Scoring proposal to address bone marrow evaluation in patients with severe unexplained osteoporosis and suspected systemic mastocytosis

Background. Osteoporosis may represent the only symptom of onset of systemic mastocytosis (SM). As distinct from patients with other mediator-related symptoms, a score to predict the association with an underlying SM in patients with unex-plained osteoporosis is lacking. Furthermore, normal serum basal tryptase (sbT) levels do not exclude SM diagnosis, and sbT levels higher than 8 ng/mL might be due to other causes, e.g., hereditary alpha-tryptasemia (HAT), that has been recently documented in about 5% of the general population. Aims. This study aimed at analyzing the clinical features of a large series of adult patients referred to our multidisciplinary team for unexplained osteoporosis and suspected SM, in the absence of skin lesions. Secondly, we aimed at identifying cri-teria able to predict the diagnosis of SM and provide an indication for bone marrow (BM) studies and also at estimating the influence of HAT in the diagnostic deci-sions. Methods. One hundred thirty-nine patients with unexplained osteoporosis who un-derwent BM evaluation from September 2009 to November 2022 were retrospec-tively studied. In the entire cohort, 28.8% of patients were males, the median age at diagnosis was 59 years (range 21-86 years) and the median sBT levels of 18.2 ng/mL (range 4-165 ng/mL). Diagnosis of SM was made according to the 2016 World Health Organization (WHO) criteria. Other causes of secondary osteoporosis had been previously excluded. Results. After BM study, 63 patients (45.3%) were diagnosed with SM, of whom 54 (85.7%) had bone marrow Mastocytosis, seven (11.1%) had indolent SM, with previously unrecognized skin lesions and two patients (3.2%) had SM with Associ-ated Hematological Neoplasm (SM-AHN). Mediator-related symptoms were re-ported in 37 SM patients (58.7%). Seventy-six patients (54.7%) did not fulfil the WHO diagnostic criteria for SM and were used as a control group. SM patients were younger than controls (median age 57 vs 61 years, respectively; p=0.0096), had higher median sbT level (25.9 vs 16.1 ng/mL, p<0.001) and presented more frequently bone fragility fractures (93.6% vs 77.6%, respectively; p=0.0092). No significant differences according to gender and the presence of mediator-related symptoms, including anaphylactic events, were found between the two groups (p=0.3473 and 0.0890, respectively). Fifty-eight patients with sbT ≥ 8 ng/mL un-derwent genetic evaluation for HAT, of whom 24 patients displayed duplication or triplication within the TPSAB1 gene encoding alpha-tryptase. Of note, 7 out of 34 patients with SM were found to have HAT (20.5%), whereas HAT was document-ed in 17/24 patients negative for SM (70.8%). Multivariate analysis identified three independent predictive factors, including age (p=0.0096), sbT level ≥19 ng/mL (p <0.0001) and the presence of vertebral fractures (p=0.0090), that were used to build a scoring model able to predict the diagnosis of SM before BM. Patients with a score <3 had a lower probability of having mastocytosis than patients with a score ≥3 (28.5% and 71.4%, respectively, p<0.0001). Of note, when our score was ap-plied to patients with a known HAT status, after the correction of sbT levels de-pending on the number of additional copies of the alpha-tryptase gene, we noted an increased specificity (79.1 vs 67.1%) with similar sensitivity (73.5 vs 71.4%). Conclusion. Our data remark the importance of considering the diagnosis of SM in cases of unexplained osteoporosis, but in our series, more than half of patients who underwent BM study in suspicion of SM were found to be negative. Thus, our pro-posed score could avoid unuseful BM studies, allowing the identification of patients with the highest probability of having mastocytosis. Further studies are needed to validate our results and also to verify if tests for HAT and KIT D816V mutation in peripheral blood in patients with unexplained osteoporosis and a score <3 can lower the risk of misdiagnosing patients with mastocytosis.