Effects of nocturnal melatonin-based tissue-bone homeostasis manipulation at varying time points on pain and central mechanisms in individuals with knee osteoarthritis: a randomized controlled trial

Apr 27, 2026Frontiers in bioengineering and biotechnology

Nighttime melatonin treatment at different times may affect pain and brain responses in people with knee osteoarthritis

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Abstract

After 4 weeks, 82 out of 88 knee osteoarthritis patients showed reduced pain levels and increased melatonin levels across all treatment groups.

Tissue-bone homeostasis manipulation (TBHM) at different times may effectively reduce pain in knee osteoarthritis patients compared to joint mobilization.
TBHM administered at 6 p.m. resulted in significantly lower pain scores compared to treatment at 1 p.m., which was also lower than treatment at 8 a.m.
Melatonin levels increased significantly in patients receiving TBHM, with the highest levels observed in the 6 p.m. group compared to the 1 p.m. and 8 a.m. groups.
EEG analysis indicated a decrease in β band activity and an increase in θ band activity in the frontal and central regions following TBHM, though differences were not statistically significant.

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BACKGROUND: Tissue-bone homeostasis manipulation (TBHM) has been proven effective for knee osteoarthritis (KOA), but its optimal timing and underlying mechanisms remain unclear. Melatonin serves as a key biomarker of circadian rhythm, while electroencephalography (EEG) evaluates pain-related central mechanisms. This study investigated the efficacy of TBHM at different time points based on circadian principles and explored potential central mechanisms using EEG.

METHODS: In this 4-week randomized controlled single-blind trial, 88 KOA patients were randomized into four groups: group A (TBHM at 8 a.m.), group B (TBHM at 1 p.m.), group C (TBHM at 6 p.m.), and group D (joint mobilization). Interventions were administered once daily (20 min/session, 5 days/week). Primary outcome was Visual Analog Scale (VAS) for pain; secondary outcomes were resting-state EEG and Hamilton Anxiety Rating Scale. Salivary melatonin levels were measured to explore circadian mechanisms. Assessments were conducted at baseline and after 4 weeks. Statistical analyses employed two-way repeated-measures ANOVA.

RESULTS: Of the 88 patients randomized, 82 completed the study. After 4 weeks, all groups showed reduced VAS scores and increased melatonin levels. Post-treatment, group C exhibited significantly lower VAS scores than group B (FDR adjusted= 0.023), and group B had significantly lower VAS scores than group A (FDR adjusted= 0.037). Although group A showed lower scores than group D, the difference was not statistically significant (FDR adjusted> 0.05). Melatonin levels increased significantly in the three TBHM groups after treatment. group C was demonstrated significantly higher melatonin levels than group B (FDR adjusted< 0.001), group B was significantly higher than group A (FDR adjusted= 0.007), and group A was higher than group D (FDR adjusted= 0.026). After treatment, a decrease in β band activity and an increase in θ band activity were observed in the frontal and central regions of groups C and B in EEG analysis, but there was no significant difference (FDR adjusted> 0.05). P P P P P P P

CONCLUSION: The TBHM at all time points can better improve the pain of KOA patients than joint mobilization, regulate cortical electrical activity, and increase the secretion of melatonin at night.

TRIAL REGISTRATION: ChiCTR2400080820. Registered on Feb.07,2024.

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Effects of nocturnal melatonin-based tissue-bone homeostasis manipulation at varying time points on pain and central mechanisms in individuals with knee osteoarthritis: a randomized controlled trial

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