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PubMed1998

Prevention of corticosteroid-induced bone loss with alendronate.

The putitive bone-sparing effect of alendronate was tested in two animal models of osteopenia: estrogen-deficient female rats and glucocorticoid-treated male rats. In the first study, 18 female Sprague-Dawley rats, 4 months of age, were ovariectomized (OVX), and an additional 6 rats were sham-operated. The OVX rats were treated with either vehicle, 17beta-estradiol (E2) (100 microg/rat/week, s.c.), or alendronate (1 mg/kg/day, on alternate days, orally). In the second study, 24 8-month-old male Wistar rats were treated with either vehicle, methyl prednisolone (7 mg/kg once a week, s.c.), prednisolone plus testosterone (16 mg/kg once every 3 weeks, i.m.), or prednisolone plus alendronate (20 microg/kg twice a week, s.c.). Prior to treatment and at the end of the 6-week treatment period, bone mineral density (BMD) of the lumbar spine was measured by dual energy x-ray absorptiometry, and mean femur weights were calculated. The OVX rats had subnormal BMD (-3.91 +/- 1.0% vs control +5.19 +/- 3.92%, P < 0.05) and femur weights (720 +/- 6 mg vs %; 746 +/- 11 mg, P < 0.05). OVX-induced bone loss was completely abolished by the administration of E2 (7.01 +/- 2.32%, P < 0.005; 748 +/- 6 mg, P < 0.01), or alendronate (24.2 +/- 2.73%, P < 0.0001; 779 +/- 11 mg, P < 0.001). In the second study in older male rats, glucocorticoids significantly decreased BMD (-9.70 +/- 3.44% vs -1.10 +/- 1.75%, P < 0.05), and femur weight (1070 +/- 14 mg vs 1180 +/- 24 mg, P < 0.01). Concomitant administration of testosterone (BMD 4.23 +/- 1.84%, P < 0.005; femur weight 1260 +/- 56 mg, P < 0.02), or alendronate (BMD 8.18 +/- 1.36%, P < 0.001; femur weight 1360 +/- 50 mg) with prednisolone, abolished the corticosteroid-induced bone loss. Bone histomorphometry showed a 34% loss of trabecular bone volume in glucocorticoid-treated rats (P < 0.05), which was prevented with both testosterone and alendronate therapies. However, at the doses used in both models, alendronate was more efficacious than either E2 or testosterone in increasing BMD and femur weight. In summary, this study demonstrated that alendronate therapy is highly effective in counteracting the osteopenia of OVX and glucocorticoid therapy.

Adrenal Cortex Hormones↗
PubMed2002

Tolerability of once-weekly alendronate in patients with osteoporosis: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To compare the upper gastrointestinal (GI) tract tolerability of once-weekly oral alendronate, 70 mg, and placebo. PATIENTS AND METHODS: This was a 12-week multicenter, randomized, double-blind, placebo-controlled study. The first patient initiated treatment on June 5, 2000, and the last patient completed treatment on March 1, 2001. The study enrolled 450 postmenopausal women and men with osteoporosis (224 took alendronate, 226 took placebo) who were ambulatory and community dwelling at 48 outpatient study centers in the United States. By design, approximately half of the patients were naive to bisphosphonates. The primary end point was upper GI tract tolerability based on the incidence of any upper GI tract adverse events. Secondary end points included the number of discontinuations due to drug-related upper GI tract adverse events and the change from baseline in bone resorption, assessed by the urinary N-telopeptide-creatinine ratio at 12 weeks. A subgroup analysis of the primary and secondary end points was performed on the patients stratified by prior bisphosphonate use. The safety and tolerability of the weekly alendronate and placebo regimens were captured as clinical and laboratory adverse events. RESULTS: A total of 11% of the alendronate patients and 13% of the placebo patients reported an upper GI tract adverse event. Discontinuations due to drug-related upper GI tract adverse events occurred in 3% of alendronate patients and 1% of placebo patients. The differences between the treatment groups for the primary and secondary end points were not significant. For the primary end point, the upper limit of the 95% confidence interval of the difference was well within the prespecified 14% comparability bound (-2.2%; 95% confidence interval, -8.3% to 3.9%). The overall incidence of upper GI tract adverse events was lower in the subgroup of patients with prior bisphosphonate exposure (8%) than in those who were bisphosphonate naive (16%). However, regardless of prior bisphosphonate exposure, the incidence of upper GI tract adverse events was similar between the alendronate and placebo patients. The urinary N-telopeptide-creatinine ratio showed a significant decrease in the alendronate patients (72% of baseline, P<.001) compared with a slight increase in the placebo patients (106% of baseline) at week 12. CONCLUSION: In this 3-month study, the incidence of upper GI tract adverse events in patients treated with once-weekly alendronate, 70 mg, was comparable to that with placebo.

Alendronate↗
PubMed2005

Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial.

OBJECTIVES: To determine the efficacy of alendronate treatment on risk of vertebral fracture in a subgroup of women from the Fracture Intervention Trial who had bone mineral density T scores between -1.6 and -2.5 at the femoral neck and to describe how soon after initiation of therapy alendronate becomes effective and whether it is consistent in women with and without existing radiographic vertebral fracture. PATIENTS AND METHODS: From May 1992 to March 1997, postmenopausal women aged 55 to 80 years were randomized to receive alendronate at 5 mg/d for 2 years and 10 mg/d thereafter or placebo for up to 4.5 years (mean, 3.8 years) in a controlled, double-blind, multicenter study. RESULTS: A total of 3737 postmenopausal women were included in the study, 1878 in the alendronate group and 1859 in the placebo group. Risk of vertebral fracture was significantly reduced by alendronate compared with placebo for clinical (relative risk [RR], 0.40; 95% confidence interval [CI], 0.19-0.76; P=.005) and radiographic (RR, 0.57; 95% CI, 0.41-0.81; P=-.002) fracture. The reductions in vertebral fracture risk were consistent in women with and without an existing radiographic vertebral fracture for clinical (RR, 0.34; 95% CI, 0.12-0.84; and RR, 0.46; 95% CI, 0.16-1.17; respectively) and radiographic (RR, 0.53; 95% CI, 0.34-0.82; and RR, 0.64; 95% CI, 0.38-1.10; respectively) fractures. In both groups, the effect of alendronate on clinical vertebral fracture was noted soon after therapy was initiated. The absolute risk of vertebral fracture was low in women without a baseline radiographic fracture. CONCLUSIONS: In women with low bone mass who do not meet the bone mineral density criterion for osteoporosis, alendronate is effective in reducing the risk of vertebral fractures. The absolute benefit of this therapy in women with a T score between -1.6 and -2.5 is greater in women with an existing vertebral fracture and/or with other risk factors. The effect of alendronate occurs early.

Aged↗
PubMed2005

Cost-effectiveness of alendronate therapy for osteopenic postmenopausal women.

BACKGROUND: Treatment guidelines recommend drug treatment to prevent fractures for some postmenopausal women who have low bone mass (osteopenia) but do not have osteoporosis or a history of clinical fractures. OBJECTIVE: To estimate the societal costs and health benefits of alendronate drug treatment to prevent fractures in postmenopausal women with osteopenia. DESIGN: Markov model with 8 health states: no fracture, post-distal forearm fracture, post-clinical vertebral fracture, post-radiographic (but clinically inapparent) vertebral fracture, post-hip fracture, post-hip and vertebral fractures, post-other fracture, and death. DATA SOURCES: Population-based studies of age-specific fracture rates and costs, prospectively measured estimates of disutility after fractures, and the Fracture Intervention Trial of alendronate versus placebo to prevent fracture. TARGET POPULATION: Postmenopausal women 55 to 75 years of age with femoral neck T-scores between -1.5 and -2.4. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Five years of alendronate therapy or no drug treatment. OUTCOME MEASURES: Costs, quality-adjusted life-years, and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: For women with no additional fracture risk factors, the cost per quality-adjusted life-year gained ranged from 70,000 dollars to 332,000 dollars, depending on age and femoral neck bone density. RESULTS OF SENSITIVITY ANALYSES: Results were sensitive to changes in fracture risk reduction attributable to alendronate and alendronate cost. LIMITATIONS: Results apply only to postmenopausal white women residing in the United States. CONCLUSION: Alendronate therapy for postmenopausal women with femoral neck T-scores better than -2.5 and no history of clinical fractures or other bone mineral density-independent risk factors for fracture is not cost-effective, assuming U.S. costs of alendronate and currently available estimates of alendronate efficacy in osteopenic women.

Aged↗
PubMed1999

[A cost-effectiveness analysis of alendronate compared to placebo in the prevention of hip fracture].

OBJECTIVE: To examine if the treatment with alendronate to prevent hip fracture (HF) in female with established osteoporosis is more cost-effectiveness than placebo, and if changes in efficacy, cost and incidence of adverse reactions of the treatment can affect the ratio, and the direction of decision. DESIGN: The study is based on a decision tree model to examine the cost-effectiveness ratio (CE) of alendronate (10 mg/d alendronate, 500 mg/d calcium and 250 IU vitamin D3) versus placebo (500 mg/d calcium and 250 IU vitamin D3). The treatment of 1000 patients with established osteoporosis and its course of events and probabilities during three years of treatment is simulated. RESULTS: The efficacy of each alternative is obtained by controlled clinical trials. The considered costs, from the first perspective of the services provider, and expressed in pesetas per year in 1998, are direct health tangibles: pharmacological treatment, HF surgery and treatment of serious adverse reactions (SAR). An analysis of simple univariate sensibility and one of incremental is applied on the efficacy, cost and incidence of adverse reactions to alendronate. The ratio CE of alendronate is 297.879 pesetas/success (patient without fracture and without SAR) and 23.301 pesetas/success for placebo. For the hypothesis of a 100% alendronate efficacy, the ratio CE is 287.217 pesetas/success and without SAR is 297.830 pesetas/success. A cost of 210 pesetas/alendronate box will determine that this alternative is as cost-effective as placebo. CONCLUSIONS: The administration of alendronate to prevent HF on postmenopausal female with established osteoporosis is not the option to take into account. Just a decrease of the cost of alendronate below its crossing value will turn it into a cost-effective alternative.

Aged↗
PubMed2001

Alendronate influences bending force of femoral diaphysis after orchidectomy in rats.

BACKGROUND AND AIMS: We examined the effect of alendronate on bone following orchidectomy-induced osteoporosis. MATERIAL AND METHODS: Eighty male rats were used. Group I (C) served as the untreated control. In group II (ALN), alendronate was administered subcutaneously (18 microg/kg). In group III (ORC), rats were castrated only. In group IV (ORC+ALN), administration of alendronate (18 microg/kg) was started immediately after castration, and in group V (ORC + ALN-21) medication was started 21 days after castration. Alendronate was given twice a week for eight weeks in the treatment groups. Bone mineral density (BMD) of the proximal femur, ultimate bending forces of femoral diaphyses, ash weights of femurs (AWcc) and the calcium content (Ca) of femoral ash were determined. Histomorphometric analysis was performed on trabecular bone of proximal tibiae. RESULTS: BMD of the proximal femur was significantly decreased by orchidectomy compared with C and ALN. However, no statistical difference was observed between alendronate-treated groups (ORC + ALN and ORC + ALN-21) and the ORC group. Histologically, alendronate reduced the trabecular bone turnover. Ultimate bending force increased significantly in the ORC+ALN-21 group compared with group C, and had a good correlation with the cortical width of tibia (r = 0.53, p < 0.001). Ash weight per bone volume (AWcc) was lowest in the ORC group, whilst alendronate maintained AWcc after orchidectomy. CONCLUSION: Alendronate increased the ultimate bending force of the femoral diaphysis after orchidectomy. On the other hand, ALN treatment was not able to maintain the BMD of the proximal femur at the pre-orchidectomy level. Our results suggest that the remodelling and modelling of bone may influence the response to ALN treatment.

Alendronate↗
PubMed2002

Effects of alendronate on structural properties of trabecular bone in dogs.

OBJECTIVE: To evaluate the effects of alendronate on the structural properties of trabecular bone. METHODS: Alendronate was administered at a daily p.o. dose of 0.5 mg/kg over a 12-week period in hound dogs (n = 8 for both the control and treated group), and the structural indices of the lumbar vertebral (L1 and L2) trabecular bone were assessed directly from 3-D images. RESULTS: Treatment with alendronate increased bone volume fraction by 9.5% and 7.7% in L1 and L2 respectively. Trabecular thickness significantly increased after alendronate treatment, whereas trabecular separation remained constant. The degree of anisotropy for the alendronate-treated group was decreased compared with that of the control group. Bone surface to volume ratio declined significantly in the alendronate-treated group, whereas alendronate induced a higher bone surface density. CONCLUSION: Alendronate increased the structural properties of canine trabecular bone after short-term treatment at a dose of 0.5 mg x k(-1) x day(-1).

Alendronate↗
PubMed2005

Alendronate inhibits intraperitoneal dissemination in in vivo ovarian cancer model.

Ovarian cancer is characterized by diffuse peritoneal carcinomatosis and often by large volumes of ascites. We previously reported that alendronate, a nitrogen-containing bisphosphonate, inhibited ovarian cancer cell migration by attenuating the activation of Rho through inhibiting the mevalonate pathway. However, questions remain about the ability of alendronate to inhibit the invasiveness of cancer cells to the adherent tissues and the growth of disseminated ovarian cancer in vivo. We established an in vivo ovarian cancer model with i.p. carcinomatosis in athymic immunodeficient mice. In the prevention model, in which alendronate administration started from the day after tumor inoculation, alendronate prevented the stromal invasion, reduced the tumor burden, and inhibited ascites accumulation. Histologic observation revealed that alendronate treatment decreased the stromal invasion of the i.p. tumor while inhibiting the metalloproteinase-2 activity in ascites. This antitumor effect might result from the inhibition of cancer cell migration and proteolytic activity. In the treatment model, in which alendronate was given from 10 days after tumor inoculation when macroscopic tumors are already implanted in the peritoneum, the antitumor effect was weaker but still significant. Furthermore, alendronate administration decreased the serum CA-125 levels of mice bearing disseminated ovarian cancer compared with those of nontreated mice. The potent effects of alendronate in reducing stromal invasion, tumor burden, and ascites suggest that it will be of value in regimens for treatment of women with ovarian cancer.

Alendronate↗
PubMed1998

Alendronate for osteoporosis. Safe and efficacious nonhormonal therapy.

OBJECTIVE: To review the evidence concerning alendronate (Fosamax) therapy for postmenopausal osteoporosis. QUALITY OF EVIDENCE: The efficacy of alendronate for postmenopausal women with osteoporosis was primarily demonstrated by two primary phase III clinical trials, three other 2-year trials, and one 3-year trial. All six trials were randomized double-blind placebo-controlled trials; 3854 postmenopausal women were studied. The Fracture Intervention Trial consisted of 2027 women with postmenopausal osteoporosis and provides the most evidence that 3 years of treatment with alendronate reduces all clinically relevant fractures, including hip fractures. MAIN FINDINGS: In postmenopausal women, alendronate has been shown to increase bone mineral density significantly at the lumbar spine, femoral neck, and trochanter and in the total body, regardless of baseline bone mineral density, age, bone turnover, or the presence of previous fractures. In addition, alendronate has been shown to reduce risk of new vertebral and hip fractures by about 50% and of all clinical fractures by about 30%. Continuous daily dosing with alendronate (10 mg) was found to be well tolerated. In addition, alendronate was shown to have no adverse effects on bone mineralization or microstructure. CONCLUSION: This evidence shows alendronate to be safe and effective; it should be considered the nonhormonal therapy of choice for treating osteoporosis in postmenopausal women at risk for hip and vertebral fractures.

Adult↗
PubMedDate not supplied

Treatment with alendronate prevents fractures in women at highest risk: results from the Fracture Intervention Trial.

BACKGROUND: The efficacy of antiresorptive therapy in preventing fractures in women at highest fracture risk, such as very elderly women or those with severe osteoporosis, is uncertain. PARTICIPANTS AND METHODS: Using data from a double-blind, randomized, placebo-controlled clinical trial that enrolled 2027 postmenopausal women aged 55 to 81 years with low femoral neck bone mineral density (BMD) and existing vertebral fractures, we examined the consistency of the effect of treatment with alendronate sodium in preventing fractures within a priori-specified risk subgroups defined at baseline by age, bone density, number of preexisting vertebral fractures, and history of postmenopausal fracture. The women were randomized to oral administration of alendronate or placebo and followed up for an average of 2.9 years. The initial dose of alendronate sodium was 5 mg/d; the dosage was increased from 5 to 10 mg/d at 24 months. New vertebral fractures, the primary end point of this arm of the trial, were defined by morphometry as a decrease of 20% and at least 4 mm in any vertebral height between baseline and a follow-up radiograph at 36 months. Incident clinical fractures, the secondary end point, included nonspine and clinical (symptomatic) vertebral fractures. All clinical fractures were confirmed with x-ray film reports or, in the case of clinical vertebral fractures, x-ray films. RESULTS: Overall, there was a 47% significant reduction in risk of new vertebral fractures in the alendronate group compared with the placebo group. The reduction in risk of new vertebral fracture was consistent across fracture risk categories including age (relative risk [RR], 0.49 in women < 75 years compared with 0.62 in those > or = 75 years), BMD (RR, 0.54 in women with a femoral neck BMD < 0.59 g/cm2 [median] compared with 0.53 in those with a BMD > or = 0.59 g/cm2), and number of preexisting vertebral fractures (RR, 0.58 in women with 1 vertebral fracture compared with 0.52 in those with > or = 2). The overall significant 28% reduction in risk of incident clinical fractures in the alendronate group compared with the placebo group was also observed within these subgroups. Compared with the number of lower-risk women, a similar or smaller number of high-risk women needed to be treated to prevent 1 fracture. For example, 8 women aged 75 years or older compared with 9 women younger than 75 years, or 4 women with 2 or more existing vertebral fractures compared with 16 women with 1 existing vertebral fracture, needed to be treated with alendronate for 5 years to prevent 1 new vertebral fracture. CONCLUSIONS: Alendronate effectively reduces fracture risk in postmenopausal women with vertebral fractures and low BMD, including those women at highest risk because of advanced age or severe osteoporosis. Since the risk reductions observed with alendronate treatment were consistent within fracture risk categories, more fractures were prevented by treating women at highest risk.

Administration, Oral↗
PubMed2003

Combination therapy with hormone replacement and alendronate for prevention of bone loss in elderly women: a randomized controlled trial.

CONTEXT: Therapy with individual antiresorptive agents has been shown to be effective for prevention and treatment of postmenopausal osteoporosis, but whether combination antiresorptive therapy with hormones and bisphosphonates is safe or efficacious or how these agents compare in elderly women is unknown. OBJECTIVE: To determine whether hormone replacement and the bisphosphonate alendronate sodium in combination are efficacious and safe, and how they compare with monotherapy in community-dwelling elderly women. DESIGN: Randomized, double-blind, placebo-controlled, clinical trial. SETTING AND PARTICIPANTS: Five hundred seventy-three community-dwelling women age 65 years or older were screened: 485 completed screening and 373 (aged 65 to 90 years) were randomized following a 3-month, open-label, run-in phase with hormone replacement and alendronate placebo. The trial was conducted at a single academic US medical center from January 1996 to May 2001. INTERVENTIONS: Participants were randomly assigned in a 2 x 2 factorial design to receive hormone replacement (conjugated equine estrogen, 0.625 mg/d, with or without medroxyprogesterone, 2.5 mg/d) and alendronate, 10 mg daily, both agents, or neither. All participants received calcium and vitamin D supplements. MAIN OUTCOME MEASURES: Annualized change in bone mineral density of the hip and spine and occurrence of adverse events. RESULTS: Bone mineral density at 3 years was significantly greater at all femoral and vertebral sites in women treated with combination therapy than with monotherapy, with mean (SD) increases of 5.9% (3.8) at the total hip, 10.4% (5.4) at the posteroanterior lumbar spine, and 11.8% (6.8) at the lateral lumbar spine. Mean (SD) increases in bone mass at the hip in women treated with alendronate alone were significantly greater than in those treated with hormone replacement therapy alone (4.2% [3.8] vs 3.0% [4.9]; P<.05, respectively), and alendronate resulted in more responders to therapy. All therapies were well tolerated and participant retention was 90% at 3 years. CONCLUSIONS: Combination therapy with hormone replacement and alendronate was efficacious and well tolerated in this cohort. Alendronate was superior to hormone replacement, and combination therapy was superior to either therapy alone. Combination therapy may represent an option for women with more severe disease or for those who have failed to achieve an adequate response to monotherapy.

Aged↗
PubMed2004

Role of alendronate in therapy for posttraumatic complex regional pain syndrome type I of the lower extremity.

OBJECTIVE: To evaluate the effects of the antiresorptive agent alendronate at a daily oral dose of 40 mg in patients with posttraumatic complex regional pain syndrome type I (CRPS I) of the lower extremity. METHODS: Forty patients were enrolled in this 8-week randomized, double-blind, placebo-controlled study of alendronate therapy for CRPS I, a condition associated with regional osteoclastic overactivity. An optional 8-week open extension of alendronate therapy (weeks 12-20) was available after a 4-week period without therapy. Clinical assessments included joint mobility, edema of the lower extremity, tolerance to pressure in the lower extremity, and levels of spontaneous pain. Urinary levels of type I collagen N-telopeptide (NTX) were assessed by enzyme-linked immunosorbent assay. Patients were examined at weeks 4, 8, 12, 16, 20, and 24. Statistical analysis included two-way factorial analysis of variance. RESULTS: In contrast to placebo-treated patients (n = 20), all of the alendronate-treated patients (n = 19) exhibited a marked and sustained improvement in levels of spontaneous pain, pressure tolerance, and joint mobility, as well as a significant reduction in urinary levels of NTX at weeks 4 and 8. The improvement was maintained at week 12. Twelve patients from each treatment group volunteered for the 8-week open trial, and all of them had a positive response to alendronate. CONCLUSION: Our findings support the use of oral alendronate in posttraumatic CRPS I. By reducing local acceleration of bone remodeling, alendronate might relieve pain by effects on nociceptive primary afferents in bone, pain-associated changes in the spinal cord, and possibly also through a central mechanism.

Administration, Oral↗
PubMed2005

Alendronate improves bone mineral density in primary biliary cirrhosis: a randomized placebo-controlled trial.

Bone loss is a well-recognized complication of primary biliary cirrhosis (PBC). Although it has been suggested that alendronate might improve bone mineral density (BMD) in PBC, no randomized placebo-controlled trial has been conducted. The primary aim of this study was to compare the effects of alendronate versus placebo on BMD and biochemical measurements of bone turnover in patients with PBC-associated bone loss. We conducted a double-blinded, randomized, placebo-controlled trial. Patients with a PBC and BMD t score of less than -1.5 were randomized to receive 70 mg per week of alendronate or placebo over 1 year. BMD of the lumbar spine and proximal femur were measured at entry and at 1 year. Changes from baseline in BMD and biochemical measurements of bone turnover were assessed. Thirty-four patients were enrolled. Seventeen patients were randomized to each arm. After 1 year, a significantly larger improvement (P = .005) in spine BMD was observed in the alendronate group (0.09 +/- 0.03 g/cm2 SD from baseline) compared with the placebo group (-0.003 +/- 0.02 g/cm2 SD from baseline). A larger improvement (P = .046) was also observed in the femoral BMD of alendronate patients versus placebo. BMD changes were independent of concomitant estrogen therapy. The rate of adverse effects was similar in both groups. In conclusion, in patients with PBC-related bone loss, alendronate significantly improves BMD compared with placebo. Although in this study oral alendronate appears to be well tolerated in patients with PBC, larger studies are needed to formally evaluate safety.

Aged↗
PubMed1995

Inhibition of antigen-presenting cell function by alendronate in vitro.

Bisphosphonates are potent inhibitors of bone resorption in vivo and are emerging as important and widely used drugs for the treatment of a variety of abnormal bone resorptive processes. In the current study we investigated the in vitro effects of 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (alendronate), a recently developed, extremely potent bisphosphonate, on the immune functions of human peripheral blood mononuclear cells (PBMCs). PBMC proliferation induced by lectins, alloantigens, and a nominal antigen (tetanus toxoid) was inhibited in a dose-dependent manner by alendronate. Pretreatment of monocytes, but not T cells, with the compound at concentrations ranging from 10(-4) to 10(-8) M was inhibitory, indicating that alendronate acts selectively on antigen-presenting cells (APCs). Alendronate did not affect the viability of monocytes or T cells or the expression of cell surface molecules known to play critical roles in antigen presentation. Alendronate exhibited dose-dependent inhibition of the production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) by activated monocytes. The inhibitory effect of 10(-6) M alendronate on PBMC proliferation was reversed by 10 U/ml recombinant rIL-1 beta, whereas other cytokines such as IL-6, TNF-alpha, and granulocyte-macrophage colony-stimulating factor (GM-CSF) had no effect. Thus, alendronate acts on monocytes to inhibit their antigen-presenting/accessory cell functions through a mechanism that can be overcome by exogenous IL-1. The inhibitory effect of this agent on cytokine production may contribute to its inhibitory effect on bone resorption.

Alendronate↗
PubMed2004

Alendronate regulates cell invasion and MMP-2 secretion in human osteosarcoma cell lines.

BACKGROUND: Osteosarcoma is the most common malignant bone tumor of childhood. Significant proportions of these patients eventually develop pulmonary metastases and succumb to their disease even after conventional multi-agent chemotherapy and surgical excision. Matrix metalloproteinase (MMP)-2 induced degradation of blood vessel basement membranes is an important pre-requisite for tumor invasion and metastasis. Bisphosphonates (BPs) have been known to inhibit tumor growth and metastasis in some tumors such as breast cancer, renal cell carcinoma, and prostate cancer, and may do so through inhibition of MMP secretion. We, therefore, tested the effect of BPs on tumor cell invasion, MMP-2 secretion, and apoptosis of osteosarcoma cell lines. PROCEDURE: Two osteosarcoma cell lines (SaOS-2, U(2)OS) were treated with alendronate (50, 100, and 150 microM) for 24 and 48 hr. Matrigel invasion assay was used to investigate the invasive potential of osteosarcoma cell lines before and after alendronate treatment. Real-time quantitative RT-PCR was used to determine the mRNA level of MMP-2 with and without alendronate treatment. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the cytokine level of MMP-2 secreted in the condition medium. BP-induced cell apoptosis was evaluated by fluorescent flow cytometric analysis. RESULTS AND CONCLUSIONS: The results showed that alendronate inhibited cell invasion of both osteosarcoma cell lines in a dose-dependent manner. Alendronate reduced the mRNA level and cellular level of MMP-2 in both cell lines in a time and dose-dependent manner. Alendronate also induced significant apoptosis in both cell lines. Our finding suggests that alendronate downregulates MMP-2 secretion and induces apoptosis in osteosarcoma cells, which may both contribute to the reduction of invasive potential of the tumor cells.

Alendronate↗
PubMed2004

The effect of alendronate on resorption of the alveolar bone following tooth extraction.

Maintenance of alveolar bone width and height following tooth loss is essential with regard to the restoration of missing teeth with endosseous dental implants or prosthodontics approaches. A various amount of alveolar ridge resorption is likely to occur after tooth extraction at the buccal and lingual alveolar bone plates. Bisphosphonates, alendronate, is well known for its potent inhibition of osteoclast-mediated bone resorption. The objective of this study was to examine the inhibitory effect of alendronate on alveolar bone resorption following tooth extraction in rats. Male Wistar Albino rats were divided into three groups: baseline group, saline-treated group and alendronate-treated group. The saline-treated group was administered with daily saline solution for 2 and 4 weeks respectively while the alendronate-treated group was given a daily amount of 0.25 mg/kg alendronate subcutaneously for the same periods. The level of urinary calcium, creatinine, and serum calcium, alkaline phosphatase and phosphate were measured. Serum alkaline phosphatase level was measured as a marker of osteoblastic activity. Histopathological sections of 4 microm thickness were obtained from the right first mandibular molar region in a bucco-lingual direction. The number of osteoclasts, osteoblasts, and haversian canals, the number and size of resorptive lacunae, and osteoid formation were evaluated histopathologically. The mean thickness of buccal and lingual alveolar bone was measured. In the alendronate-treated group, both buccal and lingual alveolar bone volume reduction was significantly less than the saline treated group. Significant reduction in serum and urinary calcium levels and the number of osteoclasts revealed the pronounced suppression of bone resorption in the alendronate-treated group.

Alendronate↗
PubMed1993

Short-term effect of alendronate on bone mass and bone remodeling in postmenopausal women.

The short-term dose-response relationship between treatment with the bisphosphonate alendronate, biochemical markers of bone turnover, and changes in lumbar spine bone mineral density (BMD) over 9 months was assessed using a double-masked controlled study design in 65 postmenopausal women (mean age 51.6 years, mean 1.5 years since last menses) receiving 5, 20, 40 mg of alendronate or placebo for 6 weeks. After 6 weeks of alendronate, serum calcium phosphate and osteocalcin decreased, and intact parathyroid hormone increased significantly in dose-dependent fashions in the alendronate-treated groups (T) compared with placebo (P). Generally similar changes (decreases) were noted in 24-h urinary calcium and pyridinoline (deoxy- and hydroxylysl pyridoline); by 30 weeks post-treatment no significant changes from baseline or between T and P were noted. Lumbar BMD by dual-energy X-ray absorptiometry demonstrated a dose-dependent response over 9 months (median % change +/- SD: -1.2 +/- 0.9 for 5 mg T, +0.7 +/- 0.8 for 20 mg T*, +1.2 +/- 1.1 for 40 mg T*;*p < 0.01 vs P). Alendronate was generally well tolerated over all dosages. These data demonstrate that short-term (6 weeks) oral alendronate treatment (5-40 mg daily) is well tolerated and effective in (reversibly) decreasing biochemical markers of bone turnover in early postmenopausal women, and in stabilizing spinal BMD over 9 months. Longer-term treatment with larger clinical populations is indicated to define more fully the potential efficacy and safety of chronic alendronate therapy.

Alendronate↗
PubMed2004

Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial.

It is commonly believed that the response to treatment in patients on alendronate is proportional to the increase in bone mineral density (BMD), and that those who lose BMD during treatment might not respond to treatment. In the Fracture Intervention Trial 6,459 women were randomly assigned to treatment with alendronate or placebo; BMD was measured annually, and new spine fractures were assessed by lateral spine films, taken at baseline and end of follow-up. Among subjects who took at least 70% of the study drug (5,220 women), we compared reductions in risk of spine fractures at end of follow-up (3 or 4 years) within various levels of change in total hip and spine BMD after 1 and 2 years of treatment, after adjustment for differences in characteristics between the treatment and control groups. Women "losing" BMD at the lumbar spine (0% to 4%) while on alendronate had a reduction of 60% in vertebral fracture risk [OR = 0.40 (0.16, 0.99)] compared to their counterparts in the placebo group. The few women that lost more than 4% did not have a significant benefit [OR = 0.15 (0.02, 1.29)]. Those who "gained" BMD (0% to 4%) during treatment had a reduction in risk of 51% [OR = 0.49 (0.30, 0.78)]. Similarly, women who "lost" total hip BMD (0% to 4%) during the first year on alendronate had a 53% decreased risk of vertebral fracture compared to their controls taking placebo [OR = 0.47 (0.27, 0.81)], whereas those "gaining" BMD (0% to 4%) had a comparable risk reduction [OR = 0.49 (0.34, 0.71)]. This was not observed for the few women who lost more than 4% [OR = 0.61 (0.11, 3.45)]. Patients who lost BMD at both the hip and spine were not protected by alendronate. Among patients who adhere to treatment with alendronate, even those who lose BMD benefit from a substantial reduction in risk of vertebral fracture. So, the reduction in bone turnover induced by alendronate might be more important than BMD changes. The few women who lose the most BMD (more than 4% per year) might not benefit from the treatment.

Absorptiometry, Photon↗