Systemic Mastocytosis (SM) comprises a heterogeneous group of disorders of mast cell proliferation. Infiltration, including skin and bone, of multiple mast cells may occur as cutaneous and systemic variants. A rare form of osteoporosis has been also described as expression of the skeletal involvement. Here, we describe a case of a 57-years-old woman with SM and, according to the clinical diagnosis, evaluate the possible mechanism underlying osteoporosis. Moreover, a review of the literature, particularly regarding the use of bisphosphonates in this rare disease is also presented.