jbm > Volume 29(4); 2022 > Article
Inojosa, Mendes, Bandeira, and Bandeira: The Role of Bisphosphonates Prior to Denosumab Treatment on Rebound Fractures: A Mini Review


Denosumab is a potent anti-resorptive medication used to treat patients at high risk for osteoporosis; however, its beneficial effects on the skeletal system are quickly reversed after discontinuation. In contrast, bisphosphonates (BPs) are anti-resorptive agents with residual effects on the bone matrix; thus, these are capable of preserving bone mass for a long time. Therefore, subsequent anti-resorptive treatment with BPs is mandatory to prevent rebound fractures. Furthermore, BP administration before denosumab treatment appears to be a reasonable strategy for reducing hyperactivation of bone remodeling. In this review, we summarize the effects of BP administration before denosumab treatment in preventing rebound fractures after denosumab discontinuation.



Anti-resorptive agents are still used as first-line treatment of osteoporosis.[1,2] Although denosumab (DMAB) can increase bone mineral density (BMD) and reduce fractures at all skeletal locations, its effects reverse quickly once treatment is discontinued.[3,4] Thus, strategies to prevent rebound fractures are urgently required. One of those strategies is the use of bisphosphonates (BPs).
In this review, we summarize the most recent evidence regarding the effects of BPs after, and especially before, DMAB treatment on several aspects of bone status to prevent rebound fractures after DMAB discontinuation.


The study was conducted using relevant articles searched using Medical Subject Terms and Keywords (MeSH), such as DMAB discontinuation, rebound fractures, and prior BP use. These articles were included in PubMed and Cochrane library and were published in English up to September 2021. The term DMAB discontinuation was matched with the following terms: osteoporosis, BPs, rebound fractures, bone turnover markers (BTMs), and BMD.
We included cohort studies, case-control studies, cross-sectional studies, case reports, case series, and review articles that discussed prior BP use to rebound fractures after DMAB discontinuation. Non-English language publications, studies without primary outcomes relating to the main theme, or articles that cited DMAB as a treatment for other pathological conditions were excluded.


BPs and DMAB are the most widely utilized treatments for postmenopausal osteoporosis. Both substances are anti-resorptive and function by slowing down the rate of remodeling and inhibiting osteoclastic activity, therefore preventing bone resorption.[1] BPs act by inhibiting farnesyl-pyrophosphate synthase, an important enzyme for osteoclast function and survival,[1] while DMAB is a monoclonal antibody with a high affinity for the activating receptor activator of nuclear factor-κB ligand (RANKL), preventing RANKL to bind to RANK.[5-7] Among the BPs, alendronate (ALE) and zoledronate (ZOL) can be absorbed into the bone matrix for a long time, thus having a residual and even permanent effect.[1,2]
Although there have been reports of vertebral fractures linked with DMAB withdrawal in recent years,[8-18] the mechanism and risk factors for this phenomenon are still unclear. It is hypothesized that it may be associated with transient increases in bone turnover following its withdrawal,[5,8] resulting in a rebound effect on BTMs, with elevation above baseline and consequent decrease in BMD.[3,5,19]
Those rebound vertebral fractures after DMAB discontinuations are defined as new vertebral fractures associated with minimal trauma or even in the absence of trauma in the context of high bone turnover and rapid bone loss in the lumbar spine. They occur within 3 to 24 months after the discontinuation of a reversible anti-resorptive therapy in the absence of secondary causes of bone loss or fracture.[12]
The most critical period for fractures appears to be the first year of treatment discontinuation. The literature has documented rebound cases between 30 and 1,080 days after the last DMAB injection.[20,21]
Despite reports of multiple vertebral fractures, there is no apparent rise in non-vertebral fractures related to DMAB discontinuation. This could be explained by the fact that the trabecular bone has a faster rate of bone remodeling than the cortical bone, owing to it being more affected by excessive skeletal remodeling after DMAB discontinuation.[20,22] In patients with thin trabeculae, such as patients with osteopenia or osteoporosis, an increase in resorption depth relative to the thickness of the trabeculae may be the reason for the occurrence of a trabecular perforation.[22,23] As opposed to the trabecular bone, osteoclastic bone resorption occurs in tunnels in cortical bone and has shorter remodeling cycles.[24]
The most significant predictors of rebound vertebral fractures following DMAB discontinuation appear to be the occurrence of previous vertebral fractures and fractures occurring during osteoporosis therapy, both of which indicate an already compromised skeleton.[20] In the post hoc analysis reported in 2018, it was investigated if participants who discontinued DMAB during the FREEDOM study and FREEDOM Extensive Trial were at increased risk of developing new fractures or worsening current vertebral fractures.[4,25] Among the 1,471 participants (1,001 DMAB and 470 placeboes) who discontinued treatment (≥2 doses), the rate (95% confidence interval [CI]) of vertebral fractures increased to 7.1 (5.2-9.0) per 100 participants/year but was similar to the rate before and after discontinuation of placebo (7.0 [5.2-8.7] and 8.5 [5.5-11.5] per 100 participants/year, respectively).[4,25] However, the majority of fracture cases included high-risk participants who had previously experienced a vertebral fracture, and there was little information available on their previous treatments. The short follow-up period after treatment imposed restrictions on this analysis (median of 0.5 years).
Previously, it was believed that the risk of rebound increased with an increase in the number of DMAB doses applied. However, in a recent retrospective study of 797 patients, Burckhardt et al. [26] did not find the number of injections as a risk factor for a rebound. On the other hand, Lamy et al. [27] evaluated 5 case series and concluded that, after administering the second dose of DMAB, there was an increased risk of the rebound effect. Bone et al. [3] found that, in patients receiving DMAB for 2 years, the BMD values of the lumbar spine and total hip returned to baseline about one year after discontinuation of the medication. Women treated for a longer period (approximately 10 years) followed by discontinuation of DMAB experienced a reduction in total hip BMD that reached lower levels than the baseline.[28] There are also reports in the literature of patients who had vertebral fractures with discontinuation of DMAB after 2 injections, with no reports of fractures being identified after a single injection.[29]


BPs may help maintain bone mass after DMAB discontinuation. The DATA follow-up study showed that patients receiving immediate anti-resorptive medication, either oral or intravenous BPs, retained the greatest gain in BMD after 4 years of DMAB therapy, which did not occur in a control group.[30] Kondo et al. [31] showed that ZOL had an advantage over BMD and BTM in patients who used DMAB for a maximum of 3 years. The preservation of bone mass gains with ZOL infusion after DMAB has also been reported in other studies [32] and there seems to be no difference between early or late administration of ZOL.[33] Thus, the benefit of an anti-resorptive therapy following DMAB in reducing the recovery of BTMs, and the consequent decrease in the risk of clinical fractures, appears to be well-established in the literature.[3,5,31-34]
However, only a few retrospective studies have evaluated the impact of BPs usage prior to DMAB on rebound fractures (Table 1). It has been suggested that the administration of BPs before treatment with DMAB also reduces BTMs, which consequently decreases the risk of rebound fractures.[3,35] Because some BPs present a prolonged residual effect on the bone matrix, they might contribute to the reduction of bone resorption that occurs after DMAB discontinuation, thereby reducing the risk of rebound fractures.[23]
In one study, 37 patients who had previously had BP treatment were retrospectively evaluated for BTMs. This was followed by sequential DMAB therapy.[36] The authors found lower serum C-terminal telopeptide (CTX) following DMAB discontinuation compared to patients who were not previously treated with BPs.[36] In another retrospective study, Anastasilakis et al. [35] found that the group who had taken ZOL for one year prior to DMAB had been able to suppress the increase of CTX up to one year. These findings reflect the rapid reversal of the biological effects of DMAB after its discontinuation and contrast with the residual skeletal effects of BPs.[24,37] Thus, monitoring BTMs following discontinuation of treatment would enable the identification of patients with a higher risk of vertebral fracture, thereby enabling the possibility of making better future therapeutic decisions.
However, regarding the prevention of bone loss after DMAB withdrawal, the benefits of prior BPs usage are still unclear. Six retrospective studies evaluated the effect of previous use of BPs on BMD in DMAB rebound [10,14,26, 38-40] but only one found an improvement in BMD with previous use of BPs.[26] The lack of details on BPs treatment duration and subsequent DMAB duration and number of injections given make these observations inconclusive (Table 1). For example, Aubry-Rozier et al. [39] conducted an observational study with 71 postmenopausal women to monitor the effects of BMD after DMAB discontinuation. However, 9% of patients had taken corticosteroids and about 23% had used aromatase inhibitors, which can be an important factor in increasing bone resorption.
Likewise, Tripto-Shkolnik et al. [14] reported a case series of high-risk patients with osteoporosis and multiple vertebral fractures after discontinuing DMAB despite prolonged prior exposure to BPs. Data were collected by phone from patients of different hospitals. They identified eight elderly women with multiple vertebral fractures, most spontaneous. The way the data were collected may well be subject to several information biases, including data on the time of BPs use, time since DMAB was stopped, and data on BTMs and BMD.[14]
In another retrospective study, Tripto-Shkolnik et al. [40] evaluated 1,380 postmenopausal women of whom 1,069 had used BPs for up to 15 years prior to the use of DMAB. The rate of osteoporotic fracture per 100 patients/year was higher in the group with previous use of BPs compared to the group without previous use, although the results were not statistically significant (relative risk, 1.67; 95% CI, 0.8-3.48).[40]
Burckhardt et al. [26] evaluated 797 patients who had discontinued the use of DMAB. The study aimed to assess risk factors for rebound and one of the conclusions was that prior treatment with BPs appeared to have only a small protective effect in preventing vertebral fractures compared to treatment after DMAB discontinuation. In this study, ibandronate was given in 27,3%, ALE in 25,7%, ZOL in 7,7%, and risedronate in 4,4%. However, there was no comparison between groups of patients with or without vertebral fractures, which limits the results of the study. In addition, only 47% of patients had previously used BPs and there were no details about treatment duration.


Rebound vertebral fractures after DMAB withdrawal is still a major concern. The studies on rebound fractures with DMAB according to previous BPs use have several limitations, including retrospective design, small sample size, the lack of timing on BPs initiation and duration of treatment. Considering these factors, it seems possible that BPs prior to DMAB could attenuate the hyperactivation of bone remodeling.


The authors would like to thank the entire UED-HAM (Unidade de Endocrinologia e Diabetes, Hospital Agamenom Magalhães), University of Pernambuco, Recife, Brazil, for providing us with the data and for allowing us to carry out the research.


Ethics approval and consent to participate

Not applicable.

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Table 1
Studies that evaluated any effects of BPs treatment prior to DMAB on BTMs, BMD and vertebral fractures after DMAB discontinuation
References Type of study Patients (N) Patients previously treated with BPs (N) Duration of BPs treatment (yr) DMAB injections DMAB discontinuation (days) Effect on BTMs Effect on BMD Prevented vertebral fractures?
Uebelhart et al. [36] Retrospective, case series 37 17 0.9-15 3.6-4.4 30-1,080 Prevented increase in CTX - -
Anastasilakis et al. [20] Retrospective, case series 24 2 0.6-3 2-10 60-300 - - No
Japelj et al. [41] Retrospective, case series 14 10 - 2-8 - - Didn’t prevent loss of BMD -
Aubry-Rozier et al. [39] Observational 63 12 0.6-11.2 2-14 180-660 - Didn’t prevent loss of BMD -
Tripto-Shkolnik et al. [40] Retrospective, case series 1,380 1,069 0.5-15.8 >2 >270 - - No
Tripto-Shkolnik et al. [14] Case reports 9 7 3-10 2-10 30-450 - Didn’t prevent loss of BMD No
Lamy et al. [15] Case reports 9 1 3 2-10 90-300 - - No
Florez et al. [42] Retrospective, case series 7 4 1-9 5-10 240-600 - - No
Lamy et al. [10] Case reports 2 2 3-4 6-7 240-360 - Didn’t prevent loss of BMD No
Burckhardt et al. [26] Retrospective, case series 797 367 - 6 - - Prevent loss of BMD Yes
Anastasilakis et al. [35] Retrospective, case series 69 30 1 - - Prevented increase in CTX Prevent loss of BMD -

BPs, bisphosphonates; DMAB, denosumab; BTMs, bone turnover markers; BMD, bone mineral density; CTX, C-terminal telopeptide.


1. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int 2014 25:2359-81. https://doi.org/10.1007/s00198-014-2794-2.
crossref pmid pmc
2. Hernlund E, Svedbom A, Ivergård M, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 2013 8:136. https://doi.org/10.1007/s11657-013-0136-1.
crossref pmid pmc
3. 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 96:972-80. https://doi.org/10.1210/jc.2010-1502.
crossref pmid
4. 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 5:513-23. https://doi.org/10.1016/s2213-8587(17)30138-9.
crossref pmid
5. Anastasilakis AD, Makras P, Yavropoulou MP, et al. Denosumab discontinuation and the rebound phenomenon: A narrative review. J Clin Med 2021 10:152. https://doi.org/10.3390/jcm10010152.
crossref pmid pmc
6. Miller PD. A review of the efficacy and safety of denosumab in postmenopausal women with osteoporosis. Ther Adv Musculoskelet Dis 2011 3:271-82. https://doi.org/10.1177/1759720x11424220.
crossref pmid pmc
7. Lorentzon M. Treating osteoporosis to prevent fractures: current concepts and future developments. J Intern Med 2019 285:381-94. https://doi.org/10.1111/joim.12873.
crossref pmid
8. Polyzos SA, Terpos E. Clinical vertebral fractures following denosumab discontinuation. Endocrine 2016 54:271-2. https://doi.org/10.1007/s12020-016-1030-6.
crossref pmid
9. Niimi R, Kono T, Nishihara A, et al. Second rebound-associated vertebral fractures after denosumab discontinuation. Arch Osteoporos 2020 15:7. https://doi.org/10.1007/s11657-019-0676-0.
crossref pmid
10. Lamy O, Fernández-Fernández E, Monjo-Henry I, et al. Alendronate after denosumab discontinuation in women previously exposed to bisphosphonates was not effective in preventing the risk of spontaneous multiple vertebral fractures: two case reports. Osteoporos Int 2019 30:1111-5. https://doi.org/10.1007/s00198-018-04820-8.
crossref pmid
11. Anastasilakis AD, Trovas G, Balanika A, et al. Progression of rebound-associated vertebral fractures following denosumab discontinuation despite reinstitution of treatment: Suppressing increased bone turnover may not be enough. J Clin Densitom 2021 24:338-40. https://doi.org/10.1016/j.jocd.2020.10.014.
crossref pmid
12. Anastasilakis AD, Makras P. Multiple clinical vertebral fractures following denosumab discontinuation. Osteoporos Int 2016 27:1929-30. https://doi.org/10.1007/s00198-015-3459-5.
crossref pmid
13. Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D, et al. Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int 2016 27:1923-5. https://doi.org/10.1007/s00198-015-3380-y.
crossref pmid
14. Tripto-Shkolnik L, Rouach V, Marcus Y, et al. Vertebral fractures following denosumab discontinuation in patients with prolonged exposure to bisphosphonates. Calcif Tissue Int 2018 103:44-9. https://doi.org/10.1007/s00223-018-0389-1.
crossref pmid
15. Lamy O, Gonzalez-Rodriguez E, Stoll D, et al. Severe rebound-associated vertebral fractures after denosumab discontinuation: 9 clinical cases report. J Clin Endocrinol Metab 2017 102:354-8. https://doi.org/10.1210/jc.2016-3170.
crossref pmid
16. Anastasilakis AD, Evangelatos G, Makras P, et al. Magnetic resonance imaging has an advantage over conventional spine X-rays in the evaluation of rebound-associated vertebral fractures following denosumab discontinuation. Endocrine 2020 69:516-8. https://doi.org/10.1007/s12020-020-02333-1.
crossref pmid
17. Anastasilakis AD, Evangelatos G, Makras P, et al. Rebound-associated vertebral fractures may occur in sequential time points following denosumab discontinuation: need for prompt treatment re-initiation. Bone Rep 2020 12:100267. https://doi.org/10.1016/j.bonr.2020.100267.
crossref pmid pmc
18. De Sousa SMC, Jesudason D. Rebound vertebral and non-vertebral fractures during denosumab interruption in a postmenopausal woman. Clin Endocrinol (Oxf) 2019 90:250-2. https://doi.org/10.1111/cen.13867.
crossref pmid
19. Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 2008 43:222-9. https://doi.org/10.1016/j.bone.2008.04.007.
crossref pmid
20. 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 32:1291-6. https://doi.org/10.1002/jbmr.3110.
crossref pmid
21. Geissler JR, Bajaj D, Fritton JC. American Society of Biomechanics Journal of Biomechanics Award 2013: cortical bone tissue mechanical quality and biological mechanisms possibly underlying atypical fractures. J Biomech 2015 48:883-94. https://doi.org/10.1016/j.jbiomech.2015.01.032.
crossref pmid pmc
22. Dempster DW. The contribution of trabecular architecture to cancellous bone quality. J Bone Miner Res 2000 15:20-3. https://doi.org/10.1359/jbmr.2000.15.1.20.
crossref pmid
23. McNamara LM, Prendergast PJ. Perforation of cancellous bone trabeculae by damage-stimulated remodelling at resorption pits: a computational analysis. Eur J Morphol 2005 42:99-109. https://doi.org/10.1080/09243860500096289.
crossref pmid
24. Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem 2010 285:25103-8. https://doi.org/10.1074/jbc.R109.041087.
crossref pmid pmc
25. 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 33:190-8. https://doi.org/10.1002/jbmr.3337.
crossref pmid
26. Burckhardt P, Faouzi M, Buclin T, et al. Fractures after denosumab discontinuation: A retrospective study of 797 cases. J Bone Miner Res 2021 36:1717-28. https://doi.org/10.1002/jbmr.4335.
crossref pmid pmc
27. Lamy O, Stoll D, Aubry-Rozier B, et al. Stopping denosumab. Curr Osteoporos Rep 2019 17:8-15. https://doi.org/10.1007/s11914-019-00502-4.
crossref pmid
28. Popp AW, Buffat H, Senn C, et al. Rebound-associated bone loss after non-renewal of long-term denosumabtreatment offsets 10-year gains at the total hip within 12 months. J Bone Miner Res 2016;31:S408.

29. Koldkjær Sølling AS, Harsløf T, Kaal A, et al. Hypercalcemia after discontinuation of long-term denosumab treatment. Osteoporos Int 2016 27:2383-6. https://doi.org/10.1007/s00198-016-3535-5.
crossref pmid
30. Leder BZ, Tsai JN, Jiang LA, et al. Importance of prompt antiresorptive therapy in postmenopausal women discontinuing teriparatide or denosumab: The Denosumab and Teriparatide Follow-up study (DATA-Follow-up). Bone 2017 98:54-8. https://doi.org/10.1016/j.bone.2017.03.006.
crossref pmid
31. Kondo H, Okimoto N, Yoshioka T, et al. Zoledronic acid sequential therapy could avoid disadvantages due to the discontinuation of less than 3-year denosumab treatment. J Bone Miner Metab 2020 38:894-902. https://doi.org/10.1007/s00774-020-01126-w.
crossref pmid pmc
32. 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 35:1207-15. https://doi.org/10.1002/jbmr.3962.
crossref pmid
33. Anastasilakis AD, Polyzos SA, Yavropoulou MP, et al. Comparative effect of zoledronate at 6 versus 18 months following denosumab discontinuation. Calcif Tissue Int 2021 108:587-94. https://doi.org/10.1007/s00223-020-00785-1.
crossref pmid
34. Laroche M, Couture G, Ruyssen-Witrand A, et al. Effect of risedronate on bone loss at discontinuation of denosumab. Bone Rep 2020 13:100290. https://doi.org/10.1016/j.bonr.2020.100290.
crossref pmid pmc
35. Anastasilakis AD, Polyzos SA, Efstathiadou ZA, et al. Denosumab in treatment-naïve and pre-treated with zoledronic acid postmenopausal women with low bone mass: Effect on bone mineral density and bone turnover markers. Metabolism 2015 64:1291-7. https://doi.org/10.1016/j.metabol.2015.06.018.
crossref pmid
36. 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 28:2701-5. https://doi.org/10.1007/s00198-017-4080-6.
crossref pmid
37. Anastasilakis AD, Tournis S, Yavropoulou MP, et al. Multiple vertebral fractures following denosumab discontinuation: Are we exaggerating? Calcif Tissue Int 2018 103:107-8. https://doi.org/10.1007/s00223-018-0409-1.
crossref pmid
38. Anastasilakis AD, Polyzos SA, Gkiomisi A, et al. Denosumab versus zoledronic acid in patients previously treated with zoledronic acid. Osteoporos Int 2015 26:2521-7. https://doi.org/10.1007/s00198-015-3174-2.
crossref pmid
39. Aubry-Rozier B, Liebich G, Stoll D, et al. Can we avoid the loss of bone mineral density one year after denosumab discontinuation? The ReoLaus Bone Project. Ann Rheum Dis 2019;78:115.

40. Tripto-Shkolnik L, Fund N, Rouach V, et al. Fracture incidence after denosumab discontinuation: Real-world data from a large healthcare provider. Bone 2020 130:115150. https://doi.org/10.1016/j.bone.2019.115150.
crossref pmid
41. Japelj M, Vidmar G, Rajic AS, et al. Bone mineral density decline following denosumab discontinuation might not be attenuated with previous bisphosphonate therapy. Endocrine Abstracts 2018;56:P188.
42. Florez H, Ramírez J, Monegal A, et al. Spontaneous vertebral fractures after denosumab discontinuation: A case collection and review of the literature. Semin Arthritis Rheum 2019 49:197-203. https://doi.org/10.1016/j.semarthrit.2019.02.007.
crossref pmid


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