alendronate, Fosamax
Short-term effects of bisphosphonates on the biomechanical properties of canine bone.

Wang X, Shanbhag AS, Rubash HE, Agrawal CM.

Department of Orthopaedics, The University of Texas Health Science Center at San Antonio, 78284-7774, USA.

Periprosthetic osteolysis and aseptic loosening of total joint replacements are believed to be initiated often by abnormal bone resorption induced by prosthetic wear debris. Bisphosphonates can inhibit bone resorption and have been successfully used clinically to treat osteoporosis and Paget's disease. In a recent study it also was shown that a third generation bisphosphonate (alendronate) is effective in preventing wear debris-induced periprosthetic osteolysis. Since inhibition of bone resorption by alendronate may disrupt the delicate balance between bone resorption and formation in normal bone remodeling, it is possible that continuous alendronate therapy may have an adverse effect on the biomechanical properties of bone. Thus the purpose of the present study was to examine the effects of systemic alendronate administration on the biomechanical properties of normal bone using a canine total hip arthroplasty model. We evaluated the biomechanical properties of femora from canines that had received total hip replacements on one side and had been given oral alendronate daily for 23 weeks. The biomechanical properties assessed were fracture toughness, elastic modulus, tensile strength, microhardness, porosity, and weight fractions of the mineral and organic phases of bone. Also, bone microstructure was examined using optical microscopy. Our results indicate that in the short term alendronate therapy does not have any adverse effects on the intrinsic biomechanical properties of canine bone. However, the long-term effects of alendronate therapy still need to be investigated.Copyright 1999 John Wiley & Sons, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10397950&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Individualizing therapy to prevent long-term consequences of estrogen deficiency in postmenopausal women.

Col NF, Pauker SG, Goldberg RJ, Eckman MH, Orr RK, Ross EM, Wong JB.

Department of Medicine, Tupper Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Mass 02111, USA.

BACKGROUND: Alendronate sodium and raloxifene hydrochloride were recently approved for the prevention of postmenopausal osteoporosis, but data on their clinical efficacy are limited. We compared these drugs with hormone replacement therapy (HRT) to help women and physicians guide postmenopausal treatment decisions. OBJECTIVE: To help physicians understand how they can best help women choose the most beneficial therapy after menopause based on their individual risk profile. METHODS: We developed a decision analytic Markov model to compare the effects of alendronate therapy, raloxifene therapy, and HRT on risks of hip fracture, coronary heart disease (CHD), breast cancer, and life expectancy. Regression models linked individual risk factors to future disease risks and were modified by drug effects on bone density, lipid levels, and associated breast cancer effects. RESULTS: Hormone replacement therapy, alendronate therapy, and raloxifene therapy have similar predicted efficacies in preventing hip fractures (estimated relative risk, 0.57, 0.54, and 0.58, respectively). Hormone replacement therapy should be more than 10 times more effective than raloxifene therapy in preventing CHD, but raloxifene therapy may not induce breast cancer. Women at low risk for hip fracture, CHD, and breast cancer do not benefit significantly from any treatment. Among women at average risk, HRT was preferred unless raloxifene therapy could reduce the risk of breast cancer by at least 66%, compared with a 47% increase for HRT. Women at high risk for CHD benefit most from HRT; women at high risk for breast cancer but low risk for CHD benefit most from raloxifene therapy, but only if it lowers the risk of breast cancer. CONCLUSION: Because of significant differences in the impact of these drugs, treatment choice depends on an individual woman's risk for hip fracture, CHD, and breast cancer.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10399897&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
A cost effectiveness analysis of calcium and vitamin D supplementation, etidronate, and alendronate in the prevention of vertebral fractures in women treated with glucocorticoids.

Buckley LM, Hillner BE.

Virginia Commonwealth University, Richmond 23298, USA. lbuckley hsc.vcu.edu

OBJECTIVE: To assess the relative costs and benefits of calcium and vitamin D supplements, cyclic etidronate, or alendronate in the prevention of vertebral fractures for women and with normal bone density and osteopenia who are about to initiate moderate dose glucocorticoid treatment. METHODS: Using a decision analysis model, we evaluated the following patients: 4 hypothetical cohorts: 30-yr-old women with normal lumbar spine (LS) bone mineral density (BMD) (t score = 0), 50-yr-old women with borderline osteopenia (t score = -1), 60-yr-old women with moderate osteopenia (t score = -1.5), and 70-yr-old women with severe osteopenia (t score = -2) treated with a mean prednisone dose of 10 mg/day for one year. The main outcomes included the development of vertebral fractures 10 years after glucocorticoid treatment and at age 80 (life-time risk) and direct and indirect costs. RESULTS: At 10 years, calcium and vitamin D supplements decreased fracture rates by 30-50% at a minimal cost (US$800 or less per vertebral fracture avoided) or at a cost saving compared to no treatment for women with osteopenia (t score -1 to -2). Etidronate and alendronate are most cost effective in women with borderline osteoporosis (t scores of -1.5 and -2) in the 10 year analysis. In the life-time analysis, calcium and vitamin D treatment yielded a cost savings compared to no treatment for all groups with osteopenia. Etidronate decreased fracture rates further in all groups at a cost of less than $2,000 per fracture prevented. Alendronate reduced the fracture risk further at cost of $3,000-7,000 per fracture avoided. CONCLUSION: Calcium and vitamin D supplements and low cost bisphosphonate regimens such as cyclic etidronate decrease the life-time vertebral fracture risk at acceptable costs and should be considered when initiating glucocorticoid treatment for women who do not have osteoporosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12508402&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Renal handling of biphosphonate alendronate in rats.

Kino I, Kato Y, Lin JH, Sugiyama Y.

Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Alendronate is a bisphosphonate that is secreted via a saturable pathway in rat kidney. This study is designed to discover if the rate-determining step in its net renal secretion is uptake into the renal tubule. The tissue uptake clearance of alendronate by the kidney, estimated from an integration plot analysis and normalized with respect to plasma protein binding, was 4.2 times higher at a tracer dose than that of inulin, indicating uptake of alendronate by the renal tubules. The uptake clearance is comparable with the net secretion clearance obtained from an infusion study, indicating that the rate-determining step in the net secretion is uptake under the tracer conditions. When the dose was increased, however, there was no reduction in uptake clearance while the net secretion clearance fell to almost zero. The urinary excretion clearance defined with respect to the steady state concentration in the kidney also fell to almost zero. This result suggests that saturation of the net secretion of alendronate is caused by saturation of membrane transport through the brush-border membrane. Thus, it would seem that there is a transport mechanism for alendronate on the brush-border membrane of kidney epithelial cells. Copyright 1999 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10440794&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Disposition of alendronate following local delivery in a rat jaw.

Yaffe A, Binderman I, Breuer E, Pinto T, Golomb G.

Department of Prosthodontics, Hebrew University Hadassah School of Dental Medicine, Jerusalem, Israel.

BACKGROUND: Recently, we have shown that local delivery of alendronate reduced significantly bone resorption activated by surgical separation of periosteum from bone. These results advocate the use of local application of alendronate in bone surgeries to prevent regional bone resorption at the surgery site. Here we investigated the efficacy of absorbtion of alendronate by the bone from a gelatin sponge soaked with radiolabeled alendronate applied topically at the surgical site. METHODS: Following elevation of the mucoperiosteal flap next to premolars and molars of the rat mandible, a gelatin sponge soaked with 10 microl of radiolabled alendronate (1 microCi/mg) was applied to exposed bone on one side. The local absorbtion of alendronate and its disposition in the contralateral side of the mandible as well as in the tibia bone were analyzed. RESULTS: The results show that 10% of total alendronate content of the gelatin sponge was absorbed in the bone locally (in the surgical site), while 0.2% was disposed in the tibia. Of interest is the fact that the surgical wound in the contralateral side increased the disposition of alendronate up to 2%. This finding is most likely the result of extravasation and diffusion of alendronate due to surgical wounding. CONCLUSION: This study strongly supports our notion that local delivery of alendronate and its affinity to bone may become a very important treatment modality to prevent resorption of bone during dental and orthopedic procedures.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10476897&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Collagenase-3 (MMP-13) and its activators in rheumatoid arthritis: localization in the pannus-hard tissue junction and inhibition by alendronate.

Konttinen YT, Salo T, Hanemaaijer R, Valleala H, Sorsa T, Sutinen M, Ceponis A, Xu JW, Santavirta S, Teronen O, Lopez-Otin C.

Department of Medicine, Helsinki University Central Hospital, Finland. yrjo.konttinen helsinki.fi

The hypothesis of the present work was that the pannus tissue overlying the articular hard tissues has an aggressive phenotype and contains the newly discovered collagenase-3 and its endogenous inducers and activators. We therefore analyzed the eventual presence of collagenase-3 and its regulation at the pannus-cartilage junction. Collagenase-3 mRNA (in situ hybridization) and enzyme protein (ABC and immunofluorescence staining) were found in the pannocytes in the pannus-hard tissue junction. Inflammatory round cells associated with the critical interface contained TNF-alpha and IL-1beta. These cytokines induced collagenase-3 secretion in cultured rheumatoid synovial fibroblasts. Procollagenase-3 activators, stromelysin-1, 72 kDa type IV collagenase/gelatinase and membrane-type 1-MMP, were also found in the pannus-hard tissue junction. Active collagenase-3 was inhibited with alendronate (IC50 = 500-750 microM). Collagenase-3, due to its substrate profile and local synthesis in a milieu favoring its activation, might play a major role in the degradation of cartilage type II and bone type I collagens. Alendronate, at concentrations attainable in vivo, is able to inhibit collagenase-3. This might offer an option to control collagenase-3-mediated tissue destruction in rheumatoid arthritis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10517187&dopt=Abstract alendronate Fosamax