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.

Sex

All

Minimum age

18 Years

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

• BACKGROUNDJohnson MR, Verstovsek S, Jorgensen JL, Manshouri T, Luthra R, Jones DM, Bueso-Ramos CE, Medeiros LJ, Huh YO. Utility of the World Heath Organization classification criteria for the diagnosis of systemic mastocytosis in bone marrow. Mod Pathol. 2009 Jan;22(1):50-7. doi: 10.1038/modpathol.2008.141. Epub 2008 Sep 19. PMID 19116630
• BACKGROUNDTheoharides TC, Valent P, Akin C. Mast Cells, Mastocytosis, and Related Disorders. N Engl J Med. 2015 Jul 9;373(2):163-72. doi: 10.1056/NEJMra1409760. No abstract available. PMID 26154789
• BACKGROUNDFrenzel L, Hermine O. Mast cells and inflammation. Joint Bone Spine. 2013 Mar;80(2):141-5. doi: 10.1016/j.jbspin.2012.08.013. Epub 2012 Oct 30. PMID 23116710
• BACKGROUNDRabenhorst A, Christopeit B, Leja S, Gerbaulet A, Kleiner S, Forster A, Raap U, Wickenhauser C, Hartmann K. Serum levels of bone cytokines are increased in indolent systemic mastocytosis associated with osteopenia or osteoporosis. J Allergy Clin Immunol. 2013 Nov;132(5):1234-1237.e7. doi: 10.1016/j.jaci.2013.06.019. Epub 2013 Jul 31. No abstract available. PMID 23910691
• BACKGROUNDBarete S, Assous N, de Gennes C, Grandpeix C, Feger F, Palmerini F, Dubreuil P, Arock M, Roux C, Launay JM, Fraitag S, Canioni D, Billemont B, Suarez F, Lanternier F, Lortholary O, Hermine O, Frances C. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis. 2010 Oct;69(10):1838-41. doi: 10.1136/ard.2009.124511. Epub 2010 Jun 22. PMID 20570833
• BACKGROUNDvan der Veer E, Arends S, van der Hoek S, Versluijs JB, de Monchy JGR, Oude Elberink JNG, van Doormaal JJ. Predictors of new fragility fractures after diagnosis of indolent systemic mastocytosis. J Allergy Clin Immunol. 2014 Dec;134(6):1413-1421. doi: 10.1016/j.jaci.2014.05.003. Epub 2014 Jun 27. PMID 24985401
• Rossini M, Zanotti R, Viapiana O, Tripi G, Idolazzi L, Biondan M, Orsolini G, Bonadonna P, Adami S, Gatti D. Zoledronic acid in osteoporosis secondary to mastocytosis. Am J Med. 2014 Nov;127(11):1127.e1-1127.e4. doi: 10.1016/j.amjmed.2014.06.015. Epub 2014 Jun 20.