Objective To explore the possible mechanism of Zuogui Pills（左归丸） in the treatment of postmenopausal osteoporosis with osteoarthritis. Methods Sixty female SD rats were randomised into sham operation group

model group

alendronate sodium group and Zuogui Pills low

medium and high dose groups

with 10 rats in each group. Ovariectomy was used to establish the model of postmenopausal osteoporosis and osteoarthritis in rats of all groups except for sham operation group. Two weeks after modeling

the rats in the sham operation group and the model group were given 1 ml/（kg·d） of distilled water by gavage; the alendronate sodium group was given 63 mg/（kg·d） of alendronate sodium suspension by gavage; Zuogui Pills low

medium and high dose groups were given 2.42

4.84

9.68 g/（kg·d） of Zuogui Pills by gavage

respectively; the interventions in all the groups were administered once daily

six times a week. After 12 weeks

the morphological changes of cartilage tissues in rats were assessed; the subchondral bone mineral density（BMD） of the left distal femur

the serum tumor necrosis factor α（TNF-α） and interleukin 1β（IL-1β） contents

the femur substance P（SP） and Runt-related transcription factor 2（Runx2） protein expression

hypothalamic SP and its receptor neurokinin 1 receptor（NK1-R） protein and mRNA expression were evaluated. Results The pathological results showed that compared to the sham operation group

the model group′s cartilage surface was damaged and cracked; the chondrocytes arranged disorderly; the BMD level of subchondral bone decreased; serum TNF-α and IL-1β levels increased; hypothalamus SP and NK1-R protein and mRNA expression levels decreased（P<0.05 or P<0.01）; the expression of Runx2 and SP decreased. Compared to those of the model group

the cartilage damage of the alendronate sodium group and Zuogui Pills medium and high dose groups were significantly improved; the BMD level of subchondral bone significantly increased; the serum TNF-α and IL-1β levels significantly decreased; thralamus SP and NK1-R protein and mRNA expression levels increased（P<0.01）; the expression of Runx2 and SP of alendronate sodium group and Zuogui Pills low dose group increased. Compared to the Zuogui Pills low group

the medium dose and the high dose groups had significantly higher expression of NK1-R mRNA in the hypothalamus（P<0.05 or P<0.01）. The IL-1β level of the high dose group was significantly lower than that of the low and middle dose group（P<0.01）. Conclusion The mechanism of Zuogui Pills in preventing and treating postmenopausal osteoporosis and osteoarthritis may be related to the regulation of the imbalance of bone metabolism through increasing levels of hypothalamic neuropeptide SP and its receptor protein and mRNA

as well as raising subchondral bone density.