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Long-Term Corticosteroid Replacement and Bone Mineral Density in Adult Women with Classical Congenital Adrenal Hyperplasia

Division of Reproductive Endocrinology, Department of Gynecology and Obstetrics (J.A.K., B.J.B., H.A.Z.), and Division of Pediatric Endocrinology, Department of Pediatrics (A.B.W., C.J.M.), Johns Hopkins School of Medicine, Baltimore, Maryland 21287; and Department of Epidemiology (K.A.C.), Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Dr. Jeremy A. King, 2330 West Joppa Road, Suite 301, Lutherville, Maryland 21093. E-mail: jking8{at}mac.com.

	Abstract

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Context: Concern has been raised regarding the potential impact of chronic glucocorticoid therapy on the bone mineral density (BMD) of patients with congenital adrenal hyperplasia (CAH).

Objective: The purpose of this investigation was to assess the impact of chronic glucocorticoid replacement in adult women with classical CAH.

Patients and Design: We used dual energy x-ray absorptiometry to evaluate lumbar spine and whole body BMD in 11 women with salt-losing (SL) CAH and 15 with the simple virilizing form. Physical characteristics and serum hormone concentrations were also measured. Results were compared with those of unaffected sisters of CAH patients (n = 9).

Main Outcome Measure: BMD was the main outcome measure.

Results: Osteopenia was noted in 45% of SL CAH patients, 13% of patients with the simple virilizing form, and 11% of controls. Lumbar spine and whole body BMDs of CAH subjects were lower than those of controls (P < 0.05). Compared with CAH subjects with normal BMD, those with osteopenia had reduced serum levels of dehydroepiandrosterone sulfate and dehydroepiandrosterone. Adrenal androgen levels were particularly suppressed among postmenopausal women receiving glucocorticoid replacement.

Conclusions: Adult women with classical CAH treated with long-term glucocorticoids are at risk for decreased BMD, especially those with the SL form. Oversuppression of adrenal androgens is associated with increased risk for bone loss in this population.

	Introduction

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CONGENITAL ADRENAL HYPERPLASIA (CAH) is a disorder resulting from a deficiency of one of five enzymes required for cortisol synthesis in the adrenal cortex. 21-Hydroxylase (21-OH) deficiency is the most common cause of CAH. A severe deficiency results in the salt-losing (SL) form, and the result of a partial deficiency is the simple-virilizing (SV) form. Management of this disorder consists of lifelong glucocorticoid supplementation to reduce excess levels of adrenal androgens (1). Concern has been raised regarding the potential impact of long-term glucocorticoid use on bone mineral density (BMD) in women with CAH. Chronic glucocorticoid therapy is a known risk factor for bone loss (2). Long-term oral steroid use has been shown to increase fracture risk among asthmatics (3) and to decrease BMD in patients with adrenal insufficiency (4). In patients with CAH, however, published data are conflicting. In previous studies of 21-OH deficiency, BMD has been shown to be unchanged (5, 6, 7, 8, 9), elevated (10, 11), or decreased (12, 13, 14). These investigations included a heterogeneous group of subjects including both sexes, both classical and nonclassical forms of the disorder, and pre- and postpubertal patients. The majority of subjects were young; five studies included prepubertal patients (5, 7, 8, 10, 11), whereas only two studies included subjects older than 35 yr of age (9, 12).

Before the advent of oral glucocorticoid replacement, few patients with 21-OH deficiency survived into adulthood. As a consequence, little is known about the long-term natural history of CAH, especially the SL form. With current treatment regimens allowing patients to enjoy a normal life expectancy, it is important to understand the long-term impact of this disease and its treatment. Our cohort, composed of older women with SL and SV CAH, offers an opportunity to examine the impact of lifelong glucocorticoid replacement. All patients completed puberty, and many are postmenopausal. The purpose of this investigation was to assess the impact of chronic glucocorticoid replacement on BMD in women with classical CAH.

	Subjects and Methods

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The study was approved by the institutional review board (formerly the joint committee of clinical investigation) of Johns Hopkins University School of Medicine. Written, informed consent was obtained from all subjects before participation. Subjects completed a questionnaire, underwent a physical examination with serological testing, and had BMD testing performed.

Subjects

All English-speaking women 21 yr of age or older who had presented in childhood to the Johns Hopkins Pediatric Endocrine Clinic for treatment of CAH due to 21-OH deficiency were eligible for participation. Eleven women with the SL form and 15 women with the SV form completed the study. Diagnoses were confirmed by review of original medical records including pediatricians’ Prader ratings of external genitalia and laboratory reports of adrenal androgen levels. All but one were Caucasian (one was Latin-American). All SL CAH participants began glucocorticoid replacement in infancy. The SV participants initiated glucocorticoid therapy at ages varying from infancy to 22 yr. All SL and one SV CAH participant were prescribed fludrocortisone (0.05–0.15 mg/d).

Women matched for age and level of education served as controls. Controls consisted of unaffected sisters (US) of CAH patients. US were studied because of their genetic and environmental similarities with the study subjects. US were contacted only if CAH patients consented to invitation and provided contact information for their sisters. None of the control women was affected by genital masculinization at birth.

Methods

Height and weight were measured with a stadiometer and a clinical scale at the time of examination for all CAH and control subjects. Body mass index (BMI) was calculated as kilograms per meter squared. Body surface area was calculated with the Mosteller formula (15). A questionnaire assessing medical and social histories was completed by all subjects. Answers were confirmed and reviewed for completeness during interviews conducted with each subject. Glucocorticoid doses were converted to growth-retarding cortisol equivalents (80 mg hydrocortisone = 16 mg prednisone = 1 mg dexamethasone) (16).

BMD assessment

Whole body and lumbar spine BMD were assessed with dual-energy x-ray absorptiometry using a QDR 4500W densitometer (Hologic, Waltham, MA) with a coefficient of variation of 1.0%.

Endocrine outcome measures

Serum 17-hydroxyprogesterone (17-OHP), testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA), and dehydroepiandrosterone sulfate (DHEAS) levels were measured in the fasting state at 0800 h before the morning corticosteroid dose. Testosterone was measured with a competitive chemiluminescent enzyme immunoassay with the Immulite Automated Analyzer (Immulite, Diagnostic Products Corp., Los Angeles, CA). Assay sensitivity was 15 ng/dl. 17-OHP, androstenedione, DHEAS, and DHEA were measured by Quest Diagnostics, Inc. (Nichols Institute, San Juan Capistrano, CA). RIAs were performed for 17-OHP, androstenedione, and DHEA. Test sensitivities were 10 ng/dl for 17-OHP, 3 ng/dl for androstenedione, and 3 ng/dl for DHEA. Intra- and interassay variations were 6% and 11.5% for 17-OHP, 8.1% and 10.2% for androstenedione, and 4.7% and 5.8% for DHEA. An immunochemiluminometric assay with a sensitivity of 4 µg/dl, and intra- and interassay variation of 3.5% and 4.7%, respectively, was performed for DHEAS.

Statistical analyses

Categorical data were summarized as frequencies and percentages, and groups were compared using Fisher’s exact test. Continuous data were summarized as medians and ranges. To assess group differences, nonparametric analysis, using the Wilcoxon test, was performed for two-group comparisons, and the Kruskal-Wallis test was performed for three-group comparisons. The Pearson product-moment correlation was used to examine the association of BMI and T-scores. Distributions of the BMD measures were tested for normality, and analysis of covariance was used to test for group differences after adjusting for age and BMI. Post hoc pairwise group comparisons were only conducted on those measures that were significant across all three groups. Analysis was performed using SAS version 9 (SAS Institute, Inc., Cary, NC). All P values are two-tailed, and P < 0.05 was considered significant.

	Results

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Patient characteristics

One hundred thirty-four women with CAH had recorded visits to the Pediatric Endocrine Clinic at Johns Hopkins over the past 50 yr. Of these, 73 were not eligible to participate because they were deceased (n = 19), lost to follow-up (n = 52), or unable to provide informed consent (n = 2). Sixty-one women with CAH (39 SL and 22 SV) as well as 13 US unaffected controls were located and invited to participate. A total of 26 subjects (11 SL and 15 SV) and nine controls completed the study. Thirteen CAH subjects were receiving oral prednisone, 10 were taking cortisol, and three were receiving dexamethasone. There were no known cases of parathyroid, kidney, or liver disease among patients.

Table 1 shows the baseline demographic and clinical characteristics of each group. The only significant difference among the three groups was in height. The median SV height was 148 cm, whereas SL and US subjects were 153 and 159 cm, respectively. Although not reaching statistical significance, there was a trend for the US to have lower BMI compared with the SL and SV groups. There were no significant differences in age or menopausal status between the CAH groups and controls. Twelve CAH subjects were postmenopausal, four of whom were receiving hormone replacement at the time of study. Four controls had completed menopause; one was receiving hormone replacement. The mean number of years of menopause was 13.9 (range, 1–28 yr) among CAH participants and 15.0 (range, 1–33 yr) among controls (P = 0.77).

Five of the 11 SL (45%) and two of 15 SV (13%) had osteopenia (defined as a T-score between –1 and –2.5). Only one (11%) of the US controls was osteopenic. No subject was found to have osteoporosis. SL and SV subjects had significantly lower z-scores, T-scores, and L-spine measurements than controls. Adjusting for age and BMI, the differences in z-score, T-score, and L-spine measurements remained significant (Table 2). When SL and SV were compared, there was a trend toward lower T-scores, z-scores, and L-score measurements among SL patients, but the differences were not significant. The relationship of T-score to BMI in each subject is depicted in Fig. 1. The T-score was significantly correlated with increasing BMI in CAH subjects (r = 0.58; P = 0.06 for SL; r = 0.63; P = 0.01 for SV), but not for US (r = 0.27; P = 0.47), although this lack of correlation could be due to the limited range of BMI for this group or to the outlier.

View larger version (6K): [in this window] [in a new window]   FIG. 1. T-score as it relates to BMI in each group. r is the Pearson correlation coefficient. A, SL patients; B, SV patients; C, unaffected sisters (when the outlier is excluded: r = 0.72; P = 0.04).

The results of hormone assays are presented in Table 2. DHEA concentrations were significantly lower among CAH subjects, and there was a trend toward lower DHEAS levels compared with controls. 17-OHP levels were significantly higher among women with CAH.

When CAH subjects with osteopenia were compared with those with normal BMD, DHEA and DHEAS levels were significantly lower among the osteopenic patients (Table 3). Age, menopausal status, BMI, and cortisol equivalents per body surface area were not significantly different, although there was an apparent trend toward lower BMIs and higher cortisol equivalents per body surface area among the osteopenic participants. In addition, the differences in 17-OHP and androstenedione concentrations approached significance.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

At the onset of the study, our clinical impression was that BMD compromise was uncommon in CAH subjects receiving chronic glucocorticoid therapy. We hypothesized that the increased BMI seen frequently among CAH patients may prevent them from sustaining bone loss. Indeed, we noted a lower (although not significant) BMI among those CAH subjects with osteopenia than in those without. However, the US, who had the lowest mean BMI, still had higher T- and z-scores than the CAH cohort. This suggests that although increasing BMI may offer some protection, it is not sufficient to protect against bone density loss in all CAH women. Decreased BMD despite increased BMI in women with CAH (age, 20–29 yr) treated with corticosteroids since birth compared with controls has been reported (13). We also observed an apparent dose effect, with SL patients (who initiated therapy the earliest) having the poorest bone density results.

Concern about decreased BMD in women with CAH has been raised in previous studies. The first published report concluded that there was no difference in whole body or regional BMD in female CAH patients receiving cortisol replacement (age, 8–32 yr) compared with controls (5). Other reports also failed to show decreased BMD in young CAH patients (6, 7, 8, 17). Only one study identified decreased BMD in pre- and postpubertal patients with the classic form of the disease (14). Most previous study populations were composed of young patients; only three women with classical CAH older than 32 yr were included (9). Although these studies suggest that cortisol replacement does not adversely affect BMD in younger individuals, concern still exists for older women.

Recent reports have demonstrated decreased BMD in adult CAH patients, attributing the decrease to excessive cortisol replacement (12, 13). Jääskeläinen and Voutilainen (12) were the first to assess BMD in a CAH population that had completed puberty. Their participants had significantly lower lumbar and femoral neck BMD scores than the controls. Subjects with the lowest femoral neck and lumbar scores were receiving the highest doses of glucocorticoids per body surface area. Hagenfeldt et al. (13) also reported a negative association of BMD with increasing corticosteroid doses.

Our results also suggest an association with oversuppression of adrenal steroidogenesis and decreased BMD in CAH women. When we stratified CAH subjects by T-scores, adrenal androgen concentrations were significantly lower in the osteopenic group. The daily cortisol equivalents per body surface area prescribed to osteopenic subjects (22 mg/m²) tended to be higher, on the average, than the dose taken by subjects with normal BMD (15 mg/m²), but these values were statistically similar. In Jääskeläinen’s study (12) of 32 patients (age, 16–52 yr), all subjects with a daily cortisol equivalent of 18 mg/m² had negative femoral neck z-scores, and all those taking at least 20 mg/m² had negative lumbar z-scores.

Unfortunately, avoiding over- or undersuppression of adrenal androgens is a difficult challenge. Exogenous steroid replacement can never duplicate the dynamic secretion of adrenal cortisol. In addition, patient compliance is often difficult to enforce and monitor.

It has been suggested that postmenopausal women taking long-term glucocorticoid replacement for 21-OH deficiency are at increased risk for bone demineralization (9). Our study does not have the power to confirm or reject this suggestion; five of 12 postmenopausal CAH subjects and one of four postmenopausal controls were osteopenic. We did note, however, that postmenopausal CAH subjects had significantly lower levels of adrenal androgens. Although menopause alone is a well-known risk factor for osteopenia and osteoporosis, it may be that after experiencing menopause, CAH women become more sensitive to exogenous glucocorticoids. A future prospective trial with controls matched for menopausal status could help establish whether menopause or other factors contribute to the increased adrenal suppression.

The number of older participants in this study allowed for better evaluation of long-term corticosteroid therapy compared with previous reports. This study does suffer from some limitations. Our ability to demonstrate statistical significance in some comparisons was limited by the wide range of some serum hormone concentrations relative to the number of study participants. Control group size was limited by the number of subjects with unaffected female siblings who were available to participate in the study. Also, the serological and morphological measures recorded for this cross-sectional study represent only one window in time. Clearly, patient compliance and response to medication can vary greatly over time. Prospective studies are needed to better understand the impact of long-term cortisol replacement on bone health in women affected by CAH.

In summary, women with CAH due to 21-OH deficiency treated with long-term glucocorticoids are at risk for decreased BMD, especially those with the SL form. Oversuppression of adrenal androgens is associated with increased risk for bone loss. A low BMI also increases risk, although a high BMI alone does not appear to protect against bone loss in all CAH patients. Patients and physicians should be aware of the potential consequences of steroid replacement on bone density. Clinicians may wish to consider dose adjustments after menopause. The best way to prevent decreased BMD in this population may be to avoid oversuppression by careful long-term monitoring of adrenal androgen levels.

	Footnotes

 
First Published Online November 8, 2005

Abbreviations: BMD, Bone mineral density; BMI, body mass index; CAH, congenital adrenal hyperplasia; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; 21-OH, 21-hydroxylase; 17-OHP, 17-hydroxyprogesterone; SL, salt losing; SV, simple virilizing; US, unaffected sister.

This work was supported by National Institute of Child Health and Human Development Grants RO1HD37940 and F32HD08544 and General Clinical Research Center Grant RR-00052.

Received April 6, 2005.

Accepted November 1, 2005.

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