The aim of the present study was to explore the clinical efficacy and safety of different methods of calcium supplementation in osteoporosis (OP). Patients with OP were divided into four groups, including the control, oral calcium supplementation, intravenous calcium supplementation and combined calcium supplementation groups. The duration of the calcium supplementation was 3-6 years. Medical records were collected and examined along with demographic data, the incidence of certain diseases and adverse reactions. All subjects in the three treatment groups exhibited statistically significant reductions in alkaline phosphatase (ALP) levels, visual analog score (VAS) and Oswestry Disability Index (ODI) compared with the respective pre-treatment values. Furthermore, compared with prior to treatment, the lumbar and hip bone mineral density (BMD) of patients receiving intravenous calcium supplementation was significantly increased. In addition, after treatment, the lumbar and hip BMD was significantly increased, whereas ALP levels, VAS and ODI were significantly decreased in the oral calcium supplementation group compared with the control group. Also, compared with the control and oral calcium supplementation groups, the BMD was significantly increased, whereas ALP, VAS, ODI, the rate of infection and tooth loss, the incidence of fragility fractures, joint replacement surgery, arrhythmia, lumbar disc herniation and cerebral infarction were significantly decreased in the two groups treated with intravenous calcium supplementation. The results of the present study may enable a better understanding of the effectiveness and safety of the different methods for supplementing calcium in OP.