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Local delivery of a selective androgen receptor modulator failed as an anabolic agent in a rat bone marrow ablation model
Authors:Hannu T Aro  Julia Kulkova  Niko Moritz  Esa K?hk?nen  Riina H Mattila
Institution:1.Orthopaedic Research Unit, Department of Orthopaedic Surgery and Traumatology, University of Turku and Turku University Hospital, Turku;2.Turku Clinical Biomaterials Centre, Institute of Dentistry, University of Turku, Turku;3.Turku University Hospital, Turku, Finland
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.Male and female hormones, which act mainly via androgen receptors (ARs) and estrogen receptors (ERs), are physiological regulators of bone remodeling (Clarke and Khosla 2009, Vanderschueren et al. 2014). Drug development programs have successfully launched non-steroidal selective estrogen receptor modulators (SERMs) for various clinical indications, including postmenopausal osteoporosis (Komm and Mirkin 2014). The common goal of the corresponding programs for non-steroidal tissue-selective androgen receptor modulators (SARMs), which act as AR ligands, is to achieve systemic anabolic effects on bones and muscles without adverse androgenic effects (Mohler et al. 2009). Preclinical models have shown that the systemic administration of SARMs can protect the skeleton from the catabolic effects of orchiectomy and ovariectomy (Gao et al. 2005, Kearbey et al. 2007), partially restore the bone mass lost by ovariectomy (Kearbey et al. 2009), and enhance the therapeutic effects of anti-resorptive drug treatment (Vajda et al. 2009). The main clinical target of SARMs is aging populations with sarcopenia and bone frailty (Mohler et al. 2009), but no SARMs have yet reached the market.ARs are highly expressed in mature osteoblasts and osteocytes (Abu et al. 1997, Wiren et al. 2002), and androgens have been traditionally claimed to have direct anabolic bone effects. Data from studies on androgen-insensitive null mice with non-functional ARs (Yeh et al. 2002, Kawano et al. 2003, Venken et al. 2006, Sinnesael et al. 2012) and in mice that overexpress ARs (Wiren et al. 2004, 2008) have confirmed the physiological significance of AR-mediated bone remodeling processes. The androgenic action may be partly compartment-specific, and anabolic effects mainly appear at periosteal surfaces (Wiren et al. 2004, 2008, 2010, 2011), but several studies have clearly demonstrated that the lack of AR action results in general trabecular bone loss (Vanderschueren et al. 2014).Clinically, there are unmet needs for bone enhancement agents in elective reconstructive procedures and also in trauma surgery. One unexplored therapeutic option would be local application of SARMs as an anabolic bone agent. In this pilot study, the osteogenic efficacy of a SARM compound (ORM-11984) was tested in a rat bone marrow ablation model. Bone marrow ablation is a unique bone-healing model in which robust endosteal intramembranous bone formation is induced transiently by surgical ablation of the bone marrow (Suva et al. 1993). ARs are present in mesenchymal stromal stem cells of the bone marrow (Bellido et al. 1995), which are among the repair cells responsible for bone-healing processes (Bais et al. 2009). We hypothesized that the intramedullary administration of ORM-11984 would have androgenic anabolic effects on bone marrow-derived precursor cells and produce a dose-dependent enhancement of the local osteogenic response.
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