A single infusion of Zoledronic Acid after terminating treatment with Denosumab prevents rebound-fractures and rapid loss of bone mineral densitiy in most, but not all patients treated for Osteoporosis

Introduction:

Discontinuation of denosumab is associated with rapid loss of bone mineral density (BMD) back to baseline and may be associated with an increased risk of rebound fractures, in particular at the spine. No sequential treatment has been established yet on how to prevent either the loss of BMD nor to prevent rebound fractures after discontinuation of denosumab.

Methods:

45 women with postmoenopausal osteoporosis were treated with denosumab 60 mg every 6 months for 2 years and one single infusion of 5 mg zoledronic acid 6 months after the last denosumab injection. Patients were controlled clinically, by DXA and by vertebral fracture assesment before the first denosumab injection, after 2 years and after 4 – 5 years. Subgroup analyses were made for patients with or without prevalent fractures, prior bisphosphonate treatment and BMD gain of > 8% versus < 8%, measured at the lumbar spine.

Results:

2 – 2.5 years after the last denosumab injection 1 vertebral fracture, and 2 peripheral fractures had occurred. Neither overall nor in any oft the subgroup analyses did BMD drop to baseline. At the lumbar spine 60 – 70% of BMD was retained. There was no apparent difference in absolute loss of BMD in patients with BMD gain of > 8% vs. < 8% while treated with denosumab. However, individual patients' BMD, mostly from the subgroup with BMD gain < 8%, dropped back to baseline or even lower, including the one patient who suffered a spontaneous vertebral fracture one year after zoledronic acid. Previous bisphosponate treatment or prevalent fractures had no impact on loss of BMD.

Discussion:

A single infusion of zoledronic acid may prevent rebound fractures of the spine after discontinuaton of denosumab in most but not all patients treated for osteoporosis. This therapeutic strategy also seems to prevent rapid bone loss back to baseline as seen in patients with no subsequent bisphosponate treatment. The amount of BMD loss does not seem to depend on prior bisphosphonate treatment, prevalent fractures or the amount of BMD gained while treated with denosumab. Whereas it seems to be reasonable to switch treatment to bisphosphonates after discontinuation of denosumab, these data also suggest that one single zoledronic acid infusion is no warranty for rapid bone loss or even rebound fractures in every individual patient. Some may need to be treated with bisphosphonates longer than one year. Prospective controlled studies on sequential therapies are needed to resolve this eminent problem.