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Glucocorticoids and OsteoporosisFrom eMedWiki

Glucocorticoids and Osteoporosis

Contents1 Glucocorticoids and Osteoporosis

1.1 Introduction1.2 Characteristics of Bone Loss

1.2.1 Bone Histomorphometry1.3 Pathogenesis

1.3.1 Gonadal Hormones1.3.2 Calcium Homeostasis1.3.3 Bone Cell Functions1.3.4 Muscle Strength

1.4 Diagnosis1.5 Management

1.5.1 Preventive measures1.5.2 Pharmacologic interventions

1.5.2.1 (1) Bisphosphonates1.5.2.2 (2) Hormone replacement Therapy (HRT)1.5.2.3 (3) Calcitonin

1.6 Further Readings1.7 References

IntroductionGlucocorticoids (Gluco= Glucose; Corti= Cortex; and Coids= steroid) are named in such a way because theyregulate glucose metabolism, are produced in the adrenal cortex, and have a steroidal structure. They are steroidhormones 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 treatmentsof diseases. These include respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease),

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Structure of Dexamethasone. Adoptedfrom[1]

autoimmune diseases (e.g., rheumatoid arthritis), gastrointestinal diseases (e.g., ulcerative colitis, inflammatorybowel disease and Crohn’s disease) and in organ transplantation [1][2].

Examples of glucocorticoids used today are [1]:

HydrocortisonePrednisolonePrednisoneMethylprednisoloneDexamethasone

Although the benefits are great, chronic excess of glucocorticoidscan have significant adverse effects. Osteoporosis and resultingfractures are the most incapacitating side effects (often calledGlucocorticoid-induced osteoporosis (GIO)) which, limits long-term glucocorticoid therapy (LTGT). GIO is the most commoncause of secondary osteoporosis [1][2][3].

Up to 6% of the Australian population over 60 years old receive glucocorticoid therapy [4]. It is estimated that30 to 50% of these patients will experience osteoporotic fractures. However, recent surveys reported that lessthan half of the patients receiving glucocorticoid therapy were investigated for osteoporosis and less than aquarter were treated, despite the availability of preventative measures and treatments. This indicates that GIO isunderestimated and often left untreated [3][5].

Characteristics of Bone LossThe 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 reductionand resultant fractures can be observed as soon as 3 months after initiation [2][6]. In a clinical trial conducted inthe 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 decreaserapidly (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 glucocorticoidsthan the cortical bones of the long bones (radius, humerus). The proximal femur in particular the Ward’striangle is also susceptible as it is composed of trabecular bone [9][10][11]. However, over LTGT, loss of corticalbones may also occur and fragility of long bones increases [11].

Bone Histomorphometry

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Mechanism of GIO. PTH: Parathyroid Hormone. Adapted from [2][9]

[11]

Reduction in wall thickness and total bone volume are observed in bone biopsies of iliac crests. Signs ofincreased bone resorption are observed: increase in eroded surfaces; osteoclast-covered surfaces; and number ofosteoclasts. In contrast, decrease in bone formation is observed with decreased osteoblast recruitment anddepression of mature osteoblast function [11][9].

PathogenesisGIO is a result of several mechanisms that contributes to loss of bone density. These include the glucocorticoideffect on [2][9][11]:

Gonadal hormone secretioncalcium homeostasisbone cell functionsmuscle strength

Gonadal Hormones

Glucocorticoids influence bone metabolismby their effects on sex hormones. This is via(1) the inhibitions of pituitary gonadotropinsecretion and (2) direct effects on gonads.Glucocorticoids inhibits the secretion ofluteinising hormone (LH) and follicle-stimulating hormone (FSH) in response togonadotropin-releasing hormone (GnRH)and therefore decrease testosterone andestrogen production by the testes and ovariesrespectively [9]. Studies of men undergoingprednisone therapy (12mg/day) showed asignificantly lower serum testosterone levelscompared to control. Trials done on ratssuggest that estrogen deficiency andglucocorticoids are additives in bone loss, thus postmenopausal women receiving glucocorticoids are at greaterrisk and should be actively prevented or treated [4][12].

Calcium Homeostasis

Glucocorticoid therapy suppresses intestinal calcium absorption, increase urinary calcium excretion, leading toa secondary hyperparathyroidism, which increases bone remodelling and results in bone loss [2]. Effects ofglucocorticoids on mineral metabolism are dose and duration dependent where chronic high doses (>20 mgprednisone daily for > 14 days) increase renal calcium excretion compared to normal calcium excretion in lowerdoses (< 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 boneerosion and biochemical indices show increased urinary hydroxyproline excretion and high levels of resorbingactivity by radiocalcium kinetics which all suggest increased bone resorption. However, the mechanism ofincreased bone resorption in glucocorticoid patients is unclear. It may be largely due to secondaryhyperparathyroidism, decreased sex hormone levels, or due to reduction of bone formation which is notcompensated 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 mineralapposition rate. Studies also show that Supraphysiologic concentrations of glucocorticoids speed up theapoptosis of osteoblasts and therefore shortening the lifespan of active osteoblasts and inhibit synthesis ofosteoblast [2].

Further, glucocorticoids inhibit the synthesis of collagen; bone protein (e.g., osteocalcin); bone matrixcomponents (e.g., mucopolysaccaride and sulfated glucosaminoglycans); and the synthesis and/or actions ofgrowth factors that have anabolic effects on bone (e.g., insulin-like growth factor 1 (IGF-1) and transforminggrowth factor beta (TGF-β)). The end result is an increased bone resorption, a decreased bone formation and anresultant loss in bone mass [9].

Muscle Strength

Loss of muscle mass and muscle weakness are common side effects of glucocorticoid therapy which is mostcommon in the pelvic girdle and can spread to the distal muscles. Myopathy and muscle weakness maycontribute to bone loss by removing the normal forces on the bone that are produced by strong musclecontraction [9].

DiagnosisAll patients starting glucocorticoid therapy should obtain a baseline BMD measurement through dual energy Xray absorptiometry or quantitative computed tomography. Since, trabecular or cancellous bone loss is morerapid than cortical bone in GIO, the lumbar spine which is primarily composed of trabecular bone, is measuredfor detection of earliest bone loss. However, measurement of the lumbar spine may be unreliable in the elderlydue 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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Investigation and management for patients on LTGT. Regularmonitoring of BMD should be done in conjunction. Adapted from [4]

[15]

Normal T score > -1Low bone mass (osteopenia) T Score -1 to -2.5

Osteoporosis T score ≤ -2.5

ManagementVarious preventive measures and treatments are currently available for GIO.

Preventive measures

Bone loss is most rapid during the initialmonths of therapy, thus preventive measuresshould also be started at the initiation oftherapy. Strategies include:

Use lowest possible dose ofglucocorticoid: as bone loss in GIO isdose and duration dependent.Stop smokingLimit alcohol consumptionParticipate in weight-bearingexercisesMaintain at least 1500mg of calciumintake per day or take CalciumsupplementationTake vitamin D supplementationTake thiazide diuretics: this helpsdecrease urinary excretion of calciumSodium restriction: this increasesdietary absorption of calcium anddecreases urinary excretion of calciumand therefore decreases the risk ofsecondary hyperparathyroidism.Use safety measures to prevent fallsincluding, nonskid shoes, safety railsand nightlights [3][2][4][9].

Pharmacologic interventions

(1) Bisphosphonates

Bisphosphonates are analogues of inorganic pyrophosphates. They have anti-resorptive actions on bone bybinding to hydrocyapatite and inhibiting activation of osteoclasts. Nitrogen-containing Bisphosphonates inhibitthe mevalonate metabolic pathway and non-nitrogen-containing bisphosphonates are metabolised into cytotoxic

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Proposed mechanisms of action of bisphosphonates in reducing boneloss[16].

analogues of adenosine triphosphate in the cell [1][16][17][17].

Half life of bisphosphonates in plasma isvery short, but half life of bisphosphonatesdeposited in bone is very long up to 10years. Therefore, effects of are sustained fora substantial period of time in bone [17].

Bisphosphonates is recommended to be usedin conjunction to calcium and vitamin Dsupplementations in the following situations:

Patient initiating glucocorticoidtherapy for >3 months.LTGT patients with BMD equal tothat of osteoporosis or have had anosteoporotic fracture.LTGT patients with ineffectivereplacement 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 ≥7.5mg/day of prednisone (or equivalent) for ≥ 3months. Risendronate is approved by the US FDA to be used forprevention and treatment of GIO with a recommended dosage of 5mg/day. Alendronate is only approved use fortreatment 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 spineBMD in LTGT male and postmenopausal women taking testosterone and estrogen respectively compared toplacebo. In LTGT postmenopausal women, the combination of bisphosphonates and HRT together showed agreater improvement in BMD than when using either agent alone. Therefore, a combination approach isrecommended [19].

(3) Calcitonin

Calcitonins act as an endogenous inhibitor of bone resorption by decreasing osteoclast formation. It isadministered as a nasal spray or a subcutaneous or intramuscular injection. It is approved by the US FDA in thetreatment 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 calcitonintreatment compared with placebo. BMD of the lumbar spine decreased 1.3% in the calcitonin treated groupcompared 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 inpatients with fracture or osteoporosis related pain, due to its analgesic effects [17].

Further ReadingsManagement 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'sPharmacology (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. Currentosteoporosis reports. 7(1):23-26.

4. ↑ 4.0 4.1 4.2 4.3 4.4 Osteoporosis Australia. (n.d.). Corticosteroid Induced Osteoporosis (CIO). Retrieved25th September, 2011 fromhttp://www.osteoporosis.org.au/images/stories/documents/internal/cio_snapshot.pdf

5. ↑ Bell, R., & Carr, A.,& Thompson, P.(1997). Managing corticosteroid induced osteoporosis in medicaloutpatients. 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 ofInternal 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 preventscorticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis & Rheumatism. 42(11):2309–2318

8. ↑ VanStaa, T.P., Leufkens, H.G., & Cooper, C. (2002). The epidemiology of corticosteroid-inducedosteoporosis: a meta-analysis. Osteoporosis international. 13(10):777–787.

9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 9.9 Lane, N.E., & Lukert, B. (1998). The science and therapy ofglucocorticoid-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 mineralcontent. 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-InducedOsteoporosis. Retrieved 30th September, 2011 fromhttp://www.endotext.org/adrenal/adrenal7/adrenalframe7.htm

12. ↑ Goulding, A., Gold, E. (1988). Effects of chronic prednisolone treatment on bone resorption and bonecomposition in intact and ovariectomized rats and in ovariectomized rats receiving beta-estradiol.

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Endocrinology. 122:482-48713. ↑ Lukert, B.P., & Raisz, L.G.(1994). Glucocorticoid-induced osteoporosis. Rheumatic Disease Clinics of

North America. 20(3):629-65.14. ↑ World Health Organisation (WHO).(2003). Prevention and management of osteoporosis : report of a

WHO scientific group Glucocorticoid-induced osteoporosis: pathogenesis, diagnosis, and management.Preventive Medicine. Retrieved 30th Spetember, 2011 fromhttp://whqlibdoc.who.int/trs/WHO_TRS_921.pdf

15. ↑ Sambrook, P.N. (2005). How to prevent steroid induced osteoporosis. Annals of the RheumaticDiseases. 64(2):176-178.

16. ↑ 16.0 16.1 Rodan, G.A., Fleisch, H.A. (1996). Bisphosphonates: Mechanisms of Action. J. Clin. Invest.97(12):2692–2696.

17. ↑ 17.0 17.1 17.2 17.3 17.4 Akesson, K.,(2003). New approaches to pharmacological treatment ofosteoporosis. Bulletin of the World Health Organization. 81(9):657-663.

18. ↑ 18.0 18.1 Grossman, J.M., Gordon, R., Ranganath, V.K., Deal, C., Caplan, L., Chen, W., Curtis, J.R.,Frust, D.E., Mcmahon, M., Patkar, N. M., Volkmann, E., & Sagg, K.G. (2010). American College ofRheumatology 2010 Recommendations for the Prevention and Treatment of Glucocorticoid-InducedOsteoporosis. Arthritis Care & Research. 62(11): 1515–1526.

19. ↑ Harris, S.T., Eriksen, E.F., Davidson, M., Ettinger, M.P., Moffett, A.H., Baylink, D.J., Crusan, C.E., &Chines, A.A. (2000). Effect of combined risedronate and hormone replacement therapies on bone mineraldensity in postmenopausal women. 86(5):1890.

20. ↑ Healey, J.H., Paget, S.A., Williams-Russo, P., Szatrowski, T.P., Schneider, R., Spiera, H., Mitnick, H.,Ales, K., & Schwartzberg, P. (1996). A randomized controlled trial of salmon calcitonin to prevent boneloss in corticosteroid-treated temporal arteritis and polymyalgia rheumatica. Calcified TissueInternational. 58(2):73–80.

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