Medical Oncology I, Istituto Oncologico Veneto, IOV-I.R.C.C.S., 35128 Padova, Italy.
Curr Med Chem. 2011;18(23):3462-7. doi: 10.2174/092986711796642490.
Malignancy-associated hypercalcemia (MAH) is one of the clinical emergencies in medical oncology, arising early or, more often, during the late phases of disease. Prevalence cannot be estimated accurately because previous figures of 5-30% of all cancer patients have progressively reduced thanks to the widespread use of bisphosphonates for the prevention of skeletal events. The classic distinction of humoral vs. osteolytic hypercalcemia is still relevant from an etiological point of view, but should not be considered as a rigid alternative since both mechanisms may be active in the same patients and the activation of the RANKL pathway is a common pathogenetic mechanism. Parathyroid hormone-related protein mimics the effects of PTH on the bone and kidney (tubular calcium resorption) and may represent an attractive druggable target, but additional agents (cytokines or other mediators) as well as ectopic production of 1,25(OH)₂D₃ may give an important contribution to humoral hypercalcemia. Conversely, bone invasion by cancer cells determines massive bone reabsorption due to the release of proteolytic enzymes and pro-osteolytic agents with paracrine activity on adjacent bone and stromal cells. When cancer patients develop headache, confusion, de-hydration and tremors hypercalcemia should be suspected although slow rise of calcium levels may produce more indolent symptoms. Bisphosphonates (with or without hydration and diuretics) may efficiently control MAH but only if an active treatment for the underlying cancer is promptly started. The anti-RANKL monoclonal antibody denosumab represents a novel agent able to revert the vicious cycle of bone metastases and data from phase III studies are currently showing promising activity in reverting bone resorption with manageable toxicity.
恶性肿瘤相关性高钙血症（MAH）是肿瘤内科的临床急症之一，可发生于疾病早期，或更常见于疾病晚期。由于双膦酸盐广泛用于预防骨骼事件，因此无法准确估计其患病率，因为之前有 5-30%的所有癌症患者的发病率逐渐降低。从病因学角度来看，体液性与溶骨性高钙血症的经典区分仍然相关，但不应被视为一种严格的替代方法，因为这两种机制可能在同一患者中均活跃，而 RANKL 通路的激活是一种常见的发病机制。甲状旁腺激素相关蛋白模拟 PTH 对骨骼和肾脏（管状钙吸收）的作用，可能是一个有吸引力的可用药靶，但其他制剂（细胞因子或其他介质）以及 1,25(OH)₂D₃ 的异位产生也可能对体液性高钙血症有重要贡献。相反，癌细胞对骨骼的侵袭导致大量骨吸收，这是由于释放具有旁分泌活性的蛋白水解酶和促溶骨剂对相邻骨骼和基质细胞的作用。当癌症患者出现头痛、意识模糊、脱水和震颤时，应怀疑高钙血症，尽管钙水平的缓慢升高可能产生更惰性的症状。双膦酸盐（有或没有水化和利尿剂）可有效控制 MAH，但前提是要及时开始针对基础癌症的积极治疗。抗 RANKL 单克隆抗体地舒单抗是一种新型药物，能够逆转骨转移的恶性循环，目前来自 III 期研究的数据显示其具有有前景的逆转骨吸收作用，且毒性可管理。
