Interest of Denosumab Treatment in Osteoporosis Associated to Systemic Mastocytosis

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Interest of Denosumab Treatment in Osteoporosis Associated to Systemic Mastocytosis

Conditions
-----------------
Osteoporosis, Systemic Mastocytosis

Intervention / Treatment
-----------------
* Drug: Denosumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental medication 1<br>Denosumab 60 mg subcutaneously injection with prefilled syringe | Drug: Denosumab<br>* Each subcutaneous injection will occur every 6 months during 3 years for a total of 7 injections<br>* Other names: XGeva®;|
| Placebo Comparator: Experimental medication 2<br>NaCl 0.9%, 20ml phial, solution for injection | Drug: Placebo<br>* Each subcutaneous injection will occur every 6 months during 3 years for a total of 7 injections<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of the lumbar spine bone mineral density (BMD) | Dual energy x-ray absorptiometry at lumbar spine (L2-L4) | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of a low energy vertebral fracture and non vertebral fracture | Lateral and front lumbar x-ray | Baseline, 1 year, 2 years and 3 years | 
| BMD at the total left hip | Dual energy x-ray absorptiometry at lumbar spine (L2-L4) | Baseline, 3 years | 
| BMD at lumbar spine and the total left hip | Dual energy x-ray absorptiometry at left femoral neck and total left hip | Baseline, 1 year, 2 years | 
| Biological assays with bone turnover marker of resorption and tryptase levels to assess mastocytosis activity | Withdrawal of 45 ml of blood | Baseline, then every 6 months in 3 years | 
| Number of serious adverse events to evaluate drug tolerance | Biological assessment: complete blood count, creatinemia, electrolytes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, c-reactive protein (CRP), phosphocalcic analyses with calcemia, phosphoremia, parathormone, vitamin D (25-OH-D), β-Human Chorionic Gonadotropin (HCG) (if needed) Clinical assessment: blood pressure, pulse, weight, height, PS, temperature | Every 6 months in 3 years | 
| Number of non-serious adverse events to evaluate drug tolerance | Biological assessment: complete blood count, creatinemia, electrolytes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, c-reactive protein (CRP), phosphocalcic analyses with calcemia, phosphoremia, parathormone, vitamin D (25-OH-D), β-Human Chorionic Gonadotropin (HCG) (if needed) Clinical assessment: blood pressure, pulse, weight, height, PS, temperature | Every 6 months in 3 years | 
| Annual variation of BMD in placebo group and number of low energy fracture compared to historical postmenopausal data | Dual energy x-ray absorptiometry at lumbar spine (L2-L4), left femoral neck and total left hip | Baseline, 1 year, 2 years, 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Systemic mastocytosis, Osteoporosis, Bone mineral density (BMD), Denosumab, RANKL