alendronate, Fosamax
Effects of continuous alendronate treatment on bone mass and mechanical properties in ovariectomized rats: comparison with pamidronate and etidronate in growing rats.

Azuma Y, Oue Y, Kanatani H, Ohta T, Kiyoki M, Komoriya K.

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

Alendronate is a potent inhibitor of bone resorption. To investigate the relationship between antiresorptive activity and bone-related side effects, we studied the effect of 2 months of daily alendronate (0.04, 0.2, 1.0 or 5.0 mg/kg/day) treatment on the strength of the femoral shaft and neck and on the bone mass of ovariectomized rats. The p.o. administration regimen began immediately after ovariectomy at 6 weeks of age, and the results were compared with pamidronate (0.2, 1.0 or 5.0 mg/kg/day) or etidronate (5.0, 25.0 or 125.0 mg/kg/day) treatment. In the femoral epiphysis and neck, a preventive effect of alendronate on loss of bone mineral density was observed at the dose of 1.0 mg/kg. The alendronate-treated group did not show significant alteration of the breaking load or the cross-sectional shape of the femoral midshaft. Similar results were obtained in the femoral neck strength and femoral neck geometry. In histomorphometric analysis of tibial metaphyses, alendronate inhibited the ratio of osteoid volume to tissue volume and the mineral apposition rate at a dose of 0.2 mg/kg compared with the ovariectomized control. In contrast, etidronate tended to increase osteoid volume/bone volume at 125 mg/kg. From these results, we conclude that p.o. alendronate-treatment prevented the decrease in bone mineral density and maintained the mechanical properties of bone after ovariectomy without impairing of bone mineralization in growing rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9655851&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
United Kingdom experience with alendronate and oesophageal reactions.

Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD.

Drug Safety Research Unit, Southampton.

Alendronate is indicated for the treatment of osteoporosis in post-menopausal women. Although the drug has been associated with reports of severe oesophagitis, there have been no studies establishing the incidence of such reactions. Information was collected on 1523 patients included in a study conducted by means of prescription-event monitoring. Dyspepsia, nausea/vomiting, and abdominal pain were the most frequently reported events in the first month of treatment. After follow-up, 20 patients (1.3%) experienced oesophageal events that were considered to be possibly related to alendronate.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9667093&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Tissue inhibitor of metalloproteinase-2 protection of matrix metalloproteinase-2 from degradation by plasmin is reversed by divalent cation chelator EDTA and the bisphosphonate alendronate.

Farina AR, Tacconelli A, Teti A, Gulino A, Mackay AR.

Department of Experimental Medicine, University of L'Aquila, Italy. farina aquila.infn.it

The degradation of tissue inhibitor of metalloproteinase (TIMP)-free matrix metalloproteinase (MMP)-2 to proteolytically inactive fragments by plasmin was inhibited in equimolar mixtures of purified TIMP-2 and TIMP-free MMP-2 and was not observed in purified MMP-2-TIMP-2 complexes. Divalent cation chelators EDTA and sodium Alendronate did not inhibit plasmin degradation of TIMP-free MMP-2 but reversed the ability of TIMP-2 to protect MMP-2 from degradation by plasmin. Our data confirm a role for plasmin in the clearance of TIMP-free MMP-2, identify a pivotal role for TIMP-2 in regulating MMP-2 longevity in plasmin-containing environments, and highlight a novel therapeutic use for chelators of divalent cations, including the bisphosphonate Alendronate, in the reversal of TIMP-2 protection of MMP-2 from degradation by plasmin. We propose that these observations are relevant to pathologies that are dependent upon plasmin and MMP-2 activity (e.g., tumor invasion and metastasis).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9679953&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
The effect of alendronate on cytokine production, adhesion molecule expression, and transendothelial migration of human peripheral blood mononuclear cells.

Pietschmann P, Stohlawetz P, Brosch S, Steiner G, Smolen JS, Peterlik M.

Department of Internal Medicine III, University of Vienna, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.

Since both osteoclasts and macrophages belong to the mononuclear phagocytic system it is conceivable that bisphosphonates not only affect bone metabolism but also inflammatory responses. The migration of mononuclear cells into perivascular tissue is a central event in inflammatory reactions. We studied the effects of the aminobisphosphonate alendronate on the transendothelial migration of human peripheral blood mononuclear cells in an in vitro model. Alendronate (at a concentration of 100 microM) significantly increased the percentage of peripheral blood mononuclear cells that migrated through endothelial cell monolayers. Similar results were obtained with another aminobisphosphonate, viz, pamidronate. An overnight treatment of the endothelial cell monolayers with alendronate did not alter the rate of peripheral blood mononuclear cells that subsequently migrated. The overnight cultivation of the peripheral blood mononuclear cells in the presence of alendronate resulted in an increased surface expression of CD54 (intercellular adhesion molecule-1, ICAM-1) in both CD14(+) and CD3(+) cells; in CD14(+) cells also the expression of CD49d (alpha4 subunit of late activation antigen-4, VLA-4) increased after alendronate treatment. Alendronate treatment of peripheral blood mononuclear cells also resulted in an increased production of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma). We conclude that alendronate has a distinct effect on the transendothelial migration of human peripheral blood mononuclear cells in vitro. Alendronate may either directly or indirectly, e.g., by augmenting the production of proinflammatory cytokines, influence the expression of certain adhesion molecules and thereby facilitate transendothelial migration. These effects could be related to the transient leukopenia reported following intravenous administration of relatively high doses of aminobisphosphonates for the treatment of hypercalcemia of malignancy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9744992&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Esophageal irritation due to alendronate sodium tablets: possible mechanisms.

Peter CP, Handt LK, Smith SM.

Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

Animal studies were done using an in vivo dog model to examine the possible mechanism for the esophageal adverse events reported with alendronate sodium tablets. These studies showed that under low pH conditions alendronate sodium can cause esophageal irritation. No esophageal irritation occurred at pH 3.5 or higher where the drug exists primarily as the sodium salt. The animal studies also showed that alendronate sodium can exacerbate preexisting esophageal damage. Exposure of the esophageal mucosa for a prolonged period to alendronate sodium tablet can also cause mild esophageal irritation. These findings suggest that the esophageal irritation in patients taking Fosamax can be from prolonged contact with the tablet, reflux of acidic gastric contents with alendronate sodium, and exacerbation of preexisting esophageal damage. The findings also suggest that other bisphosphonates can cause esophageal injury under similar conditions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9753265&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate in the treatment of primary hyperparathyroid-related osteoporosis: a 2-year study.

Parker CR, Blackwell PJ, Fairbairn KJ, Hosking DJ.

Division of Mineral Metabolism, City Hospital, Nottingham NG5 1PB, United Kingdom. cparker doctors.org.uk

We investigated the effect of alendronate on calcium, PTH, and bone mineral density in 27 female and 5 male patients with primary hyperparathyroidism. The treatment group [n = 14; T score < or = -2.5 SD at the femoral neck (FN) or T < or = -1.0 SD plus previous nonvertebral fracture] was given alendronate 10 mg/d for 24 months. The second group (n = 18; T score > -2.5 SD at the FN) was untreated. Biochemistry was repeated at 1.5, 3, 6, 12, 18, and 24 months, and dual-energy x-ray absorptiometry at 12 and 24 months. There were no significant between-group baseline differences in calcium, creatinine, or PTH. Alendronate-treated patients gained bone at all sites [lumbar spine (LS), 1 yr gain, +7.3 +/- 1.7%; P < 0.001; 2 yr, +7.3 +/- 3.1%; P = 0.04). Untreated patients gained bone at the LS over 2 yr (+4.0 +/- 1.8%; P = 0.03) but lost bone elsewhere. Calcium fell nonsignificantly in the alendronate group between baseline (2.84 +/- 0.12 mmol/liter) and 6 wk (2.76 +/- 0.09 mmol/liter), with a nonsignificant rise in PTH (baseline, 103.5 +/- 14.6 ng/liter; 6 wk, 116.7 +/- 15.6 ng/liter). By 3 months, values had reverted to baseline. In primary hyperparathyroidism, alendronate is well tolerated and significantly improves bone mineral density at the LS (with lesser gains at FN and radius), especially within the first year of treatment. Short-term changes in calcium and PTH resolve by 3 months.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12364423&dopt=Abstract alendronate Fosamax