The Comparison of Ibandronate and Zoledronic Acid After Denosumab Discontinuation

Официальное название

The Comparison of Ibandronate and Zoledronic Acid After Denosumab Discontinuation: A Randomized Non-inferiority Trial

Обзор

This study is a prospective, multicenter, open-label, randomized non-inferiority trial comparing intravenous ibandronate and zoledronic acid as sequential therapy after denosumab discontinuation in postmenopausal women with osteoporosis. This trial primarily targets patients with short-term denosumab exposure (less than three years) and is conducted as a preliminary investigation. The findings are expected to provide foundational evidence to inform the design of future studies assessing sequential therapies following longer-term denosumab treatment.

Подробное описание

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.

Вмешательства

• Препарат Ibandronate IV
  Ibandronate 3mg/3months for 12 months
• Препарат Zoledronic acid IV
  Zoledronic acid 5mg/1year for 12 months

Первичные конечные точки

• Percentage change in bone mineral density (BMD) [Срок оценки: Baseline to 24 months after treatment initiation.]

Вторичные конечные точки (4)

• Change in bone turnover makers (BTM) level [Срок оценки: Baseline to 24 months]
• Change in visual Analogue Scale (VAS) score [Срок оценки: Baseline to 24 months]
• Incidence of osteoporotic fractures [Срок оценки: During the intervention period, up to 24 months.]
• Incidence of adverse events (AEs) and serious adverse events (SAEs) [Срок оценки: During the intervention period, up to 24 months.]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Тайвань · 1 центр

• National Taiwan University Hospital — Taipei

Публикации

• Kumar S, Wang M, Kim AS, Center JR, McDonald MM, Girgis CM. Denosumab discontinuation in the clinic: implications of rebound bone turnover and emerging strategies to prevent bone loss and fractures. J Bone Miner Res. 2025 Aug 24;40(9):1017-1034. doi: 10.1093/jbmr/zjaf037. PMID 40057981
• Ha J, Jung KY, Kim KJ, Ahn SH, Kim HJ, Chung YS. Effects of Sequential Anti-Resorptive Agents on Bone Mineral Density Following Denosumab Withdrawal: A Multicenter Real-World Study in Korea (MAXCARE Study). Endocrinol Metab (Seoul). 2025 Oct;40(5):748-758. doi: 10.3803/EnM.2024.2227. Epub 2025 Feb 11. PMID 39933434
• Ramchand SK, Tsai JN, Lee H, Sassana-Khadka G, Jordan M, Ryan S, Leder BZ. The comparison of alendronate and raloxifene after denosumab (CARD) study: A comparative efficacy trial. Osteoporos Int. 2024 Feb;35(2):255-263. doi: 10.1007/s00198-023-06932-2. Epub 2023 Oct 6. PMID 37798320
• Kendler D, Chines A, Clark P, Ebeling PR, McClung M, Rhee Y, Huang S, Stad RK. Bone Mineral Density After Transitioning From Denosumab to Alendronate. J Clin Endocrinol Metab. 2020 Mar 1;105(3):e255-64. doi: 10.1210/clinem/dgz095. PMID 31665314
• Lee CC, Wang CY, Yen HK, Hung CC, Lai CY, Hu MH, Wang TM, Li CY, Fu SH. Zoledronate Sequential Therapy After Denosumab Discontinuation to Prevent Bone Mineral Density Reduction: A Randomized Clinical Trial. JAMA Netw Open. 2024 Nov 4;7(11):e2443899. doi: 10.1001/jamanetworkopen.2024.43899. PMID 39527056
• Tutaworn T, Nieves JW, Wang Z, Levin JE, Yoo JE, Lane JM. Bone loss after denosumab discontinuation is prevented by alendronate and zoledronic acid but not risedronate: a retrospective study. Osteoporos Int. 2023 Mar;34(3):573-584. doi: 10.1007/s00198-022-06648-9. Epub 2023 Jan 5. PMID 36602607
• Solling AS, Harslof T, Langdahl B. Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis: A 2-Year Randomized Study. J Bone Miner Res. 2021 Jul;36(7):1245-1254. doi: 10.1002/jbmr.4305. Epub 2021 Apr 20. PMID 33813753
• Anastasilakis AD, Papapoulos SE, Polyzos SA, Appelman-Dijkstra NM, Makras P. Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial. J Bone Miner Res. 2019 Dec;34(12):2220-2228. doi: 10.1002/jbmr.3853. Epub 2019 Oct 14. PMID 31433518

Идентификаторы

NCT: NCT07406685 · 202601190MINA

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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