Calcitriol-Mediated Hypercalcaemia and Increased Interleukins in a Patient with Sarcoid Myopathy

In this report we describe a patient with Sjo¨gren’s syndrome (SS) and calcitriol-mediated hypercalcaemia. Initially, there was no clinical evidence of sarcoidosis. The patient had hypercalcaemia associated with increased calcitriol serum levels; circulating interleukin-6 and tumour necrosis factor alpha levels were also elevated. At the beginning, therapy with clodronate was effective in decreasing the serum calcium levels. However, the serum calcitriol decreased only after chloroquine treatment was added. After 2 years of therapy, the patient developed progressive and extensive muscle weakness. A muscle biopsy revealed a very prominent non-caseating granulomatous myopathy. Corticosteroid therapy was then instituted. Although both chloroquine and corticosteroid therapy were associated with decreased serum interleukin and calcitriol levels, only corticosteroid therapy was effective in treating the sarcoid myopathy. The role of cytokines in calcitriol mediated hypercalcaemia is discussed. Received: 1 February 1999 / Accepted: 2 June 1999     

氨基酸鳌合钙联合骨化三醇治疗肾性骨病的临床观察

目的:探讨治疗继发性甲状旁腺功能亢进(SHPT)骨病的方法.方法:对48例长期血液透析的慢性肾功能衰竭患者分别给予骨化三醇及骨化三醇联合钙剂治疗,观察血清钙、磷、钙磷乘积、甲状旁腺激素(PTH)水平变化,并对两种治疗方法的结果进行比较.结果:两种治疗均可显著增加血清钙水平,降低血清磷水平,骨化三醇加钙剂治疗的疗效更为显著(P＜0.01).结论:钙荆加骨化三醇治疗SHPT骨病优于单用骨化三醇.     

骨化三醇对脂多糖炎性大鼠神经保护作用的研究

目的:观察骨化三醇对脂多糖(LPS)炎性大鼠脑组织的保护效应及作用机制。方法:健康雄性成年SD大鼠52只,随机分为三组:空白对照组6只、骨化三醇干预组23只[4μg/(kg.d)×14d]、脂肪乳剂(安慰剂)组23只[4ml/(kg.d)×14d],在第14d给药结束后1h,腹腔注射LPS 10mg/kg制造大鼠全身炎症模型,用凝胶电泳迁移率分析(EMSA)方法检测造模后3、6和9h脑组织核因子-κB(NF-κB),用ELISA方法测肿瘤坏死因子α(TN-α)、白细胞介素-10(IL-10),用苏木精-伊红(H-E)染色观察脑组织神经细胞损伤情况。结果:LPS腹腔注射使大鼠脑组织NF-κB活化、TNF-α表达增加,并随时间的延长而增高,伴有散在的大脑皮质浅表区神经元损害。骨化三醇干预能下调各时间点NFκ-B活性,降低TNF-α含量,并促进IL-10表达。骨化三醇干预减轻了神经细胞损伤程度。结论:大鼠腹腔注射LPS诱导的全身炎症状态能引发脑损伤,骨化三醇干预可能通过调节脑内炎性-抗炎因子的平衡而发挥神经保护作用。     

Failure of calcitriol treatment in a patient with malignant osteopetrosis

In an attempt to stimulate bone resportion, a 10-week-old infant with malignant infantile osteopetrosis was treated with high doses of calcitriol, a potent bone resorption stimulatory agent, combined with a low calcium diet to prevent hypercalcaemia. Although calcitriol administration was initiated at this very young age, our patient did not show any clinical, radiological, or histological improvement. Despite reports of positive results of this treatment in the literature, our patient did not reveal any signs of bone resorption. She eventually died from the complications of osteopetrosis at the age of 6 months after 88 days of therapy.     

Randomized study on oral administration of calcitriol to prevent symptomatic hypocalcemia after total thyroidectomy

BACKGROUND: Symptomatic hypocalcemia remains the main postoperative complication after total thyroidectomy. The aim of the present study was to evaluate the role of oral supplementation of calcitriol and calcium salts in preventing severe postoperative hypocalcemia after total thyroidectomy. METHODS: A consecutive series of patients undergoing total thyroidectomy followed by administration of 500 mg of calcium salts 3 times per day were randomized to 3 different postoperative medical treatments: in group A, .5 microg of calcitriol twice per day was administered to 104 patients; in group B, 1 mmicrog of calcitriol twice per day was administered to 111 patients; and in group C, 202 patients did not receive calcitriol. RESULTS: The rate of postoperative tetany in group A was 2.9%, in group B was 0%, and in group C was 7.4% (P=.03) and the rate of paresthesias was 28.8%, 17.1%, and 22.3%, respectively (P=.19). At discontinuation of calcitriol/calcium salts treatment, intact parathyroid hormone levels did not significantly differ from the preoperative levels. Receiver operating characteristic (ROC) curve analysis showed that the area under the curve for serum concentration of calcium in predicting postoperative tetany was .749, .858 and .862 on the first, second, and third postoperative day, respectively. The best cut-off value of calcemia for prediction tetany was 7.5 mg/dL, and the rate of severe hypocalcemia on the third postoperative day was 23.1% in group A, 9.9% in group B, and 27.2% in group C (P=.001). CONCLUSIONS: Oral administration of 1 microg of calcitriol twice per day and 500 mg of calcium salts 3 times per day after total thyroidectomy significantly decreases the risk of severe postoperative hypocalcemia.     

Vitamin D Analogs Versus Native Vitamin D in Preventing Bone Loss and Osteoporosis-Related Fractures: A Comparative Meta-analysis

It has been suggested that early postmenopausal women and patients treated with steroids should receive preventive therapy (calcium, vitamin D, vitamin D analogs, estrogens, or bisphosphonates) to preserve their bone mineral density (BMD) and to avoid fragility fractures. We designed the present study to compare the effects of native vitamin D to its hydroxylated analogs alfacalcidol 1-(OH)D and calcitriol 1,25(OH)₂D. All randomized, controlled, double-blinded trials comparing oral native vitamin D and its analogs, alfacalcidol or calcitriol, to placebo or head-to-head trials in primary or corticosteroids-induced osteoporosis were included in the meta-analysis. Sources included the Cochrane Controlled Trials Register, EMBASE, MEDLINE, and a hand search of abstracts and references lists. The study period January 1985 to January 2003. Data were abstracted by two investigators, and methodological quality was assessed in a similar manner. Heterogeneity was extensively investigated. Results were expressed as effect-size (ES) for bone loss and as rate difference (RD) for fracture while allocated to active treatment or control. Publication bias was investigated. Fourteen studies of native vitamin D, nine of alfacalcidol, and ten of calcitriol fit the inclusion criteria. The two vitamin D analogs appeared to exert a higher preventive effect on bone loss and fracture rates in patients not exposed to glucocorticoids. With respect to BMD, vitamin D analogs versus placebo studies had an ES of 0.36 (P < 0.0001), whereas native vitamin D versus placebo had an ES of 0.17 (P = 0.0005), the interclass difference being highly significant (ANOVA-1, P < 0.05). When restricted to the lumbar spine, this intertreatment difference remained significant: ES = 0.43 (P = 0.0002) for vitamin D analogs and ES = 0.21 (P = 0.001) for native vitamin D (analysis of variance [ANOVA-1], P = 0.047). There were no significant differences regarding their efficacies on other measurement sites (ANOVA-1, P = 0.36). When comparing the adjusted global relative risks for fracture when allocated to vitamin D analogs or native vitamin D, alfacalcidol and calcitriol provided a more marked preventive efficacy against fractures: RD = 10% (95% Confidence interval [CI-2] to 17) compared to RD = 2% (95% CI, 1 to 2), respectively. The analysis of the spinal and nonspinal showed that fracture rates differed between the two classes, thereby confirming the benefits of vitamin D analogs, with significant 13.4% (95% CI 7.7 to 19.8) and. 6% (95% CI 1 to 12) lower fracture rates for vitamin D analogs, respectively. In patients receiving corticosteroid therapy, both treatments provided similar global ESs for BMD: ES = 0.38 for vitamin D analogs and ES = 0.41 for native vitamin D (ANOVA-1, P = 0.88). When restriced to spinal BMD, D analogs provided significant effects, whereas native vitamin D did not: ES = 0.43 (P < 0.0001) and ES = 0.33 (P = 0.21), respectively. The intertreatment difference was nonsignificant (ANOVA-1, P = 0.52). Neither D analogs for native vitamin D significantly prevented fractures in this subcategory of patients: RD = 2.6 (95%CI, –9.5 to 4.3) and RD = 6.4 (95%CI, –2.3 to 10), respectively. In head-to-head studies comparing D analogs and native vitamin D in patients receiving corticosteroids, significant effects favoring D analogs were found for femoral neck BMD: ES = 0.31 at P = 0.02 and spinal fractures: RD = 15% (95%CI, 6.5 to 25). Publication bias was not significant. Our analysis demonstrates a superiority of the D analogs atfacalcidol and calcitriol in preventing bone loss and spinal fractures in primary osteoporosis, including postmenopausal women. In corticosteroid-induced osteoporosis, the efficacy of D analogs differed depending on the comparative approach: indirect comparisons led to nonsignificant differences, whereas direct comparison did provide significant differences. In this setting, D analogs seem to prevent spinal fractures to a greater extent than do native vitamin D, but this assumption should be confirmed on a comprehensive basis in multiarm studies including an inactive comparator.     

绝经后妇女骨丢失与1,25-二羟维生素D的相关性研究

目的研究随增龄和绝经发生的骨化三醇1,25(OH)2D活性和/或数量降低与骨量丢失的相关性及其影响因素,以阐明绝经后骨质疏松症的病因机理以用于指导临床防治.方法应用放免法测定了绝经后骨质疏松症妇女57例和绝经后非骨质疏松症妇女37例的血清1,25-二羟维生素D(1,25(OH)2D)、25-羟维生素D(25(OH)D)、甲旁腺素(PTH)、雌激素(E2)水平,ELISA法测定尿脱氧吡啶酚与肌酐比值等骨代谢相关指标,并进行病例对照分析.结果绝经后骨质疏松妇女血清1,25(OH)2D和25(OH)D含量分别为18 pg/ml±6pg/ml和32 ng/ml±9 ng/ml,非骨质疏松组分别为31 pg/ml±14 pg/ml和46 pg/ml±17 ng/ml, 骨质疏松妇女的血清1,25(OH)2D和25(OH)D含量明显低于非骨质疏松妇女,雌激素水平也明显降低,但PTH和Dpd/Cr水平则明显升高(P<0.01).对于绝经后妇女,L2～4的骨密度值(BMD)与血清1,25(OH)2D含量存在高度相关(r=0.693,P<0.001), BMD值的变异中有48%可以用血清1,25(OH)2D水平的变化来解释.此外,血清1,25(OH)2D与25(OH)D的相关关系密切(r=0.511, P<0.001),两者存在底物依赖合成关系.结论血清1,25(OH)2D水平与骨量值明显相关.年龄的增长,绝经年限的延长和绝经引起雌激素水平的下降,导致了血清1,25(OH)2D 水平下降,并伴有继发性PTH升高,是绝经后妇女骨量丢失加速的重要病理生理之一.     

骨化三醇在抑制大鼠同种肢体移植排斥反应中的作用

目的 探讨应用骨化三醇(1,25-二羟维生素D;简称:VD5)在抑制肢体移植排斥反应中的作用.方法 以Wistar大鼠为供者,SD大鼠为受者,建立同种肢体移植模型.随机将受者分为4组,每组12只.(1)对照组:术后不用免疫抑制剂,仅以15 ml·kg-1·d-1.生理盐水灌服.(2)他克莫司(FK506)组:将FK506用生理盐水稀释为0.5 mg/ml,术后前2周的用量为1.0 mg·kg-1·d-1,术后第3周起,每周灌服2次.(3)VD3组:将骨化三醇用生理盐水稀释为0.125 μg/ml,术后用量为2.5μg·kg-1·d-1,连续灌服4周.(4)VD3+FK506组:术后联合应用骨化三醇及FK506,用药方法和用量与FK506组和VD3组相同.术后观察各组受者移植肢体排斥反应发生的时间和存活时间;流式细胞仪检测T淋巴细胞亚群CD4+、CD8+细胞的百分率.结果 对照组、FK506组、VD3组以及VD3+FK506组肢体移植后排斥反应发生的时间分别为:(3.50±0.50)d、(13.13±1.50)d、(10.63±0.38)d和(29.25±0.63)d;移植肢体的存活时间分别为:(8.50±0.50)d、(26.25±1.50)d、(17.25±0.38)d和(62.00±0.63)d;与对照组比较,VD3组排斥反应发生的时间和移植肢体的存活时间均明显延长,差异有统计学意义(P＜0.01);VD3+FK506组抗排斥反应效果更佳,与FK506组和VD3组比较,差异有统计学意义(P＜0.01).VD3组T淋巴细胞亚群CD4+/CD8+细胞的比值明显低于对照组,VD3+FK506组又明显低于VD3组和FK506组(P＜0.01).结论 骨化三醇能明显减轻同种肢体移植排斥反应,延长移植肢体的存活时间;骨化三醇与FK506联合应用效果更佳,二者具有协同作用.     

Risk of Calcium Oxalate Nephrolithiasis after Calcium or Combined Calcium and Calcitriol Supplementation in Postmenopausal Women

Although calcium supplementation can cause hypercalciuria, the risk of nephrolithiasis has been shown to decrease rather than increase among subjects who had a higher calcium intake. Hypercalciuria is also a well-established side effect of calcitriol administration. However, the risk of nephrolithiasis is not well defined. The present study was undertaken to prospectively determine the effect of calcium with or without calcitriol on physicochemical risk factors associated with calcium oxalate nephrolithiasis in Thai postmenopausal women with osteoporosis. Subjects consisted of 53 Thai women more than 10 years postmenopausal who were randomly allocated to receive 750 mg of calcium carbonate supplement alone (n= 28) or 750 mg of calcium carbonate plus 0.5 mg calcitriol (n= 25) daily. Mean ± SEM for age was 65.3 ± 1.1 years, body weight 53.5 ± 1.3 kg. Urine samples for biochemical assays were collected at baseline and 3 months after treatment. Supersaturation for calcium oxalate stone formation was assessed from the 24 h urine constituents by the Tiselius’s index, AP(CaOx). Three months of calcium supplement alone resulted in a modest, but not significant, increase in urinary calcium (baseline, 2.90 ± 0.43 mmol/day; after treatment 3.58 ± 0.54 mmol/day) with no change in urinary oxalate, citrate or magnesium. In contrast, calcium together with calcitriol caused a significant increase in urinary calcium (baseline, 2.87 ± 0.41 mmol/day; after treatment, 4.08 ± 0.57 mmol/day; p<0.05). No significant change in other urine constituents after treatment with calcium and calcitriol was detected. Therefore, AP(CaOx) did not significantly increase either after calcium alone (baseline, 1.17 ± 0.39; after treatment, 1.36 ± 0.28) or after calcium plus calcitriol (baseline, 1.09 ± 0.17; after treatment, 1.09 ± 0.19). However, after treatments, 12 subjects (23%) – 6 receiving calcium supplement alone and 6 receiving calcium plus calcitriol supplement – had high AP(CaOx) values (greater than the upper limit of 95% CI for AP(CaOx) derived from non-stone-forming Thai women). The post-treatment/baseline ratio was 3.21 ± 0.74 for urinary calcium, 1.01 ± 0.19 for urinary oxalate, and 2.23 ± 0.42 (median 1.15) for AP(CaOx). The post-treatment/baseline ratio of calcium, but not for urinary oxalate, had a significant correlation with the post-treatment/baseline ratio of AP(CaOx). Our findings suggest that the alteration in the risk of calcium oxalate nephrolithiasis based on urinary composition is related to the alteration in urinary calcium. The risk of calcium oxalate nephrolithiasis does not increase significantly after calcium or combined calcium and calcitriol supplement in the majority of postmenopausal women with osteoporosis. Received: 10 March 1999 / Accepted: 16 November 1999