Vertebral compression fractures are a significant source of morbidity and mortality among patients of all age groups. These fractures result in both acute and chronic pain. Patients who sustain such fractures are known to suffer from more comorbidities and have a higher mortality rate compared with healthy people in the same age group. In recent years, balloon kyphoplasty has become a popular method for treating vertebral compression fractures. However, as longer-term follow-up becomes available, the effects of cement augmentation on adjacent spinal segments require investigation. Here, we have performed a retrospective chart review of 258 consecutive patients with pathologic vertebral compression fractures secondary to osteoporosis, treated by either conservative measures or balloon kyphoplasty with polymethylmethacrylate cement augmentation. Multivariate analysis of patient comorbidities was performed to assess the risks associated with subsequent adjacent and remote compression fracture at a minimum of 2 years follow-up. A total of 258 patients had 361 vertebral compression fractures. A total of 121 patients were treated nonoperatively and 137 underwent balloon kyphoplasty with polymethylmethacrylate cement augmentation. The mean follow-up for both cohorts was 2.7 years (range, 2-6 years). The kyphoplasty cohort was significantly older than the nonoperative cohort (mean age, 78.5 versus 74.2 years; p = 0.02), had 24 more patients with diabetes mellitus (37 versus 13; p = 0.05), and had 34 more patients with a history of smoking (50 versus 16; p = 0.05). However, the kyphoplasty cohort had less patients with a history of non-steroidal anti-inflammatory drug (NSAID) use (45 versus 71; p = 0.07). There were no demographic differences between groups in patients with secondary fractures. Nonoperative treatment was identified as a statistically significant independent risk factor for subsequent vertebral compression fracture [odds ratio (OR), 2.28]. Univariate analysis identified age, diabetes mellitus, smoking, NSAID usage, and female gender as risk factors for subsequent vertebral compression fracture. When adjusted for multivariate analysis, no individual factor demonstrated increased risk for subsequent fracture. Patients diagnosed with vertebral compression fractures secondary to osteoporosis suffer from multiple medical comorbidities. No particular comorbidity was identified as solely attributable for increased risk of subsequent remote or adjacent compression fractures. Patients in this series treated with nonoperative (conservative) management had a 2.28 times greater risk for a subsequent vertebral compression fracture than patients treated with balloon kyphoplasty and polymethylmethacrylate cement augmentation.