Vol. 291, Issue 1, 321-328, October 1999

Bisphosphonate Effects in Rat Unloaded Hindlimb Bone Loss Model: Three-Dimensional Microcomputed Tomographic, Histomorphometric, and Densitometric Analyses

Odile Barou¹ , Marie-Hélène Lafage-Proust, Catherine Martel, Thierry Thomas, Fabrice Tirode, Norbert Laroche, Alain Barbier, Christian Alexandre and Laurence Vico

Laboratoire de Biologie et Biochimie du Tissu Osseux, Institut National de la Santé et de la Recherche Médicale, Saint-Etienne University, France (O.B., M.-H.L.-P., T.T., N.L., C.A., L.V.); and Sanofi Recherche, Montpellier, France (C.M., F.T., A.B.)

The effects of antiresorptive drugs on bone loss remain unclear. Using three-dimensional microtomography, dual X-ray/densitometry, and histomorphometry, we evaluated tiludronate effects in the bone loss model of immobilization in tail-suspended rats after 7, 13, and 23 days. Seventy-eight 12-week-old Wistar male rats were assigned to 13 groups: 1 baseline group, and for each time point, 1 control group treated with vehicle and three tail-suspended groups treated with either tiludronate (0.5 or 5 mg/kg) or vehicle, administered s.c. every other day, during the last week before sacrifice. In primary spongiosa (ISP), immobilization-induced bone loss plateaued after day 7 and was prevented by tiludronate. In secondary spongiosa (IISP), bone loss appeared at day 13 with a decrease in trabecular thickness and trabecular number (Tb.N) as assessed by three-dimensional microtomography. Osteoclastic parameters did not differ in tail-suspended rats versus control rats, whereas bone formation showed a biphasic pattern: after a marked decrease at day 7, osteoblastic activity and recruitment normalized at days 13 and 23, respectively. At day 23, the 80% decrease in bone mass was fully prevented by high-dose tiludronate with an increase in Tb.N without preventing trabecular thinning. In summary, at day 7, tiludronate prevented bone loss in ISP. After day 13, tiludronate prevented bone loss in ISP and IISP despite a further decrease in bone formation. Thus, the preventive effects of tiludronate in this model may be related to the alteration in bone modeling with an increase in Tb.N in ISP and subsequently in IISP.