Introduction

Bone abnormalities are often seen in patients with thalassemia major (TM) and thalassaemia intermedia (TI) and have become a major cause of skeletal complications. These unusual skeletal changes include decreased bone mineral density (BMD), spontaneous fractures and spinal deformities with compression of the vertebrae and nerves often causing severe pain and discomfort (Kyriakou et al., 2008; Toumba & Skordis, 2010; Tzoulis et al., 2014; Voskaridou & Terpos, 2004). Children and adolescents with TM have lower BMD than the healthy population and suboptimal peak bone mass and fracture rates are increased and rise with age (Vogiatzi et al., 2009). TM patients have lower trabecular volumetric BMD, cortical area, cortical thickness, and periosteal circumference compared to controls, and these deficits remain unchanged after adjustment for gender, lean body mass and growth deficits (Fung et al., 2011). It has been suggested that males with TM are more frequently and severely affected from bone disease in contrast to the well-known predominance of females among patients with osteoporosis in the general population (Kyriakou et al., 2008; Wong et al., 2014). It is not clear if there are gender differences in the prevalence and severity of bone disease in TM and the exact mechanisms that may underlie a possible gender variation are not known.

According to the World Health Organization, osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. In osteoporosis, BMD is reduced, and bone microarchitecture is disrupted. BMD is the most commonly used and well-established measure of bone health. Dual Energy X-ray Absorptiometry (DXA), which is a non-invasive technique and can be performed on the hip, lumbar spine, and distal radius, is still the gold standard for the measurement of BMD. Based on DXA findings, osteoporosis is defined as a BMD T-score ≤2.5 leading to higher risk of fracture and osteopenia as a BMD T-score between –1 and –2.5, with normal values of T-score being ≥1.0. T-score is defined as the 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.

As differences in growth and pubertal timing introduce great variability in skeletal mineral mass and density, interpretation of DXA-derived results of BMD in TM patients is challenging. DXA results are strongly influenced by the child’s body size and skeletal maturation; therefore, BMD values must be adjusted for height, bone age, the Tanner stage and bone area. All DXA-derived parameters must be compared with reference data specific to the patient’s age, sex, ethnicity and the measuring equipment. The diagnosis of osteoporosis in children should not be made on the basis of densitometric criteria alone. The presence of at least one vertebral compression fracture is indicative of osteoporosis. In the absence of vertebral compression fractures, the diagnosis of osteoporosis is indicated by the presence of both a clinically significant fracture history and a BMD Z-score <-2.0 (adjusted for age and sex as appropriate) (Bishop et al., 2014).

Short stature is common in adults with TM. Children with TM are shorter than their healthy peers and often have delayed pubertal maturation. Both factors contribute to low BMD values in DXA measurements, and unless properly adjusted for, they lead to over diagnosis of osteoporosis. An additional contributing factor that interferes with BMD readings by DXA in TM is the presence of spinal degenerative skeletal changes, which can be detected only by magnetic resonance imaging (MRI) and most likely interfere with BMD values given by DXA, resulting in false diagnosis of bone disease. Moreover, in high concentrations, iron is radiographically dense; thus, excessive hepatic and cardiac iron stores may lead to potential errors in accurate BMD assessment (Drakonaki et al., 2007).

Peripheral quantitative computed tomography (pQCT) is an alternative bone densitometry technique that is able to assess volumetric BMD at peripheral sites and estimate bone geometry. pQCT has the additional advantage that peripheral sites are assessed, where iron is not accumulated. The radiation dosage to patients is slightly lower than DXA, making it appropriate for use in paediatric populations (Fung et al., 2011).

Pathogenesis

The pathogenesis of bone disease in TM is multifactorial, complicated, and still unclear. Patients with TM display an unbalanced bone turnover with an increased resorption phase and decreased formation phase, resulting in severe bone loss (Voskaridou & Terpos, 2008). Several contributing factors seem to be involved, acting independently or in concert. The primary disease causes bone marrow expansion due to ineffective erythropoiesis, leading to mechanical interruption of bone histology, cortical thinning, increased distortion and, finally, bone fragility (De Sanctis et al., 1998). Direct iron toxicity on bone impairs osteoid maturation and inhibits mineralization. Iron-chelating agents inhibit osteoblast proliferation and collagen formation and promote osteoblast apoptosis (Skordis et al., 2008). Iron chelation with Desferoxamine may induce dysplastic bone changes in the long bones that are associated with short stature and characteristic x-ray appearances. Deferasirox, at therapeutic doses, has been implicated in the increased incidence of hypercalcuria, nephrolithiasis and bone loss since it has been introduced with seemingly dose-dependent effects on hypercalcuria (Wong P 2016).

In addition, genetic factors have been shown to be involved in the pathogenesis (Wonke et al., 1998). One of the most important candidate genes for predisposition to osteoporosis is the collagen type Ia1 gene (COLIA1), which encodes type I collagen, the major protein of bone. The polymorphism at the Sp1 site of COLIA 1 has been associated with severe osteoporosis and pathological fractures of the spine and hip in TM patients in addition to the effects of the vitamin D receptor gene (VDR) polymorphisms (Voskaridou & Terpos, 2008).

Failure to progress normally through puberty is associated with failure of adequate bone mineralization and achievement of peak bone mass (Bielinski et al., 2003). In TM patients, BMD, which is already low in childhood, decreases further during and after puberty, especially in patients with absent or delayed puberty. Association between hypogonadotropic hypogonadism and osteoporosis in adult patients with TM is clearly documented (Skordis et al., 2006; Tzoulis et al., 2014). The contribution of other than sex steroid hormones on the acquisition and maintenance of bone mass is well known. BMD at the lumbar spine is lower in adult patients with growth hormone/insulin-like growth factor 1 (GH/IGF-I) deficiency, suggesting that GH/IGF-I deficiency plays an important role in the multifactorial aetiology of bone disease (Soliman et al., 2014). Additional aetiological factors include parathyroid gland dysfunction, impaired calcium homeostasis, nutritional deficiencies, hypothyroidism, diabetes mellitus, chronic hepatitis and liver disease and the lack of physical activity (Skordis et al., 2008; Voskaridou & Terpos, 2004).

Vitamin D deficiency or insufficiency may start early in TM patients, and its prevalence increases after the first decade and remains, despite vitamin D supplementation (Tzoulis et al.,2014), contributing to bone disease. Potential explanations of the high prevalence of low vitamin D are impaired 25-hydroxylation of vitamin D due to liver haemosiderosis, intestinal malabsorption of vitamin D, lack of sun exposure and impaired synthesis of vitamin D by the skin because of jaundice. However, the prevalence of vitamin D deficiency in patients with TM and the extent of its contribution to bone disease are still under debate. Severe vitamin D deficiency, defined by a vitamin D level less than 25nmol/L with accompanying elevated parathyroid hormone (PTH) and alkaline phosphatase, is rare but can cause osteomalacia (adults) and rickets (children) which in turn may increase the risk of fracture. Optimising vitamin D and calcium through diet +/- supplements is recommended, as a modifiable risk factor, in both osteoporosis and before treatment with bisphosphonate.

Bone Markers

Patients with TM and osteoporosis have elevated biochemical markers of bone resorption, such as the N-terminal or C-terminal cross-linking telopeptide of collagen type-I (NTX or CTX, respectively) and tartrate-resistant acid phosphatase type5b (TRACP-5b) that correlate with BMD of the lumbar spine in these patients (Voskaridou, 2001). This increased osteoclast activity seems to be at least partially due to an imbalance in the receptor–activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) system (Morabito et al., 2004), which is of great importance for the activation and proliferation of osteoclast precursors. The ratio of RANKL/OPG is increased in patients with TM and osteopenia/osteoporosis, suggesting their involvement in the pathogenesis of bone loss.

There is also evidence of reduced osteoblast function in TM mainly due to iron poisoning in osteoblasts and/or the result of reduced function of the GH/IGF-1axis. Wnt signaling inhibitors dickkopf-1 (Dkk-1) and sclerostin, which block osteoblast differentiation and function, are increased in the serum of TM patients with osteoporosis and inversely correlate with BMD (Voskaridou et al., 2012, 2009). Wnt inhibition seems to be a major pathway implicated in bone loss in TM.

Biochemical markers of bone metabolism that can be used in patients with TM include:

Medical treatment

Bisphosphonates (BPs) are the medications that have been used for the treatment of osteoporosis in thalassaemia in an attempt to increase BMD and alleviate symptomatology. Almost all generations of bisphosphonates have been used in various studies. Bisphosphonates inhibit osteoclastic bone resorption, by inhibiting osteoclastic recruitment and maturation, therefore preventing further bone destruction. Most of the studies did not include any control group; therefore, the results should be interpreted cautiously. The main outcomes of the studies were increase in BMD, normalization of bone markers, improve quality of life, and a decrease in the incidence of fractures. The safety of the medication was also taken into consideration. Current evidence supports the use of BPs in patients with TM-associated osteoporosis to prevent bone loss and/or to improve BMD in those with established osteoporosis.

The BPs that have been used in randomized controlled studies (Dede & Callan, 2018; Giusti, 2014; Bhardwaj et al., 2016) are:

1. Oral aledronate 10 mg/day
2. IV zoledronic acid 4 mg every 3 months
3. IV neridronate 100 mg every 6 months
4. IV pamidronate 30 mg every month

Oral administration of alendronate normalizes the rate of bone turnover and results in a rise in BMD of the spine and the hip. Pamidronate results in a significant improvement in BMD in most patients, a clear decrease of markers of bone resorption (NTX and TRAP-5b) and significant reduction of pain (Voskaridou et al., 2003). Neridronate was also associated with reduction of bone resorption, increase of BMD, reduction of back pain and improved quality of life (Forni et al., 2012). Zoledronic acid is the most potent third generation bisphosphonate to-date and has been found to be extremely efficacious in increasing BMD in TM patients (Voskaridou et al., 2006). Zoledronic acid continues to act for one more year after its discontinuation. All bisphosphonates have to be given in higher doses in TM patients with osteoporosis than the dose used in post-menopausal osteoporosis in order to produce similar effects, due to the complex aetiology of TM-associated osteoporosis.

Although there is no consensus it is recommended that the use of bisphosphonates should not exceed a period of 24 to 36 months. Patients on BPs should receive in addition to vitamin D, elemental calcium supplementation at a dose 200–1000 mg daily and they need periodical measurement of urine calcium excretion to avoid hypercalciuria that may predispose to nephrolithiasis. Patients who receive BPs are monitored for improvement of their symptoms and increase in the BMD findings based on DXA scans. A suggested treatment schedule would include Zoledronate (0.05mg/kg 6 monthly) whilst there is remaining growth potential, and the BMD remains outwith what is normal for population (lumbar spine or total body BMD <-2.0 SDS).

Further research is warranted however to establish the efficacy of medications on fracture prevention, the safety and efficacy of long-term therapy the drug free periods and the optimal duration of treatment. In addition, more trials must be conducted to clarify the exact role of each bisphosphonate, their exact dosage and their long-term benefit as well as the effects of the combination of bisphosphonates with other effective agents in TM-induced osteoporosis. Hypercalcuria is common in TM, reported up to 50%, thought to be a consequence of iron chelation, and is part of recommended annual monitoring. Bisphosphonates, in all children, have been shown to decrease 24hr urinary excretion of calcium through reduction in bone resorption and therefore may reduce the incidence of hypercalcuria in TM. To avoid problems of interpretation of urinary calcium relative to the timing of bisphosphonate dose we would recommend performing measurements immediately pre-dose.

Other novel agents that could be effective in TM associated bone disease include: teriparatide, a recombinant peptide fragment of parathyroid hormone; strontium ranelate, a second anabolic agent that seems to prevent osteoporotic fractures in postmenopausal women; and Denosunab, which is an antibody against RANKL. In a randomized, placebo-controlled, double-blind study Denosunab increased lumbar spine and wrist bone mineral density and reduced pain and bone remodeling markers, hence being another valuable option for the management of osteoporosis in TM (Voskaridou et al., 2018).

Prevention should undoubtedly be the first step in the management of bone disease in TM. Induction of puberty at a proper age and management of hypogonadism are very important steps. However, there is conflicting evidence for the clinical effectiveness of hormone replacement therapy (HRT) in maximizing bone mass in TM patients (Voskaridou et al., 2001). Effective iron chelation, improvement of haemoglobin levels, calcium and vitamin D supplementation, physical activity and smoking cessation are the main preventative measures. During the last two decades, new evidence has suggested that the reduced osteoblastic activity, which is believed to be the basic mechanism of bone loss in TM, is accompanied by a comparable increase in bone resorption. The presence of unbalanced bone turnover with an increased resorption phase has justified the use of bisphosphonates, aiming in preventing further loss of BMD. Combined therapy with bisphosphonate and HRT has also been used with encouraging results (Terpos & Voskaridou, 2010).

Osteonecrosis of the jaw (ONJ) and atypical fractures are rare, no documented case of ONJ in childhood, and are primarily related to the duration of bisphosphonate treatment. There is no evidence of any one bisphosphonate that is more likely to be implicated in either aetiology. Additional risk factors for ONJ in adults include age, the use of concomitant medication that affect bone turnover, underlying medical conditions and history of recent dental procedures.

Figure 1

Normal and osteoporotic bone morphology.

Figure 2

Classification of bone disease based on BMD measurements.

Figure 3

Interpretation of DXA findings.

Box

Summary and Recommendations.

References

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