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
*Khouloud Boujelben, Department of Endocrinology Diabetology, Hedi Chaker Hospital, Sfax University,
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
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
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).
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.
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.
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.
- Øksnes M, Ross R, Løvås K. Optimal glucocorticoid replacement in adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. janv 2015;29(1):3‑15.
- Isidori AM, Arnaldi G, Boscaro M, Falorni A, Giordano C, Giordano R, et al. Towards the tailoring of glucocorticoid replacement in adrenal insufficiency: the Italian Society of Endocrinology Expert Opinion. J Endocrinol Invest. mai 2020;43(5):683‑96.
- Rs H, H Z, Mj S, Ms C. Glucocorticoids and Bone: Consequences of Endogenous and Exogenous Excess and Replacement Therapy. Endocr Rev [Internet]. 10 janv 2018 [cité 29 juin 2022];39(5). Disponible sur: https://pubmed.ncbi.nlm.nih.gov/29905835/
- Briot K, Roux C. [Corticosteroid-induced osteoporosis]. Rev Med Interne. mai 2013;34(5):315‑23.
- Schulz J, Frey KR, Cooper MS, Zopf K, Ventz M, Diederich S, et al. Reduction in daily hydrocortisone dose improves bone health in primary adrenal insufficiency. Eur J Endocrinol. avr 2016;174(4):531‑8.
- Zelissen PM, Croughs RJ, van Rijk PP, Raymakers JA. Effect of glucocorticoid replacement therapy on bone mineral density in patients with Addison disease. Ann Intern Med. 1 févr 1994;120(3):207‑10.
- Gd B, M J, M E, J C, Ir R. Bone mineral density in patients with treated Addison’s disease. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA [Internet]. 1999 [cité 29 juin 2022];10(6). Disponible sur: https://pubmed.ncbi.nlm.nih.gov/10663342/
- Koetz KR, Ventz M, Diederich S, Quinkler M. Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J Clin Endocrinol Metab. janv 2012;97(1):85‑92.
- Proctor DN, Melton LJ, Khosla S, Crowson CS, O’Connor MK, Riggs BL. Relative influence of physical activity, muscle mass and strength on bone density. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA. 2000;11(11):944‑52.
- Lespessailles É. Ostéodensitométrie : intérêts dans la prise en charge de la fragilité osseuse. Imag Femme. déc 2020;30(4):165‑70.
- Mazziotti G, Angeli A, Bilezikian JP, Canalis E, Giustina A. Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol Metab TEM. juin 2006;17(4):144‑9.
- A C, N F, M R, Vp W, Rg M. Prevention and management of glucocorticoid-induced side effects: A comprehensive review: A review of glucocorticoid pharmacology and bone health. J Am Acad Dermatol [Internet]. janv 2017 [cité 29 juin 2022];76(1). Disponible sur: https://pubmed.ncbi.nlm.nih.gov/27986132/
- Oshagbemi OA, Burden AM, Shudofsky KN, Driessen JHM, Vestergaard P, Krings A, et al. Use of high-dose intermittent systemic glucocorticoids and the risk of fracture in patients with chronic obstructive pulmonary disease. Bone. mai 2018;110:238‑43.
- Rs W. Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med [Internet]. 7 juill 2011 [cité 29 juin 2022];365(1). Disponible sur: https://pubmed.ncbi.nlm.nih.gov/21732837/
- Hardy RS, Zhou H, Seibel MJ, Cooper MS. Glucocorticoids and Bone: Consequences of Endogenous and Exogenous Excess and Replacement Therapy. Endocr Rev. 1 oct 2018;39(5):519‑48.
- Qian X. Glucocorticoids - New Recognition of Our Familiar Friend [Internet]. 2012 [cité 29 juin 2022]. Disponible sur: https://www.intechopen.com/books/undefined/books/2538
- Suzuki Y, Ichikawa Y, Saito E, Homma M. Importance of increased urinary calcium excretion in the development of secondary hyperparathyroidism of patients under glucocorticoid therapy. Metabolism. févr 1983;32(2):151‑6.
- Paz-Pacheco E, Fuleihan GE, LeBoff MS. Intact parathyroid hormone levels are not elevated in glucocorticoid-treated subjects. J Bone Miner Res Off J Am Soc Bone Miner Res. nov 1995;10(11):1713‑8.
- Streicher C, Heyny A, Andrukhova O, Haigl B, Slavic S, Schüler C, et al. Estrogen Regulates Bone Turnover by Targeting RANKL Expression in Bone Lining Cells. Sci Rep. 25 juill 2017;7(1):6460.
- R G, Js W. The effects of glucocorticoid replacement therapy on growth, bone mineral density, and bone turnover markers in children with congenital adrenal hyperplasia. J Clin Endocrinol Metab [Internet]. déc 1997 [cité 29 juin 2022];82(12). Disponible sur: https://pubmed.ncbi.nlm.nih.gov/9398689/
- Bentivegna G, Osella G, Pia A, Terzolo M. Effects on bone health of glucocorticoid replacement therapy in primary and secondary adrenal insufficiency: A review. Curr Opin Endocr Metab Res. 2018;
- Suliman AM, Freaney R, Smith TP, McBrinn Y, Murray B, McKenna TJ. The impact of different glucocorticoid replacement schedules on bone turnover and insulin sensitivity in patients with adrenal insufficiency. Clin Endocrinol (Oxf). sept 2003;59(3):380‑7.
- Schafer AL, Shoback DM. Hypocalcemia: Diagnosis and Treatment. In: Feingold KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dhatariya K, et al., éditeurs. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000 [cité 29 juin 2022]. Disponible sur: http://www.ncbi.nlm.nih.gov/books/NBK279022/
- Arlt W, Allolio B. Adrenal insufficiency. Lancet Lond Engl. 31 mai 2003;361(9372):1881‑93.
- Romão VC, Canhão H, Fonseca JE. Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs? BMC Med. 23 janv 2013;11:17.
- Kechichian E, Ezzedine K. Vitamin D and the Skin: An Update for Dermatologists. Am J Clin Dermatol. avr 2018;19(2):223‑35.
- Heureux F, Maiter D, Boutsen Y, Devogelaer JP, Jamart J, Donckier J. [Evaluation of corticosteroid replacement therapy and its effect on bones in Addison’s disease]. Ann Endocrinol. sept 2000;61(3):179‑83.
- Leelarathna L, Breen L, Powrie JK, Thomas SM, Guzder R, McGowan B, et al. Co-morbidities, management and clinical outcome of auto-immune Addison’s disease. Endocrine. août 2010;38(1):113‑7.
- Løvås K, Gjesdal CG, Christensen M, Wolff AB, Almås B, Svartberg J, et al. Glucocorticoid replacement therapy and pharmacogenetics in Addison’s disease: effects on bone. Eur J Endocrinol. juin 2009;160(6):993‑1002.
- Braatvedt GD, Joyce M, Evans M, Clearwater J, Reid IR. Bone mineral density in patients with treated Addison’s disease. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA. 1999;10(6):435‑40.
- Jódar E, Valdepeñas MPR, Martinez G, Jara A, Hawkins F. Long-term follow-up of bone mineral density in Addison’s disease. Clin Endocrinol (Oxf). mai 2003;58(5):617‑20.
- Camozzi V, Betterle C, Frigo AC, Zaccariotto V, Zaninotto M, De Caneva E, et al. Vertebral fractures assessed with dual-energy X-ray absorptiometry in patients with Addison’s disease on glucocorticoid and mineralocorticoid replacement therapy. Endocrine. févr 2018;59(2):319‑29.
- Florkowski CM, Holmes SJ, Elliot JR, Donald RA, Espiner EA. Bone mineral density is reduced in female but not male subjects with Addison’s disease. N Z Med J. 23 févr 1994;107(972):52‑3.
- Chandy DD, Bhatia E. BONE MINERAL DENSITY IN PATIENTS WITH ADDISON DISEASE ON REPLACEMENT THERAPY WITH PREDNISOLONE. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. avr 2016;22(4):434‑9.
- Björnsdottir S, Sääf M, Bensing S, Kämpe O, Michaëlsson K, Ludvigsson JF. Risk of hip fracture in Addison’s disease: a population-based cohort study. J Intern Med. août 2011;270(2):187‑95.
- Lee P, Greenfield JR. What is the optimal bone-preserving strategy for patients with Addison’s disease? Clin Endocrinol (Oxf). août 2015;83(2):157‑61.
- Delaisse JM, Andersen TL, Kristensen HB, Jensen PR, Andreasen CM, Søe K. Re-thinking the bone remodeling cycle mechanism and the origin of bone loss. Bone. déc 2020;141:115628.
- Li SS, He SH, Xie PY, Li W, Zhang XX, Li TF, et al. Recent Progresses in the Treatment of Osteoporosis. Front Pharmacol. 2021;12:717065.
- Valero MA, Leon M, Ruiz Valdepeñas MP, Larrodera L, Lopez MB, Papapietro K, et al. Bone density and turnover in Addison’s disease: effect of glucocorticoid treatment. Bone Miner. juill 1994;26(1):9‑17.
- Nowotny H, Ahmed SF, Bensing S, Beun JG, Brösamle M, Chifu I, et al. Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis. Endocrine. mars 2021;71(3):586‑94.
- Peacey SR, Guo CY, Robinson AM, Price A, Giles MA, Eastell R, et al. Glucocorticoid replacement therapy: are patients over treated and does it matter? Clin Endocrinol (Oxf). mars 1997;46(3):255‑61.