alendronate, Fosamax
The role of serial bone mineral density testing for osteoporosis.

Crandall C.

Department of Medicine, UCLA School of Medicine, Iris Cantor-UCLA Women's Health Center, 100 UCLA Medical Plaza, Suite 250, Los Angeles, CA 90095-7023, USA.

As a whole, groups of women who gain more bone mineral density (BMD) on antiresorptive medications experience greater fracture protection, although the relationship is not clear on the individual level. A literature search (Medline 1966 to present) for randomized, controlled trials was performed with keywords serial bone density, osteoporosis, dual-energy x-ray absorptiometry, fracture, alendronate, risedronate, calcitonin, estrogen replacement therapy, and raloxifene. Also, reference lists and tables of contents from journals were searched manually for additional relevant randomized controlled trials. Trials were 2-3 years in duration, and the number of subjects ranged from 670 to 3954. Medications analyzed include alendronate, either 5 mg/day or 5 mg/day, followed by 10 mg/day; raloxifene, 60 or 120 mg/day; and combination hormone replacement therapy (HRT) of four different regimen types. There have been no controlled studies showing that change in treatment based on serial bone density measurement results in improved patient outcomes. Whereas studies have shown changes in BMD during antiresorptive therapy to be predictive of fracture reduction in groups of patients, their utility in individual patients remains inconclusive. Osteoporotic women who lose BMD in the first year of alendronate or raloxifene use will likely gain BMD in the second year of treatment, illustrating regression to the mean. Effective medication for osteoporosis should not be changed solely because of BMD loss occurring after the first year of treatment. Young, healthy, postmenopausal women taking commonly prescribed doses of estrogen or estrogen/progestin (HRT) rarely lose BMD. Bone loss over the first 12 months of HRT is independent of bone loss in the next 24 months. If bone is not lost in the first 12 months of HRT, there is a significant chance that bone density will be lost later in treatment. Half of placebo-treated women do not lose BMD over 3 years. Treatment should be continued in patients who initially lose bone density on therapy because most will gain density with continued treatment and end in gaining bone overall. Also, patients who gain large amounts of bone in the first year and lose in the second year are not necessarily failing therapy but rather may be showing that a random error in the earlier bone density change corrects itself later. Loss of BMD with alendronate, raloxifene, or combination conjugated equine estrogen/ medroxyprogesterone acetate is likely to convert to gain in BMD. More research is needed to confirm that this regression to the mean may apply to all densitometry techniques, antiresorptives, age groups, and genders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11747684&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
[The treatment of osteoporosis and bone resorption of alveoli with alendronate in rat model]

[Article in Chinese]

Wang X, Yang Z, Yu S.

Department of Stomatology, First Hospital, Peking University, Beijing 100034, China.

OBJECTIVE: To evaluate the anti-osteoporosis effect of alendronate on bone in rat model. METHODS: The osteoporosis and alveolar bone resorption animal model were established in rats. The experimental groups were given alendronate in 5 mg/kg BW by subcutaneous injection after first day of ovariectomy and dental ligature, three times a week for 6 weeks. All the animals were sacrifised 12 weeks after the operation. The blood samples were collected for determination of biochemical indices. The left femora and jaw bones were processed for histomorphometry. The right femora and mendibles were prepared for determination of bone density and bone biodynamics. RESULTS: As compared with the control groups(without alendronate), the values of experimental groups (with alendronate) were all significantly improved on bone density, bone anti-flexure ability and body weight. The alkaline phosphatase, calcium in serum of ovariectomy groups(without alendronate) were obviously increased. In the experimental group, however, these indices were close to normal levels. In histomorphometry, there were little inflammation in gingiva and no obvious bone resorption in the alveolar crests of the experimental groups; but there were obvious gingivitis and alveolar crests resorption of the control groups. CONCLUSIONS: Alendronate can effectively prevent bone loss to reduce osteoporosis in ovariectomized rats and prohibit pathological alveolar bone resorption.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11812340&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Cost effectiveness of alendronate (fosamax) for the treatment of osteoporosis and prevention of fractures.

Johnell O, Jonsson B, Jonsson L, Black D.

Department of Orthopedics, Malmo University Hospital, Malmo, Sweden.

BACKGROUND: The Fracture Intervention Trial (FIT) demonstrated that the bisphosphonate alendronate reduces the risk of hip, spine and wrist fracture in osteoporotic women by approximately one half. OBJECTIVE: To use data from FIT to conduct a cost-effectiveness analysis of alendronate. DESIGN: A Markov model was developed for a cohort of Swedish women, comparable in relative fracture risk to the women enrolled in the FIT vertebral fracture arm (i.e. age 71 years with low bone mass plus at least one prior spine fracture). The women in the model (with low bone mass and a previous spine fracture) were exposed to alendronate therapy and transitioned over time from a 'well' health state to health states of 'hip fracture', 'spine fracture', 'wrist fracture' or 'death'. All costs were calculated in 2000 Swedish kronors (SEK). TIME HORIZON: In the Markov model our base-case treatment duration was 5 years followed by a 5-year period where the benefit declined linearly to 0. RESULTS: We found that treating 71-year-old osteoporotic women with a prior spine fracture with alendronate resulted in a cost per quality-adjusted life-year (QALY) gained of SEK76000, which is well below the threshold for cost effectiveness of SEK300000. For women aged 65 years, the cost-effectiveness ratio increased to SEK173000 and for women aged 77 years, the cost-effectiveness ratio decreased to SEK52000. CONCLUSIONS: Treating older osteoporotic women with alendronate was more cost effective than treating younger women with osteoporosis, and treating osteoporotic women with prior spine fracture was more cost effective than treating osteoporotic women without prior spine fracture. However, the costs per QALY gained for all populations studied were below generally accepted thresholds for cost effectiveness.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12627984&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Pharmacokinetic and pharmacodynamic evaluation of intermittent versus continuous alendronate administration in rats.

Stepensky D, Golomb G, Hoffman A.

Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, P.O. Box 12065, Jerusalem 91120, Israel.

We studied the differences in pharmacokinetics and pharmacodynamics of the same dose of alendronate administered subcutaneously as intermittent bolus injection or continuous infusion in rats. Two rat models of bone disease were applied. Bone cancer was produced by intratibial inoculation of Walker carcinosarcoma cells, and a model of augmented bone resorption was produced by vitamin D(3) treatment of rats that had undergone thyroidparathyroidectomy. Higher amounts of alendronate were found in bones and in internal organs after bolus drug administration as compared with continuous infusion. Drug effects on plasma calcium levels and on urine calcium excretion were similar in both modes of alendronate administration. Results of the study indicate that the pharmacokinetics (disposition) of alendronate is administration-dependent. The total amount found in bone does not directly represent the amount of alendronate that is pharmacologically active at the site of action in the bone and that affects bone remodeling. The findings suggest that there is no pharmacodynamic advantage for continuous infusion of alendronate. It is concluded that the preferred mode of administration should be selected according to secondary clinical criteria (like incidence of adverse effects and convenience of administration). Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:508-516, 2002

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11835209&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Alendronate does not inhibit early bone apposition to hydroxyapatite-coated total joint implants: a preliminary study.

Mochida Y, Bauer TW, Akisue T, Brown PR.

Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

BACKGROUND: Alendronate is a pyrophosphate analogue of bisphosphonate that has been shown to inhibit osteoclastic bone resorption. Bone formation and remodeling are necessary to establish initial fixation of uncemented implants, especially those coated with a bioactive surface such as hydroxyapatite. Because the process of bone-remodeling that culminates in new-bone formation is thought to be initiated by osteoclastic bone resorption, it is appropriate to test the influence of osteoclast-inhibiting medications on bone apposition to hydroxyapatite-coated implants. METHODS: Twelve dogs underwent staged bilateral total hip arthroplasty, with twenty weeks between the first and second operations, with use of a titanium-alloy femoral stem that had a proximal macrotextured surface and a plasma-sprayed hydroxyapatite coating. Six of the dogs received oral alendronate therapy from the time of the surgery until they were killed; the other six dogs were untreated controls. The animals were killed four weeks after the second operation. Sections from matched implant sites (proximal, middle, and distal) were histologically analyzed. The linear extent of bone apposition, the linear extent and the thickness of the hydroxyapatite coating, and the total amount of cortical and trabecular bone were measured with the use of an interactive image analysis system. RESULTS: There were no significant differences in radiographic or histologic findings between the two groups at either four or twenty-four weeks. Although the extent of the hydroxyapatite coating decreased significantly with time in both groups (p < 0.01), we identified no significant influence of alendronate on the extent of bone apposition, the extent or thickness of the hydroxyapatite coating, or the cortical or trabecular bone area around the implants. CONCLUSIONS: Many patients who are receiving alendronate for osteoporosis or other disorders may also be candidates for cementless total joint arthroplasty. Although bone formation is generally thought to be initiated by and coupled with bone resorption, our results suggest that alendronate has no discernible effect on the initial fixation of or the short-term bone-remodeling around hydroxyapatite-coated femoral total joint implants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11861729&dopt=Abstract alendronate Fosamax



alendronate, Fosamax
Effects of alendronate on particle-induced osteolysis in a rat model.

Millett PJ, Allen MJ, Bostrom MP.

The Hospital for Special Surgery, New York, NY 10021, USA.

BACKGROUND: Particle-induced osteolysis is currently a major problem affecting the long-term survivorship of total joint replacements. Alendronate is a third-generation bisphosphonate that blocks osteoclastic bone resorption. The objective of this study was to determine whether alendronate could prevent particle-induced osteolysis or restore (reverse) bone loss in established osteolysis. METHODS: A rat model of particle-induced osteolysis was used. A specially designed polyethylene implant was placed in the proximal part of the right tibia of seventy-two animals. Following four weeks of healing, the animals were randomized into control groups, a prevention group, or a treatment group. In the prevention group, animals received intra-articular injections of high-density polyethylene particles (mean size, 2 m; all <10 m) at four, six, and eight weeks postoperatively. Alendronate (0.01 mg/kg/day) was administered concomitantly through an implantable pump from the fourth week through the tenth week. In the treatment group, animals were also exposed to polyethylene particles at four, six, and eight weeks, to establish bone loss, but they received alendronate subsequently, from the tenth week through the sixteenth week, to treat the bone loss. Positive (particle-only) and negative (saline-solution-only) control groups were assessed as well. Tissues were harvested at ten weeks in the prevention group and at sixteen weeks in the treatment group. Histological analyses and histomorphometric determinations of the periprosthetic bone volume were carried out. RESULTS: Histological examination showed a rim of new bone (neocortex) around the implant in the untreated and saline-solution-treated control animals (no polyethylene particles). Treatment with saline solution (no polyethylene particles) did not affect periprosthetic bone. Animals exposed to polyethylene particles had bone loss. In those that received alendronate, the bone loss was either prevented or reversed, and the quantity of neocortical and trabecular bone was increased compared with that of the controls. Alendronate effectively preserved periprosthetic bone in both the prevention and treatment groups. In the prevention arm, the mean periprosthetic bone volume of the neocortex and the surrounding trabecular bone, as determined with histomorphometry, was 21.5% +/- 6.5% in the saline-solution-treated controls (no particles), 13.1% +/- 5.9% in the particle-treated animals, and 32.6% +/- 6.4% in the alendronate-treated animals (p < 0.001). In the treatment arm, the mean periprosthetic bone volume was 27.2% +/- 5.6% in the saline-solution-treated controls, 17.7% +/- 6.2% in the particle-treated animals, and 30.2% +/- 5.9% in the alendronate-treated animals (p = 0.002). CONCLUSIONS: In our model, the intra-articular injection of polyethylene particles caused substantial bone loss around a loaded implant. Alendronate effectively prevented and treated the particle-induced periprosthetic bone loss.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11861730&dopt=Abstract alendronate Fosamax