Study participants

We evaluated data from 70 consecutive patients with PAI on conventional steroid treatment in a real-life study. Patients were consecutively referred to the Division of Endocrinology of Palermo University from January 2012 to December 2020. Patients were on conventional steroid treatment (cortisone acetate and HC), administered twice or three times a day. Thirty-five patients, 15 males and 20 females, maintained conventional steroid therapy (17 cortisone acetate and 18 HC) (group A) while the other 35, (16 who were on cortisone acetate and 19 who were on HC), 11 males and 24 females, were switched from conventional steroid treatment to DR-HC (group B) administered orally in the morning in a fasting state. Patients had a 60-month follow-up. In group A there were 5 women in menopause, while in group B there were 6 women in menopause. Exclusion criteria were the following: age18years, secondary AI (SAI), treatment with other steroids (prednisone), pregnancy, breastfeeding, premature ovarian failure, hypoparathyroidism, hyperparathyroidism, treatment with estrogens and underweight (BMI<18.5kg/m2). The switch to DR-HC was judged to be appropriate on clinical grounds in those patients who complained of fatigue and weakness, presented hyponatraemia (<134mmol/L) or hypoglycaemia (2.78mmol/L) or showed more than two comorbidities such as diabetes, osteoporosis/osteopenia, arterial hypertension and central obesity. The switch from HC to DR-HC was made with an equivalent dose, while the dose was reduced from cortisone acetate to DR-HC taking into consideration the minor steroid activity of cortisone acetate compared to HC and patients clinical characteristics.

PAI was diagnosed as recommended by international guidelines9.

In detail, among the total of 70 patients, 42 had autoimmune polyglandular syndrome (APS), while 28 had isolated autoimmune AI. Among patients with APS, 26 had combined Addisons disease and autoimmune thyroid disease, 6 had combined Addisons disease, type 1 diabetes mellitus and autoimmune hypothyroidism and 10 had combined Addisons disease, autoimmune hypothyroidism and celiac disease. Patients with celiac disease were on a stable gluten-free diet. All patients with PAI were also on stable treatment with fludrocortisone (0.050.1mg/day, once). Patients with hypothyroidism were treated with levo-thyroxine at the average dose of 1.21.5 mcg/kg. Patients with type 1 diabetes were on basal-bolus treatment on flash blood glucose monitoring. Five postmenopausal women had been treated with DHEA for a ranging period of 618months, before being included in the study.

During the 60-month treatment period, the conventional steroid and the DR-HC doses were changed based on the physicians judgement of a patients need in both groups of patients (Table 1). Each patient received instructions for treatment in special or emergency situations. Patients treated with DR-HC were instructed to add a rescue dose of HC during an intercurrent illness or stress (5 or 10mg according to severity of stress and symptoms). Overall, 8 patients had to take a rescue dose of HC, 5 of them less than 10 times and 3 of them from 20 to 30 times during the 60-month period.

The current study was carried out in accordance with the recommendations of the Paolo Giaccone Policlinico ethics committee, with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Paolo Giaccone Policlinico ethics committee (protocol 06/2021).

At baseline and after 18, 36 and 60months of conventional steroid and DR-HC treatment, clinical and bone metabolic parameters were evaluated.

Anthropometric parameters such as BMI and waist circumference (WC), measured at the midpoint between the lower rib and the iliac crest, were evaluated. In addition, sodium, potassium, serum 25hydroxyvitamin-D (vitaminD), parathyroid hormone, calcium, phosphorus, creatinine, osteocalcin and bone alkaline phosphatase were assayed.

The blood sample was taken about 2h after steroid administration (patients took the dose in the morning on waking) to avoid patients experiencing fatigue or other symptoms due to delayed intake of the drug.

In both groups, hypovitaminosis D was observed at baseline and a pharmacological supplementation was started in 26 patients of group A and 25 of group B, at the mean dose of 800 UI/day and maintained during the follow-up. Hypovitaminosis D was defined as a serum 25-hydroxy vitamin D level below the normal range (<30ng/ml). All patients supplemented with vitamin D reached the threshold of 30ng/ml.

BMD was measured by DXA at lumbar spine and femoral neck (Hologic Horizon Inc., QDR-4500W Waltham, MA) at baseline and after 18, 36 and 60months of follow-up.

In patients aged 50 or more, BMD was expressed as the T-score, comparing the results with those obtained in a sex-matched Caucasian population at the peak of bone mass. A T-score less than or equal to 2.5 SD at the neck or spine was defined as osteoporosis, whereas osteopenia was defined as a T-score between 1 and 2.5 SD. In patients younger than 50years, the results were expressed as a/the Z-score, comparing the results with those obtained in an age and sex-matched Caucasian population. A Z-score of 2.0 SD or lower was used to define a BMD below the expected range for age10. The coefficients of variation in the DXA measurements for BMD, bone mineral content (BMC) and area were 0.61%, 2.98% and 2.89%, respectively.

We also evaluated rib, femoral neck and hip fractures rate during the follow-up in both groups.

Sodium, potassium, serum 25hydroxyvitamin-D (vitamin-D), parathyroid hormone, calcium, phosphorus, creatinine, osteocalcin and bone alkaline phosphatase were measured with standard methods (Modular P800, Roche, Milan) at our hospital centralized laboratory. The intra- and interassay coefficients of variation were the following: Sodium 0.5% to 1.2% and 1.28% to 1.44%, respectively; potassium 1% to 2.1% and 2.2% to 3.08%, respectively; vitaminD 0.9% to 1.6% and 1.7% to 2.56%, respectively, parathyroid hormone 1.2% to 2.6% and 2.8% to 3.9%, respectively; calcium 1.8% to 3.5% and 3.75% to 4.23%, respectively; phosphorus 1.6% to 3.3% and 3.5% to 4.2%, respectively; creatinine 1.7% to 2.9% and 3.3% to 4.6%, respectively; osteocalcin 1.9% to 3.3% and 3.6% to 4.9%, respectively; bone alkaline phosphatase 2.7% to 3.6% and 3.8% to 5.2%, respectively.

The Statistical Packages for Social Science SPSS version 19 (SPSS, Inc., IBM, New York, USA) were used for data analysis. The normality of quantitative variables was tested with the Shapiro-Wilk test. The baseline characteristics of the groups were presented as meanSD for continuous variables, while the rates and proportions were calculated for categorical data. The differences between groups were performed using ANOVA for quantitative variables and the 2-test for categorical variables. A comparison between numerical variables at baseline, 18-, 36- and 60-month follow-up was performed with the Friedman analysis. In addition, multiple linear regression analysis was performed to identify independent predictors of the dependent variables lumbar spine and femoral neck T and Z scores and of dependent variable fracture. A p value<0.05 was considered statistically significant.

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