alendronate, Fosamax
Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals.

Lin JH, Duggan DE, Chen IW, Ellsworth RL.

Merck Sharp & Dohme Research Laboratoires, West Point, PA 19486.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is currently under investigation as an anti-osteolytic agent in the treatment of a broad range of bone disorders. This study describes the absorption and disposition of the drug in laboratory animals. Following iv administration, alendronate was rapidly cleared from plasma, either taken up and sequestered in the bone or excreted by the kidney. About 30 to 40% of the dose was excreted in the urine in 24 hr, with most of the drug being excreted in the first 3 to 4 hr. There was little or no accumulation of the drug in noncalcified tissues and only a very small fraction of the dose was excreted in the bile. Most of the dose was rapidly taken up by bone tissues: 30% in 5 min, 60% in 1 hr. Absorption of alendronate was very poor. Based on the ratios in bone of the labels from the 14C-labeled oral dose and the 3H-labeled iv dose, absorption was estimated to be about 0.9% for the rat, 1.8% for the dog, and 1.7% for the monkey. Comparison of the concentrations of alendronate in bones of the same rats in fasted (3H-labeled) and fed (14C-labeled) states indicated that food caused a substantial decrease in absorption, by about 6- to 7-fold. The terminal half-life of alendronate in bone was about 200 days for the rat. Based on urinary excretion, the terminal half-life was estimated to be about 1000 days for the dog. The long persistence of alendronate in bone was likely due to its slow dissolution rate from bone tissues.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1686238&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
The bisphosphonate alendronate (MK-217) inhibits bone loss due to ovariectomy in rats.

Seedor JG, Quartuccio HA, Thompson DD.

Department of Bone Biology and Osteoporosis Research, Merck, Sharp and Dohme Research Laboratories, West Point, PA 19486.

Estrogen deficiency in mammals is known to increase bone turnover and result in reduced bone mass. The bisphosphonate, 4-amino-1-hydroxybutylidene-1,1-bisphophonic acid disodium salt, alendronate (MK-217), is a potent inhibitor of bone resorption and was evaluated in this study for its ability to inhibit bone loss following ovariectomy in rats. Alendronate was administered sc in doses of 0.0, 0.056, 0.28, 1.40, and 7.0 mg P/kg/month, divided into two, four, or eight monthly subcutaneous injections for each dose, to female Sprague-Dawley rats (250-280 g) that underwent bilateral ovariectomy. Rats were sacrificed 12 weeks postovariectomy, the femora ashed, and the tibiae prepared for static and dynamic histomorphometric analyses. Femoral bone mass in vehicle-treated rats was reduced by 12% 12 weeks after ovariectomy compared to the nonovariectomized control group. In MK-217-treated rats femoral bone mass was significantly increased in a dose-dependent manner compared to either ovariectomized or nonovariectomized controls. Histomorphometric analysis showed significant increases in tibial trabecular bone volume with no decrease in osteoclast number. Doses delivered twice per month or eight times per month were equally effective in achieving the peak bone volume 12 weeks after ovariectomy. In conclusion, alendronate (MK-217) was effective in inhibiting bone loss due to estrogen deficiency in rats, and the magnitude of its effect was related primarily to the total amount of compound administered rather than the frequency of its administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1858520&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Pharmacokinetics of alendronate: an overview.

Lin JH, Russell G, Gertz B.

Research Laboratories, West Point, Pennsylvania, USA.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate, MK-217, Fosamax), an aminobisphosphonate, is a potent inhibitor of osteoclast-mediated bone resorption and is used for the treatment of bone disorders, osteoporosis and Pagets disease of bone. Alendronate, like all bisphosphonates, is absorbed poorly in animals and humans; oral bioavailability is less than 2% in all species studied, including humans. Systemically available alendronate disappears very rapidly from plasma, and the drug is either taken up by bone tissues or excreted by the kidneys. Renal excretion is the only route of elimination, and urinary recovery is similar among species, ranging from 30% to 50% in a 24-hour collection period. Studies in rats show that alendronate is actively secreted by an uncharacterised renal transport system, but not by anionic or cationic renal transport systems. Drug not excreted within 24 hours after dosing is believed to be sequestered in the skeleton, from which it is liberated slowly into the circulation to be eliminated renally. Once taken up by the bone, the elimination of alendronate from bone tissue is slow, ranging from 200 days in rats, 3 years in dogs and 12 years in humans. The phamacokinetics and unique targeting of alendronate to bone contribute to the utility of this drug for the management of skeletal disorders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12669737&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Comparative study of inhibitory effects by murine interferon gamma and a new bisphosphonate (alendronate) in hypercalcemic, nude mice bearing human tumor (LJC-1-JCK).

Tohkin M, Kakudo S, Kasai H, Arita H.

Shionogi Research Laboratories, Shionogi & Co. Ltd. Fukushima-ku Osaka, Japan.

The inhibitory effect of murine interferon gamma (muIFN gamma) on humoral hypercalcemia in nude mice bearing lower-jaw cancer (LJC-1-JCK), in which parathyroid-hormone(PTH)-related protein is responsible for causing humoral hypercalcemia by activating bone resorption, was examined in comparison with that of a new bisphosphonate, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate). muIFN gamma was injected into tumor-bearing nude mice for 5 days before the establishment of hypercalcemia. The increase of plasma calcium concentration was delayed and this effect continued for more than 6 days even after the injection was stopped. Alendronate markedly suppressed hypercalcemia in tumor-bearing nude mice but this inhibitory effect continued for less than 6 days. Neither muIFN gamma nor alendronate affected the tumor volume or serum PTH-related protein concentration. Injection of muIFN gamma into mice for 3 days almost completely abolished the formation of multinucleated osteoclast-like cells from bone marrow cells in vitro, whereas injection of alendronate into mice had no effect. These findings suggested that muIFN gamma suppressed the formation of osteoclasts, resulting in the prolonged decrease of plasma calcium concentration in hypercalcemic tumor-bearing nude mice, whereas alendronate is cytotoxic to functionally mature osteoclasts and inhibited osteoclastic bone resorption, resulting in a marked decrease in the plasma calcium concentration in tumor-bearing hypercalcemic nude mice.

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alendronate, Fosamax
Alendronate distributed on bone surfaces inhibits osteoclastic bone resorption in vitro and in experimental hypercalcemia models.

Azuma Y, Sato H, Oue Y, Okabe K, Ohta T, Tsuchimoto M, Kiyoki M.

Teijin Institute for Bio-Medical Research, Tokyo, Japan.

Alendronate is an aminobisphosphonate that acts as a potent inhibitor of osteoclastic bone resorption. To understand the mechanism of action of alendronate in vivo, in this study we investigated the relationship between distribution of [14C]-alendronate in rat bone and its effects on bone resorption in vitro or in rat hypercalcemic models. A single IV dose of 0.05 approximately 1.25 mg/kg inhibited the increase in plasma calcium level induced by bovine PTH or 1 alpha(OH)D3. The minimal effective dose of pamidronate (1.25 mg/kg) and etidronate (over 31.25 mg/kg) were at least 5 times and 25 times, respectively, higher than the dose of alendronate in the rat hypercalcemic model prepared by 1 alpha(OH)D3. The relative potencies of compounds in the hypercalcemic rat models reflected those of inhibitory effects on bone resorption in vitro. We conducted the ivory-slice assay under two conditions: (a) addition of a given bisphosphonate after adherence of the osteoclasts; and (b) preincubation of the ivory slices with a given bisphosphonate. The inhibitory IC50 values of alendronate under condition (b) were similar to those under condition (a). To evaluate the interaction between osteoclasts and alendronate in bone, we investigated the localization of [14C]-alendronate in the tibia of growing rats (4-day-old rats). Alendronate did not distribute uniformly in the tibia. At 1 day after injection (0.05 mg SC), dense labeling was seen primarily under osteoclasts. We injected 0.05 mg/kg of [14C]-alendronate (single i.v.) into rats [14C]-alendronate was rapidly eliminated from plasma, and mainly distributed to the bone in rats. These data suggest that alendronate which distributed on bone surface mainly contributed to the antihypercalcemic action in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7756053&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate treatment of naturally-occurring periodontitis in beagle dogs.

Reddy MS, Weatherford TW 3rd, Smith CA, West BD, Jeffcoat MK, Jacks TM.

University of Alabama, School of Dentistry, Department of Periodontics, Birmingham, USA.

The treatment of periodontal disease has been largely directed at the microbiological etiology. The prevention of bone loss by modulating the host response to the bacteria may be a useful adjunctive method in the management of periodontitis. Alendronate, an amino bisphosphonate, may inhibit bone loss in osteolytic diseases by altering osteoclast activity. The objective of this double-blind study was to evaluate alendronate inhibition of alveolar bone loss in the naturally occurring beagle dog model of periodontitis. Sixteen 7 to 9 year old beagles with moderate-to-severe periodontitis were studied for 6 months. The dogs were stratified into two groups based on initial periodontal severity. One group received 3.0 mg/kg alendronate weekly orally and the other group received a placebo. Silk ligatures were placed on the study teeth for the first 3 months of the study to exacerbate the periodontal destruction. Clinical data were collected for attachment level, gingival index, plaque index, and mobility at baseline and one-month intervals. Intraoral radiographs were made at baseline and at 3 and 6 months. The mandibles were processed for histology at month 6. The radiographs were analyzed by digital image analysis of the subtracted images. A statistically significant difference in bone mass (P < 0.001) was observed between the alendronate and placebo groups. The bisphosphonate had no effect on the clinical parameters of gingival inflammation or plaque. A trend toward decreased attachment loss and mobility was observed in favor of the alendronate group.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7776166&dopt=Abstract alendronate Fosamax