1. Osteoporosis in Thalassemia: Pathogenesis and Treatment Update Pat Mahachoklertwattana M.D. Department of Pediatrics, Ramathibodi Hospital Faculty of Medicine, Mahidol University Bangkok, THAILAND

2. Bone and BM in Thalassemia Ineffective erythropoiesis and hemolysis Defective globin chain Increased erythropoiesis Bone marrow hyperplasia Osteoporosis, bone deformity

3. Vogiatzi et al. J Bone Miner Res 2008 TM (236) TI (43)  /E (43) H (19) H/CS (20) Fracture Prevalences in Thalassemia 

4. BMD in Thalassemic Adults TM (147) TI (24)  /E (20) H (3) H/CS (4) BMD T-score Vogiatzi et al. J Bone Miner Res 2008

5. Low Spine BMD in Thalassemia % BMD <-2SD TM (202) TI (33)  /E (32) H (11) H/CS (14) Vogiatzi et al. J Bone Miner Res 2008

6. Factors Causing Osteoporosis in Thalassemia Severity of thalassemia (baseline Hb) or bone marrow hyperplasia Severity of thalassemia (baseline Hb) or bone marrow hyperplasia Iron overload or hemochromatosis Iron overload or hemochromatosis Hormone deficiencies (sex hormone, GH, IGF-1) Hormone deficiencies (sex hormone, GH, IGF-1) Vitamin & mineral deficiencies (vit D, vit C, Ca, P, Mg) Vitamin & mineral deficiencies (vit D, vit C, Ca, P, Mg) Desferrioxamine toxicity Desferrioxamine toxicity Severity of thalassemia (baseline Hb) or bone marrow hyperplasia Severity of thalassemia (baseline Hb) or bone marrow hyperplasia Iron overload or hemochromatosis Iron overload or hemochromatosis Hormone deficiencies (sex hormone, GH, IGF-1) Hormone deficiencies (sex hormone, GH, IGF-1) Vitamin & mineral deficiencies (vit D, vit C, Ca, P, Mg) Vitamin & mineral deficiencies (vit D, vit C, Ca, P, Mg) Desferrioxamine toxicity Desferrioxamine toxicity

7. Thalassemic Bone Histology Before After Hypertransfusion Pootrakul et al, N Engl J Med 1981;304:1470-3 Osteoid Mineralized bone

8. Hemoglobin vs. Total Body Bone Mineral Density (BMD) Mahachoklertwattana et al, J Bone Miner Metab 2006;24:146 Thalassemics

9. s-Transferrin Receptor vs. Total Body BMD Mahachoklertwattana et al, J Bone Miner Metab 2006;24:146 Thalassemics

10. Erythropoiesis in BM vs. BMD Increased erythropoiesis in the bone marrow is the major factor determining BMD in untransfused and undertransfused thalassemic patients Mahachoklertwattana et al, J Bone Miner Metab 2006;24:146

11. Bone and Hemochromatosis Iron accumulation in organs - Pituitary: hypopituitarism (GH, LH, FSH, PRL, ACTH deficiencies) - Liver: reduced IGF-1, 25-OH vitamin D - Gonads: hypogonadism (T or E 2 def.) - Pancreas: DM Iron accumulation in organs - Pituitary: hypopituitarism (GH, LH, FSH, PRL, ACTH deficiencies) - Liver: reduced IGF-1, 25-OH vitamin D - Gonads: hypogonadism (T or E 2 def.) - Pancreas: DM Iron accumulation in bone: disturb bone formation and mineralization Iron accumulation in bone: disturb bone formation and mineralization

12. Mahachoklertwattana et al. J Clin Endocrinol Metab 2003;88:3966 Thalassemic Bone Iron deposit (blue line) Thick osteoid

13. Histomorphometry in Suboptimally-Treated Thalassemics Bone formation Bone formation O.Th, OV, MS, BFR O.Th, OV, MS, BFR Bone resorption Bone resorption ES, N. Oc ES, N. Oc Bone formation & Bone resorption Bone formation & Bone resorption + defective mineralization due to Fe deposit + defective mineralization due to Fe deposit   Mahachoklertwattana et al. J Clin Endocrinol Metab 2003;88:3966

14. BMD, IGF-1, Vitamin D in Sub-optimally Transfused Thalassemics Study 48 thalassemic children and adolescents Study 48 thalassemic children and adolescents Delayed bone age and osteoporosis were common Delayed bone age and osteoporosis were common Low IGF-1 and 25-OHD were common osteoporosis Low IGF-1 and 25-OHD were common osteoporosis The spinal bone was most severely affected The spinal bone was most severely affected Mahachoklertwattana et al. Clin Endocrinol 2003;58:273

15. Thalassemic Boys IGF-1 Age (years)

16. Vitamin D in Thalassemia Vogiatzi et al. J Bone Miner Res 2008 N = 361 (TM = 236,  /E = 43, TI = 43, HbH = 19, HbH/CS = 20) 25 (OH) vitamin D <11 ng/mL 12% 11-30 ng/mL 70% 11-30 ng/mL 70% >30 ng/mL 18% >30 ng/mL 18%

17. Pituitary-Gonadal Axis in  -Thalassemia Delayed puberty, 1 o & 2 o amenorrhea Delayed puberty, 1 o & 2 o amenorrhea Pituitary gonadotrope hemochromatosis Pituitary gonadotrope hemochromatosis 1 o gonadal failure primarily induced by 1 o gonadal failure primarily induced by chemotherapy used for BMT chemotherapy used for BMT Decreased sex steroids osteoporosis Decreased sex steroids osteoporosis Anapliotou et al, Clin Endocrinol 1995;42:279

18. Genetic Variants Associated with Low BMD in Thalassemia Collagen Type 1 a 1 (COL1A 1) polymorphism (at the Sp1 site) Wonke et al, Br J Haematol 1998;103:350 Collagen Type 1 a 1 (COL1A 1) polymorphism (at the Sp1 site) Wonke et al, Br J Haematol 1998;103:350 Vitamin D receptor (VDR) BsmI BB and Fok1 polymorphisms Dresner Pollack et al, Br J Haematol 2000;111:902 Vitamin D receptor (VDR) BsmI BB and Fok1 polymorphisms Dresner Pollack et al, Br J Haematol 2000;111:902

19. Thalassemia: Optimal Treatment vs. Bone Loss Conventional treatment:  Normalization of hemoglobin  Effective Fe chelation  Hormonal replacement  Ca and vitamin D supplement However, the patients continue to lose bone mass Lasco et al, Osteoporos Int 2001;12:570 Carmina et al, Calcif Tiss Intern 2004:74:68

20. Bone Remodeling: Bone Formation and Resorption in Thalassemia In optimally-treated patients, -Bone formation markers (OC, BAP) were improved to normal or mildly elevated -Bone resorption markers (NTX, TRACP-5b) were markedly elevated Drener Pollack et al, Br J Haematol 2000;111:902 Voskaridou et al, Br J Haematol 2001;112:36 Morabito et al, J Bone Miner Res 2004;19:722

21. Bisphosphonates Treatment in Thalassemia Pamidronate (30 mg monthly) and zoledronate (4 mg q 3 mo) for 12 mo Pamidronate (30 mg monthly) and zoledronate (4 mg q 3 mo) for 12 mo Significantly decrease bone markers (NTX, CTX, TRACP-5b, BAP, OC) in thalassemics Significantly decrease bone markers (NTX, CTX, TRACP-5b, BAP, OC) in thalassemics A significant improvement of lumbar BMD A significant improvement of lumbar BMD Both bisphosphonates seem to be effective treatment for thalassemic osteoporosis Voskaridou et al, Br J Haematol 2003;123:730 Voskaridou et al, Haematologica 2006;91:1193

22. Uncoupling of Bone Turnover in Thalassemics Uncoupling of bone turnover occurred in both optimally- and suboptimally-treated thalassemics Treatment SuboptimalOptimal Bone formation N or N or Bone resorption N or N or

23. BMD in Thalassemia: Effects of BMT A cross-sectional study in 33 patients post-BMTA cross-sectional study in 33 patients post-BMT BMD was improved following BMTBMD was improved following BMT Patients transplanted for >6 y had higher absolute BMD values as compared to those with shorter post-transplant durationPatients transplanted for >6 y had higher absolute BMD values as compared to those with shorter post-transplant duration Leung et al, Bone Marrow Transplant 2005;36:331

24. Possible Reasons for BMD Improvement Following BMT Increased bone formation (increased OC) with no change of bone resorptionIncreased bone formation (increased OC) with no change of bone resorption Reduced BM expansion (increased Hb)Reduced BM expansion (increased Hb) Decreased iron accumulationDecreased iron accumulation Discontinuation of iron-chelating agent (desferrioxamine)Discontinuation of iron-chelating agent (desferrioxamine) Leung et al, Bone Marrow Transplant 2005;36:331

25. Management of Thalassemic Bone Diseases Optimal blood transfusion (Hb >10-12 g/dL) Adequate Fe chelation (ferritin <1,000  g/L) Adequate Fe chelation (ferritin <1,000  g/L) Encourage physical activity and exercise Encourage physical activity and exercise Adequate vitamin D, Ca and Zn intake Adequate vitamin D, Ca and Zn intake Optimal treatment of endocrine complications Optimal treatment of endocrine complications Antiresorptive therapy: bisphosphonates Antiresorptive therapy: bisphosphonates Bone marrow transplantation Bone marrow transplantation

26. Conclusion The pathogenesis of bone diseases in thalassemia is complexThe pathogenesis of bone diseases in thalassemia is complex Bone deformity and impaired bone formation in untransfused or suboptimally-treated patientsBone deformity and impaired bone formation in untransfused or suboptimally-treated patients Increased bone resorption in optimal treatmentIncreased bone resorption in optimal treatment Antiresorptive therapy seem to be effective in optimally-treated thalassemicsAntiresorptive therapy seem to be effective in optimally-treated thalassemics Treatment with BMT could improve BMDTreatment with BMT could improve BMD