Efficacy of Zoledronic Acid in the Treatment of Nonmalignant Painful Bone Marrow Lesions: A Triple-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial (ZoMARS)

Abstract

Bone marrow lesions (BML) represent areas of deteriorated bone structure and metabolism characterized by pronounced waterequivalent signaling within the trabecular bone on magnetic resonance imaging (MRI). BML are associated with repair mechanisms subsequent to various clinical conditions associated with inflammatory and non-inflammatory injury to the bone. There is no approved treatment for this condition. Bisphosphonates are known to improve bone stability in osteoporosis and other bone disorders and have been used off-label to treat BML. A randomized, triple-blind, placebo-controlled phase III trial was conducted to assess efficacy and safety of single-dose zoledronic acid (ZOL) 5 mg iv with vitamin D 1000 IU/d as opposed to placebo with vitamin D 1000 IU/d in 48 patients (randomized 2:1) with BML. Primary efficacy endpoint was reduction of edema volume 6 weeks after treatment as assessed by MRI. After treatment, mean BML volume decreased by 64.53% (AE41.92%) in patients receiving zoledronic acid and increased by 14.43% (AE150.46%) in the placebo group (p = 0.007). A decrease in BML volume was observed in 76.5% of patients receiving ZOL and in 50% of the patients receiving placebo. Pain level (visual analogue scale [VAS]) and all categories of the pain disability index (PDI) improved with ZOL versus placebo after 6 weeks but reconciled after 6 additional weeks of follow-up. Six serious adverse events occurred in 5 patients, none of which were classified as related to the study drug. No cases of osteonecrosis or fractures occurred. Therefore, single-dose zoledronic acid 5 mg iv together with vitamin D may enhance resolution of bone marrow lesions over 6 weeks along with reduction of pain compared with vitamin D supplementation only.

Influence of Vitamin D and C on Bone Marrow Edema Syndrome—A Scoping Review of the Literature

“…Therapy: Apart from three studies [7,20,21], all articles report on therapies of BMES, but among all remaining 57 articles, only one randomized, controlled phase III trial (level of evidence I) exists [22]. Most other are case reports, retrospective case series and few observational studies, mostly retrospective.…”

“…The only RCT by Seefried et al compares the use of zolendronate plus PWB and vitamin D/calcium substitution to placebo and PWB, vitamin D/calcium. A significant difference in the edema volume reduction in favor of zolendronate is stated, as well as a significant reduction of pain level after 3 and 6 weeks by zolendronate [22]. Bartl et al conducted a prospective observational study, comparing ibandronate to a conservative regimen [33].…”

Advantages of cone beam computed tomography for evaluation of subchondral insufficiency fractures of the knee compared with MRI

“…In the case of an infracted subchondral bone plate, surgery is often recommended. Based on other factors such as anatomic location and lesions size, the most suitable surgical option is determined, such as core decompression, osteochondral grafting, autologous chondrocyte implantation or, in the case of severe ndings, partial or total knee arthroplasty [6, 19,25,29,33,34]. Furthermore, accurate veri cation of the bony lesion and therefore the subchondral bone plate is also important to evaluate possible progression.…”

“…Limitations of this study include the inability to compare BME extent between MRI and CBCT and the lack of comparison between CBCT and other x-ray-based imaging techniques such as conventional x-ray and MDCT. Novel CT techniques such as dual-energy CT (DECT) also have the potential to detect and quantify BME based on the differential energy-dependent x-ray absorption behaviors [29][30][31]. Virtual noncalcium techniques can suppress the high attenuation of trabecular bone and enable detection of subtle changes in bone marrow constitution.…”

Animal Models of Bone Marrow Lesions in Osteoarthritis

“…(2) JBMR Plus (WOA) n 2 of 9 BOWEN ET AL. have been mixed; some have indicated that bisphosphonates can reduce the volume of the BML, (25) whereas others did not observe a significant effect on BML size, (26) suggesting that expansion of an established BML is not driven by remodeling alone. The clinical study focused on individuals with late-stage osteoarthritis requiring arthroplasty, however, and it remains possible that antiresorptive agents can interrupt BMLs and associated pain earlier in joint pathogenesis.…”