Do peripheral melatonin agonists improve bone fracture healing? The effects of agomelatine and ramelteon on experimental bone fracture

Melatonin improves fracture healing, but the long-term use of melatonin seems impracticable in the treatment of fracture due to side effects caused by hormonal stress on chronological rhythm. Ramelteon (RAMEL) and agomelatine (AGO) are non-selective peripheral melatonin receptor (MT) agonists. This study investigated the effects on bone fracture healing of these MT agonists, which do not affect the central nervous system. The rats were divided into 6 groups, including Group 1 (SHAM): sham operated group; Group 2 (FRACTURE): femoral fracture control; Group 3 (FR + AGO30): femoral fracture + agomelatine 30 mg/kg; Group 4 (FR + AGO60): femoral fracture + agomelatine 60 mg/kg; Group 5 (FR + RAMEL3): femoral fracture + ramelteon 3 mg/kg; and Group 6 (FR + RAMEL6): femoral fracture + ramelteon 6 mg/kg. After 21 days, the rats were subjected to X-ray imaging. Bone healing was evaluated with hematoxylin-eosin (HE) staining. Messenger RNA (mRNA) expressions of bone formation markers, such as bone alkaline phosphatase (ALP), osteocalcin (OC), and osteopontin (OP), were evaluated by real-time polymerase chain reaction (RT-PCR) and with immunohistochemistry (IHC) staining. The radiographic fracture healing scores were statistically significantly higher in the FR + AGO60 group and the FR + RAMEL3 group than in the FRACTURE group. The histopathology and molecular results supported the radiographic results. It was shown that agomelatine and ramelteon increase bone fracture healing, leading to the conclusion that a preference for agomelatine, an antidepressant, and ramelteon, a sleep aid, will increase bone fracture healing in patients with fractures.