Bone and muscle protective potential of the prostate-sparing synthetic androgen 7a-methyl-19-nortestosterone: Evidence from the aged orchidectomized male rat model Katrien Venken a , Steven Boonen a,b , Erik Van Herck a , Liesbeth Vandenput a , Narender Kumar c , Regine Sitruk-Ware c , Kalyan Sundaram c , Roger Bouillon a , Dirk Vanderschueren a, T a Laboratory for Experimental Medicine and Endocrinology, Onderwijs en Navorsing, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium b Leuven University Center for Metabolic Bone Diseases and Division of Geriatric Medicine, Katholieke Universiteit Leuven, Leuven, Belgium c Center for Biomedical Research, Population Council, New York, NY 10021, USA Received 31 August 2004; revised 14 December 2004; accepted 14 January 2005 Available online 19 March 2005 Abstract This study reports the preclinical evaluation of the bone and muscle protective potential of the synthetic androgen 7a-methyl-19- nortestosterone (MENTk), as assessed in the aged orchidectomized rat model. Aged (13-month-old) orchidectomized Wistar rats were treated with different doses of MENT (4, 12 or 36 Ag/day) subcutaneously for 16 weeks via mini-osmotic pumps. Analysis of the effects of androgen deficiency versus MENT replacement was performed using quantitative computed tomography (pQCT), dual energy X-ray absorptiometry (DEXA) and biochemical markers of bone turnover. At the end of the study period, prostate weight in orchidectomized rats treated with low- (4 Ag/day) or mid-dose (12 Ag/day) MENT remained significantly lower compared to the sham-operated animals (À47% and À25%, respectively). High-dose MENT (36 Ag/day), on the other hand, induced prostate hypertrophy (+21% versus sham). Low-, mid- and high-dose MENT were found to be effective in suppressing the acceleration of bone remodeling following orchidectomy, as assessed by osteocalcin and deoxypyridinoline. In addition, low-, mid- and high-dose were able to prevent the orchidectomy-induced bone loss, as evaluated by DEXA at the femur and total-body and by pQCT at the femur. Compared to sham-operated animals, the low- and mid-dose MENT groups showed no decline in lean body mass and no muscle atrophy (as measured by m. quadriceps weight) at 16 weeks, whereas high-dose MENT was associated with a significant decline in lean body mass (À8.5% versus sham) and quadriceps weight (À10.6%). We conclude that, in the aged orchidectomized rat model, low- and mid-doses of the synthetic androgen MENT have bone and muscle protective effects and do not induce prostate hypertrophy. The bone protective action of high-dose MENT, however, occurs at the expense of muscle wasting and prostate hypertrophy. Our findings support the need for human studies to explore the potential of MENT as an option for androgen replacement in aging men. D 2005 Elsevier Inc. All rights reserved. Keywords: Androgens; Orchidectomy; Bone; Lean body mass; Fat mass Introduction Sex steroids play a major role in the maintenance of bone mass in both women and men [1]. Aging, however, results in the steady decline of sex steroids with concomitant decline in bone mass [2,3]. Testosterone deprivation in men induces a degree of bone loss which is similar to the bone loss observed in early menopause or following surgical ovar- iectomy [4,5]. Within 1 year after castration, lumbar spine bone mineral density (BMD) has declined by about 5–10%, followed by a more gradual but continuing decrease in axial BMD [4–7]. Significant bone loss, albeit to a lesser extent, is also observed at appendicular skeletal sites, including the hip. In addition to the decline in BMD, aging men lose 8756-3282/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2005.01.003 T Corresponding author. Fax: +32 16344268. E-mail address: dirk.vanderschueren@uz.kuleuven.ac.be (D. Vanderschueren). Bone 36 (2005) 663 – 670 www.elsevier.com/locate/bone