1 Introduction

Mastocytosis is a rare neoplastic disease of the mast cell and its hematopoietic progenitor, occurring in about 1/10,000 individuals, broadly divided into cutaneous and systemic disease [1]. Usually treated by dermatologists, allergists and hematologists, the focus of patient and health care professionals is often the obvious disturbing skin and vascular manifestations of rashes, pruritus, and flushing, related to mast cell degranulation. Although very common, the bone involvement in systemic mastocytosis may be asymptomatic.

2 KIT and the regulation of mast cells

In a normal individual, KIT ligand, also known as stem-cell factor (SCF) present in the hematopoietic microenvironment, binds the CD117 (KIT) transmembrane tyrosine kinase receptor, to form a dimer that activates intrinsic tyrosine kinase activity, and triggers mast cell development. KIT encodes a transmembrane receptor with intrinsic tyrosine kinase activity (KIT), which is activated by binding to stem cell factor (SCF or Kit ligand), the major mast-cell growth and differentiation factor.

Upon differentiation of hematopoietic progenitors into mature cells, KIT expression is down-regulated in all lineages, except mast cells, which retain high levels of cell surface KIT expression. The interaction between KIT and its ligand, SCF, plays a key role in regulating mast cell proliferation, maturation, adhesion, chemotaxis, and survival [2].

Mastocytosis is frequently associated with somatic gain-of-function point mutations within KIT. In a majority of cases of adult systemic mastocytosis (SM) the D816V mutation is found [3]. The somatic point mutation in codon 816 (most commonly Asp816Val) of the proto-oncogene KIT, permits activation and constitutive auto-phosphorylation of Kit, so that Kit does not need to bind to an activating ligand for its function [4]. Mast cell progenitors migrate from the blood into various tissues, including the skin, lungs, and mucosal interfaces, where they acquire tissue-specific phenotypes determined by the local microenvironment [5]. Cytokine signals, epigenetic modifications and other micro-environmental factors can substantially and, in some cases, rapidly and reversibly alter the phenotype of these cells and influence their function [6].

Abnormal clonal mast-cell expansion and accumulation in tissues may be influenced by response to endogenous or exogenous stimuli, in one or more tissues. The distinguishing feature of mastocytosis is the presence of multifocal clusters of abnormal mast cells. In contrast to normal mast cells, the mast cells of mastocytosis are variable in appearance, ranging from round to fusiform variants with long, polar cytoplasmic processes, and may display cytoplasmic hypogranularity with uneven distribution of fine granules, as well as atypical nuclei with monocytoid appearance [7]. Mastocytosis is characterized by varying degrees of mast cell proliferation, accompanied by symptoms of mast cell activation and degranulation in most patients.

3 Clinical disease

Mastocytosis can affect both children and adults. When diagnosed in infancy and children, it usually manifests as cutaneous mastocytosis, without systemic involvement, and with a good prognosis. In general, most children experience resolution or fading of skin lesions by adolescence [8]. Although approximately 60–80 % of patient with cutaneous mastocytosis have gain-of-function KIT mutations, patients with cutaneous mastocytosis usually do not fulfill the criteria for the diagnosis of systemic mastocytosis [9]. Adult-onset systemic mastocytosis patients usually have the activating mutation found in their skin and bone marrow. When mastocytosis is present in any extracutaneous tissue (most often the bone marrow, proven by biopsy) it is termed systemic mastocytosis (SM). Almost half of the individuals with mastocytosis are adults. Furthermore, almost all adults will have systemic disease if one looks closely enough [1]. Adult-onset SM patients usually have the activating mutation found in their skin and bone marrow. Therefore, unlike children, most adults with skin lesions have systemic disease, with bone marrow involvement and a persistent and progressive course [4].

SM is a heterogeneous group of disorders with variable prognosis, varying from indolent to “smoldering” to life-threatening disease [5]. Aggressive SM, which is characterized by specific tissue damage associated with mast cells, is most commonly identified in the bone marrow, liver, gastrointestinal tract, and cortical bone. Some of the most aggressive systemic mastocytosis presentations may occur without any skin manifestations [10].

4 Mastocytosis and the bone

4.1 Clinical manifestations

In adults, skeletal manifestations are one of the frequent findings of SM, occurring in about 50 % of patients, but this may often be asymptomatic [11]. Bone abnormalities reported in systemic mastocytosis include low bone mass or osteopenia, osteopenia with lytic lesions, and osteoporosis by bone density alone, osteoporosis with atraumatic fracture, osteosclerosis, and isolated lytic lesions of bone [10]. Recent studies concur that osteoporosis is the most frequent bone abnormality among patients diagnosed with mastocytosis. To date, the description of bone abnormalities includes not only the clinical manifestations (fractures), but also changes in surrogate markers such as bone mineral density, and biochemical bone turnover markers, such as bone specific alkaline phosphatase (bALP), C-telopeptide, osteocalcin, and osteoprotegerin (OPG) levels (Tables 1 and 2).

Table 1 Studies reporting fracture rate and risk factors in patients with mastocytosis in reverse order of the year of publication
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Barete et al. evaluated a cohort of 75 patients with SM and found out that, while 40 % of the patients presented with other clinical symptoms of mastocytosis, half already had bone involvement [19]. Clinical presentation may vary. Patients may be asymptomatic and yet have findings on bone density screening including osteopenia (from 33 to 60 %) or diffuse osteoporosis by BMD (10–38 %) or even osteosclerosis (5.3–10 %) (References 11–20; and Table 2). Symptoms include poorly localized bone pain, osteoporosis, pathologic fractures, and skeletal deformities. Sometimes pain due to a lytic lesion is the first presentation, and occasionally lesions may be detected on X-ray, without any history of pain [25]. The prevalence of fracture varies, in part based on sample size, method of selection of patients in study, and other factors. In the larger studies of patients with systemic mastocytosis, the incidence of vertebral fractures was almost 39 % (varies from 21 to 43 %) (References 14, 22; Table 1 and Fig. 1). Some fractures may occur in isolated lytic lesions of mastocytomas (19). Note that in some studies, the reported prevalence of osteoporosis is less than the fracture incidence, demonstrating that the bone fragility of mastocytosis is not always linked to the bone density (References 11, 15, 18, 22; and Fig. 1).

Table 2 Studies reporting bone density measurement, imaging studies and biochemical markers of bone turnover in patients with mastocytosis in reverse order of the year of publication
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Fig. 1
figure 1

Number of fractures and osteoporosis diagnosis in the patients with systemic mastocytosis in different studies in order of population size

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Both focal osteolytic and osteosclerotic bone lesions have been reported and, unlike in most other bone disease, the coexistence of these lesions is not rare [26]. Also fractures are associated with both osteoporosis and osteosclerosis [24].

4.2 Risk factors

In the largest study of fracture prevalence in SM by Seitz et al., the prevalence of osteoporosis is not reported [14]. In Van der Veer’s large study of 228 patients with SM, independent risk predictors of future femoral fracture included: male sex, high levels of bone resorption, serum type I collagen C-telopeptide (CTX), low hip bone mineral density, absence of urticaria pigmentosa, and alcohol intake at the time of SM diagnosis [13]. It is also unclear how osteoporosis due to menopause might be separated from effects of mastocytosis on bone. Therefore, low bone density and other parameters in men might demonstrate the effects of mastocytosis on bone better than in women, and therefore might be more predictive. While tryptase level may predict mast cell mass, conversely, it might best relate to higher bone density, though this high bone density in mastocytosis does not protect against fracture [23].

Guillaume et al. have shown that bone turnover is elevated in mastocytosis patients, since markers of both bone resorption and bone formation were elevated, as compared with healthy individuals. This group postulates that the overall increased levels of bone turnover markers may reflect an increase in the number of osteoclasts and osteoblasts, correlated with expansion of mast cell number and activity [15].

5 Histomorphometric analysis

In patients with osteoporosis, the histomorphometric analysis revealed an increased number of both osteoclasts and osteoblasts, together with deterioration of trabecular bone structure [21, 27].

6 Etiology

However, the pathophysiology of bone loss in the context of mastocytosis is not fully understood. Even when there are findings of osteosclerosis by bone density, accelerated bone turnover is found [28].

As both increased bone formation, and increased bone loss have been found, the mediators may be variable in different patients, or act to variable degree. Guillaume found that, not only were biochemical markers significantly higher in mastocytosis patients than in the controls, but these markers were especially high in patients with advanced SM [15].

The level of tryptase, a marker of mast cell burden in SM, may correlate with serum levels of alkaline phosphatase, a marker of bone formation, and is associated with higher bone density [23, 28]. Indeed the highest levels of both tryptase and bone turnover markers are found in SM patients with increased bone density and “osteosclerotic” bone appearance. Guillaime et al. also report that, conversely, tryptase levels correlate significantly with markers of bone resorption, such as CTX and deoxypyridinoline, and also with osteoprotegerin (OPG) a marker of bone formation. Therefore increased bone turnover occurs [15].

A series of cellular and molecular players coordinate the balance between bone-forming osteoblasts and bone-degrading osteoclasts in bone in a highly complex manner. Both parathyroid hormone (PTH) and the Wnt signaling pathway stimulate osteoblast genesis. The Wnt pathway controls and determines mesenchymal bone cell differentiation into osteoblasts, chondrocytes, and fat cells. It leads to increased production of both RANKL from osteoblasts and bone stromal cells and OPG, from osteoblasts. Next, RANKL binds to its receptor, RANK -the receptor activator of nuclear factor kappa-β, a member of the tumor necrosis factor receptor (TNFR) molecular sub-family-, present on osteoclasts and their precursors, to increase osteoclast differentiation and activation to resorb bone, and, simultaneously, to decrease osteoclast aptosis. Meanwhile, OPG competitively binds to RANKL, blocking RANKL from binding to the RANK receptor, thereby decreasing osteoclast activation and number.

Elevated bone levels of both RANKL and OPG are observed in mastocytosis [11, 22]. Mastocyte products, such as tryptase, may activate osteoblasts, increase OPG production, increasing bone turnover and formation. Supporting this, Laroche postulates that interferon α may reduce inflammation, in turn reducing tryptase secretion, thereby complementing bisphosphonate therapy of osteoporosis in mastocytosis [17].

The Wnt signaling pathway of bone is also regulated by receptor inhibitors such as Dickkopf-1 (DKK1), from several sources, and sclerostin (SOST), produced only by the osteocyte. DKK1 inhibits the Wnt/ β catenin pathway, by tightly binding to LRP6 and preventing it from binding to Fz (frizzled), so the Fz –LRP6 complex cannot form (Reference 29; and Fig. 2).

Fig. 2
figure 2

Mechanism of mastocytosis effects on bone

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Rossini found increased levels of serum DKK1 in 46 patients with mastocytosis, compared to controls. While DKK1 serum levels were positively correlated with CTX, correlating to greater bone resorption, yet this marker also correlates with PTH level and bone specific alkaline phosphatase (bALP), a marker of bone formation. However, the level of DKK1 did not relate to extent of osteoporosis or osteosclerosis in these patients, so Rossini concluded that the marker elevation had little clinical import [11]. While Rabenhorst found elevated sclerostin (SOST) levels in patients with mastocytosis and bone disease, Rossini did not find elevated SOST compared to controls and he went on to surmise that SOST had no particular role in the pathogenesis of bone changes in mastocytosis [11, 22]. Although Rossini went on to postulate that the Wnt /β catenin signaling pathway is not important in mastocytosis, he never showed evidence to support this conclusion (11).

Histamine, the most abundant product of mast cells, acts directly on both osteoclasts and their precursors through autocrine/paracrine mechanisms. Histamine increases bone resorption, both indirectly, by increasing the expression of RANKL in osteoblasts, and directly, by stimulating the formation and activation of osteoclasts and their precursors [26]. Histamine might also act through its bone receptor, to decrease osteogenesis. A genetic knock out mouse for histamine production had increased production of active vitamin D (calcitriol), and lower PTH levels, decreased osteoclast number and increased bone density. It was postulated that the increased calcitriol also led to decreased osteoclasts. The authors proposed that anti-histamines might be useful to treat post-menopausal women and patients with SM [30]. In a study of patients with SM, the adequate 25 vitamin D, with low calcitriol levels found also indicated a renal impairment in 1 α hydroxylation activity of the kidney. Treatment with anti-histamines elevated the calcitriol levels and led to increased bone density [31]. While it is known that vitamin D may increase the differentiation of multi-potential stromal cells (MSCs) in bone to osteoblasts, there is in vitro evidence that the overexpression of the vitamin D receptor (VDR) in tumor cells, such as osteosarcoma cells, may activate both osteocalcin and the histamine receptor H1 (HRH1). The activated HRH1, negatively feeds back to decrease the osteogenic differentiation of MSCs, thereby minimizing vitamin D effect. Also some anti-histamines are shown to block the HRH1 receptor [32].

The activating D816V mutation of the tyrosine-kinase growth factor receptor KIT, commonly found in systemic mastocytosis, may itself relate to the bone disease, as KIT expression has been found on osteoclasts that resorb bone. Conversely, activated osteoblasts (the cells of bone formation) may increase KIT activation [33]. However, a study by Broesby-Olsen et al. did not find that the level of mutation correlated with the Z score (that represents standard of deviation of bone loss compared to normal age-matched contemporaries without MS) [34]. Furthermore, whether the somatic KIT mutations are also present in osteoclasts or osteoblasts has not been investigated.

Heparin released from mast cells, might also increase PTH-mediated bone resorption, through the Wnt signaling pathway. Also, increased PTH may stimulate osteoblasts to secrete factors activating the KIT pathway, in turn activating mastocytes [27].

The imbalance between bone formation and resorption is likely a result of either neoplastic infiltration or the local release of mediators, including tryptase, histamine, heparin, lipid mediators, and cytokines by mast cells (Fig. 2).

7 Treatment

In 1990, Graves et al. proposed using a medication to prevent mast cell degranulation, ketotifen, to help decrease bone pain and increase bone density in one case of systemic mastocytosis in a patient with concurrent decrease in 1,25 vitamin D [31]. Past studies of cromolyn, anti-histamines, sodium fluoride showed no effectiveness. Chemotherapeutic agents such as chlorambucil and mithramycin, had variable results [35].

Bisphosphonates, including clodronate, alendronate, pamidronate and zoledronic acid, are the first line agents used in treatment of mastocytosis and osteoporosis [36] and have a role in the associated refractory bone pain [37–39]. Cundy et al. treated a 63 year old woman with a history of urticaria, who had not responded to chlorambucil nor mithramycin, with a successful response to oral clodronate. However, this individual, with a 20 years delay in the appearance of osteopenia, a history of acromegaly and consequent hypogonadotropic hypogonadism, is not likely to be representative [40]. A study by Barete et al. used bisphosphonate therapy in 23 patients with mastocytosis and osteoporosis, with a good response of lumbar spine BMD, but no mean change in hip BMD, though 3 patients had a decline in hip BMD. In addition, no subjects developed new vertebral fractures [19]. In Rossini’s study of 25 patients, treatment with intravenous zoledronic acid improved both spine and hip BMD, decreased serum markers of formation (bALP) and resorption (CTX). Also, no patient had a new fracture during the observation period (References 19, 23; and Table 3).

Table 3 Reported treatment of osteoporosis in the patients with mastocytosis in reverse order of the years of publication
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Perhaps reduction of inflammation might link to bone stability or even improvement. When interferon therapy is initiated, mast cells degranulate releasing histamine, but then the mast cells are depleted. In a study of three SM patients with vertebral fractures causing pain, α interferon therapy improved the bone density, as pain abated contemporaneously, permitting analgesic agents to be stopped. One patient in this study had two successful subsequent treatments with interferon α alone, as symptoms recurred off therapy [35]. Interferon may act synergistically with bisphosphonates. In a longer and more complicated study, ten patients who had developed fractures while on alendronate, improved their bone density and no longer fractured while on a combination of α-interferon and pamidronate [17].

Theoretically, the anti-histamines used by patients to alleviate flushing and itching might also have a small role in counteracting bone effects of histamines. In general, both H1 and H2 inhibitors increase calcitriol levels, decrease PTH and slow down bone resorption in ovarectomized mice [27, 30]. However, it is not known if H2 blockers might inhibit calcium absorption and, therefore, may have a detrimental effect.

8 Possible future therapies

Although RANKL and osteoprotegerin (OPG) levels have been noted to be elevated in the bone disease of mastocytosis, we could not find any studies using denosumab, a congener of osteoprotegerin. Also, a potential new agent might be sclerostin, though sclerostin levels appear unchanged in one study of bone [11].

As systemic mastocytosis may be a premalignant condition, leading rarely to a leukemic condition, we would not suggest the use of teriparatide as an anabolic agent for patients with mastocytosis.

9 Further questions

As in all forms of bone loss, it is unclear when to initiate therapy. Should a bone drug be started for an isolated low T score (e.g., when T score is less than -2.0 or -2.5), or only when there is a compression fracture regardless of T score? Can response in SM be measured properly with bone density? Response to therapy might be difficult to evaluate, especially in a patient with mixed lytic and sclerotic lesions. Furthermore, it also unknown how long therapy should be continued for maximum benefit.

10 Conclusions

The true incidence and development of bone abnormalities has never been discovered, as most reports are retrospective, in that clinical bone abnormalities are noted first. The study by Laroche et al. of SM patients in Table 1, though not retrospective, is not included in Fig. 1, because prior vertebral fracture was a requisite for inclusion [17].

Rarely, in indolent cases, the bone disease predates the clinical diagnosis of mastocytosis. The variability in presentation of bone disease also is unexplained, as patients may have osteopenia, osteoporosis with or without fracture, isolated islands of dissolution, or even osteopetrosis with or without fracture. Occasionally, two different bone conditions occur in the same patient. As there is uncertainty in the literature about when to start treatment in common conditions of post-menopausal bone loss, with attempts to provide a risk indicator, such as FRAX, there is even more difficulty when we don’t even know or understand the course of bone loss proceeding to fracture in patients with mastocytosis. Appreciating the heterogeneity in pathology and biochemistry, there might be several different solutions too. Clinical research study on the progression and treatment of bone disease is needed. Though mastocytosis is a rare disease, and the bone disease may be silent, there is considerable risk of fracture in this population.