The aims of ZOLARMAB2 are fourfold. First, the investigators want to investigate if multiple infusions of zoledronate can prevent the rebound activation of bone turnover and the subsequent bone loss in patients previously treated with denosumab and if there is difference between infusing zoledronate at fixed time-points after the last injection of denosumab or when bone turnover is increased.

Second, the investigators want to investigate if bone loss will resume after controlling the rebound activation of bone turnover during the first year after denosumab discontinuation and if this can be prevented by yearly infusions of zoledronate.

Third, the investigators want to investigate the underlying pathophysiological mechanisms by investigating biochemical markers, osteoclast and osteoblast activation signals in the bone and bone marrow, and the pool of preosteoclasts/mature osteoclasts before and after treatment with zoledronate.

Fourth, the investigators want to investigate the effect of denosumab discontinuation on muscle mass and muscle strength and on insulin sensitivity.

This study has two parts. The first part (year 1) is a randomized open label, interventional study in 200 postmenopausal women investigating if treatment with zoledronate prevents bone loss after denosumab treatment. Zoledronate will be administered as an infusion six months after the last injection of denosumab followed by zoledronate infusions 3 and 6 months thereafter (groups 3+4) or followed by zoledronate infusions when bone turnover is increased (p-carboxy-terminal collagen crosslinks (p-CTX) > 0.4 ug/l which corresponds to the upper 50 % of the normal range for premenopausal women) (groups 1+2). Fifty patients will be randomised to each group. The patients in groups 1+2 will be monitored and if (p-CTX) is above 0.4 ug/l at month 3 or 6 zoledronate will be administered. If a patient in groups 3+4 experiences an osteoporotic clinical vertebral or hip fracture, zoledronate will be administered irrespective of p-CTX.

The second part is a 2-year randomised, double-blind, interventional study in the women completing part 1. Patients in groups 1+3 will receive yearly infusions of zoledronate 5 mg and patients in groups 2+4 will receive yearly infusions of placebo.

The patients will be monitored with DXA of the hip and spine 3, 6, 12, 24, and 36 months after baseline. Zoledronate will be administered to the patients allocated to the placebo group during phase 2 if BMD decreases more than 5% at the lumbar spine, total hip or femoral neck after months 12.

Inclusion Criteria:

• Postmenopausal women (postmenopausal for at least two years)
• Age ≥ 40 years
• Treatment for at least two years with denosumab
• Last denosumab injection less than six months ago
• At least 2 lumbar vertebrae that can be evaluated by DXA

Exclusion Criteria:

• Low-energy vertebral fracture within the last ten years
• Multiple low-energy vertebral fractures (> 3) at any time
• Low-energy hip fracture within the last 12 months
• BMD T-score < -2.5 (lumbar spine, total hip or femoral neck)
• Zoledronate treatment for more than three years prior to denosumab treatment within the last ten years
• Alendronate treatment for more than three years prior to denosumab treatment within the last five years or for more than five years within the last 10 the years
• Treatment with other bisphosphonates (risedronate, ibandronate) for more than three years prior to denosumab treatment within the last five years
• Diabetes Mellitus
• Ongoing treatment with systemic glucocorticoids
• Metabolic bone disease (for example osteogenesis imperfecta, Paget's disease of bone)
• Hormone replacement therapy
• Active cancer within the last 5 years with the exception of basal cell skin cancer
• Estimated glomerular filtration rate (eGFR) ≤ 35 mL/min
• Contraindications for zoledronate according to the SPC
• Unable to read and understand Danish
• Immobility