Romosozumab and denosumab are monoclonal antibodies for the treatment of osteoporosis. Both have a rapid offset of effect resulting in loss of bone density (BMD) gained on-treatment and, in some cases, multiple vertebral fractures following treatment cessation. We recently reported disappointing results from transitioning patients from denosumab to intravenous zoledronate at the time the next denosumab injection is due. The present report re-assesses the role of bisphosphonates following the use of denosumab. In the FRAME trial, osteoporotic women were randomized to romosozumab or placebo for 1 year, then both groups were provided with open-label denosumab for the subsequent 2 years. In women completing this study at our center, we offered treatment with either oral or intravenous bisphosphonates. In the eleven women opting for intravenous treatment, zoledronate was given after a median delay of 65 days from trial-end, in the hope that this might increase skeletal uptake of the drug and, thereby, its efficacy to maintain bone density. In these women, spine BMD was 17.3% above baseline at trial-end, and still 12.3% above baseline a year later, a 73% (CI: 61%, 85%) retention of the treatment benefit. The comparable BMD figures for the total hip were 10.7 and 9.2% above baseline, a 87% (CI: 77%, 98%) retention of treatment effect. In contrast, those not receiving treatment after the conclusion of the FRAME trial lost 80–90% of the BMD gained on-trial in the following 12 months. Women treated with risedronate showed an intermediate response. In the zoledronate group, mean PINP 6 months post-FRAME was 23 ± 4 µg/L and at 12 months it was 47 ± 8 µg/L, suggesting that repeat zoledronate dosing is needed at 1 year to maintain the BMD gains. In conclusion, delaying administration of intravenous bisphosphonate when transitioning from short-term denosumab appears to increase the extent to which the gains in BMD are maintained.
Osteoporosis Anti-resorptives Anabolics DXA Biochemical markers of bone turnover
This is a preview of subscription content, log in to check access.
Supported by the Health Research Council of New Zealand. The authors are grateful to Greg Gamble for statistical advice.
Compliance with Ethical Standards
Conflict of interest
IRR has received research grants and honoraria from Amgen, Novartis, Merck, and Lilly. AMH and BM have nothing to declare.
Human and Animal Rights and Informed Consent
The study was approved by our regional ethics committee.
Bone HG, Bolognese MA, Yuen CK et al (2011) 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 96:972–980CrossRefPubMedGoogle Scholar
Miller PD, Bolognese MA, Lewiecki EM et al (2008) 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 43:222–229CrossRefPubMedGoogle Scholar
Popp AW, Zysset PK, Lippuner K (2016) Rebound-associated vertebral fractures after discontinuation of denosumab—from clinic and biomechanics. Osteoporos Int 27:1917–1921CrossRefPubMedGoogle Scholar
Popp AW, Buffat H, Senn C et al. (2016) Rebound-associated bone loss after non-renewal of long-term denosumab treatment offsets 10-year gains at the total hip within 12 months. J Bone Miner Res 31(suppl):S408Google Scholar
Aubry-Rozier B, Gonzalez-Rodriguez E, Stoll D et al (2016) Severe spontaneous vertebral fractures after denosumab discontinuation: three case reports. Osteoporos Int 27:1923–1925CrossRefPubMedGoogle Scholar
Anastasilakis AD, Polyzos SA, Makras P et al (2017) Clinical features of 24 patients with rebound-associated vertebral fractures following denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. https://doi.org/10.1002/jbmr.3110PubMedGoogle Scholar
Anastasilakis AD, Makras P (2016) Multiple clinical vertebral fractures following denosumab discontinuation. Osteoporos Int 27:1929–1930CrossRefPubMedGoogle Scholar
Lamy O, Gonzalez-Rodriguez E, Stoll D et al (2017) Severe rebound-associated vertebral fractures after denosumab discontinuation: 9 clinical cases report. J Clin Endocrinol Metab 102:354–358CrossRefPubMedGoogle Scholar
Brown JP, Ferrari S, Gilchrist N et al (2016) Discontinuation of denosumab and associated fracture incidence: analysis from FREEDOM and its extension. J Bone Miner Res 31(supp):S32–S33Google Scholar
Freemantle N, Satram-Hoang S, Tang ET et al (2012) Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int 23:317–326CrossRefPubMedGoogle Scholar
Reid IR, Horne AM, Mihov B et al (2017) Bone loss after denosumab: only partial protection with zoledronate. Calcif Tissue Int 101:371–374CrossRefPubMedGoogle Scholar
Lehmann T, Aeberli D (2017) Possible protective effect of switching from denosumab to zoledronic acid on vertebral fractures. Osteoporos Int 28:3067–3068CrossRefPubMedGoogle Scholar
Reid IR (2017) Targeting sclerostin in postmenopausal osteoporosis: focus on romosozumab and blosozumab. Biodrugs 31:289–297CrossRefPubMedGoogle Scholar
McClung MR, Grauer A, Boonen S et al (2014) Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 370:412–420CrossRefPubMedGoogle Scholar
Cosman F, Crittenden DB, Adachi JD et al (2016) Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 375:1532–1543CrossRefPubMedGoogle Scholar
Saag KG, Petersen J, Brandi ML et al (2017) Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 377:1417–1427CrossRefPubMedGoogle Scholar
McClung MR, Chines A, Brown JP et al (2014) Effects of 2 years of treatment with romosozumab followed by 1 year ofdenosumab or placebo in postmenopausal women with low bone mineral density. J Bone Miner Res 29:S53Google Scholar
Eastell R, Christiansen C, Grauer A et al (2011) Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. J Bone Miner Res 26:530–537CrossRefPubMedGoogle Scholar
Grey A, Bolland MJ, Horne A et al (2017) Duration of antiresorptive activity of zoledronate in postmenopausal women with osteopenia: a randomized, controlled multidose trial. CMAJ 189:E1130-E1136CrossRefPubMedPubMedCentralGoogle Scholar
Miller PD, Pannacciulli N, Brown JP et al (2016) Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J Clin Endocrinol Metab 101:3163–3170CrossRefPubMedPubMedCentralGoogle Scholar
Black DM, Delmas PD, Eastell R et al (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822CrossRefPubMedGoogle Scholar
Cummings SR, San Martin J, McClung MR et al (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765CrossRefPubMedGoogle Scholar
Leder BZ, Tsai JN, Jiang LA et al (2017) Importance of prompt antiresorptive therapy in postmenopausal women discontinuing teriparatide or denosumab: the Denosumab and Teriparatide Follow-up study (DATA-Follow-up). Bone 98:54–58CrossRefPubMedGoogle Scholar