The effects of synthetic conjugated estrogens, a (cenestin) on trabecular bone structure and strength in the ovariectomized rat model

Lane, N. E.; Kumer, J. L.; Majumdar, S.; Khan, M.; Lotz, J.; Stevens, R. E.; Klein, R.; Phelps, K. V.

Affiliations

¹Department of Medicine, University of California at San Francisco, San Francisco, California

²Department of Radiology, University of California at San Francisco, San Francisco, California

³Department of Orthopedic Surgery, University of California at San Francisco, San Francisco, California

⁴Department of Clinical & Medical Affairs, Duramed Pharmaceuticals, Inc., Cincinnati, Ohio, USA

Abstract and keywords

This study evaluated the effect of Cenestin, a synthetic conjugated estrogens product, on the maintenance of trabecular bone microarchitecture, bone strength, and of bone turnover in the ovariectomized (ovx) rat model. Two doses of Cenestin were chosen in an attempt to approximate the equivalent human oral doses of 0.3 mg and 0.625 mg. Forty-nine 6-month-old retired female breeder Sprague-Dawley rats were randomly assigned to one of four groups: (1) shamoperated + vehicle; (2) ovx + vehicle; (3) ovx + day 1 post-ovariectomy Cenestin (8.12 mg/kg); (4) ovx + day 1 post-ovariectomy Cenestin (16.24 mg/kg) for 8 weeks. Trabecular structure of the right proximal tibia of each rat was imaged noninvasively by microCT. A compression test to induce a tibial plateau fracture was performed to determine the mechanical properties of the proximal tibia. Urine was collected on days 0, 14, 28, 42 and 56 and serum on days 0, 28 and 56 to assess biochemical markers of bone turnover including deoxypyridinoline crosslinks and osteocalcin. Both biochemical markers of bone turnover were analyzed by ELISA. Trabecular bone mass, structure, and connectivity density in the Cenestin-treated groups did not differ statistically (p>0.05) from those of the sham-operated + vehicle-treated rats, but all were significantly higher (p<0.05) than in the ovx + vehicle-treated rats. Structure Model Index, a measure of trabecular plate morphometry, in Cenestin-treated rats maintained a more equal mix of plate- and rod-like structures similar to the sham group, whereas the ovx group had predominantly rod-like trabeculae. Fracture load in the Cenestin (16.24 mg/kg) treated group was 31% (p<0.01) higher than in the sham + vehicle-treated group and 61% (p<0.05) higher than in the ovx + vehicle-treated group. Both the sham-operated + vehicletreated and Cenestin-treated groups showed significantly lower urinary deoxypyridinoline crosslink excretion at all timepoints and serum osteocalcin at day 56 compared with the ovx + vehicle-treated group. In summary, Cenestin maintained trabecular bone microarchitecture and strength in an ovariectomized rat model of estrogen deficiency.

Keywords: Ovariectomized rats; Synthetic conjugated estrogens; Trabecular bone structure and strength

Links

DOI: 10.1007/s001980200113

PubMed: 12378371

WoS: 000178720300008

Cited Works (15)

Year	Entry
1995	Lane NE, Thompson JM, Strewler GJ, Kinney JH. Intermittent treatment with human parathyroid hormone (hPTH[1‐34]) increased trabecular bone volume but not connectivity in osteopenic rats. J Bone Miner Res. October 1995;10(10):1470-1477.
1997	Chavassieux PM, Arlot ME, Reda C, Wei L, Yates AJ, Meunier PJ. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest. September 15, 1997;100(6):1475-1480.
1993	Balena R, Toolan BC, Shea M, Markatos A, Myers ER, Lee SC, Opas EE, Seedor JG, Klein H, Frankenfield D, Quartuccio H, Fioravanti C, Clair J, Brown E, Hayes WC, Rodan GA. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest. December 1993;92(6):2577-2586.
1995	Boyce RW, Wronski TJ, Ebert DC, Stevens ML, Paddock CL, Youngs TA, Gundersen HJG. Direct stereological estimation of three-dimensional connectivity in rat vertebrae: effect of estrogen, etidronate and risedronate following ovariectomy. Bone. February 1995;16(2):209-213.
1988	Wronski TJ, Cintron M, Doherty AL, Dann LM. Estrogen treatment prevents osteopenia and depresses bone turnover in ovariectomized rats. Endocrinology. August 1988;123(2):681-686.
1998	Lane NE, Thompson JM, Haupt D, Kimmel DB, Modin G, Kinney JH. Acute changes in trabecular bone connectivity and osteoclast activity in the ovariectomized rat in vivo. J Bone Miner Res. February 1998;13(2):229-236.
2000	Laib A, Barou O, Vico L, Lafage-Proust MH, Alexandre C, Rügsegger P. 3D micro-computed tomography of trabecular and cortical bone architecture with application to a rat model of immobilisation osteoporosis. Med Biol Eng Comput. May 2000;38(3):326-332.
2001	Laib A, Kumer JL, Majumdar S, Lane NE. The temporal changes of trabecular architecture in ovariectomized rats assessed by MicroCT. Osteoporos Int. November 2001;12(11):936-941.
1997	Hildebrand T, Rüegsegger P. A new method for the model-independent assessment of thickness in three-dimensional images. J Microsc (Oxford). 1997;185(1):67-75.
1985	Cummings SR, Kelsey JL, Nevitt MC, O'Dowd KJ. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev. 1985;7:178-208.
1996	Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. December 7, 1996;348(9041):1535-1541.
1992	Lufkin EG, Wahner HW, O'Fallon WM, Hodgson SF, Kotowicz MA, Lane AW, Judd HL, Caplan RH, Riggs BL. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med. July 1, 1992;117(1):1-9.
2002	Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, LaCroix AZ, Black DM. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med. March 2002;112(4):281-289.
1987	Lorensen WE, Cline HE. Marching cubes: a high resolution 3D surface construction algorithm. Comput Graph. 1987;21(4):163-169.
1997	Hildebrand T, Rüegsegger P. Quantification of bone microarchitecture with the structure model index. Comput Methods Prog Biomed. 1997;1(1):15-23.

Cited By (4)

Year	Entry
2004	Goss PE, Qia S, Josse RG, Pritzker KP., Mendes M, Hu H, Waldman SD, Grynpas MD. The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone. March 2004;34(3):384-392.
2004	Nägele E, Kuhn V, Vogt H, Link TM, Müller R, Lochmüller E-M, Eckstein F. Technical considerations for microstructural analysis of human trabecular bone from specimens excised from various skeletal sites. Calcif Tiss Int. 2004;75(1):15-22.
2007	Brouwers JEM, van Rietbergen B, Huiskes R. No effects of in vivo micro-CT radiation on structural parameters and bone marrow cells in proximal tibia of wistar rats detected after eight weekly scans. J Orthop Res. October 2007;25(10):1325-1332.
2008	Campbell GM, Buie HR, Boyd SK. Signs of irreversible architectural changes occur early in the development of experimental osteoporosis as assessed by in vivo micro-CT. Osteoporos Int. October 2008;19(10):1409-1419.