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The purpose of the present study was to examine the effects of combined administration of alendronate (ALN) and alfacalcidol (ALF) on the cancellous and cortical bone mass of the tibia in orchidectomized rats. Fifty male Sprague-Dawley rats, 3 mo of age, were randomized by the stratified weight method into five groups: age-matched control, orchidectomy, and orchidectomy with administration of ALN (2.5 μg/kg, s.c., 5 times a week), ALF (0.05 μg/kg, p.o., 5 times a week), or ALN+ALF. The total experimental period was 12 wk. Orchidectomy reduced the cancellous bone mass of the proximal tibial metaphysis and maturation-related cortical bone gain of the tibial diaphysis as a result of increased trabecular bone resorption and decreased periosteal bone formation and also increased endocortical bone erosion and formation. ALN suppressed trabecular bone resorption and endocortical bone erosion and formation and increased periosteal bone formation, while ALF increased the number of osteoblasts and suppressed trabecular bone resorption and markedly increased periosteal and endocortical bone formation. Thus, both ALN and ALF prevented the orchidectomy-induced reduction in the cancellous bone mass and maturation-related cortical bone gain. Combined administration of ALN and ALF increased the cancellous bone mass as compared with the values observed in age-matched controls by causing more marked suppression of trabecular bone resorption. The present study showed the beneficial effects of combined administration of ALN and ALF on the cancellous bone mass of the tibia in orchidectomized rats.

The beneficial effects of alfacalcidol (ALF) on bone mass, bone formation, and bone resorption have been established in ovariectomized rats. Our previous studies showed that high-dose glucocorticoid (GC) administration (methylprednisolone sodium succinate, 5.0 mg/kg, s.c., 3 times a week) for 4 wk induced cancellous osteopenia without significantly affecting cortical bone mass in Sprague-Dawley rats, and that high-dose GC administration for 8 wk also resulted in cortical osteopenia. The purpose of the present study was to examine the effects of ALF on cancellous and cortical bone mass in GC-treated rats. Forty female Sprague-Dawley rats, 3 mo of age, were randomized by the stratified weight method into four groups of 10 rats each, as follows: age-matched control group (CON); 8-wk GC administration with administration of vehicle during the latter 4 wk of treatment (GC group); 8-wk GC administration with administration of a low dose of ALF (0.08 Ag/kg) during the latter 4 wk of treatment (low-dose ALF group); 8-wk administration of GC with administration of a high dose ofALF (0.16 microg/kg) during the latter 4 wk of treatment (high-dose ALF group). The GC (methylprednisolone sodium succinate, 5.0 mg/kg) was administered subcutaneously 3 times a week, and ALF was administered orally 5 times a week. At the end of the experiment, static and dynamic bone histomorphometric analyses were performed on cancellous bone of the proximal tibial metaphysis and cortical bone of the tibial diaphysis. Eight-week GC administration resulted in loss of the cancellous bone volume/total tissue volume (BV/TV) and percent cortical area (Ct Ar) as a result of decreased trabecular bone formation, increased trabecular and endocortical bone resorption, and decreased periosteal bone formation. Low-dose ALF restored the cancellous BV/TV by mildly suppressing bone resorption and restoring bone formation, whereas high-dose ALF increased it beyond the value observed in the age-matched controls by strongly suppressing bone resorption and markedly increasing bone formation. Both low- and high-dose ALF prevented the GC-induced reduction of the percent Ct Ar by increasing periosteal bone formation and suppressing endocortical bone resorption. The effects of ALF on cancellous bone mass, bone formation, and bone resorption were all dose-dependent. The present study showed the beneficial effects of ALF on cancellous and cortical bone mass in GC-treated rats.

Objectives: To compared the effects of risedronate (Ris) and calcitriol (Cal) on cancellous bone in rats with glucocorticoid (GC)-induced osteopenia. Materials and Methods: Thirty female Sprague-Dawley rats, 4 mo of age, were randomly divided by the stratified weight method into three groups of 10 rats each according to the following treatment schedule: 8-wk GC administration with 4-wk vehicle (control), Ris, and Cal as therapeutic treatment initiated after 4-wk GC administration. The GC (methylprednisolone sodium succinate, 5.0 mg/kg, s.c.), Ris (10 μg/kg, s.c.), and Cal (0.1 μg/kg, p.o.) were administered 3 times a week. At the end of the 8-wk treatment period, two-dimensional (2D) bone histomorphometric analysis was performed for cancellous bone of the proximal tibial metaphysis, 3D micro-computed tomographic analysis was performed for the distal femoral metaphysis, and the mechanical strength of the distal femoral metaphysis was evaluated by a compression test. Results: Ris and Cal treatment increased both 2D and 3D cancellous bone mass. However, Ris treatment exhibited more pronounced effects on 2D and 3D cancellous bone mass than Cal treatment, and the effects of both Ris and Cal treatment were greater on 3D cancellous bone mass than on 2D cancellous bone mass. The response of 2D and 3D cancellous bone mass to Ris treatment was characterized by its effect on trabecular number and thickness, which was associated with markedly suppressed bone resorption and bone formation in terms of suppressed bone turnover. On the other hand, the response of 2D cancellous bone mass to Cal treatment was attributed to the effect of Cal on 2D trabecular thickness, and the response of 3D cancellous bone mass to Cal treatment might be characterized by the effect of Cal on 3D trabecular number and thickness, with a more marked effect of trabecular thickness. These effects were primarily due to mildly suppressed bone resorption and maintained or even increased bone formation. Despite the differential effect of Ris and Cal treatment on the cancellous bone structure and bone metabolism, both treatment increased the maximum load and braking energy of the distal femoral metaphysis to a similar extent, suggesting different mechanisms for improving bone strength. Conclusions: This study showed the differential effects of Ris and Cal on cancellous bone in rats with GC-induced osteopenia.

The purpose of the present study was to examine the effect of pretreatment with risedronate and/or vitamin K2 and treatment continuation with reduced dosing frequency of the drugs on the early cancellous bone loss induced by ovariectomy (OVX) in rats. Eighty female Sprague-Dawley rats, 4 mo of age, were randomized by the stratified weight method into eight groups (n=10 in each group); rats subjected to OVX, but not sham-operated rats, were treated with vehicle, risedronate, vitamin K2 (menatetrenone), or risedronate+vitamin K2 for 4 wk before the surgery, and the treatment was either discontinued (pretreatment groups) or continued after the surgery (treatment continuation groups) for 2 wk. Sham-operated rats (controls) were treated with the vehicle throughout the experimental period. During the 4 wk prior to the surgery (pretreatment), risedronate and vitamin K2 were administered five times a week either subcutaneously at a dose of 2.5 μg/kg body weight (risedronate) or orally at the dose of 30 mg/kg body weight (vitamin K2). During the 2 wk after the surgery (treatment continuation), the dosing frequency of the drugs was reduced to twice a week. Risedronate and vitamin K2 had an anti-resorptive effect on the bone. Pretreatment with risedronate alone, but not vitamin K2 alone, prevented the loss of the cancellous bone volume/total volume (BV/TV) of the proximal tibial metaphysis after OVX. Treatment continuation with vitamin K2 alone prevented the loss of the cancellous BV/TV after OVX, while treatment continuation with risedronate alone increased the cancellous BV/TV to beyond the values in controls. Pretreatment with risedronate+vitamin K2 had a more beneficial effect in increasing the cancellous bone mass than pretreatment with risedronate alone. Treatment continuation with risedronate and/or vitamin K2 appeared to have a more beneficial effect in increasing the cancellous bone mass than the respective pretreatment. Neither the total tissue area nor the cortical area of the tibial diaphysis was affected by any treatment. The present study demonstrated that pretreatment with risedronate had a beneficial effect on the early cancellous bone loss after OVX in rats, with a more beneficial effect when combined with vitamin K2. Moreover, even though the dosing frequency of the drugs was reduced after OVX, treatment continuation appeared to be more beneficial than pretreatment for increasing the cancellous bone mass.

The purpose of the present study was to compare the effects of risedronate (RIS) and alfacalcidol (ALF) on the cortical and cancellous bone mass and mechanical properties in ovariectomized rats in a head-to-head fashion. Forty female Sprague-Dawley rats, 7 mo of age, were randomized into six groups: the sham-operated control (Sham) group, and five ovariectomized groups: treated with vehicle, RIS (0.1, 1.0, or 2.5 mg/kg, p.o., daily), and ALF (0.5 μg/kg, p.o., daily). At the end of the 8-wk experimental period, bone histomorphometric analyses of the cancellous bone of the proximal tibial metaphysis and cortical bone of the tibial disphysis was performed, and the mechanical properties of the bone were evaluated at the femoral distal metaphysis (FDM) and femoral diaphysis (FD). RIS prevented the decrease in the cancellous bone volume/total tissue volume (BV/TV) noted in ovariectomized rats in a dose-dependent manner, by suppressing increases in cancellous bone formation and resorption, without any apparent effect on the Ct Ar or maximum load of the FDM or FD. On the other hand, ALF increased the cancellous BV/TV, Ct Ar, and maximum load of the FDM or FD, by mildly decreasing cancellous bone formation and resorption, increasing periosteal and endocortical bone formation, and preventing an increase in endocortical bone resorption. Thus, the present study clearly showed that RIS and ALF had differential effects on the cortical and cancellous bone mass and mechanical properties in ovariectomized rats.

The purpose of the present study was to compare the therapeutic effects of alendronate and alfacalcidol on the cancellous and cortical bone mass and mechanical properties in ovariectomized osteopenic rats in a head-to-head fashion. Twenty-five female Sprague-Dawley rats, 7 mo of age, were randomly divided by the stratified weight method into four groups: the sham-operated control (Sham) group and three ovariectomized groups treated with vehicle, alendronate (2.5 mg/kg, p.o., daily), or alfacalcidol (0.5 microg/kg, p.o., daily). Treatment was started 6 wk after the surgery and continued for 6 wk. At the end of the experiment, urinary deoxypyridinoline (DPD) and serum osteocalcin (OC) levels were evaluated, and cancellous and cortical bone histomorphometric analyses were performed for the proximal tibial metaphysis and tibial diaphysis, respectively. Alendronate prevented the elevation of the urinary DPD level induced by ovariectomy (OVX), and markedly decreased the serum OC level to below the value observed in the Sham group, while alfacalcidol prevented the elevation of the urinary DPD and serum OC levels induced by OVX. Alendronate increased the cancellous bone volume/total tissue volume (BV/TV) relative to the values observed in the OVX-Vehicle group by preventing the increases in the eroded surface/bone surface (ES/BS), osteoclast surface (OcS)/BS, and bone formation rate (BFR)/BS induced by OVX. However, it decreased the mineral apposition rate (MAR) in the ovariectomized osteopenic rats to below the value observed in the Sham group. It also prevented the increase in the marrow area (Ma Ar) caused by OVX. Alfacalcidol increased the BV/TV relative to the values observed in the OVX-Vehicle group by decreasing the ES/BS and OcS/BS, but maintaining the BFR/BS. The effect of alfacalcidol on the BV/TV was more pronounced than that of alendronate, despite the less pronounced suppression of OcS/BS by this drug in the ovariectomized osteopenic rats. In addition, this drug increased the cortical area (Ct Ar) and prevented the increase in the Ma Ar in the ovariectomized osteopenic rats by decreasing the endocortical ES/BS, and even increasing the endocortical BFR/BS. Furthermore, it also prevented the reduction in the maximum load of the femoral distal metaphysis in the ovariectomized osteopenic rats. Thus, the present study clearly showed that alendronate and alfacalcidol had differential therapeutic effects on the cancellous and cortical bone mass and mechanical properties in ovariectomized osteopenic rats.

We examined the effect of vitamin K and vitamin D supplementation on calcium balance in young rats fed a normal or low calcium diet. Eighty female Sprague-Dawley rats, 6 wk of age, were randomized by the stratified weight method into eight groups with 10 rats in each group: 0.5% (normal) or 0.1% (low) calcium diet, 0.5% or 0.1% calcium diet+vitamin K (vitamin K2, menatetrenone, 30 mg/100 g, food intake), 0.5% or 0.1% calcium diet+vitamin D (25 microg/100 g, food intake), and 0.5% or 0.1% calcium diet+vitamin K+vitamin D. The duration of the study was 10 wk. Vitamin K supplementation promoted the reduction in urinary calcium excretion and retarded the abnormal elevation of serum PTH level in rats fed a low calcium diet, and stimulated intestinal calcium absorption in rats fed a normal calcium diet. Vitamin D supplementation stimulated intestinal calcium absorption with prevention of the abnormal elevation of serum PTH levels and prevented hypocalcemia in rats fed a low calcium diet, and stimulated intestinal calcium absorption in rats fed a normal calcium diet. The stimulation of intestinal calcium absorption was associated with increased serum 1,25-dihydroxyvitamin D levels. An additive effect of vitamin K and vitamin D on intestinal calcium absorption was found only in rats fed a normal calcium diet. This study shows the differential effects of vitamin K and vitamin D supplementation on calcium balance in young rats fed a normal or low calcium diet.