Can a Steroid Swap Protect Bone Health in Adrenal Insufficiency?

Patients with adrenal insufficiency had significant improvements in bone and metabolic markers on a once-daily, low-dose steroid regimen compared with conventional treatment, a randomized trial found.

Among 46 participants, several markers of bone turnover showed significant slowing with once-daily prednisolone (2-5 mg) over 120 days versus multiple-daily standard-dose regimens of hydrocortisone:

• Carboxylated osteocalcin: mean treatment difference -1.22 ng/mL (95% CI -2.35 to -0.10, P=0.04)
• Undercarboxylated osteocalcin: -1.38 ng/mL (95% CI -2.32 to -0.44, P=0.005)
• Urinary N-terminal telopeptide: -9.34 nmol/mmol (95% CI -15.4 to -3.29, P=0.002)
• Procollagen type 1 N-terminal propeptide: -13.8 ng/mL (95% CI -22.2 to -5.49, P<0.001)

Prednisolone-treated patients also exhibited significantly better metabolic profiles, Karim Meeran, MD, of Imperial College London, and colleagues reported in JAMA Network Open. Adverse event frequency was comparable between groups, with no adrenal crises reported.

“Around the world, we have always been taught that hydrocortisone is the best treatment for adrenal insufficiency, and it is given twice or thrice daily because it has a short half-life,” Meeran told MedPage Today. “We thought that very low doses [of prednisolone] could be used instead of the traditional hydrocortisone given as 10 mg in the morning, 5 mg at noon, and 2.5 mg in the afternoon.”

“Prednisolone is very cheap and was thought to be inferior because higher doses are associated with osteoporosis,” he added. “Imagine our surprise to find that not only was there lower bone turnover, but prednisolone caused patients to be less overweight and have a better HbA1c.”

Some — but not all — patients with adrenal insufficiency could opt for prednisolone as an alternative, argued Mira Emilova Boyanova, MD, of Acibadem City Clinic University Hospital Tokuda Sofia in Bulgaria, in an accompanying commentary.

“Patients with secondary adrenal insufficiency could benefit from a low-dose prednisolone regimen in which cortisol deficiency is only partial,” she wrote. It could also be an option for patients with reduced medication adherence or in countries where hydrocortisone isn’t available. However, an important exception is pediatric patients who are still growing, for whom hydrocortisone remains the preferred treatment.

While low-dose prednisolone may decrease the risk of fractures, it “needs to be proven in patients with primary adrenal insufficiency alone, not in small-sample groups of patients with primary and/or secondary adrenal insufficiency,” she critiqued. “In fact, the decrease in bone turnover markers in the study by Meeran et al is negligible compared with the decrease seen with antiresorptive agents; thus, one could argue the real clinical implications of this finding. Moreover, some of the patients in the study were already receiving an antiresorptive drug.”

This double-blind, crossover randomized clinical trial, conducted from September 2019 to December 2023, enrolled participants with primary or secondary adrenal insufficiency for at least 6 months, who were on stable hormone replacement for at least 3 months. None had glucocorticoid-induced adrenal insufficiency or were treatment-naive.

Average age was 55 years, 52.2% were male, 13% were on antiresorptive bone therapy, and 16 of 46 participants had primary adrenal insufficiency. All participants with primary adrenal insufficiency continued receiving fludrocortisone at their usual doses. Median daily doses were 20 mg for hydrocortisone and 3.5 mg for morning prednisolone.

Metabolic improvements were significantly greater in the prednisolone group compared with hydrocortisone over 120 days:

• Weight reduction: -1.87 kg (95% CI -3.02 to -0.72, P=0.002)
• BMI: -0.522 (95% CI -1.01 to -0.04, P=0.04)
• Waist circumference: -2.26 cm (95% CI -3.97 to -0.56, P=0.01)
• HbA1c: -1.23 mmol/mol (95% CI -1.95 to -0.51, P=0.001)

There were no between-group differences in subjective health outcomes.

The most common adverse events were viral illnesses, lethargy, and COVID-19 infection. Three serious adverse events occurred, including two episodes of gastroenteritis; all three participants were treated with intravenous hydrocortisone. There were also 17 episodes of doubling glucocorticoid dose without an associated adverse effect in nine participants for subjective perceived stress.

The study was limited by its short follow-up period and use of biomarkers as opposed to event outcome data, the researchers acknowledged.

Meeran added that a “real-world” version of the study is underway. “It would be good if some American centers also converted patients from hydrocortisone to prednisolone. If anyone does so, it would be best if data was collected on patients before switching, so that more real-world data can be collected,” he said.