Bone manifestations of SM: Part Two

SM patients frequently experience bone pain, with one study finding 54% reporting it, with 18% reporting it as severe or intolerable. Another study (Barete 2010) of 75 mastocytosis patients found that 49% had bone involvement, 23% had osteoporosis (with 17% having vertebral fracture), 8% had osteosclerosis and 4% had a mixed pattern. When considering just ISM patients, 51% had osteoporosis with or without fracture. Fracture was more likely in older patients, male patients, and in patients with urinary n-methylhistamine levels above the normal cutoff (160 umol/mol creatinine.) A 2002 study on men with osteoporosis also found that men with osteoporosis and above normal n-methylhistamine levels were found to have bone marrow infiltration by mast cells.

One study (Guillaume 2013) looked at not only radiographic markers of bone abnormalities, but also at how serum markers associated with bone metabolism correlated to findings. In this study, bone mineral density was abnormal in 63% of patients, with 9/24 patients having osteoporosis and 15/24 having osteopenia. There was not found to be any relationship between the lesions seen or BMD alterations and age, sex, WHO mastocytosis type, tryptase level, serum parathyroid hormone level or serum 25-hydroxyvitamin D3 level.

However, levels of c-telopeptide, deoxypyridinoline and osteoprotegerin were highly associated with mastocytosis severity and tryptase level. C-telopeptides of type I collagen and deoxypyridinoline are markers of bone resorption, osteoprotegerin is a marker of osteoclast differentiation, and bone specific alkaline phosphatase is a marker of bone formation. Additionally, bone specific alkaline phosphatase was found to be correlate with tryptase level. In particular, higher levels of c-telopeptide and osteoprotegerin are associated advanced SM and high baseline tryptase levels. This study found that SM patients with c-telopeptide level above 2800 pmol/L had advanced disease 77% of the time; with deoxypyridinoline above 5.9 nmol/L had advanced disease 67% of the time; and osteoprotegerin above 5.5 pmol/L had advanced disease 67% of the time. Furthermore, all SM patients had higher levels of these markers when compared to healthy controls, regardless of WHO variant (SM vs ASM.)

A different study (Rossini 2011) found that bone turnover markers in serum did not correlate well with BMD or serum tryptase in ISM patients with osteoporosis. However, they were found to correlate well with bone turnover levels and serum tryptase in ISM patients with osteosclerosis. In particular, osteosclerosis was associated more with high baseline tryptase and high bone turnover markers. Osteosclerosis is more closely associated with aggressive forms of SM, including ASM and SM-AHNMD, and has been reported in 8-19% of patients with various forms of SM in multiple studies. Scattered sclerotic lesions have been noted in smoldering systemic mastocytosis (SSM) patients.

Previous studies had reported 3-8% of SM patients having an “osteopetrosis-like abnormality,” which has since been described as “skeletal disease caused by increased bone turnover.” The exact reason for this finding is unclear, but mast cells are known to stimulate osteoblast proliferation and activation. This increases production of osteoprotegerin, which in turn limits bone resorption.

In evaluating the WHO diagnostic criteria for mastocytosis, Escribano et al evaluated parameters found in ASM patients. 8/11 of them had C-findings that did not involve pathologic fracture. 7/8 of these patients had low LDH and increased B2 microglobulin, both of which are unusual in ISM. The other 3 patients met the criteria for ASM only because of their bone lesions. These patients first experienced pathologic fracture from lesions 18, 8 and 5 years after diagnosis with ASM, and 39, 34 and 15 years from SM diagnosis, respectively. All three patients had normal LDH and B2 microglobulin levels, with only 1/3 patients having progression of other disease parameters.

Bisphosphonate therapy is usually recommended for any SM patient with osteoporosis. It increases vertebral BMD and prevents osteoporotic fractures, but is less effective at increasing hip and femoral neck BMD. Dr. Pardanini recommends following guidelines for bisphosphonate use in multiple myeloma as a guide for use in SM. Interferon-a is the next line therapy for treating mastocytosis related bone pain and osteoporosis, particularly in patients who have new vertebral fractures despite bisphosphonate therapy. In severe cases, radiation therapy can help manage pain and bone loss.



Rossini M, Zanotti R, Bonadonna P, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone. 2011;49(4):880-885.

Barete S, Assous N, de Gennes C, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis. 2010; 69(10):1838-1841.

Biosse-Duplan M, Baroukh B, Dy M, de Vernejoul MC, Saffar JL. Histamine promotes osteoclastogenesis through the differential expression of histamine receptors on osteoclasts and osteoblasts. Am J Pathol. 2009;174(4):1426-1434.

Brumsen C, Papapoulos SE, Lentjes EG, Kluin PM, Hamdy NA. A potential role for the mast cell in the pathogenesis of idiopathic osteoporosis in men. Bone. 2002 Nov;31(5):556-61.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine, Vol 126, No 1, January 2013

Reinacher-Schick, S. Petrasch, B.J. Longley, C. Teschendorf, U. Graeven, W. Schmiegel. c-Kit mutation and osteopetrosis-like osteopathy in a patient with systemic mast cell disease. Ann Hematol, 77 (1998), pp. 131–134

van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans, J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Peter Valent, Wolfgang R. Sperr and Cem Akin. How I treat patients with advanced systemic mastocytosis. December 23, 2010; Blood: 116 (26.)

Laura Sánchez-Muñoz, Ivan Alvarez-Twose, Andrés C García-Montero, Cristina Teodosio, María Jara-Acevedo, Carlos E Pedreira, Almudena Matito, Jose Mario T Morgado, Maria Luz Sánchez, Manuela Mollejo, David Gonzalez-de-Olano, Alberto Orfao and Luis Escribano. Evaluation of the WHO criteria for the classification of patients with mastocytosis. Modern Pathology (2011) 24, 1157–1168.

Pardinini, Animesh. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). April 18, 2013; Blood: 121 (16.)