Circadian rhythm of bone turnover markers in breast cancer patients with bone metastases and in control subjects

Background: Circadian rhythmicity is an essential feature of bone metabolism. The assessment of diurnal variation in bone resorption and formation markers in cancer patients with bone metastases could provide further insights on tumour induced derangement in bone turnover. Methods: 21 ambulatory breast cancer patients with bone metastases and 20 age-matched controls entered the study. Blood and urine specimens in both groups were collected starting at 8 am every 4 hours till midnight and every 2 hours till 8 am to assess alkaline phosphatase (ALP), Calcium, (Ca), albumin (ALB), cortisol, osteocalcin, cross-laps (CTX) and parathyroid hormone (PTH) in blood and deoxy-pyridinoline (DPD) and n-telopeptide (NTX) in urine. Results: Serum cortisol showed a marked circadian rhythm either in controls or in patients: MESOR 116 ng/dl vs 103.1 ng/dl, amplitude 60.9 ng/dl vs 54.8 ng/dl, acrophase at 6.00 am, (p<0.001) vs at 11.00 am, (p<0.001) respectively. Urinary DPD expressed as variation from individual MESOR showed a significant circadian rhythm either in patients: amplitude 15.4% and acrophase at 9h59 (p<0.001) or in controls: amplitude 13.9%, acrophase at 8h12 (p<0.001). Also urinary NTX showed a diurnal rhythm either in patients: amplitude 11.4%, acrophase at 4h49 (p<0.001) or in controls: amplitude 30.9% at 7h25 (p<0.001). A marked rhythmicity was evident for serum CTX in controls: amplitude 37%, acrophase at 5h55 (p<0.001) and in patients: amplitude 25,2%, acrophase at 2h40 (p<0.001).A significant trend of rhythmicity was evident in cancer patients for osteocalcin (amplitude 5.3%, acrophase 4h50, p=0.08) and PTH (amplitude 18%, acrophase 15h37, p=0.05). No significant circadian rhythm was found for Ca and ALP. Conclusions: Bone resorption markers maintain a circadian rhythmicity in cancer patients. On the basis of these results a randomised trial comparing Zoledronic acid administration day versus night has been conducted. Forty four patients have been enrolled, data on changes in bone turnover markers between the 2 treatment arms will be provided at the meeting