Cyclic variations of bone resorption mediators and markers in the different phases of the menstrual cycle

Female hormones are very important in regulating bone homeostasis; the drop of estrogen levels occurring at menopause is linked to a dramatic prevalence of bone resorption on formation. Only a small number of studies investigated the relationship between changes in circulating female sex hormones and the markers and mediators of bone homeostasis and they showed conflicting results. To explore such relationships we studied 20 young fertile healthy women, aged between 19 and 32 years. None had received hormone treatment for at least 6 months. We assayed luteinizing hormone, follicle-stimulating hormone, progesterone and 17β-estradiol, as well as the levels of osteoprotegerin (OPG), C-terminal telopeptide of collagen type I (CTx) and RANKL (receptor activator of nuclear factor-B ligand) in samples drawn from every subject at four different times during the menstrual cycle when estrogens are lowest, at the start of the cycle: T ₀ (2–4th day); when estrogens are highest, in the pre-ovulatory period: T ₁₄ (12–14th day); when progesterone activity is highest, in the advanced luteal phase: T ₂₆ (24–26th day); and again at the start of the next cycle: T ₀₁ (2–4th day). We observed that CTx levels are highest at the start of the cycle, decreased significantly from T ₀ to T ₂₆ (pfwe = 0.0455) and then increased from T ₂₆ to T ₀₁ (pfwe = 0.0415); OPG, on the other hand, which was also highest at the start of the cycle, decreased significantly from T ₀ to T ₁₄ (pfwe = 0.02) and then increased, though not significantly, from T ₁₄ to T ₀₁; no variation was observed in RANKL values at any time. We observed inverse correlations between estradiol and OPG levels, which became highly significant at T ₀₁ between estradiol nadir and OPG peak levels (pfw = 0.0095). Furthermore, the increase of estradiol from T ₀ to T ₁₄ was negatively correlated with the concomitant decrease of OPG (pfwe = 0.0277), as was the fall of estradiol from T ₂₆ to T ₀₁ with the OPG peak levels, both at T ₀₁ (pfw = 0.0045) and at T ₀ (pfwe = 0.0381). We also observed direct correlations between the OPG levels and the variations of progesterone in the preceding intervals, but they never attained statistical significance. We conclude that OPG and CTx fluctuation during the menstrual cycle are likely due to the physiological variations of sex steroids levels.