alendronate, Fosamax
Alendronate modulates osteogenesis of human osteoblastic cells in vitro.

Tsuchimoto M, Azuma Y, Higuchi O, Sugimoto I, Hirata N, Kiyoki M, Yamamoto I.

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

The bisphosphonates, which are carbon-substituted pyrophosphates, have been studied extensively both in vivo and in vitro to elucidate their effects on bone tissues and cells. However, because these agents were shown to have a potent inhibitory effect on bone resorption, the majority of studies have focused on only this aspect of bone metabolism. There appears to be less information regarding the direct effect of bisphosphonates on bone formation, so thus we undertook experiments to investigate the effects of bisphosphonates, especially alendronate, on the mineralization and matrix protein synthesis of human osteoblastic cells in vitro. The data show that the bisphosphonates, alendronate, etidronate and pamidronate, suppressed 1,25-dihydroxycholecalciferol (1,25(OH)2D3)-stimulated mineralization of human osteoblastic cells at high concentrations, while relatively lower concentrations of alendronate and etidronate potentiated mineralization of the cells in the presence of 1,25(OH)2D3. The potentiation of mineralization with alendronate was accompanied by increased synthesis of bone matrix proteins, osteocalcin and collagen, and the mRNA of pro alpha(I) collagen. These findings show that in addition to their well-known effects on bone resorption, bisphosphonates have significant and direct effects on osteogenesis in osteoblasts in vitro. The actual mechanism remains to be further investigated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7861665&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate increases skeletal mass of growing rats during unloading by inhibiting resorption of calcified cartilage.

Bikle DD, Morey-Holton ER, Doty SB, Currier PA, Tanner SJ, Halloran BP.

Department of Medicine, University of California, San Francisco.

Loss of bone mass during periods of skeletal unloading remains an important clinical problem. To determine the extent to which resorption contributes to the relative loss of bone during skeletal unloading of the growing rat and to explore potential means of preventing such bone loss, 0.1 mg P/kg alendronate was administered to rats before unloading of the hindquarters. Skeletal unloading markedly reduced the normal increase in tibial mass and calcium content during the 9 day period of observation, primarily by decreasing bone formation, although bone resorption was also modestly stimulated. Alendronate not only prevented the relative loss of skeletal mass during unloading but led to a dramatic increase in calcified tissue in the proximal tibia compared with the vehicle-treated unloaded or normally loaded controls. Bone formation, however, assessed both by tetracycline labeling and by [3H]proline and 45Ca incorporation, was suppressed by alendronate treatment and further decreased by skeletal unloading. Total osteoclast number increased in alendronate-treated animals, but values were similar to those in controls when corrected for the increased bone area. However, the osteoclasts had poorly developed brush borders and appeared not to engage the bone surface when examined at the ultrastructural level. We conclude that alendronate prevents the relative loss of mineralized tissue in growing rats subjected to skeletal unloading, but it does so primarily by inhibiting the resorption of the primary and secondary spongiosa, leading to altered bone modeling in the metaphysis.

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alendronate, Fosamax
On the absorption of alendronate in rats.

Lin JH, Chen IW, deLuna FA.

Merck Research Laboratories, West Point, Pennsylvania 19486.

Alendronate is an antiosteolytic agent under investigation for the treatment of a number of bone disorders. Since the compound is a zwitterion with five pKa values and is completely ionized in the intestine at the physiological pH, absorption is poor; less than 1% of an oral dose is available systemically in rats. In the present studies, absorption was found to be predominantly in the upper part of the small intestine. Administration of buffered solutions of alendronate (pH 2-11) did not improve absorption. Whereas food markedly impaired the absorption of alendronate, EDTA enhanced absorption in a dose-dependent manner. Pretreatment of rats with ulcerogenic agents, mepirizole, acetylsalicylic acid, or indomethacin, resulted in a 3-7-fold increase in the oral absorption of alendronate. The absorption of phenol red, added as an indicator of intestinal tissue damage, was also increased in rats with experimental peptic ulcers. The enhanced absorption of alendronate observed in rats with experimental peptic ulcers was attributed to the alteration of the integrity of the intestinal membrane.

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alendronate, Fosamax
Uptake of alendronate by bone tissue in hypocalcemic and hypercalcemic rats.

Lin JH, Chen IW, Deluna FA.

Merck Research Laboratories, West Point, PA 19486.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of osteoporosis. Earlier studies in rats from this laboratory have demonstrated that systemically administered alendronate was taken up by bone tissues to the extent of 60-70% of the dose and excreted by the kidneys, 30-40%, and that renal excretion was the only route of elimination of the drug. In this study, a classic three-compartment model was used to determine the kinetics of bone uptake of alendronate in hypo- and hypercalcemic rats. Following intravenous administration (1 mg/kg), the apparent uptake clearance (CL,up) by tibia was approximately 0.18 ml/min/g of bone for control rats, 0.25 ml/min/g for hypocalcemic rats, and 0.05 ml/min/g for hypercalcemic rats. Like other organs, uptake of drugs by bone tissues would be controlled by the plasma flow rate (Q), the fraction of unbound drugs in plasma (fp), and the intrinsic ability of bone uptake (CLin) as described by the equation: CL,up = Q(1 - e-fp.CLin/Q). The plasma flow rate to the tibia of rats was reported to be approximately 0.25 ml/min/g. The unbound fraction of alendronate in plasma of control, hypo-, and hypercalcemic rats was 0.03, 0.45, and 0.035, respectively. By applying the equation, the intrinsic ability (CLin) of bone uptake was estimated to be approximately 10, 2.3, and 1.6 ml/min/g for control, hypo-, and hypercalcemic rats, respectively, indicating that the intrinsic ability of bone to bind alendronate was decreased in both hypo- and hypercalcemic rats.

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alendronate, Fosamax
Nonlinear kinetics of alendronate. Plasma protein binding and bone uptake.

Lin JH, Chen IW, deLuna FA.

Merck Research Laboratories, West Point, PA 19486.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation in the treatment of osteoporosis. The purpose of this study was to examine the plasma protein binding and the ability of bone to bind alendronate, and their effects on the distribution of the drug to bone tissues. In addition, the species differences in plasma protein binding and bone uptake between rats and dogs were studied. Following intravenous administration (0.8 or 1 mg/kg), the apparent uptake clearance (CL,up) by tibia in dogs and rats was approximately 0.075 and 0.18 ml/min/g bone tissue, respectively. The binding of alendronate to plasma protein was species-dependent; the drug was highly bound to rat plasma, but not to dog plasma. The unbound fraction of alendronate was approximately 0.03 for the rat and 0.53 for the dog. Binding studies with purified serum albumin revealed the presence of displacer(s) in dog plasma. This may explain the low binding of alendronate in dog plasma. Like other organs, uptake of drugs by bone tissue is controlled by the plasma flow (Q), the fraction of unbound drug in plasma (fp), and the intrinsic ability of bone to bind the drug (CLin) as described by the equation: CL,up = Q(1-e-tp.CLin/Q). Plasma flow to the tibia of dogs and rats is reported to be approximately 0.09 and 0.25 ml/min/g, respectively. By applying the equation, the CLin was estimated to be approximately 10 ml/min/g for the rat and 0.3 ml/min/g for the dog. These results indicate that both plasma protein binding and bone uptake were species-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

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alendronate, Fosamax
Duration of the effects of intravenous alendronate in postmenopausal women and in patients with primary hyperparathyroidism and Paget's disease of bone.

Adami S, Zamberlan N, Mian M, Dorizzi R, Rossini M, Braga B, Gatti D, Bertoldo F, Locascio V.

Istituto di Semeiotica e Nefrologia Medica, University of Verona, Italy.

The effect of a single intravenous (i.v.) infusion of 5 mg alendronate was studied in ten patients with Paget's disease, six patients with primary hyperparathyroidism and ten osteopenic postmenopausal women. Urinary hydroxyproline excretion significantly decreased within few days in all patients (from 113 +/- 67.9 to 58 +/- 35 mmol/mol Cr in Paget's disease, from 21.8 +/- 9 to 12.9 +/- 6 mmol/mol Cr in hyperparathyroidism, from 18.7 +/- 9.5 to 8.5 +/- 4.3 mmol/mol Cr in postmenopausal women). In the patients with Paget's disease urinary hydroxyproline remained suppressed over the 6 months of follow-up, whereas it rose toward pretreatment values within 4 and 6 weeks in the patients with primary hyperparathyroidism and in postmenopausal osteopenic women, respectively. Plasma alkaline phosphatase significantly fell only after 4-6 weeks in patients with primary hyperparathyroidism and in Pagetic patients. In the latter group alkaline phosphatase continued to decline thereafter and a plateau became apparent after 2 months. In postmenopausal women the serum alkaline phosphatase remained unchanged. Thus, the same dose of alendronate induces comparable fractional decreases of bone resorption in the three groups of patients, but the effect is persistent only in Paget's disease. This is consistent with the hypothesis that alendronate inhibits osteoclastic activity only at the level of the existing resorption sites. In osteoporotic and primary hyperparathyroid patients, as soon as the treatment is withdrawn, the appearance of new sites of resorption is not inhibited and bone turnover is resumed to pre-treatment values.(ABSTRACT TRUNCATED AT 250 WORDS)

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