Accepted Manuscript

Effects on bone health of glucocorticoid replacement therapy in primary and

secondary adrenal insufficiency: a review.

G. Bentivegna, G. Osella, A. Pia, M. Terzolo

PII: S2451-9650(17)30019-4
DOI: 10.1016/j.coemr.2018.02.008
Reference: COEMR 20

To appear in: Current Opinion in Endocrine and Metabolic Research

Received Date: 7 November 2017

Accepted Date: 28 February 2018

Please cite this article as: Bentivegna G, Osella G, Pia A, Terzolo M, Effects on bone health of
glucocorticoid replacement therapy in primary and secondary adrenal insufficiency: a review., Current
Opinion in Endocrine and Metabolic Research (2018), doi: 10.1016/j.coemr.2018.02.008.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT
Effects on bone health of glucocorticoid replacement therapy in primary and secondary adrenal
insufficiency: a review.

G. Bentivegna, G. Osella, A. Pia, M. Terzolo

Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin,
Italy.

Abstract

PT
This review focuses on the effects of glucocorticoid replacement therapy on bone health in patients with
primary and secondary adrenal insufficiency. The negative impact of glucocorticoids on bone is related to a

RI
number of factors, namely dose and type of steroid used, duration of therapy, and cumulative dose.
Although “substitutive” in nature, GRT often produce cortisol levels that may be over the true physiological
range; therefore, patients may be chronically exposed to a slight cortisol excess potentially affecting bone

SC
health and increasing the risk of fractures. Glucocorticoids are the first cause of secondary osteoporosis.
They act on bone impairing not only bone mineral density (BMD) but also bone quality, so BMD obtained by
DXA measurements does not fully reflect the negative effects on the skeleton. We explore scientific

U
literature on this focus. A lot of papers are related to small series of patients studied several years ago;
most of these studies evaluated BMD effects and results are often conflicting, with few data about
AN
fractures. The recent guidelines suggest, for the replacement therapy of adrenal insufficiency, the use of
daily doses of glucocorticoid lower than previously used and new glucocorticoid formulations become
available, potentially safer, with lower deleterious effects on bone health.
M

Introduction
D

Glucocorticoid replacement therapy (GRT) changed the natural history of Addison's disease; before its
introduction, 2-year mortality was around 80%, with all patients dying within five years from diagnosis [1].
TE

Nevertheless, considerable morbidity and mortality of adrenal insufficiency still remains, not only as a
consequence of the disease itself but also for over- or under-treatment resulting in Cushing-like
detrimental effects or in adrenal crisis, respectively [2].The deleterious effects of chronic steroid therapy
EP

are mainly due to an increase in the cardiovascular risk profile [3] and in the impairment of the
musculoskeletal system (myopathy [4]and osteoporosis [5]). This review focuses on the effects of GRT on
bone health. The negative impact of glucocorticoids on bone is well known being related to a number of
C

factors, namely dose and type of steroid used, duration of therapy, and cumulative dose. Although
“substitutive” in nature, GRT often produce cortisol levels that may be over the true physiological range;
AC

therefore, patients may be chronically exposed to a slight cortisol excess that can potentially affect bone
health increasing the risk of fractures.

Primary adrenal insufficiency (PAI) or Addison’s Disease and secondary adrenal insufficiency (SAI) are two
different clinical entities. In SAI, other hormone deficiencies (GH, thyroid hormones, gonadotropins and
gonadal hormones), or their replacement therapies, can produce additive effects on bone health and BMD
(Bone mineral density). In PAI, the possible association of other autoimmune diseases can play an
adjunctive negative role on bone health. Furthermore, Løvås et al [6] in 2009 reported how the individual
risk of glucocorticoid induced osteoporosis (GIOP) in adrenal insufficiency is influenced by genetic
polymorphisms, especially in genes encoding P-glycoproteins, but also 11-B-hydroxylase and glucocorticoid
receptors. A common polymorphism (rs19045642) of the P-Glycoprotein acting as the efflux transporter of
Glucocorticoids (GCs) has been associated with reduced function resulting in increment of intracellular
cortisol levels (since less cortisol is pumped out of the cell) and increased risk of GIOP. Due to its role in the
 ACCEPTED MANUSCRIPT
peripheral activation of cortisone to cortisol, variable activity of the enzyme 11-B-hydroxylase type 1 is
associated with the risk of osteoporosis. In their study, Løvås et al. found a slight increase in BMD and bone
formation markers in the few homozygote carriers for a polymorphism associated with reduced activity of
this enzyme, which leads to reduced activation of cortisol.

PATOPHYSIOLOGY OF GLUCOCORTICOID INDUCED OSTEOPOROSIS (GIOP)

Glucocorticoids exert important actions on bone [7,8]: they inhibit osteoblast activity and promote their

PT
apoptosis; increase osteoclast activity; influence calcium metabolism by inhibiting intestinal absorption and
increasing renal excretion; influence production and action of other hormones that regulate bone and
calcium metabolism (gonadotropins, sex steroids, GH, IGF-I). GIOP occurs in two phases: a rapid BMD fall,

RI
probably related to an increased bone resorption, followed by a slower BMD decline caused by impaired
bone formation5. It is well known that GCs cause a decrease in bone mineral density, but they also alter the
bone “quality” providing a risk of fracture higher than that simply explained by densitometric data [9]. In

SC
GRT, hydrocortisone (HC) and cortisone acetate (CA) are the most common steroids used, more rarely
prednisone (PDN), prednisolone or dexamethasone. CA and PDN are pro-drugs that need to be activated by
the 11 β-hydroxysteroid dehydrogenase type 1, so polymorphism in this enzyme could produce individual
differences [6], even if no study has confirmed that this assumption has a relevant clinical impact.

U
The following issues on bone health in patients with PAI and SAI deserve special attention:
AN
1. Differences in doses and type of steroid used.
2. Concomitant androgen deficiency.
M

3. Concomitant GH deficiency.
D
TE

1. Differences in doses and type of steroid used in PAI and SAI

EP

In the past, conventional GRT regimens consisted of doses that have been proven to be excessive
(averaging more than 30 mg/day of hydrocortisone). Esteban et al [10] in 1991, demonstrated that
endogenous cortisol production is lower than expected (equivalent to 5-7 mg/m2 and not 12-15 mg/m2 as
C

previously considered).
AC

A recent prospective observational study [11] of 1166 patients (about 30% with PAI, 70% with SAI) shows a
great heterogeneity in type, dose and timing of GRT used. This reflects the lack of effective measures to
determine the optimal substitutive dose, which is individualized on the basis of health status or signs and
symptoms of under of over treatment. In this prospective multinational observational survey, HC was the
most used drug (87.4%), followed by prednisolone (5.1%), CA (4%) or dexamethasone (0.1%). Daily doses of
HC ranged from 5 to 45 mg, with 80% of patients taking a dose between 15 and 30 mg; 12.6% more than 30
mg, and 7.2% below 15 mg.

Up to 10-15 years ago, studies on the effects of GRT on BMD in PAI and SAI patients provided conflicting
results. Two small studies (including 15 and 25 patients, respectively) did not observe a significant
reduction in BMD [12,13] during long-term replacement therapy, while other studies showed reduction of
BMD in both sexes [14], or only in post-menopausal women with PAI and SAI [15,16], or only in women
with PAI [17]. However, there are also reports of reduced BMD limited to the male sex [18,19]. In the study
 ACCEPTED MANUSCRIPT
of Braatvedt et al [18], mean BMD was not different from normal controls in the whole group of 19 men
and 10 women (3 premenopausal and 7 postmenopausal) but mean BMD was negatively correlated with
current and cumulative GCs dose per Kg of body weight, and duration of PAI. Hypogonadism (either
primary then secondary) was common in men (42%) and these patients showed the lowest BMD. Also
Zelissen et al [19], found a linear correlation between BMD and the daily dose of HC per Kg of body weight,
but only in men. Adult men (31 patients in total) treated for at least 10 years with a dose less than 13.6
mg/m2 had normal BMD in contrast to those receiving more than 16.4 mg/m2.

More recent studies seem to provide more concordant conclusions, especially on dose dependent effects.

PT
Koetz et al [20] found that BMD was not significantly reduced in 81 patients who received low-dose GCs
(daily HC equivalent dose of 21.9 ± 4.9 mg/die). BMD values in patients with PAI were normal, with the
subgroup of post-menopausal women showing the lowest T-scores. Interestingly, patients on PDN showed

RI
in comparison with those on HC significantly reduced Z-scores at femoral neck, Ward’s triangle and lumbar
spine at L1-L2 (but not at L1-L4).

Lovas et al [6] found that patients with PAI (both males and females) taking around 30 mg or more of HC

SC
had lower BMD values than healthy controls.

Schultz et al [21] reported that reduction of daily dose of HC improves BMD values without increasing the

U
risk of adrenal crisis. On the other side, the increase of steroid dose significantly reduced BMD values.

Many studies show lowest BMD values in patients with PAI taking prednisolone (Koetz et al [20], Schultz
AN
[21] et al, Chandy et al [22], Lovas et al [6] than those taking HC. In some countries prednisolone is the only
steroid available; however, prospective studies comparing the safety of prednisolone and HC are not
available.
M

Reduced BMD represents only one of the many risk factors for fracture. The incidence of fragility fractures
should be the most relevant endpoint of studies on bone health, but to our knowledge only one study [23]
D

focused on the risk of hip fracture in a population of 3219 patients with PAI compared with 31557 controls
(data extracted from the Swedish National Patient Register and the Total Population Register). During the
TE

observed period from 1964 to 2006, the authors observed 221 hip fractures in patients with PAI (6.9%) and
846 fractures in controls (2.7%), HR 1.8 (95% CI 1.6-2,) p <0.001. Risk was higher in the first year either
before or after the diagnosis, leading to speculate that the combination of a low cortisol concentration
before diagnosis and a mild over treatment in the first year after diagnosis may results in a pronounced
EP

increase in the bone turnover rate. In women, age ≤ 50 years at diagnosis conferred a higher risk of hip
fractures in comparison with controls, probably because women with PAI often experience premature
autoimmune ovarian failure. This result, coupled with the observation that fracture risk was not increased
C

in men, may also imply that the deficiency in adrenal androgens in women with PAI is more important than
previously thought. To our knowledge, also about the risk of vertebral fractures, there are only one paper
AC

and an Editorial recently published [24,25]. Camozzi et al reported the prevalence of morphometric
vertebral fractures in 61 patients with AD on GRT and mineralocorticoids therapy in comparison with 47
age and sex-matched healthy controls. They found a risk of morphometric vertebral fractures three times
higher in patients that in control. The higher risk was not related with BMD value at any site, and no
difference were found between BMD values in patients with or without fractures [24]. However, it is not
clear if the Authors accounted for a possible falsely increase of BMD in patients due to crush fractures [25].
Patients treated with fludrocortisones had significantly higher BMD values at all sites except for the lumbar
spine [24].

A recent systematic review and meta-analysis [26] compared the effects of different glucocorticoid
regimens on different outcomes: quality of life, bone mineral density, adrenal crises and death. The meta-
 ACCEPTED MANUSCRIPT
analysis assessed eleven studies and showed inconsistent results on the influence of total daily steroid dose
on BMD, ranging from negative effects and no effects at all. Treatment with glucocorticoid, either type
then doses, did not show any relationship also with quality of life and rates of adrenal crises.

The key question of what is the optimal bone-preserving strategy in PAI has been answered in recent
reviews as a daily replacement dose of 0.2-0.3 mg/Kg of HC equivalents [27,28] associated with 0.1-0.3 mg
of fludrocortisone, and a selective use of androgens, especially in patients with very low androgens levels
and/or androgen deficiency symptoms.

A recent Endocrine Society Clinical Practice Guideline suggests the use of HC (15-25 mg daily) or cortisone

PT
acetate (20-35 mg daily). As an alternative, prednisolone 3-5 mg daily may be used, while it is argued
against the use of dexamethasone [29].

RI
New different molecules and treatment regimens can in future improve GRT, mimicking more closely the
physiological circadian cortisol rhythm of cortisol. Two different modified-release HC formulation are now
licensed (Plenadren® and Chronocort®) that are potentially able to improve some clinical outcomes in

SC
patients with PAI and SAI, even if their relative high cost and still limited availability are important caveats
[30]. Treatment with Plenadren® seems to provide a more physiological cortisol profile and in some
patients shows a beneficial effect on glucose metabolism, bone and body composition without increasing

U
adrenal crisis and/or infections [31]. Recently, Frara et al [32] evaluate the effects on bone of Plenadren®,
in 14 patients with a history of median 10 years of hypopituitarism, 2 on recombinant human Growth
AN
Hormone (rhGH) treatment, treated at least for one year with conventional GCs regimens and then shifted
to Plenadren® for 2 years. They obtained lumbar spine, femoral neck and total hip BMD at baseline and
after 2 years. Patients showed a significant increase of BMD value at lumbar spine and femoral neck, not
M

significant at total hip (the median changes were respectively + 10%, + 11,5 %, +3.1%). Despite the
limitations (small number of patients, possible bias in patient selection and retrospective nature of the
study), these conclusions speak in favor of these interestingly GCs formulation in minimizing the side
D

effects of GRT.
TE

The table 1 summarizes the main clinical studies on the effects of GRT on bone mineral density. In
EP

particular, we suggest to the readers 3 recent reviews evaluating different clinical outcome in patients with
adrenal insufficiency: Johannsson et al [2], Bensing et al [33], Mazziotti et al [30].
C

2. Deficiency of adrenal androgens and effect of replacement.

AC

In men, both androgens and oestrogens regulate skeletal homeostasis. In women, the fall of oestrogens
levels at the time of menopause causes a rapid increase in bone resorption and a rapid bone loss, playing
the central role in the pathogenesis of postmenopausal osteoporosis. Although the primary source of
oestrogen in premenopausal women is the ovaries, the primary source in postmenopausal women
becomes the adrenal glands producing androgens then converted to oestrogens by the enzyme aromatase.

Some studies report lowest BMD values in PAI hypogonadic men [18,19] and in PAI post-menopausal
women [15,16], suggesting that replacement with androgens can increase BMD.

In a 12-month randomized, placebo-controlled study, Miller et al [34] found a positive effect of

testosterone patch delivering 300 micrograms daily vs placebo on mean hip (P = 0.023) and radius BMD (P =
0.007), a positive effect on body composition (fat free mass and thigh muscle area), and improved
 ACCEPTED MANUSCRIPT
neurobehavioral function (mood and sexual function) in 51 women in reproductive age, with severe
androgen deficiency and SAI due to hypopituitarism.

A randomized controlled trial conduct by Gurnell et al [35] shows that replacement with DHEA
(Dehydroepiandrosterone) reverts bone loss at femoral neck. A total of 100 subjects with PAI were
randomized to receive either 50 mg daily of micronized DHEA or placebo orally for 12 months (49 DHEA, 51
placebo). During the 12 months of the study, there was a progressive decrease in BMD at most sites. In
patients receiving DHEA, there was a marked and significant reversal of this trend at the femoral neck.
Other studies on DHEA therapy in postmenopausal women (not affected by adrenal insufficiency) have

PT
shown selective improvement of BMD at this skeletal site [36-38].

Koetz et al [20] found that the 17 patients treated with DHEA have significantly higher lumbar Z-score and
significantly lower NTX serum levels (expression of lower bone resorption) than the 41 patients who were

RI
left untreated.

In the Endocrine Society Clinical Practice Guideline [29] it is suggested first to demonstrate androgen

SC
deficit, and then to treat deficient patients with a re-evaluation after six months. If patients show some
improvements in libido, depressive symptoms, and/or low energy levels, despite otherwise optimized
glucocorticoid and mineralocorticoid replacement, it is advised to continue replacement therapy with

U
androgens. AN
3. Growth Hormone Deficit (GHD) and effect of replacement.
M

GH and IGF-1 are a well-known anabolic stimulus for bone. The most important effect is enhancing bone
formation by promoting genesis and differentiation of osteoblasts with positive effects on longitudinal
D

growth. It has also been demonstrated that GH inhibits the activity and expression of 11β--hydroxysteroid
dehydrogenase type 1 [39]. This enzyme converts the inactive metabolite cortisone to the active hormone
TE

cortisol and in patients with GHD the activity of 11β-HSD type 1 is increased [40,41].

GH deficiency is associated with decreased BMD and increased fracture risk [42,43]. Long-term observation
EP

during GH replacement showed a biphasic change in BMD, with an initial decrease around 6 months after
therapy initiation, followed by a subsequent increase after at least 1 year of GH replacement [44].
C

The influence of GCs on bone health in patients with pituitary insufficiency has been explored in two large
studies from the KIMS database in which GC replacement therapy was associated with a reduced BMD [45]
AC

even if without increased fracture [46]. Regretfully, GC doses used are not reported.

Agnarsson et al [47] in an open prospective longitudinal study, analyzed the effects of GC replacement on
BMD before and after 2 years of GH therapy in patients with hypopituitarism. Of 175 patients, 98 were GC
insufficient, and were treated with cortisone acetate (60%) or HC (40%). The mean HC equivalent dose was
20.9 ± 5.0 mg/die. GH replacement for two years increased BMD at femoral neck (but not at lumbar spine)
in hypopituitary patients, both GC-sufficient and GC-insufficient receiving GRT. In this study, no difference
in BMD was seen at baseline between GC-sufficient and GC-insufficient patients. The same authors in a
previous study found that GC replacement therapy in women with hypopituitarism was independently
associated with reduced BMD, compared with women with an intact hypothalamus-pituitary-adrenal axis
[48]. The discrepancy between the two studies, has been explained with a more homogenous population in
the second study [47].
 ACCEPTED MANUSCRIPT
A meta-analysis by Barake et al [49] systematically investigated the effects of rhGH therapy on BMD and
bone mineral content in adults with GHD (either isolated or in the context of hypopituitarism). A beneficial
effect on BMD of rhGH replacement therapy for more than 1 year was reported; the effect was affected by
gender, age and treatment duration.

Some cross-sectional studies reported an increased prevalence of vertebral fractures in adults with
untreated GHD [50-52]. Mazziotti et al [51], investigated whether GRT may influence the prevalence of
fragility vertebral fractures in a group of male patients with GHD, in relation to age, BMD, rhGH treatment,
and other pituitary deficiencies. The authors evaluated 51 adult hypopituitaric men (mean age 55 years). All

PT
patients had glucocorticoid deficiency (25 treated with HC and 26 with cortisone acetate, at median daily
doses of 30 and 35 mg, respectively). At the beginning of the study, 21 patients were on replacement
therapy with rhGH, whereas 30 patients had never received rhGH. Vertebral fractures were observed in 31

RI
patients (60.8%). Fractures were single in 9 patients, whereas the remaining 22 showed two or more
fractures. In untreated GHD, vertebral fractures occurred more frequently in patients who had received an
higher HC equivalent dose (current and cumulative) compared with patients who had received lower doses

SC
of the drug and furthermore fractured patients showed significantly higher urinary cortisol values
compared with patients without vertebral fractures. The association between glucocorticoid over-
replacement and vertebral fractures in untreated GHD patients was independent from BMD. In contrast, in
treated GHD patients, the prevalence of vertebral fractures was not influenced by cumulative and current

U
cortisone doses. Mazziotti et al [53] confirmed this prevalence in a prospective study. After six years of
AN
follow-up, 30% of patients have an incident fracture and the risk of fractures was closely related with the
lack of GH replacement and with a prior fracture. The Authors conclude that GH replacement can protect
the skeleton from the deleterious effects of GC overtreatment in hypopituitary patients.
M
D

CONCLUSION. In this review we tried to summarize the available data on the impact of GRT on bone health
in PAI and SAI.
TE

Many patients in GRT for PAI or SAI report an impaired quality of life. This may be often due to an over or
under replacement treatment and in the inability of current therapeutic regimens to mimic closely the
physiological cortisol circadian rhythm. Osteoporosis and fractures are important adverse events of GRT
EP

but our knowledge on this issue is unfortunately hampered by the small statistical power and the
observational, retrospective or cross-sectional design of most of the available studies. Moreover, most
studies reported data bone mineral density (even if with sometimes conflicting results) while there is a lack
C

of information on the incidence and prevalence of fragility fractures in patients with PAI or SAI.
AC

Larger and longitudinal studies are needed, especially because in recent years the daily dose of GC used for
replacement has been substantially reduced.

In the contest of primary and secondary adrenal insufficiency, clinicians should have to focus on the
individual risk of fragility fractures at the time of diagnosis for subsequent careful follow-up and to choose
the better replacement regimen able to avoid signs and symptoms of under-treatment minimizing at the
same time the negative effects of an over-treatment. Usually, the daily dose of glucocorticoids should not
exceed 20-25 mg daily of HC equivalent doses to avoid impairment of bone health. Attention must be paid
also to concomitant androgen or growth hormone deficiency. New molecules or HC formulations could in
the future improve the quality of GRT in patients with primary and secondary adrenal insufficiency.
 ACCEPTED MANUSCRIPT
References[1] D. Dunlop, Eighty-six cases of Addison disease. British Medical Journal. 1963. 887-891.[2] G.
Johannsson, A. Falorni, S. Skrtic, H. Lennernäs, M. Quinkler, J.P. Monson, P.M. Stewart, Adrenal
insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy. Clinical
endocrinology. 2015, 82, 2-11.[3] R. Giordano, S. Marzotti, M. Balbo, S. Romagnoli, E. Marinazzo, R.
Berardelli, G. Migliaretti, A. Benso, A. Falorni, E. Ghigo, Metabolic and cardiovascular profile in patients with
Addison’s disease under conventional glucocorticoid replacement. Journal of Endocrinological
Investigation, 2009. Volume 32, Issue 11, 917-923.

[4] O. Schakman, H. Gilson, J.P. Thissen, Mechanisms of glucocorticoid-induced myopathy. Journal of

PT
Endocrinology. 2008, 197, 1-10.[5] R.S. Weinstein, Glucocorticoid-induced bone disease. New England
Journal of Medicine. 2011, 365, 62-70.[6] K. Løvås, C.G Gjesdal, M. Christensen, A.B. Wolff, B. Almås, J.
Svartberg, K.J. Fougner, U. Syversen, J. Bollerslev, J.A. Falch, P.J. Hunt, V.K. Chatterjee, E.S. Husebye,

RI
Glucocorticoid replacement therapy and pharmacogenetics in Addison’s disease: effects on bone. European
Journal of endocrinology. 2009, 160,993-1002.[7] G. Mazziotti, A. Angeli, J.P. Bilezikian, E. Canalis, A.
Giustina, Glucocorticoid-induced Osteoporosis: an update. Trends in Endocrinology and Metabolism.

SC
Elsevier Ltd,2006. Volume 17, Issue 4, 144-149.

[8] E. Canalis, J.P. Bilezikian, A. Angeli, A. Giustina, Perspective on glucocorticoid-induced osteoporosis.

Bone. 2004, Volume 34, Issue 4, 593-598.

U
[9] M. Steinbuch, T.E. Youket, S. Cohen, Oral glucocorticoid use is associated with an increased risk of
AN
fracture. Osteoporosis International. 2004, 15, 323–328. DOI:10.1007/s00198-003-1548-3.[10] N.V.
Esteban, T. Loughlin, A.L. Yergey, J.K. Zawadzki, J.D. Booth, J.C. Winterer, F.L. Loriaux, Daily cortisol
production rate in man determined by stable isotope dilution/mass spectrometry. Journal of Clinical
Endocrinology and Metabolism. 1991, 72,39-45.[11] R.D. Murray, B. Ekman, S. Uddin, C. Marelli, M.
M

Quinkler, P.M. Zelissen, the EU-AIR Investigators, Management of glucocorticoid replacement in adrenal
insufficiency shows notable heterogeneity-data from the EU-AIR (European Adrenal Insufficiency Registry).
Clinical Endocrinology. 2017, 86, 340-346.[12] W. Arlt, C. Rosenthal, S. Hahner, B. Allolio, Quality of
D

glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol
measurements. Clinical Endocrinology. 2006, 64, 384–389.
TE

[13] E. Jódar, M.P. Valdepeñas, G. Martinez, A. Jara, F. Hawkins, Long-term follow-up of bone mineral
density in Addison’s disease. Clinical Endocrinology, 2003. Volume 58, Issue 5, pages 617–620.
EP

[14] F. Heureux, D. Maiter, Y. Boutsen, J.P. Devogelaer, J. Jamart, J. Donckier, Evaluation of corticosteroid
replacement therapy and its effect on bones in Addison's disease. Annales d’Endocrinologie. 2000, 61(3),
179-183.
C

[15] M.A. Valero, M. Leon, M.P. Ruiz Valdepeñas, L. Larrodera, M.B. Lopez, K. Papapietro, A. Jara, F.
AC

Hawkins, Bone density and turnover in Addison’s disease: effect of glucocorticoid treatment. Bone and
Mineral, 1994. Volume 26, Issue 1, pages 9 –17.[16] J.P. Devogelaer, J. Crabbé, C. Nagant de Deuxchaisnes,
Bone mineral density in Addison’s disease: evidence for an effect of adrenal androgens on bone mass.
British Medical Journal (Clinical Research Ed.), 1994. Volume 294, No.6675, pages 798–800.

[17] C.M. Florkowski, S.J. Holmes, J.R. Elliot, R.A. Donald, E.A. Espiner, Bone mineral density is reduced in
female but not male subjects with Addison’s disease. The New Zealand Medical Journal, 1994. 107 (972), 52
–53.

[18] G.D. Braatvedt, M. Joyce, M. Evans, J. Clearwater, I.R. Reid, Bone mineral density in patients with
treated Addison’s disease. Osteoporosis International. 1999, Volume 10, 435–440.
 ACCEPTED MANUSCRIPT
[19] P.M. Zelissen, R.J. Croughs, P.P. Van Rijk, J.A. Raymakers, Effect of glucocorticoid replacement therapy
on bone mineral density in patients with Addison disease. Annals of Internal Medicine. Volume 120 (3),
(1994), 207–210.

[20] K.R. Koetz, M. Ventz, S. Diederich, M. Quinkler, Bone mineral density is not significantly reduced in
adult patients on low-dose glucocorticoid replacement therapy. Journal of Clinical Endocrinology and
Metabolism. 97 (1), (2012), 85 –92.

[21] J. Schulz, K.R. Frey, M.S. Cooper, K. Zopf, M. Ventz, S. Diederich and M. Quinkler, Reduction in daily HC
dosage improves bone health in primary adrenal insufficiency. European journal of endocrinology. 174

PT
(2016), 531-538.

[22] D.D. Chandy and E. Bhatia, Bone Mineral Density in Patients with Addison Disease On Replacement

RI
Therapy with Prednisolone. Endocrine Practice, 2016. Volume 22, Issue 4, 434-439.

[23] S. Björnsdottir, M. Sääf, S. Bensing, O. Kämpe, K. Michaëlsson, J.F. Ludvigsson, Risk of hip fracture in
Addison’s disease: a population-based cohort study. Journal of internal medicine. 270 (2011), 187-195.

SC
[24] V. Camozzi, C. Betterle, A.C. Frigo, V. Zaccariotto, M. Zaninotto, E. De Caneva, P. Lucato, W. Gomiero, S.
Garelli, C. Sabbadin, M. Savà, M. Dalla Costa, M. Boscaro, G. Luisetto, Vertebral fractures assessed with

U
dual-energy X-ray absorptiometry in patients with Addison’s disease on glucocorticoid and
mineralocorticoid replacement therapy. Endocrine, 2017. DOI 10.1007/s12020-017-1380-8.
AN
[25] H. Falhammar, Skeletal fragility induced by overtreatment of adrenal insufficiency. Endocrine, 2017.
DOI 10.1007/s12020-017-1501-4.
M

[26] A. Al Nofal, I. Bancos, K. Benkhadra, N.M. Ospina, A. Javed, E. Kapoor, K. Muthusamy, J.P. Brito, A.F.
Turcu, Z. Wang, L. Prokop, D.Z. Erickson, A.N. Lteif, N. Natt, M.H. Murad, Glucocorticoid replacement
therapy regimens in chronic adrenal insufficiency: a systematic review and meta-analysis. Endocrine
D

practice AACE, 2017. Vol 23, Issue 1, 17-31.

[27] P. Lee, J.R. Greenfield, What is the optimal bone-preserving strategy in Addison disease? Clinical
TE

Endocrinology. 83 (2015), 157-161.

[28] M.J. Seibel, M.S. Cooper, H. Zhou, Glucocorticoid induced osteoporosis: mechanism, management and
future perspectives. Lancet Diabetes and endocrinology, 2013. Volume 1, Issue 1, 59-70.
EP

[29] S.R. Bornstein, B. Allolio, W. Arlt, A. Barthel, A. Don-Wauchope, G.D. Hammer, E.S. Husebye, D.P.
Merke, M Hassan Murad, C.A. Stratakis, D.J. Torpy, Diagnosis and treatment of primary adrenal
C

insufficiency: An Endocrine Society Clinical Practice Guidelines. Journal of Clinical Endocrinology and
Metabolism, 2016. Volume 101, Issue 2, 364-389.
AC

[30] G. Mazziotti, A.M. Formenti, S. Frara, E. Roca, P. Mortini, A. Berruti and A. Giustina, Management of
endocrine disease: Risk of overtreatment of patients with adrenal insufficiency: Current and Emerging
Aspects. European Journal of Endocrinology. 177 (2017), R 231-248.
[31] T. Pilli, R. Forleo, S. Cardinale, V. Cenci and F. Pacini, Treatment of patients with primary and secondary
adrenal insufficiency with hydrocortisone modified-release (Plenadren®). Endocrine Abstracts,
(2017) 49; EP60. DOI:10.1530, endoabs.49.EP6.
[32] S. Frara, S. Chiloiro, T. Porcelli, A. Giampietro, G. Mazziotti, L. De Marinis, A. Giustina, Bone safety of
dual-release hydrocortisone in patients with hypopituitarism. Endocrine, 2018. DOI 10.007/s12020-017-
1512-1.

[33] S. Bensing, A.L. Hulting, E.S. Husebye, O. Kämpe, K. Løvås, Epidemiology, quality of life and
complications of primary adrenal insufficiency. European Journal of Endocrinology, 2016. 175 (3), R107-
 ACCEPTED MANUSCRIPT
R116K.K. Miller, B.M.K. Biller, C. Beauregard, J.G. Lipman, J. Jones, D. Schoenfeld, J.C. Sherman, B.
Swearingen, J. Loeffler, A. Klibanski, Effects of Testosterone Replacement in Androgen-Deficient Women
with Hypopituitarism: A Randomized, Double-Blind, Placebo-Controlled Study. The Journal of Clinical
Endocrinology & Metabolism, 2006. Volume 91, Issue 5, 1683–1690.
[34] K.K. Miller, B.M.K. Biller, C. Beauregard, J.G. Lipman, J. Jones, D. Schoenfeld, J.C. Sherman, B.
Swearingen, J. Loeffler, A. Klibanski, Effects of Testosterone Replacement in Androgen-Deficient Women
with Hypopituitarism: A Randomized, Double-Blind, Placebo-Controlled Study. The Journal of Clinical
Endocrinology & Metabolism, 2006. Volume 91, Issue 5, 1683–1690.

PT
[35] E.M. Gurnell, P.J. Hunt, S.E. Curran, C.L. Conway, E.M. Pullenayegum, F.A. Huppert, J.E. Compston,
J.Herbert, and V.K. Chatterjee,Long-Term DHEA Replacement in Primary Adrenal Insufficiency: A
Randomized, Controlled Trial. Journal of Clinical Endocrinology and Metabolism, 2008. 93(2), 400-409.

RI
[36] P. Diamond, L. Cusan, J.L. Gomez, A. Bélanger, F. Labrie, Metabolic effects of 12-month percutaneous
Dehydroepiandrosterone replacement therapy in postmenopausal women. Journal of Endocrinology. 150
(1996), S 43–S50.

SC
[37] E.E. Baulieu, G. Thomas, S. Legrain, N. Lahlou, M. Roger, B. Debuire, V. Faucounau, L. Girard, M.P.
Hervy, F. Latour, M.C. Leaud, A. Mokrane, H. Pitti-Ferrandi, C. Trivalle, O. de Lacharrière, S. Nouveau, B.

U
Rakoto-Arison, J.C. Souberbielle, J. Raison, Y. Le Bouc, A. Raynaud, X. Girerd, F. Forette,
Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a socio-
AN
biomedical issue. Proceedings of the National Academy of Sciences of the United States of America, 2000.
97 (8), 4279–4284.

[38] K.S. Nair, R.A. Rizza, P. O'Brien, K. Dhatariya, K.R. Short, A. Nehra, J.L. Vittone, G.G. Klee, A. Basu, R.
M

Basu, C. Cobelli, G. Toffolo, C. Dalla Man, D.J. Tindall, L.J. 3rd Melton, G.E. Smith, S. Khosla, M.D. Jensen,
DHEA in elderly women and DHEA or Testosterone in elderly men. New England Journal of Medicine ,2006.
Volume 355, 1647–165.
D

[39] J.S. Moore, J.P. Monson, G. Kaltsas, P. Putignano, P.J. Wood, M.C. Sheppard, G.M. Besser, N.F. Taylor,
TE

P.M. Stewart, Modulation of 11-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-
like growth factor: in vivo and in vitro studies. Journal of Clinical Endocrinology and Metabolism, 1999.
Volume 84, Issue 11, 4172– 4177.
EP

[40] J.U. Weaver, L. Thaventhiran, K. Noonan, J.M. Burrin, N.F. Taylor, M.R. Norman, J.P. Monson, The
effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in
hypopituitary adults. Clinical Endocrinology, 1994. Volume 41, Issue 5, 639 – 648.
C

[41] S.V. Gelding, N.F. Taylor, P.J. Wood, K. Noonan, J.U. Weaver, D.F. Wood, J.P. Monson, The effect of
growth hormone replacement therapy on cortisol - cortisone interconversion in hypopituitary adults:
AC

evidence for growth hormone modulation of extra-renal 11-hydroxysteroid dehydrogenase activity. Clinical
Endocrinology, 1998.Volume 48, Issue 2, 153–162.

[42] S.J. Holmes, G. Economou, R.W. Whitehouse, J.E. Adams, S.M. Shale, Reduced bone mineral density in
patients with adult onset growth hormone deficiency. Journal of Clinical Endocrinology and Metabolism,
1994. Volume 78, Issue 3, 669 – 674.

[43] T. Rosen, L. Wilhelmsen, K. Landin-Wilhelmsen, G. Lappas and B.A. Bengtsson, Increased fracture
frequency in adult patients with hypopituitarism and GH deficiency. European Journal of Endocrinology,
1997. 137, 240-245.

[44] C. Ohlsson, B-A Bengtsson, O.G.P. Isaksson, T.T. Andreassen and M.C. Slootweg, Growth hormone and
bone, Endocrine Reviews, 1998, 19(1): 55–79.
 ACCEPTED MANUSCRIPT
[45] N.A. Tritos, S.L. Greenspan, D. King, A. Hamrahian, D.M. Cook, P.J. Jönsson, M.P. Wajnrajch, M.
Koltowska-Häggstrom, and B.M.K. Biller, Unreplaced sex steroid deficiency, corticotropin deficiency, and
lower IGF-I are associated with lower bone mineral density in adults with growth hormone deficiency: a
KIMS database analysis. The Journal of Clinical Endocrinology & Metabolism, 2011. 96 (5),1516 –1523.

[46] C. Wüster, R. Abs, B.A. Bengtsson, H. Bennmarker, U. Feldt-Rasmussen, E. Hernberg-Ståhl, J.P. Monson,
B. Westberg, P. Wilton; KIMS Study Group and the KIMS International Board. Pharmacia & Upjohn
International Metabolic Database. The influence of growth hormone deficiency, growth hormone
replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density.

PT
Journal of Bone and Mineral Research, 2001.Volume 16, No 2,398 – 405.

[47] H. Ragnar Agnarsson, G. Johannsson, O. Ragnarsson, The Impact of Glucocorticoid Replacement on

Bone Mineral Density in Patients with Hypopituitarism Before and After 2 Years of Growth Hormone

RI
Replacement Therapy. The Journal of Clinical Endocrinology & Metabolism, 2014. Volume 99, Issue 4, 1479
–1485.

SC
[48] O. Ragnarsson, H. Filipsson Nyström, G. Johannsson, Glucocorticoid replacement therapy is
independently associated with reduced bone mineral density in women with hypopituitarism. Clinical
Endocrinology, 2012.Volume 76, Issue 2, 246 –252.

U
[49] M. Barake, A. Klibanski, N.A. Tritos, Effects of Recombinant Human Growth Hormone Therapy on Bone
Mineral Density in Adults with Growth Hormone Deficiency: A Meta-Analysis. The Journal of Clinical
AN
Endocrinology & Metabolism,2014. Volume 99, Issue 3, 852-860.

[50] G. Mazziotti, A. Bianchi, S. Bonadonna, M. Nuzzo, V. Cimino, A. Fusco, L. De Marinis, A. Giustina,

Increased prevalence of radiological spinal deformity in adult patients with GH deficiency: influence of GH
M

replacement therapy. Journal of Bone and Mineral research, 2006. Volume 21, Issue 4, 520-528.

[51] G. Mazziotti, T. Porcelli, A. Bianchi, V. Cimino, I. Patelli, C. Mejia, A. Fusco, A. Giampietro, L. De Marinis
D

and A. Giustina, Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males
with GH deficiency. European Journal of Endocrinology, 2010. 163,15-20.
TE

[52] G. Mazziotti, A. Bianchi, V. Cimino, S. Bonadonna, P. Martini, A. Fusco, L. De Marinis, A. Giustina, Effect
of gonadal status on bone mineral density and radiological spinal deformities in adult patients with growth
hormone deficiency. Pituitary, 2008. Volume 11, Issue 1, 55-61.
EP

[53] G. Mazziotti, M. Doga, S. Frara, F. Maffezzoni, T. Porcelli, L. Cerri, R. Maroldi, A. Giustina. Incidence of
morphometric vertebral fractures in adult patient with growth hormone deficiency. Endocrine, 2016.
C

Volume 52, Issue 1, 103-110.

AC
 ACCEPTED MANUSCRIPT
Table 1

Synopsis of main clinical studies on the effects of GRT on bone mineral density. Abbreviations: AD (Addison
disease), BMD (Bone mineral density), CA (Cortisone Acetate), DHEA (Dehydroepiandrosterone), GCs
(Glucocorticoids), GHD (Growth Hormone deficit), GRT (Glucocorticoid replacement therapy), HC
(Hydrocortisone), OP (Osteoporosis), PAI (Primary adrenal insufficiency), PDN (Prednisone), Pts (patients),
SAI (Secondary adrenal insufficiency).

PT
Study,reference N° of Pts PAI/SAI TYPE OF AIM OF RESULTS
number, year STUDY THE STUDY
Devogelaer [16] 35 35/0 Observational To evaluate if the Replacement do
1994 replacement not cause loss

RI
dose of cortisone of bone mass in
acetate and the men and pre-
adrenal menopausal

SC
androgens women.
deficiency cause Dramatic loss of
OP (BMD was bone mass in
measured by post-

U
single photon menopausal
absorptiometry women.
AN
at radius).
Zellissen [19] 91 91/0 Cross- To evaluate the Decreased BMD
1994 sectional effect of GRT on in 30% of male
BMD in PAI in GRT, the daily
M

(Most women dose of HC per

were pre- Kg of body
menopausal) weight was
higher than in
D

men with
normal BMD.
TE

Valero [15] 30 30/0 Prospective To determine the Replacement

1994 effect of long- with low doses
term of GCs did not
replacement with cause
EP

HC (30 mg/day) significant

or prednisone trabecular bone
(7.5 mg/day). loss.
C
AC

Florkowski [17] 14 14/0 Observational To examine Women with

1994 clinical and PAI showed a
biochemical greater than
parameters and expected
BMD in a group reduction in
of subjects with BMD compared
PAI to males.
 ACCEPTED MANUSCRIPT
Braatvedt [18] 29 29/0 Observational To investigate BMD was
1999 the relationships negatively
between BMD correlated with
and GC dose. current and
cumulative GCs
dose per Kg of
body weight
and duration of
disease.
Jodar [13] 25 25/0 Cross- To evaluate long- No significant

PT
2003 sectional term changes in reduction of
BMD and bone BMD after 48-
turnover markers 60 months of
in patients with follow-up.

RI
AD treated with A considerable
HC or PDN. proportion of
patients treated

SC
with PDN
showed DXA T-
scores in the
range of

U
osteoporosis.
Løvås [6] 292 292 Cross- To evaluate the BMD at femoral
AN
2009 sectional effects of GRT on neck and
bone. lumbar spine
was slightly but
significantly
M

reduced (mean
doses 26.5-40
mg of HC
equivalents).
D

Koetz [20] 122 81/0 Cross- To verify if BMD Normal BMD in

2012 sectional was reduced in patients with
TE

AD treated with AD treated with

lower GRT and lower dose of
influence of type GRT: pts on
of steroids and PDN showed
EP

DHEA treatment lower BMD;

DHEA
treatment has a
beneficial effect
C

in women with
AD.
AC

Schulz [21] 90 57/0 Prospective To evaluate the Do not change

2016 long-term effects the dose
of a change in GC showed
dose in PAI. unchanged
BMD values.
Increasing
doses produced
a significant
decrease in
femoral neck Z-
scores.
Decreasing
doses produced
a significantly
increase in
 ACCEPTED MANUSCRIPT
lumbar spine
and hip Z-score.
Camozzi [24] 61 61/0 Observational To assess bone Risk of
2017 damage in terms morphometric
of BMD and vertebral
vertebral fractures was 3
fractures in times higher in
patients with AD AD than
in GRT and controls. No
mineralocorticoid correlation with

PT
therapy (75/87). BMD value at
any site;
Patients treated
with

RI
fludrocortisone
had significantly
higher

SC
densitometric
values at all
site, except
lumbar spine.

U
Frara [32] 14 0/14 Prospective To evaluate the After 24 months
2018 effects of dual- of therapy with
®
AN
release Plenadren , Pts
hydrocortisone showed a
®
(Plenadren ) on significant
bone, in terms of increase of
M

BMD, in Pts with BMD values at

SAI. lumbar spine
Pts were treated and femoral
with HC or CA for neck, without
D

at least 12 significant
months (median change in total
TE

dose 20 and 28 hip.

mg) and then Furthermore, a
treated with significant
® decrease in
Plenadren for 2
EP

years. All pts had fasting plasma

GHD, 2 were glucose was
treated. found, without
significant
C

change in
plasmatic lipids.
AC
 ACCEPTED MANUSCRIPT
In this review we tried to summarize the available data on the impact of glucocorticoid replacement
therapy on bone health in primary and secondary adrenal insufficiency.
The following issues on bone health in patients with primary and secondary adrenal insufficiency deserve
special attention:
1. Differences in doses and type of steroid used.
2. Concomitant androgen deficiency.
3. Concomitant GH deficiency.

PT
RI
U SC
AN
M
D
TE
C EP
AC