Zoledronic Acid to Maintain Bone Mass After Denosumab Discontinuation: AfterDmab

Denosumab, a monoclonal antibody against the receptor activator of nuclear
factor *-* ligand (RANKL), is a potent antiresorptive agent [1] commonly
prescribed in patients with postmenopausal osteoporosis. In phase 3 clinical
studies long-term treatment with denosumab increased bone mineral density (BMD)
continuously with more than 80% of patients with osteoporosis (T-score < -2.5)
attaining BMD values in the range of osteopenia (T-score between-1.0 and -2.5)
or even in the normal range [2]. Such increases are associated with decreases
in fracture risk and raise the possibility of treatment discontinuation.
However, in phase 2 clinical studies, discontinuation of denosumab resulted in
a rebound response of bone turnover markers, which rose above baseline at 3
months and remained elevated until reaching again baseline levels within
approximately 30 months after the last dose. Bone mineral density (BMD) gains
were also lost and BMD values readched original baseline values after 2 years
off-treatment [3, 4]. In contrast, bisphosphonates remain within the skeleton
acting for several months or even years after discontinuation [4] while
maintaining BMD despite the cessation of treatment [5,6]. We hypothesize,
therefore, that a single intravenous dose of the potent bisphosphonate
zoledronic acid after discontinuation of denosumab therapy in patients who have
reached osteopenic or normal BMD values will consolidate the effect of
denosumab on BMD and will prevent bone loss .

1. Primary objective: to investigate changes in BMD of the lumbar spine (LS)
one year after treatment discontinuation in denosumab-treated women and in
denosumab-treated women who received a single infusion of zoledronic acid after
treatment discontinuation.

2. Secondary objective : to investigate Changes in BMD of the femoral neck (FN)
of the non-dominant hip and changes in bone turnover markers and parameters of
bone metabolism throughout the study.

2 year Interventional, parallel assignment, open label, randomized clinical
trial.
Patients will be recruited at the outpatient clinics for Metabolic Bone
Diseases of the 424 General Military Hospital, Thessaloniki, Greece, at the
Department of Endocrinology of the 251 General Airforce and VA Hospital,
Athens, Greece and at the outpatient of the LUMC Center for Bone Quality,
Leiden, the Netherlands
Postmenopausal Caucasian women treated with denosumab who become osteopenic
with treatment (BMD T-score of > -2.5 and < -1.0 at the LS and/or the
non-dominant FN) will be randomly assigned to a single intravenous infusion of
zoledronic acid 5mg (Zol group, n=40) or only calcium/d3 supplements (Denosumab
group, n=40) after discontinuation of the therapy.

Treatment with zoledroninezuur after denosumab discontinuation.

The burden will be minimal. Currently there is no information nor policy about
the follow-up treatment of patients previously treated with denosumab, a
commonly prescribed anti-osteoporotic drug. This study aims to provide more
insight if follow up treatment is needed and integrates with the standard care
of our Co-ordinated Care Trajectory Osteoporosis.