The Comparison of Ibandronate and Zoledronic Acid After Denosumab Discontinuation

Osteoporosis has been recognized by the World Health Organization (WHO) as the second most prevalent global epidemic disease, following coronary heart disease. Untreated osteoporosis may lead to a vicious cycle of recurrent fractures, resulting in disability and even mortality. In clinical practice, antiresorptive agents are commonly used as first-line therapy. Denosumab is widely preferred due to its convenient administration and potent suppression of bone turnover. However, its antiresorptive effect is reversible; discontinuation of denosumab is associated with rebound increases in bone turnover markers (BTMs) and rapid bone mineral density (BMD) loss. Therefore, subsequent antiresorptive therapy is required to prevent fracture occurrence. Zoledronic acid has been shown to effectively suppress post-denosumab rebound bone turnover and is currently considered the standard sequential treatment following denosumab discontinuation.

The objective of this study is to demonstrate that ibandronate, when used as a sequential therapy after denosumab discontinuation, provides protection comparable to zoledronic acid in patients with short-term denosumab exposure (< 3 years). This study aims to generate preliminary clinical evidence to support future trials and to offer an alternative post-denosumab treatment strategy in clinical practice. Participants will receive one year of ibandronate or zoledronic acid therapy, initiated 6 months (± 1 week) after the last dose of denosumab, followed by a total of two years of follow-up. Eligible participants will be randomized in a 1:1 ratio, with an estimated sample size of 26 patients per group.

Inclusion criteria

• Postmenopausal women aged 50 to 85 years.
• BMD T-score ≤ -1.5 and > -3.0 at the lumbar spine or total hip.
• Regular treatment with denosumab administered every 6 months for at least 1 year and less than 3 years (3 to 5 doses).
• Physically and mentally capable of understanding and complying with the study protocol and follow-up.
• Signed informed consent.

Exclusion criteria

• History of fragility or osteoporotic fracture within the past 12 months.
• Current or prior treatment within the past 12 months with osteoporosis medications other than denosumab, including Romosozumab, Teriparatide, Alendronate, Ibandronate, Zoledronic acid, Risedronate and Raloxifene.
• Allergy to bisphosphonates.
• Secondary osteoporosis.
• Metabolic bone diseases.
• Any autoimmune disease.
• Requirement for long-term use of medications known to affect bone metabolism (e.g., systemic glucocorticoids or hormone therapy).
• Primary or metastatic bone tumors.
• Cancer patients, except for in situ carcinoma and non-melanoma skin cancer, unless fully treated and in remission for five years.
• Hypocalcemia.
• Vitamin D deficiency (serum 25-hydroxyvitamin D < 25 ng/mL).
• Renal disease (eGFR < 35 mL/min/1.73 m²) or dialysis patients.
• Planned dental procedures (e.g., extractions, implants) within the next year.
• Smoking more than one pack per day (except for those who have quit for over ten years).