Abstract
Purpose
This study was conducted to examine the bone and body composition effects of S-4, an aryl-propionamide derived Selective Androgen Receptor Modulator (SARM) in an ovariectomy induced model of accelerated bone loss.
Methods
One hundred twenty female Sprague–Dawley rats aged to twenty-three weeks were randomly assigned to twelve treatment groups. Drug treatment was initiated immediately following ovariectomy and continued for one hundred twenty days. Whole body bone mineral density (BMD), body composition, and lumbar vertebrae BMD were measured by dual energy x-ray absorptiometry. More stringent regional pQCT and biomechanical strength testing was performed on excised femurs.
Results
We found that S-4 treatment maintained whole body and trabecular BMD, cortical content, and increased bone strength while decreasing body fat in these animals.
Conclusions
The data presented herein show the protective skeletal effects of S-4. Our previous reports have shown the tissue selectivity and muscle anabolic activity of S-4. Together these data suggest that S-4 could reduce the incidence of fracture via two different mechanisms (i.e., via direct effects in bone and reducing the incidence of falls through increased muscle strength). This approach to fracture reduction would be advantageous over current therapies in these patients which are primarily antiresorptive in nature.
Similar content being viewed by others
References
E. Dennison and C. Cooper. Epidemiology of osteoporotic fractures. Horm. Res. 54(Suppl 1):58–63 (2000).
P. Kannus, S. Niemi, J. Parkkari, M. Palvanen, A. Heinonen, H. Sievanen, T. Jarvinen, K. Khan, and M. Jarvinen. Why is the age-standardized incidence of low-trauma fractures rising in many elderly populations? J. Bone Miner. Res. 17:1363–1367 (2002).
L. J. Melton, 3rd, C. S. Crowson, and W. M. O’Fallon. Fracture incidence in Olmsted County, Minnesota: comparison of urban with rural rates and changes in urban rates over time. Osteoporos. Int. 9:29–37 (1999).
United Nations. Dept. of Economic and Social Affairs., United Nations. Dept. of International Economic and Social Affairs., and United Nations. Dept. of Economic and Social Affairs. Population Division., United Nations, New York, 1998.
F. H. Anderson, R. M. Francis, and K. Faulkner. Androgen supplementation in eugonadal men with osteoporosis—effects of 6 months of treatment on bone mineral density and cardiovascular risk factors. Bone 18:171–177 (1996).
A. Goulding and E. Gold. Flutamide-mediated androgen blockade evokes osteopenia in the female rat. J. Bone Miner. Res. 8:763–769 (1993).
C. Lea, N. Kendall, and A. M. Flanagan. Casodex (a nonsteroidal antiandrogen) reduces cancellous, endosteal, and periosteal bone formation in estrogen-replete female rats. Calcif. Tissue Int. 58:268–272 (1996).
C. K. Lea and A. M. Flanagan. Physiological plasma levels of androgens reduce bone loss in the ovariectomized rat. Am. J. Physiol. 274:E328–E335 (1998).
C. K. Lea, V. Moxham, M. J. Reed, and A. M. Flanagan. Androstenedione treatment reduces loss of cancellous bone volume in ovariectomised rats in a dose-responsive manner and the effect is not mediated by oestrogen. J. Endocrinol. 156:331–339 (1998).
J. H. Tobias, A. Gallagher, and T. J. Chambers. 5 alpha-Dihydrotestosterone partially restores cancellous bone volume in osteopenic ovariectomized rats. Am. J. Physiol. 267:E853–E859 (1994).
S. Bhasin and W. J. Bremner. Clinical review 85: emerging issues in androgen replacement therapy. J. Clin. Endocrinol. Metab. 82:3–8 (1997).
W. Gao, C. E. Bohl, and J. T. Dalton. Chemistry and structural biology of androgen receptor. Chem. Rev. 105:3352–3370 (2005).
D. Yin, Y. He, M. A. Perera, S. S. Hong, C. Marhefka, N. Stourman, L. Kirkovsky, D. D. Miller, and J. T. Dalton. Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor. Mol. Pharmacol. 63:211–223 (2003).
D. Yin, W. Gao, J. D. Kearbey, H. Xu, K. Chung, Y. He, C. A. Marhefka, K. A. Veverka, D. D. Miller, and J. T. Dalton. Pharmacodynamics of selective androgen receptor modulators. J. Pharmacol. Exp. Ther. 304:1334–1340 (2003).
J. D. Kearbey, D. Wu, W. Gao, D. D. Miller, and J. T. Dalton. Pharmacokinetics of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide, a nonsteroidal selective androgen receptor modulator. Xenobiotica 34:273–280 (2004).
W. Gao, P. J. Reiser, C. C. Coss, M. A. Phelps, J. D. Kearbey, D. D. Miller, and J. T. Dalton. Selective Androgen Receptor Modulator (SARM) treatment improves muscle strength and body composition, and prevents bone loss in orchidectomized rats. Endocrinology 146:4887–4897 (2005).
D. Gaddy-Kurten, J. K. Coker, E. Abe, R. L. Jilka, and S. C. Manolagas. Inhibin suppresses and activin stimulates osteoblastogenesis and osteoclastogenesis in murine bone marrow cultures. Endocrinology 143:74–83 (2002).
R. Narayanan, M. R. Allen, D. Gaddy, S. A. Bloomfield, C. L. Smith, and N. L. Weigel. Differential skeletal responses of hindlimb unloaded rats on a vitamin D-deficient diet to 1,25-dihydroxyvitamin D3 and its analog, seocalcitol (EB1089). Bone 35:134–143 (2004).
C. H. Turner and D. B. Burr. Basic biomechanical measurements of bone: a tutorial. Bone 14:595–608 (1993).
D. N. Kalu and R. R. Hardin. Evaluation of the role of calcitonin deficiency in ovariectomy-induced osteopenia. Life Sci. 34:2393–2398 (1984).
H. G. Burger and S. R. Davis. The role of androgen therapy. Best Pract Res Clin Obstet Gynaecol 16:383–393 (2002).
S. Ott. Osteoporosis and Bone Physiology, 1998.
L. A. Lipsitz, I. Nakajima, M. Gagnon, T. Hirayama, C. M. Connelly, and H. Izumo. Muscle strength and fall rates among residents of Japanese and American nursing homes: an International Cross-Cultural Study. J. Am. Geriatr. Soc. 42:953–959 (1994).
J. L. Newton, R. A. Kenny, R. Frearson, and R. M. Francis. A prospective evaluation of bone mineral density measurement in females who have fallen. Age Ageing 32:497–502 (2003).
C. K. Lea and A. M. Flanagan. Ovarian androgens protect against bone loss in rats made oestrogen deficient by treatment with ICI 182,780. J. Endocrinol. 160:111–117 (1999).
K. Hanada, K. Furuya, N. Yamamoto, H. Nejishima, K. Ichikawa, T. Nakamura, M. Miyakawa, S. Amano, Y. Sumita, and N. Oguro. Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis. Biol. Pharm. Bull. 26:1563–1569 (2003).
A. Falahati-Nini, B. L. Riggs, E. J. Atkinson, W. M. O’Fallon, R. Eastell, and S. Khosla. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J. Clin. Invest. 106:1553–1560 (2000).
B. C. Van Der Eerden, E. F. Gevers, C. W. Lowik, M. Karperien, and J. M. Wit. Expression of estrogen receptor alpha and beta in the epiphyseal plate of the rat. Bone 30:478–485 (2002).
B. C. Van Der Eerden, J. Van De Ven, C. W. Lowik, J. M. Wit, and M. Karperien. Sex steroid metabolism in the tibial growth plate of the rat. Endocrinology 143:4048–4055 (2002).
K. M. Wiren, A. Chapman Evans, and X. W. Zhang. Osteoblast differentiation influences androgen and estrogen receptor-alpha and -beta expression. J. Endocrinol. 175:683–694 (2002).
L. C. Hofbauer, R. M. Ten, and S. Khosla. The anti-androgen hydroxyflutamide and androgens inhibit interleukin-6 production by an androgen-responsive human osteoblastic cell line. J. Bone Miner. Res. 14:1330–1337 (1999).
Acknowledgments
The outstanding technical assistance and advice of Juhyun Kim, Dr. Jun Yang, Dr. Victor Shen, and Dr. Mitch Steiner are gratefully acknowledged. Supported by a grant from GTx, Inc., Memphis, TN.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kearbey, J.D., Gao, W., Narayanan, R. et al. Selective Androgen Receptor Modulator (SARM) Treatment Prevents Bone Loss and Reduces Body Fat in Ovariectomized Rats. Pharm Res 24, 328–335 (2007). https://doi.org/10.1007/s11095-006-9152-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-006-9152-9