title: Local delivery of a selective androgen receptor modulator failed as an anabolic agent in a rat bone marrow ablation model.
abstract: OBJECTIVE
  Selective androgen receptor modulators (SARMs) have been developed to have systemic anabolic effects on bones and muscles without the adverse effects of steroidal androgens. One unexplored therapeutic option is the targeted application of SARMs for the enhancement of local new bone formation. We evaluated the osteogenic efficacy of a locally released SARM (ORM-11984).
  
  
  METHODS
  ORM-11984 was mixed with a copolymer of L-lactide and ɛ-caprolactone (PLCL). An in vitro dissolution test confirmed the sustainable release of ORM-11984 from the matrix. A bone marrow ablation model was used in female Sprague-Dawley rats. Implants containing 10%, 30%, or 50% ORM-11984 by weight or pure PLCL were inserted into the medullary canal of the ablated tibia. At 6 and 12 weeks, the volume of intramedullary new bone and the perimeter of bone-implant contact were measured by micro-computed tomography and histomorphometry.
  
  
  RESULTS
  Contrary to our hypothesis, there was a negative correlation between the amount of new bone around the implant and the dose of ORM-11984. There was only a mild (and not statistically significant) enhancement of bone formation in ablated bones subjected to the lowest dose of the SARM (10%).
  
  
  CONCLUSIONS
  This study suggests that intramedullary/endosteal osteogenesis had a negative, dose-dependent response to locally released SARM. This result highlights the complexity of androgenic effects on bones and also suggests that there are biological limits to the targeted local application of SARMs.
authors.affiliation: a 1 Orthopaedic Research Unit, Department of Orthopaedic Surgery and Traumatology, University of Turku and Turku University Hospital , Turku.|c 3 Turku University Hospital , Turku, Finland.
authors.forename: Hannu T
authors.initials: HT
authors.lastname: Aro
authors.affiliation: a 1 Orthopaedic Research Unit, Department of Orthopaedic Surgery and Traumatology, University of Turku and Turku University Hospital , Turku.
authors.forename: Julia
authors.initials: J
authors.lastname: Kulkova
authors.affiliation: a 1 Orthopaedic Research Unit, Department of Orthopaedic Surgery and Traumatology, University of Turku and Turku University Hospital , Turku.|b 2 Turku Clinical Biomaterials Centre, Institute of Dentistry, University of Turku , Turku.
authors.forename: Niko
authors.initials: N
authors.lastname: Moritz
authors.affiliation: c 3 Turku University Hospital , Turku, Finland.
authors.forename: Esa
authors.initials: E
authors.lastname: Kähkönen
authors.affiliation: a 1 Orthopaedic Research Unit, Department of Orthopaedic Surgery and Traumatology, University of Turku and Turku University Hospital , Turku.
authors.forename: Riina H
authors.initials: RH
authors.lastname: Mattila
mesh_terms: D045930:Anabolic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000728:Androgens / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow / Q000502:physiology / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D010012:Osteogenesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000187:drug effects*; D013977:Tibia / Q000254:growth & development / Q000601:surgery; D055114:X-Ray Microtomography
chemical_list: D045930:Anabolic Agents; D000728:Androgens; D004343:Drug Implants; D011944:Receptors, Androgen