The use of once-daily, low-dose prednisolone for glucocorticoid replacement in adrenal insufficiency yields substantial improvements in bone turnover and cardiometabolic health markers compared with multiple-dose hydrocortisone, according to the results of a crossover randomized clinical trial.
In a cohort of patients with primary or secondary adrenal insufficiency, the primary outcome of bone turnover over 4 months of treatment was slowed with prednisolone vs hydrocortisone, as evidenced by significantly lower levels of multiple bone markers at day 120, reported first author Dr Sirazum Choudhury from Imperial College Healthcare NHS Trust, London, UK, and colleagues.
The mean treatment difference was −1.22 ng/mL (95 percent confidence interval [CI], −2.35 to −0.10) for carboxylated osteocalcin (p=0.04), −1.38 ng/mL (95 percent CI, −2.32 to −0.44) for undercarboxylated osteocalcin (p=0.005), −9.34 nmol/mmol (95 percent CI, −15.4 to −3.29) for urinary N-terminal telopeptide (p=0.002), and −13.8 ng/mL (95 percent CI, −22.2 to −5.49) for procollagen type 1 N-terminal propeptide (p<0.001). [JAMA Netw Open 2026;9:e262982]
Additionally, larger improvements in cardiometabolic parameters were observed during prednisolone than hydrocortisone treatment. The mean treatment difference was −1.87 kg (95 percent CI, −3.02 to −0.72) for weight (p=0.002), −0.522 kg/m2 (95 percent CI, −1.01 to −0.04) for BMI (p=0.04), −2.26 cm (95 percent CI, −3.97 to −0.56) for waist circumference (p=0.01), and −1.23 mmol/mol (95 percent CI, −1.95 to −0.51 mmol/mol) for HbA1c (p=0.001).
“The potential mechanism of once-daily prednisolone causing less weight gain than multiple doses of hydrocortisone includes a lower steroid exposure or the possibility that once-daily therapy has different effects on the circadian rhythm to multiple daily doses,” Choudhury and colleagues pointed out.
“There were no differences in safety measures or subjective health outcomes, including all 36-Item Short-Form Health Survey domains and Addison’s Disease-Specific Quality of Life Questionnaire,” they said.
Some but not all
“The preferred corticosteroid used for replacement therapy in adrenal insufficiency is hydrocortisone… not only because of the shorter half-life but also because it has substantial mineralocorticoid activity (1:1 ratio with glucocorticoid effect), as opposed to 4:0.8 ratio for prednisolone,” said Dr Mira Emilova Boyanova from Acıbadem City Clinic Tokuda Hospital, Sofia, Bulgaria, in an accompanying editorial. [JAMA Netw Open 2026;9:e262995]
As an alternative to hydrocortisone, low-dose prednisolone can be used “in some but not all patients,” Boyanova added. These include patients with secondary adrenal insufficiency in which cortisol deficiency is only partial, patients with reduced therapy adherence, and those residing in countries where hydrocortisone is not available.
“An important exception is individuals who are still growing in whom hydrocortisone is still the preferred treatment of choice,” she said.
An advantage of using prednisolone, according to Boyanova, lies in the drug’s longer half-life, which may prevent the occurrence of inadequately low cortisol levels and a deficiency of metabolic fuels throughout the night.
Meanwhile, the potential decrease in the risk of fractures with low-dose prednisolone “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,” Boyanova said. “In fact, the decrease in bone turnover markers in the study by [Choudhury and colleagues] is negligible compared with the decrease seen with antiresorptive agents. Thus, one could argue the real clinical implications of this finding.”
Crossover trial
The trial included 46 patients (median age 55 years, 52.2 percent male, mean weight 79 kg, median BMI 25.9 kg/m2) with adrenal insufficiency for ≥6 months and were undergoing stable hormone replacement therapy for ≥3 months. Of these patients, 16 had primary adrenal insufficiency and 30 had secondary adrenal insufficiency. All patients had been receiving glucocorticoid replacement therapy for ≥2 years, and those with primary adrenal insufficiency were receiving fludrocortisone at their usual doses.
The patients were randomly assigned to receive low-dose prednisolone in the morning (with placebos at noon and afternoon) (n=24) or hydrocortisone at morning, noon, and afternoon (n=22) for 4 months. All patients were crossed over to the alternative treatment for an additional 4 months. The median dose used in the study was 20 mg for hydrocortisone and 3.5 mg for prednisolone.