An increased bone mineral density is an adverse prognostic factor in patients with systemic mastocytosis

Purpose Systemic mastocytosis (SM) is characterized by the expansion of clonal mast cells that infiltrate various organ systems. The extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) defined by a nearly normal life expectancy and advanced SM (AdvSM) defined by poor prognosis. In ISM, measurement of the bone mineral density (BMD) frequently reveals osteoporosis. In contrast, the clinical implication of an increased BMD and osteosclerosis remains unclear. Methods BMD was evaluated in 61 patients with mastocytosis (ISM, n = 29, 48%; AdvSM, n = 32, 52%). We correlated the prevalence of osteoporosis, increased BMD and osteosclerosis with clinical parameters, disease variant and prognosis. Results Osteoporosis was detected in 11/29 (38%) patients with ISM but only in 2/32 (6%) patients with AdvSM (p = 0.004). An increased BMD was detected in 1/29 (3%) patients with ISM and 24/32 (75%) patients with AdvSM (p < 0.001) while osteosclerosis was only detected in AdvSM patients (16/32, 50%). AdvSM patients with increased BMD had higher levels of bone marrow mast cell infiltration, higher serum tryptase and alkaline phosphatase levels compared to ISM as well as higher number of high-molecular risk mutations (p < 0.05). In addition, we found that the prognosis of AdvSM patients with increased BMD is inferior compared to those without increased BMD (median overall survival 3.6 years versus not reached, p = 0.031). Conclusions Osteoporosis is a common feature in ISM but not in AdvSM. An increased BMD is frequently present in AdvSM but not in ISM and is associated with more advanced disease and inferior outcome.


Introduction
Systemic mastocytosis (SM) is a rare hematological neoplasm characterized by the expansion of clonal mast cells that infiltrate various organ systems, e.g., bone marrow, liver, spleen, gastrointestinal tract, lymph nodes and skin (Horny et al. 1985;Valent et al. 2001Valent et al. , 2003Metcalfe 2008;Jawhar et al. 2015). According to the World Health Organization (WHO), the extent of organ infiltration and subsequent organ damage distinguishes between indolent SM (ISM) and advanced SM (AdvSM). AdvSM comprises patients with SM and an associated hematologic neoplasm (SM-AHN), aggressive SM (ASM) and mast cell leukemia (MCL) (Arber et al. 2016).
ISM patients usually present with a low mast cell burden and have a nearly normal life expectancy while AdvSM Andreas Reiter and Mohamad Jawhar have contributed equally.
* Mohamad Jawhar mohamad.jawhar@medma.uni-heidelberg.de 1 3 patients usually have a high disease burden, multiple-organ damage and poor prognosis with median overall survival of approximately 3-4 years (Jawhar et al. 2016(Jawhar et al. , 2017a(Jawhar et al. , b, 2019Valent et al. 2017;Sperr et al. 2019). Because bone and bone marrow (BM) involvement is a characteristic and frequent feature in SM patients, measurement of the bone mineral density (BMD) plays an important role in the diagnostic workup. According to the literature, the prevalence of osteoporosis (T score of ≤ − 2.5 standard deviation, SD) in ISM patients ranges between 14 and 66% (Harvey et al. 1989;Floman and Amir 1991;Brumsen et al. 2002b;Kushnir-Sukhov et al. 2006;Donker et al. 2008;Mathew et al. 2009;Rossini et al. 2011). However, the association between SM subtypes and increased BMD or osteosclerosis is yet unknown.
We, therefore, sought to evaluate the prevalence of osteoporosis, increased BMD and osteosclerosis and their impact on clinical characteristics and prognosis in a large cohort of well-characterized patients with various subtypes of SM.

Materials and methods
In this retrospective analysis, a total of 61 patients (ISM, n = 29, 48%; AdvSM, n = 32, 52%) were included within our German Registry on Disorders of Eosinophils and Mast Cells.
All patients were scanned on a 16 row CT Scanner (SOMATOM Emotion 16, Siemens Healthcare Sector, Forchheim, Germany). Scans of L1, L2 and L3 were conducted using the following protocol: 120 kV, 250 mAs, and slice thickness 10 mm. Additionally, an in-scan calibration phantom (Siemens OSTEO phantom) was placed beneath the spine during the image acquisition to convert CT values to BMD. The study design adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board of the Medical Faculty of Mannheim, Heidelberg University (Heidelberg, Germany). All patients gave written informed consent.
The results were expressed as T score (standard deviation, SD below the mean of young healthy adults) and as Z score (SD below the age-and gender-matched mean reference value). According to established WHO criteria, osteoporosis was defined as a lumbar spine T score of ≤ − 2.5 SD (Kanis 1994). Increased BMD and osteosclerosis were defined as Z score > 1 SD and > 2 SD, respectively. Because the median age of our cohort was high and following the guidelines of the International Society for Clinical Bone Densitometry (ISCD), we applied the Z score for diagnostic purposes of osteoporosis (Rossini et al. 2011). Severe mastocytosisrelated osteopenia was defined as a lumbar spine Z score of < − 2 SD (Valent et al. 2007).
All statistical analyses considered clinical and laboratory parameters obtained at time of imaging. Overall survival (OS) was measured from the date of diagnosis to date of death or last visit. OS probabilities were estimated with the Kaplan-Meier method and compared by the log-rank test in univariate analysis. The Wilcoxon-Mann-Whitney U test was used to compare continuous variables and medians of distributions. For categorical variables, two patient groups were compared with the Fisher's exact test. All tests were two sided, retaining p < 0.05 as statistically significant.

Discussion
So far, only little is known about differences in the prevalence of decreased or increased BMD in the various SM subtypes finally leading to the diagnosis of osteoporosis or osteosclerosis. In addition, the impact of an altered BMD on complications and outcome remains largely unknown (Huang et al. 1987;Johansson et al. 1996; Barete et al. 2010;Manara et al. 2010;Rossini et al. 2011). We, therefore, evaluated T and Z scores in a larger number of patients with ISM and AdvSM. Osteoporosis is a typical feature of ISM and has been attributed to the local release of mediators such as histamine, heparin or mast cell-derived proteases (Harvey et al. 1989;Floman and Amir 1991;Brumsen et al. 2002a;Kushnir-Sukhov et al. 2006;Donker et al. 2008;Mathew et al. 2009). In line with previous reports (Harvey et al. 1989;Floman and Amir 1991;Brumsen et al. 2002b;Kushnir-Sukhov et al. 2006;Donker et al. 2008;Mathew et al. 2009;Rossini et al. 2011), osteoporosis was detected in 38% of our patients with ISM but in only 6% of the cases with AdvSM. According to Rossini et al., a Z score < 2.0 indicating mastocytosis-related severe osteopenia was identified in 10% of our ISM patients. However, another 14% of the ISM patients examined showed false high BMD values due to fractures and/or vertebroplasty in the lumbar spine.
ISM patients with osteoporosis had a significantly lower median mast cell infiltration in the bone marrow and a lower median serum tryptase level as compared to ISM patients without osteoporosis (Johansson et al. 1996;Kushnir-Sukhov et al. 2006;Rossini et al. 2014). A significant positive correlation was observed between serum tryptase levels and T score BMD in the subgroup of ISM. Johansson et al. assumed that mast cell mediators stimulating osteoclasts are dominant in patients with a moderate increase of mast cells, while the osteoblast-stimulating effect of histamine prevails in patients with high histamine metabolite excretion (Johansson et al. 1996).
In contrast to ISM, the vast majority of our AdvSM patients had no osteoporosis but an increased BMD or even osteosclerosis. AdvSM patients with increased BMD/osteosclerosis had a more aggressive phenotype, e.g., a higher mast cell burden in the bone marrow compared to our ISM patients, and the same was found to hold true for serum tryptase, KIT D816V EAB and alkaline phosphatase. In addition, we found that patients with increased BMD have an inferior outcome as compared to AdvSM patients with normal BMD. Almost all AdvSM patients with a normal BMD had an SM-AHN with a dominating AHN and a relatively low mast cell burden.
Osteosclerosis is observed in a number of hematologic neoplasms and is recognized as an adverse prognostic (Rollison et al. 2008) feature in myeloproliferative neoplasms (MPN) such as primary myelofibrosis, secondary myelofibrosis, polycythemia vera and essential thrombocythemia. Two previous studies with six SM patients have shown that osteosclerosis was associated with more advanced SM subtypes (Kushnir-Sukhov et al. 2006;Barete et al. 2010). In a recent MRI-based study, a diffuse sclerotic bone marrow pattern of the spine was associated with a significantly higher MC burden, organ dysfunction and inferior survival (Riffel et al. 2019).
The pathophysiology of AdvSM-related increased BMD/osteosclerosis is poorly understood. Mast cell-derived mediators and cytokines may exert a direct stimulatory effect on osteoblast recruitment, proliferation, and activity, while tryptase may increase osteoprotegerin, reducing osteoclast activity and favouring osteosclerosis rather than osteoporosis (Johansson et al. 1996;Chiappetta and Gruber 2006;Gregson et al. 2013).
In conclusion, (1) osteoporosis is a common feature in ISM but not in AdvSM, (2) an increased BMD and osteosclerosis are frequently present in AdvSM but not in ISM, (3) in AdvSM, an increased BMD/osteosclerosis is associated with a more aggressive phenotype, high-risk molecular aberrations, and inferior survival. Also, magnetic resonance imaging (MRI) images of the spine showed diffuse osteosclerosis with a very low signal both in T1-weighted (d) and turbo inversion recovery magnitude (TIRM)-sequences (e) Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes  were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.