Changes in bone turnover during the menstrual cycle in cynomolgus monkeys

It is well established that estrogen deficiency at menopause results in increased bone turnover, which is reflected in increased concentrations of markers of bone formation and bone resorption in serum and urine. Since serum 17beta-estradiol concentrations vary markedly throughout the menstrual cycle, one would expect to see changes in bone turnover as well. Studies in humans have not yielded consistent results, perhaps because of differences in diet and activity throughout the test period. Therefore, we examined changes in bone biomarkers throughout the menstrual cycle in cynomolgus macaques. Seven intact female cynomolgus macaques (Macaca fascicularis) were evaluated. Vaginal swabs for menstrual blood were performed 3 times/week to determine the stage of the reproductive cycle. Blood and urine were collected at weekly or biweekly intervals for a total of eight samples per monkey for analysis of serum 17beta-estradiol, progesterone, parathyroid hormone (PTH), osteocalcin, bone-specific alkaline phosphatase (BSAP), and urinary CrossLapstrade mark. Cycle lengths were determined, and collection days were adjusted to a standardized length of 28 days for all monkeys. Values for bone biomakers were evaluated as % mean for each monkey cycle. By fitting the data to a sine wave (cosinor analysis), serum osteocalcin, BSAP, and urinary CrossLaps demonstrated significant cycles with peaks at days 2.6, 7.3, and 27.8, respectively. Serum osteocalcin and urinary CrossLaps were inversely correlated to serum 17beta-estradiol. Urinary CrossLaps were significantly lower in the week just prior to and during ovulation when estradiol was elevated. No rhythm was detected in serum PTH. A peak in bone resorption when serum 17beta-estradiol is at its nadir is consistent with the hypothesis that estrogen decreases bone turnover.