alendronate, Fosamax
Bisphosphonates and tetracycline: experimental models for their evaluation in calcium-related disorders.

Cohen H, Solomon V, Alferiev IS, Breuer E, Ornoy A, Patlas N, Eidelman N, Hagele G, Golomb G.

Dept. of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, Israel.

PURPOSE: This work was aimed at synthesizing novel bisphosphonates (BPs) and examining them in comparison to clinically used BPs such as pamidronate and alendronate, and to tetracycline, in order to evaluate their potential as anticalcification and antiresorption agents. The correlation between the various models was examined in order to establish facile experimental models for pre-screening of potential compounds. METHODS: Nitrogen-containing heterocyclic, novel BPs such as 2-(3-methylimidazolio) ethylidene-1,1-bisphosphonic acid betaine (VS-5b), 2-(2-dimethylamino-4-pyrazinio)ethylidene-1,1-bisphosphonic acid betaine (VS-6b), and 2-(2-alpha-pyridylethylthio) ethylidene-1,1-bisphosphonic acid (ISA-225), were synthesized and evaluated in comparison to clinically used BPs, in various experimental models of resorption and calcification. RESULTS: The physicochemical properties of the novel compounds are slightly different than the BPs in clinical use: the pKa values are lower, the affinity for hydroxyapatite is lower and the solubilities of the calcium salts are higher. The anticalcification potencies of the novel compounds were high and ranked as follows: alendronate = pamidronate > VS-6b = VS-5b = ISA-225 > tetracycline. The in vivo antiresorption activity of VS-5b and VS-6b in comparison to that of the clinically employed, pamidronate, was shown to be similar and higher, respectively. CONCLUSIONS: The anticalcification activity of the novel compounds as well as that of tetracycline was lower than that of alendronate. The antiresorption activity of VS-6b was similar to that of pamidronate. A good correlation between the different models was found, enabling the facile screening of novel compounds. The activities of tetracycline and EDTA highlight the distinct behavior of BPs as "crystal poison." In addition, tetracycline was found to be a potent anticalcification agent in the ectopic calcification model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9587958&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Comparative study of potential for bisphosphonates to damage gastric mucosa of rats.

Peter CP, Kindt MV, Majka JA.

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

Bisphosphonates have generally few clinical adverse effects, the most common being gastrointestinal disturbances. It is generally believed that bisphosphonates with a primary amine are more irritating to the gastrointestinal tract than those without a primary amine. The objective of this study was to compare the gastric irritation potential of an amino bisphosphonate (alendronate) to that of two nonamino bisphosphonates (risedronate and etidronate) in a rat model at pharmacologically equivalent and clinically relevant doses. The doses used were 1, 5, 10, and 30 mg/kg/day for alendronate and risedronate and 40, 200, 400, and 1200 mg/kg/day for etidronate. These doses represent 5-150 times the recommended clinical dose. The drugs were given orally, daily by gavage for four weeks. The gastric irritation potential was assessed by gross and microscopic evaluation of multiple sections of the stomach. This study showed that, at pharmacologically equivalent doses, the gastric irritation potential for alendronate is no greater than that for etidronate or risedronate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9590415&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo.

Giuliani N, Pedrazzoni M, Negri G, Passeri G, Impicciatore M, Girasole G.

Istituto di Clinica Medica Generale e Terapia Medica, University of Parma, Italy.

Recent in vitro findings suggest that bisphosphonates, potent inhibitors of osteoclastic bone resorption, may also have a direct action on osteoblasts. The purpose of this study was to search for potential effects of etidronate and alendronate on the formation of early and late osteoblastic cell precursors by measuring the number of colony-forming units for fibroblasts (CFU-F) and colony-forming units for osteoblasts (CFU-OB) in murine and human bone marrow cultures. In murine marrow cultures, etidronate (10(-5) to 10(-9) mol/L) significantly stimulated the formation of CFU-F with a maximal effect at 10(-5) mol/L (mean increase over control values+/-SD: 106+/-17%;p < 0.001), whereas alendronate had a biphasic effect, being stimulatory at concentrations below 10(-7) mol/L (78+/-5%; p < 0.001), and inhibitory at higher doses. The formation of CFU-OB was also inhibited by both bisphosphonates at the highest concentrations (10(-5) mol/L and 10(-6) mol/L), but it was significantly stimulated at lower concentrations (from 10(-7) to 10(-9) mol/L for etidronate and 10(-7) to 10(-10) mol/I, for alendronate; p < 0.001). In human bone marrow cultures, alendronate (10(-8) to 10-(12) mol/L) increased CFU-F formation with a maximal effect at 10(-10) mol/L (161+/-12 %; p < 0.01). CFU-OB formation, observed only in the presence of dexamethasone (10(-8) mol/L), was markedly stimulated by alendronate at the above concentrations with a maximal increase at 10(-10) mol/L (133+/-34%; p < 0.001). The in vivo short-term effects of bisphosphonates on the formation of early osteoblast precursors were also studied in bone marrow cultures from young female mice treated with weekly subcutaneous injections of etidronate (0.3, 3, and 30 mg/kg) or alendronate (0.3, 3, and 30 microg/kg) and from aging female mice treated with the two lowest doses of both drugs. After 1 month of treatment, etidronate (0.3 and 3 mg/kg) and alendronate (0.3 and 3 microg/kg) significantly increased the number of CFU-F colonies in the bone marrow from young and old animals, whereas the highest dose of both drugs had no effect in young mice. Our results, together with previously reported observations of bone-forming effects in osteoporosis, suggest that bisphosphonates may have, in vivo, a potentially relevant influence on cells of the osteoblastic lineage, distinct from their inhibitory action on osteoclasts.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9600778&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate/interleukin-1beta cotreatment increases interleukin-6 in bone and UMR-106 cells: dose dependence and relationship to the antiresorptive effect of alendronate.

Sanders JL, Tarjan G, Foster SA, Stern PH.

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611, USA.

Aminobisphosphonates inhibit bone resorption but have been shown to elicit acute-phase-like elevations in interleukin-6 (IL-6) in bone in vitro. The current studies were carried out to determine the relationship between the antiresorptive effects of the aminobisphosphonate alendronate and its effects on IL-6. Resorption was elicited in cultured 19-day fetal rat limb bones by 72 h treatment with interleukin-1beta (IL-1beta). Bone mass was quantitated at the end of the culture period to assess resorption. IL-6 was determined by bioassay (7TD1 cell proliferation). IL-1beta (18 and 180 pM) stimulated bone resorption and increased IL-6. Alendronate (70 microM) inhibited the IL-1beta-stimulated resorption. Alendronate alone did not affect IL-6 production by the bones. The IL-6 production from bones stimulated with 18 pM IL-1beta was not significantly affected by alendronate, but the IL-6 production from bones stimulated with 180 pM IL-1beta plus alendronate (21 and 70 microM) was higher than with IL-1beta alone. Indomethacin (1 mM) inhibited the IL-6 increase elicited by 180 pM IL-1beta and the enhanced IL-6 production elicited by cotreatment with IL-1beta and alendronate. Since bone cultures contain multiple cell types, further experiments were carried out to determine whether alendronate could increase IL-1beta-stimulated IL-6 production in an osteoblast cell line, UMR-106. Alendronate alone did not affect IL-6 in UMR-106 cells. Alendronate (70 microM) in combination with IL-1beta (180, 1.8, or 8 nM), or 7 microM alendronate, in combination with 8 nM IL-1beta, significantly increased IL-6 in 48 h cell cultures. The results from the bone organ cultures show that alendronate can enhance IL-6 production elicited by higher concentrations of the cytokine IL-1beta in bone, but that this effect on IL-6 does not prevent the inhibitory actions of alendronate on bone resorption. The results with the UMR106 cells indicate that one cellular site at which this enhancement of IL-6 production can occur is the osteoblast.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9610742&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate blocks TGF-beta1 stimulated collagen 1 degradation by human prostate PC-3 ML cells.

Stearns ME.

Allegheny University of the Health Sciences, Department of Pathology, Philadelphia, PA 19102-1192, USA. stearnsm wpo.auhs.edu

We have previously shown that alendronate can prevent human PC-3 ML tumor cell metastasis to the bone (Wang and Stearns, 1991, Differentiation, 48, 115-25). In this paper, ELISAs and Western blots showed that TGF-beta1 stimulated the secretion of a 72 kDa matrix metalloproteinase 2 (MMP-2) to enhance the solubilization of radiolabeled collagen 1 by metastatic human prostate PC-3 ML cells. A potent bisphosphonate compound, alendronate, inhibited MMP-2 secretion to block solubilization of collagen 1. Alendronate failed to inhibit MMP-2 activity directly, but instead appeared to block cellular secretion of MMP-2. Alendronate failed to inhibit secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2; the inhibitor of MMP-2) and the decrease in collagen 1 solubilization observed may occur, in part, from changes in the molar stoichiometry of TIMP-2 to MMP-2. We conclude that alendronate may be a potent inhibitor of bone resorption based on its ability to block MMP-2 secretion by tumor cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9626812&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
[Drug clinics. The drug of the month. Alendronate (Fosamax)]

[Article in French]

Scheen AJ.

Service de Diabetologie, Universite de Liege.

Alendronate (Fosamax, Merck Sharp & Dohme) is an aminobisphosphonate which inhibits bone turnover by suppressing the activity of osteoclasts without increasing the risk of osteomalacia. Alendronate is highly effective at preventing bone loss associated to absence of endogenous estrogen and induces a sustained increase in bone mass. Fosamax is indicated and reimbursed in the treatment of osteoporosis in postmenopausal women, with either an history of bone fracture confirmed by X-ray exam or obvious osteoporosis assessed by bone mineral density measurement. The recommended dosage is 10 mg once daily, continuously. The drug should be absorbed after an overnight fast to improve its bioavailability and with a big glass of plain water to reduce the risk of oesophageal ulcerations. Large randomized controlled trials for up to 3 years have demonstrated that alendronate is able to reduce the risk and rate of occurrence of vertebral and nonvertebral fractures in postmenopausal women.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9641020&dopt=Abstract alendronate Fosamax