The Effects of Glucocorticoid Replacement Therapy on Growth, Bone Mineral Density, and Bone Turnover Markers in Children with Congenital Adrenal Hyperplasia

Abstract

Even with current so called physiologic doses of glucocorticoid replacement therapy, children with congenital adrenal hyperplasia (CAH) often show relative short stature and delayed bone maturation, an observation that suggests possible long-term effects on bone metabolism of daily transient post-absorptive hypercortisolemia. In 28 patients with 21-hydroxylase or 17 alpha-hydroxylase deficiency (16 females and 12 males, ages 4.9-22 yr) who had received oral cortisol 10-15 mg/M2/day for 4.7-22 yr, we studied cortisol bioavailability, growth, bone maturation, vertebral bone mineral density, and various markers of bone formation and resorption. Patients were grouped according to mean on-therapy serum 170H-progesterone or progesterone levels as tight control (170HP < 10 nmol/L), fair control (170HP 10-40 nmol/L or progesterone 1.0-1.5 nmol/L), or poor control (170HP > 40 nmol/L). There was no difference in peak post-absorptive serum cortisol or area under the concentration-time curve, and only three patients had a peak serum cortisol of more than 700 nmol/L. There was no difference in present height Z-score (-0.96; -0.24; -0.6), height Z-score at age 2 yr (-1.5; +0.4; -1.3), or current growth velocity Z-score (-0.1; +1.2; -2.2) between the groups, but bone maturation Z-score was significantly delayed (-1.63) in the tight control group and advanced (+0.8) in the poor control group. Present height was highly correlated (r = 0.8) with height at age 2 yr. Serum calcium, phosphorus, alkaline phosphatase, parathormone, and 25OH-vitamin D levels were all normal. There was no difference between the groups in age-corrected vertebral bone mineral density, and no difference in serum osteocalcin, procollagen peptide, or collagen C-terminal telopeptide, nor in urinary amino-terminal telopeptide. The data suggest that current methods of cortisol replacement do not significantly influence bone formation, resorption or density during childhood and therefore should not contribute to adult osteoporosis. The possibility remains that hypercortisolemia during infancy produces the short stature and delayed bone maturation that are present by the age 2 yr.

Height, Bone Mineral Density and Bone Markers in Congenital Adrenal Hyperplasia

“…There was only a tendency for NC patients to have not significantly higher osteocalcin levels, reflecting either a better osteoblast function following a lower corticosteroid dosage or perhaps only a different age. Our results on bone markers of neoformation and resorption are in agreement with those of Girgis and Winter [4], while other authors found lower than normal osteocalcin [22, 23, 24]and NTx [24]levels in their patients. There is no clear explanation for these different findings.…”

“…Our findings of a reduced aBMD are consistent with those of one study in adults [8], but not with others carried out in children and young adults [4, 5, 6]. The reason for the divergent results is not clear, however we think that differences in patient selection and/or the fact that our group of patients was larger than that evaluated in other studies might be an explanation.…”

“…This could lead to a lower peak bone mass, which is considered a main risk factor for osteoporosis in adult life. However, data in the literature are discordant, since either unchanged [4, 5, 6]or increased [7]BMD has been reported in children and young adults with CAH, while reduced BMD has been found in adults [8]. In our study we assessed height, BMD and bone turnover in a cohort of CAH patients.…”

Bone mineral density, bone markers, and fractures in adult males with congenital adrenal hyperplasia

“…In children and young adults, bone mineral density (BMD) was reported to be increased (4), normal (5,6), or decreased (7). Other pediatric studies found decreased BMD in males (8), in long-term treated girls (9), and at puberty (10).…”

How Can Molecular Biology Contribute to the Management of Congenital Adrenal Hyperplasia?

“…Such studies are scarce. Common to all reports, however, is short stature and often some degree of obesity [3, 11, 12, 13]. This could be interpreted as sequels of less than optimal management during childhood and adolescence, though in the Finnish study, those diagnosed at an early age achieved greater adult height than those with late diagnosis [14].…”