Impact of glucocorticoid replacement therapy on bone mineral density in adults with Addison disease
Dhouha Ben Salah, Khouloud Boujelben*,Hamdi frikha,Mouna Elleuch,Nadia Charfi,Fatma Mnif,Mouna Mnif,Nabila Rekik ,Faten Hadjkacem,Mohamed Abid
Department of Endocrinology Diabetology, Hedi Chaker Hospital, Sfax University, Tunisia
*Corresponding author
*Khouloud Boujelben, Department of Endocrinology Diabetology, Hedi Chaker Hospital, Sfax University,
Tunisia
DOI: 10.55920/JCRMHS.2023.04.001153
FIGURE 1: Average daily HC dose during follow up of patients with AD
Thirty-nine (78 %) patients received a mean daily HC dose greater than 11 mg/m².
Mean cumulative HC dose was 374,636 ± 283,821 mg (range, 60 – 1184, 94 mg) corresponding to 5.924 ± 4.648mg/kg (range, 0.875-17.238 mg/kg).
Bone Turnover markers
Mean serum calcium and phosphorus levels were 2,29 ± 0,13 mmol/l (range,1,9-2,55 mmol/l) and 1,10 ±0,18 mmol/l (range,0,8-1,66 mmol/l),respectively.
Hypocalcemia was observed in 18 % of patients after a mean AD duration of 11,9 ± 7,1 years (range,4-26 years) and a mean cumulative HC dose of 317,7±211,7 mg (range,75-702 mg).
In fact, hypocalcemia had no significant correlation with none of glucocorticoid replacement duration (p=0.397) or glucocorticoid dose (p=0.680).
Mean ALP was 77,2 ±28,5 IU/l (range,15-190 IU/l). Patients presenting an increased ALP level (18 %) received higher cumulative HC intake but without statistical significance (413,4 ± 348 mg versus 365,5 ± 271 mg ;p =0,7 ).
Mean vitamin D level was 22,28 ± 14,14 ng/ml (range,5,6-78,6 ng/ml).Hypovitaminosis D was observed in 66% of patients.
All patients with hypocalcemia had hypovitaminosis D.
Mean PTH level was 51,79 ± 23,84 pg/ml (range,16,36-139 pg/ml).An elevated PTH level was observed in 20 % of patients who presented all vitamin D deficiency.
Finally, biochemical parameters of bone turnover in patients with AD showed no significant correlation with none of AD duration or glucocorticoid dose.
BMD in patients with AD
The average BMD at lumbar spine and femoral neck was 0,928 ± 0,174 g/cm² (range,0,596-1,287 g/cm²) and 0,945 ± 0,145 g/cm², (range,0.687-1.265g/cm²) ,respectively.
The data on BMD at both lumbar spine and femoral neck were shown in Table 1.
TABLE 1: Results of bone densitometry in lumbar spine and femoral neck
Abbreviation: SD, standard deviation.
The T-scores at lumbar spine were lower than at femoral neck. Similarly, lumbar spine Z-scores were lower than at femoral site.
Twenty-four (48 %) patients had reduced BMD (less than 2 standard deviations [SD] of the mean value of an age-matched reference population).Among these patients, twelve had osteoporosis, corresponding to 24 % of all patients included in our study. Also, osteopenia was observed in 24 % of patients.
But, no patient had a history of spontaneous or traumatic fracture.
Predictive factors for low BMD in patients with AD
Patients with low BMD were significantly older than those with normal BMD (53.6 ±11.8 years versus 45.17 ± 15.04 years, p=0.04).
As well, BMD was significantly more frequent in postmenopausal women (risk ratio = 3.7, p=0.049) (p=0.049).
No significant BMD variation was observed according to BMI (p=0.71) or AD duration
(p=0.79).
PTH level was higher in patients with decreased BMD but without a statistically significant association (56 ± 21.8 pg/ml versus 48.1 ±25.4 pg/ml, p=0.1).
Also, vitamin D level was lower in patients presenting low BMD compared to those with normal BMD but still without statistically significant correlation (19 ± 10,2 ng/ml versus 25,2 ± 16,6 ng/ml , p=0.2).
As for glucocorticoid therapy dose, although it was higher in patients with reduced BMD, no correlation was observed between cumulative HC dose and low BMD.
Table 2 shows daily and cumulative glucocorticoid dose variation between patients with normal BMD and those with low bone mass.
TABLE 2: Correlation between glucocorticoid dose and BMD
Abbreviation: BMD, bone mineral density.
Predictive factors for osteoporosis in patients with AD
Patients who developed osteoporosis were significantly older than those with normal BMD (p=0,018). The menopause was also a significant predictor of incident osteoporosis (p=0,006).Furthermore, osteoporosis was significantly more prevalent among females (p=0,046). No significant association was found between osteoporosis and AD duration as show in Table 3.
TABLE 3: Relationships between osteoporosis and patients ‘clinical/laboratory data
Abbreviation: BMI, Body Mass Index
Then, we studied the effect of glucocorticoid replacement therapy on BMD and the occurrence of osteoporosis in patients with AD.
Daily and cumulative HC dose were higher in patients with osteoporosis than those with normal osteodensitometry (26,5±8,3 mg/day versus 25,6 ±6,3 mg/day; 462,2±373,2 mg versus 344,6±245,5 mg) but none of these factors had significant impact on the occurrence of osteoporosis as shown in Table 4.
TABLE 4: Correlation between glucocorticoid dose and BMD
Abbreviation: AD, Addison Disease ; CI, Corticotropic Insufficiency; BMD, Bone Mineral Density.
Some studies have also investigated the risk of osteoporotic fractures in AD patients.
A Swedish study examined the risk of hip fracture in patients with AD who showed a higher risk compared to healthy controls (6.9% vs. 2.7% in controls; p<0.001) (35).
Similarly, Camozzi et al (32) showed that 31.1% of patients with AD had at least one vertebral fracture related to osteoporosis, compared with only 12.8% of control subjects (odds ratio = 3.09).
Predictive factors of low BMD in patients with AD
*Disease duration
Lee et al (36) have demonstrated that bone loss occurs early in AD, even before diagnosis, since glucocorticoids promote osteoblastic precursor differentiation and therefore hypocorticism might result in osteoblastic immaturity and reduced bone mass.
Studies investigating the correlation between AD duration and bone status are heterogeneous and their results are contradictory. However, the majority of findings have not reported a correlation between disease duration and BMD (6,8,28,31,34).
*Age
Bone demineralization in the general population begins progressively from the age of 25 years and increases linearly with age.
In fact, aging leads to an osteoformation decrease by a reduction of osteoblast activity as well as an acceleration of bone resorption due to a state of hyperparathyroidism secondary to the hypovitaminosis D frequently observed in the elderly subject.
This bone loss increases rapidly after menopause in women and remains constant in men (37,38).
In AD patients, the curve of bone mass evolution according to age is similar to that of the general population.
Thus, Jodar and al (31) observed that no BMD variation according to age was found. Similarly, Valero et al (39) in their cross-sectional study of 30 AD patients with an average age of 52.2 years, reported the same result.
In our study, patients with low BMD were older than those with normal BMD but without significant difference.
*Menopause
Various studies studying BMD in AD patients reported a more frequent bone loss (osteopenia and/or osteoporosis) in menopausal women (5,32,33,39).
In a comparative study reported by Camozzi et al (32), none of the menopausal women in the control group experienced an osteoporotic fracture. While, menopausal AD women had a fracture rate of 53 %.
This finding suggests a major impact of glucocorticoid replacement therapy in the occurrence of atraumatic fractures in menopausal AD women.
*Glucocorticoid dose
Most of studies concur that optimal glucocorticoid replacement therapy requires a daily dose of 15 to 20 mg equivalent to 10-12 mg/m² (1,40).
A recent Endocrine Society Clinical Practice Guideline recommended a daily HC dose of 15-25 mg for patients with AD (2).But, most of AD patients seemed to be on supraphysiological glucocorticoid doses, resulting in catabolic repercussions on bone health.
In our study, 78% of patients received a daily HC dose greater than 11 mg/m².Higher mean cumulative HC doses, particularly in patients with osteoporosis, were observed in patients with low BMD.
Several studies have examined the impact of HC dose on bone health in patients with AD (5,6,30,41).
In a study involving 91 patients with AD ,Zelissen et al (6) observed that mean BMD was negatively correlated with current glucocorticoid dose but only in men (p=0.032).Patients treated with a daily HC dose less than 13.6 mg/m² had normal BMD instead of those receiving more than 16.4 mg/m².
In another prospective study, Schulz el al (5) reported that HC dose reduction from 30.8±8.5 mg/d to 21.4±7.2 mg/d induced a significant improvement in lumbar spine and femoral Z-scores in 90 AD patients (from -0, 93±1.2 to -0.65±1.5 (p<0.05) and from -0.40±1.0 to -0.28±1.0 (p<0.05), respectively) (5).
In contrast, Koetz et al observed that lower glucocorticoid dose didn’t improve BMD in 81 AD patients (8 ) .
These same findings were also reported by Jodar et al (31), Florkowski et al (33), Valero et al (39) and Chandy et al ‘ studies (34).
Finally, the vast majority of medical researches concur that high cumulative glucocorticoid dose is associated with an increased prevalence of bone demineralization in AD patients.
Table 6 summarizes several studies assessing glucocorticoid dose‘s impact on BMD in patients with AD.
TABLE 6: Synopsis of main clinical studies assessing the impact of glucocorticoid dose on BMD in patients with AD
Abbreviation: Hc, hydrocortisone; BMD ,bone mineral density; AD,Addison disease; CD : cumulative dose.
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