title: The circadian rhythm of biochemical markers of bone resorption is normally synchronized in breast cancer patients with bone lytic metastases independently of tumor load.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Breast Unit, Azienda Istituti Ospitalieri, Cremona, Viale Concordia 1, I-26100 Cremona, Italy. daniele.generali@gmail.com
authors.forename: Daniele
authors.initials: D
authors.lastname: Generali
authors.forename: Alfredo
authors.initials: A
authors.lastname: Berruti
authors.forename: Marco
authors.initials: M
authors.lastname: Tampellini
authors.forename: Andrea
authors.initials: A
authors.lastname: Dovio
authors.forename: Sara
authors.initials: S
authors.lastname: Tedoldi
authors.forename: Simone
authors.initials: S
authors.lastname: Bonardi
authors.forename: Marcello
authors.initials: M
authors.lastname: Tucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Allevi
authors.forename: Sergio
authors.initials: S
authors.lastname: Aguggini
authors.forename: Manuela
authors.initials: M
authors.lastname: Milani
authors.forename: Alberto
authors.initials: A
authors.lastname: Bottini
authors.forename: Luigi
authors.initials: L
authors.lastname: Dogliotti
authors.forename: Alberto
authors.initials: A
authors.lastname: Angeli
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary*; D001862:Bone Resorption / Q000378:metabolism*; D001943:Breast Neoplasms / Q000473:pathology*; D002940:Circadian Rhythm; D005260:Female; D006801:Humans; D008875:Middle Aged; D047368:Tumor Burden
chemical_list: D015415:Biomarkers