Glucocorticoids and Osteoporosis

Glucocorticoids and Osteoporosis - eMedWiki
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Glucocorticoids and Osteoporosis

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Glucocorticoids and Osteoporosis

Contents
1 Glucocorticoids and Osteoporosis
1.1 Introduction
1.2 Characteristics of Bone Loss
1.2.1 Bone Histomorphometry
1.3 Pathogenesis
1.3.1 Gonadal Hormones
1.3.2 Calcium Homeostasis
1.3.3 Bone Cell Functions
1.3.4 Muscle Strength
1.4 Diagnosis
1.5 Management
1.5.1 Preventive measures
1.5.2 Pharmacologic interventions
1.5.2.1 (1) Bisphosphonates
1.5.2.2 (2) Hormone replacement Therapy (HRT)
1.5.2.3 (3) Calcitonin
1.6 Further Readings
1.7 References
Introduction
Glucocorticoids (Gluco= Glucose; Corti= Cortex; and Coids= steroid) are named in such a way because they
regulate glucose metabolism, are produced in the adrenal cortex, and have a steroidal structure. They are steroid
hormones that bind to glucocorticoid receptor present in almost every cell in the body.
They are a part of the immune system feedback mechanism that inhibits inflammation. Therefore,
glucocorticoids are potent anti-inflammatory and immunosuppressive agents that are widely used in treatments
of diseases. These include respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease),
http://php.med.unsw.edu.au/medwiki/index.php?title=Glucocorticoids_and_Osteoporosis
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autoimmune diseases (e.g., rheumatoid arthritis), gastrointestinal diseases (e.g., ulcerative colitis, inflammatory
bowel disease and Crohns disease) and in organ transplantation [1][2].
Examples of glucocorticoids used today are [1]:
Hydrocortisone
Prednisolone
Prednisone
Methylprednisolone
Dexamethasone
Although the benefits are great, chronic excess of glucocorticoids
can have significant adverse effects. Osteoporosis and resulting
fractures are the most incapacitating side effects (often called
Glucocorticoid-induced osteoporosis (GIO)) which, limits longterm glucocorticoid therapy (LTGT). GIO is the most common
cause of secondary osteoporosis [1][2][3].
Structure of Dexamethasone. Adopted

from[1]
Up to 6% of the Australian population over 60 years old receive glucocorticoid therapy [4]. It is estimated that
30 to 50% of these patients will experience osteoporotic fractures. However, recent surveys reported that less
than half of the patients receiving glucocorticoid therapy were investigated for osteoporosis and less than a
quarter were treated, despite the availability of preventative measures and treatments. This indicates that GIO is
underestimated and often left untreated [3][5].
Characteristics of Bone Loss

The severity of bone loss depends on the dose, duration of therapy, age of the patient and underlying disease.
Reduction in bone mass is most rapid during the first year of glucocorticoid therapy and significant reduction
and resultant fractures can be observed as soon as 3 months after initiation [2][6]. In a clinical trial conducted in
the USA, vertebral fractures were observed in 17% of patients receiving glucocorticoids within their first year,
which shows how quickly osteoporosis and resulting fractures may occur [7]. However, fracture rates decrease
rapidly (within one year) after cessation of glucocorticoid therapy which indicates that the risk is reversible [4]
[8].
Trabecular bone and the cortical rim of the vertebral body are more susceptible to the effects on glucocorticoids
than the cortical bones of the long bones (radius, humerus). The proximal femur in particular the Wards
triangle is also susceptible as it is composed of trabecular bone [9][10][11]. However, over LTGT, loss of cortical
bones may also occur and fragility of long bones increases [11].
Bone Histomorphometry
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Reduction in wall thickness and total bone volume are observed in bone biopsies of iliac crests. Signs of
increased bone resorption are observed: increase in eroded surfaces; osteoclast-covered surfaces; and number of
osteoclasts. In contrast, decrease in bone formation is observed with decreased osteoblast recruitment and
depression of mature osteoblast function [11][9].
Pathogenesis
GIO is a result of several mechanisms that contributes to loss of bone density. These include the glucocorticoid
effect on [2][9][11]:
Gonadal hormone secretion
calcium homeostasis
bone cell functions
muscle strength
Gonadal Hormones
Glucocorticoids influence bone metabolism
by their effects on sex hormones. This is via
(1) the inhibitions of pituitary gonadotropin
secretion and (2) direct effects on gonads.
Glucocorticoids inhibits the secretion of
luteinising hormone (LH) and folliclestimulating hormone (FSH) in response to
gonadotropin-releasing hormone (GnRH)
and therefore decrease testosterone and
estrogen production by the testes and ovaries
respectively [9]. Studies of men undergoing
prednisone therapy (12mg/day) showed a
Mechanism of GIO. PTH: Parathyroid Hormone. Adapted from [2][9]
significantly lower serum testosterone levels
[11]
compared to control. Trials done on rats
suggest that estrogen deficiency and
glucocorticoids are additives in bone loss, thus postmenopausal women receiving glucocorticoids are at greater
risk and should be actively prevented or treated [4][12].
Calcium Homeostasis
Glucocorticoid therapy suppresses intestinal calcium absorption, increase urinary calcium excretion, leading to
a secondary hyperparathyroidism, which increases bone remodelling and results in bone loss [2]. Effects of
glucocorticoids on mineral metabolism are dose and duration dependent where chronic high doses (>20 mg
prednisone daily for > 14 days) increase renal calcium excretion compared to normal calcium excretion in lower
doses (< 10 mg daily) [9][13].
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Bone Cell Functions

Glucocorticoids exert multifactorial effect on bone cells and bone remodelling.
First, histomorphometric and calcium kinetic studies show increased number of Osteoclast and cancellous bone
erosion and biochemical indices show increased urinary hydroxyproline excretion and high levels of resorbing
activity by radiocalcium kinetics which all suggest increased bone resorption. However, the mechanism of
increased bone resorption in glucocorticoid patients is unclear. It may be largely due to secondary
hyperparathyroidism, decreased sex hormone levels, or due to reduction of bone formation which is not
compensated by reduction in osteoclast bone reduction [11][9].
Second, evidence in vivo and vitro suggest glucocorticoids inhibit osteoblast numbers, lifespan, and function.
Histomorphometric studies reveal decreased number of osteoid seams, reduced wall thickness and low mineral
apposition rate. Studies also show that Supraphysiologic concentrations of glucocorticoids speed up the
apoptosis of osteoblasts and therefore shortening the lifespan of active osteoblasts and inhibit synthesis of
osteoblast [2].
Further, glucocorticoids inhibit the synthesis of collagen; bone protein (e.g., osteocalcin); bone matrix
components (e.g., mucopolysaccaride and sulfated glucosaminoglycans); and the synthesis and/or actions of
growth factors that have anabolic effects on bone (e.g., insulin-like growth factor 1 (IGF-1) and transforming
growth factor beta (TGF-)). The end result is an increased bone resorption, a decreased bone formation and an
resultant loss in bone mass [9].
Muscle Strength
Loss of muscle mass and muscle weakness are common side effects of glucocorticoid therapy which is most
common in the pelvic girdle and can spread to the distal muscles. Myopathy and muscle weakness may
contribute to bone loss by removing the normal forces on the bone that are produced by strong muscle
contraction [9].
Diagnosis
All patients starting glucocorticoid therapy should obtain a baseline BMD measurement through dual energy X
ray absorptiometry or quantitative computed tomography. Since, trabecular or cancellous bone loss is more
rapid than cortical bone in GIO, the lumbar spine which is primarily composed of trabecular bone, is measured
for detection of earliest bone loss. However, measurement of the lumbar spine may be unreliable in the elderly
due to osteophyte formations. Therefore, the femoral neck is often measured in conjunction for patients over 60
[2].
Based on the BMD measurements, patient can then be categorised into the following categories [14]:
Type
T Score
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Normal
T score > -1
Low bone mass (osteopenia) T Score -1 to -2.5

Osteoporosis
T score -2.5
Management
Various preventive measures and treatments are currently available for GIO.
Preventive measures
Bone loss is most rapid during the initial
months of therapy, thus preventive measures
should also be started at the initiation of
therapy. Strategies include:
Use lowest possible dose of
glucocorticoid: as bone loss in GIO is
dose and duration dependent.
Stop smoking
Limit alcohol consumption
Participate in weight-bearing
exercises
Maintain at least 1500mg of calcium
intake per day or take Calcium
supplementation
Take vitamin D supplementation
Take thiazide diuretics: this helps
decrease urinary excretion of calcium
Sodium restriction: this increases
dietary absorption of calcium and
decreases urinary excretion of calcium
and therefore decreases the risk of
secondary hyperparathyroidism.
Use safety measures to prevent falls
including, nonskid shoes, safety rails
and nightlights [3][2][4][9].
Investigation and management for patients on LTGT. Regular

monitoring of BMD should be done in conjunction. Adapted from [4]
[15]
Pharmacologic interventions
(1) Bisphosphonates
Bisphosphonates are analogues of inorganic pyrophosphates. They have anti-resorptive actions on bone by
binding to hydrocyapatite and inhibiting activation of osteoclasts. Nitrogen-containing Bisphosphonates inhibit
the mevalonate metabolic pathway and non-nitrogen-containing bisphosphonates are metabolised into cytotoxic
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analogues of adenosine triphosphate in the cell [1][16][17][17].

Half life of bisphosphonates in plasma is
very short, but half life of bisphosphonates
deposited in bone is very long up to 10
years. Therefore, effects of are sustained for
a substantial period of time in bone [17].
Bisphosphonates is recommended to be used
in conjunction to calcium and vitamin D
supplementations in the following situations:
Patient initiating glucocorticoid
therapy for >3 months.
LTGT patients with BMD equal to
Proposed mechanisms of action of bisphosphonates in reducing bone
that of osteoporosis or have had an
loss[16].
osteoporotic fracture.
LTGT patients with ineffective
replacement therapy (HRT) results or does not tolerate to HRT well [18].
Risedronate and alendronate are two most commonly used oral Bisphosphonates used in adults receiving 7.5
mg/day of prednisone (or equivalent) for 3months. Risendronate is approved by the US FDA to be used for
prevention and treatment of GIO with a recommended dosage of 5mg/day. Alendronate is only approved use for
treatment with a recommended dosage of 5mg/day or 10mg/day in postmenopausal women [2].
(2) Hormone replacement Therapy (HRT)
HRT is considered in LTGT patients who develop hypogonadism. Studies reveal an improved lumbar spine
BMD in LTGT male and postmenopausal women taking testosterone and estrogen respectively compared to
placebo. In LTGT postmenopausal women, the combination of bisphosphonates and HRT together showed a
greater improvement in BMD than when using either agent alone. Therefore, a combination approach is
recommended [19].
(3) Calcitonin
Calcitonins act as an endogenous inhibitor of bone resorption by decreasing osteoclast formation. It is
administered as a nasal spray or a subcutaneous or intramuscular injection. It is approved by the US FDA in the
treatment of postmenopausal osteoporosis but not for GIO. Treatment with calcitonin in GIO is only considered,
when bisphosphonates are contraindicated or not well tolerated [17][18].
Studies of calcitonin in GIO patients showed that there was significantly less bone loss after 1 year of calcitonin
treatment compared with placebo. BMD of the lumbar spine decreased 1.3% in the calcitonin treated group
compared with 5.0% in placebo (P=0.05) [20]. However, there is no evidence of reduced fractures. Therefore,
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calcitonin is a second line drug used as an alternative to biphosphonates and HRT. Calcitonin is also used in
patients with fracture or osteoporosis related pain, due to its analgesic effects [17].
Further Readings
Management of GIO
http://www.osteoporosis.org.au/images/stories/documents/internal/cio_snapshot.pdf
Prevention of Osteoporosis
http://php.med.unsw.edu.au/medwiki/index.php?title=Prevention_of_Osteoporosis
References
1. 1.0 1.1 1.2 1.3 1.4 Rang, H.P., Dale, M.M., Ritter, J.M., & Flower, R.J. (2007). Rang and Dale's
Pharmacology (6th Edition), Philadelphia: Elsevier Limited.
2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 McIlwain, H.H.(2003). Glucocorticoid-induced osteoporosis:
pathogenesis, diagnosis, and management. Preventive Medicine. 36(1): 243-9.
3. 3.0 3.1 3.2 Silverman, S.L., & Lane, N.E.(2009). Glucocorticoid-induced osteoporosis. Current
osteoporosis reports. 7(1):23-26.
4. 4.0 4.1 4.2 4.3 4.4 Osteoporosis Australia. (n.d.). Corticosteroid Induced Osteoporosis (CIO). Retrieved
25th September, 2011 from
http://www.osteoporosis.org.au/images/stories/documents/internal/cio_snapshot.pdf
5. Bell, R., & Carr, A.,& Thompson, P.(1997). Managing corticosteroid induced osteoporosis in medical
outpatients. Current osteoporosis reports. Journal of the Royal College of Physicians. 31(2):158-161.
6. Lukert, B.P.(1990). Glucocorticoid-induced osteoporosis: pathogenesis and management. Annals of
Internal Medicine. 112(5):352-64.
7. Cohen, S., Levy, R.M., Keller, M., Boling, E., Emkey, R.D., Greenwald, M., Zizic, T.M., Wallach, S.,
Sewell, K.L., Lukert, B.P., Axelrod, D.W., & Chines, A.A.(1990). Isedronate therapy prevents
corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebocontrolled, parallel-group study. Arthritis & Rheumatism. 42(11):23092318
8. VanStaa, T.P., Leufkens, H.G., & Cooper, C. (2002). The epidemiology of corticosteroid-induced
osteoporosis: a meta-analysis. Osteoporosis international. 13(10):777787.
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glucocorticoid-induced bone loss. Endocrinology and Metabolism Clinics. 27(2): 465-483.
10. Lann, R.F., Buihs, Erning, W.C., Lemmens, J.A. Corstens, F.H., Ruijs, S.H., Putte, L.B. & Riel, P.L.
(2002). Differential effects of glucocorticoids on cortical appendicular and cortical vertebral bone mineral
content. Calcified Tissue International. 52(1):5-9.
11. 11.0 11.1 11.2 11.3 11.4 11.5 Alesci, S., Martino, M.U., & Ilias, I.(2011).Glucocorticoid-Induced
Osteoporosis. Retrieved 30th September, 2011 from
http://www.endotext.org/adrenal/adrenal7/adrenalframe7.htm
12. Goulding, A., Gold, E. (1988). Effects of chronic prednisolone treatment on bone resorption and bone
composition in intact and ovariectomized rats and in ovariectomized rats receiving beta-estradiol.
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Lukert, B.P., & Raisz, L.G.(1994). Glucocorticoid-induced osteoporosis. Rheumatic Disease Clinics of
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17.0 17.1 17.2 17.3 17.4 Akesson, K.,(2003). New approaches to pharmacological treatment of
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