Discussion

We present a case of diffuse osteosclerosis secondary to SM. Although rare, osteosclerosis has significant clinical implications, as it is frequently secondary to several serious conditions (Table 2), including malignant (infiltrative lymphoma or leukemia, osteoblastic metastases) or hematological (myelosclerosis, mastocytosis) disorders [8]. Other causes include congenital (osteopetrosis) and metabolic (hypoparathyroidism) processes.

Differential diagnoses | Relevant investigations
Hematological disorders
Myelofibrosis | Blood filmBone marrow and trephine (BMAT)Protein electrophoresisFree light chain ratio
Sickle cell disease
Osteosclerosing multiple myeloma
Mastocytosis | Serum tryptase, BMAT
Malignancy—osteoblastic metastases
Prostate and breast | Breast mammographyRenal tract imaging
Lymphoma: infiltrative | Flow cytometryBlood filmBiopsy
Leukemia: infiltrative
Metabolic
Renal osteodystrophy | UEC, PTH, CMP, BTM, bone biopsy
Hypothyroidism | TFT
Hypoparathyroidism | PTH, CMP
Poisoning
Fluorosis | Urinary fluoride
Idiopathic
Paget disease | bsALP, XR, bone scan
Genetic: sclerosing bone dysplasias (includes, but not exclusive to):
Osteopetrosis | Genetic testing
Pyknodysostosis
Osteomesopyknosis
Hyperostosis
Other
Hepatitis C-associated osteosclerosis (HCAO) | Hep C serology

SM is an uncommon neoplastic disease of mast cells, characterized by proliferation and accumulation in skin and other organs. It is diagnosed based upon minor and major criteria and is associated with a c-KIT gain-of-function mutation, which is found in >80% of cases [10, 11]. KIT-negative SM are very uncommon and associated with lower mast cell burden, variable tryptase levels and limited response to KIT-targeted therapies [11]. Mast cells in bone marrow may secrete mediators that promote osteoclastic or osteoblastic activity. It should be considered as a differential diagnosis in any individual presenting with atopic symptoms and unexplained osteoporosis/osteosclerosis. Management of indolent and smoldering mastocytosis is aimed at symptom control, with cytoreductive therapies generally reserved for advanced SM to mitigate organ damage and extend survival [12]. Our patient fulfilled at least 1 major criterion (multifocal dense infiltrates of mast cells with ≥15 mast cells in aggregates in bone marrow biopsies) and 1 minor criterion (persistently elevated serum tryptase >20 ng/mL, SI: >20 μg/L).

Once a diagnosis of SM is made, identification of “B and C” findings would highlight the degree of mast cell burden and organ involvement/dysfunction. This allows for classification of SM which may require targeted and systemic therapy [10]. These findings were absent in our patient.

Bone disease in mastocytosis either manifests as osteoporosis or sclerotic bone lesions. Osteoporosis is more common than osteosclerosis (50% of SM cases vs 5% to 6% of indolent SM cases) [4], although osteosclerosis is reported in up to 75% of cases with aggressive SM, which carries a poorer prognosis (median life expectancy of 41 months) [13]. The mechanism underlying mastocytosis-related bone disease remains poorly understood, but it is thought to be related to inflammatory mediators secreted by mast cells, resulting in an imbalance in osteoblastic and osteoclastic activity. Bone loss in mastocytosis has been associated with pro-inflammatory mediators (histamine, heparin, tumor necrosis factor [TNF] alpha, and interleukin (IL)-1, IL-6, IL-17) that lead to increased osteoclastic or reduced osteoblastic activity [4]. An immunosuppressive profile (lower interferon-gamma [IFN-γ] and IL-6) has been associated with mastocytosis-related osteosclerosis [4]. In contrast to osteoporosis cases, markedly elevated tryptase levels, higher levels of bone formation/turnover markers, and lower receptor activator of nuclear factor kappa-B ligand (RANKL) levels have been observed in diffuse bone disease compared to healthy controls [2]. In our patient, lack of end-organ involvement classified her as indolent SM. However, regular surveillance is highly recommended to monitor for transformation.

Although treatment of the underlying pathology remains key to reversing or preventing progression of osteosclerosis due to other causes, published literature is limited in the context of SM. Although one case report demonstrated resolution of osteosclerosis after allogenic stem cell hematopoietic stem cell transplant and subsequent cytoreductive therapy after one year [14], SM-related osteosclerosis is not a current indication for cytoreductive therapy. In contrast, studies have predominantly addressed osteoporosis associated with SM. Review of the literature has suggested improved BMD and suppression of bone turnover markers after use with bisphosphonates, in particular intravenous zoledronic acid [12], as well as denosumab [15] once alternative causes for osteoporosis have been considered [16]. However, a caveat to this includes the risk of developing an acute-phase reaction, which may be mitigated with pre-medications with simple analgesia and/or short-course corticosteroids [4]. Additionally, evidence for anabolic agents (eg, teriparatide) is limited and not recommended due to the theoretical risk of worsening mast cell proliferation and abnormal growth, especially if concerns for mast cell infiltration in bone [3].

In conclusion, we present a case of diffuse osteosclerosis secondary to mastocytosis and provided a comprehensive list of the differential diagnoses for sclerotic bone disease. The underlying mechanisms and clinical course associated with osteosclerosis remain poorly understood. This case contributes to the limited existing literature; however, further robust studies are required to clarify the pathogenesis and prognosis in SM-related osteosclerosis.