Generali Daniele, Berruti Alfredo, Tampellini Marco, Dovio Andrea, Tedoldi Sara, Bonardi Simone, Tucci Marcello, Allevi Giovanni, Aguggini Sergio, Milani Manuela, Bottini Alberto, Dogliotti Luigi, Angeli Alberto
Breast Unit, Azienda Istituti Ospitalieri, Cremona, Viale Concordia 1, I-26100 Cremona, Italy.
Bone. 2007 Jan;40(1):182-8. doi: 10.1016/j.bone.2006.06.023. Epub 2006 Aug 24.
Bone metastases are devastating events resulting in disruption of local bone remodeling processes. Physiological bone turnover has a circadian rhythm. No data are available on the circadian pattern of bone turnover markers in patients with bone metastases.
Twenty post-menopausal women with breast cancer (BC) at first disease relapse and at least one bone metastasis were consecutively recruited. Twenty healthy women served as controls. Patients were free from concomitant chemotherapy/endocrine therapy. Throughout a 24-h period, urine samples were collected at 4-h intervals, and blood samples were collected at 4-h intervals between 08:00 and 24:00, and at 2-h intervals between 24:00 and 08:00. Serum osteocalcin (OC), total and bone-alkaline phosphatase (tALP and bALP, respectively) and C-terminal telopeptide of type I collagen (CTX), and urinary NTX and free deoxypyridinoline (fDPD) were measured together with serum parathyroid hormone (PTH) and serum and urinary calcium and phosphorus. Temporal variations of measured analytes were assessed by ANOVA and the COSINOR model.
At 08:00, patients had higher levels of bone resorption indices (NTX, CTX and fDPD) than controls (p<0.0001). tALP and bALP, but not OC, were higher in patients than controls (p<0.001). PTH, serum and urinary calcium and urinary phosphorus did not differ between groups; serum phosphorus was higher in controls (p<0.0001). A circadian rhythm was evident for CTX and fDPD values in both patients and controls. A circadian rhythm in NTX, OC, phosphorus and PTH was apparent in controls only. However, it was detected also in patients when percent changes from MESOR were considered. Serum phosphorus showed a circadian rhythm, while no rhythm was detected for tALP, bALP, serum and urinary calcium. The rhythmicities in cancer patients were normally synchronized, and rhythmic parameters were independent of tumor load in the skeleton, age and menopausal status.
This is the first study to yield information on the maintenance of the temporal program of bone turnover in bone metastatic cancer patients. Whether administration of bisphosphonates in the nighttime leads to a different outcome with respect to the current administration in the morning is a matter of future research.
骨转移是破坏性事件，会导致局部骨重塑过程中断。生理性骨转换具有昼夜节律。目前尚无关于骨转移患者骨转换标志物昼夜模式的数据。
连续招募20名首次疾病复发且至少有一处骨转移的绝经后乳腺癌（BC）女性患者。20名健康女性作为对照。患者未同时接受化疗/内分泌治疗。在24小时内，每隔4小时收集一次尿液样本，在08:00至24:00之间每隔4小时采集一次血样，在24:00至08:00之间每隔2小时采集一次血样。检测血清骨钙素（OC）、总碱性磷酸酶和骨碱性磷酸酶（分别为tALP和bALP）、I型胶原C端肽（CTX）、尿NTX和游离脱氧吡啶啉（fDPD），同时检测血清甲状旁腺激素（PTH）以及血清和尿钙、磷。通过方差分析和余弦模型评估所测分析物的时间变化。
08:00时，患者的骨吸收指标（NTX、CTX和fDPD）水平高于对照组（p<0.0001）。患者的tALP和bALP高于对照组，但OC不高于对照组（p<0.001）。两组间PTH、血清和尿钙以及尿磷无差异；对照组血清磷较高（p<0.0001）。患者和对照组的CTX和fDPD值均呈现明显的昼夜节律。仅对照组的NTX、OC、磷和PTH存在昼夜节律。然而，当考虑相对于中值（MESOR）的变化百分比时，患者中也检测到了昼夜节律。血清磷呈现昼夜节律，而tALP、bALP、血清和尿钙未检测到昼夜节律。癌症患者的节律通常是同步的，节律参数与骨骼中的肿瘤负荷、年龄和绝经状态无关。
这是第一项提供骨转移性癌症患者骨转换时间程序维持信息的研究。夜间给予双膦酸盐相对于目前早晨给药是否会产生不同结果是未来研究的课题。
