We demonstrated lower bone-density measures at the spine and for the WB in adolescent athletes with amenorrhea, compared with athletes with eumenorrhea and control subjects, and lower bone density at the hip, compared with athletes with eumenorrhea. Our findings raise concerns regarding the deleterious effects of a hypogonadal state on bone metabolism, despite the known beneficial effects of exercise, particularly high-impact load exercises44
and weight-bearing exercises,45
on bone mass and geometric characteristics in adolescents. Lower bone density in athletes with amenorrhea was associated with lower levels of both bone formation and bone-resorption markers, indicating a state of reduced bone turnover. Important independent predictors of bone-density measures included body-composition parameters such as lean mass and BMI z
scores, levels of IGF-I (a surrogate marker of nutritional status), and diagnostic category (athletes with amenorrhea, athletes with eumenorrhea, or control subjects). For athletes with amenorrhea, duration of amenorrhea was an independent inverse predictor of bone density, controlling for IGF-I levels, body composition, and other measures.
Although studies have examined bone metabolism in adult athletes,6–14
few studies have addressed this question in adolescent athletes, especially in comparison with a group of nonathletic control subjects. Because as many as 23.5% of high school athletes may have menstrual irregularities1
and because the adolescent years are a critical time for bone mass accrual,15
these data are important to obtain. Our data indicated that, whereas athletes with normal menstrual function have preservation of bone mass and may have slightly higher bone mass, compared with nonathletic control subjects, loss of menses in athletes is associated with lower bone-density measures. Athletes with amenorrhea had lower bone density than did athletes with eumenorrhea and control subjects, controlling for levels of IGF-I (a surrogate marker of nutritional status), body composition, and bone age in a regression model. Duration of amenorrhea did not correlate with BMD in athletes with amenorrhea in a simple correlational analysis. It is possible that our study was underpowered to detect this association or that this measure does not capture the extent of gonadal dysfunction in athletes with amenorrhea. Of importance, we measured the duration of amenorrhea since the last menstrual period and not the lifetime duration of oligomenorrhea/amenorrhea, which might have been more predictive of bone-density measures. When duration of amenorrhea was added to a regression model for athletes with amenorrhea that included BMI z
scores, lean mass, bone age, IGF-I levels, activity scores, and menarchal age, it did significantly predict several measures of bone density in the larger regression model. These data suggest complex interactions between duration of amenorrhea and other covariates predicting bone density in athletes with amenorrhea.
We did not measure estradiol levels in this study, and the degree of hypoestrogenism may predict bone-density measures. However, because of the great variability in estradiol levels across the menstrual cycle, these levels may not be helpful, as evidenced by our studies with adolescent girls with anorexia nervosa.30
In those studies, we compared estradiol levels measured randomly in anorexia nervosa with estradiol levels measured in the early follicular phase in healthy control subjects, and we did not find an association between estradiol levels and bone-density measures.30
Nevertheless, the contribution of hypogonadism to low bone density in athletes with amenorrhea is indicated by (1) data from our regression models, as discussed above, and (2) greater deficits in bone-density measures in athletes with amenorrhea, compared with athletes with eumenorrhea, in our subset analysis of 16 athletes with amenorrhea and 13 athletes with eumenorrhea for whom BMI z
scores, activity levels, and age did not differ and the only difference was the presence or absence of amenorrhea.
Athletes with amenorrhea have lower bone density not only in comparison with athletes with eumenorrhea but also in comparison with nonathletic control subjects with normal menstruation. Therefore, in addition to the beneficial effects of exercise on bone density being lost in girls who develop amenorrhea, amenorrhea may actually be deleterious to bone health. Nichols et al1
reported lower bone density at the femoral trochanter, although not at the spine, in athletes with amenorrhea, compared with athletes with eumenorrhea, but those authors did not compare the groups with nonathletic control subjects. Our data, in contrast, indicate lower bone density at the spine and in the WB in adolescent athletes with amenorrhea, compared with athletes with eumenorrhea and control subjects. Our study also raises concerns regarding the rate of bone mass accrual and subsequent peak bone mass in adolescent athletes with amenorrhea. Studies examining bone mass accrual over time in athletes are lacking and are important for determining whether peak bone mass is affected in these adolescents.
Important predictors of bone density other than amenorrhea included nutritional measures such as IGF-I levels and body-composition parameters such as lean mass and BMI z
scores. Associations of BMI and lean mass with bone density are consistent with findings in other studies with athletes46
and other populations.30
Although subjects in our study were within a normal range for BMI, athletes with amenorrhea had lower BMI z
scores than athletes with eumenorrhea and lower IGF-I levels than control subjects. Lean mass was an important predictor of bone density in athletes with amenorrhea and in the group as a whole. Although lean mass in athletes with eumenorrhea was somewhat greater than that in athletes with amenorrhea and control subjects, these differences were not statistically significant and, despite preservation of lean mass, athletes with amenorrhea had lower bone density, compared with athletes with eumenorrhea and control subjects. For athletes with amenorrhea, the relatively lower nutritional status, as evidenced by low IGF-I levels, and the state of hypogonadism likely contributed to lower bone density despite preservation of lean mass. Vitamin D intake and calcium intake were higher in athletes with amenorrhea, compared with athletes with eumenorrhea and control subjects, primarily through increased use of supplements; this likely reflects concerns of care providers regarding bone density and therefore increased prescription of these supplements for girls with amenorrhea. Of note, high cortisol levels have been reported in some studies of adult athletes with amenorrhea in comparison with athletes with eumenorrhea,47
although not in all studies,48
and cortisol has known deleterious effects on bone. Although we did not measure cortisol levels for our subjects, this would be important to examine in future studies.
The approach described by Mølgaard et al42
differentiates between reported low bone density resulting from short bones (based on height z
scores) and that resulting from “thin” bones (based on measures of BA for height), and “light” bones (based on measures of BMC for BA). Whereas short bones are not necessarily at greater risk of fractures, thin bones (low BA for height) and light bones (low BMC for BA) have impaired strength. Athletes with amenorrhea had lower BMC for BA at the spine and lower WB BA for height than did athletes with eumenorrhea, although values did not differ from those in control subjects. Similar to other measures of bone density, beneficial effects of exercise on these measures seem to be lost in athletes who stop menstruating. Although athletes with amenorrhea did report more fractures than athletes with eumenorrhea, this difference was not statistically significant, and larger numbers of subjects are required to demonstrate whether fracture risk is increased in athletes with amenorrhea. Given that bone-density z
scores were less than –2 in only 2 of our subjects with amenorrhea, it is unlikely that the bone-density measures we report in this study were low enough to cause increased fracture risk.
Markers of bone turnover were decreased in athletes with amenorrhea, compared with control subjects. This is in contrast to what may be expected, given the state of hypogonadism in athletes with amenorrhea. Estrogen inhibits bone resorption,49,50
and deficiency of estrogen, as in athletes with amenorrhea, would be expected to be associated with increased bone resorption. Overall, bone age was the strongest predictor of bone-turnover markers, and girls with greater bone age (and therefore less residual growth potential) had lower levels of bone-turnover markers. This is consistent with the fact that bone-turnover decreases in late adolescence, when little growth potential remains. Levels of IGF-I also predicted N-telopeptide levels, and the suboptimal nutritional state in athletes with amenorrhea seems to result in reduced bone turnover overall. In athletes with eumenorrhea, levels of bone-turnover markers were intermediate between those in control subjects and those in athletes with amenorrhea but did not differ significantly from either. This finding is unexpected, given that bone density was slightly greater in athletes with eumenorrhea than in the other 2 groups, leading to expectations of higher levels of bone formation markers and lower levels of bone-resorption markers in athletes with eumenorrhea, compared with both control subjects and athletes with amenorrhea. Somewhat lower levels of bone-turnover markers in athletes with eumenorrhea than in control subjects may be related to the somewhat lower IGF-I levels in athletes with eumenorrhea. However, these data need to be confirmed in future studies.
It is important to determine the factors that lead to hypogonadism in some but not all athletes. One possible contributor is the lower fat mass in athletes with amenorrhea, compared with athletes with eumenorrhea and control subjects, and we showed in other studies that fat mass is an important predictor of menstrual function.51
Importantly, a negative state of energy balance caused by nutrient intake that is inadequate to balance the expenditure associated with exercise (rather than the stress of exercise) is thought to be instrumental in the development of hypogonadotropic hypogonadism in athletes.52,53
A limitation of our study is the lack of details regarding nutritional intake and daily energy expenditure in our subjects. Although IGF-I levels and composite activity scores did not differ between athletes with amenorrhea and athletes with eumenorrhea, a complete assessment of energy intake and energy expenditure would have enabled us to determine whether athletes with amenorrhea were in a negative state of energy balance, accounting for their hypogonadotropic state. On the basis of the lower BMI and fat mass but equivalent activity scores in this group, compared with athletes with eumenorrhea, dietary intake in athletes with amenorrhea would be expected to be significantly lower than that in athletes with eumenorrhea, consistent with the greater frequency of disordered eating observed for athletes with amenorrhea. In addition, although screening questions ensured that athletes with amenorrhea and athletes with eumenorrhea met inclusion criteria for endurance athletes, the activity scores derived from the exercise questionnaire we used in this study did not take into account differences in types of exercise.54
Questionnaires that provide a composite measure of average daily energy expenditure, based on the nature of exercise and assigned metabolic equivalents, should be useful in this regard.55
Another limitation is that we concentrated on IGF-I levels and the hypogonadal state as possible predictors of bone metabolism in this study of adolescent athletes with amenorrhea, athletes with eumenorrhea, and control subjects, given the critical roles of IGF-I and estrogen in increasing bone density in adolescents. In future studies, it will be important to measure levels of other hormones known to affect bone density, such as 24-hour urinary free cortisol levels, thyroid hormone levels, and levels of some of the appetite-regulating peptides. It will also be important to obtain history regarding lifetime duration of oligomenorrhea, rather than just duration of amenorrhea, as an indicator of gonadal status. Finally, there is a possibility of referral bias in studies such as this, in which girls at some risk for low bone density may be more likely to be referred for assessment of bone density.