# The Prevalence Of Osteoporosis Is Low in Adult Cutaneous Mastocytosis Patients

<figure><img src="image_1.png" /></figure>

Yannick Degboé, MD, PhD<sup>a,b,c</sup>, Maella Severino-Freire, MD<sup>c</sup>, Guillaume Couture, MD<sup>a</sup>, Pol-André Apoil, MD, PhD<sup>c,d</sup>, Nicolas Gaudenzio, PhD<sup>b</sup>, Olivier Hermine, MD, PhD<sup>e</sup>, Adeline Ruyssen-Witrand, MD, PhD<sup>a,f</sup>, Carle Paul, MD, PhD<sup>b,c</sup>, Michel Laroche, MD<sup>a</sup>, Arnaud Constantin, MD, PhD<sup>a,b</sup>, and Cristina Bulai Livideanu, MD<sup>b,c</sup> Toulouse and Paris, France

**What is already known about this topic?** A subset of patients presents with abnormal clonal bone marrow mast cells and clinical repercussions, but do not fulfill the systemic mastocytosis (SM) World Health Organization (WHO) criteria. The SM is associated with vertebral osteoporosis and vertebral fractures.

**What does this article add to our knowledge?** Abnormal clonal bone marrow mast cell presence with clinical repercussions in patients not fulfilling the SM WHO criteria is not associated with osteoporosis and fractures in cutaneous mastocytosis, but is associated in monoclonal mast cell activation syndrome.

**How does this study impact current management guidelines?** Osteoporosis in cutaneous mastocytosis usually differs from that of SM and should be managed differently.

**BACKGROUND:** Systemic mastocytosis (SM) is a clonal disorder of mast cells (MCs) frequently associated with vertebral osteoporosis (OP) and subsequent vertebral fractures (VFs). The natural history of this OP remains unclear. Importantly, we do not know whether OP represents an early event triggered alongside MC abnormalities, and whether MC clonality is sufficient to trigger osteoporosis.

**OBJECTIVE:** To describe OP in patients with medullar clonality in cutaneous mastocytosis (CM) and monoclonal mast cell activation syndrome (MMAS) and to compare their osteoporosis characteristics with those of nonadvanced SM patients (bone marrow mastocytosis and indolent systemic mastocytosis).

**METHODS:** We retrospectively analyzed clinical, biological, and densitometric data of 27 CM, 13 MMAS, and 135 SM patients from the Mastocytosis Expert Center (CEREMAST) in Toulouse, France.

**RESULTS:** The OP (respectively 3.7, 30.8, and 34.1%) and VFs (0.0%, 15.4%, and 20%) were less frequent in CM than in MMAS and SM, despite the presence of clonal MCs in the bone marrow. Most patients with OP and VFs in the non-SM groups

had the usual risk factors for OP. Interestingly, the only non-SM patient with a typical SM-like OP had high bone marrow tryptase, developed bone marrow *KIT* mutation during follow-up, and had a family history of SM. Our data show that OP is not a common clinical finding in CM but is frequent in MMAS. When OP and VFs occur in CM and MMAS patients, they differ from the usual phenotype of SM bone fragility.

**CONCLUSIONS:** Our findings suggest that, in most CM patients, the meaning and management of OP differs from that of OP in MMAS and nonadvanced SM. Prospective longitudinal studies and the validation of predictors are needed to identify CM and MMAS patients developing SM-related OP. © 2024 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). (J Allergy Clin Immunol Pract 2024;12:1306-12)

**Key words:** Systemic mastocytosis; Clonal mast cell disorder; Osteoporosis; Fracture

<footnote><sup>a</sup>Rheumatology Centre, Toulouse University Hospital and University Toulouse III, Toulouse, France</footnote>

<footnote><sup>b</sup>INFINITY—Toulouse Institute for Infectious and Inflammatory Diseases, INSERM UMR1291— CNRS UMR5051— University Toulouse III, Toulouse, France</footnote>

<footnote><sup>c</sup>Department of Dermatology and Mastocytosis Expert Centre (CEREMAST), Toulouse University Hospital and University Toulouse III, Toulouse, France</footnote>

<footnote><sup>d</sup>Department of Immunology, Toulouse University Hospital and University Toulouse III, Toulouse, France</footnote>

<footnote><sup>e</sup>Department of Hematology and Mastocytosis Expert Centre (CEREMAST), Necker Children's Hospital and Paris Descartes University, Assistance Publique Hôpitaux de Paris, Paris, France</footnote>

<footnote><sup>f</sup>Centre d'Investigation Clinique de Toulouse CIC1436, Inserm, Team PEPSS, Toulouse, France</footnote>

<footnote>No funding has been received for this study.</footnote>

<footnote>Conflicts of interest: The authors declare that they have no relevant conflicts of interest.</footnote>

<footnote>Received for publication December 29, 2022; revised February 7, 2024; accepted for publication February 16, 2024.</footnote>

<footnote>Available online February 27, 2024.</footnote>

<footnote>Corresponding author: Yannick Degboé, MD, PhD, Rheumatology Centre, Toulouse University Hospital and University Toulouse III, Hôpital Pierre Paul Riquet, 1 Place du Dr Baylac, 31059 Toulouse Cedex 9, France. E-mail: degboe.y@chu-toulouse.fr.</footnote>

<footnote>2213-2198</footnote>

<footnote>© 2024 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</footnote>

<footnote>https://doi.org/10.1016/j.jaip.2024.02.021</footnote>
Abbreviations used

BMM-Bone marrow mastocytosis

BMT-Bone marrow tryptase

BMD-Bone mineral density

CEREMAST-Mastocytosis Expert Center

CM-Cutaneous mastocytosis

IL-Interleukin

ISM-Indolent systemic mastocytosis

MC-Mast cell

MH-Methylhistamine

MMAS-Monoclonal mast cell activation syndrome

OP-Osteoporosis

SM-Systemic mastocytosis

ST-Serum tryptase

VF-Vertebral fracture

WHO-World Health Organization

INTRODUCTION

Systemic mastocytosis (SM) is a rare clonal disorder defined by the proliferation and/or accumulation of abnormal clonal mast cells (MCs) in extracutaneous organs, especially the bone marrow.¹,² Knowledge of the frequent bone involvement in SM, particularly in the indolent form (ISM) and in bone marrow mastocytosis (BMM), is important for Allergists/Immunologists to be aware of.³⁻⁵ Densitometric osteoporosis (OP) is a common skeletal event affecting about a quarter of patients with ISM.⁶⁻¹¹ This OP predominates in trabecular/vertebral bone. The ISM-specific OP results in fractures in approximately 18% to 37% of the patients, who frequently have multiple vertebral fractures.⁶,⁷,⁹,¹¹,¹² Importantly, this phenotype also affects young adults and males.

To date, the occurrence of OP in SM is thought to be related to mediators released by abnormal MCs, resulting in altered bone remodeling and excessive bone loss.⁵,¹³⁻¹⁶ These mediators include histamine, interleukin (IL)-1, IL-6, receptor activator of nuclear kappa B ligand, tumor necrosis factor.¹⁷⁻²⁰ Analysis of ISM patients highlighted a potential role for IL-6²⁰,²¹ and histamine metabolite methylhistamine, high methylhistamine in urine representing a predictor of osteoporotic manifestations, independently associated with OP.¹¹ Whether and how *KIT* mutation modulates the osteoclastic potential, especially in osteoclast precursors (monocytes), is not yet understood.²²

The natural history of bone fragility in SM and its occurrence at an early disease stage is currently poorly understood. Notably, we do not know whether early OP precedes systemic expression of SM (corresponding to the fulfilment of SM diagnostic criteria), and whether MC clonality is sufficient to trigger OP. Similarly, we do not know whether bone loss is progressive after disease onset or occurs at specific periods such as early stage or systemic expression onset. A better understanding of these points may help to improve the management of OP in SM, and also in bona fide cutaneous mastocytosis (CM) and monoclonal mast cell activation syndrome (MMAS), with a medullar clonal MC population.

METHODS

Aims

The primary objective of this study was to describe OP and fragility fractures in patients with bone marrow clonality and CM or

MMAS diagnosis. The secondary objective was to compare OP characteristics of these CM and MMAS patients with nonadvanced SM patients.

Patients

We retrospectively analyzed the data of all successive adult patients with nonadvanced-SM, CM or MMAS from our Mastocytosis Expert Center (CEREMAST) at the University Hospital of Toulouse (CHU Toulouse) between 2004 and 2020.⁷,¹²,²³,²⁴ All nonadvanced-SM patients fulfilled the revised 2022 World Health Organization (WHO diagnostic criteria for BMM or for ("typical") ISM.²⁵,²⁶ Medullar MC clonality was defined as the presence of CD25 expression and/or presence of KIT D816V mutation in medullar MC. We analyzed patients with CM (based on the 2016 criteria²⁷) and patients with MMAS (based on the Consensus papers²⁸,²⁹). All these CM and MMAS patients had clonal medullar MC. However, none of these patients had major bone marrow criterion or 3 minor criteria for SM diagnosis. All patients had enough complementary investigations to classify their disease with certainty.

This study was approved by the institutional review board of Necker Enfants Malades Hospital and was carried out in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients.

Data collection

We collected the following data at diagnosis:

- Demographic: age at diagnosis, age at disease onset.

- Clinical signs of mastocytosis: cutaneous phenotype, presence of MC activation symptoms.

- Fracture profile: history of osteoporotic fracture, fracture type, number of vertebral fractures (VFs), OP risk factors (smoking, self-reported excessive alcohol intake > 20 g/d for women and > 30 g/d for men, body mass index < 19 kg/m², endocrinopathy, early menopause, oral corticosteroid usage, age > 65 y at inclusion, history of inflammatory rheumatism).

- Background treatment: MC reduction therapy, OP treatment, glucocorticoids (general and local), hormonal deprivation for breast and prostate cancer.

- MC disease classification/diagnosis: results of bone marrow biopsy, results of bone marrow aspirate, results of MC phenotyping (CD2, CD25), results of *KIT* point mutation at exon 17, level of serum tryptase (ST), results of skin biopsy (see reference 7 for further details).

- Densitometric assessment: bone mineral density (BMD), T-score and Z-score at hip and lumbar spine (L1-4) sites.

- Bone morphological assessment: plain radiography of thoracolumbar spine.

- Biological assessment: ST, bone marrow tryptase (BMT), serum crosslaps, osteocalcin.

Additional details are available in reference 7.

Bone morphological assessment

Osteoporotic patients were defined as having an osteoporotic fracture identified by anamnesis or by systematic radiographic assessment, or as having densitometric OP according to the current definitions: (1) T-score of -2.5 standard deviation (SD) or lower at the femoral neck or lumbar spine, or (2) Z-score -2.0 SD or lower (premenopausal women and men ≤ 50 y at BMD assessment time-point).⁹,³⁰⁻³²
The BMD was measured using dual x-ray absorptiometry (Lunar Prodigy, GE Healthcare UK) and analyzed by 2 investigators (Y. D. and G. C.).

Vertebral fractures were assessed for all patients by systematic thoracolumbar spine radiographs to identify prevalent fractures using Genant semiquantitative method.33 All radiographs were performed at the time-point of BMD analysis and independently analyzed by 2 experienced rheumatologists (Y. D. and M. E.[see Acknowledgments]). Disagreements were resolved by a third party (M. L).

## Statistical analysis

Variables were described as means and SD. Dichotomous and ordinal variables were described as numbers and frequencies. Normality was tested by a Shapiro-Wilk normality test. Comparisons between subgroups were performed using: Student t-test for the normally distributed data, and a nonparametric Wilcoxon rank-sum test for non-normally distributed data. For multiple groups comparisons, we used the analysis of variance test for normally distributed variates, and the Kruskal-Wallis test for non-normally distributed variates. The Fisher exact test (or $\chi^2$ test if appropriate) were used for dichotomous variables. Frequencies were compared using a $\chi^2$ or a Fischer exact test. A P value less than .05 was considered statistically significant with a 95% confidence interval (95% CI). All analyses were performed using the GraphPad Prism v9.5.0 (GraphPad Software, Inc., La Jolla, CA.

# RESULTS

## Patient characteristics

We analyzed 27 CM patients, 13 MMAS patients, and 135 nonadvanced SM patients (23 BMM and 112 ISM) with a complete dataset (Table I). Except for age at diagnosis/first symptoms, which was older in the MMAS group, demographic characteristics were similar across groups (Table I).

## Osteoporosis profile in CM, MMAS, and nonadvanced SM patients

Osteoporosis in non-advanced-SM is typically described as trabecular with multiple vertebral fractures. Among non-advanced-SM, BMM and ISM did not differ in terms of hip T-scores, lumbar T-scores and frequency of osteoporotic fractures (Figure E1; available in this article's Online Repository at www.jaci-inpractice.org). In our cohort, OP was more frequent in SM and MMAS patients than in CM patients (Table II). This OP often occurred in the presence of risk factors in CM and MMAS patients; OP without risk factors represented 20.0% (1 out of 5) of total CM and MMAS patients (Table III) and 43.5% (20 out of 46) of SM patients with OP (non-significant p value). In terms of fractures, we observed significantly fewer fractures in the CM patients, especially vertebral fractures. Lumbar BMD was higher in CM patients compared to MMAS and SM patients. CM patients had higher lumbar T-scores and lumbar BMD than their MMAS and SM counterparts. Five SM patients were excluded from lumbar spine BMD analysis because of heterogenous values mostly related to vertebral fractures. No patient was excluded for this reason in the CM/MMAS groups. No difference was observed at the hip site. Six patients from the SM group and 1 patient from the CM group had osteosclerosis defined by a T-score or Z-score > +2 SD at lumbar spine and/or hip. Crosslaps levels were similar, but BMT was higher overall in the SM group, especially in patients with OP and fragility

fractures (Figure 1; Table E1; available in this article's Online Repository at www.jaci-inpractice.org).

Five out of 40 CM/MMAS patients displayed osteoporotic features (Table III), all of whom were women. Most of them (4 of 5) had risk factors for OP. We observed 3 different profiles among these patients: (1) patient 1 (CM), a young woman without risk factors for OP with moderate densitometric OP (baseline lumbar Z-score -2.1 SD; 1.017 g/cm²; normal hip BMD) and with stable BMD over 3 years of follow-up. (2) patient 2 (MMAS), a postmenopausal woman who experienced a decrease in lumbar BMD despite using oral bisphosphonates. She had multiple other risk factors for OP. Annual zoledronate stabilized her BMD with rapid decrease after zoledronate discontinuation. Interestingly, patient 2 developed a bone marrow KIT mutation at low level (0.1%) during follow-up, had high BMT, and her daughter was diagnosed with ISM with OP. (3) 3 postmenopausal women (MMAS) experienced lumbar BMD decrease and 2 of them (patients 4 and 5) developed fragility fractures during follow-up in the context of multiple meaningful risk factors.

## Longitudinal evolution of BMD in CM and MMAS patients

We performed densitometric follow-up for 31 patients (77.5%) in the CM/MMAS cohort (Figure 2; Figure E2; available in this article's Online Repository at www.jaci-inpractice.org). The duration between the first 2 densitometries was at least 1 year (mean 18.4 mo; SD 8.9). Lumbar and hip BMDs remained stable during follow-up at the population scale.

## DISCUSSION

In this study, we aimed to describe OP in patients with clonal bone marrow MC, diagnosed as CM or MMAS, and to determine whether it presents in the same way as in nonadvanced SM patients. Our results indicate that OP is less frequent in CM than in SM and MMAS. In addition, the CM and MMAS with OP patients do not exhibit the usual OP profile of SM. In the few cases observed, these patients had major additional risk factors for OP (such as age and menopause).

The observation of MMAS patient 2 (Table III) with (1) familial case of ISM + OP, (2i) low level of bone marrow KIT mutation, (3) high BMT, and (4) "difficult to treat" OP needing long-term zoledronate to maintain BMD, suggest common underlying mechanisms for OP between MMAS and ISM. The OP is more prevalent in MMAS than in CM. However, based on our data, the presence of abnormal clonal medullar MC (especially *KIT* mutated) in CM/MMAS patients (but not fulfilling diagnostic criteria for SM) does not appear to be sufficient to trigger OP and subsequent fragility fractures. This is in line with the description of murine models with *KIT* mutation. Mutations developed in late progenitors³⁴ do not recapitulate SM features like early mutated progenitors.³⁵ Additional dysregulation(s) not screened in routine assessment may be needed to trigger OP in these patients. We hypothesize that mutation in osteoclast precursors (including monocyte) may be involved.²²

We observed that patients with OP, either MMAS or SM, had higher levels of BMT. Moreover, SM patients with fragility fractures had the highest level of BMT. This SM result is in line with our previous reports.⁷,¹² We hypothesize that high BMT is a marker of bone fragility driven by MCs, which will need to be
<table><caption>TABLE I. Patients' characteristics</caption><thead><tr><th>Characteristics</th><th>CM (n = 27)</th><th>MMAS (n = 13)</th><th>SM (n = 135)*</th><th>P value†</th></tr></thead><tbody><tr><td><strong>Criteria for SM</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Major: MC multifocal dense infiltrate (%)</td><td>0/27 (0.0)</td><td>0/13 (0.0)</td><td>56/119 (47.1)</td><td>&lt;.0001</td></tr><tr><td>3 Minor criteria (%)</td><td>0/27 (0.0)</td><td>0/13 (0.0)</td><td>105/135 (77.8)</td><td>&lt;.0001</td></tr><tr><td>At least 1 minor criteria (%)</td><td>27/27 (100.0)</td><td>13/13 (100.0)</td><td>135/135 (100.0)</td><td>NS</td></tr><tr><td>Minor: &gt;25% atypical cells (%)</td><td>5/27 (18.5)</td><td>2/13 (15.4)</td><td>94/133 (70.7)</td><td>&lt;.0001</td></tr><tr><td>Minor: CD2+/CD25+ MCs (%)</td><td>10/27 (37.0)</td><td>4/13 (30.8)</td><td>78/92 (84.9)</td><td>&lt;.0001</td></tr><tr><td>Minor: KIT mutation (%)</td><td>23/27 (85.2)</td><td>9/13 (69.2)</td><td>122/131 (93.1)</td><td>.015</td></tr><tr><td>Minor: ST &gt; 20 ng/mL (%)</td><td>3/27 (11.1)</td><td>2 (15.4)</td><td>95/135 (70.4)</td><td>&lt;.0001</td></tr><tr><td>ST (ng/mL), median (range)</td><td>10.7 (23.0)</td><td>7.6 (48.5)</td><td>27.1 (334.1)</td><td>&lt;.0001</td></tr><tr><td><strong>Clinical characteristics</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Men, n (%)</td><td>11 (40.7)</td><td>7 (53.8)</td><td>58 (43.0)</td><td>NS</td></tr><tr><td>Age at diagnosis, y (SD)</td><td>38.9 (13.1)</td><td>50.7 (13.4)</td><td>46.1 (15.8)</td><td>.018 (NS/NS/.023)</td></tr><tr><td>Age at first symptoms, y (SD)</td><td>30.8 (11.5)</td><td>45.2 (11.9)</td><td>39.0 (15.8)</td><td>.011 (.016/NS/.0437)</td></tr><tr><td>Maculopapular lesions, n (%)</td><td>27 (100.0)</td><td>0 (0.0)</td><td>112 (83.0)</td><td>&lt;.0001</td></tr><tr><td>MC mediator release symptoms, n (%)</td><td>21 (77.8)</td><td>13 (100.0)</td><td>115 (85.2)</td><td>NS</td></tr></tbody></table>

NS, Nonsignificant.

*Nonadvanced SM; refers to 23 BMM patients and 112 ISM patients (no advanced SM).

†One-way analysis of variance test for normally distributed variates, Kruskal-Wallis test for non-normally distributed variates; comparison: across conditions (MMAS vs CM/MMAS vs SM/CM vs SM); $\chi^2$ or Fischer exact test for proportions.

<table><caption>TABLE II. Bone baseline characteristics of CM, MMAS, and SM patients</caption><thead><tr><th>Characteristics</th><th>CM (n = 27)</th><th>MMAS (n = 13)</th><th>SM (n = 135)*</th><th>P value†</th></tr></thead><tbody><tr><td>OP, n (%)</td><td>1 (3.7)</td><td>4 (30.8)</td><td>46 (34.1)</td><td>.007</td></tr><tr><td>OP without risk factors, n (%)</td><td>1 (3.7)</td><td>0 (0.0)</td><td>20 (14.8)</td><td>NS (.103)</td></tr><tr><td>Fractures, n (%)</td><td>0 (0.0)</td><td>2 (15.4)</td><td>27 (20.0)</td><td>.008</td></tr><tr><td>Vertebral fracture, n (%)</td><td>0 (0.0)</td><td>2 (15.4)</td><td>25 (18.5)</td><td>.013</td></tr><tr><td>Multiple VFs, n (%)</td><td>0 (0.0)</td><td>1 (7.7)</td><td>14 (10.4)</td><td>NS (.104)</td></tr><tr><td>Peripheral fracture, n (%)</td><td>0 (0.0)</td><td>1 (7.7)</td><td>13 (9.6)</td><td>NS</td></tr><tr><td>Lumbar T-score (SD)</td><td>-0.3 (1.4)</td><td>-1.5 (1.5)</td><td>-1 (1.5)</td><td>0.034 (.019/NS/.043)</td></tr><tr><td>Lumbar Z-score (SD)</td><td>-0.2 (1.6)</td><td>-1.3 (0.9)</td><td>-0.7 (1.4)</td><td>NS</td></tr><tr><td>Lumbar BMD, g/cm<sup>2</sup> (SD)</td><td>1.156 (0.172)</td><td>1.006 (0.191)</td><td>1.075 (0.190)</td><td>.036 (.018/NS/.047)</td></tr><tr><td>Lumbar densitometric OP, n (%)</td><td>1 (3.7)</td><td>4 (30.8)</td><td>20 (15.2)</td><td>.021</td></tr><tr><td>Hip T-score (SD)</td><td>-0.3 (1.1)</td><td>-0.9 (1.3)</td><td>-0.7 (1.3)</td><td>NS</td></tr><tr><td>Hip Z-score (SD)</td><td>-0.1 (0.9)</td><td>-0.7 (0.9)</td><td>-0.2 (0.9)</td><td>NS</td></tr><tr><td>Hip BMD, g/cm<sup>2</sup> (SD)</td><td>0.976 (0.142)</td><td>0.908 (0.195)</td><td>0.921 (0.170)</td><td>NS</td></tr><tr><td>Hip densitometric OP, n (%)</td><td>0 (0.0)</td><td>1 (7.7)</td><td>6 (4.5)</td><td>NS</td></tr><tr><td>Bone pain (%)</td><td>1 (3.7)</td><td>1 (7.7)</td><td>15 (11.1)</td><td>NS</td></tr><tr><td>CTX, pg/mL (SD)</td><td>428 (270)</td><td>476 (310)</td><td>428 (316)</td><td>NS</td></tr><tr><td>BMT, ng/mL (SD)</td><td>194 (353)</td><td>89 (196)</td><td>1,481 (4,910)</td><td>&lt;.0001</td></tr></tbody></table>

CTX, Crosslaps; NS, nonsignificant.

*Nonadvanced SM; refers to 23 BMM patients and 112 ISM patients (nonadvanced SM).

†One-way analysis of variance test for normally distributed variates, Kruskal-Wallis test for non-normally distributed variates; comparison: across conditions (MMAS vs CM/MMAS vs SM/CM vs SM); $\chi^2$ test for proportions.

confirmed in a different cohort. Currently, confounding factors such as menopause or other OP risk factors impede any firm conclusion.

The clinical consequences of medullar clonal MC in patients without SM is still a matter of debate. It must be demonstrated whether these patients develop ISM features. In our cohort, 3 patients (2 CM, 1 MMAS) evolved from putatively “pre-ISM” to ISM.

Moreover, descriptions of OP occurrence in ISM or even in CM and MMAS, remain challenging because (1) densitometric OP is asymptomatic, (2) osteoporotic VFs can be asymptomatic, (3) some nonadvanced SM patients present with OP as an isolated inaugural manifestation of the disease (in our cohort: 9 of 135 SM; 6.7%).

Many SM, CM, and MMAS patients were referred to our expert center because of dermatological or allergic manifestations. These characteristics need to be considered to better describe the natural history of OP in SM. Consequently, OP should be routinely assessed for in patients with suspected ISM/BMM.

The main limitations of this study are the low number of CM/MMAS patients and the fact that sometimes the CD25 can be reactional and not the signature of clonality of MCs. However, we have provided new data regarding bone status of this specific subset of patients. Future longitudinal studies about the evolution of bone status in these patients are essential to better describe the natural history of OP in the different forms of mastocytosis.
<table><caption>TABLE III. Individual data of CM and MMAS patients with osteoporotic fracture</caption><thead><tr><th>Characteristics</th><th>Patient 1 (♀)</th><th>Patient 2 (♀)</th><th>Patient 3 (♀)</th><th>Patient 4 (♀)</th><th>Patient 5 (♀)</th></tr></thead><tbody><tr><td>Diagnosis features</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Diagnosis</td><td>CM</td><td>MMAS</td><td>MMAS</td><td>MMAS</td><td>MMAS</td></tr><tr><td>Age at diagnosis/first symptoms/inclusion, y</td><td>42/40/42</td><td>50/40/47</td><td>65/63/65</td><td>62/50/63</td><td>77/60/77</td></tr><tr><td>Bone marrow KIT mutation</td><td>+</td><td>—</td><td>—</td><td>+</td><td>+</td></tr><tr><td>CD2/CD25+</td><td>—</td><td>+</td><td>+</td><td>—</td><td>NA</td></tr><tr><td>Atypical cells*</td><td>+</td><td>—</td><td>—</td><td>—</td><td>—</td></tr><tr><td>ST, ng/mL</td><td>11.0</td><td>21.0</td><td>3.6</td><td>15.0</td><td>9.2</td></tr><tr><td>BMT, ng/mL</td><td>58.9</td><td>732</td><td>3.7</td><td>60</td><td>94</td></tr><tr><td>Bone characteristics</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>OP risk factors</td><td>-</td><td>Cancer hormone deprivation, Steroids, smoking, menopause, daughter with ISM and OP</td><td>Menopause</td><td>Menopause<br>Breast cancer hormone deprivation</td><td>Menopause<br>Elderly<br>Chronic kidney disease stage G3b</td></tr><tr><td>Bone phenotype at baseline</td><td>Lumbar OP</td><td>Lumbar OP</td><td>Lumbar OP</td><td>Lumbar OP<br>1 VF<br>Initial bone loss despite zoledronate<br>1 VF associated with anastrazole (relapse)</td><td>Lumbar and hip OP<br>2 VF, hip, wrists</td></tr><tr><td>Bone events during follow-up</td><td>None</td><td>Lumbar BMD degradation<br>Bone marrow KIT mutation at low level during follow-up (0.1%)</td><td>Lumbar BMD degradation</td><td></td><td>Fractures: 4 VF, shoulder, pelvis bone; stabilization with denosumab</td></tr><tr><td>Baseline lumbar BMD, g/cm²</td><td>0.879</td><td>0.808</td><td>0.894</td><td>0.782</td><td>0.780</td></tr><tr><td>Baseline lumbar OP†</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Baseline hip BMD, g/cm²</td><td>0.720</td><td>0.823</td><td>0.908</td><td>0.799</td><td>0.577</td></tr><tr><td>Baseline hip OP†</td><td>—</td><td>—</td><td>—</td><td>—</td><td>+</td></tr><tr><td>Baseline CTX, pg/mL</td><td>835</td><td>198</td><td>1,260</td><td>339</td><td>229</td></tr></tbody></table>

NA, Not applicable.

*Atypical cells refers to marrow MCs.

†OP refer to T-score ≤ −2.5 SD.

<figure><img src="image_2.png" /><figcaption>FIGURE 1. Baseline tryptase levels in (A) bone marrow and (B) serum. FF, fragility fracture; SM, nonadvanced systemic mastocytosis (ISM and BMM). The black line corresponds to the median value.</figcaption></figure>
<figure><img src="image_3.png" /><figcaption>FIGURE 2. (A–D) Longitudinal densitometric follow-up of CM and MMAS patients. *DXA1*, first densitometry; *DXA2*, second densitometry; *NS*, nonsignificant *P* value with 2-tailed paired *t*-test.</figcaption></figure>

## CONCLUSION

Patients with MMAS and with nonadvanced SM have a similar frequency of OP. Conversely, OP is not common among CM patients and is often associated with traditional risk factors. In most cases, its characteristics do not appear similar to OP in characterized nonadvanced SM.

## Acknowledgments

We would like to thank. Mathilde Negretto (clinical research associate) for the database management. We would also like to thank Beatrice Monmarty (radiology technician) for performing the densitometry and Marine Eischen (MD, rheumatologist) for the spine radiograph analysis.

Y. Deghoé and C.B. Livideanu were responsible for conceptualization, data curation, and supervision. Y. Deghoé was responsible for format analysis, original draft preparation, manuscript review, and editing. Y. Deghoé, P.-A. Apoil, O. Hermine, C. B. Livideanu handled the investigation. Y. Deghoé, A. Ruyssen-Witrand, and C. B. Livideanu developed the methodology. Y. D Deghoé, O. Hermine, C. B. Livideanu handled project administration; Resources: Y. Deghoé, M. Severno-Friere, G. Couture, P.-A. Apoil, C. Paul, M. Laroche, and C. B. Livideanu were responsible for resources. All authors reviewed the final version of the manuscript for intellectual content and approved it.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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