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Abstract
Background and purpose — 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%).
Interpretation — 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.
HA: planning of the study, and writing and revision of the manuscript. JK: µ-CT imaging of bone specimens, analysis of µ-CT data, histological and histomorphometrical analysis of bone sections, participation in the statistical analysis, and writing and revision of the manuscript. NM: participation in planning of the study, participation in µ-CT, histological and histomorphometrical analysis, statistical analysis, and writing and revision of the manuscript. EK: participation in planning of the study, and animal surgery. RM: participation in the animal surgery and retrieval of the bone specimens.
This work was supported by Orion Corporation, Finland. The sponsor was not involved in the data analysis. JK is a PhD student in the National Doctoral Programme of Musculoskeletal Disorders and Biomaterials (TBDP) in Finland.