Nussbaum S R
Endocrine Unit, Massachusetts General Hospital, Boston.
Endocrinol Metab Clin North Am. 1993 Jun;22(2):343-62.
The principal pathophysiologic alteration in severe hypercalcemia accompanying hyperparathyroidism and malignancy is enhanced osteoclastic bone resorption. Hypercalcemia impairs renal mechanisms that lead to sodium and calcium excretion; PTH and PTHrP acting on renal tubules enhance further calcium reabsorption. Although rehydration is often necessary as an initial therapy of hypercalcemia, the cornerstone of therapy is to inhibit osteoclastic bone resorption. The bisphosphonates, plicamycin, gallium, and calcitonin all inhibit osteoclastic bone resorption. Calcitonin is the most rapidly acting agent. Toxicities of calcitonin are minimal, yet its therapeutic efficacy is limited by lack of potency and tachyphylaxis. The second-generation bisphosphonates such as pamidronate represent a class of compounds that are extremely effective in inhibiting the metabolic function of the osteoclast. Given in a single infusion, a significant majority of patients will have normalization of corrected serum calcium lasting, on average, 1-2 weeks. Therapeutic benefit will be of greater duration because most patients remain only minimally symptomatic until corrected serum calcium rises above 11.5 mg/dL. Side effects of low-grade fever, hypophosphatemia, hypomagnesemia, and hypocalcemia may occur. Gallium nitrate is a potent inhibitor of bone resorption and may be of increased clinical value when more efficient administration protocols can be developed. Plicamycin, available for two decades, has cumulative toxicities and is less potent than the aminobisphosphonates. Renal insufficiency often accompanies severe hypercalcemia. The nephrotoxicity of gallium nitrate and plicamycin should preclude their use when there is moderate impairment of renal function, and amino bisphosphonates become the treatment of choice in these patients. Although several authors have advocated individualized approaches to the management of hypercalcemia, the potency and duration of action of the aminobisphosphonates make them a reasonable treatment choice for most patients with symptomatic hypercalcemia. Most importantly, the most effective therapy for hypercalcemia is to recognize and treat the underlying disease. Acute primary hyperparathyroidism requires surgery. The effective treatment of hypercalcemia of malignancy allows the introduction of tumor-specific therapy, limits morbidity, and shortens and deintensifies hospitalization. At times, the most appropriate and compassionate decision (particularly in patients with malignancy who have exhausted all therapeutic options and have relentless bone pain) is to withhold therapy for hypercalcemia. Future therapies directed at the osteoclast, such as more potent later-generation bisphosphonates; inhibitors of osteoclast attachments and inhibitors of peptides, which stimulate osteoclastic bone resorption, may permit safe, easily administered, outpatient therapies that will improve the quality of life for hypercalcemic patients.
甲状旁腺功能亢进和恶性肿瘤伴发的严重高钙血症的主要病理生理改变是破骨细胞性骨吸收增强。高钙血症损害导致钠和钙排泄的肾脏机制；作用于肾小管的甲状旁腺激素（PTH）和甲状旁腺激素相关蛋白（PTHrP）进一步增强钙的重吸收。虽然补液常常是高钙血症初始治疗所必需的，但治疗的关键是抑制破骨细胞性骨吸收。双膦酸盐、普卡霉素、镓和降钙素均能抑制破骨细胞性骨吸收。降钙素是起效最快的药物。降钙素的毒性极小，但其治疗效果因效力不足和快速减敏而受限。第二代双膦酸盐如帕米膦酸代表一类能极其有效地抑制破骨细胞代谢功能的化合物。单次输注给药后，绝大多数患者校正血清钙将恢复正常，平均持续1 - 2周。治疗益处持续时间会更长，因为在校正血清钙升至11.5mg/dL以上之前，大多数患者仅表现出轻微症状。可能会出现低热、低磷血症、低镁血症和低钙血症等副作用。硝酸镓是一种强效的骨吸收抑制剂，当能制定出更有效的给药方案时，其临床价值可能会增加。已上市二十年的普卡霉素有累积毒性，且效力低于氨基双膦酸盐。严重高钙血症常伴有肾功能不全。当肾功能中度受损时，硝酸镓和普卡霉素的肾毒性应使其禁用，氨基双膦酸盐成为这些患者的治疗选择。尽管有几位作者主张对高钙血症的管理采用个体化方法，但氨基双膦酸盐的效力和作用持续时间使其成为大多数有症状高钙血症患者合理的治疗选择。最重要的是，高钙血症最有效的治疗方法是识别并治疗潜在疾病。急性原发性甲状旁腺功能亢进需要手术治疗。恶性肿瘤高钙血症的有效治疗能使肿瘤特异性治疗得以开展，限制发病率，并缩短住院时间和降低住院强度。有时，最合适且人道的决定（尤其是在已用尽所有治疗选择且有难以忍受的骨痛的恶性肿瘤患者中）是停止高钙血症的治疗。针对破骨细胞的未来治疗方法，如效力更强的新一代双膦酸盐；破骨细胞附着抑制剂和刺激破骨细胞性骨吸收的肽类抑制剂，可能会带来安全、易于给药的门诊治疗，从而改善高钙血症患者的生活质量。
