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L Rejnmark, AL Lauridsen, P Vestergaard, L Heickendorff, F Andreasen and L Mosekilde

OBJECTIVE: Diurnal variations in plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D) have previously only been investigated in young individuals, and these studies have failed to demonstrate a diurnal rhythm. We have studied whether plasma levels of 1,25(OH)(2)D and vitamin D-binding protein (DBP) vary in a diurnal rhythm in postmenopausal women. METHODS: Blood and urine were sampled with 2- and 4-h intervals in order to assess diurnal variations in plasma levels of 1,25(OH)(2)D, DBP and parathyroid hormone (PTH), as well as in plasma levels and urinary excretion rates of calcium and phosphate. Additionally, the free 1,25(OH)(2)D index was calculated (the molar ratio of 1,25(OH)(2)D to DBP). RESULTS: Plasma 1,25(OH)(2)D exhibited a diurnal rhythm (P<0.01) with a nadir in the morning (99+/-12 pmol/l), followed by a rapid increase to a plateau during the day (113+/-13 pmol/l, i.e. 14% above nadir level; P=0.005). A similar pattern of variation was found in plasma levels of DBP with peak levels 15% above nadir levels (P<0.01). The free 1,25(OH)(2)D index did not vary in a diurnal rhythm. PTH and plasma levels and urinary excretions of calcium and phosphate exhibited a diurnal pattern of variation. The diurnal rhythm of DBP was correlated with the rhythm of 1,25(OH)(2)D (r=0.47, P<0.01) and plasma albumin (r=0.76, P<0.01). Moreover, the rhythm of plasma calcium and PTH varied inversely (r=-0.36, P=0.02). CONCLUSIONS: With the disclosure of a diurnal rhythm of total plasma 1,25(OH)(2)D, all major hormones and minerals related to calcium homeostasis have now been shown to exhibit diurnal variations. In clinical studies, the diurnal variations of 1,25(OH)(2)D and DBP must be considered, i.e. blood sampling must be standardised according to the time of day.

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P Vestergaard, J Lindholm, JO Jorgensen, C Hagen, HC Hoeck, P Laurberg, L Rejnmark, K Brixen, LO Kristensen, U Feldt-Rasmussen and L Mosekilde

OBJECTIVE: To evaluate if fracture risk was increased in patients with Cushing's syndrome due to the increased endogenous cortisol production. DESIGN: Cohort. METHODS: A self-administered questionnaire was mailed to 125 patients with Cushing's syndrome diagnosed between 1985 and 1999 in Denmark. The response of each patient was compared with that of three age- and gender-matched control subjects randomly drawn among respondents to the same questionnaire from the background population. RESULTS: One hundred and four patients (83%) responded. The median age of the patients was 48 years (range 19-85 years). Sixty-eight had pituitary disease, 28 had adrenal disease, four had had both pituitary and adrenal surgery while four had not undergone surgery at the time of the study. The median time from diagnosis to surgery was 0.2 (range 0-3) years. Eighty-six percent were cured following surgery. There was an increased fracture risk within the last 2 years prior to diagnosis (incidence rate ratio 6.0, 95% confidence intervals (CI): 2.1-17.2). More than 2 years prior to diagnosis and following diagnosis there was no difference in fracture risk between patients and controls. The patients had more low-energy fractures than the controls (relative risk 5.4, 95% CI: 1.4-20.1). There was no difference in fracture risk between patients with adrenal or pituitary disease. CONCLUSIONS: Patients with Cushing's syndrome had an increased fracture risk in a narrow time interval before diagnosis, while no increase in fracture risk could be demonstrated after diagnosis and treatment.