1. Introduction
Despite its inert appearance, bone is a dynamic tissue that is continuously resorbed by osteoclasts and neoformed by osteoblasts. The bone remodeling, which is a highly complex process, is under the control of local and systemic factors that all together contribute to bone homeostasis. Besides osteoclasts and osteoblasts, it has been demonstrated that osteocytes, which comprise 90–95% of the total bone cells, play a key role during the bone remodeling cycle [ 1 ]. Osteocytes act as orchestrators producing factors, such as RANKL and sclerostin, that influence osteoclast and osteoblast activities [ 2 ]. In the last decade, numerous studies have supported the role of some factors released by osteocytes in the pathogenesis of metabolic bone diseases [ 3 ], but also of rheumatological [ 4 ] and systemic diseases [ 5 , 6 ].
Osteoporosis is a common skeletal disorder characterized by compromised bone strength that predisposes patients to an increased risk of fracture [ 7 ]. A thorough search for underlying causes of the disease reveals that up to 30% of post-menopausal women and between 50 and 80% of men suffer from diseases or have factors contributing to osteoporosis [ 8 , 9 ]. Among the secondary forms of osteoporosis, hematological diseases play a very important role. It seems logical to think that, given the close relationships between bone and bone marrow, alterations in the latter can also have a significant impact on bone health. Studies conducted in animal models showed that bone cells interact with hematopoietic cells, providing a supportive microenvironment needed to maintain erythropoiesis and myelopoiesis [ 10 ]. Nevertheless, the effects of hematological diseases on bone are not only caused by the close interconnections between bone marrow cells and bone but are also due to a whole series of circulating factors, such as cytokines, that can alter bone turnover, increasing the activity of osteoclasts and/or reducing the action of osteoblasts. There is mounting evidence that anemia per se, that characterizes several hematological diseases, may also be associated with bone fragility [ 10 ]. Among the hypothesized mechanisms of this association, hypoxia seems to play an important role. In fact, hypoxia is a potent stimulator of erythropoietin production that stimulates osteoclast precursors and induces bone loss [ 11 ]. Iron deficiency, which is observed in chronic blood loss, may also affect bone health. Iron, in fact, is an essential cofactor for hydroxylation of prolyl and lysil residues of procollagen and participates in vitamin D metabolism through the cytochromes P450 [ 12 ]. Finally, bone tissue can be affected by systemic complications related to hematological diseases [ 9 ]. Among these pathological conditions, those for which we have more scientific evidence to support a negative effect on bone health are monoclonal gammopathies of undetermined significance and multiple myeloma, systemic mastocytosis, thalassemia major, sickle cell disease, and hemophilia.
2. Data Source and Search
A literature search strategy was developed by an experienced team of specialists by consulting the MEDLINE platform. The literature search performed included published papers and reviews updated to December 2019. The search strategy used a combination of controlled key words (e.g., “monoclonal gammopathies of undetermined significance”, “multiple myeloma”, “systemic mastocytosis”, “thalassemia major”, “sickle cell disease”, “hemophilia”, “osteoporosis”, “bone metabolism”, and “fracture”). The search results were limited to papers published in English.
3. Monoclonal Gammopathy of Undetermined Significance
Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by increased production of an abnormal monoclonal paraprotein of which serum levels are less than 30 g/L, infiltration of the bone marrow by a clonal population of plasma cells less than 10% but without any evidence of end-organ involvement. MGUS is a common condition especially in the elderly, and the risk of progression to multiple myeloma is approximately 1% per year [ 13 ].
3.1. Bone Involvement
Among its different recognized complications, MGUS appears to also be associated with bone health outcomes. In fact, MGUS patients have neither lytic lesions in the bone nor hypercalcemia, but they present a greater risk of developing osteoporosis and vertebral and hip fractures [ 14 , 15 , 16 , 17 ]. One study described that 53.8% of patients with MGUS were osteopenic and 26.2% had osteoporosis, and those with lower bone mineral density were more likely to have had vertebral fractures. Fracture risk in these patients does not depend on the immunoglobulin class of MGUS nor on the concentration of paraprotein, suggesting that all patients with MGUS have an increased risk of fracture [ 18 ]. Studies employing high-resolution peripheral quantitative computed tomography measurement of radium showed an increase in bone size with greater cortical porosity and reduced cortical and trabecular thickness and, therefore, reduced bone strength [ 19 , 20 ]. In addition, other studies have highlighted the presence of high levels of bone markers (osteocalcin, alkaline phosphatase, and others) in patients with MGUS, indicating abnormal bone turnover [ 21 , 22 ]. In a study conducted by Thorsteinsdottir et al. [ 23 ], the risk of fractures was not significantly increased in individuals with MGUS (HR, 1.19; 95% CI, 0.94–1.50), but when patients were divided according to gender, men with MGUS had a significantly increased risk of fractures, compared with those men without MGUS (HR, 1.49; 95% CI, 1.03–2.08). No increased risk of fractures was found in women with MGUS compared with those without MGUS (HR, 1.02; 95% CI, 0.74–1.40). The reasons for this increased risk of fractures, especially in male subjects with MGUS, are yet to be elucidated. However, MGUS seems to be associated with uncoupling of bone turnover, with increased bone resorption and reduced bone formation due to a higher production of proinflammatory and bone resorptive cytokines [ 24 ]; moreover, female sex hormones could possibly play a protective role.
3.2. Treatment
Patients affected by MGUS might benefit from therapy to prevent osteoporosis and fractures. The use of bisphosphonates (alendronate or zoledronate) in MGUS patients is effective in improving bone mineral density (BMD), but there is no clear evidence for a reduction of skeletal fracture risk [ 25 , 26 ]. In these subjects, calcium, and vitamin D supplementation is mandatory. It is important to monitor serum calcium levels, because the progression of MGUS to multiple myeloma, although rare, may occur [ 27 ].
4. Multiple Myeloma
Multiple myeloma (MM) is a frequent hematological malignancy in the elderly with an annual mortality rate of 4.1/100,000 [ 28 ]. It is characterized by infiltration of the bone marrow by clonally transformed plasma cells (≥10%) and the subsequent production of monoclonal proteins in the blood and/or urine also accompanied by organ damage. Active myeloma is defined by the presence of one or more of the CRAB criteria: serum calcium elevation (calcium >11 mg/dL), renal dysfunction (creatinine >2 mg/dL), anemia (hemoglobin <10 mg/dL), and bone disease (one or more osteolytic lesions) [ 29 ]. In the absence of CRAB features, one or more of the following conditions is required: clonal bone marrow plasma cell percentage ≥60%, serum free light chain ratio ≥100 and ≥1 focal lesions on magnetic resonance studies. Premalignant stages of MM, including MGUS and smoldering myeloma, lack these symptoms and signs [ 29 ].
4.1. Bone Involvement
Bone disease often occurs during MM. It can cause osteolytic lesions and osteopenia or osteoporosis in about 80% of cases. The most affected skeletal site is the axial skeleton, in particular the vertebral bodies (49%), skull (35%), pelvis (34%), and ribs (33% of patients) [ 30 ]. The development of osteolytic bone disease is one of the most important features that typically correlates with progression of the disease from a premalignant state into active MM [ 31 ]. Bone disease in myeloma (MBD) can lead to serious complications such as fractures, spinal cord compression, and hypercalcemia, resulting in reduced quality of life due to severe pain, psychological disorders, loss of autonomy, and a significant increase in mortality [ 30 , 32 ].
The pathogenesis of lytic lesions and progressive bone mass loss in multiple myeloma is due to the imbalance of bone remodeling, determined by the activation of osteoclastogenesis and the simultaneous inhibition of osteoblastogenesis including the increase in osteocyte apoptosis. MM cells interfere with physiologic bone remodeling by secreting different cytokines such as receptor activator of NF-κ B ligand (RANKL), interleukin (IL)-1, IL-6, and chemokine C–C motif ligand 3 (CCL3) that promote osteoclast proliferation and activity. MM cells can also upregulate the osteoblast inhibitors dickkopf-1 (DKK1) and sclerostin, thereby inhibiting osteoblastogenesis [ 33 , 34 , 35 , 36 , 37 ]. Moreover, MM can determine the deregulation of the bone compartment, creating a permissive microenvironment for MM cell expansion [ 38 ]. To date, it is known that bone marrow stromal cells (BMSCs) can interact with MM cells via adhesion molecules, thus promoting MM cell retention within the bone marrow and contributing to increased osteolytic bone lesions [ 39 ]. Both MM and BMSCs cells, apart from the above-mentioned cytokines, can also secrete other factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1), TGF-β, angiopoietin-1 (Ang-1), platelet-derived growth factor (PDGF), and basic-fibroblast growth factor (bFGF) [ 40 , 41 ], which have been seen to be associated with increased angiogenesis, osteoclastogenesis, and tumor growth in MM [ 42 ]. Additionally, mesenchymal stem cells in MM patients with advanced bone disease have been found to produce activin A, possibly due to an intrinsic genetic defect in BMSCs of these patients. Activin A is an osteoclast-activating factor and an inhibitor of osteoblast differentiation. In MM patients, a correlation between elevated serum levels of activin A and lytic bone lesions has been found ( Figure 1 ) [ 43 , 44 ].
4.2. Treatment
MBD treatment aims to reduce the complications and occurrence of related skeletal events (SRE). The use of bisphosphonates, known anticatabolic agents, especially pamidronate and zoledronic acid, given monthly intravenously, is recommended in all patients with symptomatic MM in order to prevent pathological vertebral fractures or other SREs and relieve pain due to bone disease [ 45 , 46 ]. Moreover, bisphosphonates may also have anti-tumor and immunomodulatory activity [ 47 ], and clearly they can be used to treat osteoporosis in low- and intermediate-risk asymptomatic MM. A recent meta-analysis found no evidence of superiority of any specific bisphosphonate (amino or non-amino) for any outcome. However, zoledronate was found to be better than placebo and etidronate for improving overall survival and reducing vertebral fractures [ 48 ], and it has been seen to be more effective than pamidronate for the treatment of hypercalcemia of malignancy [ 49 ]. Denosumab, a human anti-RANKL monoclonal antibody, given subcutaneously, has also proven to be an effective treatment strategy in MM. It binds with high affinity and specificity to RANKL and inhibits bone resorption [ 50 ]. The efficacy of denosumab compared to zoledronate was evaluated in a large, randomized clinical trial that showed no difference between the two types of treatment [ 51 ]. Unlike zoledronate, denosumab can be administered in patients with impaired renal function, which is very important given that kidney dysfunction is common in MM and often represents a limit to the use of bisphosphonates. However, there are no recommendations regarding treatment duration, while caution is advised in case of interruption, since denosumab has a rebound effect [ 52 ].
New anti-cancer therapeutic agents for MM that also have effects on bone metabolism are proteasome inhibitors, such as bortezomib and carfilzomib, and Wnt system modulators like DKK1 and sclerostin antagonists. In the first group, bortezomib, by inhibiting the proteasome, stimulates the activity and number of osteoblasts with a consequent increase in bone formation and simultaneously inhibits osteoclastogenesis and osteoclast bone resorption activity [ 53 , 54 ]. In addition, bortezomib partially inhibits osteocyte autophagy and apoptosis induced by MM and consequently increases the number of viable osteocytes [ 54 ]. Other possible therapeutic options include BHQ880 and romosozumab. The first one is an anti-DKK1 IgG1 antibody, which stimulates osteoblast differentiation and inhibits myeloma cell growth via alteration of the bone marrow microenvironment [ 55 , 56 ]. BHQ880 in combination with zoledronate and anti-myeloma treatments was well-tolerated and increased bone mineral density in patients with relapsing or refractory MM [ 57 ]. Romosozumab, on the other hand, is a humanized anti-sclerostin monoclonal antibody, which has been seen to be useful, in preclinical studies in MM, in preventing the development of MBD in the early stages of the disease and in reducing osteolysis by increasing bone mass in advanced MM [ 58 , 59 ]. Since sclerostin inhibition does not have significant antitumor activity, combination strategies can be essential to achieve anti-MM and bone-protective effects.
Since sclerostin is produced by osteocytes, romosozumab may be a more effective therapeutic strategy. On the contrary, as DKK1 is mainly produced in MM by malignant plasma cells and not all patients express it, there could be individual differences in response to anti-DKK1 therapies [ 33 ].
Ongoing research primarily revolves around agents that stimulate bone formation by restoring balanced bone turnover, thus improving BMD, slowing down disease progression and restoring bone damage.
5. Systemic Mastocytosis
Systemic mastocytosis (SM) is a hematological disease characterized by neoplastic proliferation of abnormal mast cells and their accumulation in various organs other than skin (bone marrow, bones, spleen, lymph nodes, and the gastrointestinal tract) [ 60 ]. It represents the most aggressive form of mastocytosis, mainly affecting adult subjects, and it may be associated with multiorgan dysfunction and reduced survival [ 61 ], whereas cutaneous mastocytosis is more frequent in children and consists of skin-limited disease without systemic involvement and a good prognosis [ 62 ]. In most cases, SM is caused by a mutation in the gene that codes for the KIT receptor, a transmembrane receptor with tyrosine-kinase activity expressed by mast cells. The interaction between KIT and its ligand, stem cell factor (SCF), plays an important role in the regulation of proliferation, maturation, adhesion, chemotaxis, and survival of mast cells [ 63 ]. The WHO classification [ 60 ] includes SM between chronic myeloproliferative neoplasms and describes various forms with a heterogeneous clinical presentation and prognosis. To make the diagnosis of SM, a major criterion and one minor criterion, or three minor criteria must be satisfied ( Table 1 ). In the diagnosis of SM, the measurement of serum tryptase appears to be a good screening tool, though bone marrow biopsy should be considered if there is suspicion of false positives and in patients with normal serum tryptase if there are other clinical signs that suggest SM. Among clinical manifestations, anaphylaxis is the most severe and can be triggered by physical stimuli, emotional factors, drugs, alcohol, surgery, and others [ 60 ].
5.1. Bone Involvement
In adults, SM frequently causes bone involvement: osteopenia and/or osteoporosis, bone fractures, osteolytic and/or sclerotic lesions, and diffuse osteosclerosis. In recent years, numerous epidemiological studies have been published on bone involvement in SM [ 64 , 65 , 66 ]. Many of these included elderly patients, which could be a confounding factor of the prevalence estimate. Others, instead considering only the clinically apparent fractures, underestimate the results. However, most studies have shown that osteoporosis is the most frequent bone abnormality in patients with SM, and its prevalence varies from 10 to 38% [ 67 ]. The data on vertebral fractures are significantly more prevalent in men than in women (20 vs. 14%) [ 64 ]. Another bone alteration that can occur in SM is local or diffuse osteosclerosis, which has a prevalence ranging from 5.3 to 10% [ 67 ]. Its prevalence is probably underestimated due to the absence of symptoms and the need for skeletal X-rays to make a diagnosis. Furthermore, in SM patients, focal osteosclerotic and osteolytic bone lesions can often coexist [ 67 ]. In these patients a higher bone turnover has been found in both osteoporosis and osteosclerosis [ 68 ]; therefore, fractures can be associated with both of these disorders. In addition, the level of tryptase may predict mast cell mass and simultaneously best correlate to higher bone density; however, this high bone density does not protect against fracture in SM patients [ 69 ].
The reduction in bone mass mainly concerns trabecular rather than cortical bone, as demonstrated by the greater prevalence of osteoporosis and vertebral fractures relative to non-vertebral ones. This appears to be due to the infiltration of mast cells in the bone marrow and the local release of mediators like histamine, heparin, tryptase, tumor necrosis factor, IL-1, IL-17, and IL-6, with effects both on osteoblasts and osteoclasts [ 70 , 71 , 72 ]. Once produced by mast cells, histamine, for example, is capable of increasing bone resorption, both directly by stimulating the differentiation and activation of osteoclasts and their precursors and indirectly by increasing the expression of RANKL in osteoblasts [ 73 ].
The bone pathophysiology in SM is very complex, and the factors that determine a low BMD rather than a form of osteosclerosis or both are still poorly understood. However elevated bone levels of both RANKL and osteoprotegerin (OPG) have been found in mastocytosis [ 74 , 75 ]. It is thought that tryptase produced by mastocytes could activate osteoblasts and increase the production of OPG, thereby increasing bone turnover and formation. For this reason, interferon α, which would be able to reduce inflammation and consequently the secretion of tryptase, could also be used to treat osteoporosis in mastocytosis as a complementary therapy to bisphosphonates [ 76 ]. On the other hand, in a study conducted by Rossini et al. [ 74 ], the authors found that patients with mastocytosis had elevated serum DKK1 levels when compared with controls, which correlated positively with CTX levels and increased bone resorption, while Rabenhorst highlighted elevated sclerostin levels in patients with mastocytosis and bone disease [ 75 ]. It is therefore reasonable to think that the RANK/RANKL/OPG system and the Wnt-signaling pathway are involved in the pathogenesis and prevalence of one with respect to the other, determining the phenotypic alteration of bone manifestations [ 67 , 77 ].
5.2. Treatment
The therapeutic approach to mastocytosis and osteoporosis is based on the integration of vitamin D and the use of antiresorptive drugs such as bisphosphonates. Bisphosphonates, both oral and parenteral, have a positive effect on the lumbar spine BMD but much less on the femoral one [ 78 , 79 ].
The infusion of zoledronate 5 mg once a year resulted in an average increase in lumbar and femoral BMD [ 80 ]. Alpha interferon therapy administered in combination with bisphosphonates has been shown to improve bone density, reduce pain, and prevent further fractures [ 76 ]. Perhaps the reduction of inflammation could lead to stability or even to the improvement of bone disease.
Since mast cells have been found to produce RANKL [ 75 , 81 ], the monoclonal anti-RANKL antibody denosumab could be used in patients’ refractory or intolerant to bisphosphonates with positive results for BMD [ 82 ]. On the contrary, teriparatide being an anabolic agent indicates some safety problems due to possible growth and proliferation of abnormal mast cells and possible induction of more aggressive forms of SM. For these reasons, its use is not recommended in mastocytosis. More longitudinal data are needed for a better understanding of the evolution of bone involvement and the impact of treatments in SM.
6. Thalassemia Major
Thalassemia major (TM) is a hereditary blood disorder characterized by decreased hemoglobin production caused by defective globin synthesis. Common symptoms of the disease are anemia, splenomegaly, and cranial and facial bone enlargement. These bone deformities are due to marked expansion of the bone marrow secondary to anemia and ineffective erythropoiesis [ 83 , 84 ].
6.1. Bone Involvement
Nevertheless, along with the improvement of transfusion and chelating regimens, thalassemic patients are frequently affected by osteoporosis and osteopenia [ 85 , 86 , 87 ]. The prevalence of fractures in TM patients ranges from 16 to 49%, depending on the study population and method of data collection [ 88 , 89 , 90 ]. Vertebral fractures are usually asymptomatic and underestimated, and their prevalence varies from 2.6 to 13% [ 91 , 92 ].
The pathogenesis of bone loss in TM is not yet fully clarified [ 87 ]. Multiple factors can play a role in bone involvement in these patients: bone marrow expansion, hypogonadism, altered pattern of cytokines, deficit GH-IGF-1, iron bone deposit, deferoxamine bone toxicity, genetic background, and vitamin D deficiency [ 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 ]. All of these pathogenic factors can cause impaired bone turnover, directly and/or indirectly, depressing bone formation and increasing bone resorption ( Figure 2 ).
The mechanism responsible for osteoclast activation in thalassemic patients could be related to the altered cytokine network and in particular to alteration of the RANK/RANKL/OPG system, as we observed in our previous study [ 101 ]. Recently, the Wnt pathway has been proposed to participate in the pathogenesis of osteoporosis in TM, and negative modulators of this signaling system, such as DKK-1 and sclerostin, have been also associated with BMD in TM patients [ 102 ]. One of the most important factors determining bone destruction in thalassemic patients is represented by bone marrow expansion. In fact, ineffective erythropoiesis despite current regular transfusion regimens is only partially suppressed in these patients. Nowadays, it is known that bone loss in TM largely involves the trabecular bone, and this fact could be due to the close interaction between bone marrow and bone remodeling. Therefore, in TM patients, the most affected site is the lumbar spine due to its constitution of mainly trabecular bone [ 87 ].
6.2. Treatment
The management of TM to date based on appropriate transfusion and chelating regimens has been successful in extending life expectancy, decreasing comorbidities and improving quality of life.
Chelation therapy is used in order to prevent iron overload in organs like the liver, heart, and endocrine glands [ 103 ]. For many years, deferoxamine has been used subcutaneously to treat iron overload, but since its chelating action is not entirely specific for iron, new oral chelating agents have been developed. In addition, hormone replacement therapy can be used to correct hypogonadism since it causes severe bone mass loss in patients with TM [ 104 , 105 ]. Bone marrow transplantation seems to be a very promising option [ 106 ]. Regarding TM-related osteoporosis, it is important to ensure that patients have an adequate intake of calcium, vitamin D in particular, and regular physical activity [ 107 ]. There are some experiences with different bisphosphonate regimens (clodronate, alendronate, zoledronate, and neridronate), followed in general by an increase in BMD, in particular zoledronate, but without evidence of a fracture rate reduction [ 108 , 109 ].
More recently, Voskaridou et al. [ 110 ] observed that Denosumab 60 mg every 6 months, administered subcutaneously in a group of transfusion-dependent thalassemic patients, determined a significant increase in lumbar BMD compared to placebo, with a reduction of bone resorption markers and pain scores, but did not modify femoral BMD. Regarding other therapies, there is limited evidence of a partial effect of strontium ranelate and teriparatide on vertebral BMD [ 111 , 112 ].
7. Sickle Cell Disease
Sickle cell disease (SCD) is an inherited blood disorder caused by a single amino acid substitution in the β-globin chain that results in the production of the characteristic Hemoglobin S (HbS). When HbS is deoxygenated, red blood cells are deformed, assuming the typical sickle shape from which the name of the disease derives. SCD is the most important blood disorder over the world for prevalence and social impact, affecting about 300,000 new-borns every year, especially in Sub-Saharan African regions [ 113 ].
7.1. Bone Involvement
The prevalence of osteopenia and osteoporosis in young adults with SCD is extremely high and exceeded 60% in several studies [ 114 , 115 ]. The most affected sites are: the lumbar spine (55%), the radius (30%), and the femoral neck (15%) [ 115 ].
Bone loss in SCS depends on different factors: growth retardation, delayed puberty, vitamin D insufficiency, low physical activity, malnutrition, and release of inflammatory cytokines [ 116 ].
It is also possible to observe high-BMD values in SCD patients, especially in those with the S/beta-thalassemia genotypes [ 117 ]. It has been observed that osteosclerosis patients had multiple infarctions in the studied bones, due to vaso-occlusive episodes, that led to reduced osteoclast activity and increased BMD. The RANK/RANKL/OPG system could undoubtedly participate in these processes [ 118 ]. Also, sex steroids, in particular a deficit of estradiol both in male and female subjects, could contribute to the bone damage [ 119 ].
7.2. Treatment
To date, there are no specific studies concerning the treatment of osteoporosis/osteopenia in patients with SCD, but since vitamin D deficiency is very common [ 120 ], supplementation is reasonable as in the general population.
8. Hemophilia
Hemophilia is a rare X-linked inherited bleeding disorder, characterized by a deficiency of coagulation factor (F) VIII (FVIII) (hemophilia A, 85% of cases) or IX (FIX) (hemophilia B) in plasma [ 121 ]. FVIII, also known as anti-hemophiliac factor, plays an essential role in the process of blood clotting. In particular, once active, FVIIIa acts as a necessary cofactor for FIXa, which in the presence of Ca2+ and phospholipids forms a complex that converts FX to its active form, FXa. The latter catalyzes the conversion of prothrombin to thrombin, resulting in clot formation [ 122 ]. For this reason, affected individuals experience uncontrolled bleeding, both spontaneously or after trauma or surgery, which typically occurs into joints (hemarthrosis) and muscles, but any site can be interested [ 123 ]. Although the spectrum of bleeding manifestations can be variable, from superficial ecchymosis to lethal hemorrhage in the central nervous system [ 124 ], the phenotype is primarily determined by the residual amount of the deficient coagulation factor, with severe disease defined as <1%, moderate with 1–5% and mild hemophilia with 6–40% FVIII or FIX [ 122 ]. The current standard of care for the treatment of bleeding episodes and prophylaxis regimens is replacement therapy using plasma derived or recombinant coagulation factor concentrates [ 124 ].
8.1. Bone Involvement
In patients with hemophilia (PWH), low BMD or osteoporosis is frequently observed, although the exact pathogenetic mechanisms are not completely elucidated [ 122 ]. In fact, 27% of PWH have osteoporosis and 43% have low bone density [ 125 ]. Men with hemophilia A and B exhibit a significant reduction in both lumbar spine and hip BMD, which appears to begin in childhood [ 122 ]. The meta-analysis of Iorio et al. [ 126 ] in 2010 confirmed the association between severe hemophilia and low BMD, which is also confirmed by a systematic review and meta-analysis published by Paschou et al. in 2014 [ 121 ].
In recent years, there are data in the literature that demonstrate an increased rate of bone resorption among patients with hemophilia [ 122 ]. The reasons of this negative effect of hemophilia on bone health are numerous. First of all, hemophilic arthropathy caused by spontaneous intra-articular bleeding leads to structural changes of the joints [ 127 ] and the consequent reduction in patients’ physical activity may compromise the acquisition of peak bone mass during childhood and affect BMD in adult life [ 128 ]. Blood-borne virus infections, such as hepatitis C virus (HCV) or human immunodeficiency virus (HIV), are highly prevalent in patients with hemophilia and, since they have been associated with low bone mass, they could provide a second pathophysiologic link [ 125 ]. Furthermore, 25-hydroxyvitamin D concentrations were shown to be independent predictors of low BMD in men with hemophilia A and B [ 129 ]. Over the last few years, some evidence has indicated a novel effect for FVIII outside of the coagulation system. In fact, it may promote bone formation by a thrombin-mediated mitogenic effect on osteoblasts [ 122 ].
8.2. Treatment
Most of the authors do not recommend routine screening in individuals with hemophilia who are <40 years of age in the absence of a low trauma fracture. Patients with HIV, advanced arthropathy, and/or low BMI should be considered for screening DXA [ 130 ]. The only clinical trial for the treatment of low BMD in patients with hemophilia evaluated the effect on BMD of a 12-month-long monthly oral administration of 150 mg Ibandronate, a bisphosphonate, in 10 adults (mean age of 43.5 years) [ 131 ]. In this cohort, ibandronate was well tolerated and led to a 4.7% increase in BMD in the lumbar spine, but not to significant changes in the total hip or femoral neck [ 131 ]. In PWH, prevention of osteoporosis is of fundamental importance and it should include factor replacement therapy administered on a regular basis to prevent bleeding, a diet adequate in calcium and vitamin D, physical exercise, and limitation of tobacco and alcohol use, as well as limitation of the duration of immobilization [ 122 ]. Teriparatide, raloxifene, or bisphosphonates should be avoided to treat osteoporosis in young hemophilics. However, elderly hemophilics may be treated with these drugs, including denosumab [ 132 ].
9. Conclusions
Hematological diseases represent a frequent cause of secondary osteoporosis. The disease may already be known at the time of anamnestic collection or may be diagnosed thanks to the routine laboratory and clinical investigations to which patients are subjected. Investigations commonly conducted to exclude secondary forms of osteoporosis include, among others, a full blood count, erythrocyte sedimentation rate (ESR), and serum or urine protein electrophoresis, which can help to diagnose paraproteinemia or an anemia. Obviously, other second-level examinations (tryptase, hemoglobin electrophoresis, serum immunofixation, bone marrow biopsy, etc.) and a hematological consultation are necessary to complete the diagnosis. Hematological diseases can determine bone involvement due to direct or indirect mechanisms. In general, their final effect is unbalanced bone turnover with increased bone resorption due to high RANKL levels and reduced bone formation caused by inhibition of Wnt-signaling ( Figure 3 ). These patients should undergo a complete bone check-up, with evaluation of calcium phosphate metabolism, bone turnover markers, vitamin D levels, densitometric exams at the lumbar and femoral levels and, in selected patients, a lateral X-ray of the spine for any asymptomatic vertebral fractures. In general, the therapeutic approach of these patients includes calcium and vitamin D supplementation, and some lifestyle changes, such as the reduction of excessive alcohol intake, smoking cessation, and daily physical activity. Most of the data in the literature supports the use of reabsorption inhibitors such as bisphosphonates in these pathological conditions. Recently, there has also been some evidence of beneficial effects of denosumab. Strict cooperation between the hematologist and bone specialist (internist, endocrinologist, rheumatologist, etc.) is critical to prevent bone fractures in hematologic patients and to ensure a good quality of life.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
References
1. Florencio-Silva R. Sasso G.R. Sasso-Cerri E. Simões M.J. Cerri P.S. Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells Biomed. Res. Int. 2015 2015 421746 10.1155/2015/421746 26247020 PMC4515490
2. Neve A. Corrado A. Cantatore F.P. Osteocytes: Central conductors of bone biology in normal and pathological conditions Acta Physiol. 2012 204 317 330 10.1111/j.1748-1716.2011.02385.x 22099166
3. Gaudio A. Pennisi P. Bratengeier C. Torrisi V. Lindner B. Mangiafico R.A. Pulvirenti I. Hawa G. Tringali G. Fiore C.E. Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss J. Clin. Endocrinol. Metab. 2010 95 2248 2253 10.1210/jc.2010-0067 20305005
4. Intemann J. De Gorter D.J.J. Naylor A.J. Dankbar B. Wehmeyer C. Importance of osteocyte-mediated regulation of bone remodelling in inflammatory bone disease Swiss Med. Wkly. 2020 150 20187 10.4414/smw.2020.20187 32031236
5. Gaudio A. Privitera F. Pulvirenti I. Canzonieri E. Rapisarda R. Fiore C.E. Relationships between osteoprotegerin, receptor activator of the nuclear factor kB ligand and serum levels and carotid intima-media thickness in patients with type 2 diabetes mellitus Panminerva Med. 2014 56 221 225 25056244
6. Gaudio A. Fiore V. Rapisarda R. Sidoti M.H. Xourafa A. Catalano A. Tringali G. Zanoli L. Signorelli S.S. Fiore C.E. Sclerostin is a possible candidate marker of arterial stiffness: Results from a cohort study in Catania Mol. Med. Rep. 2017 15 3420 3424 10.3892/mmr.2017.6390 28339088
7. Lorentzon M. Cummings S.R. Osteoporosis: The evolution of a diagnosis J. Intern. Med. 2015 277 650 661 10.1111/joim.12369 25832448
8. NIH Consensus Development Panel on Osteoporosis Prevention D Therapy. Osteoporosis prevention, diagnosis, and therapy JAMA 2001 285 785 795 10.1001/jama.285.6.785 11176917
9. Mirza F. Canalis E. Management of endocrine disease: Secondary osteoporosis: Pathophysiology and management Eur. J. Endocrinol. 2015 173 R131 R151 10.1530/EJE-15-0118 25971649 PMC4534332
10. Valderrábano R.J. Wu J.Y. Bone and blood interactions in human health and disease Bone 2019 119 65 70 10.1016/j.bone.2018.02.019 29476979 PMC11370649
11. Hiram-Bab S. Liron T. Deshet-Unger N. Mittelman M. Gassmann M. Rauner M. Franke K. Wielockx B. Neumann D. Gabet Y. Erythropoietin directly stimulates osteoclast precursors and induces bone loss FASEB J. 2015 29 1890 1900 10.1096/fj.14-259085 25630969
12. Toxqui L. Vaquero M.P. Chronic iron deficiency as an emerging risk factor for osteoporosis: A hypothesis Nutrients 2015 7 2324 2344 10.3390/nu7042324 25849944 PMC4425147
13. Kyle R.A. Durie B.G. Rajkumar S.V. Landgren O. Blade J. Merlini G. Kröger N. Einsele H. Vesole D.H. Dimopoulos M. International Myeloma Working Group. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management Leukemia 2010 24 1121 1127 10.1038/leu.2010.60 20410922 PMC7020664
14. Melton L.J. 3rd Rajkumar S.V. Khosla S. Achenbach S.J. Oberg A.L. Kyle R.A. Fracture risk in monoclonal gammopathy of undetermined significance J. Bone Miner. Res. 2004 19 25 30 10.1359/jbmr.0301212 14753733
15. Bida J.P. Kyle R.A. Therneau T.M. Melton L.J. 3rd Plevak M.F. Larson D.R. Dispenzieri A. Katzmann J.A. Rajkumar S.V. Disease associations with monoclonal gammopathy of undetermined significance: A population-based study of 17,398 patients Mayo Clin. Proc. 2009 84 685 693 10.4065/84.8.685 19648385 PMC2719521
16. Kristinsson S.Y. Tang M. Pfeiffer R.M. Bjorkholm M. Blimark C. Mellqvist U.H. Wahlin A. Turesson I. Landgren O. Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: A population-based study Blood 2010 116 2651 2655 10.1182/blood-2010-04-282848 20610813 PMC3324256
17. Piot J.M. Royer M. Schmidt-Tanguy A. Hoppé E. Gardembas M. Bourrée T. Hunault M. François S. Boyer F. Ifrah N. Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance Blood Cancer J. 2015 5 e345 10.1038/bcj.2015.71 26314987 PMC4558595
18. Pepe J. Petrucci M.T. Nofroni I. Fassino V. Diacinti D. Romagnoli E. Minisola S. Lumbar bone mineral density as the major factor determining increased prevalence of vertebral fractures in monoclonal gammopathy of undetermined significance Br. J. Haematol. 2006 134 485 490 10.1111/j.1365-2141.2006.06217.x 16848794
19. Ng A.C. Khosla S. Charatcharoenwitthaya N. Kumar S.K. Achenbach S.J. Holets M.F. McCready L.K. Melton L.J. 3rd Kyle R.A. Rajkumar S.V. Bone microstructural changes revealed by high-resolution peripheral quantitative computed tomography imaging and elevated DKK1 and MIP-1α levels in patients with MGUS Blood 2011 118 6529 6534 10.1182/blood-2011-04-351437 22042700 PMC3242716
20. Farr J.N. Zhang W. Kumar S.K. Jacques R.M. Ng A.C. McCready L.K. Rajkumar S.V. Drake M.T. Altered cortical microarchitecture in patients with monoclonal gammopathy of undetermined significance Blood 2014 123 647 649 10.1182/blood-2013-05-505776 24227822 PMC3907752
21. Woitge H.W. Horn E. Keck A.V. Auler B. Seibel M.J. Pecherstorfer M. Biochemical markers of bone formation in patients with plasma cell dyscrasias and benign osteoporosis Clin. Chem. 2001 47 686 693 10.1093/clinchem/47.4.686 11274019
22. Laroche M. Attal M. Dromer C. Bone remodelling in monoclonal gammopathies of uncertain significance, symptomatic and non symptomatic myeloma Clin. Rheumatol. 1996 15 347 352 10.1007/BF02230356 8853167
23. Thorsteinsdottir S. Lund S.H. Lindqvist E.K. Thordardottir M. Sigurdsson G. Costello R. Burton D. Steingrimsdottir H. Gudnason V. Eiriksdottir G. Bone disease in monoclonal gammopathy of undetermined significance: Results from a screened population-based study Blood Adv. 2017 21 2790 2798 10.1182/bloodadvances.2017010454 29296931 PMC5745135
24. Veronese N. Luchini C. Solmi M. Sergi G. Manzato E. Stubbs B. Monoclonal gammopathy of undetermined significance and bone health outcomes: A systematic review and exploratory meta-analysis J. Bone Miner. Metab. 2018 36 128 132 10.1007/s00774-017-0817-8 28243796
25. Pepe J. Petrucci M.T. Mascia M.L. Piemonte S. Fassino V. Romagnoli E. Minisola S. The effects of alendronate treatment in osteoporotic patients affected by monoclonal gammopathy of undetermined significance Calcif. Tissue Int. 2008 82 418 426 10.1007/s00223-008-9145-2 18528609
26. Berenson J.R. Yellin O. Boccia R.V. Flam M. Wong S.F. Batuman O. Moezi M.M. Woytowitz D. Duvivier H. Nassir Y. Zoledronic acid markedly improves bone mineral density for patients with monoclonal gammopathy of undetermined significance and bone loss Clin. Cancer Res. 2008 14 6289 6295 10.1158/1078-0432.CCR-08-0666 18829511
27. van de Donk N.W. Palumbo A. Johnsen H.E. Engelhardt M. Gay F. Gregersen H. Hajek R. Kleber M. Ludwig H. Morgan G. The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: Recommendations from the European Myeloma Network Haematologica 2014 99 984 996 10.3324/haematol.2013.100552 24658815 PMC4040895
28. Moreau P. San Miguel J. Sonneveld P. Mateos M.V. Zamagni E. Avet-Loiseau H. Hajek R. Dimopoulos M.A. Ludwig H. Einsele H. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann. Oncol. 2017 28 Suppl. 4 iv52 iv61 10.1093/annonc/mdx096 28453614
29. Rajkumar S.V. Kumar S. Multiple Myeloma: Diagnosis and Treatment Mayo Clin. Proc. 2016 91 101 119 10.1016/j.mayocp.2015.11.007 26763514 PMC5223450
30. Silbermann R. Roodman G.D. Myeloma bone disease: Pathophysiology and management J. Bone Oncol. 2013 2 59 69 10.1016/j.jbo.2013.04.001 26909272 PMC4723362
31. Greipp P.R. San Miguel J. Durie B.G. Crowley J.J. Barlogie B. Bladé J. Boccadoro M. Child J.A. Avet-Loiseau H. Kyle R.A. International staging system for multiple myeloma J. Clin. Oncol. 2005 23 3412 3420 10.1200/JCO.2005.04.242 15809451
32. Zagouri F. Kastritis E. Zomas A. Terpos E. Katodritou E. Symeonidis A. Delimpasi S. Pouli A. Vassilakopoulos T.P. Michalis E. Hypercalcemia remains an adverse prognostic factor for newly diagnosed multiple myeloma patients in the era of novel antimyeloma therapies Eur. J. Haematol. 2017 99 409 414 10.1111/ejh.12923 28675766
33. Vallet S. Filzmoser J.M. Pecherstorfer M. Podar K. Myeloma Bone Disease: Update on Pathogenesis and Novel Treatment Strategies Pharmaceutics 2018 10 202 10.3390/pharmaceutics10040202 30355994 PMC6321035
34. Sezer O. Heider U. Zavrski I. Kühne C.A. Hofbauer L.C. RANK ligand and osteoprotegerin in myeloma bone disease Blood 2003 101 2094 2098 10.1182/blood-2002-09-2684 12424190
35. Giuliani N. Lisignoli G. Colla S. Lazzaretti M. Storti P. Mancini C. Bonomini S. Manferdini C. Codeluppi K. Facchini A. CC-chemokine ligand 20/macrophage inflammatory protein-3α and CC-chemokine receptor 6 are overexpressed in myeloma microenvironment related to osteolytic bone lesions Cancer Res. 2008 68 6840 6850 10.1158/0008-5472.CAN-08-0402 18703490
36. Udagawa N. Takahashi N. Katagiri T. Tamura T. Wada S. Findlay D.M. Martin T.J. Hirota H. Taga T. Kishimoto T. Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors J. Exp. Med. 1995 182 1461 1468 10.1084/jem.182.5.1461 7595216 PMC2192181
37. Spaan I. Raymakers R.A. van de Stolpe A. Peperzak V. Wnt signaling in multiple myeloma: A central player in disease with therapeutic potential J. Hematol. Oncol. 2018 11 67 10.1186/s13045-018-0615-3 29776381 PMC5960217
38. Podar K. Chauhan D. Anderson K.C. Bone marrow microenvironment and the identification of new targets for myeloma therapy Leukemia 2009 23 10 24 10.1038/leu.2008.259 18843284 PMC3418600
39. Michigami T. Shimizu N. Williams P.J. Niewolna M. Dallas S.L. Mundy G.R. Yoneda T. Cell-cell contact between marrow stromal cells and myeloma cells via VCAM-1 and alpha(4)beta(1)-integrin enhances production of osteoclast-stimulating activity Blood 2000 96 1953 1960 10.1182/blood.V96.5.1953 10961900
40. Hideshima T. Podar K. Chauhan D. Anderson K.C. Cytokines and signal transduction Best Pract. Res. Clin. Haematol. 2005 18 509 524 10.1016/j.beha.2005.01.003 16026734
41. Gupta D. Treon S.P. Shima Y. Hideshima T. Podar K. Tai Y.T. Lin B. Lentzsch S. Davies F.E. Chauhan D. Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: Therapeutic applications Leukemia 2001 15 1950 1961 10.1038/sj.leu.2402295 11753617
42. Giuliani N. Storti P. Bolzoni M. Palma B.D. Bonomini S. Angiogenesis and multiple myeloma Cancer Microenviron. 2011 4 325 337 10.1007/s12307-011-0072-9 21735169 PMC3234322
43. Terpos E. Kastritis E. Christoulas D. Gkotzamanidou M. Eleutherakis-Papaiakovou E. Kanellias N. Papatheodorou A. Dimopoulos M.A. Circulating activin-A is elevated in patients with advanced multiple myeloma and correlates with extensive bone involvement and inferior survival; no alterations post-lenalidomide and dexamethasone therapy Ann. Oncol. 2012 23 2681 2686 10.1093/annonc/mds068 22492699
44. Vallet S. Mukherjee S. Vaghela N. Hideshima T. Fulciniti M. Pozzi S. Santo L. Cirstea D. Patel K. Sohani A.R. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease Proc. Natl. Acad. Sci. USA 2010 107 5124 5129 10.1073/pnas.0911929107 20194748 PMC2841922
45. Berenson J.R. Lichtenstein A. Porter L. Dimopoulos M.A. Bordoni R. George S. Lipton A. Keller A. Ballester O. Kovacs M.J. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group New Engl. J. Med. 1996 334 488 493 10.1056/NEJM199602223340802 8559201
46. Terpos E. Sezer O. Croucher P.I. García-Sanz R. Boccadoro M. San Miguel J. Ashcroft J. Bladé J. Cavo M. Delforge M. The use of bisphosphonates in multiple myeloma: Recommendations of an expert panel on behalf of the European Myeloma Network Ann. Oncol. 2009 20 1303 1317 10.1093/annonc/mdn796 19465418
47. Raje N. Anderson K.C. Introduction: The evolving role of bisphosphonate therapy in multiple myeloma Blood 2000 96 381 383 10.1182/blood.V96.2.381 10887095
48. Mhaskar R. Kumar A. Miladinovic B. Djulbegovic B. Bisphosphonates in multiple myeloma: An updated network meta-analysis Cochrane. Database Syst. Rev. 2017 12 CD003188 10.1002/14651858.CD003188.pub4 29253322 PMC6486151
49. Major P. Lortholary A. Hon J. Abdi E. Mills G. Menssen H.D. Yunus F. Bell R. Body J. Quebe-Fehling E. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials J. Clin. Oncol. 2001 19 558 567 10.1200/JCO.2001.19.2.558 11208851
50. Kostenuik P.J. Nguyen H.Q. McCabe J. Warmington K.S. Kurahara C. Sun N. Chen C. Li L. Cattley R.C. Van G. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-in mice that express chimeric (murine/human) RANKL J. Bone Miner. Res. 2009 24 182 195 10.1359/jbmr.081112 19016581
51. Raje N. Terpos E. Willenbacher W. Shimizu K. García-Sanz R. Durie B. Legieć W. Krejčí M. Laribi K. Zhu L. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: An international, double-blind, double-dummy, randomised, controlled, phase 3 study Lancet Oncol. 2018 19 370 381 10.1016/S1470-2045(18)30072-X 29429912
52. Tsourdi E. Langdahl B. Cohen-Solal M. Aubry-Rozier B. Eriksen E.F. Guañabens N. Obermayer-Pietsch B. Ralston S.H. Eastell R. Zillikens M.C. Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS Bone 2017 105 11 17 10.1016/j.bone.2017.08.003 28789921
53. von Metzler I. Krebbel H. Hecht M. Manz R.A. Fleissner C. Mieth M. Kaiser M. Jakob C. Sterz J. Kleeberg L. Bortezomib inhibits human osteoclastogenesis Leukemia 2007 21 2025 2034 10.1038/sj.leu.2404806 17581612
54. Toscani D. Palumbo C. Dalla Palma B. Ferretti M. Bolzoni M. Marchica V. Sena P. Martella E. Mancini C. Ferri V. The Proteasome Inhibitor Bortezomib Maintains Osteocyte Viability in Multiple Myeloma Patients by Reducing Both Apoptosis and Autophagy: A New Function for Proteasome Inhibitors J. Bone Miner. Res. 2016 31 815 827 10.1002/jbmr.2741 26551485
55. Fulciniti M. Tassone P. Hideshima T. Vallet S. Nanjappa P. Ettenberg S.A. Shen Z. Patel N. Tai Y.T. Chauhan D. Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma Blood 2009 114 371 379 10.1182/blood-2008-11-191577 19417213 PMC2714212
56. Heath D.J. Chantry A.D. Buckle C.H. Coulton L. Shaughnessy J.D. Jr. Evans H.R. Snowden J.A. Stover D.R. Vanderkerken K. Croucher P.I. Inhibiting Dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma J. Bone Miner. Res. 2009 24 425 436 10.1359/jbmr.081104 19016584
57. Iyer S.P. Beck J.T. Stewart A.K. Shah J. Kelly K.R. Isaacs R. Bilic S. Sen S. Munshi N.C. A Phase IB multicentre dose-determination study of BHQ880 in combination with anti-myeloma therapy and zoledronic acid in patients with relapsed or refractory multiple myeloma and prior skeletal-related events Br. J. Haematol. 2014 167 366 375 10.1111/bjh.13056 25139740
58. Delgado-Calle J. Anderson J. Cregor M.D. Condon K.W. Kuhstoss S.A. Plotkin L.I. Bellido T. Roodman G.D. Genetic deletion of Sost or pharmacological inhibition of sclerostin prevent multiple myeloma-induced bone disease without affecting tumor growth Leukemia 2017 31 2686 2694 10.1038/leu.2017.152 28529307 PMC5699973
59. McDonald M.M. Reagan M.R. Youlten S.E. Mohanty S.T. Seckinger A. Terry R.L. Pettitt J.A. Simic M.K. Cheng T.L. Morse A. Inhibiting the osteocyte-specific protein sclerostin increases bone mass and fracture resistance in multiple myeloma Blood 2017 129 3452 3464 10.1182/blood-2017-03-773341 28515094 PMC5492093
60. Valent P. Akin C. Metcalfe D.D. Mastocytosis: 2016, pdated WHO classification and novel emerging treatment concepts Blood 2017 129 1420 1427 10.1182/blood-2016-09-731893 28031180 PMC5356454
61. Lim K.H. Tefferi A. Lasho T.L. Finke C. Patnaik M. Butterfield J.H. McClure R.F. Li C.Y. Pardanani A. Systemic mastocytosis in 342 consecutive adults: Survival studies and prognostic factors Blood 2009 113 5727 5736 10.1182/blood-2009-02-205237 19363219
62. Uzzaman A. Maric I. Noel P. Kettelhut B.V. Metcalfe D. Carter M.C. Pediatric-onset mastocytosis: A long term clinical follow-up and correlation with bone marrow histopathology Pediatr. Blood Cancer 2009 53 629 634 10.1002/pbc.22125 19526526 PMC2786499
63. von Bubnoff N. Gorantla S.H. Kancha R.K. Lordick F. Peschel C. Duyster J. The systemic mastocytosis-specific activating cKit mutation D816V can be inhibited by the tyrosine kinase inhibitor AMN107 Leukemia 2005 19 1670 1671 10.1038/sj.leu.2403887 16015383
64. Rossini M. Zanotti R. Bonadonna P. Artuso A. Caruso B. Schena D. Vecchiato D. Bonifacio M. Viapiana O. Gatti D. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis Bone 2011 49 880 885 10.1016/j.bone.2011.07.004 21782049
65. van der Veer E. van der Goot W. de Monchy J.G. Kluin-Nelemans H.C. van Doormaal J.J. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis Allergy 2012 67 431 438 10.1111/j.1398-9995.2011.02780.x 22229787
66. Seitz S. Barvencik F. Koehne T. Priemel M. Pogoda P. Semler J. Minne H. Pfeiffer M. Zustin J. Püschel K. Increased osteoblast and osteoclast indices in individuals with systemic mastocytosis Osteoporos. Int. 2013 24 2325 2334 10.1007/s00198-013-2305-x 23436077
67. Greene L.W. Asadipooya K. Corradi P.F. Akin C. Endocrine manifestations of systemic mastocytosis in bone Rev. Endocr. Metab. Disord. 2016 17 419 431 10.1007/s11154-016-9362-3 27239674
68. Rossini M. Viapiana O. Adami S. Idolazzi L. Zanotti R. Gatti D. Rapid skeletal turnover in radiographic mimic of osteopetrosis might be secondary to systemic mastocytosis [corrected] J. Bone Miner. Res. 2015 30 945 10.1002/jbmr.2456 25639963
69. Kushnir-Sukhov N.M. Brittain E. Reynolds J.C. Akin C. Metcalfe D.D. Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis Int. Arch. Allergy Immunol. 2006 139 265 270 10.1159/000091172 16449817
70. Theoharides T.C. Boucher W. Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients Lnt. Arch. Allergy lmmunol. 2002 128 344 350 10.1159/000063858 12218373
71. Dobigny C. Saffar J.L. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: Evidence obtained by using receptor antago nists in a rat synchronized resorption model J. Cell Physiol. 1997 173 10 18 10.1002/(SICI)1097-4652(199710)173:1<10::AID-JCP2>3.0.CO;2-M 9326444
72. Biosse-Duplan M. Baroukh B. Dy M. de Vernejoul M.C. Saffar J.L. Histamine promotes osteoclastogenesis through the differential expression of histamine receptors on osteoclasts and osteoblasts Am. J. Pathol. 2009 174 1426 1434 10.2353/ajpath.2009.080871 19264900 PMC2671373
73. Rossini M. Zanotti R. Viapiana O. Tripi G. Orsolini G. Idolazzi L. Bonadonna P. Schena D. Escribano L. Adami S. Bone involvement and osteoporosis in mastocytosis Immunol. Allergy Clin. North Am. 2014 34 383 396 10.1016/j.iac.2014.01.011 24745681
74. Rossini M. Viapiana O. Zanotti R. Tripi G. Perbellini O. Idolazzi L. Bonifacio M. Adami S. Gatti D. Dickkopf-1 and sclerostin serum levels in patients with systemic mastocytosis Calcif. Tissue Int. 2015 96 410 416 10.1007/s00223-015-9969-5 25694360
75. Rabenhorst A. Christopeit B. Leja S. Gerbaulet A. Kleiner S. Förster A. Raap U. Wickenhauser C. Hartmann K. Serum levels of bone cytokines are increased in indolent systemic mastocytosis associated with osteopenia or osteoporosis J. Allergy Clin. Immunol. 2013 132 1234 1237.e7 10.1016/j.jaci.2013.06.019 23910691
76. Laroche M. Livideanu C. Paul C. Cantagrel A. Interferon alpha and pamidronate in osteoporosis with fracture secondary to mastocytosis Am. J. Med. 2011 124 776 778 10.1016/j.amjmed.2011.02.038 21787907
77. Guillaume N. Desoutter J. Chandesris O. Merlusca L. Henry I. Georgin-Lavialle S. Barete S. Hirsch I. Bouredji D. Royer B. Bone complications of mastocytosis: A link between clinical and biological characteristics Am. J. Med. 2013 126 75.e1 e7 10.1016/j.amjmed.2012.07.018 23200108
78. Barete S. Assous N. de Gennes C. Grandpeix C. Feger F. Palmerini F. Dubreuil P. Arock M. Roux C. Launay J.M. Systemic mastocytosis and bone involvement in a cohort of 75 patients Ann. Rheum. Dis. 2010 69 1838 1841 10.1136/ard.2009.124511 20570833
79. Cundy T. Beneton M.N. Darby A.J. Marshall W.J. Kanis J.A. Osteopenia in systemic mastocytosis: Natural history and responses to treatment with inhibitors of bone resorption Bone 1987 8 149 155 10.1016/8756-3282(87)90014-7 3606906
80. Rossini M. Zanotti R. Viapiana O. Tripi G. Idolazzi L. Biondan M. Orsolini G. Bonadonna P. Adami S. Gatti D. Zoledronic acid in osteoporosis secondary to mastocytosis Am. J. Med. 2014 127 1127.e1 e4 10.1016/j.amjmed.2014.06.015 24954632
81. Ali A.S. Lax A.S. Liljeström M. Paakkari I. Ashammakhi N. Kovanen P.T. Konttinen Y.T. Mast cells in atherosclerosis as a source of the cytokine RANKL Clin. Chem. Lab Med. 2006 44 672 674 16681444 10.1515/CCLM.2006.117
82. Orsolini G. Gavioli I. Tripi G. Viapiana O. Gatti D. Idolazzi L. Zanotti R. Rossini M. Denosumab for the Treatment of Mastocytosis-Related Osteoporosis: A Case Series Calcif. Tissue Int. 2017 100 595 598 10.1007/s00223-017-0241-z 28229176
83. Pootrakul P. Hungsprenges S. Fucharoen S. Baylink D. Thompson E. English E. Lee M. Burnell J. Finch C. Relation between erythropoiesis and bone metabolism in thalassemia New Engl. J. Med. 1981 304 1470 1473 10.1056/NEJM198106113042406 7231478
84. Ruggiero L. De Sanctis V. Multicentre study on prevalence of fractures in transfusion dependent thalassemic patients J. Pediatr. Endocrinol. Metab. 1998 11 773 778 10091145
85. Poggi M. Sorrentino F. Pugliese P. Smacchia M.P. Daniele C. Equitani F. Terlizzi F. Guitarrini M.R. Monti S. Maffei L. Longitudinal changes of endocrine and bone disease in adults with β-thalassemia major receiving different iron chelators over 5 years Ann. Hematol. 2016 95 757 763 10.1007/s00277-016-2633-y 26957357
86. Jensen C.E. Tuck S.M. Agnew J.E. Koneru S. Morris R.W. Yardumian A. Prescott E. Hoffbrand A.V. Wonke B. High prevalence of low bone mass in thalassaemia major Br. J. Haematol. 1998 103 911 915 10.1046/j.1365-2141.1998.01108.x 9886300
87. Gaudio A. Morabito N. Catalano A. Rapisarda R. Xourafa A. Lasco A. Pathogenesis of Thalassemia Major-associated Osteoporosis: A Review with Insights from Clinical Experience J. Clin. Res. Pediatr. Endocrinol. 2019 11 110 117 10.4274/jcrpe.galenos.2018.2018.0074 29991466 PMC6571534
88. Fung E.B. Harmatz P.R. Milet M. Coates T.D. Thompson A.A. Ranalli M. Mignaca R. Scher C. Giardina P. Robertson S. Fracture prevalence and relationship to endocrinopathy in iron overloaded patients with sickle cell disease and thalassemia Bone 2008 43 162 168 10.1016/j.bone.2008.03.003 18430624 PMC2500183
89. Vogiatzi M.G. Macklin E.A. Fung E.B. Vichinsky E. Olivieri N. Kwiatkowski J. Cohen A. Neufeld E. Giardina P.J. Prevalence of fractures among the Thalassemia syndromes in North America Bone 2006 38 571 575 10.1016/j.bone.2005.10.001 16298178 PMC4594870
90. Vogiatzi M.G. Macklin E.A. Fung E.B. Cheung A.M. Vichinsky E. Olivieri N. Kirby M. Kwiatkowski J.L. Cunningham M. Holm I.A. Bone disease in thalassemia: A frequent and still unresolved problem J. Bone Miner. Res. 2009 24 543 557 10.1359/jbmr.080505 18505376 PMC3276604
91. Engkakul P. Mahachoklertwattana P. Jaovisidha S. Chuansumrit A. Poomthavorn P. Chitrapazt N. Chuncharunee S. Unrecognized vertebral fractures in adolescents and young adults with thalassemia syndromes J. Pediatr. Hematol. Oncol. 2013 35 212 217 10.1097/MPH.0b013e3182841574 23511490
92. Anapliotou M.L. Kastanias I.T. Psara P. Evangelou E.A. Liparaki M. Dimitriou P. The contribution of hypogonadism to the development of osteoporosis in thalassemia major: New therapeutic approaches Clin. Endocrinol. 1995 42 279 287 10.1111/j.1365-2265.1995.tb01876.x 7758233
93. Soliman A.T. El Banna N. Abdel Fattah M. El Zalabani M.M. Ansari B.M. Bone mineral density in prepubertal children with β-thalassemia: Correlation with growth and hormonal data Metabolism 1998 47 541 548 10.1016/S0026-0495(98)90237-2 9591744
94. Scacchi M. Danesi L. Cattaneo A. Valassi E. Pecori Giraldi F. Argento C. D’Angelo E. Mirra N. Carnelli V. Zanaboni L. Bone demineralization in adult thalassaemic patients: Contribution of GH and IGF-I at different skeletal sites Clin. Endocrinol. 2008 69 202 207 10.1111/j.1365-2265.2008.03191.x 18221395
95. Lasco A. Morabito N. Gaudio A. Crisafulli A. Meo A. Denuzzo G. Frisina N. Osteoporosis and beta-thalassemia major: Role of the IGF-I/IGFBP-III axis J. Endocrinol. Invest. 2002 25 338 344 10.1007/BF03344015 12030605
96. Morabito N. Russo G.T. Gaudio A. Lasco A. Catalano A. Morini E. Franchina F. Maisano D. La Rosa M. Plota M. The “lively” cytokines network in beta-Thalassemia Major-related osteoporosis Bone 2007 40 1588 1594 10.1016/j.bone.2007.02.020 17412659
97. Bordat C. Constans A. Bouet O. Blanc I. Trubert C.L. Girot R. Cournot G. Iron distribution in thalassemic bone by energy-loss spectroscopy and electron spectroscopic imaging Calcif. Tissue Int. 1993 53 29 37 10.1007/BF01352012 8348382
98. Chan Y.L. Pang L.M. Chik K.W. Cheng J.C. Li C.K. Patterns of bone diseases in transfusion-dependent homozygous thalassaemia major: Predominance of osteoporosis and desferrioxamine-induced bone dysplasia Pediatr. Radiol. 2002 32 492 497 10.1007/s00247-002-0664-0 12107582
99. Dandona P. Menon R.K. Houlder S. Thomas M. Hoffbrand A.V. Flynn D.M. Serum 1,25 dihydroxyvitamin D and osteocalcin concentrations in thalassemia major Arch. Dis. Child. 1987 62 474 477 10.1136/adc.62.5.474 3496858 PMC1778375
100. Gaudio A. Morabito N. Xourafa A. Currò M. Caccamo D. Ferlazzo N. Macrì I. La Rosa M.A. Meo A. Ientile R. Role of genetic pattern on bone mineral density in thalassemic patients Clin. Biochem. 2010 43 805 807 10.1016/j.clinbiochem.2010.04.070 20444423
101. Morabito N. Gaudio A. Lasco A. Atteritano M. Pizzoleo M.A. Cincotta M. La Rosa M. Guarino R. Meo A. Frisina N. Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: New pieces of the puzzle J. Bone Miner. Res. 2004 19 722 727 10.1359/jbmr.040113 15068494
102. Voskaridou E. Christoulas D. Plata E. Bratengeier C. Anastasilakis A.D. Komninaka V. Kaliontzi D. Gkotzamanidou M. Polyzos S.A. Dimopoulou M. High circulating sclerostin is present in patients with thalassemia-associated osteoporosis and correlates with bone mineral density Horm. Metab. Res. 2012 44 909 913 10.1055/s-0032-1312618 22581647
103. Borgna-Pignatti C. Marsella M. Iron Chelation in Thalassemia Major Clin. Ther. 2015 37 2866 2877 10.1016/j.clinthera.2015.10.001 26519233
104. Dede A.D. Trovas G. Chronopoulos E. Triantafyllopoulos I.K. Dontas I. Papaioannou N. Tournis S. Thalassemia-associated osteoporosis: A systematic review on treatment and brief overview of the disease Osteoporos. Int. 2016 27 3409 3425 10.1007/s00198-016-3719-z 27503175
105. Lasco A. Morabito N. Gaudio A. Buemi M. Wasniewska M. Frisina N. Effects of hormonal replacement therapy on bone metabolism in young adults with beta-thalassemia major Osteoporos. Int. 2001 12 570 575 10.1007/s001980170079 11527055
106. Origa R. β-Thalassemia Genet. Med. 2017 19 609 619 10.1038/gim.2016.173 27811859
107. Giusti A. Pinto V. Forni G.L. Pilotto A. Management of beta-thalassemia-associated osteoporosis Ann. NY Acad. Sci. 2016 1368 73 81 10.1111/nyas.13041 27060977
108. Tsartsalis A.N. Lambrou G.I. Tsartsalis D. Savvidis C. Karantza M. Terpos E. Kanaka-Gantenbein C. Chrousos G.P. Kattamis A. The role of biphosphonates in the management of thalassemia-induced osteoporosis: A systematic review and meta-analysis Hormones 2018 17 153 166 10.1007/s42000-018-0019-3 29858849
109. Gaudio A. Morabito N. Xourafa A. Macrì I. Meo A. Morgante S. Trifiletti A. Lasco A. Frisina N. Bisphosphonates in the treatment of thalassemia-associated osteoporosis J. Endocrinol. Invest. 2008 31 181 184 10.1007/BF03345587 18362512
110. Voskaridou E. Ntanasis-Stathopoulos I. Papaefstathiou A. Christoulas D. Dimopoulou M. Repa K. Papatheodorou A. Peppa M. Terpos E. Denosumab in transfusion-dependent thalassemia osteoporosis: A randomized, placebo-controlled, double-blind phase 2b clinical trial Blood Adv. 2018 2 2837 2847 10.1182/bloodadvances.2018023085 30381400 PMC6234378
111. Morabito N. Catalano A. Gaudio A. Morini E. Bruno L.M. Basile G. Tsiantouli E. Bellone F. Agostino R.M. Piraino B. Effects of strontium ranelate on bone mass and bone turnover in women with thalassemia major-related osteoporosis J. Bone Miner. Metab. 2016 34 540 546 10.1007/s00774-015-0689-8 26204844
112. Tournis S. Dede A.D. Savvidis C. Triantafyllopoulos I.K. Kattamis A. Papaioannou N. Effects of teriparatide retreatment in a patient with β-thalassemia major Transfusion 2015 55 2905 2910 10.1111/trf.13237 26174236
113. Pinto V.M. Balocco M. Quintino S. Forni G.L. Sickle cell disease: A review for the internist Int. Emerg. Med. 2019 14 1051 1064 10.1007/s11739-019-02160-x 31385153
114. Miller R.G. Segal J.B. Ashar B.H. Leung S. Ahmed S. Siddique S. Rice T. Lanzkron S. High prevalence and correlates of low bone mineral density in young adults with sickle cell disease Am. J. Hematol. 2006 81 236 241 10.1002/ajh.20541 16550513
115. Garadah T.S. Hassan A.B. Jaradat A.A. Diab D.E. Kalafalla H.O. Kalifa A.K. Sequeira R.P. Alawadi A.H. Predictors of abnormal bone mass density in adult patients with homozygous sickle-cell disease Clin. Med. Insights Endocrinol. Diabetes 2015 8 35 40 10.4137/CMED.S24501 25987854 PMC4426937
116. Bordbar M.R. Haghpanah S. Zarei T. Dabbaghmanesh M.H. Omrani G.R. Saki F. Evaluation of bone mineral density in children with sickle-cell anemia and its associated factors in the south of Iran: A case-control study Arch. Osteoporos. 2017 12 70 10.1007/s11657-017-0364-x 28779437
117. De Luna G. Ranque B. Courbebaisse M. Ribeil J.A. Khimoud D. Dupeux S. Silvera J. Offredo L. Pouchot J. Arlet J.B. High bone mineral density in sickle cell disease: Prevalence and characteristics Bone 2018 110 199 203 10.1016/j.bone.2018.02.003 29428552
118. Voskaridou E. Stoupa E. Antoniadou L. Premetis E. Konstantopoulos K. Papassotiriou I. Terpos E. Osteoporosis and osteosclerosis in sickle cell/beta-thalassemia: The role of the RANKL/osteoprotegerin axis Haematologica 2006 91 813 816 16704959
119. Sadat-Ali M. Al-Elq A. Sultan O. Al-Turki H. Secondary osteoporosis due to sickle cell anemia: Do sex steroids play a role? Indian J. Med. Sci. 2008 62 193 198 10.4103/0019-5359.40984 18579978
120. Boettger P.C. Knupp C.L. Liles D.K. Walker K. Vitamin D Deficiency in Adult Sickle Cell Patients J. Natl. Med. Assoc. 2017 109 36 43 10.1016/j.jnma.2016.10.003 28259214
121. Paschou S.A. Anagnostis P. Karras S. Annweiler C. Vakalopoulou S. Garipidou V. Goulis D.G. Bone mineral density in men and children with haemophilia A and B: A systematic review and meta-analysis Osteoporos. Int. 2014 25 2399 2407 10.1007/s00198-014-2773-7 25001982
122. Rodriguez-Merchan E.C. Valentino L.A. Increased bone resorption in hemophilia Blood Rev. 2019 33 6 10 10.1016/j.blre.2018.05.002 29857920
123. Tang G.H. Norris E. Petrucci J. James P.D. Lee A. Poon M.C. Floros G. Boma-Fischer L. Teitel J. Nisenbaum R. Bone health in symptomatic carriers of haemophilia A: A protocol for a multicentre prospective matched-cohort study BMJ Open 2019 9 e032891 10.1136/bmjopen-2019-032891 31796490 PMC7003383
124. Mansouritorghabeh H. Rezaieyazdi Z. Bone Density Status in Bleeding Disorders: Where Are We and What Needs to be Done? J. Bone Metab. 2017 24 201 206 10.11005/jbm.2017.24.4.201 29259958 PMC5734944
125. Gerstner G. Damiano M.L. Tom A. Worman C. Schultz W. Recht M. Stopeck A.T. Prevalence and risk factors associated with decreased bone mineral density in patients with haemophilia Haemophilia 2009 15 559 565 10.1111/j.1365-2516.2008.01963.x 19187193
126. Iorio A. Fabbriciani G. Marcucci M. Brozzetti M. Filipponi P. Bone mineral density in haemophilia patients. A meta-analysis Thromb. Haemost. 2010 103 596 603 20076854 10.1160/TH09-09-0629
127. Hoots W.K. Rodriguez N. Boggio L. Valentino L.A. Pathogenesis of haemophilic synovitis: Clinical aspects Haemophilia 2007 13 Suppl. 3 4 9 10.1111/j.1365-2516.2007.01533.x 17822514
128. Forsyth A.L. Quon D.V. Konkle B.A. Role of exercise and physical activity on haemophilic arthropathy, fall prevention and osteoporosis Haemophilia 2011 17 e870 e876 10.1111/j.1365-2516.2011.02514.x 21435116
129. Anagnostis P. Vakalopoulou S. Slavakis A. Charizopoulou M. Kazantzidou E. Chrysopoulou T. Vyzantiadis T.A. Moka E. Agapidou A. Garipidou V. Reduced bone mineral density in patients with haemophilia A and B in Northern Greece Thromb. Haemost. 2012 107 545 551 22318743 10.1160/TH11-08-05563
130. Kempton C.L. Antoniucci D.M. Rodriguez-Merchan E.C. Bone health in persons with haemophilia Haemophilia 2015 21 568 577 10.1111/hae.12736 26172840
131. Anagnostis P. Vyzantiadis T.A. Charizopoulou M. Adamidou F. Karras S. Goulis D.G. Karagiannis A. Garipidou V. Vakalopoulou S. The effect of monthly ibandronate on bone mineral density and bone turnover markers in patients with haemophilia A and B and increased risk for fracture Thromb. Haemost. 2013 110 257 263 23740140 10.1160/TH13-01-0030
132. Ghosh K. Shetty S. Bone health in persons with haemophilia: A review Eur. J. Haematol. 2012 89 95 102 10.1111/j.1600-0609.2012.01803.x 22587752