Interest of Denosumab Treatment in Osteoporosis Associated to Systemic Mastocytosis
Interest of Denosumab Treatment in Osteoporosis Associated to Systemic Mastocytosis
The study is looking at the efficacy of subcutaneously administrated denosumab 60 mg every 6
 months versus placebo after 3 years, by analyze of lumbar spine bone mineral density (BMD) in
 systemic mastocytosis.

 Investigators hypothesize that use of denosumab subcutaneously in patients with osteoporosis
 related to systemic mastocytosis is effective and safe to improve bone mineral density and
 prevent new bone events, based on targeted specific RANKL secretion by mast cells and short
 half-life of denosumab.
Systemic mastocytosis (SM) represents a heterogenous group of disease characterized by
 abnormal proliferation of mast cells caused by activating mutations in c-Kit receptor; a
 tyrosine kinase family receptor present in mast cell that control cell proliferation.
 Prevalence of SM is estimated to 1/20 000 person. According to the World Health Organization
 (WHO) criteria (Johnson et al, 2009), SM can be separated into two different groups :
 indolent SM and aggressive SM.

 Aggressive SM are defined by a poor prognostic disease either because of an important mast
 cell tumor mass as sarcoma mastocytosis or mast cell leukemia, or due to an association with
 an other myeloid hemopathy as myelodysplasic/myeloproliferative syndrome.

 Indolent SM are the most common cases with a very good prognostic similar to general
 population. Symptoms related to mast cell proliferation in indolent SM are very various
 (Theoharides et al., 2015) and could be divided into 2 entities : those related to mast cell
 proliferation in tissue as the urticaria pigmentosa and those related to the mast cell
 degranulation.

 There are many clinical relevant mediators released by mast cells after activation that could
 have putative effects on different systems as cardiovascular, cutaneous, neurologic,
 digestive, systemic, respiratory and musculoskeletal (Frenzel et al., 2013). Tryptase,
 histamine, prostaglandin, interleukine-6 and Tumor Necrosis Factor (TNF)-α are the most
 common and ubiquitous mediators released by mast cells but there are also some specific
 mediator targeting an organ as RANKL ; expression of RANKL by mast cells directly control
 regulation of osteoclast activity and is involved in osteoporosis associated to SM
 (Rabenhorst et al., 2013).

 In systemic mastocytoses, bone lesions are found in about half of patients. A third have
 osteoporosis defined as a lumbar spine or hip bone T score of -2,5 Standard Deviation (SD) or
 less. In most cases, osteoporosis was complicated at least by one vertebral fracture with
 pain and functional disorders (Barete et al, 2010). The median time to fragility fracture
 after mastocytoses diagnosis is up to 5 years, even in very young population usually
 considering as low risk of fracture in non mastocytoses associated osteoporosis (Van de Veer
 et al., 2014)

 By default, these patients are generally treated with bisphosphonate per os or intravenously
 with some efficiency on bone mineral density gain and bone turnover marker decrease (Rossini
 et al, 2014). However, no study with bisphosphonate in SM has showed durable prevention of
 new bone events and there are no randomized studies that proved their efficacy in systemic
 mastocytosis. Moreover, these drugs are not well tolerated in SM wether per os due to
 worsening of digestive symptoms by mast cells activation, or intravenously with an important
 number of acute phase characterized by some systemic symptoms as fever ; really experiences
 with intravenous biphosphonate but very increased in SM. Additional, the use of a
 bisphosphonate ask the question of the residual long-term effect of this drug that may be
 several years or even decades with a significant risk of atypical fracture secondary to a
 adynamic bone remodeling (Edwards et al. , 2013) and the long-term presence of crystals of
 bisphosphonate in the skeleton, particularly worrying in women of childbearing age. In
 postmenopausal osteoporosis, importance of residual long-term effect is weighted with
 advanced median age of patient. The fact that mostly patients with a systemic mastocytosis
 are young people led to restrict the use of bisphosphonate due to those effects.

 Among different treatment available in post menopausal osteoporosis, the use of an anti-RANKL
 antibody, denosumab, in SM associated osteoporosis could be interesting. First, denosumab has
 already shown significant efficacy in the treatment of postmenopausal osteoporosis in women
 (Cummings et al , 2009). Second, this treatment is proposed every 6 months by a subcutaneous
 injection with very few side effects and half-life drug is shorter than biphosphonate with
 probably low residual long-time effect. Third, as mast cells expressed mainly RANKL with a
 direct role on bone turnover in SM. The use of a specific drug seems to be obvious and
 attractive.
Inclusion Criteria:

 -  Male or female >/= 18 years of age at time of informed consent

 -  Willingness and ability to sign informed consent, comply with scheduled visits,
 treatment plan, laboratory tests and other study procedures.

 -  Patient with Indolent systemic or cutaneous mastocytosis according to WHO criteria
 (Appendix 4) with any specific treatment including corticosteroid, chemotherapy and
 immunomodulating drugs.

 -  Patient with:

 -  osteoporosis defined as bone mineral density T score ≤ -2.5 at the lumbar spine,
 OR

 -  osteopenia defined as BMD T-score >-2,5 and ≤ -1 at the lumbar spine and low
 energy fracture (defined as fractures that are associated with decreased bone
 mineral density. Are excluded fractures of skull, face, mandible, metacarpals,
 fingers, or toes, pathologic fracture, and fracture that are associated with
 severe trauma).

 (in case of osteoarthritis at the lumbar spine, the T score at left femoral neck or total
 left hip can be used to define osteoporosis or osteopenia)

 Exclusion Criteria:

 -  Patient with aggressive mastocytosis or/and Associated Hematologic Non-Mastocytosis
 Disease (AHNMD)

 -  Patient with conditions that influence bone metabolism (primitive hyperparathyroidism,
 hyperaldosteronism, hypercorticism, etc …)

 -  Patient treated with intravenous bisphosphonate within 1 year prior to enrolment or
 with any other antiosteoporotic treatment within 3 months before enrolment. (per os
 bisphosphonate, strontium ranelate) Calcium and vitamin supplementation will be
 accepted

 -  Patient previously treated with denosumab

 -  Patient with hypocalcemia and/or hypo25-hydroxyvitamin D level non substituted prior
 enrolment

 -  Woman without contraceptive treatment if of childbearing age.

 -  Pregnant or breastfeeding woman

 -  Patient with contraindication to denosumab

 -  Patient with medical, psychiatric or other conditions that may interfere with patient
 safety

 -  Patient with dental problem that need any dental surgery within 6 months after
 enrolment.

 -  Patient with clearance of creatinine less than 30 mL/min/1,73m2 (MDRD) or patient
 receiving dialysis