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Objective: Patients who remain critically ill for prolonged periods and require tracheotomy, defined as chronic critical illness (CCI), display elevated levels of bone resorption. The measurement of bone turnover markers reveals that osteoclastic bone resorption is not only enhanced but also uncoupled from osteoblastic bone formation. We examine the effect of ibandronate on bone turnover in patients with CCI. Methods: This study is a prospective, double-blind, placebo-controlled trial, in which 20 postmenopausal female participants with CCI were followed for an 11-day period after the administration of a single intravenous dose of ibandronate (3 mg). All participants were treated with ergocalciferol (2000 IU daily), calcium carbonate (1250 mg daily), and calcitriol (0.25 μg daily). Results: The ibandronate group showed a 34% decrease in serum C-telopeptide (CTX) levels (a marker of osteoclastic activity) on day 6, while the placebo group showed a 13% increase (P = .01). By day 11, CTX levels in ibandronate group were not significantly different than baseline or from the placebo group. Osteocalcin (OCN) levels (a marker of osteoblast activity) increased by 78% compared to baseline in the ibandronate group (P = .01) and by 42% in the placebo group (P = .05). There were no significant differences in OCN between the 2 groups throughout the study. Parathyroid hormone levels remained constant throughout the study. No adverse events were observed. Conclusion: A single dose of intravenous ibandronate causes a significant but transient reduction in osteoclast activity in patients with CCI, which persists over a 6-day period.