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

• Hormone deficiencies (sex hormone, GH, IGF-1)Hormone deficiencies (sex hormone, GH, IGF-1)

• Vitamin & mineral deficiencies Vitamin & mineral deficiencies

(vit D, vit C, Ca, P, Mg)(vit D, vit C, Ca, P, Mg)

• Desferrioxamine toxicityDesferrioxamine toxicity

• Severity of thalassemia (baseline Hb) or bone Severity of thalassemia (baseline Hb) or bone

marrow hyperplasiamarrow hyperplasia

• Iron overload or hemochromatosisIron overload or hemochromatosis

• Hormone deficiencies (sex hormone, GH, IGF-1)Hormone deficiencies (sex hormone, GH, IGF-1)

• Vitamin & mineral deficiencies Vitamin & mineral deficiencies

(vit D, vit C, Ca, P, Mg)(vit D, vit C, Ca, P, Mg)

• Desferrioxamine toxicityDesferrioxamine toxicity

Thalassemic Bone HistologyThalassemic Bone Histology

BeforeBefore AfterAfter

HypertransfusionHypertransfusionPootrakul et al, N Engl J Med 1981;304:1470-3

Osteoid

Osteoid

Mineralized bone

Mineralized bone

Hemoglobin vs. Total Body Hemoglobin vs. Total Body Bone Mineral Density (BMD)Bone Mineral Density (BMD)

Mahachoklertwattana et al, J Bone Miner Metab 2006;24:146Mahachoklertwattana et al, J Bone Miner Metab 2006;24:146

ThalassemicsThalassemics

s-Transferrin Receptor vs. Total Body BMDs-Transferrin Receptor vs. Total Body BMD

Mahachoklertwattana et al, J Bone Miner Metab 2006;24:146Mahachoklertwattana et al, J Bone Miner Metab 2006;24:146

ThalassemicsThalassemics

Erythropoiesis in BM vs. BMDErythropoiesis in BM vs. BMD

Increased erythropoiesis in the bone Increased erythropoiesis in the bone

marrow is the major factor determining marrow is the major factor determining

BMD in BMD in untransfuseduntransfused and and undertransfusedundertransfused

thalassemic patientsthalassemic patients

Mahachoklertwattana et al, J Bone Miner Metab 2006;24:146

Bone and HemochromatosisBone and Hemochromatosis

• Iron accumulation in organs Iron accumulation in organs - Pituitary: hypopituitarism (GH, LH, FSH, - Pituitary: hypopituitarism (GH, LH, FSH, PRL, ACTH deficiencies) PRL, ACTH deficiencies)

- Liver: reduced IGF-1, 25-OH - Liver: reduced IGF-1, 25-OH vitamin D vitamin D - Gonads: hypogonadism (T - Gonads: hypogonadism (T or Eor E22 def.) def.) - Pancreas: DM - Pancreas: DM

• Iron accumulation in bone: disturb bone Iron accumulation in bone: disturb bone formation and mineralization formation and mineralization

Mahachoklertwattana et al. J Clin Endocrinol Metab 2003;88:3966

Thalassemic BoneThalassemic Bone

Iron deposit (blue line)

Thick osteoid

Histomorphometry in Histomorphometry in Suboptimally-Treated ThalassemicsSuboptimally-Treated Thalassemics

• Bone formationBone formation

O.Th, OV, MS, BFRO.Th, OV, MS, BFR

• Bone resorptionBone resorption

ES, N. Oc ES, N. Oc

Bone formation & Bone resorptionBone 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

BMD, IGF-1, Vitamin D in BMD, IGF-1, Vitamin D in Sub-Sub-optimally Transfused Thalassemicsoptimally Transfused Thalassemics

• Study 48 thalassemic children and adolescentsStudy 48 thalassemic children and adolescents

• Delayed bone age and osteoporosis were commonDelayed bone age and osteoporosis were common

• Low IGF-1 and 25-OHD were common Low IGF-1 and 25-OHD were common

osteoporosisosteoporosis

• The spinal bone was most severely affectedThe spinal bone was most severely affected

Mahachoklertwattana et al. Clin Endocrinol 2003;58:273

Mahachoklertwattana et al. Clin Endocrinol 2003;58:273

Thalassemic BoysThalassemic BoysIGF-1IGF-1

Age (years)Age (years)

Vitamin D in ThalassemiaVitamin D in Thalassemia

Vogiatzi et al. J Bone Miner Res 2008Vogiatzi et al. J Bone Miner Res 2008

N = 361 (TM = 236, N = 361 (TM = 236, /E = 43, TI = 43, /E = 43, TI = 43, HbH = 19, HbH/CS = 20) HbH = 19, HbH/CS = 20)

2525 (OH) vitamin D (OH) vitamin D <11 ng/mL <11 ng/mL 12% 12%

111-301-30 ng/mL 70%ng/mL 70%

>>30 ng/mL 30 ng/mL 18% 18%

Pituitary-Gonadal Axis inPituitary-Gonadal Axis in-Thalassemia-Thalassemia

• Delayed puberty, 1Delayed puberty, 1oo & 2 & 2oo amenorrhea amenorrhea

• Pituitary gonadotrope hemochromatosisPituitary gonadotrope 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

shorter post-transplant duration shorter post-transplant duration

Leung et al, Bone Marrow Transplant 2005;36:331Leung et al, Bone Marrow Transplant 2005;36:331

Possible Reasons for BMD Improvement Possible Reasons for BMD Improvement Following BMTFollowing BMT

• Increased bone formation (increased OC) with Increased bone formation (increased OC) with no change of bone resorptionno change of bone resorption

• Reduced BM expansion (increased Hb)Reduced BM expansion (increased Hb)

• Decreased iron accumulationDecreased iron accumulation

• Discontinuation of iron-chelating agent Discontinuation of iron-chelating agent (desferrioxamine)(desferrioxamine)

Leung et al, Bone Marrow Transplant 2005;36:331Leung et al, Bone Marrow Transplant 2005;36:331

Management of Thalassemic Bone DiseasesManagement of Thalassemic Bone Diseases

• Optimal blood transfusion (Hb >10-12 g/dL)Optimal blood transfusion (Hb >10-12 g/dL)

• Adequate Fe chelation (ferritin <1,000 Adequate Fe chelation (ferritin <1,000 g/L)g/L)

• Encourage physical activity and exerciseEncourage physical activity and exercise

• Adequate vitamin D, Ca and Zn intake Adequate vitamin D, Ca and Zn intake

• Optimal treatment of endocrine complicationsOptimal treatment of endocrine complications

• Antiresorptive therapy: bisphosphonatesAntiresorptive therapy: bisphosphonates

• 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