary M, El Maghraoui A, et al. Consensus evidence-based clinical practice guidelines for the diagnosis and treat-to-target management of osteoporosis in Africa: an initiative by the African Society of Bone Health and Metabolic Bone Diseases. Arch Osteoporos 2021;16:176.PubMedPMC
  • 73. Ferrari S, Lippuner K, Lamy O, Meier C. 2020 Recommendations for osteoporosis treatment according to fracture risk from the Swiss Association against Osteoporosis (SVGO). Swiss Med Wkly 2020;150:w20352.ArticlePubMedPDF

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      Long-Term Efficacy and Safety of Denosumab: Insights beyond 10 Years of Use
      Image Image
      Fig. 1. Prediction of the duration of denosumab treatment and percentage change from baseline in lumbar spine bone mineral density. Adapted from Lee et al. [27]. FREEDOM, Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months.
      Fig. 2. Prediction of the duration of denosumab treatment and percentage change from baseline in total hip bone mineral density. Adapted from Lee et al. [27]. FREEDOM, Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months.

      Fig. 1.

      Fig. 2.

      Long-Term Efficacy and Safety of Denosumab: Insights beyond 10 Years of Use
      Medical organization Guideline
      Endocrine Society For women with postmenopausal osteoporosis at high risk of fracture after 5–10 years of use, continue denosumab or switch to another osteoporosis treatment.
      American Association of Clinical Endocrinologists No specific comments regarding denosumab use beyond 10 years.
      American College of Physicians No specific comments regarding denosumab use beyond 10 years.
      UK National Osteoporosis Guideline Group Benefits and risks of prolonged treatment durations with denosumab should be examined via well-designed, real-world evidence studies.
      Canadian Medical Association No specific comments regarding denosumab use beyond 10 years.
      Swiss Association against No specific comments regarding denosumab use beyond 10 years.
      Osteoporosis Russian Association for Osteoporosis No specific comments regarding denosumab use beyond 10 years.
      Taiwanese Osteoporosis Association Treatment with denosumab for up to and exceeding 10 years is justified in patients with severe osteoporosis.
      Korean Society for Bone and Mineral Research No specific comments regarding denosumab use beyond 10 years.
      African Society of Bone Health and Metabolic Diseases No specific comments regarding denosumab use beyond 10 years.
      Table 1. Guidelines from Various Medical Organizations on the Effectiveness and Safety of Long-Term Denosumab Administration beyond 10 Years

      Table 1.

      Endocrinol Metab : Endocrinology and Metabolism
      © Korean Endocrine Society.
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