Fukumoto S, Matsumoto T, Takebe K, Onaya T, Eto S, Nawata H, Ogata E
Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Japan.
J Clin Endocrinol Metab. 1994 Jul;79(1):165-70. doi: 10.1210/jcem.79.1.8027221.
The effect of a new third generation bisphosphonate, YM175 (cycloheptylamino-methylene bisphosphonate), on serum calcium (Ca) and intact PTH levels was examined in 79 malignancy-associated hypercalcemia patients with serum Ca levels higher than 2.75 mmol/L. A single infusion of 2.5, 5, and 10 mg YM175 reduced serum Ca levels in a dose-dependent manner. YM175 was about 6 times more potent than 3-amino-hydroxypropylidene-1,1-bisphosphonate. Among 23 patients treated with 10 mg YM175, serum Ca decreased by more than 0.5 mmol/L in 20 patients and was normalized in 11 patients. Serum intact PTH was subnormal in all of these patients before treatment and remained subnormal in 12 patients (suppressed PTH group), but was elevated to normal or high levels after treatment in the remaining 11 patients (responsive PTH group). Serum Ca was significantly higher throughout the study period in the suppressed PTH group, and mean serum Ca at the nadir did not decrease below 2.90 mmol/L in this group. However, the rate or magnitude of reduction in serum Ca was not different in the two groups. Polynomial regression analysis revealed that the threshold of serum Ca for PTH secretion was elevated to 2.75 mmol/L in the responsive PTH group, whereas it was about the upper limit of normal when both groups were combined (2.59 mmol/L). Furthermore, in the responsive PTH group, the threshold for PTH secretion during the decreasing serum Ca phase (days 4 and 6) was higher than that during the increasing serum Ca phase (days 10 and 14). The changes in the threshold for PTH secretion were also observed in patients treated with lower doses of YM175. These results demonstrate that YM175 is one of the most potent currently available bisphosphonates, and that the threshold for PTH secretion is elevated in at least some malignancy-associated hypercalcemia patients. In addition, there appears to be a difference in the threshold for PTH secretion between the decreasing and increasing serum Ca phases similar to the previously reported hysteresis phenomenon.
在79例血清钙水平高于2.75 mmol/L的恶性肿瘤相关性高钙血症患者中，研究了新型第三代双膦酸盐YM175（环庚基氨基亚甲基双膦酸盐）对血清钙（Ca）和完整甲状旁腺激素（PTH）水平的影响。单次输注2.5、5和10 mg YM175可使血清钙水平呈剂量依赖性降低。YM175的效力约为3-氨基-羟丙基亚丙基-1,1-双膦酸盐的6倍。在接受10 mg YM175治疗的23例患者中，20例患者的血清钙下降超过0.5 mmol/L，11例患者的血清钙恢复正常。所有这些患者治疗前血清完整PTH均低于正常水平，12例患者治疗后仍低于正常水平（PTH抑制组）。其余11例患者治疗后血清PTH升高至正常或高水平（PTH反应组）。在整个研究期间，PTH抑制组的血清钙显著更高，该组血清钙最低点时的平均血清钙未降至2.90 mmol/L以下。然而，两组血清钙降低的速率或幅度并无差异。多项式回归分析显示，PTH反应组中PTH分泌的血清钙阈值升高至2.75 mmol/L，而两组合并时约为正常上限（2.59 mmol/L）。此外，在PTH反应组中,血清钙下降阶段（第4天和第6天）PTH分泌的阈值高于血清钙上升阶段（第10天和第14天）。在接受较低剂量YM175治疗的患者中也观察到PTH分泌阈值的变化。这些结果表明，YM175是目前可用的效力最强的双膦酸盐之一，并且至少在一些恶性肿瘤相关性高钙血症患者中，PTH分泌的阈值升高。此外，血清钙下降阶段和上升阶段之间PTH分泌阈值似乎存在差异，类似于先前报道的滞后现象。
