Wayne State University School of Medicine Detroit, Michigan 48201
Address correspondence and requests for reprints to: Michael Kleerekopper, Division of Endocrinology, Wayne State University, 4201 St. Antoine, Detroit, Michigan 48201.
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An elegant clinical study by Girgis and Winter published in this issue of JCEM (see page 3926) (5) offers an opportunity to evaluate a different paradigm with respect to the effect of steroids on the skeletonthe treatment of congenital adrenal hyperplasia (CAH). The treatment dose of hydrocortisone these children were targeted to receive was 1015 mg/m2 per day. This dose of hydrocortisone, which is twice the estimated cortisol production rate (6), is required to suppress ACTH secretion. While we as clinicians try to optimize our therapeutic regimens for our patients we recognize that even with the best of intent our patients are not fully compliant with our therapeutic directions. Capitalizing on this, these investigators were able to classify the patients into those with tight, fair, and poor control based on the degree to which 17-hydroxyprogesterone levels were suppressed with glucocorticoid therapy. With normalization of androgen hypersecretion there was a slight delay in skeletal maturation. At the other end of the spectrum with poor control and hyperandrogenism, skeletal maturation was enhanced. However, there was minimal clinical impact resulting from these three different degrees of therapeutic control of CAH. In particular, the enhanced skeletal maturation associated with poor control was not associated with a greater decrement in current stature. This observation led the authors to speculate that the short stature of CAH is already determined by therapy-induced hypercortisolemia during first two years of life.
While possibly the most plausible explanation for their observation, other mechanisms must also be considered. Because final adult height has not as yet been achieved, it is difficult to extrapolate these observations to ultimate short stature and failure to achieve height potential. In a diverse ethnic population, in a study of limited size, it is difficult to control for this variable as well as for gender. Short stature may be viewed on normative population data and also on available height potential. What do we know about the heights of parents and grandparents of the children with CAH? The concept of a "critical time period", birth to two years is novel and intriguing, but is it real?
Intriguing as it might be to accept and further explore the possibility that much of the damage to skeletal growth and development is accomplished during the first two years of life with substantial hypercortisolemia, there are some concerns that should be raised. In particular, one could question the data that exclusively focuses on regional bone mineral density (BMD) in the lumbar spine. While reference databases do exist for children and these have been appropriately applied, these databases may not be robust. Chronological age may not be the best referent for children for any measure of growth and development including BMD, but there is no consensus about the best approach to account for this. Two-dimensional (areal) BMD as measured by dual energy xray absorptiometry (DXA) may suffice for cross-sectional studies, as reported by Girgis and Winter (5), but they are probably inadequate for longitudinal studies during growth. The vertebral bodies increase in size in all dimensions, and this cannot be assessed in the standard two-dimensional areal BMD measurement. This approach completely ignores the vertebral growth plate. True three-dimensional studies using quantitative computed tomography is a preferred method (7), but its application is limited by many technical problems, not the least of which is the radiation exposure. Others have combined an antero-posterior DXA with a lateral DXA to derive bone mineral apparent density (BMAD) (8), while longitudinal studies at our institution have focused more on bone mineral content (BMC) rather than BMD (9).
As with stature, there was no significant correlation in the study by Girgis and Winter (5) between control of CAH and BMD. Aggressive treatment of CAH is associated with shorter stature, yet bone mineral density is normal. Normal skeletal growth and development is difficult and complex to understand and even more difficult and more complex to study in detail. Final adult height and peak adult bone mass are under strong genetic influence modified by the hormonal factors, local skeletal factors (identified and yet to be identified), and by diet and lifestyle factors also both identified and yet to be identified. It would appear from several sources that genetic influences predominate (10, 11). The modulating effects of hormones, local factors, diet and lifestyle probably contribute little except in that small group of growing youngsters where abnormalities in one or more of these factors are most marked, such as in CAH.
We should quickly add that we should not ignore those factors such as diet and lifestyle that can be modified even if the overall impact on growth and development is quite small. None of us will be around to ascertain whether an additional one percent gain in bone mass resulting from additional calcium and/or exercise during growth will translate into a lesser likelihood of sustaining an osteoporotic fracture much later in life. Short-term studies in teenagers point out the additive benefits of calcium and exercise (12, 13). Cross-sectional studies demonstrated almost 30 yr ago that a higher lifetime dietary calcium intake and (presumably, but not explicitly stated) life-long higher physical activity resulted in a lesser prevalence of osteoporotic hip fractures (14).
It should be noted that the authors included two patients with 17-hydroxylase deficiency in their study who were assigned to the fair control group. These individuals differ from the other patients in the study group with 21-hydroxylase deficiency in that they are deficient in adrenal androgens. Therefore, they do not have the potential to advance their bone age. In addition they will not spontaneously go through puberty, which may again affect their bone age. Consequently, these two patients may have lowered the bone age Z-score in the fair control group.
This consideration aside, it is not clear that the current report adjusted BMD for skeletal maturation or for stature, nor are we certain how such adjustments might affect the results. We recently reported preliminary data indicating that by age 12, children had already attained 82% (boys) to 88% (girls) of expected adult height but only 55% of midparental bone mass (15). This would suggest that there is substantial opportunity for consolidation of bone mass once peak adult height has been attained. In the present study, while not statistically significant, there is already a difference of more than two standard deviations in both skeletal maturity and current growth velocity between those with poor and tight control. If poor control of CAH results in accelerated skeletal maturity by this age (the mean age of the three poorly controlled patients in the current study was 12.6 yr) with an already slowed growth velocity, it is quite possible that there will be a substantial deficit in peak bone mass and BMD evident in a few years. It is premature to conclude fully that CAH will not be associated with a greater risk of osteoporosis later in life.
While there was a highly significant correlation between height at age two years and current height (r = 0.80), this accounts for only 50% of the variance in current height. As pointed out, this short stature at age 2 confirms the work of others and raises serious concerns about optimal therapy from the outset. Because these patients receive glucocorticoids at doses higher than for physiological replacement, they may be at risk of developing osteoporosis with advancing age (16). However this should not be taken as an indication to become relaxed about control of androgen production during childhood in patients with CAH. For now the best that can be concluded is that, after age two years and up to the early post-pubertal years, there is little impact of the degree of control of CAH on skeletal growth and development. Further studies will be needed to see if more appropriate BMD measurements confirm this conclusion and whether this apparent lack of clinical impact at age 12 is still present at age 22 and 32. Whether other investigators will have the diligence to repeat this excellent clinical research conducted by Girgis and Winter remains to be seen.
Received September 30, 1997.
Accepted October 1, 1997.
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