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Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Literature review (part 2)

There have been several publications on bone involvement in SM. Importantly, not all of these papers define SM the same way. Some define it as ISM, while others define it as ISM, SSM, SM-AHNMD and ASM. (I personally am sloppy about not specifying when I mean ISM versus when I mean any all the systemic proliferative groups. So if it’s not clear, please ask.) Another thing to be aware of is that the terminology for osteosclerosis is not consistent. It is sometimes referred to as osteocondensation (this is primarily a term used by French researchers). I have done some digging recently on this and cannot find any indication that these two terms do not represent the same phenomenon (increased deposition of bone), so if anyone knows of any papers or sources that say they are different, please let me know.

A 2010 paper (Barete 2010) defines SM as ISM, SSM, SM-AHNMD and ASM. They divided the study into two groups: Variant 1 (non-aggressive), ISM and SSM; and Variant 2 (aggressive), SM-AHNMD and ASM.

Overall (ISM, SSM, SM-AHNMD and ASM), 49% of patients had some form of bone involvement. Osteoporosis was most common, occurring in 31% of patients. 17% had a vertebral fracture. 8% had osteosclerosis. 4% had a mixed pattern, so more than one type of bone involvement. 5% had osteopenia with a previous fracture (this could be unrelated to mast cell disease, like an arm broken in a fall). Only one patient had a focal area of osteolysis with spontaneous fracture.

56% of variant 2 (aggressive) group had osteoporosis, compared to 23% of variant 1. However, when they excluded people who were classified as variant 2 based upon bone involvement, the association dropped to 17% variant 2 with osteoporosis and 23% of variant 1. Osteoporosis associated with vertebral fracture affected 48% variant 1 and 8% variant 2. Osteoporosis was also found to be associated with fewer GI symptoms, with 39% variant 1 having GI issues while 65% variant 2 did.

A total of six patients (out of a total group of 75) had osteosclerosis. One ISM, one SSM, three ASM and one SM-AHNMD patient had osteosclerosis. This translates to two in the variant 1 group and four in the variant 2 group, so twice as many in the aggressive group (ASM, SM-AHNMD) as in the non-aggressive group. 66% of patients in variant 2 with osteosclerosis had a blood count abnormality (anemia, thrombocytopenia, eosinophilia) vs 12% in variant 1. 83% of patients in variant 2 with osteosclerosis had received cytoreductive therapy vs 33% in variant 1, and higher tryptase level was associated with osteosclerosis. Overall, this means that osteosclerosis was associated with a more severe disease presentation (a patient with ISM and osteosclerosis may have a blood count abnormality), but this study does not provide any insight as to whether osteosclerosis is a marker associated with progression toward ASM or SM-AHNMD.

A 2011 paper (Guillaume 2011) assessed bone involvement in a group of CM and SM patients. In this study, SM included ISM, ASM and SM-AHNMD. 45 patients were included.  They found one patient with osteolysis, eight with osteocondensation (a form of osteosclerosis), four with a mixed pattern and three with fractures. They found no association between the presence of radiologic lesions (lesions detected by imaging techniques) and severity (here classified as non-aggressive: ISM and CM, and advanced: ASM and SM-AHNMD).

This study also looked at chemical markers used for bone remodeling. They found that markers associated with both bone resorption and bone formation were higher in mastocytosis patients than in the general population. The higher levels were thought to represent increased number of osteoblasts and osteoclasts due to the increase in mast cells. Osteoprotegerin was also higher in mastocytosis patients. This is a protein released by osteoblasts that regulates the activity of osteoclasts. Levels of C-telopeptide were significantly higher in patients with SM-AHNMD or ASM than in patients with ISM or CM.

A 2011 paper (Rossini 2011) investigated the relationship between tryptase and bone turnover markers (bone specific alkaline phosphatase, C-telopeptide, osteocalcin) in ISM patients. A total of 82 patients were enrolled in the study. 36% had bone involvement. 20% had osteoporosis, with 18.7% found in the spine and 2.5% at the hip. Five patients had a history of bone breaks outside of the spine. 27 patients had vertebral fractures. Two patients had osteosclerotic features and also had particularly high tryptase levels. Another study previously reported that high tryptase can be associated with increased bone density (Kushnir-Sukhov 2006).

This study had a large amount of ISM patients without skin lesions (55%). A very important finding of this particular study was that ISM patients without skin lesions are at the same risk for osteoporosis. As lesions are often one of the more identifiable markers of mastocytosis, the author raises the very valid point that osteoporosis may in some people be the only sign of latent ISM.

This paper reported that “diffuse osteosclerosis associated with SM is not a[n] “osteopetrosis-like osteopathy”, as previously reported, but a skeletal disease characterized by increased bone turnover.” This is important, as they have previously been equated for lack of distinction. The author further notes that the “pathophysiology of SM-related osteosclerosis remains obscure, although it is known that MCs can exert a direct stimulatory effect on osteoblast proliferation, recruitment, and activity.”

This study found that bone mineral density and serum tryptase did not correlate with the serum markers of bone turnover. However, it did find that ISM patients with osteosclerosis had higher tryptase and bone turnover markers (bone specific alkaline phosphatase and C-telopeptides of type I collagen) than ISM patients with other types of bone involvement.

(Literature review continued tomorrow)


Maurizio Rossini, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.

Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128:344–50.

Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.

Kushnir-Sukhov NM, Brittain E, Reynolds JC, Akin C, Metcalfe DD. Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis. Int Arch Allergy Immunol. 2006;139(3):265-70. Epub 2006 Jan 30.

Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.

Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7

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.