# Strategies for denosumab discontinuation in postmenopausal osteoporosis

Yannick Degboé, Guillaume Couture

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Yannick Degboé, Guillaume Couture. Strategies for denosumab discontinuation in postmenopausal osteoporosis. Joint Bone Spine, 2026, 93 (2), pp.105954. 10.1016/j.jbspin.2025.105954. hal-05515405

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Review

# Strategies for denosumab discontinuation in postmenopausal osteoporosis

Yannick Degboé<sup>a,b,*</sup>, Guillaume Couture<sup>a</sup>

<figure><img src="image_4.png" /></figure>

## ARTICLE INFO

**Article history:**
Accepted 4 August 2025
Available online 28 August 2025

**Keywords:**
Denosumab
Rebound phenomenon
Fracture
Bisphosphonates
Discontinuation
Osteoporosis treatment

## ABSTRACT

Discontinuation of denosumab in postmenopausal osteoporosis causes a rebound phenomenon with a rapid increase in bone turnover markers and accelerated bone loss, often within 6–12 months. Without an appropriate relay therapy, up-to 10% of the patients experience multiple vertebral fractures. This phenomenon is linked to a multifactorial dysregulation of bone remodelling. In 2021, the European Calcified Tissue Society (ECTS) proposed guidelines for discontinuing denosumab in patients with postmenopausal osteoporosis. Our review covers the latest research on risk stratification for rebound phenomenon, the various relay treatment options based on risk levels, and the recommended follow-up for these patients. Post-denosumab treatment is important. Bisphosphonates therapy and regular monitoring of serum CTX (crosslaps) represent the cornerstone of the management of rebound phenomenon following denosumab discontinuation in postmenopausal osteoporosis.

© 2025 The Authors. Published by Elsevier Masson SAS on behalf of Société Française de Rhumatologie. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

## 1. Introduction

Denosumab, a monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), is a potent antiresorptive agent, approved for the treatment of postmenopausal osteoporosis [1]. Its ten-year safety profile appears satisfactory [2]. Importantly, the biological effect of denosumab is associated with a transient (i.e., limited to the period of drug exposure) and robust inhibition of bone turnover markers [3,4]. This inhibition of bone turnover markers is accompanied by an inhibition of bone resorption as evidenced by a reduction in the eroded surface and an increase of BMD [4–6].

At present, expert consensus holds that treatment discontinuation can be proposed in patients achieving the therapeutic target defined by the practitioner, taking into account the following items: the absence of bone loss (BMD decrease < 0.03 g/cm²; as minimal prerequisite); no fracture during treatment; no new risk factors; and in patients with a history of severe fracture, a femoral T-score ≥ -2.5 or -2.0 [7]. However, denosumab discontinuation requires proper management to avoid the so-called “rebound phenomenon” consisting of excessive bone resorption, associated with new incident vertebral fractures (VFx) [8–10].

## 2. Rebound phenomenon

### 2.1. Description of the phenomenon

In contrast to bisphosphonates, denosumab does not possess remanent properties [11]. Over the last decade, a number of reports have highlighted a “rebound phenomenon” after denosumab discontinuation, associating [10]:

* rapid and important increase in bone turnover, with elevated marker levels usually within the first six months off-treatment, above baseline levels;

* decrease in BMD, especially at lumbar spine;

* an unexpected increased risk of (multiple) VFx.

In the post hoc analysis of the FREEDOM trial and its extension, the annualized risk of VFx was 7.1%, with a 3.4% risk of multiple vertebral fractures [10]. Additional observational studies showed a similar incidence of VFx (from 8.5 to 10.5%) [12,13]. Rebound phenomenon is significant during the first 12 months off-treatment (18 months after the last injection), generally with a peak occurring at six months off-treatment [14]. The first VF occurs on average

<footnote><sup>a</sup> Rheumatology Department, CHU de Toulouse, université de Toulouse, Toulouse, France</footnote>

<footnote><sup>b</sup> Institut toulousain des maladies infectieuses et inflammatoires, Inserm U1291, Toulouse, France</footnote>

<footnote>* Corresponding author: Service de rhumatologie, hôpital Pierre-Paul-Riquet, CHU Purpan, TSA 40031, 31059 Toulouse cedex 9, France.
E-mail address: Degboe.y@chu-toulouse.fr (Y. Degboé).</footnote>
<table><caption>**Table 1**
Main risk factors associated with vertebral fractures at denosumab withdrawal.</caption><thead><tr><th>Risk factors</th><th>References</th></tr></thead><tbody><tr><td>Factors related to the patient's physiology</td><td></td></tr><tr><td>Prevalent vertebral fractures</td><td>[10,14,24,25,30]</td></tr><tr><td>Younger age</td><td>[28-30]</td></tr><tr><td>Higher baseline levels of bone resorption markers (crosslaps)</td><td>[28,29,31]</td></tr><tr><td>Greater gain in hip BMD under denosumab</td><td>[25,30,34]</td></tr><tr><td>Greater gain in lumbar BMD under denosumab</td><td>[33,34]</td></tr><tr><td>Factors related to treatment management</td><td></td></tr><tr><td>Absence of bisphosphonates prior to denosumab</td><td>[14,26]</td></tr><tr><td>Absence of bisphosphonates after denosumab</td><td>[14,25]</td></tr><tr><td>Longer treatment duration with denosumab</td><td>[24,27-30,32,34]</td></tr><tr><td>Longer duration off-therapy</td><td>[10,24]</td></tr><tr><td>Evolution of post-denosumab BMD</td><td></td></tr><tr><td>Greater loss of hip BMD off-therapy</td><td>[14,24,30]</td></tr><tr><td>Rate of BMD loss</td><td>[10,24]</td></tr></tbody></table>

BMD: bone mineral density.

13 months (median 12.0) after the last denosumab injection, and 75% of VFs occur between 6 and 15 months after the last denosumab injection [14]. Importantly, this phenomenon differs from the decrease in BMD observed after teriparatide withdrawal in the absence of an antiresorptive relay [15]. These differ in terms of the intensity of the phenomenon, its pathophysiology and the associated risk of VFx.

Four mechanisms reviewed in [16] are suspected of driving the rebound phenomenon following discontinuation of denosumab. First, RANKL may increase the number of osteoclast precursors and recycled osteoclasts (called osteomorphs), subsequently increasing the potential for bone resorption when therapeutic pressure is stopped (i.e., denosumab withdrawal) [17-19]. Second, RANKL targeting suppresses the production of osteoprotegerin (OPG: a decoy receptor for RANKL and a negative regulator of osteoclastogenesis) production by osteoblasts and osteocytes. The delayed production of OPG after denosumab withdrawal is not sufficient to control osteoclast activity [20,21]. Third, inhibiting RANKL reduces the ability of osteocytes to trigger bone microdamage repair. RANKL is a necessary factor in promoting osteoclast activity at these sites, thus initiating bone remodelling and repairing microcracks [22]. Finally, the ability of the bone tissue to adapt to mechanical strain (mechanostat of Frost) may be disrupted once denosumab has been withdrawn [23].

## 2.2. Risk factors

Table 1 reports the main risk factors identified as explanations for multiple vertebral fractures associated with rebound phenomenon. These factors include: longer denosumab treatment duration (especially when transitioning off-denosumab after more than 2.5 years); longer duration of off-treatment period; the absence of pre- and post-denosumab bisphosphonate treatment; a higher baseline (at denosumab discontinuation) level of the bone resorption marker crosslaps (CTX; which correlates with duration of denosumab treatment), younger age; history of prevalent VFx; greater BMD gain during treatment; greater hip BMD loss off-therapy; and BMD loss rate [10,14,24-34]. Factors most robustly associated with subsequent multiple VFx were the absence of prior bisphosphonate treatment, the presence of prior VFx, longer off-treatment (denosumab) and longer on-treatment durations, and the rate of hip BMD loss after denosumab discontinuation. Interestingly, several case reports have documented the occurrence of severe hypercalcemia, and even vertebral fractures, following discontinuation of denosumab in patients with primary

hyperparathyroidism. This suggests that clinicians should be vigilant about underlying calcium-phosphate metabolism disorders, as these may influence the expression of the rebound phenomenon.

## 3. Post-denosumab regimen

The optimal strategy for mitigating the rebound phenomenon and the risk of VFx after denosumab withdrawal is still matter of debate. Various treatment regimens have been assessed in this view (see Fig. 1).

### 3.1. Zoledronic acid

In line with the pathophysiology of the rebound phenomenon, one objective is to control the overshoot of bone resorption following denosumab withdrawal. To date, when the maintenance of denosumab is not considered, the European Calcified Tissue Society (ECTS) proposes bisphosphonates as antiresorptive bridging therapy [30]. Importantly, dedicated studies (mostly retrospective studies, with a few randomized controlled trials) show discrepancies regarding the protective effect. These discrepancies are mostly related to the heterogeneity in bridging therapy protocol (type of bisphosphonates, treatment duration, dosage, initiation date, etc.) and in the intrinsic risk of the rebound phenomenon and multiple VFx in the studied population (see Table 1) [14,25,28,29,32,35-42]. Given its strong antiresorptive properties, zoledronic acid (ZOL) is the most widely studied candidate for a bridging therapy following the discontinuation of denosumab. ZOL appears to be effective in patients who are at low risk: it stabilizes BMD, maintains the suppression of bone remodelling markers, and controls the risk of multiple VFx. However, this strategy only partially mitigates the risk of multiple VFx and of bone loss in patients at high risk [28,37,41,42]. Most data showed that ZOL was less effective in maintaining BMD when previous denosumab treatment had exceeded 2.5 years. The study with the best methodological level showed that ~40% patients failed to maintain spine BMD six months after their first ZOL infusion, ~60% failed maintain spine BMD 12 months after their first ZOL infusion, and two patients (3.3%) experienced incident VFx during the study [28].

The added value of multiple zoledronate infusions has been explored in two retrospective studies following an algorithm based on the ECTS position statement, and in a murine model [33,34,43]. These studies highlighted that:

* repeated infusions may be useful for patients at high risk of VFx and BMD loss;

* some patients need up to three ZOL infusions to get the rebound phenomenon under control;

* that high bone turnover markers predict BMD loss at the lumbar spine.

### 3.2. Oral bisphosphonates

Data about alendronate and risedronate as treatments following denosumab withdrawal are both limited and heterogeneous [26,39,40,44-46]. Alendronate successfully preserves BMD after short-term use of denosumab (12 months) and multiple VFx are not reported in such cases [39,44,46]. After longer exposures to denosumab, risedronate was less potent than alendronate and ZOL at preventing BMD loss [40,45]. Short-term use of risedronate (35 mg gastro-resistant for three months) did not prevent BMD loss when patients were transitioning from denosumab [26].
<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Efficacy in preventing rebound phenomenon and associated vertebral fractures according to the level of evidence.</figcaption></figure>

### 3.3. Teriparatide

Transition from denosumab to teriparatide was assessed by the DATA-Switch study [47]. In this study, first-line treatment lasted two years. Transitioning from teriparatide to denosumab and combination therapies was beneficial with regard to BMD. Transitioning from denosumab to teriparatide, however, resulted in transient bone loss at the hip and spine as well as progressive bone loss at the radius shaft. As such, switching from denosumab to teriparatide should be avoided.

### 3.4. Raloxifene

Raloxifene is a selective oestrogen receptor modulator (SERM) with antiresorptive activity. Its use has been proposed as an alternative to bisphosphonates following denosumab treatment in two retrospective observational studies (after an average 2.5 injections of denosumab; range 2–5) and one open-label randomized controlled trial (after two injections of denosumab) [44,48,49]. In the retrospective studies, raloxifene was not effective in preventing rebound phenomenon and new VFx, especially in patients at high risk (e.g., with a history of vertebral fractures or low BMD before denosumab) [48,49]. Conversely, in the CARD open-label study, the authors did not observe an overshoot in bone remodelling: instead, CTX and PINP levels increased gradually before returning to baseline levels over 6 to 12 months. Raloxifene partially preserved spine and hip BMD [44]. Such divergences may be linked to the duration of denosumab exposure, which tends to be longer in the retrospective studies. These works suggest that the antiresorptive properties of raloxifene are insufficient to control rebound phenomenon in cases when denosumab has been used for longer than two years.

### 3.5. Romosozumab

Romosozumab is an anti-sclerostin antibody with dual osteoanabolic and antiresorptive effects that reduces fracture risk within 12 months. A few studies and case reports had explored its effects on the bone in patients transitioning from denosumab sequentially [50–55]. When transitioning from short-term denosumab (12 months), patients' lumbar BMD improved while their hip BMD remained the same [53]. However, 2 out of 16 patients experienced a significant loss in hip BMD. In a larger study of 259 osteoporotic patients, when focusing on the subgroup of 40 patients who had been pre-treated with denosumab, romosozumab efficacy was negatively affected by the duration of previous therapy [54]. Spine BMD gain was significant but lower in patients who

had been pre-exposed to more than one year of denosumab (average 32 months). No significant changes were observed at the hip, regardless of prior exposure to denosumab. No rebound-associated VFx were reported. Another study including 45 patients switching from denosumab (among 148 patients) confirmed that the efficacy of romosozumab was affected by prior treatment, with similar trends regarding BMD [50]. The authors reported multiple vertebral fractures in a patient whose romosozumab treatment had been initiated nine months after their last denosumab infusion [50,51].

In addition, a case series of three patients depicted an alternative treatment regimen with an "overlapping sequential approach" [56]. Romosozumab was initiated three months after the last denosumab injection to ensure an anabolic effect before the bone resorption overshoot. Denosumab was then restarted 6 months after romosozumab initiation to blunt the increase in bone turnover. This strategy achieved important BMD gain. Another study suggested that the benefits of romosozumab and denosumab are similar and overlap [55]. Although the results are promising, this strategy still needs to be validated through larger, controlled studies. The rebound phenomenon must also be assessed in the longer term and after a potential second course of denosumab.

Whether romosozumab treatment following denosumab is a safe and effective way to control the rebound phenomenon remains unclear. When initiated after a short duration of denosumab, the efficacy of romosozumab seems partly diminished, but without major risk of multiple VFx. On the contrary, its use after long-term denosumab is not supported by current data, and additional studies are needed to explore its efficacy in such cases.

### 3.6. Progressive withdrawal

In an attempt to attenuate rebound phenomenon at denosumab withdrawal, some authors have evaluated progressively withdrawing denosumab by gradually reducing doses. This strategy has proven ineffective in preventing rebound phenomenon both from a clinical and from a pharmacokinetic-pharmacodynamic point of view [57,58]. However, in line with the phase II study, maintaining a low dose (15 mg) of denosumab was sufficient to prevent complete BMD loss and to keep CTX levels low.

## 4. Management of denosumab discontinuation

### 4.1. Bone remodelling markers

An increase in serum tartrate-resistant acid phosphatase (TRAP) and RANKL appears to be an early marker of the rebound phe-
<figure><img src="image_6.png" /><figcaption>**Fig. 2.** Proposed strategy to manage denosumab discontinuation. CTX: crossslaps; ZOL: zoledronic acid; *: consider repeated ZOL infusions if CTX are > 300–400 pg/mL 3 or 6 months after the first ZOL infusion in patients at high risk.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Fig. 3.** Proposed timeline for monitoring. CTX: crossslaps; DXA: osteodensitometry; ZOL: zoledronic acid; *: in case oral bisphosphates relay therapy, consider a use ≥ 12 months.</figcaption></figure>

nomenon, even preceding associated bone loss [17]. However, these are not accessible in routine practice.

Among the available biological tools in routine practice, CTX levels are a suitable biomarker of bone remodelling overshoot and its consequences. The level of CTX at the time of denosumab discontinuation is correlated with lumbar spine BMD changes [28,32,33]. In one study, a value of 453 ng/L (or pg/mL) represented the best cut-off compromise to discriminate patients who are susceptible to worsened BMD from those with stable BMD (sensitivity 78%; specificity 67%) [33].

Persistent elevated CTX levels are associated with bone loss and VFx. Consequently, elevated CTX levels after post-denosumab bridging therapy are in favour of an increased risk of bone loss. Two observational studies showed that, six months after the first ZOL infusion, the average CTX level in patients who maintained BMD was close to 400 ng/L (ranging from 336 to 412 ng/L) [33,59]. A lower CTX threshold, < 212 ng/L six months after first ZOL infusion identified patients with stable BMD during follow-up with 100% sensitivity [33].

## 4.2. Current guidelines

The recommended management of denosumab discontinuation is currently based on the ECTS position statement published in 2021 [30]. The major points to consider are denosumab duration and stratification of fracture risk (Fig. 2).

In patients transitioning from short-term denosumab treatment (i.e., up to five injections) and with low fracture risk, oral bisphosphonates or ZOL for 12 to 24 months are proposed and need to

be adapted to bone turnover markers and BMD evolution. Oral Bisphosphonates should be started six months after last denosumab injection and used for at least one year. Recent data highlight that bone turnover markers potentially need to be monitored in patients who had undergone short-term denosumab therapy and have a high fracture risk [33].

In patients transitioning from long-term denosumab treatment (i.e., more than five injections) and/or with high fracture risk, ZOL treatment should be considered a priority. ZOL should be started six months after last denosumab injection, with repeated monitoring of bone turnover markers to identify the need for additional ZOL infusion (Fig. 3). A pragmatic approach is to propose CTX assessment at least three and six months after ZOL infusion. Prolonged monitoring should be considered in patients with high risk of rebound phenomenon. Based on recent data, repeated ZOL infusion should be proposed in patients with CTX ≥ 300–400 ng/L after first ZOL infusion [33,59]. A CTX value < 212 ng/L six months after first ZOL infusion appears to be a strong marker of later BMD stability [33]. However, it is important to note that guiding retreatment with ZOL based on this lower threshold may carry a risk of overtreatment. Patients with low CTX level at 6 months have a minimal risk of rebound phenomenon and may not need prolonged CTX monitoring.

In cases in which a CTX measurement is not available, a second ZOL infusion six months after the first should be considered in the high-risk group of patients. When ZOL is not an option, possible alternatives include oral bisphosphonates (especially alendronate) for 12 to 24 months or denosumab continuation for up to 10 years.

DXA should be performed at year one off-denosumab.
In case of incident VFx one to two years following the withdrawal of denosumab, vertebroplasty and monotherapy with teriparatide should be avoided while re-initiating denosumab treatment might be considered. In rare cases, a combination of denosumab and teriparatide for two years followed by zoledronate might be considered, but there are not sufficient data at present to support this strategy [30,60].

## 5. Conclusion

The rebound phenomenon and the associated multiple VFx pose a challenge to discontinuing denosumab. Post-denosumab treatment is necessary. Carefully evaluating fracture risk and monitoring bone turnover markers, such as CTX, represent the cornerstones of the management of denosumab withdrawal. For high-risk populations, repeated ZOL infusions should be considered.

## Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

## Disclosure of interest

The authors declare that they have no competing interest.

## References

[1] Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361(8):756-65.

[2] Bone HG, Wagman RB, Brandi ML, 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(7):513-23.

[3] Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 2004;19(7):1059-66.

[4] Eastell R, Christiansen C, Grauer A, et al. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res 2011;26(3):530-7.

[5] Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 2009;24(1):153-61.

[6] Brown JP, Reid IR, Wagman RB, et al. Effects of up to 5 years of denosumab treatment on bone histology and histomorphometry: the FREEDOM study extension. J Bone Miner Res 2014;29(9):2051-6.

[7] Briot K, Roux C, Thomas T, et al. 2018 update of French recommendations on the management of postmenopausal osteoporosis. Joint Bone Spine 2018;85(5):519-30.

[8] Anastasilakis AD, Polyzos SA, Makras P, et al. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res 2017;32(6):1291-6.

[9] Boonen S, Ferrari S, Miller PD, et al. Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk-a perspective. J Bone Miner Res 2012;27(5):963-74.

[10] Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 2018;33(2):190-8.

[11] Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab 2011;96(4):972-80.

[12] McClung MR, Wagman RB, Miller PD, et al. Observations following discontinuation of long-term denosumab therapy. Osteoporos Int 2017;28(5):1723-32.

[13] Zanchetta MB, Boailchuk J, Massari F, et al. Significant bone loss after stopping long-term denosumab treatment: a post FREEDOM study. Osteoporos Int 2018;29(1):41-7.

[14] Burckhardt P, Faouzi M, Buclin T, et al. Fractures after denosumab discontinuation: a retrospective study of 797 cases. J Bone Miner Res 2021;36(9):1717-28.

[15] Lindsay R, Scheele WH, Neer R, et al. Sustained vertebral fracture risk reduction after withdrawal of teriparatide in postmenopausal women with osteoporosis. Arch Intern Med 2004;164(18):2024-30.

[16] Ferrari S, Langdahl B. Mechanisms underlying the long-term and withdrawal effects of denosumab therapy on bone. Nat Rev Rheumatol 2023;19(5):307-17.

[17] Kim AS, Taylor VE, Castro-Martinez A, et al. Temporal patterns of osteoclast formation and activity following withdrawal of RANKL inhibition. J Bone Miner Res 2024;39(4):484-97.

[18] McDonald MM, Khoo WH, Ng PY, et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 2021;184(5):1330-47.e13.

[19] Schini M, Gossiel F, Saini T, et al. The effects of denosumab on osteoclast precursors in postmenopausal women: a possible explanation for the overshoot phenomenon after discontinuation. J Bone Miner Res 2025;40(3):301-6.

[20] El-Masri BM, Andreasen CM, Laursen KS, et al. Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect. Bone Res 2024;12(1):62.

[21] Fu Q, Bustamante-Gomez NC, Reyes-Pardo H, et al. Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation. JCI Insight 2023;8(18):1-15.

[22] Nakashima T, Hayashi M, Fukunaga T, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011;17(10):1231-4.

[23] Hart NH, Nimphius S, Rantalainen T, et al. Mechanical basis of bone strength: influence of bone material, bone structure and muscle action. J Musculoskelet Neuronal Interact 2017;17(3):114-39.

[24] Cosman F, Huang S, McDermott M, et al. Multiple vertebral fractures after denosumab discontinuation: FREEDOM and FREEDOM extension trials additional post hoc analyses. J Bone Miner Res 2022;37(11):2112-20.

[25] Everts-Graber J, Reichenbach S, Gahl B, et al. Risk factors for vertebral fractures and bone loss after denosumab discontinuation: a real-world observational study. Bone 2021;144:115830.

[26] Laroche M, Couture G, Ruyssen-Witrand A, et al. Effect of risedronate on bone loss at discontinuation of denosumab. Bone Rep 2020;13:100290.

[27] Popp AW, Varathan N, Buffat H, et al. Bone mineral density changes after 1 year of denosumab discontinuation in postmenopausal women with long-term denosumab treatment for osteoporosis. Calcif Tissue Int 2018;103(1):50-4.

[28] Solling AS, Harslof T, Langdahl B. Treatment with zoledronate subsequent to denosumab in osteoporosis: a randomized trial. J Bone Miner Res 2020;35(10):1858-70.

[29] Solling AS, Harslof T, Langdahl B. Treatment with zoledronate subsequent to denosumab in osteoporosis: a 2-year randomized study. J Bone Miner Res 2021;36(7):1245-54.

[30] Tsourdi E, Zillikens MC, Meier C, 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.

[31] Uebelhart B, Rizzoli R, Ferrari SL. Retrospective evaluation of serum CTX levels after denosumab discontinuation in patients with or without prior exposure to bisphosphonates. Osteoporos Int 2017;28(9):2701-5.

[32] Makras P, Appelman-Dijkstra NM, Papapoulos SE, et al. The duration of denosumab treatment and the efficacy of zoledronate to preserve bone mineral density after its discontinuation. J Clin Endocrinol Metab 2021;106(10):e4155-62.

[33] Grassi G, Ghielmetti A, Zampogna M, et al. Zoledronate after denosumab discontinuation: is repeated administrations more effective than single infusion? J Clin Endocrinol Metab 2024;109(10):e1817-26.

[34] Laursen N, Solling AS, Harslof T, et al. Clinical experience with denosumab discontinuation. Osteoporos Int 2025;36(3):435-46.

[35] Everts-Graber J, Reichenbach S, Gahl B, et al. Effects of zoledronate on bone mineral density and bone turnover after long-term denosumab therapy: observations in a real-world setting. Bone 2022;163:116498.

[36] Laroche M, Couture G, Ruyssen-Witrand A, et al. Effect of risedronate on bone loss at discontinuation of denosumab. Bone Rep 2020;13:100290.

[37] Anastasilakis AD, Papapoulos SE, Polyzos SA, et al. Zoledronate for the prevention of bone loss in women discontinuing denosumab treatment. A prospective 2-year clinical trial. J Bone Miner Res 2019;34(12):2220-8.

[38] Freemantle N, Satram-Hoang S, Tang ET, et al. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int 2012;23(1):317-26.

[39] Tsai JN, Jordan M, Lee H, et al. One versus 2 years of alendronate following denosumab: the CARD extension. Osteoporos Int 2024;35(12):2225-30.

[40] Ha J, Jung KY, Kim KJ, et al. Effects of sequential anti-resorptive agents on bone mineral density following denosumab withdrawal: a multicenter real-world study in Korea (MAXCARE study). Endocrinol Metab (Seoul) 2025;1-11 [ahead of print].

[41] Everts-Graber J, Reichenbach S, Ziswiler HR, et al. A single infusion of zoledronate in postmenopausal women following denosumab discontinuation results in partial conservation of bone mass gains. J Bone Miner Res 2020;35(7):1207-15.

[42] Grassi G, Chiodini I, Palmieri S, et al. Bisphosphonates after denosumab withdrawal reduce the vertebral fractures incidence. Eur J Endocrinol 2021;185(3):387-96.

[43] Kim AS, Taylor VE, Castro-Martinez A, et al. Early and multiple doses of zoledronate mitigates rebound bone loss following withdrawal of receptor activator of nuclear factor kappa-B ligand inhibition. J Bone Miner Res 2025;40(3):413-27.

[44] Ramchand SK, Tsai JN, Lee H, et al. The comparison of alendronate and raloxifene after denosumab (CARD) study: a comparative efficacy trial. Osteoporos Int 2024;35(2):255-63.
[45] Tutaworn T, Nieves JW, Wang Z, et al. Bone loss after denosumab discontinu-
ation is prevented by alendronate and zoledronic acid but not risedronate: a
retrospective study. Osteoporos Int 2023;34(3):573-84.

[46] Kendler D, Chines A, Clark P, et al. Bone mineral density after transitioning from denosumab to alendronate. J Clin Endocrinol Metab 2020;105(3):pe255-64.

[47] Leder BZ, Tsai JN, Uihlein AV, et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet 2015;386(9999):1147-55.

[48] Ebina K, Hashimoto J, Kashii M, et al. Effects of follow-on therapy after denosumab discontinuation in patients with postmenopausal osteoporosis. Mod Rheumatol 2021;31(2):485-92.

[49] Ha J, Kim J, Jeong C, et al. Effect of follow-up raloxifene therapy after denosumab discontinuation in postmenopausal women. Osteoporos Int 2022;33(7):1591-9.

[50] Ebina K, Tsuboi H, Nagayama Y, et al. Effects of prior osteoporosis treatment on 12-month treatment response of romosozumab in patients with post-menopausal osteoporosis. Joint Bone Spine 2021;88(5):105219.

[51] Kashii M, Ebina K, Kitaguchi K, et al. Romosozumab was not effective in pre-
venting multiple spontaneous clinical vertebral fractures after denosumab
discontinuation: a case report. Bone Rep 2020;13:100288.

[52] Krikelis M, Gazi S, Trovas G, et al. Progression of multiple vertebral fractures after denosumab discontinuation under treatment with romosozumab. A case-report. Joint Bone Spine 2024;91(5):105754.

[53] McClung MR, Bolognese MA, Brown JP, et al. Skeletal responses to romosozumab after 12 months of denosumab. JBMR Plus 2021;5(7):e10512.

[54] Tominaga A, Wada K, Okazaki K, et al. Effect of the duration of previous osteoporosis treatment on the effect of romosozumab treatment. Osteoporos Int 2022;33(6):1265-73.

[55] Piasentier A, Fanti A, Birtolo MF, et al. Early administration of romosozumab prevents rebound of bone resorption related to denosumab withdrawal in fractured post-menopausal women: a real-world prospective study. J Endocrinol Invest 2025;48(5):1249-56.

[56] Kumar S, Gild ML, McDonald MM, et al. A novel sequential treatment approach between denosumab and romosozumab in patients with severe osteoporosis. Osteoporos Int 2024;35(9):1669-75.

[57] Laroche M, Couture G, Degboe Y. Discontinuation of denosumab: gradual decrease in doses preserves half of the bone mineral density gain at the lumbar spine. JBMR Plus 2023;7(7):e10731.

[58] Martinez-Reina J, Calvo-Gallego JL, Martin M, et al. Assessment of strategies for safe drug discontinuation and transition of denosumab treatment in PMO-insights from a mechanistic PK/PD model of bone turnover. Front Bioeng Biotechnol 2022;10:886579.

[59] Liebich G, Lamy O, Aubry-Rozier B, et al. Maintenance of bone resorption markers in the low premenopausal range during the year following denosumab discontinuation is associated to bone density preservation. The ReoLaus study. Bone 2023;172:116764.

[60] Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 2013;382(9886):50-6.