Bone Loss After Romosozumab/Denosumab: Effects of Bisphosphonates

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.