Tissue biopsy is the gold standard for differentiating osteoporotic vertebral compression fractures from malignant lesions. However, the necessity of routine biopsies during percutaneous vertebroplasty and kyphoplasty is debated due to the low malignancy detection rates. This study aims to identify key predictors of positive biopsy outcomes in patients undergoing these procedures, with the goal of refining biopsy selection criteria to enhance diagnostic yield and improve clinical decision-making. We conducted a retrospective cohort study involving 295 patients who underwent percutaneous vertebroplasty and kyphoplasty with biopsy between June and December 2023. Clinical data, including age, gender, fracture aetiology, imaging findings, and biopsy results, were collected. Binary logistic regression analysis was employed to identify significant predictors of positive biopsy outcomes. The biopsy results revealed an overall malignancy rate of 1.01% (3/295). Among the 17 cases with abnormal (positive) biopsy findings, 17.6% were malignant, while the remainder were benign. Significant predictors included age (OR = 0.936), gender (OR = 0.307 for males), fracture aetiology (OR = 5.300 for fractures with no apparent cause), and imaging abnormalities (OR = 8.388). This study underscores the low malignancy detection rate in routine biopsies for vertebral compression fractures, advocating for a more selective approach by reserving biopsies for patients with specific high-risk factors. A targeted biopsy strategy, informed by enhanced pre-operative screening, could improve diagnostic accuracy and treatment outcomes, optimizing clinical management.