Oral Presentation ANZBMS-MEPSA-ANZORS 2022

Clinical Case:

A 69-year-old female was referred to the dermatology clinic with asymptomatic pigmented macules and papules which began on her abdomen and gradually spread to affect her face, neck, back and proximal limbs [Images 1a-c]. Stroking of the lesions evoked urticaria (positive Darier sign) consistent with cutaneous mastocytosis, which was confirmed by punch biopsy. She reported increasing lethargy, diarrhoea and intermittent flushing episodes, without weight loss, night sweats, or anaphylactic episodes. Serum tryptase was elevated at 220 mcg/L (NR <11). Bone marrow biopsy demonstrated 60% infiltration of bone marrow by abnormal mast cells expressing CD117, CD2, CD25 and tryptase. CT lumbar spine demonstrated multiple sclerotic foci within L2, L4, L5 vertebral bodies, sacrum and ileum without lytic bony lesions or pathological fractures [Image 2a-c].  Management included the protein kinase inhibitor midostaurin, antihistamines and topical corticosteroids.

Her other medical background included hypertension, hypercholesterolemia, and a distant history of a left humerus fracture following a traumatic fall.

The patient was well-known to the osteoporosis clinic for management of significantly reduced bone mineral density. She had received a single dose of intravenous zoledronic acid 4 mg several years prior, which was followed by a pronounced acute phase reaction. A DEXA scan performed shortly after the patient had been diagnosed with systemic mastocytosis demonstrated significant interval decline with LS T-score -2.5 SD (-5.3% over 2 years), left total hip T-score -1.0 SD (-5.3%), although her true bone density may be even lower due to osteosclerosis [Image 3]. Subcutaneous denosumab 60mg was commenced and careful post-dosing supervision documented no hypersensitivity reaction. At current review in May 2022, the patient continues on six-monthly denosumab with calcium and Vitamin D supplementation, without minimal trauma fractures. A recent DEXA scan showed significant improvement at the LS (+18.7% since denosumab commencement) and left total hip (+10.3%). Her serum tryptase levels remain elevated between 160-200 mcg/L on midostaurin 100 mg twice daily [Image 4].

 

Laboratory and Medical Imaging Findings:

[Image 1] Cutaneous pigmented macules and papules

1a- Lower abdomen- time of diagnosis

1b- Neck region- current

1c- Upper chest- current

[Image 2a-c] CT lumbar spine with multiple sclerotic foci within lumbar vertebral bodies and pelvis, without lytic lesions or loss of vertebral height.

 

[Image 3] Lumbar spine and left total hip BMD in relation to antiresorptive therapy and diagnosis of SM

 

[Image 4] Serum tryptase levels

 

Literature Review:

Systematic mastocytosis (SM) arises from clonal proliferation of abnormal mast cells that accumulate in various tissues including the skin, bone, gastrointestinal tract, spleen and lymph nodes [1]. Activating mutations of the receptor tyrosine kinase KIT on the surface of mast cells have been implicated in the pathogenesis. Mastocytosis can present as a spectrum, ranging from cutaneous mastocytosis and indolent SM, to more aggressive forms including hematological neoplasms and mast cell leukaemia [1]. The multikinase inhibitor midostaurin inhibits KIT D816V, the driver mutation present in SM, with response rates of 60% in an open-label study [2].

Infrequently, mastocytosis may initially present as osteoporosis with fractures or sclerotic/lytic bone lesions on imaging, and bony pain due to marrow infiltration. Skeletal involvement occurs in up to 70% of SM, and prevalence of osteoporosis ranges between 18-37% [3]. Vertebral fractures were are common, affecting up to 14-20% of patients [4]. Older age, male sex and higher urinary histamine metabolites are independent predictors of osteoporotic fractures [3, 5].

The lumbar spine is the most common site of involvement [5]. Osteoporosis may result from bone marrow infiltration of mast cells, or due to the release of tryptase, histamine and heparin directly activating osteoclasts and the RANK-L pathway to promote excess bone resorption [5]. Studies examining associations between bone mineral density and urinary histamine metabolite excretion have theorised that mediators favouring osteoclast activity predominate in patients with moderate increase in mast cells, whereas mediators favouring osteoblast activity prevail in those with much higher increases in mast cell numbers [6]. This is supported by findings in advanced SM, where the majority of patients had increased bone mineral density or osteosclerosis, with higher marrow mast cell burden and tryptase levels [7]. Osteosclerosis in this setting, as in other haematological neoplasms, is associated with more aggressive phenotype and poorer prognosis [7].

Predominance of osteoclastic activity and bone resorption is the driver of SM-related osteoporosis, and thus antiresorptive agents have been utilized in its treatment. Zoledronic acid and denosumab have been studied in small case series with significant improvements in bone mineral density and suppression of bone turnover markers [8, 9]. In particular, upregulation of RANK-L signaling in SM and the effects of denosumab in inhibiting this pathway makes this a potentially promising therapeutic agent. Furthermore, the denosumab study showed decrease in serum tryptase levels in all four patients, raising the hypothesis of a negative feedback signal to mast cells from suppressed osteoclast activity, or possibly a direct effect on mast cell function [8]. The role of newer osteoanabolic agents affecting the WNT/β-catenin pathway may also be revealing, as increased levels of sclerostin have been reported in SM patients [10].

In summary, SM is an uncommon cause of secondary osteoporosis and should be suspected particularly when there are symptoms suggestive of mast cell activation. SM can be confirmed with serum tryptase and bone marrow biopsy. Our case highlighted the efficacy of denosumab in reversing the associated decline in bone mineral density.

 

Take Home Messages:

1. SM results from abnormal mast cell proliferation and accumulation in various organs, commonly affecting the skin and skeleton.
2. SM is a rare cause of secondary osteoporosis and should be suspected in a patient with unexplained osteoporosis, symptoms of mast cell activation and elevated serum tryptase.
3. Osteoporosis associated with SM may be related to tryptase, histamine and heparin release from mast cells activating osteoclasts and RANK-L pathway.
4. Antiresorptive therapy with RANK- L inhibitors remains the mainstay of osteoporosis treatment by counteracting mast cell-induced bone resorption.