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Bone Health Issues in Thalassemia
Review Article
BONE HEALTH ISSUES IN THALASSEMIA Anju Virmani and A Mahajan Senior Consultant, Apollo Centre for Advanced Pediatrics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr Anju Virmani, Senior Consultant, Pediatric Endocrinology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Advances in the management of thalassemia have led to marked improvements in the life span and quality of life of children and young adults. This poses new challenges for the treating physicians. There is now increasing recognition that thalassemics have impaired bone health which is multifactorial in etiology. This paper aims to highlight the factors that predispose these patients to osteoporosis and suggests measures to minimise the impact on bone health. Key words: Thalassemia, Osteopenia, Osteoporosis.
Till a few decades ago, thalassemic patients had severe bone deformities due to marrow expansion, but did not survive long enough to have problems of adolescence and young adulthood. Now with optimal transfusions and chelation, survival and quality of life have improved dramatically. At the same time, regular blood transfusions and the consequent iron deposition in various endocrine glands can potentially cause several endocrinopathies with increasing age. Issues like growth, hypogonadism and compromised bone health, with increased fracture risk, are therefore, becoming more important [1,2]. This is particularly crucial in the Indian context, where deficiency of Vitamin D and calcium, low exercise levels, rickets and osteomalacia, and osteoporosis are already prevalent in the general population [3]. It is now well accepted that nearly half of the total bone density accrual occurs during childhood and adolescence. The peak bone density attained in adolescence largely determines fracture risk. Hypogonadism, and consequent cytokine abnormalities, are well known to cause low bone density in any condition, and play a major role in causing poor bone health in thalassemia [4]. Therefore pediatricians must ensure that the impact of factors affecting bone accrual is minimized [5]. The young thalassemic today no longer has the deformed bones of earlier generations, but continues to have several factors which contribute to poor bone health (Table 1). These factors need to be addressed aggressively from an early age if bone density is to be improved. Furthermore, it has been shown that regular screening and proper management of possible endocrine complications can possibly secure normal bone health in these patients [6]. 355
This results in a variety of bone problems: bone pain and/ or deformity, frank rickets or osteomalacia, osteopenia, osteoporosis, pathological fractures, and occasionally spinal deformities and nerve compression. Fracture risk is of course related to bone strength, but also to muscle size, function and activity levels. Attention must be paid to improving bone and muscle health in order to minimize fracture risk and other adverse consequences. Thalassemics have been found to have low levels of Vitamin D, which is linked not only to bone health, but also decreased cardiac function, muscle weakness, glucose insensitivity, and refractory congestive heart failure [7]. Both for the families as well as the treating physicians, understandably, the major focus is on achieving optimal transfusion and chelation. As a consequence, other important facets of care are often ignored. A number of measures can go a long way in minimising the adverse impact of this disease on bone health. By and large, they are inexpensive and can be easily incorporated in their care. What is required is increased awareness and constant reinforcement to the families regarding these measures. A conscious effort must be made to pay attention to the following: •
To maintain optimal pre-transfusion haemoglobin.
•
Ongoing encouragement to increase the intake of low fat milk products.
•
Annual monitoring phosphorus levels.
•
Regular supplementation of Vitamin D, encouragement to get sun exposure on the bare skin. Vitamin D
of
serum
calcium
and
Apollo Medicine, Vol. 6, No. 4, December 2009
Review Article
ethnicity, etc. In a child whose growth is compromised, interpretation becomes even more difficult. Serial scans annually or every two years are the best way to monitor these patients.
Table 1. Factors adversely affecting bone mass accrual in thalassemics (i)
Chronic anemia, ill health, poor weight bearing
(ii)
Marrow expansion in those poorly transfused
(iii)
Poor calcium intake
(iv)
Reduced Vitamin D levels, worsened by low sun exposure, skin pigmentation and hepatic involvement
(v)
Low levels of exercise
(vi)
Hypoparathyroidism
(vii)
Hypothyroidism
•
(viii) Hypogonadotrophic hypogonadism (ix)
Insufficiency of GH, IGF-1, IGF-BP3, other growth factors
(x)
Direct toxicity of iron, chelators, on the bone
sachets given every 1-3 months are a safe, inexpensive way of maintaining adequate Vitamin D levels.
Bisphosphonate therapy is useful in a subgroup of patients because thalassemia is associated with high bone turnover, with increased resorption and remodelling. Generally, it is reserved for those who have deteriorating bone density in spite of other measures. Over-treatment can actually result in increased brittleness of bone, and increased fracture risk [8,9].
Growth charting, Vitamin D supplementation, encouragement of adequate calcium intake and active exercise, and gonadal hormone replacement at the right age are simple, inexpensive measures which would go a long way in reducing the morbidity and mortality due to poor bone health in thalassemics. REFERENCES
•
Once hypoparathyroidism is suspected, calcitriol should be started in place of cholecalciferol.
•
Monitoring of serum T4 and TSH levels annually after 10 years of age.
1. Vogiatzi MG, Autio KA, Schneider R, Giardina PJ. Low bone mass in prepubertal children with thalassemia major: insights into the pathogenesis of low bone mass in thalassemia. J Pediatr Endocrinol Metab 2004; 17: 14151421.
•
Ongoing encouragement to undertake physical activity, especially weight bearing games like running and jumping.
2. Karimi M, Ghiam AH, Hashiemia A, et al. Bone mineral density in beta-thalassemia major and intermedia. Indian Pediatr 2007; 44(1): 29-32.
•
Regular measurement of height, at least every 6 months, with charting on a growth chart on which the target height (i.e. mid-parental height, which gives the genetic potential) is marked.
•
•
Regular monitoring of the pubertal status from 12 years. Delayed or absent puberty is a major contributor to poor bone accrual and/or increased bone loss, and should be addressed. Secondary gonadal failure can also occur later in life, even after a normal puberty, and may not be detected unless looked for. In case of primary gonadal failure, gonadal replacement therapy should be initiated no later than 14 years; starting with very low doses, and building up gradually. If gonadal failure occurs later in life, HRT in adult doses should be begun promptly.
•
If growth falters and the child is euthyroid, growth hormone assessment and replacement may be required.
•
Monitoring of bone mineral density (BMD) using DXA is useful to give an idea of fracture risk. Several factors affect the reading: age, growth status,
Apollo Medicine, Vol. 6, No. 4, December 2009
356
3. Marwaha RK, Tandon N, Reddy D, et al. Vitamin D and bone mineral density status of healthy school children in northern India. Am J Clin Nutr 2005; 82 (2): 477-482. 4. Morabito N, Gaudio A, Lasco A, et al. Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle. J Bone Mineral Res 2004; 19:722-727. 5. Voskaridou E, Terpos E. Pathogenesis and management of osteoporosis in thalassemia. Pediatric endocrinology reviews 2008; 6 (Suppl 1): 86-93. 6. Christoforidis A, Kazantzidou E, Tsatra I, et al. Normal lumbar bone mineral density in optimally treated children and young adolescents with E-thalassaemia major. Hormones 2007; 6(4):334-340. 7. Wood JC, Claster S, Carson S, et al. Vitamin D deficiency, cardiac iron and cardiac function in thalassemia major. Br J Hematol 2008; 141(6):891-894. 8. Gaudio A, Morabito N, Xourafa A, et al. Bisphosphonates in the treatment of thalassemia-associated osteoporosis. J Endocrinol Invest.2008; 31(2):181-184. 9. Mamtani M, Kulkarni H. Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a metaanalysis and systematic review. Osteoporos Int. 2009.
BONE HEALTH ISSUES IN THALASSEMIA Anju Virmani and A Mahajan Senior Consultant, Apollo Centre for Advanced Pediatrics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Correspondence to: Dr Anju Virmani, Senior Consultant, Pediatric Endocrinology, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India. Advances in the management of thalassemia have led to marked improvements in the life span and quality of life of children and young adults. This poses new challenges for the treating physicians. There is now increasing recognition that thalassemics have impaired bone health which is multifactorial in etiology. This paper aims to highlight the factors that predispose these patients to osteoporosis and suggests measures to minimise the impact on bone health. Key words: Thalassemia, Osteopenia, Osteoporosis.
Till a few decades ago, thalassemic patients had severe bone deformities due to marrow expansion, but did not survive long enough to have problems of adolescence and young adulthood. Now with optimal transfusions and chelation, survival and quality of life have improved dramatically. At the same time, regular blood transfusions and the consequent iron deposition in various endocrine glands can potentially cause several endocrinopathies with increasing age. Issues like growth, hypogonadism and compromised bone health, with increased fracture risk, are therefore, becoming more important [1,2]. This is particularly crucial in the Indian context, where deficiency of Vitamin D and calcium, low exercise levels, rickets and osteomalacia, and osteoporosis are already prevalent in the general population [3]. It is now well accepted that nearly half of the total bone density accrual occurs during childhood and adolescence. The peak bone density attained in adolescence largely determines fracture risk. Hypogonadism, and consequent cytokine abnormalities, are well known to cause low bone density in any condition, and play a major role in causing poor bone health in thalassemia [4]. Therefore pediatricians must ensure that the impact of factors affecting bone accrual is minimized [5]. The young thalassemic today no longer has the deformed bones of earlier generations, but continues to have several factors which contribute to poor bone health (Table 1). These factors need to be addressed aggressively from an early age if bone density is to be improved. Furthermore, it has been shown that regular screening and proper management of possible endocrine complications can possibly secure normal bone health in these patients [6]. 355
This results in a variety of bone problems: bone pain and/ or deformity, frank rickets or osteomalacia, osteopenia, osteoporosis, pathological fractures, and occasionally spinal deformities and nerve compression. Fracture risk is of course related to bone strength, but also to muscle size, function and activity levels. Attention must be paid to improving bone and muscle health in order to minimize fracture risk and other adverse consequences. Thalassemics have been found to have low levels of Vitamin D, which is linked not only to bone health, but also decreased cardiac function, muscle weakness, glucose insensitivity, and refractory congestive heart failure [7]. Both for the families as well as the treating physicians, understandably, the major focus is on achieving optimal transfusion and chelation. As a consequence, other important facets of care are often ignored. A number of measures can go a long way in minimising the adverse impact of this disease on bone health. By and large, they are inexpensive and can be easily incorporated in their care. What is required is increased awareness and constant reinforcement to the families regarding these measures. A conscious effort must be made to pay attention to the following: •
To maintain optimal pre-transfusion haemoglobin.
•
Ongoing encouragement to increase the intake of low fat milk products.
•
Annual monitoring phosphorus levels.
•
Regular supplementation of Vitamin D, encouragement to get sun exposure on the bare skin. Vitamin D
of
serum
calcium
and
Apollo Medicine, Vol. 6, No. 4, December 2009
Review Article
ethnicity, etc. In a child whose growth is compromised, interpretation becomes even more difficult. Serial scans annually or every two years are the best way to monitor these patients.
Table 1. Factors adversely affecting bone mass accrual in thalassemics (i)
Chronic anemia, ill health, poor weight bearing
(ii)
Marrow expansion in those poorly transfused
(iii)
Poor calcium intake
(iv)
Reduced Vitamin D levels, worsened by low sun exposure, skin pigmentation and hepatic involvement
(v)
Low levels of exercise
(vi)
Hypoparathyroidism
(vii)
Hypothyroidism
•
(viii) Hypogonadotrophic hypogonadism (ix)
Insufficiency of GH, IGF-1, IGF-BP3, other growth factors
(x)
Direct toxicity of iron, chelators, on the bone
sachets given every 1-3 months are a safe, inexpensive way of maintaining adequate Vitamin D levels.
Bisphosphonate therapy is useful in a subgroup of patients because thalassemia is associated with high bone turnover, with increased resorption and remodelling. Generally, it is reserved for those who have deteriorating bone density in spite of other measures. Over-treatment can actually result in increased brittleness of bone, and increased fracture risk [8,9].
Growth charting, Vitamin D supplementation, encouragement of adequate calcium intake and active exercise, and gonadal hormone replacement at the right age are simple, inexpensive measures which would go a long way in reducing the morbidity and mortality due to poor bone health in thalassemics. REFERENCES
•
Once hypoparathyroidism is suspected, calcitriol should be started in place of cholecalciferol.
•
Monitoring of serum T4 and TSH levels annually after 10 years of age.
1. Vogiatzi MG, Autio KA, Schneider R, Giardina PJ. Low bone mass in prepubertal children with thalassemia major: insights into the pathogenesis of low bone mass in thalassemia. J Pediatr Endocrinol Metab 2004; 17: 14151421.
•
Ongoing encouragement to undertake physical activity, especially weight bearing games like running and jumping.
2. Karimi M, Ghiam AH, Hashiemia A, et al. Bone mineral density in beta-thalassemia major and intermedia. Indian Pediatr 2007; 44(1): 29-32.
•
Regular measurement of height, at least every 6 months, with charting on a growth chart on which the target height (i.e. mid-parental height, which gives the genetic potential) is marked.
•
•
Regular monitoring of the pubertal status from 12 years. Delayed or absent puberty is a major contributor to poor bone accrual and/or increased bone loss, and should be addressed. Secondary gonadal failure can also occur later in life, even after a normal puberty, and may not be detected unless looked for. In case of primary gonadal failure, gonadal replacement therapy should be initiated no later than 14 years; starting with very low doses, and building up gradually. If gonadal failure occurs later in life, HRT in adult doses should be begun promptly.
•
If growth falters and the child is euthyroid, growth hormone assessment and replacement may be required.
•
Monitoring of bone mineral density (BMD) using DXA is useful to give an idea of fracture risk. Several factors affect the reading: age, growth status,
Apollo Medicine, Vol. 6, No. 4, December 2009
356
3. Marwaha RK, Tandon N, Reddy D, et al. Vitamin D and bone mineral density status of healthy school children in northern India. Am J Clin Nutr 2005; 82 (2): 477-482. 4. Morabito N, Gaudio A, Lasco A, et al. Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle. J Bone Mineral Res 2004; 19:722-727. 5. Voskaridou E, Terpos E. Pathogenesis and management of osteoporosis in thalassemia. Pediatric endocrinology reviews 2008; 6 (Suppl 1): 86-93. 6. Christoforidis A, Kazantzidou E, Tsatra I, et al. Normal lumbar bone mineral density in optimally treated children and young adolescents with E-thalassaemia major. Hormones 2007; 6(4):334-340. 7. Wood JC, Claster S, Carson S, et al. Vitamin D deficiency, cardiac iron and cardiac function in thalassemia major. Br J Hematol 2008; 141(6):891-894. 8. Gaudio A, Morabito N, Xourafa A, et al. Bisphosphonates in the treatment of thalassemia-associated osteoporosis. J Endocrinol Invest.2008; 31(2):181-184. 9. Mamtani M, Kulkarni H. Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a metaanalysis and systematic review. Osteoporos Int. 2009.