High-dose melatonin for early tibial fracture healing: A prospective study of safety, feasibility, and preliminary biological effects.

Abstract

Tibial shaft fractures represent a prevalent orthopedic challenge, particularly in public health systems, due to delayed healing and limited access to biological adjuvants. Melatonin, a pleiotropic indoleamine with antioxidant and osteogenic properties, has demonstrated consistent efficacy in preclinical bone repair models; however, its clinical application, especially at pharmacological doses, remains poorly explored. This prospective controlled study evaluated the effects of high-dose melatonin (30 mg/day) on early bone healing, safety, and tolerability following reamed intramedullary nailing for diaphyseal tibial fractures. Twenty-five adults (18-60 years) with closed tibial shaft fractures (AO/OTA 42-A/B/C) were sequentially allocated to a melatonin group (n = 12) or a standard care control group (n = 13), with nightly oral melatonin administered for 49 consecutive postoperative days. Primary outcomes included serum alkaline phosphatase (ALP) levels and the Radiographic Union Score for Tibial fractures (RUST) assessed at 21 and 49 days, while secondary outcomes encompassed adverse events, treatment adherence, and sleep quality. Both groups showed significant increases in ALP and RUST scores over time (p < 0.001), reflecting expected fracture healing progression; however, no significant between-group differences were observed for ALP (p = 0.324) or RUST scores (p = 0.261). The intervention was well tolerated, with high adherence (91.7%), no serious adverse events, and only one report of mild, transient daytime sleepiness. High-dose melatonin was safe and feasible but did not accelerate early biochemical or radiographic bone healing within the 49-day follow-up, supporting the need for larger randomized trials with longer follow-up and more sensitive biomarkers.