Bisphosphonate treatment in children with acute lymphoblastic leukemia and osteonecrosis – radiological and clinical findings in a national cohort

<b>Background: </b>Osteonecrosis (ON) is a recognized complication of childhood ALL, but its optimal management remains unestablished. This study evaluated the effect of bisphosphonate (BP) treatment on the evolution of ON lesions in childhood ALL. <b>Material and Methods: </b>We included a national cohort of ALL patients diagnosed with symptomatic ON before 18 years of age and treated with BPs (<i>N</i> = 10; five males). Patients were followed both clinically and with serial MRIs. ON lesions were graded according to the Niinimäki classification. <b>Results: </b>The 10 patients had a total of 55 ON lesions. The median age was 13.3 years at ALL diagnosis and 14.8 years at ON diagnosis. Four patients had received HSCT before the ON diagnosis. BPs used were pamidronate (<i>N</i> = 7), alendronate (<i>N</i> = 2) and ibandronate (<i>N</i> = 1). The duration of BP treatment varied between 4 months and 4 years. In 4/10 patients, BP treatment was given during the chemotherapy. BPs were well-tolerated, with no severe complications or changes in kidney function. At the end of follow up 13/55 (24%) ON lesions were completely healed both clinically and radiographically; all these lesions were originally graded 3 or less. In contrast, ON lesions originally classified as grade 5 (joint destruction; <i>N</i> = 4) remained at grade 5. All grade 5 hip joint lesions needed surgical treatment. During BP treatment, the pain was relieved in 7/10 patients. At the end of follow-up, none of the patients reported severe or frequent pain. <b>Conclusion: </b>BP treatment was safe and seemed effective in relieving ON-induced pain in childhood ALL. After articular collapse (grade 5) lesions did not improve with BP treatment. Randomized controlled studies are needed to further elucidate the role of BPs in childhood ALL-associated ON.

**背景：** 骨坏死（Osteonecrosis, ON）是儿童急性淋巴细胞白血病（Acute Lymphoblastic Leukemia, ALL）公认的并发症，但其最佳诊疗方案迄今尚未明确。本研究旨在评估双膦酸盐（bisphosphonate, BP）治疗对儿童急性淋巴细胞白血病相关性骨坏死病灶转归的影响。
**材料与方法：** 本研究纳入一项全国性队列研究中的10例患者，均为18岁前确诊症状性骨坏死且接受双膦酸盐治疗的儿童急性淋巴细胞白血病患者（其中男性5例）。所有患者均接受临床随访及系列磁共振成像（Magnetic Resonance Imaging, MRI）检查，骨坏死病灶依据尼尼迈基（Niinimäki）分级标准进行分期。
**结果：** 10例患者共计存在55处骨坏死病灶。患者确诊急性淋巴细胞白血病时的中位年龄为13.3岁，确诊骨坏死时的中位年龄为14.8岁。4例患者在确诊骨坏死前接受过造血干细胞移植（Hematopoietic Stem Cell Transplantation, HSCT）。所用双膦酸盐类药物包括帕米膦酸二钠（7例）、阿仑膦酸钠（2例）及伊班膦酸钠（1例）。双膦酸盐治疗的持续时间为4个月至4年不等，10例患者中有4例在化疗期间接受了双膦酸盐治疗。双膦酸盐耐受性良好，未出现严重并发症或肾功能异常。随访结束时，共计13处（24%）骨坏死病灶在临床及影像学上完全愈合，此类病灶初始分级均为3级及以下。与之相反，初始分级为5级（关节破坏，共4处）的骨坏死病灶始终维持5级。所有5级髋关节病灶均需接受外科手术治疗。双膦酸盐治疗期间，10例患者中有7例疼痛得到缓解；随访结束时，无患者报告存在重度或频繁性疼痛。
**结论：** 双膦酸盐治疗安全性良好，可有效缓解儿童急性淋巴细胞白血病相关性骨坏死引发的疼痛，但对于已发生关节塌陷（5级）的病灶，双膦酸盐治疗未能改善其病情。未来需开展随机对照试验，以进一步明确双膦酸盐在儿童急性淋巴细胞白血病相关性骨坏死中的应用价值。