Oral treatment with a new bisphosphonate, YM175, for 13 wk resulted in increased bone tissue mass by both intramembranous and endochondral ossification processes in adult beagle dogs. Intramedullary bone formation due to intramembranous process was observed in dogs treated with a highly toxic dose of YM175. The newly formed woven bone trabeculae, showing immature to relatively mature figures, were present between the preexisting cancellous bone. The immature bone consisted of spindle-shaped mesenchymal cells with osteoid tissues. Many active osteoblasts surrounded the immature woven bone, while only few osteoclasts were seen on the surfaces of the new bone. Endochondral bone change was observed at the costochondral junction in all YM175-treated groups. Accumulation of unresorbed mineralized cartilage with its covering of bone at this site resulted in an increase in length of the area of primary spongiosa. Although the endochondral bone change induced by YM175 was due to a bisphosphonate-induced inhibitory effect on bone resorption, the intramedullary bone formation is unique to YM175.
Canalis E. , McCarthy T., and Centrella M. (1989). The regulation of bone formation by local growth factors. In: Bone and Mineral Research/6, WA Peck (ed). Elsevier Science Publishers B.V., Amsterdam, pp. 27-56.
2.
Cantrill JA and Anderson DC (1990). Treatment of Paget's disease of bone. Clin. Endocrinol. 32: 507-518.
3.
Carano A., Teitelbaum SL, Konsek JD, Schlesinger PH, and Blair HC (1990). Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J. Clin. Invest. 85: 456-461.
4.
Centrella M. , McCarthy TL, and Canalis E. (1992). Growth factors and cytokines . In: Bone, Vol. 3: Bone Metabolism and Mineralization, BK Hall (ed). CRC Press, Boca Raton, Florida , pp. 47-72.
5.
Courtney CL , Kim SN, Walsh KM, Watkins JR, and Dominick MA (1991). Proliferative bone lesions in rats given anticancer compounds. Toxicol. Pathol. 19: 184-188.
6.
Faccini JM and Teotia SPS (1974). Histopathological assessment of endemic skeletal fluorosis. Calcif. Tissue Res. 16: 45-57.
7.
Fitton A. and McTavish D. (1991). Pamidronate. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs41: 289-318.
8.
Fleisch H. (1987). Bisphosphonates-History and experimental basis . Bone8(suppl.1): S23-S28.
9.
Gaunt SD and Pierce KR (1985). Myelopoiesis and marrow adherent cells in estradiol-treated mice. Vet. Pathol. 22: 403-408.
10.
Heaney RP and Saville PD (1976). Etidronate disodium in postmenopausal osteoporosis . Clin. Pharmacol. Ther. 20: 593-604.
11.
Hock JM, Gera I., Fonseca J., and Raisz G. (1988). Human parathyroid hormone-(1-34) increases bone mass in ovariectomized and orchidectomized rats. Endocrinology122: 2899-2904.
12.
Horowitz E. , Miller JL, and Rose LI (1991). Etidronate for hypercalcemia of malignancy and osteoporosis. Am. Fam. Physician43: 2155-2159.
13.
Hughes DE, MacDonald BR, Russell RGG, and Gowen M. (1989). Inhibition of osteoclast-like cell formation by bisphosphonates in long-term cultures of human bone marrow. J. Clin. Invest. 83: 1930-1935.
14.
Jee WSS , Ueno K., Deng YP, and Woodbury DM (1985). The effects of prostaglandin E2 in growing rats: Increased metaphyseal hard tissue and cortico-endosteal bone formation. Calcif. Tissue Int. 37: 148-157.
15.
Jowsey J., Riggs BL, Kelly PJ, Hoffman DL, and Bordier P. (1971). The treatment of osteoporosis with disodium ethane-1-hydroxy- 1,1-diphosphonate. J. Lab. Clin. Med. 78: 574-584.
16.
Jung A., Bisaz S., and Fleisch H. (1973). The binding of pyrophosphate and two diphosphonates by hydroxyapatite crystals. Calcif. Tissue Res. 11: 269-280.
17.
King WR, Francis MD, and Michael WR (1971). Effect of disodium ethane-1-hydroxy-1,1,-diphosphonate on bone formation. Clin. Orthop. 78: 251-270.
18.
Milhaud G., Labat ML, and Moricard Y. (1983). (Dichloromethylene)diphosphonate-induced impairment of T-lymphocyte function. Proc. Natl. Acad. Sci. USA80: 4469-4473.
19.
Miller SC and Jee WSS (1975). Ethane-1-hydroxy-1,1-diphosphonate (E HDP) effects on growth and modeling of the rat tibia. Calcif. Tissue Res. 18: 215-231.
20.
Miller SC and Jee WSS (1977). The comparative effects of dichloromethylene diphosphonate (Cl2MDP) and ethane-1-hydroxy-1,1-disphosphonate (EHDP) on growth and modeling of the rat tibia. Calcif. Tissue Res. 23: 207-214.
21.
Miller SC and Jee WSS (1979). The effect of dichloromethylene diphosphonate. a pyrophosphate analog. on bone and bone cell structure in the growing rat. Anat. Rec. 193: 439-462.
22.
Noda M. and Camilliere JJ (1989). In vivo stimulation of bone formation by transforming growth factor-β. Endocrinology124: 2991-2994.
23.
Palmer N. (1993). Bones and joints. In: Pathology of Domestic Animals, Vol. 1, KVF Jubb, PC Kennedy, and N Palmer (eds). Academic Press, San Diego, California, pp. 1-181.
24.
Quarles LD, Gitelman HJ, and Drezner MK (1988). Induction of de novo bone formation in the beagle. A novel effect of aluminum. J. Clin. Invest. 81: 1056-1066.
25.
Quarles LD, Gitelman HJ, and Drezner MK (1989). Aluminum-induced de novo bone formation in the beagle. A parathyroid hormone-dependent event. J. Clin. Invest . 83: 1644-1650.
26.
Reitsma PH , Bijvoet OLM , Verlinden-Ooms H., and Wee-Pals LJA. (1980). Kinetic studies of bone and mineral metabolism during treatment with (3-amino-1-hydroxypropylidene)- 1,1-bisphosphonate (APD) in rats. Calcif. Tissue Int. 32: 145-157.
27.
Russell RGG , Mühlbauer RC, Bisaz S., Williams DA, and Fleisch H. (1970). The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the dissolution of hydroxyapatite in vitro and bone resorption induced by parathyroid hormone in tissue culture and in thyroparathyroidectomized rats. Calcif. Tissue Res. 6: 183-196.
28.
Schenk R., Merz WA, Mühlbauer R., Russell RGG, and Fleisch H. (1973). Effect of ethane-1-hydroxy-1,1-diphosphonate (E HDP) and dichloromethylene diphosphonate (Cl2MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif. Tissue Res. 11: 196-214.
29.
Shinoda H., Adamek G., Felix R., Fleisch H., Schenk R., and Hagan P. (1983). Structure-activity relationships of various bisphosphonates . Calcif. Tissue Int. 35: 87-99.
30.
Simmons DJ and Grynpas MD (1990). Mechanisms of bone formation in vivo. In: Bone, Vol. 1: The Osteoblast and Osteocyte, BK Hall (ed). The Telford Press, Caldwell, New Jersey, pp. 193-302.
31.
Snow GR and Anderson C. (1986). Short-term chronic fluoride administration and trabecular bone remodeling in beagles: A pilot study, Calcif. Tissue Int. 38: 217-221.
32.
Trechsel U.Schenk R.Bonjour JP, Russell RGG, and Fleisch H. (1977). Relation between bone mineralization. Ca absorption. and plasma Ca in phosphonate-treated rats. Am. J. Physiol . 232: E298-E305.
33.
Ueno K.Haba T.Woodbury D.Price P.Anderson R., and Jee WSS (1985). The effects of prostaglandin E2 in rapidly growing rats: Depressed longitudinal and radial growth and increased metaphyseal hard tissue mass. Bone6: 79-86.
34.
Urist MR (1989). Bone morphogenetic protein, bone regeneration, heterotopic ossification and the bone-bone marrow consortium. In: Bone and Mineral Research/6, WA Peck (ed). Elsevier Science Publishers B.V., Amsterdam, pp. 57-112.
35.
Weatherell JA and Weidmann SM (1959). The skeletal changes of chronic experimental fluorosis. J. Pathol. Bacteriol . 78: 233-241.
36.
Weisbrode SE and Capen CC (1977). The ultrastructural effect of estrogens on bone cells in thyroparathyroidectomized rats. Am. J. Pathol. 87: 311-322.
37.
Weisbrode SE and Capen CC (1991). Hormonal effect on bone, rat. In: Cardiovascular and Musculoskeletal Systems, TC Jones, U Mohr, and RD Hunt (eds). Springer-Verlag, Berlin, Heidelberg, pp. 263-273.
38.
Woodard JC and Jee WSS (1991). Skeletal system. In: Handbook of Toxicologic Pathology, WM Haschek and CG Rousseaux (eds). Academic Press, San Diego, California, pp. 489-537.
