To construct a new prediction nomogram to predict the risk of musculoskeletal pain in patients with primary osteoporosis who receive zoledronic acid intravenously for the first time.Clinical data of 368 patients with primary osteoporosis who received the first intravenous injection of zoledronic acid in our hospital from December 2019 to December 2022 were studied. Patients were divided into a musculoskeletal pain group (n = 258) and a non-musculoskeletal pain group (n = 110) based on the presence or absence of musculoskeletal pain 3 days after injection. Statistically significant predictors were screened by logistic regression analysis and the minimum absolute contraction and selection operator (LASSO) to construct a nomogram. The nomogram was evaluated by the receiver operating characteristic (ROC) curve, the calibration curve, the C-index, and the decision curve analysis (DCA) and verified in a validation cohort.The independent predictors of the nomogram were age, serum 25-hydroxyvitamin D, NSAIDs, prior Vitamin D intake, and BMI. The area under the ROC curve (AUC) was 0.980 (95% CI, 0.915-0.987), showing excellent predictive performance. The nomogram c index was 0.980, and the nomogram c index for internal verification remained high at 0.979. Moreover, calibration curves show that the nomogram has good consistency. Finally, the DCA showed that the net benefit of the nomogram was 0.20-0.49.Musculoskeletal pain is a common symptom of APR in OP patients treated with intravenous zoledronic acid. Risk factors for musculoskeletal pain after zoledronic acid injection in OP patients were: non-use of NSAIDs, youth (<80 years old), serum 25 (OH) D<30ng /mL, no prior intake of vitamin D, BMI<24 kg /m2. A nomogram constructed from the above predictors can be used to predict musculoskeletal pain after the first zoledronic acid injection.© 2023. BioMed Central Ltd., part of Springer Nature.