Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis: A 2-Year Randomized Study

Abstract

Increased bone turnover and rapid bone loss follow discontinuation of denosumab. We investigated the long-term efficacy of zoledronate (ZOL) in maintaining bone mineral density (BMD) after discontinuation of denosumab. In this randomized, open-label, interventional study, we included 61 postmenopausal women and men older than 50 years discontinuing denosumab after 4.6 AE 1.6 years. We administered ZOL 6 months (6 M) or 9 months (9 M) after the last denosumab or when bone turnover had increased (observation group [OBS]). ZOL was readministrated if p-cross-linked C-terminal telopeptide (p-CTX) increased ≥1.26 μg/L or BMD decreased ≥5%. The results after 12 months have previously been published; here we report the outcome after 24 months (ClinicalTrials NCT03087851). Fifty-eight patients completed the study. From 12 to 24 months after the initial ZOL, lumbar spine (LS) BMD was maintained: 0.9 AE 0.9%, 0.4 AE 0.8%, and 0.3 AE 0.7% in the 6 M, 9 M, and OBS groups, respectively (p > .05, no between-group differences). Similarly, total hip (TH) and femoral neck (FN) BMD did not change in any group during year 2. From baseline to 24 months after ZOL, LS BMD decreased by 4.0 AE 0.8%, 4.1 AE 0.8%, and 4.3 AE 1.5% in the 6 M, 9 M, and OBS groups, respectively (p < .001, no between-group differences). Significant bone loss (LS, TH, or FN) was found in all groups 24 months after ZOL: 6 M group: n = 12 (60%), 9 M group: n = 7 (37%), and OBS group: n = 10 (53%). P-CTX did not change significantly during the second year (p > .05, no between-group differences). No patient fulfilled the CTX or fracture criteria for retreatment during year 2; however, 9 patients were retreated at M24 due to BMD loss ≥5%. Two patients sustained a non-vertebral fracture during year 2. Treatment with ZOL subsequent to long-term denosumab did not fully prevent increased bone turnover and bone loss during the first year; however, CTX remained with the reference range and BMD was maintained during the second year.

Osteoclast Recycling and the Rebound Phenomenon Following Denosumab Discontinuation

“…Current approaches following denosumab discontinuation aim to prevent the rebound changes in bone remodelling to avoid bone loss and reduce risk of fractures [ 68 ]. Randomised controlled trials of sequential bisphosphonate, which prevent mature osteoclasts from resorbing bone, have not succeeded in consistently prevent rebound bone loss following denosumab discontinuation [ 77 ]. Sequential treatment with the PTH-analogue teriparatide following denosumab discontinuation leads to accelerated BMD loss [ 78 ].…”

Osteoporosis in men

“…84 Care needs to be taken to ensure adequate intake of calcium and vitamin D as hypocalcaemia is an adverse effect, particularly in patients with chronic kidney disease, so measurement of calcium and creatinine before the 6-monthly injection is advised. After long-term therapy in men and women, stopping denosumab is associated with an overshoot in bone turnover and an increase in the risk of vertebral fractures; the overshoot in bone turnover in men as well as women can be partially prevented by zoledronate, but we don't know if this reduces the risk of vertebral fracture 85 .…”

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: Osteoporosis management

“…Counselling patients regarding this is a prerequisite for its use, and physicians should have a planned exit strategy before initiating this drug. Zoledronate is probably the best drug to transition to after denosumab (58,59,60). Transitioning to parathyroid hormone analogues accelerates bone loss, so is not appropriate.…”