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Departments of Endocrinology, Metabolism and Diabetes (H.Fa., M.T.), Molecular Medicine and Surgery (H.Fa., A.N., M.T.), Paediatric Surgery (A.N.), and Women and Child Health (K.H.), Karolinska University Hospital and Karolinska Institute, SE-171 76 Stockholm, Sweden; and Departments of Endocrinology (H.Fi.), Paediatric Surgery (G.H.), and Obstetrics and Gynaecology (P.-O.J.), Sahlgrenska University Hospital and Sahlgrenska Academy, SE-413 45 Gothenburg, Sweden
Address all correspondence and requests for reprints to: Dr. Henrik Falhammar, Department of Endocrinology, Metabolism and Diabetes, D2:04, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: henrik.falhammar{at}karolinska.se.
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Abstract |
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Objective: Our objective was to evaluate bone mineral density (BMD), fracture prevalence, and markers of bone metabolism in adult females with CAH.
Design: This was a cross-sectional observational study.
Setting: Tertiary care referral centers were used in this study.
Participants: We studied 61 women, aged 18–63 yr, with genetically verified CAH due to 21-hydroxylase deficiency. They were patients with salt wasting (n = 27), simple virilizing (n = 28), and nonclassical 21-hydroxylase deficiency (n = 6). A total of 61 age-matched women were controls.
Main Outcome Measures: History of fractures was recorded. Total body, lumbar spine, and femoral neck BMD were measured by dual-energy x-ray absorptiometry. The World Health Organization criteria for osteopenia and osteoporosis were used. Serum marker of bone resorption, β-C telopeptide was studied.
Results: The mean glucocorticoid dose in hydrocortisone equivalents was 16.9 ± 0.9 mg/m2. Patients had lower BMD than controls at all measured sites (P < 0.001). In patients younger than 30 yr old, 48% were osteopenic vs. 12% in controls (P < 0.009). In patients 30 yr or older, 73% were osteopenic or osteoporotic vs. 21% in controls (P < 0.001). BMD was similar in the two classical forms and had no obvious relationship to genotypes. β-C-telopeptide was decreased in older patients. More fractures were reported in patients than controls (P < 0.001). The number of vertebrae and wrist fractures almost reached significance (P = 0.058).
Conclusions: Women with CAH have low BMD and increased fracture risk. BMD should be monitored, adequate prophylaxis and treatment instituted, and glucocorticoid doses optimized from puberty.
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Introduction |
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Glucocorticoids have been available since the beginning of the 1950s, making it possible for many patients with CAH to survive. Over the years, concerns about long-term adverse effects of glucocorticoids have arisen. It is well established that endogenous Cushing’s syndrome and pharmacological glucocorticoid therapy can affect peak bone mass in growing individuals and generate osteoporosis via multiple mechanisms, resulting in increased bone resorption and suppression of bone formation. Decreased intestinal calcium absorption and increased renal calcium excretion may lead to secondary hyperparathyroidism. IGFs, their binding proteins, and the secretion of gonadal steroids may also be affected (4).
Although it is established practice to try to minimize glucocorticoid doses in the management of patients with CAH to avoid effects of overtreatment, the ideal dose, which both normalizes adrenal androgen production and treats cortisol deficiency, is often difficult to find in the individual patient. The doses given must often be supraphysiological. A recent report has shown that doses of 20 or more mg/d hydrocortisone equivalents are associated with unfavorable metabolic effects in patients with hypopituitarism. However, being GH deficient, these patients may be more sensitive to adverse effects of glucocorticoids (5). We have recently reported that serum adrenal androgens were markedly suppressed in adult women with CAH, indicating overtreatment (6).
Previous reports on bone mineral density (BMD) in CAH patients have been conflicting because some authors observed normal (7, 8, 9, 10, 11, 12, 13), some elevated (14, 15), and some decreased BMD (16, 17, 18, 19, 20). The discrepancies may reflect differences in age of patients, type and severity of enzyme deficiencies, and various therapeutic regimes. Swedish women with CAH should have a high risk of osteoporosis and, consequently, fractures because the frequency of osteoporotic fractures is high in the Scandinavian countries (21). Women generally have lower BMD than men. Consequently, they are more vulnerable than men to additive catabolic effects of supraphysiological glucocorticoid doses on bone tissue. In the studies mentioned previously, BMD was only reported in a few women with 21-hydroxylase deficiency who were 30 yr or older. In addition, no previous study has reported fracture data in patients with CAH.
The aim of the present study was to investigate BMD, fracture prevalence, and markers of bone metabolism in a larger cohort of adult women with 21-hydroxylase deficiency compared with age-matched controls. Adults younger than 30 yr of age were compared with older patients to disclose possible effects appearing after long-term glucocorticoid treatment. BMD was also compared between the different clinical forms: the two classical variants [the more severe salt-wasting (SW) and less serious simple virilizing (SV)]; and the milder NC form. In addition, putative relationships between BMD and the various mutations of the CYP21A2 gene were evaluated.
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Subjects and Methods |
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Recruitment and characteristics of patients and controls have been reported previously (6). Briefly, the patient group comprised 61 women with CAH (median age 30 yr, range 18–63). Diagnoses were verified by review of original pediatric and adult records, including genital examinations, laboratory reports of adrenal steroids, and mutation analyses of the CYP21A2 gene (22).
All patients received glucocorticoids: prednisolone (n = 30, mean dose 6.3 ± 0.32 mg); hydrocortisone (n = 17, mean dose 33.3 ± 2.1 mg); cortisone acetate (n = 5, mean dose 40 ± 2.5 mg); dexamethasone (n = 7, mean dose 0.55 ± 0.08 mg); and a combination of two glucocorticoids (n = 2). Fludrocortisone was taken by 50 patients (82%).
The patient group younger than 30 yr old comprised 11 SW, 13 SV, and three NC, and the group 30 yr or older comprised 16 SW, 15 SV, and three NC. Median age in the younger group was 24 yr (range 18–29, n = 27) and the older group 35 yr (range 30–63, n = 34). There were 11 patients older than 40 and four older than 50 yr of age. Five patients were postmenopausal.
Patients were also divided into the three largest groups of genotypes, with the milder of the two mutations representative of the genotype: Null/Null, I2splice, and I172N.
Female controls born on the same date as the CAH patients were recruited from local population registries. Five of them were postmenopausal. The only preset exclusion criteria were glucocorticoid therapy, advanced malignancy, and severe mental or psychiatric disturbance with inability to consent to the study. The controls were examined within 1 yr from their age-matched patients.
The study was approved by the research ethics committees of the Karolinska Institute, Stockholm, and the Gothenburg University, Gothenburg, Sweden. All participants gave written informed consent.
Study protocol
Patients and controls were examined as outpatients at the Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm (n = 50) or the Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital, Gothenburg (n = 11), Sweden.
Medical histories were obtained from all patients and controls. Blood samples were collected in the morning after an overnight fast.
BMD
Whole body, lumbar spine (L2–L4), femoral neck BMD, body fat, and lean body mass were estimated by dual-energy x-ray absorptiometry (DXA) in 57 patients and 60 control subjects using a Lunar Model DPX-L or Prodigy equipment (Lunar Radiation, Madison, WI) using a standard procedure as previously described (23). The two instruments were calibrated to each other. Values expressed as g/cm2 were compared in patients and controls. The BMD values were also expressed as SD scores (SDS) from the mean of an age and sex-matched reference group (Z score) provided by the manufacturers and SDS from the mean of young adults (T score). In three patients that were assessed by Hologic QDR 4500 (Hologic Inc., Waltham, MA), only T and Z scores were reported. The World Health Organization (WHO) definitions of osteopenia and osteoporosis were applied (i.e. T score between –1 and –2.5 SD at any measured site was defined as osteopenia, and values below –2.5 SD were defined as osteoporosis) (24). However, the WHO criteria were set up to be applied to postmenopausal women, and not to premenopausal women with presumably low-peak bone mass. Despite this we have chosen to use these criteria because they identify different degrees of low bone mass. To explore the impact on the results of the differences in skeletal dimensions between the patients, who were on average 6.8 cm shorter, and the age-matched controls, we also calculated the volume-adjusted bone mineral apparent density (BMAD g/cm3) of the vertebrae and femoral neck using the formulas proposed by Carter et al. (25): BMAD = bone mineral content (BMC)/bone area1.5 for lumbar spine, and BMC/bone area2 for femoral neck. We applied the formula proposed by Katzman et al. (26) to whole body measurements: BMAD = BMC/(bone area2: height). We also compared Z scores of patients and controls in the height range of 160–169 cm.
Fractures
All types of clinical fractures were recorded and verified by x-ray. Fractures in the vertebrae, wrist, and hip were considered to be associated with osteoporosis.
Glucocorticoid supplementation
The present doses of glucocorticoids were converted to hydrocortisone equivalents using: antiinflammatory equivalents (30 mg hydrocortisone = 37.5 mg cortisone acetate = 7.5 mg prednisolone = 0.75 mg dexamethasone) (27); and growth-retarding equivalents (30 mg hydrocortisone = 37.5 mg cortisone acetate = 6 mg prednisolone = 0.375 mg dexamethasone) (28). Thereafter, hydrocortisone equivalents were reported in mg and mg per body surface (mg/m2).
Biochemical assays
Serum testosterone was measured by fluoroimmunoassay (AutoDelfia, Wallac Inc., Turku, Finland). The RIA method was used for the determination of serum androstenedione (DiaSorin S.p.A., Saluggia, Italy). Serum dehydroepiandrostendione sulfate (DHEAS) and PTH were measured on Nichols Advantage automatic immune analyzer (Nichols Institute Diagnostics, San Clemente, CA); the reference limits of PTH were 12–55 ng/liter. Serum alkaline phosphatase (ALP) was measured on SYNCHRON LX Systems (Beckman Coulter Inc., Fullerton, CA); the reference limit was less than 3.8 µkat/liter. Serum β-C-telopeptide of type I collagen (CTX) was measured on a Roche Elecsys 1010/2010 immunoassay analyzer (Roche Diagnostics Ltd., Basel, Switzerland); the reference limits were less than 550 ng/liter in premenopausal women and less than 1000 ng/liter in postmenopausal women. IGF-I was determined in serum by RIA (29). When IGF-I levels were expressed as SDS, they were calculated from the regression line of values in 448 healthy subjects, aged 20–96 yr (30).
The within and between assay coefficients of variation were: CTX, 2 and 17.9%; IGF-I, 4 and 11%; PTH, 6.7 and 8.7%; testosterone, 5.7 and 4.2%, androstenedione, 9.0 and 9.3%; and DHEAS, 4.4 and 8.7%.
Statistics
Results are presented as mean ± SEM if not otherwise stated. Comparisons between groups were performed by an unpaired t test when data were normally distributed. Otherwise, the Mann-Whitney rank sum test was used, and in these cases, median and range were stated. When 2 x 2 frequency table calculations were performed, 
2 with Yates correction were used or when the expected frequency was small (<5), Fisher’s exact test. Correlations between variables were assessed using least squares linear and multiple regression analysis. Testosterone, androstenedione, and DHEAS values were log transformed before analysis to obtain a more closely approximated gaussian distribution. Statistical significance was set at P < 0.05. Statistical analyses were performed using SigmaStat for Windows (Jandel Scientific, Erkarath, Germany).
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Results |
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Patients with CAH exhibited lower BMD at all measured sites compared with controls (P < 0.001) (Fig. 1
). A total of 40 patients (62%) fulfilled the WHO criteria for osteopenia/osteoporosis compared with 10 controls (16%) (P < 0.001). In the group younger than 30 yr old, patients displayed lower BMD at all measured sites compared with controls. A total of 48% compared with 12% (P = 0.009) was osteopenic in this group (Table 1). In the group 30 yr or older, patients had lower BMD at all measured sites compared with controls, and 73% compared with 21% (P < 0.001) were osteopenic/osteoporotic.
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). Furthermore, the frequency of osteopenia/osteoporosis tended to be higher in older than younger patients (P = 0.093).
The two classical forms of CAH (SW and SV) had lower BMD and higher frequency of osteopenia/osteoporosis than controls. The only difference between SW and SV was a lower femoral neck T score in the SV group (P = 0.047). In the milder NC form, BMD did not differ between patients and controls (Table 2). When comparing this small group of patients (n = 6) with the classical forms, the only difference was a higher total body BMD in NC compared with SV (measured as g/cm2, P = 0.038; T score, P = 0.039).
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), lumbar spine (data not shown), and femoral neck (data not shown); the I2splice group showed only a tendency compared with controls (P = 0.099). The frequency of osteoporosis/osteopenia was significantly higher in the Null/Null (seven vs. one; P = 0.030) and I172N (18 vs. six; P = 0.002) groups compared with controls. BMD was not significantly different at any site when the three genotype groups were compared.
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Using the volume-adjusted BMAD, differences between patients and controls persisted (P values being 0.004, 0.005, and < 0.001) for lumbar spine, femoral neck, and total body, respectively.
The height was 160–169 cm in 31 women with CAH and 31 controls. In this subset the differences in BMD between these women with CAH and controls were similar to the entire group. Z scores in patients vs. controls were: total body 0.0772 ± 0.145 vs. 0.933 ± 0.137 (P < 0.001); lumbar spine –0.736 ± 0.150 vs. 0.520 ± 0.232 (P < 0.001); and femoral neck –0.567 ± 0.165 vs. 0.227 ± 0.212 (P = 0.002).
The results were similarly calculated with and without inclusion of patients on hormone replacement therapy (n = 2), or bisphosphonates (n = 2) or with elevated PTH (n = 5).
Fractures
More fractures were reported in patients compared with controls (31 fractures in 18 individuals vs. two fractures in two individuals; P < 0.001). Fractures in patients were: vertebral (detected due to clinical symptoms) (n = 4), wrist (n = 7), ankle (n = 9), finger or toe (n = 6), clavicle (n = 1), scaphoid (n = 1), elbow (n = 1), rib (n = 1); and in controls, wrist (n = 2).
Subgroups with significant differences in fracture prevalence compared with controls were: older women, the SW and SV groups (Tables 1 and 2) and the genotypes Null/Null (seven vs. zero; P = 0.005) and Il72N (eight vs. one; P = 0.023). The difference between patients and controls in osteoporotic fractures (i.e. vertebrae, wrist, and hip) almost reached significance (P = 0.058; P = 0.054 in 
30 yr).
Approximately half the patients with fractures had osteopenia and one had osteoporosis. Of the two control women with fractures, one was normal and one osteopenic.
Medication
The glucocorticoid doses were similar in younger and older patients when comparing hydrocortisone equivalents (antiinflammatory equivalents: 29.4 ± 1.7 vs. 26.6 ± 1.4 mg or 18.1 ± 1.1 vs. 15.9 ± 0.9 mg/m2; P = not significant), and when comparing patients with SW, SV, and NC (antiinflammatory equivalents: 29.5 ± 1.5 vs. 26.5 ± 1.6 vs. 25.8 ± 4.5 mg or 17.7 ± 0.96 vs. 16.4 ± 1.0 vs. 15.2 ± 3.1 mg/m2; P = not significant). In addition, hydrocortisone growth-retarding equivalents in mg or mg/m2 were similar in all groups (data not shown). No correlations were observed between BMD at the different sites and the present dose of glucocorticoids, expressed as hydrocortisone equivalents (antiinflammatory or growth-retarding equivalents) per body surface. Neither was any correlation found between CTX and the present dose of glucocorticoids, expressed as hydrocortisone equivalents (antiinflammatory or growth-retarding equivalents) per body surface. The lifetime dose exposure of glucocorticoids was not available; however, the doses had been rather stable for at least the last 4–5 yr.
There were no differences between the groups concerning intake of calcium and vitamin D supplementation, bisphosphonates, oral contraceptives, or hormone replacement therapy (Tables 1 and 2).
Biochemical tests
Serum CTX levels were reduced in the older group of patients both compared with controls (P = 0.01) and younger patients (P < 0.001). Serum ALP was slightly increased in the older group of patients (P = 0.045) compared with controls; both groups had three individuals each with levels above the reference range. IGF-I SDS in all patients were higher than in controls (–0.69 ± 0.11 vs. –1.02 ± 0.11; P = 0.045), and when measured in µg/liter, younger individuals exhibited, as expected, elevated levels compared with older individuals (Table 1). Serum calcium and phosphate were similar in all comparisons.
PTH was only measured in patients, and no difference between the groups was recorded. Three women with CAH aged 38, 57, and 63 yr had elevated PTH: 91, 64, and 128 ng/liter, respectively. They were considered to have secondary hyperparathyroidism because ionized calcium levels were in the lower normal range. Two more patients, aged 28 and 33 yr, had elevated PTH (60 and 62 ng/liter) in combination with midnormal ionized calcium. The 25-hydroxyvitamin D levels were not determined.
Relationships between BMD and other parameters
In patients, total body BMD (T score) was correlated to body fat mass (r = 0.50; P < 0.001) and lean body mass (r = 0.57; P < 0.001), both expressed as mass related to body height (kg/m2). In controls there was a weak positive correlation between total body BMD and body fat mass (r = 0.29; P = 0.026), and lean body mass (r = 0.31; P = 0.017). There were no significant correlations between BMD and the markedly suppressed serum androgens with testosterone concentrations below detection limit in 44% of the patients or any associations between BMD and androgens in the controls. A correlation was found between CTX and femoral neck BMD in patients (r = 0.395; P = 0.002), but no other correlations were found, in patients or controls, between BMD at different sites and CTX or ALP.
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Discussion |
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DXA measurements of BMD depict areal bone density, and bone thickness is not considered. This can lead to an underestimate of BMD in small and an overestimate in large bones. We calculated BMAD (g/cm3) with formulas reported to reduce the confounding effect of bone size (25). Even with this approach, bone density was significantly reduced in our patients at all measured sites, indicating that the differences found were real and not only due to measurement bias.
This is also supported by the finding in the present study that the patients and controls with normal height (160–169 cm) had the same differences in BMD, as was found in the entire study population. Still, in very short individuals, an overestimation of osteopenia/osteoporosis may occur with conventional DXA measurements. However, DXA remains a useful tool for follow-up in the management of individual patients.
Osteoporosis is a strong risk factor for fractures, and to our knowledge, this study is the first to indicate a higher frequency of fractures in women with CAH. When only osteoporotic fractures (vertebrae, wrist, and hip) were considered, the difference almost reached significance (P = 0.058). This finding should be confirmed in larger studies. Because the trauma that led to fractures was not ascertained, we cannot entirely exclude that differences in lifestyle between patients and controls may have partly influenced the results.
To our knowledge we are the first to be able to present a patient cohort with a size allowing comparisons between different phenotypes and genotypes. Low BMD was not associated with a particular genotype or phenotype. Thus, the reason why adult women with CAH are osteopenic/osteoporotic is probably lifetime exposure to glucocorticoids, which we (17) and others have previously shown (16). The glucocorticoid doses used in the present study were higher than those recommended for adults in the consensus statement from 2002 (prednisolone 2–4 mg/m2 daily) (31) but similar to those reported in some recent studies (19, 20, 32). In the present study, no correlation was found between BMD and glucocorticoid doses expressed in two different hydrocortisone equivalents per body surface, however, only the present dose of glucocorticoids was registered, and not the accumulated lifetime dose. Our patients were treated with supraphysiological glucocorticoid doses as the androgens were markedly suppressed (6). Subnormal concentrations of testosterone and DHEAS were found in 62 and 92% of patients, respectively, compared with 8 and 0% in the controls. Androstenedione was significantly lower in patients than in controls, although rarely suppressed to subnormal values. Although there was no correlation between current BMD and androgens, it is possible that androgen deficiency per se may be of importance for the development of low BMD, in addition to the direct catabolic effects of glucocorticoids on bone. This may be especially important in postmenopausal women.
The bone resorption marker CTX was significantly lower in the older patients than in controls. This was unexpected, as Sciannamblo et al. (20) observed both elevated CTX and bone-specific ALP concentrations studying young individuals, some still growing. However, the effect of elevated glucocorticoid doses on the skeleton comprises an initial rapid effect on bone density considered a result of bone resorption followed by a slower progressive phase when bone mineral declines because of impaired bone formation (33). Possibly our patients treated for many years had predominantly low bone formation but also unexplained low bone resorption as CTX was decreased compared with controls. Because we only measured total ALP, we cannot decide whether the slight increase in older women was attributed to bone or liver-derived ALP.
A few patients exhibited PTH levels above the upper level of the reference range concomitant with low normal calcium concentrations, and they were all osteopenic. This can be interpreted as secondary hyperparathyroidism, likely attributable to glucocorticoid therapy. Furthermore, CAH patients had elevated IGF-I SDS of about 35% compared with controls. Elevation of that magnitude or more has been described both in patients with endogenous Cushing’s syndrome (34), in children on chronic glucocorticoid therapy for nephrotic syndrome (35), and during short-term glucocorticoid administration to healthy individuals (36). IGF-I is a GH-regulated growth factor that is important for bone tissue throughout life. The probable mechanism for elevated IGF-I is that glucocorticoids induce a state of IGF-I resistance. This could be the reason for growth retardation in children on glucocorticoids. With high-dose GH treatment, this resistance can be overcome, and growth rate increases (36).
Our findings of low BMD and increased fracture rate emphasize the importance of active monitoring of BMD in CAH patients. Osteoporosis prophylaxis such as physical activities, calcium and vitamin D supplementation, and bisphosphonates could be considered. However, optimizing the doses of glucocorticoids should always be the primary option.
In conclusion, the present study addressed the prevalence of fractures, osteopenia, and osteoporosis in adult females with CAH on long-term glucocorticoid therapy. The frequency of fractures was significantly elevated in patients 30 yr or older. Moreover, the frequency of osteopenia and osteoporosis in patients was increased regardless of age group, phenotypes, genotypes, and height compared with controls. This is probably due to overtreatment with glucocorticoids, indicated by low androgens. Physicians should regularly consider dose adjustments of glucocorticoids and monitor BMD and fractures in women with CAH.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: The authors have nothing to declare.
First Published Online September 18, 2007
Abbreviations: ALP, Alkaline phosphatase; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; CAH, congenital adrenal hyperplasia; CTX, β-C-telopeptide of type I collagen; DHEAS, dehydroepiandrostendione sulfate; DXA, dual-energy x-ray absorptiometry; NC, nonclassical; SDS, SD scores; SV, simple virilizing; SW, salt-wasting; WHO, World Health Organization.
Received April 2, 2007.
Accepted September 7, 2007.
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