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. [ABSTRACT FROM AUTHOR]