GLUCOCORTICOID GLUCOCORTICOID INDUCED OSTEOPOROSISINDUCED OSTEOPOROSIS

Sham A. Cader, Michał Banaś, Eugeniusz J. KucharzSham A. Cader, Michał Banaś, Eugeniusz J. Kucharz

Department of Internal Medicine and RheumatologyDepartment of Internal Medicine and RheumatologyMedical University of SilesiaMedical University of Silesia

KatowiceKatowice

Osteoporosis is a disease of the skeleton in which the amount of

calcium present in the bones slowly decreases to the point

where the bones become brittle and prone to fracture, in other words

the bone loses it’s density

THERE ARE TWO MAJOR TYPES THERE ARE TWO MAJOR TYPES OF OF OSTEOPOROSISOSTEOPOROSIS

• Primary osteoporosisPrimary osteoporosis

• Secondary osteoporosisSecondary osteoporosis

Primary osteoporosisPrimary osteoporosis

There are two primary types of osteoporosis• Type I or the high turnover type: Occurs in

women between the ages of 50 and 75

• Type II or the low turnover type : Also known as age related or senile osteoporosis results when the process of resorption and formation of bone are no longer coordinated

Secondary osteoporosisSecondary osteoporosis

Caused by known factors or diseasesCaused by known factors or diseases• Medications (long term corticosteroids, excessive thyroid hormones,

anty-siezure medications, antacids, immunosuppressive drugs etc.)

• Lack of Sunlight

• Cigarettes,alkohol and coffee

• Culture or Ethnicity

• Being underweight

• Dietary factors

• Depression

• Too much and too little exercise

GLUCOCORTICOID-INDUCED OSTEOPOROSIS

Glucocorticoid therapy is a known risk factor of developing osteoporosis induced by drugs

• Steroids are widely used in the medical practice to treat various diseases; asthma, systemic connective tissue diseases, other autoimmune diseases and in transplantology

• Various studies in different centers had shown that the usage of 5mg predinisone per day caused increased bone loss in the first 6 to 12 months

PATHOGENESISPATHOGENESIS

The pathogenesis of glucocorticoid induced bone loss is multifactorial and complex. The exact mechanism is not clearly defined

• Effect on calcium-phosphate homeostasis• Effect on sex hormones• Effect on bone formation, bone resorption and the

bone metabolism regulating processes

Effect on calcium-phosphate homeostasis

Calcium and Phosphates metabolism are precisely dependant on parathormaon (PTH) and

1,25 dihydroxycholecalciferol• It was stated that glucocorticoids down regulate 1,25-

dihydroxy vitamin D receptors in mouse osteoblasts and human osteosarcoma cells but meantime up regulate the receptors in rat osteoblasts and increase nuclear uptake of 1,25dihydroxy vit.D

• Glucocorticoids increase the expression of parathyroid (PTH) hormone receptors in osteoblasts and enhance the response by osteoblasts to PTH

Glucocorticoids inhibit intestinal calcium absorption

The real mechanism is poorly understood:

• Possibly is related to an inhibition of intestinal absorption by vit D independent factors

• Expression of the gene encoding calbindin-D28K (a protein involved in intestinal calcium transport)

In patients recieving glucocortycoids, serum levels of vit.D metabolites are usually in the normal range, serum levels of PTH is variable and generally has been reported to be normal

• In one study PTH was reduced to normal levels by administration of intravenous Calcium

Lukert et al. Arch.Internal Med. 1976

This could explain why parathyroidectomy prevents excessive bone loss in glucocorticoid-induced osteoporosis in laboratory animals

• Cosman et al. stated that serum osteocalcin levels were decreased within the 72h and secondary hyperthyroidism was demonstrated in two weeks after high doses of glucocorticoid administration

EFFECT ON SEX HORMONESEFFECT ON SEX HORMONES

• Glucocorticoids inhihibit gonadotropins, sex steroids and adrenal androgen production and release

• These sex hormones such as estradiol, estrone, dihydroepiandrosteron androstendion and progesterone generally decrease bone resorption, their absencency accelerates bone loss

Effect on bone formation, bone resorption and bone metabolism regulation processes

• Prolonged glucocorticoid therapy inhibits synthetic function of pre-existing osteoblasts

• Glucocortocoids also produce a dose-related inhibition of osteoblasts maturation percursors

• Decrease number of osteoblasts in the matrix and the synthesis of both type I collagen and non-collagenous proteins by osteoblasts

PATHOMECHANISM

• Effects of glucocorticoids on the expression of oncogenes

• Inhibition of prostaglandin E2 (PGE2), Transforming growth factor 1 ( TGF 1) and Insulin like growth factors (IGF) particularly transcription and synthesis of IGFs

IGF-I has been shown to be the most IGF-I has been shown to be the most important local regulator in the important local regulator in the differentiation, maturation and differentiation, maturation and recruitment of osteoblastsrecruitment of osteoblasts

• IGFs bind with insulin like growth factor proteins (IGFBPs)

• Six of which characterized to date

(IGFBP-1 to IGFBP-6)

These proteins modulate the activities of the IGFs both systematically and locally

95% of IGFs in the circulation are tightly bound to IGFBPs

• These complexes are restricted to the vascular space and serve to limit biovariability of IGFs to target tissues

• The growth hormone(GH) dependent IGFBP-3 is an important determinant of BMD (bone mass density) in a healthy person

Only 5% of circulating IGFs are bound to Only 5% of circulating IGFs are bound to IGFBPs 1,2 and 4IGFBPs 1,2 and 4

These complexes can cross the capillary barrier and gain access to specific tissues

• IGFBP-4 inhibits bone cell growth• IGFBP-5 stimulates bone cell growth and

enhances the effect of IGF-I• IGFBP-6 binds IGF-II with 20 to 100 times higher

affinity than IGF-I and is an important local factor determining the anabolic expression of free IGF-II

• Glucocorticoids reduce the IGFBP- 3,4,5 expression and increase IGFBP-6 transcription and the synthesis in osteoblasts which limits the accessibility and activity of IGF-I and IGF-II

• Glucocorticoids oppose the effects of TGF- on cell replication in osteoblasts

Glucocorticoids also have an indirect effects on:

• Local growth factors such as TGF- 1-2-3 • Acidic and basic fibroblast growth factors(FGF)• Platelet-derived growth factors- (PDGF ) and

PDGF- • Bone morphogenetic proteins• Cytokines (IL-6, IL-11)• Colony stimulating factors (CSF)They have direct action on the collagen and collagenases leading to both decreased formation and increased resorptionof bones

• Weinsten et al. in 1998 studied and have demonstrated that glucocorticoids promote apoptosis of osteoblasts and osteocytes in a mouse model

• Lorenz et al. in 1999 have demonstrated the effect of glucocorticoids on osteoprotegrin (OPG)

EFFECT OF GLUCOCORTICOIDS ON OSTEOPROTEGRIN (OPG)

• OPG is a recently identified cytokin from the member of tumor necrosis factor receptors

• Osteoprotegrin binds the osteoprotegrin legand (OPG-L) which is the final effector of osteoclastogenesis

• Glucocorticoids promote osteoclastogenesis by inhibiting OPG and concurrently stimulating OPG-L production by osteoblasts, thereby enhancing bone resorption

Prevention and treatmentPrevention and treatment

• Optimal therapeutic dosage

• Regular follow-ups of BMD

• Regular exercise

• Suitable diet

• Exclude risk factors Smoking, alcohol etc.

• Pharmacological therapy

PHARMACOLOGICAL THERAPYPHARMACOLOGICAL THERAPY

• Calcium substituition and vitamin D• Thiazide diuretics• Hormone replacement therapy• Bisphosphonates ( Etidronate, Alendronate,

Pamidronate)• Calcitonin• Anabolic steroids• Fluoride