First Place — Resident Basic Science Award 1993: Risedronate Activity in the Fetal and Neonatal Mouse

Abstract

Otosclerosis, chronic otitis media with and without cholesteatoma, and Paget's disease of bone are just a few of the many diseases of the ear that exhibit abnormalities of bone modeling and remodeling. These diseases result in chronic infection, vestibular dysfunction, and hearing loss. Bisphosphonates are a promising new class of drugs potentially useful in the treatment of these disorders. Currently used in diseases with high rates of bone turnover (Paget's disease of bone, hypercalcemia of malignancy, and osteoporosis), they have been found to be strong inhibitors of bone resorption. A third generation bisphosphonate, 2-(3-pyrindyl)-hydroxyethylidene bisphosphonate (risedronate) is being investigated for toxicity, increased efficacy, and oral administration. In this study the in vitro and in vivo anti-resorptive activity of risedronate was quantified by measuring calcium release in a neonatal mouse calvarial culture system. This model was used to test direct in vitro effects, in vivo exposure in neonatal mice, and the possible effects of in utero and lacteal exposure. Calcium release activated by parathyroid hormone (PTH) was significantly inhibited when risedronate was only present in the pre-incubation media. When risedronate was administered subcutaneously to neonatal mice it resulted in a significant decrease in PTH-activated calcium release in explanted calvaria in vitro. Transplacental and lactational transfer of biologically effective risedronate was not demonstrated in this study; however, a paradoxic increase in PTH-stimulated calcium release in vitro from calvaria theoretically exposed transplacentally and lacteally was noted. This effect was unexplained by the data.

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References

Chole

. Osteoclasts in chronic otitis media, cholesteatoma, and otosclerosis. Ann Otol Rhinol Laryngol 1981; 97: 661–66.

Davis

. Pathology of otosclerosis: a review. Am J Otolaryngol 1987;8:273–81.

Lim

Saunders

. Active otosclerotic foci in the stapes. An electron microscopic study. Acta Otolaryngol (Stockh) 1975; 80: 255–68.

Lim

Saunders

. Otosclerotic stapes: morphological and microchemical correlates. An electron microscopic and x-ray analytical investigation. Ann Otol Rhinol Laryngol 1977; 86: 525–40.

Ruedi

Acquired cholesteatoma. Arch Otolaryngol 1963; 78:252–61.

Chole

. Cellular and subcellular events of bone resorption in human and experimental cholesteatoma: the role of osteoclasts. Laryngoscope 1984;94:76–95.

Grippaudo

Histopathological studies of the ossicles in chronic otitis media. J Laryngol Otol 1958;72:177–89.

Lim

Robinson

Saunders

. Morphologic and immunohistochemical observation of otosclerotic stapes: a preliminary study. Am J Otolaryngol 1987;8:282–95.

Petrovic

Stutzman

Shambaugh

. Experimental studies on pathology and therapy of otospongiosis. Am J Otol 1985;6:43–50.

10.

Orisek

Chole

. Pressures exerted by experimental cholesteatomas. Arch Otolaryngol 1987;113:386–91.

11.

Macri

Chole

. Bone erosion in experimental cholesteatoma—the effects of implanted barriers. OTOLARYNGOL HEAD NECK SURG 1985;93:3–17.

12.

Thomsen

Jorgensen

Bretlau

Kristensen

. Bone resorption in chronic otitis media. A histological and ultra-structural study. I. Ossicular necrosis. J Laryngol Otol 1974; 88: 975–81.

13.

Adachi

Chole

Yee

Indomethacin inhibition of middle ear bone resorption. Arch Otolaryngol 1991; 117: 267–9.

14.

Rabdjija

Schwartz

Goldhaber

Inhibition of A23187-stimulated bone resorption in tissue culture by serum and indomethacin. Bone Miner 1987;3:1–11.

15.

Galasko

CSB

Bennet

Relationship of bone destruction in skeletal metastases to osteoclast activation and prostaglandins. Nature 1976;263:508–10.

16.

Torbinejad

Clagett

Engel

A cat model for the analysis of mechanisms of bone resorption: induced bone loss by stimulated immune complexes and inhibition by indomethacin. Calcif Tissue Int 1979;29:207–14.

17.

Thompson

Rodan

. Indomethacin inhibition of tenotomy-induced bone resorption in rats. J Bone Miner Res 1988;3:409–14.

18.

Sudmann

Bang

Indomethacin-induced inhibition of haversian remodeling in rabbits. Acta Orthop Scand 1979; 50:621–27.

19.

Moriyama

Huang

Kato

Abramson

Effects of pressure on bone resorption in the middle ear of rats. Ann Otol Rhinol Laryngol 1985;94:60–4.

20.

Attie

. Treatment of hypercalcemia. Endocrinol Metab Clin North Am 1989;18:807–28.

21.

Lukert

Raisz

. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990; 112: 352–64.

22.

Singer

. Role of the bisphosphonate Etidronate in the therapy of cancer-related hypercalcemia. Semin Oncol 1990; 17 (Suppl 17):34–9.

23.

Kansi

McCloskey

Taube

O'Rourke

Rationale for the use of bisphosphonates in bone metastases. Bone 1991; 12 (Suppl 12):S13–S18.

24.

Fleisch

Bisphosphonates: a new class of drugs in diseases of bone and calcium metabolism. Cancer Res 1989;116:1–28.

25.

Fleisch

Experimental basis for the use of bisphosphonates in Paget's disease of bone. Clin Orthop 1987;217:72–8.

26.

Weinerman

Bockman

. Medical therapy of osteoporosis. Orthop Clin North Am 1990;21:109–24.

27.

Lando

Hoover

Finerman

Stabilization of hearing loss in Paget's disease with calcitonin and etidronate. Arch Otolaryngol Head Neck Surg 1988;114:891–4.

28.

Sietsema

Ebertino

Salvagno

Bevan

. Antiresorptive dose-response relationships across three generations of bisphosphonates. Drugs Exp Clin Res 1989; XV(9): 389–96.

29.

Tinling

Richardson

Chole

. Risedronate is a potent inhibitor of calcium release in vitro. J Bone Miner Res (Submitted for publication).

30.

Goldhaber

Remodeling of bone in tissue culture. J Dent Res 1966; 45 (Suppl 45):490–9.

31.

Tasjian

Jr Voelkel

Levine

Goldhaber

Evidence that the bone resorption stimulating factor produced by mouse fibrosarcoma cells is prostaglandin E2. J Exp Med 1972;136:1329–43.

32.

Rowe

Ettre

. Uptake of a fluorinated bisphosphonate by cultured bones. Bone 1988;9:297–301.

33.

Weinerman

Bockman

. Medical therapy of osteoporosis. Orthop Clin North Am 1990;21:109–24.

34.

Adachi

Chole

. Inhibition of osteoclast recruitment at a local site by 1-hydroxyetheylidene-1, 1-bisphosphonate (HEBP). Ann Otol Rhinol Laryngol 1990;99 (9):738–41.

35.

Petrovick

Subsman

Disphosphonates: a potential medication for evolutive otospongiosis. Proceedings of the fourth symposium, (CEMO). Educ Med Hygiene 1988; 84: 275–82.

36.

Vernejoul

. Aveniear des disphosphonates. Presse Med 1987;16:26.

37.

Bouman

Poublon

. The detrimental effect of amino-hydroxypropylidene bisphosphonate (APD) in otospongiosis. Eur Arch Otorhinolaryngol 1991;248:218–21.

38.

Ikeo

Takaya

Yamauchi

Miwa

Shioji

Sakaiyama

Effect of ethane-1-hydroxyl-1, 1-diphosphonate (EHDP) on fetal mice during pregnancy — chemical changes in skin collagen. J Osaka Dent Univ 1987;21:45–53.

39.

Sakiyama

Tada

Yamamoto

The effect of ethane-1-hydroxy-1, 1-diphosphonate (EHDP) on fetal mice during pregnancy—with emphasis on implantation and fetal weight. J Osaka Dent Univ 1985;19:87–90.

40.

Van der Pluijm

Lowik

De Groot

Modulation of PTH-stimulated osteoclastic resorption by bisphosphonates in fetal mouse bone explants. J Bone Miner Res 1991;6:1203–1210.

41.

Van der Pluijm

Binderup

Bramm

Disodium 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1, 1-bisphosphonate (EB-1053) is a potent inhibitor of bone resorption in vitro and in vivo. J Bone Miner Res 1992;7 (8):981–6.