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Daily oral clodronate treatment was evaluated in Sprague-Dawley rats for its ability to inhibit estrogen-deficiencyinduced changes in femoral neck, femoral diaphysis, and lumbar vertebrae (L4 -L5). Six-month-old ovariectomized (OVX) rats were administered by gavage a vehicle (Veh) or clodronate (100 or 500 mg/kg/day). Shamoperated (SHAM) control rats received the vehicle (n ‫؍‬ 15/group). Treatment was started on the day of operation and continued for 3 months. Trabecular bone volume (BV/TV) and structural variables (trabecular number, Tb.N; thickness, Tb.Th; separation, Tb.Sp; and trabecular bone pattern factor, Tb.Pf) were assessed on secondary spongiosa of the right femoral neck. Furthermore, cantilever bending test of the left femoral neck and compression test of L4, ash weight of L5, and morphometric studies of femoral diaphysis were carried out, and serum and urinary markers of bone turnover were determined. The OVX/Veh group had higher levels of serum osteocalcin and alkaline phosphatase and higher urinary excretion of deoxypyridinoline/creatinine than the SHAM/Veh group at 3 months postsurgery, and clodronate reduced these changes. BV/TV of femoral neck, bone mass of L5, and the maximum loads of the femoral neck and L4 were lower after OVX than SHAM operation. Although clodronate prevented trabecular bone loss in the femoral neck and preserved Tb.Pf at the SHAM control level, it failed to preserve the mechanical strength at the femoral neck. However, in lumbar vertebrae, clodronate prevented the loss of bone mass and mechanical properties. Furthermore, there was a good positive correlation between maximum load of L4 and the ash weight of L5 (n ‫؍‬ 58, r ‫؍‬ 0.69, p < 0.001). In the femoral neck (n ‫؍‬ 55), Tb.Pf correlated negatively with BV/TV and Tb.N (r ‫؍‬ ؊0.59 and r ‫؍‬ ؊0.55; p < 0.001, respectively) and positively with Tb.Sp (r ‫؍‬ 0.61, p < 0.001). In femoral mid-diaphysis, there were no significant changes in cortical bone geometry in any of the groups. We conclude that orally administered clodronate suppresses the enhanced bone turnover in adult OVX rats and preserves trabecular bone volume and connectivity in the femoral neck. In the axial skeleton, clodronate has a beneficial effect on lumbar vertebral bone mass and strength. (J Bone Miner Res 1998;13:287-296)

The purpose of this study was to investigate the ability of clodronate to prevent ovariectomy (OVX)-induced osteopenia in aged rats. Fourteen-month-old female Sprague-Dawley rats (n = 166) were randomized into six groups. One group was sacrificed at the start of the study, four groups were ovariectomized, and one group was sham-operated (Sham). The OVX rats were given subcutaneously either vehicle (veh) or clodronate at doses of 3, 7, or 25 mg/kg once a week for 3 months, and the Sham rats were given the vehicle. At all dose levels clodronate inhibited trabecular bone loss in the distal femur and in the fourth lumbar vertebral body (L4), and decreased bone resorption as evidenced by urinary deoxypyridinoline excretion. The lowest dose of clodronate preserved serum osteocalcin and endosteal bone formation of secondary spongiosa in L4 at the level of the Sham/veh group. The OVX-induced increase in periosteal bone formation of femoral diaphysis was unaffected by two smaller doses of clodronate, but was decreased to the level of Sham rats after the highest dose. After 3 mg/kg clodronate, the percentage of femoral cortical bone area and the mean relative cortical thickness were higher compared with the OVX/veh group. There was a good positive correlation between the maximum load in three-point bending of the tibia and tibial ash weight. Normal lamellar pattern of newly formed cancellous and cortical bone was found after clodronate treatment. No signs of adverse accumulation of osteoid or any deleterious effect on mechanical strength of long bones and lumbar vertebrae were found.

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Orally administered clodronate was evaluated for its ability to inhibit increase of bone turnover in ovariectomized (OVX) rats. Six -month~ old GVX Sprague-Dawley rats were administered by gavage a vehicle (veh) or clodronate (clod) at doses of 100 or 500 mg/kg/d five times a week. Sham-operated rats received the vehicle. Treatment began on the day of ovariectomy and continued for 3 months. At the end of the study, blood and 24-hour urine samples were collected from fasted rats. Serum osteocalcin (S-OC) and alkaline phosphatase (S-ALP) were determined by RIA and by a colorimetric method, respectively. Urinary excretion of free deoxypyridinoline was measured using an ELISA assay-(Pyrilinks-D, Metra Biosystems) and expressed as the ratio to urinary creatinine (DPD/Cr). Statistical analyses were performed by analysis of variance. Comparisons were carried out using linear contrasts. Results are given as means (SE) and corresponding p values: