Effects of Black Cohosh (Cimicifuga racemosa) and Estrogen on Metaphyseal Fracture Healing in the Early Stage of Osteoporosis in Ovariectomized Rats

Abstract

Osteoporosis and its accompanying, predominantly metaphyseal, fractures are a major health problem. Black cohosh (Cimicifuga racemosa) and estrogen positively influence osteoporotic bone. Both substances may improve fracture healing in early osteoporosis as well. In 48 twelve-week-old ovariectomized or, respectively, sham-operated (SHAM) rats, a standardized metaphyseal tibia osteotomy with bridging T-plate fixation was performed. During the healing process of 35 days, rats received soy-free (SHAM, osteopenic C), estrogen- (E) or Cimicifuga racemosa- (CR) supplemented diets. After sacrifice, the callus formation was analyzed with regard to biomechanical quality, morphology, quantity, time course of new bone built and gene expression. CR induced a high rate of metaphyseal callus formation. The biomechanical properties and the amount of new callus formation indicated that fracture healing was still in progress. Therefore, gene expression of osteoblasts was comparatively high. Body weight and the trabecular structure were influenced little by CR. Estrogen improved the biomechanical properties of the callus. Resistance to microfracturing was significantly enhanced in the E group and even superior to SHAM. Remodeling of the callus formation had already begun. The trabecular network and the typical endosteal fracture healing were especially improved. Osteoporotic metaphyseal fracture healing was improved by estrogen more than by Cimicifuga racemosa. The process of fracture healing occurred nearly physiologically. The generation of callus formation was supported by Cimicifuga racemosa as well, but the five-week duration of application was too short for Cimicifuga racemosa to show its complete potential. Already-initiated Cimicifuga racemosa therapy for menopausal symptoms could be continued during fracture healing without hesitation.

osteoporosis prophylaxis - estrogen - Cimicifuga (Actaea) racemosa - Ranunculaceae - metaphyseal fracture healing - osteoporosis

References

• 1 Roussouw J E, Anderson G L, Prentice R L, LaCroix A Z, Kooperberg C, Stefanick M L, Jackson R D, Beresford S A, Howard B V, Johnson K C, Kotchen J M, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial.  JAMA. 2002;  288 321-333
• 2 Haas J S, Kaplan C P, Gerstenberger E P, Kerlikowske K. Changes in the use of postmenopausal hormone therapy after the publication of clinical trial results.  Ann Intern Med. 2004;  140 184-188
• 3 Hsia J, Langer R D, Manson J, Kuller L, Johnson K C, Hendrix S L, Pettinger M, Heckbert S R, Greep N, Crawford S, Eaton C B, Kostis J B, Caralis P, Prentice R. Women's Health Initiative Investigators . Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative.  Arch Intern Med. 2006;  166 357-365
• 4 Salpeter S R, Walsh J M E, Ormiston T M, Greyber E, Buckley N S, Salpeter E E. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.  Diabetes Obes Metab. 2006;  6 538-554
• 5 Zandi P P, Carlson M C, Plassman B L, Welsh-Bohmer K A, Mayer L S, Steffens D C, Breitner J C. Cache County Memory Study Investigators . Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache county study.  JAMA. 2002;  288 2123-2129
• 6 Horwitz K B. The year in basic science: update of estrogen plus progestin therapy for menopausal hormone replacement implicating stem cells in the increased breast cancer risk.  Mol Endocrinol. 2008;  22 2743-2750
• 7 Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study.  Lancet. 2003;  362 419-427
• 8 Tarakida A, Higuchi T, Mizunuma H. Evidence of hormone replacement therapy for osteoporosis.  Maturitas. 2007;  DOI: PMID: 18830040
• 9 L'Hermite M, Simoncini T, Fuller S, Genazzani A R. Could transdermal estradiol + progesterone be a safer postmenopausal HRT? A review.  Maturitas. 2008;  60 185-201
• 10 Gambacciani M, Pepe A, Cappagli B, Palmieri E, Genazzi A R. The relative contributions of menopause and aging to postmenopausal reduction in intervertebral disc height.  Climacteric. 2007;  10 298-305
• 11 Canonico M, Oger E, Plu-Bureau G, Conard J, Meyer G, Lévesque H, Trillot N, Barrellier M T, Wahl D, Emmerich J, Scarabin P Y. for the Estrogen and Thromboembolism Risk (ESTHER) Study Group . Hormone therapy and venous thromboembolism among postmenopausal women.  Circulation. 2007;  115 840-845
• 12 Kolios L, Sehmisch S, Daub F, Rack T, Tezval M, Stuermer K M, Stuermer E K. Equol but not genistein improves early metaphyseal fracture healing in osteoporotic rats.  Planta Med. 2009;  75 459-465
• 13 Savoca S, D'Agosta S, Lombardo G. Evaluation of the hematochemical parameters and bone mineral density of women in physiological menopause treated with hormone replacement therapy with nomegestrol acetate and surgical menopause treated with estrogen replacement. Part II.  Minerva Ginecol. 2007;  59 215-222
• 14 Boonen S, Marin F, Obermayer-Pietsch B, Simoes M E, Barker C, Glass E V, Hadji P, Lyritis G, Oertel H, Nickelsen T, McCloskey E V. EUROFORS Investigators . Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis.  J Clin Endocrinol Metab. 2008;  93 852-860
• 15 Curtis R, Goldhahn J, Schwyn R, Regazzoni P, Suhm N. Fixation principles in metaphyseal bone – a patent based review.  Osteoporos Int. 2005;  16 54-64
• 16 McCann R M, Colleary G, Geddis C, Clarke S A, Jordan G R, Dickson G R, Marsh D. Effect of osteoporosis on bone mineral density and fracture repair in a rat femoral fracture model.  J Orthop Res. 2008;  26 384-393
• 17 Hao Y L, Zhang G, Wang Y S, Qin L, Hung W Y, Leung K, Pei F X. Changes of microstructure and mineralized tissue in the middle and late phase of osteoporotic fracture healing in rats.  Bone. 2007;  41 631-638
• 18 Stuermer E K, Sehmisch S, Rack T, Wenda E, Seidlova-Wuttke D, Tezval M, Wuttke W, Frosch K H, Stuermer K M. Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis. A new fracture-healing model at the tibia in rat.  Lang Arch Surg. 2008;  DOI: PMID: 19048282
• 19 Borrelli F, Erst E. Cimicifuga racemosa: a systematic review of its clinical efficacy.  Eur J Clin Pharmacol. 2002;  58 235-241
• 20 Seidlova-Wuttke D, Jarry H, Becker T, Christoffel V, Wuttke W. Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats: bone, fat and uterus.  Maturitas. 2003;  44 39-50
• 21 Viereck V, Gründker C, Friess S C, Frosch K H, Raddatz D, Schoppet M, Nisslein T, Emons G, Hofbauer L C. Isopropanolic extract of black cohosh stimulates osteoprotegerin production by human osteoblasts.  J Bone Miner Res. 2005;  20 2036-2043
• 22 Liu J, Burdette J E, Xu H, Gu C, van Breemen R B, Bhat K P, Booth N, Constantinou A I, Pezzuto J M, Fong H H, Farnsworth N R, Bolton J L. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms.  J Agric Food Chem. 2001;  49 2472-2479
• 23 Walji R, Boon H, Guns E, Oneschuk D, Younus J. Black cohosh (Cimicifuga racemosa [L.] Nutt.): safety and efficacy for cancer patients.  Support Care Cancer. 2007;  15 913-921
• 24 Seidlova-Wuttke D, Hesse O, Jarry H, Christoffel V, Spengler B, Becker T, Wuttke W. Evidence for selective estrogen receptor modulator activity in a black cohosh (Cimifuga racemosa) extract: comparison with estradiol-17beta.  Eur J Endocrinol. 2003;  149 351-362
• 25 Rahn B A. The fluorochrome sequence labeling of the bone.  Nova Acta Leopold. 1976;  44 249-255
• 26 Stürmer E K, Seidlova-Wuttke D, Sehmisch S, Rack T, Wille J, Frosch K H, Wuttke W, Stürmer K M. Standardized bending and breaking test for the normal and osteoporotic metaphyseal tibias of the rat: effect of estradiol, testosterone, and raloxifene.  J Bone Miner Res. 2006;  21 89-96
• 27 Schenk R K. The histological preparation of undecalcified bone.  Acta Anat. 1965;  60 3-19
• 28 Seidlova-Wuttke D, Stuermer K M, Stuermer E K, Sehmisch S, Wuttke W. Contrasting effects of estradiol, testosterone and of a black cohosh extract on density, mechanical properties and expression of several genes in the metaphysic of the tibia and on fat tissue of orchidectomized rats.  Maturitas. 2006;  55 64-74
• 29 Parfitt A M, Drezner M K, Glorieux F H, Kanis J A, Malluche H, Meunier P J, Ott S M, Recker R R. bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee.  J Bone Miner Res. 1987;  2 595-610
• 30 Nikolaou V S, Efstathopoulos N, Kontakis G, Kanakaris N K, Giannoudis P V. The influence of osteoporosis in femoral fracture healing time.  Injury. 2009;  40 665-668
• 31 Seidlova-Wuttke D, Jarry H, Wuttke W. Effects of estradiol benzoate, raloxifen and an ethanolic extract of Cimicifuga racemosa in nonclassical estrogen regulated organs of ovariectomized rats.  Planta Med. 2009;  DOI: PMID: 19350480
• 32 Wuttke W, Seidlová-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers.  Maturitas Supplement. 2003;  44 67-77
• 33 Sehmisch S, Boeckhoff J, Wille J, Seidlova-Wuttke D, Rack T, Tezval M, Wuttke W, Stuermer K M, Stuermer E K. Vitex agnus castus as prophylaxis for osteopenia after orchidectomy in rats compared with estradiol and testosterone supplementation.  Phytother Res. 2009;  23 851-858
• 34 Thompson D D, Simmons H A, Pirie C M, Ke H Z. FDA Guidelines and animal models for osteoporosis.  Bone. 1995;  17 125-133