alendronate, Fosamax
Histomorphometrical analysis of the effects of the bisphosphonate alendronate on bone loss caused by experimental periodontitis in monkeys.

Weinreb M, Quartuccio H, Seedor JG, Aufdemorte TB, Brunsvold M, Chaves E, Kornman KS, Rodan GA.

Department of Oral Biology, Tel-Aviv University School of Dental Medicine, Israel.

This study tested the efficacy of alendronate, a bisphosphate, in reducing alveolar bone loss caused by experimental periodontitis in cynomolgus monkeys. Periodontitis was initiated in adult monkeys by ligating mandibular molar teeth at the cementoenamel junction (CEJ) and subsequently inoculating the ligature with Porphyromonas (Bacteroides) gingivalis. Contralateral, homologous non-ligated teeth served as controls. Animals received, intravenously, either saline (placebo) or alendronate at 0.05 or 0.25 mg/kg every 2 weeks for 16 weeks. After the animals were sacrificed, coronal sections through mandibular molars were subjected to histomorphometrical analysis. No overt side-effects were observed in any of the animals participating in this study. In placebo-treated animals, ligation and inoculation resulted in significant bone loss both at the CEJ and at the furcation. Alendronate at 0.05 mg/kg significantly reduced bone loss associated with the experimental periodontitis at both sites. In contrast, the dose of 0.25 mg/kg was ineffective in attenuating alveolar bone loss in the furcation area and only slightly effective in preventing it at the CEJ area. The results of the histomorphometric analysis correlate closely with those of the radiographic analysis of the same experiment. These data indicate that alendronate could reduce the loss of alveolar support associated with periodontitis and suggest that bisphosphonates, by virtue of their significant inhibitory action on osteoclasts, may become a treatment modality in the battle against alveolar bone destruction during periodontal disease.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8113951&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Role of calcium in plasma protein binding and renal handling of alendronate in hypo- and hypercalcemic rats.

Lin JH, Chen IW, deLuna FA, Hichens M.

Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania.

Alendronate (4-amino-1-hydroxybutylidine-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation for the treatment of osteoporosis. Earlier studies in animals from this laboratory disclosed that systemically administered alendronate is rapidly taken up by bone tissues to the extent of 60% to 70% of the dose and excreted by the kidney, 30% to 40% in 24 hr, and that renal excretion is the only route of elimination. This study was designed to explore the effect of calcium on plasma protein binding and the renal handling of alendronate. The binding of alendronate to rat plasma was concentration, pH and calcium dependent. The fraction of unbound drug in rat plasma increased from about 3% to 9% over a drug concentration range of 0.2 to 10 micrograms/ml. Supplementation of calcium strongly augmented the binding to serum albumin. The binding of alendronate in plasma increased with increasing pH from about 50% at pH 6.6 to 98% at pH 8.6. The effects of pH on the binding of calcium and of alendronate to serum albumin were qualitatively similar. Under steady-state conditions, the binding of alendronate was substantially lower in hypocalcemic rats but unchanged in hypercalcemic rats. Although hypocalcemia caused a significant decrease in the renal secretion of alendronate, there was no effect on the renal secretion of tetraethylammonium bromide and p-aminohippuric acid. The differential effect of hypocalcemia suggests that calcium may play an important role in the renal handling of alendronate. However, hypercalcemia resulted in a substantial decrease of renal secretion of all three compounds and the decreased renal secretion was associated with a marked decrease in the glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8246140&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
The effects of the aminobisphosphonate alendronate on thyroid hormone-induced osteopenia in rats.

Yamamoto M, Markatos A, Seedor JG, Masarachia P, Gentile M, Rodan GA, Balena R.

Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, Pennsylvania 19486.

Hyperthyroidism, either endogenous or iatrogenic, leads to increased bone turnover and osteopenia. This study was conducted to examine (1) whether thyroid hormone excess in rats causes bone changes similar to those seen in patients with hyperthyroidism, and (2) the effects of the aminobisphosphonate alendronate on the thyroid hormone-induced bone changes. Sprague-Dawley male rats, divided into four groups, received L-thyroxine (T4) 250 micrograms/kg/day (+T4) or vehicle (-T4) subcutaneously six times per week and alendronate 1.75 mg/kg (+ALN) or vehicle (-ALN) orally twice a week. Rats were sacrificed after 3 weeks of treatment, blood samples were analyzed for serum T4, triiodo-L-thyronine (T3), and osteocalcin, and the proximal tibiae were processed for histomorphometric analysis. Serum T4 and T3 levels measured 20-24 hours after the last injection were 2 to 2.5-fold higher in +T4 groups than in -T4 groups. Serum osteocalcin was significantly (P < 0.05) higher in +T4/-ALN group than in the other groups, which were not statistically different from each other. T4 treatment (+T4/-ALN) significantly decreased the amount of cancellous bone volume (-45%) and increased osteoid surface (+254%), osteoblast surface (+111%), and osteoclast surface (+176%) relative to control values. Alendronate increased the bone volume above control values in both T4-treated (+T4/+ALN) and untreated (-T4/+ALN) rats, and prevented the T4-induced increase in bone turnover in +T4/+ALN rats. It is concluded that (1) excess thyroid hormone induces cancellous bone loss associated with high bone turnover in the rat, and (2) this bone loss can be prevented by alendronate through the inhibition of osteoclastic activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8275357&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Continuous alendronate treatment throughout growth, maturation, and aging in the rat results in increases in bone mass and mechanical properties.

Guy JA, Shea M, Peter CP, Morrissey R, Hayes WC.

Department of Orthopaedic Surgery, Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts.

Alendronate (4-amino-1-hydroxybutylidene bisphosphonate) is a novel amino bisphosphonate that is being developed for the treatment of osteolytic bone disorders such as osteoporosis. As part of a 2-year carcinogenicity study, we investigated the morphologic and biomechanical effects of long-term alendronate (ALN) therapy, given throughout skeletal growth, maturation, and aging, on rat vertebrae and femora. Three treatment groups, receiving either deionized water, low- (1.00 mg/kg), or high-dose (3.75 mg/kg) ALN, were given daily oral treatment for 105 weeks. Results from mechanical tests indicate that ALN therapy (in males) increased the vertebral ultimate compressive load by 96% in the high- and 51% in the low-dose groups when compared with controls. ALN similarly increased the male ultimate femoral bending load by 59% in the high- and 31% in the low-dose groups. Vertebrae and femora from female rats treated with both high- and low-dose ALN also failed at significantly higher loads than controls, but no differences were seen between low- and high-dose groups. Morphologic analysis of both male and female vertebrae revealed a dose-dependent increase in area fraction of bone. Rats receiving high-dose ALN had a greater area fraction of bone than those receiving low doses. Both groups were greater than controls. Thus, the administration of ALN resulted in increased femoral cortical bending load when compared with control animals, as well as increased vertebral ultimate compressive load commensurate with a dose-related preservation of vertebral bone.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8275358&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Clinical pharmacology of alendronate sodium.

Gertz BJ, Holland SD, Kline WF, Matuszewski BK, Porras AG.

Merck Research Laboratories, Rahway, New Jersey 07065-0914.

Clinical studies have been performed to investigate the pharmacokinetics and pharmacodynamics of alendronate, an inhibitor of bone resorption for the treatment of osteoporosis. Alendronate is one of the most potent bisphosphonates currently undergoing clinical investigation (> 100-fold more potent than etidronate in vivo). The pharmacokinetics of alendronate are similar to those of other bisphosphonates. After a 2-h intravenous infusion, plasma concentrations of alendronate decline rapidly to approximately 5% of initial values within 6 h. About 50% of a systemic dose is excreted unchanged in the urine in the 72 h following administration. By analogy to its behavior in animals the remainder is assumed to be taken up by the skeleton. After sequestration into bone, the elimination of alendronate is very prolonged. The terminal half-life was estimated to be greater than 10 years. Despite prolonged skeletal residence, the biological effects of alendronate begin to diminish post-treatment, since the duration of effect reflects factors besides dose and cumulative drug exposure. When taken after an overnight fast, 2 h before breakfast, the oral bioavailability of alendronate averages approximately 0.75% of dose with substantial variability (coefficient of variation 55%-75%) both between and within subjects. Reducing the wait before food from 2 h to 1 h, or even 30 min, produces a mean reduction in absorption of 40%. Since the clinical efficacy of alendronate is indistinguishable whether it is given 30 min, 1h, or 3 h before a meal, the observed variability in bioavailability within this range is of little consequence. Dosing up to at least 2 h after a meal dramatically reduces absorption (80%-90%).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8298197&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effects of the bisphosphonate, alendronate, on parturition in the rat.

Minsker DH, Manson JM, Peter CP.

Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania 19486.

Alendronate is a bisphosphonate which inhibits bone resorption. In female fertility studies in rats, dosages of 10 and 15 mg/kg/day produced physical signs of toxicity at parturition, including tremors, dystocia, and death in the dams and these were associated with neonatal deaths. These effects were associated with hypocalcemia in the dams but the fetuses were normocalcemic. There was no one critical period of treatment during gestation for these effects; they were instead proportional to length of treatment. Neonatal deaths were due to protracted deliveries rather than a direct effect of alendronate on the pups. Intravenous calcium supplementation (9.3 mg/dam) prevented the above-described adverse effects on dams and pups. In rats, fetal skeletal ossification is at its greatest rate in late gestation, and during this period free calcium is preferentially transported to the fetal compartment. The females meet this increased demand by calcium mobilization via increased bone resorption. We conclude that the maternotoxicity of alendronate in rats is due to the designed pharmacologic activity of this bisphosphonate; the drug prevents bone resorption and thereby denies the dam an important source of calcium at a time when fetal demand for this mineral is at its peak. The alendronate-induced hypocalcemia adversely affects parturition because uterine muscle contraction is a calcium-dependent process.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8346538&dopt=Abstract alendronate Fosamax