No loss of biomechanical effects after withdrawal of short-term PTH treatment in an aged, osteopenic, ovariectomized rat model.

The aim of the study was to assess the biomechanical effects of short-term PTH treatment and withdrawal on bone mass and strength in an aged, osteopenic, ovariectomized (ovx) rat model. Additionally, the effect of sequential therapy with PTH and the bisphosphonate, risedronate, the effect of longterm PTH monotherapy, and the effect of long-term risedronate monotherapy were assessed. 96 4-month-old rats were randomized into nine groups. Eight groups were ovariectomized and one group was sham operated. 12 months after surgery, treatment regimens were initiated (OW) and were continued for either 2 weeks (2 W) or 12 weeks (12 W). The treatment regimens were as follows: (1) baseline ovx (OW); (2) ovx-saline (2 W); (3) ovx-PTH 1-34 (2 W); (4) intact-saline (12 W); (5) ovx-saline (12 W); (6) ovx-risedronate (12 W); (7) ovx-PTH 1-34 (12 W); (8) ovx-PTH 1-34 (2 W), followed by pause (10 W); and (9) ovx-PTH 1-34 (2 W), accompanied by risedronate (12 W). The effect of therapy (endpoint) was measured at three skeletal sites: vertebral bodies; femoral cortical bone; and femoral necks. The results revealed an anabolic, time-dependent effect of PTH 1-34 at all skeletal sites. No loss of anabolic effect was observed 10 weeks after discontinuation of 2 week PTH treatment in this rat model. Risedronate given in sequential therapy with PTH produced no significant effect on biomechanical properties at any skeletal sites when compared with 2 week PTH followed by a 10 week pause. However, when risedronate was given alone, a positive effect was seen at the vertebral site after a 12 week treatment. On the basis of this study with short-term PTH treatment of aged, osteopenic, ovariectomized rats, there seemed to be a significant effect of PTH on the biomechanical properties and no loss of effect even 10 weeks after PTH withdrawal.

A comparison of the effects of two anabolic agents (fluoride and PTH) on ash density and bone strength assessed in an osteopenic rat model.

The aim of this investigation was to compare the effects of sodium fluoride (NaF) and parathyroid hormone (PTH) on ash density and strength in an osteopenic rat model. The study comprised 66 female virgin rats divided into the following 11 groups, each comprising six animals: baseline controls; baseline ovariectomized (ovx); intact controls (5 and 16 weeks), ovx controls (5 and 16 weeks); ovx-treated with PTH (0.02 mg/kg per day, 5 and 16 weeks); ovx treated with NaF (10 mg/kg per day, 5 and 16 weeks); ovx-treated with NaF (1.0 mg/kg per day, 16 weeks). Ovariectomy was performed at 12 weeks of age, 14 weeks prior to start of treatment. Ash density, bone fluoride content, and biomechanical analyses were performed on femoral cortical bone, the right femoral neck, and the sixth lumbar vertebral body. ovx had no effect on cortical bone, whereas the femoral neck displayed a significantly lower bone strength in ovx baseline animals compared with intact baseline rats (p < 0.05). Vertebral ash density was found to be significantly decreased in ovx rats after 5 and 16 weeks (p < 0.05). Treatment with fluoride had little effect on the osteopenic rat skeleton. Cortical ash density was significantly lower than ovx and intact groups in the high-dose-treated rats after 5 (p < 0.01) but not after 16 weeks. High doses of fluoride for 16 weeks induced a significant increase in maximum load and normalized strength in cortical bone when compared with intact animals (p < 0.05), but not at the other bone sites. Cortical bone strength was not different from the ovx animals at either timepoint. In fluoride-treated animals, femoral neck bone strength, vertebral body bone strength, bone quality, and ash density were found to be at about ovx levels and, in the vertebral body, significantly lower than intact animals (p < 0.05, p < 0.01). In contrast, treatment with PTH increased ash density, bone strength, and bone quality to above ovx levels (p < 0.01), and above the level of the intact animals also, although significant values were reached for cortical bone strength only (p < 0.01). Additionally, biomechanical competence and ash density measurements were significantly higher in PTH-treated rats compared with fluoride-treated rats. In conclusion, this study has shown that PTH has a highly anabolic effect and is capable of effectively restoring ovx-induced loss of bone mass and biomechanical competence. In addition, in this osteopenic rat model, PTH proved much more advantageous than treatment with fluoride, which failed to restore the ovx-induced loss of bone strength.

The ferret as a small animal model with BMU-based remodeling for skeletal research.

UNLABELLED: The need exists for a small animal model with bone metabolic unit (BMU)-based remodeling to mimic the bone loss found in postmenopausal women. The purpose of this investigation was to evaluate the ferret as a potential model for skeletal research. Specifically, we determined whether the ferret: 1) exhibits evidence of BMU-remodeling, 2) has a skeletal response to parathyroid hormone (PTH) similar to other remodeling species, and 3) loses bone in response to reduced estrogen levels. METHODS: Using three sets of experiments, we determined the response of female ferrets to ovariectomy/light cycle manipulation or to administration of PTH. Scanning electron microscopy, light microscopy, determination of estrogen levels and/or single-photon absorptiometry (SPA) were used for evaluation. RESULTS: The ferret was found to exhibit BMU-based remodeling, and may therefore provide a small animal remodeling species for skeletal research. Ferrets reach skeletal maturity between four and seven months of age as evidenced by closure of the growth plate and maturation of trabecluae from thin rods to thick rods and plates. PTH treatment resulted in a marked increase in bone mass accompanied by the PTH-induced tunneling phenomenon known to occur in dogs and humans but not rats. The response to PTH supports the use of the ferret in studies of bone anabolic agents. Bone mass in the proximal tibia was significantly reduced when estrogen depletion was induced by either bilateral ovariectomy or short light/dark cycles (8 hour light, 16 hour dark). Maintenance of intact ferrets under short-light conditions mimiced ovariectomy in terms of serum estrogen levels, uterine weights, and tibial BMD.(ABSTRACT TRUNCATED AT 250 WORDS)

Intermittent treatment of prostaglandin E2 with risedronate is more anabolic than prostaglandin E2 alone in the proximal tibial metaphysis of ovariectomized rats.

This study is designed to test how intermittent application of prostaglandin E2 (PGE2) and risedronate (Ris) alone or in combination acts on the cancellous bone mass in estrogen-deficient rats. Sprague-Dawley rats were ovariectomized (ovx) or sham-ovx'd at 6 months of age. PGE2 (6mg/kg/d), Ris (5 micrograms/kg/twice a week) or PGE2 plus Ris were given for 60 days to ovx rats immediately after operation and followed by 60 days without treatment. The drugs were then reapplied for another 60 days. Static histomorphometry was performed on the secondary spongiosa of proximal tibial metaphysis (PTM). Sixty days of ovx lost trabecular bone and number, Ris prevented ovx-induced bone loss. PGE2 added 48% extra cancellous bone, but the new bone was completely lost after 60 days of withdrawal. Another 60 days of PGE2 treatment only partially restored the trabecular bone, the bone mass was still -42% lower than that of sham-ovx controls. Co-treatment of PGE2 with Ris added the same amount of bone as PGE2 alone after the first 60 days treatment period, but differed from PGE2 alone in that the new bone lost less during the 60 days withdrawal period. Re-application of co-treatment for another 60 days added more extra bone. We concluded that intermittent co-treatment with anabolic and anti-resorptive agents is more effective than anabolic agent alone in long-term therapy of cancellous bone in estrogen-deficient rats.

Intermittent treatments of prostaglandin E2 plus risedronate and prostaglandin E2 alone are equally anabolic on tibial shaft of ovariectomized rats.

Effects of intermittent administration of prostaglandin E2 (PGE2), risedronate (Ris) and their combination on bone mass were studied on the cortical bone of tibial shafts of ovariectomized (ovx) rats. Six month old ovx rats were treated immediately after operation with subcutaneous injections of 6 mg PGE2/kg/d, 5 micrograms Ris/kg/2x/wk or their combination for 60 days each of an on/off/on cycle. PGE2 alone and in combination with Ris added the same amount of new bone in the first 60 days on period. During the 60 days off period, newly added endocortical and marrow trabecular bone disappeared in PGE2 alone treatment groups. In co-treatment group, the marrow trabeculae were only partly lost. There was no difference in total bone area between co-treatment and PGE2 alone groups after another 60 days on treatment. Our findings indicate that co-treatment was better in the maintenance of newly added endocortical and marrow trabecular bone during the off period; however, it formed less bone than PGE2 alone during the second treatment period, and ended up with the same amount of bone with both treatments.

Risedronate plus prostaglandin E2 is superior to prostaglandin E2 alone in maintaining the added bone after withdrawal in a non-growing bone site in ovariectomized rats.

Effects of risedronate and prostaglandin E2 (PGE2) alone or in combination on the distal tibia, a non-growing bone site with closed epiphysis at 3 months of age, were studied in ovariectomized (ovx) rats. Six-month-old Sprague-Dawley female rats were either ovx or sham-ovx. Rats were treated immediately after operation either with risedronate (5 micrograms/kg/2x/wk), PGE2 (6 mg/kg/d), or risedronate+PGE2 for 60 days (on-groups) and followed by 60 days without treatment (off-groups). Trabecular area, width and numbers were determined in metaphyseal cancellous bone of the distal tibia. No significant bone loss or structural changes were observed in the distal tibial metaphysis after 120 days of ovx. Risedronate alone did not produce any effect on bone mass during the treatment and the withdrawal periods. PGE2 alone increased the trabecular bone mass associated with thickened trabeculae and increased trabecular numbers. However, some of the newly formed bone was lost at the end of 60 days withdrawal. Combination of risedronate and PGE2 treatment added the same amount of bone mass as PGE2 alone, and the added new bone was maintained during the 60 days withdrawal. These results indicate that treatment with risedronate and PGE2 can preserve the anabolic effect of PGE2 on bone mass for at least 60 days after treatment.

The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strength--assessed in a sexually mature, ovariectomized rat model.

The aim of the study was to determine the effect of parathyroid hormone (PTH), the antiresorptive agents estrogen and bisphosphonate (risedronate), and also the combination of PTH with these antiresorptive drugs on femoral cortical bone mass, dimensions and strength in a sexually mature, ovariectomized rat model. A total of 138, 3-month-old Sprague-Dawley rats were randomized into seven groups: 1--sham operated (control); 2--ovariectomized (OVX); 3--OVX plus estrogen; 4--OVX plus bisphosphonate (risedronate [NE]; 5--OVX plus hPTH (1-34); 6--OVX plus hPTH (1-34) and estrogen; 7--OVX plus hPTH (1-34) and risedronate. Treatment regimens were initiated 4 weeks after OVX and were continued for 5 and 15 weeks for each treatment group. Changes in bone mass (ash content), cross-sectional area, cortical thickness and dimensions and bone strength were assessed in middiaphyseal, femoral specimens. The results revealed that ovariectomy had no effect on cortical bone mass and biomechanical competence. OVX rats treated with estrogen and also OVX rats treated with risedronate showed no significant difference from either OVX or control groups. After only 5 weeks of treatment, hPTH monotherapy increased ash content, cross-sectional area, cortical thickness and compressive bone strength (load) significantly. After 15 weeks of treatment, OVX rats treated with PTH monotherapy or PTH in combination with risedronate showed identical load-values. These values were significantly higher than those seen in both control and OVX rats. However, PTH in combination with estrogen failed to augment cortical bone strength over control or OVX levels after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

PTH has a more pronounced effect on vertebral bone mass and biomechanical competence than antiresorptive agents (estrogen and bisphosphonate)--assessed in sexually mature, ovariectomized rats.

The aim of the study was to determine the effect of PTH, the antiresorptive agents estrogen and bisphosphonate (Risedronate), and also the combination of PTH with the antiresorptive drugs on vertebral bone mass and biomechanical competence in a sexually mature, ovariectomized rat model. A total of 138 3-month-old Sprague-Dawley rats were randomized into seven groups: (1) sham operated (control); (2) ovariectomized (OVX); (3) OVX plus estrogen; (4) OVX plus bisphosphonate [Risedronate (NE)]; (5) OVX plus hPTH (1-34); (6) OVX plus hPTH (1-34) and estrogen; and, finally, (7) OVX plus hPTH (1-34) and Risedronate. Treatment regimens were initiated 4 weeks after OVX and were continued for 5 and 15 weeks for each treatment group. Changes in bone mass (ash content) and biomechanical competence were assessed on lumbar vertebral body L4. The results revealed that the Risedronate-treated OVX animals had a higher vertebral bone mass than the OVX group. hPTH (1-34) on its own had a pronounced anabolic effect and increased bone mass 20-25% and bone strength 70-80% over control levels. Neither combination therapy with estrogen nor with Risedronate provided any further advantage. The combination of PTH with Risedronate, though, seemed to allow a continued increase in both bone mass and strength during the whole treatment period.(ABSTRACT TRUNCATED AT 250 WORDS)

The positive effect of parathyroid hormone on femoral neck bone strength in ovariectomized rats is more pronounced than that of estrogen or bisphosphonates.

This study elucidates the effect of PTH, estrogen, and the bisphosphonate Risedronate (NE-58095) on femoral neck bone strength in ovariectomized (OVX) rats aged 90 days at the beginning of the investigation. Furthermore, the effects of these monotherapies were compared with those of concurrent treatment with PTH plus estrogen or PTH plus bisphosphonate. Four weeks after surgery the rats were randomized into a sham-operated vehicle-treated group, an OVX vehicle-treated group, and the various treatment groups and followed for 5 and 15 weeks. The proximal one-third of the left femur was then subjected to geometrical measurements and biomechanical testing. Neither ovariectomy nor the different treatment regimens influenced femoral neck geometry. OVX rats exhibited a decrease in femoral neck bone strength compared with control rats. This was most evident after 5 weeks. Treatment of OVX rats with Risedronate or estrogen alone tended to increase bone strength to control level, though these findings were nonsignificant. In contrast, treatment with PTH showed a highly significant increase in femoral neck biomechanical competence. Concurrent treatment with PTH plus estrogen or PTH plus Risedronate also significantly increased the femoral neck bone strength, but neither showed any advantage over treatment with PTH alone. It is concluded that treatment with PTH increases the strength of the femoral neck in estrogen-depleted rats in a highly significant manner, and that this effect is much more pronounced than the effect of the two antiresorptive agents estrogen or Risedronate. Thus, these findings provide further support for the anabolic effect of PTH and add weight to the argument for the promising potential of PTH in the treatment of postmenopausal osteoporosis.