Mechanism of circadian variation in bone resorption¹

Abstract

The diurnal variation in bone resorption markers is poorly understood and may contain essential information about regulation of bone resorption. To explore the acute regulation of bone resorption we studied bone turnover in 14 postmenopausal women during a randomized, crossover, 24 h study of oral glucose tolerance test (OGTT), normal diet, or fasting. Whereas fasting counteracted variation in bone resorption, as measured by serum C-telopeptide fragments of collagen type 1 degradation (s-CTx), OGTT and normal diet induced a 50% reduction (p < 0.001) over 2 h. For OGTT, s-CTx reverted to baseline levels after 6 h, and for normal diet s-CTx remained suppressed during the afternoon and returned to baseline overnight. Repeated OGTT at 8:00 A.M. and 8:00 P.M. in nine postmenopausal women demonstrated that identical reductions in s-CTx could be obtained at both timepoints with an intermediate return to baseline between tests. A 2 h randomized, crossover study of OGTT and fasting in 23 men and premenopausal women similarly revealed a 50% decrease in s-CTx. A randomized, crossover 2 h study of insulin tolerance test compared with fasting in six men and premenopausal women demonstrated a 20%–30% decrease in s-CTx (p < 0.01–0.05). Nine hour follow-up of ten healthy individuals during a crossover experiment of OGTT, protein, and fat intake revealed a comparable 50% reduction in s-CTx, but distinct profiles of serum glucose and serum insulin. Bone resorption was reduced by intake of food, glucose, fat, and protein and counteracted by fasting, and this seems to have been be independent of age and gender. Both exogenous and endogenous insulin stimulation tests induced a reduction in bone resorption, but this was only partial when compared with the reduction observed during food intake.

Introduction

Osteoporosis is a serious and common disease that occurs worldwide.3 The single most important risk factor for osteoporosis is estrogen deficiency, and it has been estimated that up to one third of postmenopausal women will be affected if left untreated.3 A primary event leading to osteoporotic bone loss is the increase in bone turnover associated with menopause. The acute increase in bone resorption seen with circadian variation takes place with a peak in the early morning, and the lowest level in the afternoon.18 This variation is independent of gender, age, and stage of osteoporosis, although an elevated baseline level is seen in postmenopausal women.5, 6, 12, 18, 19 It is also independent of physical activity, thus 3 days of bed-rest showed no change in variation in premenopausal women.19 In some studies, circadian variation in plasma cortisol has been assessed as a possible factor. Neither cortisol-insufficient individuals substituted intermittently with cortisol to eliminate circadian variation17 nor cortisol-clamp studies in healthy postmenopausal women8 demonstrated any influence on circadian variation in bone resorption. Parathyroid hormone (PTH)-clamp studies in pre- and postmenopausal women showed that circadian variation in bone turnover is also independent of serum PTH concentration.10 Recently, one study of premenopausal women demonstrated that circadian variation in bone resorption, as measured by urinary excretion of C-telopeptide fragments of collagen type 1 (CTx) degradation, was significantly diminished during fasting.16 Therefore, we designed a series of studies to elucidate the possible effects of components of food intake upon circadian variation in markers of bone turnover.