alendronate, Fosamax
Alendronate-associated esophageal injury: pathologic and endoscopic features.

Abraham SC, Cruz-Correa M, Lee LA, Yardley JH, Wu TT.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. sabraha welchlink.welch.jhu.edu

Ingestion of alendronate sodium (Fosamax) by osteoporotic patients can be associated with esophagitis and esophageal ulcer. Alendronate can damage the esophagus both by toxicity from the medication itself and by nonspecific irritation secondary to contact between the pill and the esophageal mucosa, similar to other cases of "pill esophagitis." Despite its wide use, the histologic appearances of alendronate-associated esophageal ulceration have not been previously described in detail, nor is this type of medication-induced injury commonly appreciated by pathologists when evaluating biopsies from ulcer sites. We report a series of 10 patients who experienced erosive/ulcerative esophagitis while ingesting alendronate, and describe the associated endoscopic and pathologic features. Biopsies from all patients showed inflammatory exudate and inflamed granulation tissue as characteristic of any ulcer site. Polarizable crystalline foreign material was present in six of 10 biopsies (60%). Multinucleated giant cells within the inflammatory exudate were present near this crystalline foreign material in three of 10 biopsies (30%). Adjacent squamous epithelium typically showed active inflammation and a reactive appearance with enlarged, hyperchromatic nuclei. Multinucleated squamous epithelial giant cells were present in two of 10 cases (20%). Microorganisms were unusual; scattered fungi and/or viral inclusions were present in only two of 10 biopsies (20%). Recognition of alendronate-associated erosive or ulcerative esophagitis, particularly in postmenopausal women, and communication of this possibility to the clinician can improve patient care.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10619269&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase.

Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G.

Infectious Disease, Merck Research Laboratories (R80-A14), Rahway, New Jersey, 07065, USA. jim_bergstrom merck.com

Alendronate, a nitrogen-containing bisphosphonate, is a potent inhibitor of bone resorption used for the treatment and prevention of osteoporosis. Recent findings suggest that alendronate and other N-containing bisphosphonates inhibit the isoprenoid biosynthesis pathway and interfere with protein prenylation, as a result of reduced geranylgeranyl diphosphate levels. This study identified farnesyl disphosphate synthase as the mevalonate pathway enzyme inhibited by bisphosphonates. HPLC analysis of products from a liver cytosolic extract narrowed the potential targets for alendronate inhibition (IC(50) = 1700 nM) to isopentenyl diphosphate isomerase and farnesyl diphosphate synthase. Recombinant human farnesyl diphosphate synthase was inhibited by alendronate with an IC(50) of 460 nM (following 15 min preincubation). Alendronate did not inhibit isopentenyl diphosphate isomerase or GGPP synthase, partially purified from liver cytosol. Recombinant farnesyl diphosphate synthase was also inhibited by pamidronate (IC(50) = 500 nM) and risedronate (IC(50) = 3.9 nM), negligibly by etidronate (IC50 = 80 microM), and not at all by clodronate. In osteoclasts, alendronate inhibited the incorporation of [(3)H]mevalonolactone into proteins of 18-25 kDa and into nonsaponifiable lipids, including sterols. These findings (i) identify farnesyl diphosphate synthase as the selective target of alendronate in the mevalonate pathway, (ii) show that this enzyme is inhibited by other N-containing bisphosphonates, such as risendronate, but not by clodronate, supporting a different mechanism of action for different bisphosphonates, and (iii) document in purified osteoclasts alendronate inhibition of prenylation and sterol biosynthesis. Copyright 2000 Academic Press.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10620343&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate and etidronate do not regulate interleukin 6 and 11 synthesis in normal human osteoblasts in culture.

Engel E, Serrano S, Marinoso ML, Lloreta J, Ulloa F, Nogues X, Diez-Perez A, Carbonell J.

Bone and Joint Physiopathology Research Unit, Institut Municipal d'Investigacio Medica, Universitat Pompeu Fabra, Barcelona, Spain.

Bisphosphonates exert a potent inhibitory effect on bone resorption. Several studies have been performed, with contradictory results, to ascertain whether the effect of bisphosphonates on osteoclasts could be produced, at least in part, by modulation of the synthesis of resorption-promoting factors by osteoblasts. The aim of this study was to evaluate the effect of etidronate (10-4-10-9 M) and alendronate (10-7-10-12 M) on the production of IL-6 and IL-11 using human osteoblast cultures. Cytokines were quantified by ELISA, and mRNA expression was tested. Treatment with alendronate and etidronate had no effect on the synthesis of IL-6 or IL-11, and IL-6 and IL-11 mRNA levels. These results were obtained both in nonstimulated cultures and in cultures stimulated by means of TNF-a, IL-1b, and TNF-a+IL-1b, with or without FCS. In conclusion, a possible indirect osteoclast-mediated effect of alendronate and etidronate on bone resorption would not be exerted through reduction in osteoblastic synthesis of IL-6 and IL-11.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12522661&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
The intracellular target for the antiresorptive aminobisphosphonate drugs in Dictyostelium discoideum is the enzyme farnesyl diphosphate synthase.

Grove JE, Brown RJ, Watts DJ.

Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Western Bank, UK.

Aminobisphosphonate (aBP) drugs inhibit osteoclast-mediated bone resorption and also growth of amoebas of Dictyostelium discoideum apparently by interaction with the same intracellular target. Identification of the target in Dictyostelium therefore could also identify the target in osteoclasts. The aBPs (100 microM alendronate and 30 microM YM-175) inhibited conversion of [14C]mevalonate into sterols by cultures of Dictyostelium amoebas. One of three enzymes (isopentenyl diphosphate [IDP] isomerase, farnesyl diphosphate [FDP] synthase, and squalene synthase) appeared to be the target for this inhibition because conversion of [14C]IDP into squalene, the immediate precursor for sterol biosynthesis, was inhibited in extracts of wild-type amoebas by alendronate (IC50 = 75 nM) or risedronate (IC50 = 30 nM) whereas, when the extract had been prepared from amoebas of strains selected for having partial resistance to the growth-inhibitory effects of alendronate (strain MR102) or risedronate (strain RB101), the values of IC50 were increased to 700 nM for alendronate (MR102 extract) or 130 nM for risedronate (RB101 extract). Neither IDP isomerase nor squalene synthase was inhibited significantly by alendronate or risedronate but both of these aBP drugs, and all others tested, inhibited FDP synthase. Determination of the nucleotide sequences of complementary DNAs (cDNAs) encoding FDP synthase in the wild-type and aBP-resistant strains of Dictyostelium indicated that there had been no changes in the amino acid sequence of the enzyme in the mutant strains. However, both mutant strains overproduce FDP synthase. It is concluded that FDP synthase is the intracellular target for the aBP drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10804029&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Elevation of histidine decarboxylase activity in the mandible of mice by Prevotella intermedia lipopolysaccharide and its augmentation by an aminobisphosphonate.

Funayama H, Mayanagi H, Takada H, Endo Y.

Department of Pediatric Dentistry, School of Dentistry, Tohoku University, Seiryo-machi, Aoba-ku Sendai 980, Japan.

Lipopolysaccharide (LPS) produced by Gram-negative bacteria is an important cause of inflammation. Aminobisphosphonates are potent inhibitors of bone resorption but have inflammatory side-effects. Here, the effects of LPS from Prevotella intermedia (a prevalent Gram-negative bacterium both in periodontitis and endodontal infections) and alendronate (an aminobisphosphonate) on the activity of the histamine-forming enzyme, histidine decarboxylase (HDC), were examined in mouse mandible. Intravenous injection of P. intermedia LPS increased HDC activity in the mandible, maximal activity being induced within 3-6 h of the injection. The elevation of HDC activity was dependent on the dose of LPS, 10 microg/kg (0.25 microg/mouse) producing a significant elevation in enzyme activity. Intraperitoneal injection of alendronate (40 micromol/kg) also produced an increase in HDC activity. Moreover, the elevation of HDC activity induced by P. intermedia LPS was markedly augmented in mice given alendronate 3 days before the LPS injection. These results (i) suggest that P. intermedia LPS may stimulate the synthesis of histamine in the mandible and that the newly formed histamine may make at least some contribution to the development of inflammation (apical periodontitis and/or osteomyelitis); (ii) should encourage the clinical testing of antihistaminergic agents against inflammation; and (iii) confirm that care needs to be taken when administering aminobisphosphonates to patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10869492&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
A histopathological investigation on the effects of the bisphosphonate alendronate on resorptive phase following mucoperiosteal flap surgery in the mandible of rats.

Kaynak D, Meffert R, Gunhan M, Gunhan O, Ozkaya O.

Ankara University Faculty of Dentistry, Department of Periodontology, Turkey.

BACKGROUND: The present study was designed to examine histopathologically whether local delivery of aminobisphosphonate (alendronate) could be effective in preventing the alveolar bone resorption associated with mucoperiosteal flaps. METHODS: Following mucoperiosteal flap elevation in the molar region of the rat mandible, a surgical pellet soaked with aminobisphosphonate was locally applied on the exposed bone surface and covered by flap. The determined parameters with a semi-quantitative subjective method for the histopathological evaluation were as follows: existing inflammatory cell infiltration of the related periodontal tissue; fibrotic component content and bundles of collagen fibers; the number and morphology of osteoclasts of the alveolar bone and interdental septum; existing resorption lacunae (osteoclast surfaces); and existing osteoblastic activity (forming surfaces). RESULTS: The results showed that while there were no detectable statistically significant differences between the saline and alendronate-treated groups on the existing inflammatory cell infiltration (ICI), number of osteoclasts, and osteoblastic activity, the results for the fibrotic and collagen component, osteoclast morphologies, and existing resorption lacunae were statistically significant. CONCLUSIONS: These results suggest that local application of the aminobisphosphonate alendronate can be used as an adjunct in therapy for reducing bone resorption following surgery. It can also be suggested for consideration that, even for the surgical approaches in dentistry where bone graft materials and/or dental implants are needed, using bisphosphonate may achieve a new dimension in periodontal therapy in the near future.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10872961&dopt=Abstract alendronate Fosamax