alendronate, Fosamax
Treatment with risedronate or alendronate prevents hind-limb immobilization-induced loss of bone density and strength in adult female rats.

Mosekilde L, Thomsen JS, Mackey MS, Phipps RJ.

Department of Cell Biology, Institute of Anatomy, University of Arhus, Arhus, Denmark. lm ana.au.dk

Immobilization leads to rapid loss of bone mass and mechanical competence, and long-term immobilization or repeated periods of short-term immobilization can have serious skeletal consequences and may lead to increased fracture liability. The aim of the present preclinical study was, therefore, to assess whether two antiresorptive agents, risedronate (Ris) or alendronate (Aln), would be capable of preventing immobilization-induced loss of bone mass and strength in rats. The study was designed as a dose-response study, and the site-specific effects of immobilization and of treatment are described. Four-month-old virgin female Sprague-Dawley rats were divided into eight groups with 12 animals in each group: (1) immobilized (Imm) control; (2) normal control; (3) Imm + Ris 0.1 mg/kg body weight/day (b.w./day); (4) Imm + Ris 0.2 mg/kg b.w./day; (5) Imm + Ris 1.0 mg/kg b.w./day; (6) Imm + Aln 0.2 mg/kg b.w./day; (7) Imm + Aln 1.0 mg/kg b.w./day; and (8) Imm + Aln 2.0 mg/kg b.w. /day. In groups 1 and 3-8, the right hind leg was immobilized with an elastic bandage. The study period was 28 days. The effects of unilateral hind-limb immobilization and of treatment were determined by dual-energy X-ray absorptiometry (DEXA) measurements on tibiae and by biomechanical testing of femora at three different sites: diaphysis; femoral neck; and distal metaphysis. Bilateral measurements were performed (on the immobilized and nonimmobilized legs). Immobilization induced a significant loss of bone mineral density (BMD) at the proximal tibial metaphysis, but no change at the mid-diaphysis. Furthermore, immobilization induced a loss of bone strength at the two femoral metaphyses, but no change was seen in three-point bending of the diaphysis. Both risedronate and alendronate treatment showed a dose-dependent protection against the immobilization-induced loss of bone density and strength at the metaphyses. We conclude that, in rats, short-term hind-limb immobilization affects only the metaphyses and that no changes are seen in the diaphysis. Both risedronate and alendronate can prevent immobilization-induced bone loss at the metaphyses. The present study confirms the importance of examining several skeletal sites when testing the efficacy of therapeutic agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11062350&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
The effect of topical delivery of novel bisacylphosphonates in reducing alveolar bone loss in the rat model.

Yaffe A, Golomb G, Breuer E, Binderman I.

Department of Prosthodontics, Hebrew University Hadassah School of Dental Medicine, Jerusalem, Israel.

BACKGROUND: Periodontal surgery stimulates osteoclast activity, leading to varying amounts of alveolar crest loss. We have established that topical application of 20 mg/ml of alendronate placed at the surgical mucoperiosteal site produced a striking reduction of alveolar bone loss in the rat model. The aim of this investigation was to examine the antiresorptive efficacy of 3 novel bisacylphosphonates topically delivered at the surgical site, in comparison to alendronate and etidronate which are in clinical use. METHODS: Mucoperiosteal flap (MF) surgery was performed on the buccal and lingual aspects next to molars on both sides of the rat mandible. A gelatin sponge soaked in the bisphosphonate solution prepared by dissolving 20 mg of the bisphosphonate (alendronate, etidronate, VS-5, VS-6, ISA-13, SuBP) in 1 ml of saline was applied to exposed bone on the right side of the mandible (experimental, MF + BPs ) and the left side was treated with saline only (control, MF + S). Sections were evaluated for bone loss using microradiography pattern and amount. RESULTS: The 3 novel bisacylphosphonates, VS-5 VS-6, and ISA-13 were more effective than etidronate, and less effective than alendronate. The most effective among this group was ISA-13 followed by VS-5 and VS-6. CONCLUSION: We conclude that ISA-13-like alendronate is effective in reducing alveolar bone loss when delivered at surgical sites. Since ISA-13 is well absorbed through mucose tissues, we suggest that ISA-13 efficacy on reducing bone loss should be tested by its application on the mucosal tissue.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11063394&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Antagonistic effects of different classes of bisphosphonates in osteoclasts and macrophages in vitro.

Frith JC, Rogers MJ.

Department of Medicine and Therapeutics, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, United Kingdom. j.c.frith abdn.ac.uk

Nitrogen-containing bisphosphonates, such as alendronate and ibandronate, inhibit bone resorption by preventing protein prenylation in osteoclasts, whereas non-nitrogen-containing bisphosphonates, such as clodronate, are metabolized to nonhydrolyzable analogs of ATP, resulting in osteoclast apoptosis. Because these two classes of bisphosphonates have different molecular mechanisms of action, we examined in vitro whether combined treatment with clodronate and alendronate would alter antiresorptive effectiveness. Although, in cultures of rabbit osteoclasts, the antiresorptive effect of 10 microM alendronate was increased by the addition of clodronate, the effect of higher concentrations of alendronate was not altered by addition of clodronate. Furthermore, the inhibition of protein prenylation in osteoclasts caused by higher alendronate concentrations was partially prevented by cotreatment with clodronate. As in osteoclasts, the inhibition of protein prenylation in J774 cells caused by alendronate or ibandronate treatment was dose-dependently prevented by cotreatment with clodronate. Furthermore, alendronate-induced J774 apoptosis was significantly inhibited in the presence of clodronate. The presence of clodronate also decreased the short-term cellular uptake of [14C]ibandronate. These observations suggest that combined treatment with clodronate could enhance the antiresorptive effect of a low concentration of nitrogen-containing bisphosphonate, but clodronate can also antagonize some of the molecular actions and effects of higher concentrations of nitrogen-containing bisphosphonates. The exact molecular basis for the antagonistic effects between bisphosphonates remain to be determined, but could involve competition for cellular uptake by a membrane-bound transport protein.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12568397&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate stimulates collagenase 3 expression in osteoblasts by posttranscriptional mechanisms.

Varghese S, Canalis E.

Department of Research, Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105, USA.

Bisphosphonates inhibit bone resorption by reducing osteoclastic cell number and activity. Alendronate is a nitrogen-containing bisphosphonate analog used in the treatment of postmenopausal osteoporosis. The effects of alendronate in osteoclasts are well documented; however, there is limited information on the actions of alendronate in osteoblasts (Ob's). In this study, we investigated the effects of alendronate at concentrations of 1-100 microM on the synthesis of collagenase 3 or matrix metalloproteinase 13 (MMP-13) and tissue inhibitors of MMPs (TIMPs) 1, 2, and 3 in primary Ob-enriched cells from 22-day-old fetal rat calvariae. Alendronate at concentrations higher than 10 microM markedly stimulated the synthesis of collagenase messenger RNA (mRNA) and immunoreactive protein in Ob's. Alendronate did not stimulate the transcriptional rate of the collagenase 3 gene. However, in transcriptionally arrested cells, alendronate prolonged the half-life of collagenase transcripts. Alendronate did not alter the expression of TIMP 1 and 2, but modestly stimulated the expression of TIMP 3. The actions of alendronate in Ob's suggest potential additional effects in bone remodeling.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11127199&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effect of alendronate on immature human dental root explants.

Sommercorn LM, Di Fiore PM, Dixit SN, Koerber A, Lingen MW, Veis A.

Northwestern University Dental School, Chicago, IL, USA.

This study investigated the use of alendronate in the formation of new dentin in vitro. Extracted human premolar and molar teeth with immature apices were grown in tissue culture medium for 60 days. Six control specimens were grown without alendronate in the medium, and 22 experimental specimens were grown with alendronate at [10(-9) M] in the medium. Newly formed dentin was stained with tetracycline and procion brilliant red at days 1 to 3, 30 to 33, and 60. Specimens were decalcified and 5-micron sections were prepared for examination using fluorescent microscopy. New dentin formation was measured in microns at the most apical region, at 125-micron from the apical measurement and at 250-micron from the apical measurement. The alendronate group had 57.15% more growth than the control group at the most apical region, and this difference was significant (p = 0.0001). The results indicate that alendronate at [10(-9) M] is effective in accelerating dentin formation in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11199704&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
[Comparative study in postmenopausal women with osteoporosis (sodium alendronate, calcium and HRT vs sodium alendronate and calcium]

[Article in Spanish]

Da Silva LLibre R, Murillo K, Chu D.

Hospital Santo Tomas.

In 1995 Alendronate was approved by the FDA for the treatment of Post-Menopause Osteoporosis. Their use for the preventive treatment on Osteopenic patients is approved in 1996. Calcium is a very important element in the treatment of Osteoporosis, because it is the only one that acts in the mineralization phase. It is well known that the first line to stop the loss of DMO in Post-Menopausic women are Estrogens. If we add TRH to the therapy, the effects of Alendronate will raise significantly. The first group (A) of 32 patients received Alendronate, Calcium and TRH. In the second group (B), there were 35 patients and they received Alendronate and Calcium. The groups were statistically compared and selected. In both groups the lumbar column was more affected than the hips. The use of TRH associated with Alendronate for the lumbar column significantly raised the percentage of change of DMO in 24 months. The change percentage was of 9% of DMO for group A and 5.25% for group B, giving a significant difference of 3.75% of DMO. For the hips the use of TRH associated with Alendronate did not have any difference in raise between both groups. In the next twelve months there was a change of 3.2% of DMO more in group A than in group B. In 24 months the change of DMO in the hips was of 7.95% in group A and 4.75% for group B. The TRH decrease the vasomotor symptoms, and improves the hormonal levels (FSH and Estradiol) keeping their benefits effective (Cardioprotectors, Neuroprotectors, etc.) but it potentiates the decrease of the bone reabsorption shown by the Alendronate. This significantly increases the change of percentage of DMO, obtaining densiometrics and clinical improvements in less time than using only Alendronate and Calcium. Also decreases the price of the treatment and the risk of fracture in less time, offering in that way a better quality of life to our patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11214558&dopt=Abstract alendronate Fosamax