La terapia dell osteoporosi nel soggetto talassemico Therapy of Thalassemia Major-Induced Osteoporosis Ashraf Soliman, Vincenzo De Sanctis Mohamed A Yassin,
Institutes Departments of Pediatric Endocrinology, Hematology* and Clinical chemistry #Hamad Medical Center (HMC), Doha - Qatar. Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital**, 44121 Ferrara - Italy
Disclosure statement Conflict statement Nothing to declare No Conflict among authors
A World Health Organization (WHO) working group and consensus conference have defined osteoporosis A disease characterized by: 1. low bone mass and 2. micro architectural deterioration of bone tissue, 3. leading to enhanced bone fragility and 4. a consequent increase in fracture risk
Thalassemia- Osteoporosis The second most common cause of endocrinopathy in patients with beta thalassemia major (BTM). Osteopenia and severe osteoporosis represent the leading cause of morbidity in BTM patients. The prevalence of osteoporosis in these patients is as high as 50%, with higher rates in males Increased osteoclastic activity with or without decreased bone formation are proposed mechanisms Annals of the New York Academy of Sciences, 2005, 1054, 462 6,
The RANK/RANKL pathway RANKL is a key that promotes osteoclast formation and activation, and prolongs osteoclast survival. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL and prevents its interaction with RANK thereby inhibiting osteoclast formation, function and survival. Alteration of the RANK/RANKL/OPG system in favor of increased osteoclastic activity and enhanced osteoblastic dysfunction is proposed as an important mechanism in the etiology of osteoporosis in BTM. Endocr Rev 2008;29:155-92. Clin Endocrinol (Oxf). 2003;58(3):273-9
In Thalassemic Patients The ratio of srankl/opg is increased in TM with low BMD. Alterations in the RANK/RANKL/OPG system in favor of osteoclasts are characteristic in thalassaemia due to not clearly delineated mechanisms Hematology. 2006;11(3):197 202. British Journal of Haematology. 2001;112(1):36 41. Osteoporosis International. 2001;12(7):570 575. Journal of Bone and Mineral Research. 2004;19(5):722 727.
OPG/RANKL system acts as an important paracrine mediator of bone metabolism A central role of the OPG/RANKL system in development of bone abnormalities in TM patients. There is higher circulating levels of RANKL-No differences in plasma levels of OPG ---- high RANKL / OPG ratio and increased osteoclastic activity. Urinary levels of pyridinium cross-links, (bone resorption) were higher in TM patients than controls and positively correlated with plasma levels of RANKL.
BTM patients display Unbalanced bone turnover characterized by 1. Enhanced resorption rates (indicated by high levels of pyridinium cross-links) and 2. Decreased neoformation phase (evidenced by low levels of osteocalcin (an osteoblastderived protein) N. Morabito, et al. Journal of Bone and Mineral Research, 2004,19, 722
Impairment of Osteoblast Activity Increased serum levels of Dickkopf-1 (Dkk1) and sclerostin have been found in TM patients. Dickkopf-1 is an inhibitor of Wnt signalling, which is crucial for osteoblast differentiation; Sclerostin is produced by the osteocyte and has anti-anabolic effects on bone formation. Higher circulating levels of Dkk1 and sclerostin correlated with reduced BMD of lumbar spine and distal radius. 1. increased bone resorption and 2. reduced bone formation markers. Voskaridou E. Horm Metab Res. 2012, 44(12):909-13.
Osteoporosis in TM patients is multifactorial + partially understood Genetic Acquired
Genes : The collagen type Ia1 (COLIA1) gene, which encodes type I collagen, the major protein of bone Polymorphism at the Sp1 site of COLIA 1 gene has been associated with severe osteoporosis and pathologic fractures of the spine and hip in TM patients. Polymorphism at the Sp1 site of the COLIA 1 gene was present in approximately 30% of TM patients, who were heterozygotes (Ss), and in 4% who were homozygotes (SS) for these changes. N.B. Patients with TM carrying the Sp1 mutation may develop severe osteoporosis of the spine and the hip more frequently than patients who do not carry this mutation. Early detection of this mutation is important to start treatment before fractures occur. Voskaridou E,. Pediatr Endocrinol Rev. 2008;6(Suppl 1):86-93 Guzeloglu-Kayisli O. Pediatr Int 2008;50:474-476
Acquired factors a) Bone marrow expansion, secondary to ineffective erythropoiesis b) Direct toxic effects of iron overload on osteoblast number and activity; c) Deleterious effects of desferrioxamine on the bone metabolism, negative impact of chelation therapy on fibroblast proliferation and collagen synthesis. d) Associated endocrine complications, calcium and zinc deficiencies and low vitamin D levels. e) Liver and kidney issues; f) Nutritional deficiencies.
1.Marrow Expansion 1. Mechanical interruption of bone, 2. cortical thinning, 3. bone distortion, and 4. increased fragility. The negative relationships between : 1. Hb and RANKL levels 2. Erythropoietin and OPG/RANKL ratio Suggests that medullary expansion may act through enhanced RANKL levels in increasing bone resorption. Carlo Perisano, et al. Physiopathology of Bone Modifications in -Thalassemia Anemia, Volume 2012 (2012), ID 320737,
2. Iron Toxicity: Animal Studies Fe overload on bone remodeling demonstrated: 1. decreased osteoblast recruitment and 2. decreased collagen synthesis, Resulting in decreased bone formation. Human Studies Iron deposition along the mineralization fronts is associated with increased osteoid seams. Focal thickened osteoid seams are found together with focal iron deposits along osteoid surfaces. Fe deposition in bone impairs osteoid maturation and inhibits local mineralization. As a result, focal osteomalacia develops.
(iron stain; X500) of undecalcified bone section illustrates the thick linear deposition of iron (blue line) along the mineralization front (thick arrows). The un-mineralized zone is also stained blue, but with lighter intensity (areas between thin arrows). Active osteoblasts (arrowheads) are also present along the osteoid surface.
Possible mechanism Iron interferes with osteoid maturation and mineralization by: The incorporation of iron into crystals of calcium hydroxyapatite, Affects the growth of calcium hydroxyapatite crystals and increases osteoid in bone tissue.
Can inhibit: 3. Chelation therapy with 1. DNA synthesis, desferrioxamine (DFX) 2. osteoblast and fibroblast proliferation, 3. differentiation of osteoblast precursors and 4. collagen formation. 5. In high doses it enhances osteoblast apoptosis. The toxic effects of DFX can also be due to a deficiency of trace elements such as copper and zinc. Pratelli L, Pediatr Endocrinol Metab. 2006 Nov;19(11):1335-42
4. Impaired Calcium Homeostasis: TM patients have high prevalence of VDD: North America, 12.8% < 10 ng/ml, 82% < 30ng/ml India : 80% VDD. Thaliland: 90% VDD VDD may start early in TM, before the occurrence of hypoparathyroidism. VDD is critical for : Ca homeostasis & mineralization of the skeleton, especially during pubertal growth spurt VDD can ------osteomalacia and Osteoporosis. Soliman A et al. Mediterr J Hematol Infect Dis. 2013
5. Endocrine dysfunction 1.Hypogonadism 2.Impaired GH-IGF-I axis and Hypoparathyroidism, Hypothyroidism, Diabetes mellitus Contributes to decreased bone formation and increased bone resorption.
In Thalassemia Major Gonadotrophin deficiency as well as Defective growth hormone (GH) insulin-like growth factor-i (IGF-I) axis are common. The anabolic effects of sex steroids, GH and IGF-I on bone formation are important for the acquisition of bone mass, especially during childhood and puberty. Pediatr Endocrinol Rev. 2011; 8 (Suppl 2) :284-9 Clin Endocrinol (Oxf). 2008;69:202-207
Androgens RANKL/OPG Androgens block RANKL-induced osteoclastic formation. Testosterone and 5DHT mediate an androgen receptor-induced specific inhibition of OPG mrna expression. RANKL expression was found to be up-regulated in osteoblastic cells from androgen receptor-deficient mice Eur J Endocrinol. 2002;147:269-73. Biochemical and Biophysical Research Communications. 2009;389:550-5. Endocrinology. 2001;142:3800-08. J Bone Miner Res. 2005;20:2224-32.
Defective GH-IGF-I axis in thalassemia Low IGF-I : Osteoclasts express IGF-1 receptors and IGF-1 has direct effects on their function. GH and IGF-1 stimulate the production of OPG and its accumulation in the bone matrix. In thalassemic patients, it is suggested that decreased OPG production with increased RANKL/OPG ratio can induce more osteoclastic activity. J Clin Endocrinol Metab. 2002 Sep;87(9):4273-9. Exp Cell Res 2004, 294:149 158
In Thalassemia: Low Androgens Increases RANKL induced osteoclastic activity Low IGF-I Decreases OPG expression that increases RANKL activity
Treatment of Osteoporosis in thalassemia
Bone markers Bone formation markers Serum bone specific alkaline phosphatase Serum osteocalcin Serum type 1 procollagen telopeptide (C-terminal/Nterminal): C1NP or P1NP Bone resorption markers Urinary hydroxyproline Urinary total pyridinoline (PYD) Urinary free deoxypyridinoline (DPD) Urinary collagen type 1 crosslinked N-telopeptide (NTX) Urinary or serum collagen type 1 cross-linked C-telopeptide (CTX) Tartrate-resistant acid phosphatase 5b
Bisphosphonates (BPs) A group of molecules analogous to inorganic pyrophosphate. They concentrate within bones, binding specifically to its inorganic components. BPs also enter osteoclasts and inhibit their bone destruction ability via several cellular mechanisms Alendronate, Pamidronate, and Zoledronate are effective anti-resorptive BP.
Bisphosphonate treatment of TM Mamtani M et al. Osteoporos Int 2010;21:183-187 Yigitoglu PH et al. Turk J Phys Med Rehab 2012;58:154-158 Otrock ZK, et al. Ann Hematol 2008;87:947-948 Patıroğlu T, et al. Turk J Hematol 2008;25:79-82 Gilfillan CP, et al Calcif Tissue Int 2006;79:138-144
Zoledronate Zoledronate (4mg IV Q 3mon) for 1 year improves : Significant increase in BMD in : lumbar spine, femoral neck, trochanter, and total hip Decreases the number of painful sites. Decreases : C-telopeptide of collagen type-i(ctx), balp, CICP, and (osteocalcin) OC Esophageal irritation is a side effect. Ann Hematol. 2006 Sep;85(9):605-9. Haematologica. 2006 Sep;91(9):1193-202 Mamtani M et al. Osteoporos Int 2010;21:183-187 Ann Hematol. 2007 Jan;86(1):23-30
Pamidronate (30 or 60 mg i.v. infusion - once a month over 12 months) Decreases: N-telopeptide of Collagen (INTX), Tartrate-resistant acid phosphatase isoform -5b (TRACP-5b) OPG, and OC Br J Haematol. 2003 Nov;123(4):730-7 BMD : Increases lumbar spine, (similar in patients of both treatment groups) These data suggest that pamidronate, at a monthly dose 30 mg IV is effective
Alendronate PO vs Clodronate IM BOTH NOT Sign EFFECTIVE Alendronate oral 10 mg of alendronate daily BMD lumbar spine and femoral neck increased (NS) Better than placebo Clodronate IM 100 mg of clodronate intramuscularly every 10 days BMD lumbar spine and femoral neck (no change) Better than placebo J. Bone Miner. Metab. 21: 402 408 Pediatr Endocrinol Rev. 2008 Oct;6 Suppl 1:144-8.
Bisphosphonate in TM Drug Patient No age BMD before BMD after Haematologica 93: 1588 1590. Acta Haematol. 119: 40. Zoledronic acid Q 3 months IV 66 Hip- 2y Lumbar 2y Increased Increased Aledronate PO 24 20 Lumbar: -2.7 Hip: -2.03 Lumbar:-1yr Hip: -2.6-2.01 Increased 4% Increased 3.1 % JPEM, 1998 11, 795 Osteoporos. Int, 2005 Br. J. Haematol. 123: 730 737. PER, 2008 Pamidronate IV 15 mg IV 30 mg IV 60 mg infusion/month 20 26 29 Lumbar: -1yr Hip : 1 yr Lumbar : -2.8 Hip: - 2.13 Increased in all Increased with 60mg -2.1-2.07 Morabito et al Osteoporos. Int. 13: 644 649. P O daily alendronate Vs IM /10d clodronate 9 8 Lumbar And Hip 2 years Increased Same Vs Placebo 8 Decreased
Side Effects of Bisphosphonate Fever and flu like symptoms Hypocalcaemia Bone and joint pain constipation or diarrhea usually only last for a few days it is important to drink plenty of fluids (6 to 8 glasses a day) Tiredness and low energy levels Feeling sick is usually mild and gets better after a few days
Uncommon short-term safety issues : Nephrotoxicity Anterior uveitis. Atrial fibrillation and flutter Osteonecrosis of the jaw
Effects of Calcitonin (CT) in TM Twenty-four patients with an age range of 10-24 years. 14 received 100 IU nasal CT and 250 mg calcium 3 times a week. 10 were followed up as a control with only routine therapy. After 1 year on CT: bone pain disappeared and radiological signs of osteoporosis had improved significantly (p < 0.01) in the treatment group. CT had no important side effects. Canatan et al. Acta Haematol, 1995;93:20-24
Denosumab Is a fully human monoclonal antibody to the receptor activator of nuclear factor kappab ligand RANKL. Inhibits osteoclast formation, Decreases bone resorption, Increases bone mineral density (BMD) The efficacy and safety of Denosumab in BTMinduced osteoporosis has not been tested Anastasilakis ADHorm Metab Res. 2009;41(10):721.
Collagen telopeptide
A systematic review and a meta-analysis. Nine RCTs involving 10.329 participants. Denosumab universally decreased bone markers and increased lumbar and hip BMD. Denosumab was not associated with a significant reduction in fracture risk [OR (95% CI) 0.74 (0.33 to 1.64), p=0.45]. Denosumab has not yet proved its efficacy on fracture risk reduction while?increased infection risk questions its safety. Anastasilakis ADHorm Metab Res. 2009;41(10):721.
Not recommended Pediatric use : May impair bone growth in children with open growth plates and may inhibit eruption of dentition Pregnancy Category: May cause fetal harm when administered pregnant women based on animal studies; in utero resulted in increased fetal loss, stillbirths, and postnatal mortality, including absent lymph nodes, abnormal bone growth and decreased neonatal growth Women with reproductive potential must use highly effective contraception during therapy and for at least 5 months after the last dose
Objective: To evaluate the efficacy and safety of Denosumab in patients with BTM-induced osteoporosis on : 1. The biochemical (bone turnover markers) 2. Radiological parameters of bone mineralization
Osteoporosis as per WHO criteria Osteopenia : T score of < -1.0 Osteoporosis : T score < -2.5 BMD of lumbar spine and right femoral neck were measured by DEXA scan using a calibrated dual energy X-ray absorption method.
Design and Patients: Longitudinal study for a year Patients: 30 (19 M, 11 F) ( 18 32 yr) on regular Bld Transfusion-dependent BTM patients above 18 years with no history of treatment with bisphosphonates BMD T-scores between -2.5 and -4.0 at the lumbar spine [LS] or total hip [TH]). All patients were on vitamin D replacement Pubertal development (Tanner s stage 5) None has IGT, hypothyroidism, hypoparathyroidism or other systemic illness.
Investigations Serum ferritin levels (3488 +/- 1557ng/ml). Every patient underwent DEXA scan as baseline and after 12 months of Denosumab therapy. Biochemical evaluation, at baseline 1, 3, 6,12 months Serum creatinine, Na, K, calcium, phosphorus, Parathormone (PTH), Bone specific alkaline phosphatase (ALP) Type 1 collagen carboxy telopetide (1CCT) (ELISA)
Treatment Denosumab 60 mg was administered subcutaneously twice yearly for a year.
Before treatment mean ± SD After treatment mean ± SD Type 1 collagen telopeptide 1634 ± 471 406±211* PTH 31±17.4 38±34.6 Calcium 2.13±0.28 2.03±0.16 Phosphate ( PO4) 1.51±0.45 1.49±0.24 Bone Akaline phosphatase u/l 97 +/- 100 88 +/- 98 BMD Femur 0.918 +/- 0.12 1.15 +/- 0.17* BMD SDS Femur (-) 2.14±0.18 (-) 1.44 ± 0.21* BMD SDS lumber (-) 2.77±0.27 (-) 1.45 ± 0.63* IGF-I 175±102 200±106 IGF-I SDS -2.7 +/- 1.6-2.55 +/- 1.4 Testosterone (males) 16.1±6.2 18.8±5.1
Results: Denosumab therapy for a year Significant increase in BMD - 9.2% at the lumbar spine and - 6.0% at the total hip. Decreased serum ICCT levels by 56% at 1 month and normalized them in all patients at 1 year.
Side effects in our patients Pain in the back and/or extremities 4/30 Nausea 3/30. Asymptomatic hypocalcaemia in 2/30 None required stopping therapy
Conclusion Denosumab therapy for a year significantly increased : 1. bone mineral density at vertebral and hips of patients with BTM and 2. Associated with a rapid and sustained reduction in bone turnover markers. Further studies are required to confirm longterm effects of this therapy
RECOMMENDATIONS 1. Prevention & Monitoring The early identification of osteopenia and osteoporosis is of paramount importance, ( BMD every 2 years starting 12 years) Delayed diagnosis and inadequate treatment may lead to significant osteoporosis, skeletal abnormalities, fractures, spinal deformities, nerve compression and growth failure. 1. Effective iron chelation, 2. Improvement of hemoglobin levels, and Nutrition 3. Adequate hormonal replacement, (Sex steroids, GH, T4) 4. Calcium and vitamin D, zinc administration 5. physical activity (Exercise program) Are the main measures for the prevention of the disease.
RECOMMENDATIONS & 2. Treatment For patients with established osteoporosis: Definitive treatment should be considered: 1. Bisphosphonate 2. Calcitonin 3. Denosumab 4.?? Teriparatide (a recombinant peptide fragment of PTH)
Pediatric Endocrinology Reviews (PER) Volume 11 No 2 September 2013