To assess the safety and efficacy of oral 50 mg Zoledronic acid (ZA) bisphosphate once-a-week for 6-weeks to placebo among patients with chronic low back pain (cLBP) and Modic changes (MC) on MRI. A parallel, double-blinded randomized controlled study was performed at a single center, consisted of 25 subjects with cLBP and MC that received ZA (n = 13) or placebo (n = 12). Evaluation was at baseline, 2-weeks, 4-weeks, 3-months and 6-months for assessment of LBP/leg pain intensity, disability (Oswestry-Disability-Index:​ ODI), health-related quality-of-life (RAND-36), and mental component summary scores (MCS). Type 2 MC at baseline (56%) were prevalent. In the ZA group, LBP intensity was lower at 4-weeks in comparison to placebo (5.1 ± 1.9 vs. 6.9 ± 1.8, p = 0.038) (minimal clinically important difference [MCID] = 1.5). LBP intensity reduced at 4-weeks and 3-months in the ZA-treated group in comparison to baseline. Although there was no difference in ODI, subscale RAND-36 metrics for physical function (p = 0.038), energy/fatigue (p = 0.040) and pain (p = 0.003) were improved at 3-months compared to placebo, with moderate significant difference for pain at 6-months (p = 0.051). Correlated MCS scores to baseline also improved at 3-months (p = 0.035) and 6-months (p = 0.028) by 6.9 and 6.8, respectively, (MCID = 3.8). A reduction in MC endplate affected area at 6-month follow-up was noted in the ZA group (−0.67 ± 0.69 cm²), while in the placebo group no change in size was observed (0.0 ± 0.15;​ p = 0.041). Three subjects withdrew from the study and no long-lasting adverse events. Oral ZA was a safe and effective treatment that reduced MC volume, improved LBP symptoms and quality-of-life measures in cLBP subjects with MCs.