Effects of Anti RANK ligand Denosumab on Beta Thalassemia induced osteoporosis Mohamed Yassin 1 Ashraf T. Soliman2, Mohamed O. Abdelrahman3, Vincenzo De Sanctis 4 Departments of, 1 Hematology 2Pediatric Endocrinology, and 3 Clinical Chemistry, Hamad Medical Center (HMC), Doha, Qatar, 4 Department of Pediatrics, Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, 44121 Ferrara, Italy
Osteoporosis Osteoporosis is a disease characterized by low bone mass and microarchitectural deterioration of bone issue, leading to enhanced bone fragility and a consequential increase in fracture risk.. Osteoporosis is the silent disease that makes bones prone to fracture and is a major public health
T-score Number of standard deviations (SD) that a patient s bone mass is above or below the mean peak bone mass for a 30-year-old healthy woman T-score 1 to +1 = normal BMD 1 SD decrease in T-score = 10% to 15% decrease in BMD Z-score Number of SDs that a patient s bone mass is above or below the mean bone mass for age- and sex-matched controls
Bone Disease in Patients With Haemoglobinopathies Abnormalities in children with undermanaged thalassemia include Enlarged cranial and facial bones Spinal deformities Nerve compression Spontaneous fractures All thalassemia and SCD patients: effects of bone marrow expansion and other imbalances Localized changes in bone (loss and formation) Generalized decrease in bone mineral density (BMD), osteppenia/osteoporosis Mikroinfarction of vertebral bone marrow (fish mouth)
Acquired Factors in the Pathogenesis of Thalassemia and SCD-Induced Osteoporosis Iron overload and chelation therapies Iron deposition in bone Impaired maturation of bone cells (osteoids) Local mineralisation High-dose iron chelation therapy with desferoxamine Differentiation and proliferation of bone-forming cells (osteoblasts) Collagen (bone matrix) formation Osteoblast programmed cell death (apoptosis) Deficiencies in vitamins and minerals Vitamin D deficiency Impaired regulation of bone metabolism Zinc deficiency Prevalent in hemoglobinopathies and associated with low bone mineral density Role of zinc is not well defined, but might involve activation of bone-specific alkaline phosphatase (balp) and inhibition of osteoclast activity 1,2 1. King JC. Am J Clin Nutr. 1996;64(3):375-376; 2. Reviewed in Voskaridou E, et al. Br J Haematol. 2004;127(2):2004; 127-139.
Genetic predisposition to reduced BMD Polymorphisms in genes that play key roles in bone maintenance and remodeling: - Collagen type I - Vitamin D receptor - Transforming growth factor β 1 - Calcitonin receptor - Oestrogen receptor - Interleukin 6 To date, although some genetic traits correlate with thalassaemia-induced osteoporosis, their roles in its development are unclear Reviewed in Voskaridou E, et al. Br J Haematol. 2004;127(2):127-139.
Bone Metabolism: A Balance Between Osteoblasts and Osteoclasts Reproduced from Seeman E, et al. N Engl J Med. 2006;354(21):2250-2261.
Biochemical Markers of Bone Metabolism Enzymes, protein fragments, or other molecules released into blood as a result of bone turnover In order to be clinically useful, markers should be Highly specific to bone Detectable in body fluids (blood or urine) using standard assay methods (chemical, enzymatic or immunologic)
Biochemical Markers of Bone Metabolism Formation Resorption BALP Collagen type I propeptides Osteocalcin Calcium TRAcP-5b BSP OH-proline OH-lysine glycosides Pyridinium crosslinks Collagen type I telopeptides (eg, NTX, CTX) Osteoblasts Bone matrix Osteoclasts
The RANK/RANKL RANKL is a key that promotes osteoclast formation pathway 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 Endocr Rev in 2008;29:155-92. the etiology of Clin Endocrinol (Oxf). 2003;58(3):273-9 osteoporosis in BTM.
In Thalassemic Patients The ratio of srankl/opg is increased in patients with TM and low BMD. Alterations in the RANK/RANKL/OPG system in favor of osteoclasts are characteristic in thalassaemia due to complicated 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.
BTM- Hormones and RANK RANKL- OPG Patients with BTM frequently system have 1. Gonadotrophin and sex steroid deficiency 2. Defective growth hormone (GH) insulin-like growth factor-i (IGF-I) axis 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 increases the proliferation of osteoblast-like cells in culture, and induce osteoblast differentiation. RANKL expression was found to be up-regulated in osteoblastic cells from androgen receptordeficient mice J Bone Miner Res 1992; 7: 41-6. 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.
Androgens RANKL/OPG Androgens block RANKL-induced osteoclastic formation. Testosterone increases the proliferation of osteoblast-like cells in culture, and induce osteoblast differentiation. RANKL expression was found to be up-regulated in osteoblastic cells from androgen receptor-deficient mice J Bone Miner Res 1992; 7: 41-6. 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.
Low IGF-I : Defective GH-IGF-I axis in thalassemia Osteoclasts express IGF-1 receptors and IGF-1 has direct effects on their function. GH and IGF-I 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
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.
RANKL: An Essential Mediator of Osteoclasts
Osteoprotegerin (OPG): The Decoy Receptor of RANKL Osteoclast formation, function, and survival RANKL inhibited by OPG RANK OPG Growth factors Hormones Cytokines CFU-M Prefusion osteoclast Multinucleated osteoclast Osteoblast lineage Bone Inactive osteoclast
RANKL/OPG Balance Drives Osteoclast Activity Alterations of the RANKL / OPG ratio are critical in the pathogenesis of bone diseases that result in increased bone resorption 1-3 Promotes OC activation Prevents OC activaion OC Activity
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
Design and Patients: Longitudinal study for a year Patients: 30 (19 M, 11 F) ( 18 32 yr) on regular Bld Transfusiondependent BTM patients above 18 years with No history of treatment with bisphosphonates BMD T-scores < -2.5 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. No fracture reported.
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)
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
Table 2 : Biochemical and bone mineral density data in males and females thalassaemia major patients before and after treatment with Denosumab * p < 0.01 after Denosumab versus before treatment Males Females Before After Before After Type 1 collagen telopeptide (pg/ml) 1754±512 423±200* 1439±362 373±237* PTH (ng/ml) 33±20 40.5±39.1 28.5±14.2 36.1±29.9 Calcium (mmol/l) 1.97±0.35 2.07±0.17 2.12±0.13 2.19±0.13 Phosphate (mmol/l) 1.47±0.45 1.52±0.26 1.54±0.48 1.41±0.16 BMD SDS 1 Femur (-)2.1±0.19 (-)1.42±0.24* -2.13±0.18-1.48±0.16* BMD SDS Lumbar (-)2.8±0.34 (-)1.6±0.32* -2.67±0.99-1.20±0.89* IGF-1 (ng/ml) 196±118 215±123 156±78 188±83 IGF-1 SDS -2.7 +/-1.3-2.3 ±1.4-2.8 +/- 1.4-2.7+/-1.5
Results: Denosumab therapy for a year Significant increase in BMD of : 9.2% (95% CI, 8.2 to 10.1) at the lumbar spine and 6.0% (95% CI, 5.2 to 6.7) at the total hip. Decreased serum ICCT levels by 56% at 1 month and normalized them in all patients at 1 year.
0 Bone Mineral Density Before vs 1 year after Denosumab BMD SDS Femur BMD SDS lumber -0.5-1 -1.5 Before Deno After Deno -2-2.5-3
Correlations Significant correlations were found between BMD T score before and 1year after Denosumab in : Lumbar vertebrae (r = = 0.752, p < 0.001) and Hips (r = 0.758 respectively p < 0.001).
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
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 vertebrae 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