Glucocorticoids for Adrenal Hyperplasia Hard on the Bones

 People with classic congenital adrenal hyperplasia (CAH) may suffer from impaired bone health, largely due to standard treatments.

Most often caused by a genetic mutation in the 21-hydroxylase enzyme, this rare disorder is typically managed by exogenous glucocorticoids given in supraphysiologic doses higher than those needed to treat adrenal insufficiency alone.

"Increased risks of low bone mineral density [BMD], osteoporosis, and fracture due to long-term use of glucocorticoids have been observed in classical [CAH] patients," said Tania Bachega, MD, PhD, of the University of São Paulo in Brazil.

"These [bone] effects are particularly pronounced in patients with higher cumulative glucocorticoid doses," she noted at ENDO 2025, the annual meeting of the Endocrine Society.

BMD Impacts

When pediatric CAH patients are transitioning to adult care, they should have a baseline BMD measurement with a dual-energy x-ray absorptiometry (DXA) scan, said Bachega. This advice is also backed by clinical practice guidelinesopens in a new tab or window from the Endocrine Society.

Regular BMD screening should also be performed in patients who have been treated with a prolonged period of higher-than-average glucocorticoid dosing or patients who have sustained a nontraumatic fracture, according to the guidelines.

Excessive glucocorticoid exposure can pose one of the biggest threats to CAH patients' bone health, since glucocorticoids decrease osteoblast activity, which promotes new bone formation. Glucocorticoids also stimulate the production of osteoclasts, which break down old bone.

In a 2008 retrospective studyopens in a new tab or window of adults with CAH, 44.7% had bone demineralization. There were also significant negative effects of total cumulative glucocorticoid and total average glucocorticoid on lumbar T-scores (P<0.001, P=0.002) and femoral T-scores (P=0.006, P<0.001), mostly during puberty.

In a cross-sectional observational studyopens in a new tab or window, women with CAH had lower BMD at all measured sites -- total body, lumbar spine, and femoral neck -- compared with age-matched controls. Nearly half (48%) of women with CAH under age 30 were osteopenic compared with 12% of controls, and 73% of those over 30 were osteopenic or osteoporotic versus 21% of controls.

Data suggest that bone loss is not associated with a particular CAH genotype or phenotype, but rather is linked to glucocorticoid exposure.

"These data underscore the need to avoid excessive glucocorticoid exposure," the guideline authors noted.

Risk for Lifelong Short Stature

In addition to the impact on BMD, glucocorticoid treatment can also lead to short stature in adulthood.

According to a 35-study meta-analysisopens in a new tab or window, adults with CAH had an average height score that was 1.4 standard deviations (about 10 cm) shorter than the general population.

Patients that used mineralocorticoids during childhood had a better height outcome in adulthood compared with those who didn't use mineralocorticoids across the studies (P=0.02). This may be because "mineralocorticoid replacement ensures euvolemia, which diminishes corticotropin stimulation and subsequent adrenal androgen synthesis," wrote authors of a 2020 reviewopens in a new tab or window.

"The growth-suppressing effect of glucocorticoids is especially apparent during infancy and puberty, and doses exceeding 15 to 20 mg per square meter of body-surface area per day during these developmental periods decrease final adult height," they noted.

To monitor growth and bone health, it is recommended that pediatric patients undergo annual bone age assessments until near-adult height is achieved. X-rays shouldn't be used to assess bone age in patients under age 2.

The guidelines also point out that reduced height velocity is a sign of "protracted overtreatment" of CAH, while accelerated height velocity and advanced bone maturation are signs of "protracted undertreatment."

Because longer-acting glucocorticoids can lead to growth suppression, short-acting hydrocortisone is the preferred treatment option during childhood. A 2003 studyopens in a new tab or window reported that the estimated growth-suppressive effect of prednisolone was about 15-fold more potent than that of hydrocortisone.

"Although prednisolone and dexamethasone treatments are effective in suppressing adrenal androgens in children with CAH, these more potent drugs are more likely than hydrocortisone to impede statural growth and cannot be routinely recommended," the guideline authors stated.

"The adult height of patients with CAH correlates negatively with the dose of glucocorticoid administered in early puberty; patients treated with less than 20 mg of hydrocortisone/m² per day at the start of puberty are significantly taller than those given higher hydrocortisone doses," they wrote. "Therefore, as with younger patients, it is important during puberty to treat with the lowest effective dose to achieve treatment goals."

Once growth is almost or fully complete, patients can transition to long-acting glucocorticoids, the guideline authors advised.

https://www.medpagetoday.com/spotlight/endo-classicc-ongenital-adrenal-hyperplasia/117578