Osteoporosis in Osteoporosis in Thalassemia: Thalassemia: Pathogenesis Pathogenesis and Treatment Update and Treatment Update Pat Mahachoklertwattana M.D. Pat Mahachoklertwattana M.D. Department of Pediatrics, Ramathibodi Hospital Department of Pediatrics, Ramathibodi Hospital Faculty of Medicine, Mahidol University Faculty of Medicine, Mahidol University Bangkok, THAILAND Bangkok, THAILAND
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Osteoporosis in Thalassemia: Pathogenesis and Treatment Update Pat Mahachoklertwattana M.D. Department of Pediatrics, Ramathibodi Hospital Faculty of Medicine,
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Osteoporosis in Thalassemia: Osteoporosis in Thalassemia: Pathogenesis and Treatment UpdatePathogenesis and Treatment Update
Pat Mahachoklertwattana M.D.Pat Mahachoklertwattana M.D.
Department of Pediatrics, Ramathibodi Hospital Department of Pediatrics, Ramathibodi Hospital Faculty of Medicine, Mahidol UniversityFaculty of Medicine, Mahidol University
Bangkok, THAILANDBangkok, THAILAND
Bone and BM in ThalassemiaBone and BM in Thalassemia
Ineffective erythropoiesis and hemolysis Ineffective erythropoiesis and hemolysis
Defective globin chain
Increased erythropoiesis
Bone marrow hyperplasia
Osteoporosis, bone deformity
30
11
38
12
19
0
5 5 5
00
10
20
30
40
50
1-2 Fractures
≥3 Fractures
Vogiatzi et al. J Bone Miner Res 2008Vogiatzi et al. J Bone Miner Res 2008
TM TM (236)(236)
TI TI (43)(43)
/E /E (43)(43)
H H (19)(19)
H/CS H/CS (20)(20)
Fracture Prevalences in ThalassemiaFracture Prevalences in Thalassemia
BMD in Thalassemic AdultsBMD in Thalassemic Adults
TM TM (147)(147)
TI TI (24)(24)
/E /E (20)(20)
H H (3)(3)
H/CS H/CS (4)(4)
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
Spine
Femur
BMD BMD T-scoreT-score
Vogiatzi et al. J Bone Miner Res 2008Vogiatzi et al. J Bone Miner Res 2008
44
60
44
67
58
75
13
0
50
00
20
40
60
80
100
Age 11-19 y
Age >20 y
Low Spine BMD in ThalassemiaLow Spine BMD in Thalassemia% BMD <-2SD% BMD <-2SD
TM TM (202)(202)
TI TI (33)(33)
/E /E (32)(32)
H H (11)(11)
H/CS H/CS (14)(14) Vogiatzi et al. J Bone Miner Res 2008Vogiatzi et al. J Bone Miner Res 2008
Factors Causing Osteoporosis in Factors Causing Osteoporosis in ThalassemiaThalassemia
Factors Causing Osteoporosis in Factors Causing Osteoporosis in ThalassemiaThalassemia
• Severity of thalassemia (baseline Hb) or bone Severity of thalassemia (baseline Hb) or bone
marrow hyperplasiamarrow hyperplasia
• Iron overload or hemochromatosisIron overload or hemochromatosis
• 11oo gonadal failure primarily induced by gonadal failure primarily induced by
chemotherapy used for BMTchemotherapy used for BMT
• Decreased sex steroids Decreased sex steroids osteoporosisosteoporosis
Anapliotou et al, Clin Endocrinol 1995;42:279
Genetic Variants Associated with Genetic Variants Associated with Low BMD in ThalassemiaLow BMD in Thalassemia
• Collagen Type 1 a 1 (COL1A 1) Collagen Type 1 a 1 (COL1A 1) polymorphism (at the Sp1 site)polymorphism (at the Sp1 site)
Wonke et al, Br J Haematol 1998;103:350Wonke et al, Br J Haematol 1998;103:350
• Vitamin D receptor (VDR) BsmI BB Vitamin D receptor (VDR) BsmI BB and Fok1 polymorphisms and Fok1 polymorphisms Dresner Pollack et al, Br J Haematol Dresner Pollack et al, Br J Haematol
2000;111:9022000;111:902
Thalassemia: Thalassemia: Optimal Treatment vs. Bone LossOptimal Treatment vs. Bone Loss
Conventional treatment:Conventional treatment:
Normalization of hemoglobinNormalization of hemoglobin
Effective Fe chelationEffective Fe chelation
Hormonal replacement Hormonal replacement
Ca and vitamin D supplementCa and vitamin D supplement
However, the patients continue to However, the patients continue to lose bone masslose bone mass Lasco et al, Osteoporos Int 2001;12:570Lasco et al, Osteoporos Int 2001;12:570
Carmina et al, Calcif Tiss Intern 2004:74:68Carmina et al, Calcif Tiss Intern 2004:74:68
Bone Remodeling: Bone Formation and Bone Remodeling: Bone Formation and Resorption in ThalassemiaResorption in Thalassemia
In optimally-treated patients, In optimally-treated patients,
- Bone formation markers (OC, BAP) were Bone formation markers (OC, BAP) were improved to improved to normal or mildly elevatednormal or mildly elevated
- Bone resorption markers (NTX, TRACP-5b) Bone resorption markers (NTX, TRACP-5b) were were markedly elevatedmarkedly elevated
Drener Pollack et al, Br J Haematol 2000;111:902Drener Pollack et al, Br J Haematol 2000;111:902Voskaridou et al, Br J Haematol 2001;112:36Voskaridou et al, Br J Haematol 2001;112:36
Morabito et al, J Bone Miner Res 2004;19:722Morabito et al, J Bone Miner Res 2004;19:722
Bisphosphonates Treatment in ThalassemiaBisphosphonates Treatment in Thalassemia
• Pamidronate (30 mg monthly) and zoledronate Pamidronate (30 mg monthly) and zoledronate
(4 mg q 3 mo) for 12 mo(4 mg q 3 mo) for 12 mo
• Significantly decrease bone markers (NTX, CTX, Significantly decrease bone markers (NTX, CTX,
TRACP-TRACP- 5b, BAP, OC) in thalassemics5b, BAP, OC) in thalassemics
• A significant improvement of lumbar BMDA significant improvement of lumbar BMD
Both bisphosphonates seem to be effective Both bisphosphonates seem to be effective
treatment for thalassemic osteoporosistreatment for thalassemic osteoporosis
Voskaridou et al, Br J Haematol 2003;123:730Voskaridou et al, Br J Haematol 2003;123:730Voskaridou et al, Haematologica 2006;91:1193Voskaridou et al, Haematologica 2006;91:1193
Uncoupling of Bone Turnover Uncoupling of Bone Turnover in Thalassemicsin Thalassemics
Uncoupling of bone turnover occurred in Uncoupling of bone turnover occurred in both optimally- and suboptimally-treated both optimally- and suboptimally-treated thalassemicsthalassemics
TreatmentTreatment
Suboptimal Suboptimal OptimalOptimal
Bone formationBone formation N or N or
Bone resorptionBone resorption N or N or
BMD in Thalassemia: Effects of BMT 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 Patients transplanted for >>6 y had higher 6 y had higher
absolute BMD values as compared to those with absolute BMD values as compared to those with
• Bone marrow transplantationBone marrow transplantation
ConclusionConclusion• The pathogenesis of bone diseases in The pathogenesis of bone diseases in
thalassemia is complexthalassemia is complex
• Bone deformity and impaired bone formation in Bone deformity and impaired bone formation in untransfused or suboptimally-treated patientsuntransfused or suboptimally-treated patients
• Increased bone resorption in optimal treatmentIncreased bone resorption in optimal treatment
• Antiresorptive therapy seem to be effective in Antiresorptive therapy seem to be effective in optimally-treated thalassemicsoptimally-treated thalassemics
• Treatment with BMT could improve BMDTreatment with BMT could improve BMD