GEOMAR, Helmholtz-Center for Ocean Research Kiel, Germany.
GEOMAR, Helmholtz-Center for Ocean Research Kiel, Germany; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta, Indonesia.
Bone. 2024 Nov;188:117210. doi: 10.1016/j.bone.2024.117210. Epub 2024 Jul 28.
To further explore the clinical applicability of the calcium (Ca) isotope marker (CIM), we determined the Ca/Ca isotope ratio in blood serum and urine. This ratio is expressed in the conventional δ-notation (as defined in the text below) specifically as CIM-serum for serum and as CIM-urine for urine. Our study tested the hypothesis that CIM values can differentiate between positive and negative bone mineral balance (BMB) across a diverse clinical population considering variables such as age, gender, and diet. The threshold values (CIM-serum: -0.85 ± 0.06 ‰ and CIM-urine: 0.23 ± 0.06 ‰) established in the OsteoGeo study (NCT02967978, Eisenhauer et al., 2019) were evaluated in 2320 participants as part of a surveillance study referred to as Osteolabs study. The earlier study revealed women with osteoporosis had an average CIM-serum value of -0.91 ± 0.21 ‰ (N = 24) and a CIM-urine value of 0.18 ± 0.33 ‰ (N = 71) that are significantly below the threshold values (p = 0.02 for urine, one-sided Wilcoxon rank test, p < 0.001 for serum, one-sided Student's t-test). Diseases affecting BMB such as osteoporosis, acute and chronic kidney disease (CKD), hyperthyroidism, breast cancer, prostate cancer, and myeloma were associated with significantly lower average CIM values, falling below the equilibrium thresholds and indicating negative BMB. In contrast, patients receiving osteoprotective treatments such as denosumab, Romosozumab, bisphosphonates, or hormone replacement therapy for certain diseases, had CIM values above the equilibrium thresholds indicating a positive BMB. Additionally, Ca supplements taken by some of the patients ((N = 22 (serum), N = 49 (urine), median dose: 500 mg) showed a Ca isotope composition approximately 1 ‰ higher than that from a normal diet. Consequently, their CIM values need to be adjusted to account for the amount and duration of supplementation to be comparable to those with a normal diet. Participants taking vitamin D (237 women; 58 men) showed no significant difference from the average values of the study group. Counterintuitively, the possible impact of malnutrition on individual BMB was most pronounced in vegans, who exhibited the highest average CIM-urine values compared to patients on a normal diet (p < 0.001, N = 17). The results of this study were consistent with the registered OsteoGeo study (NCT02967978) and other earlier published Ca isotope-based studies on BMB. We confirm that the CIM threshold values determined in the OsteoGeo study are generally valid for this much larger and diverse surveillance study group covering a diverse population encompassing various medical conditions and therapies.
为了进一步探索钙（Ca）同位素标志物（CIM）的临床适用性，我们测定了血清和尿液中的 Ca/Ca 同位素比值。该比值以传统的 δ 符号表示（见下文定义），具体表示为血清中的 CIM-血清（CIM-serum）和尿液中的 CIM-尿液（CIM-urine）。我们的研究检验了一个假设，即在考虑年龄、性别和饮食等变量的情况下，CIM 值可用于区分不同临床人群的阳性和阴性骨矿物质平衡（BMB）。OsteoGeo 研究（NCT02967978，Eisenhauer 等人，2019 年）中建立的阈值（CIM-血清：-0.85±0.06‰和 CIM-尿液：0.23±0.06‰）在 2320 名参与者中进行了评估，作为 Osteolabs 研究的监测研究的一部分。该前期研究表明，患有骨质疏松症的女性 CIM-血清值的平均值为-0.91±0.21‰（N=24），CIM-尿液值为 0.18±0.33‰（N=71），显著低于阈值（尿液，单侧 Wilcoxon 秩检验，p=0.02；血清，单侧学生 t 检验，p<0.001）。影响 BMB 的疾病，如骨质疏松症、急性和慢性肾病（CKD）、甲状腺功能亢进症、乳腺癌、前列腺癌和骨髓瘤，与显著较低的平均 CIM 值相关，低于平衡阈值，表明存在负 BMB。相比之下，接受骨保护治疗的患者，如地舒单抗、Romosozumab、双膦酸盐或激素替代疗法治疗某些疾病，CIM 值高于平衡阈值，表明存在正 BMB。此外，一些患者（（N=22（血清），N=49（尿液），中位数剂量：500mg）服用了钙补充剂，其钙同位素组成比正常饮食高约 1‰。因此，需要调整他们的 CIM 值以考虑补充的量和时间，使其与正常饮食的 CIM 值相比较。服用维生素 D 的参与者（237 名女性；58 名男性）与研究组的平均值无显著差异。违反直觉的是，营养不良对个体 BMB 的可能影响在纯素食者中最为明显，他们的平均 CIM-尿液值与正常饮食的患者相比最高（p<0.001，N=17）。这项研究的结果与已注册的 OsteoGeo 研究（NCT02967978）和其他早期发表的基于 Ca 同位素的 BMB 研究一致。我们证实，OsteoGeo 研究中确定的 CIM 阈值通常适用于涵盖各种医疗条件和治疗的这种更大和更多样化的监测研究组。
