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THERE ARE TWO MAJOR TYPES OF OSTEOPOROSIS

GLUCOCORTICOID INDUCED OSTEOPOROSIS Sham A. Cader, Michał Banaś, Eugeniusz J. Kucharz Department of Internal Medicine and Rheumatology Medical University of Silesia Katowice.

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THERE ARE TWO MAJOR TYPES OF OSTEOPOROSIS

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  1. GLUCOCORTICOID INDUCED OSTEOPOROSISSham A. Cader, Michał Banaś, Eugeniusz J. KucharzDepartment of Internal Medicine and RheumatologyMedical University of SilesiaKatowice

  2. 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

  3. THERE ARE TWO MAJOR TYPES OF OSTEOPOROSIS • Primary osteoporosis • Secondary osteoporosis

  4. Primary 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

  5. Secondary osteoporosis Caused by known factors or diseases • Medications (long termcorticosteroids, 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

  6. 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

  7. PATHOGENESIS 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

  8. 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

  9. 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

  10. 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

  11. EFFECT 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

  12. 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

  13. 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

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

  15. 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

  16. 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

  17. Only 5% of circulating IGFs are bound to IGFBPs 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

  18. 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

  19. 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 resorption of bones

  20. 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)

  21. 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

  22. Prevention and treatment • Optimal therapeutic dosage • Regular follow-ups of BMD • Regular exercise • Suitable diet • Exclude risk factors Smoking, alcohol etc. • Pharmacological therapy

  23. PHARMACOLOGICAL THERAPY • Calcium substituition and vitamin D • Thiazide diuretics • Hormone replacement therapy • Bisphosphonates ( Etidronate, Alendronate, Pamidronate) • Calcitonin • Anabolic steroids • Fluoride

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