Background　Osteoporosis　is　a　disease　threatening　the　health　of　millions　of　individuals.　Melatonin　is　found　to　be　a　potential　anti-osteoporosis　drug.　However,　whether　melatonin　plays　a　role　against　osteoporosis　at　different　stages　of　the　menopause　and　the　underlying　mechanisms　are　unknown.　Methods　Ovariectomy　was　utilized　as　a　model　of　perimenopausal　and　postmenopausal　osteoporosis.　A　total　of　100　mg/kg　melatonin,　or　solvent　alone,　was　added　to　the　drinking　water　of　the　rats　over　8　weeks.　Perimenopausal　rats　immediately　received　intervention　following　ovariectomy　while　postmenopausal　rats　received　intervention　8　weeks　after　ovariectomy.　All　rats　underwent　overdose　anesthesia　following　intervention　after　which　blood　samples　and　femurs　were　collected　for　further　analysis.　Rat　femurs　were　scanned　using　micro-CT　and　examined　histologically.　The　serum　levels　of　melatonin　and　osteogenic　biochemical　markers　were　measured　and　the　expression　of　osteogenesis-associated　genes　(Runx2,　Sp7)　were　quantified　by　real-time　quantitative　PCR.　Alkaline　phosphatase　(ALP)　activity　and　the　gene　expression　(Col1a1,　Runx2,　Alpl,　and　Bglap)　were　measured　after　bone　marrow　mesenchymal　stem　cells　(BMSCs)　were　osteogenically　induced,　both　with　and　without　melatonin　in　vitro.　ALP　staining　and　Alizarin　Red　S　staining　were　used　to　identify　osteogenesis.　Results　Analysis　by　micro-CT　and　histological　staining　demonstrated　that　bone　mass　decreased　and　bone　microarchitecture　deteriorated　over　time　after　ovariectomy.　Intervention　with　melatonin　increased　bone　mass　in　normal,　perimenopausal,　and　postmenopausal　osteoporotic　rats.　Serum　levels　of　ALP　continuously　increased　after　ovariectomy　while　osteocalcin　levels　initially　rose,　then　decreased.　Melatonin　increased　the　serum　levels　of　ALP　and　osteocalcin　and　mRNA　expression　levels　of　Runx2　and　Sp7　in　normal　and　postmenopausal　rats,　the　opposite　of　the　markers　in　perimenopausal　rats.　In　vitro　study　demonstrated　that　100　mu　mol/L　melatonin　increased　the　mRNA　expression　of　Col1a1,　Runx2,　and　Alpl　three　and/or　seven　days　after　intervention,　and　Alpl　and　Bglap　14　d　after　intervention.　Melatonin　increased　ALP　activity　and　the　extent　of　ALP　and　matrix　mineralization　in　the　late　stage　of　osteogenesis.　Conclusions　Bone　mass　continuously　decreased　after　ovariectomy,　while　melatonin　increased　bone　mass　and　ameliorated　bone　metabolism　in　normal,　perimenopausal,　and　postmenopausal　osteoporotic　rats　due　to　the　induction　of　osteogenic　differentiation　in　BMSCs.