Alendronate gastric ulcers. (1/413)

BACKGROUND: It appears likely that drugs other than NSAIDs may cause ulcers and ulcer complications (e.g. potassium chloride). Alendronate (Fosamax) is used in the treatment and prevention of metabolic bone disease and has also been associated with severe oesophageal damage and stricture. We have previously shown that the dose of alendronate used for Paget's disease (40 mg) causes gastric damage similar to NSAIDs. The usual dose for the treatment of postmenopausal osteoporosis is 10 mg per day. AIM: To investigate whether the 10 mg dose of alendronate causes gastric ulcers. METHODS: We performed an endoscopist-blind, crossover, randomized, single-centre comparison of 10 mg of alendronate/day and placebo in volunteers aged 40 years or more. Video-endoscopy was used to evaluate the presence and degree of mucosal damage to the oesophagus, stomach, or duodenal bulb after 7 and 14 days of treatment. RESULTS: Twenty-four healthy volunteers participated, including 15 women and nine men, ranging in age from 41 to 52 years. Visible gastric mucosal damage was present in nine (38%) who received alendronate compared to three (13%) in the placebo group. There was a marked difference in the severity of mucosal damage; there were no ulcers or large erosions in those receiving placebo. In contrast, potentially clinically significant gastric mucosal injury was seen in six subjects receiving alendronate (two developed antral ulcers and four had large (4-8 mm) superficial antral erosions) compared to none in the placebo group (P = 0.0219). One subject developed oesophageal damage in the form of multiple linear superficial erosions in the mid and distal oesophagus. Duodenal injury was not seen. CONCLUSION: Alendronate causes gastric ulceration, suggesting that alendronate use may be associated with ulcer complications such as acute upper gastrointestinal bleeding. The results of this study suggest the need for post-marketing surveillance to clarify the nature, frequency and magnitude of any potential gastrointestinal side-effects associated with the use of this drug.  (+info)

Clinic visits and hospital admissions for care of acid-related upper gastrointestinal disorders in women using alendronate for osteoporosis. (2/413)

CONTEXT: About 1 in 3 women taking alendronate for osteoporosis report gastrointestinal symptoms, a rate much higher than that found during clinical trials. OBJECTIVE: To establish the frequency of outpatient visits and hospital admissions for acid-related upper gastrointestinal disorder (ARD) among women taking alendronate and to identify potential risk factors. METHODS: A retrospective database analysis identified 812 women with osteoporosis who had filled one or more 10-mg alendronate prescriptions from October 1995 through October 1996. RESULTS: One hundred (12.3%) of the 812 women received healthcare for ARD, a clinical encounter rate of 28.5 per 100 person-years. A reference group of 362,109 women from the same health plan had 17.6 ARD encounters per 100 person-years. Excluding women who had ARDs before receiving alendronate, alendronate users were 1.6 (95% CI = 1.2, 2.7) times more likely to have an ARD encounter than nonusers. Risk of having ARD increased with age [users aged 70 years and older had a relative risk of 1.5 (95% confidence interval (CI) 1.0-2.30) compared with younger women] and with concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDS) (relative risk 1.7, 95% CI 1.1-2.6). CONCLUSIONS: Elderly alendronate users or those concurrently taking NSAIDS should be carefully monitored because of their high risk of having ARD. Cost/benefit analyses of alendronate treatment for osteoporosis should include costs of treating ARD.  (+info)

Alendronate induces antinociception in mice, not related with its effects in bone. (3/413)

The antinociceptive effect of alendronate was studied. The bisphosphonate was i.p. administered and two tests were carried out: acetic acid in mice and formalin test in rats. In the acetic acid test, alendronate induced a dose-dependent antinociceptive effect that was statistically significant for the doses of 10, 20 and 40 mg/kg, and could be detected 48 hr after its administration. In the formalin test, however, alendronate, at the doses of 10 and 20 mg/kg, did not modify the pain score nor the number of flinches, when it was administered either 30 or 60 min before the test. However it must be noted that doses inducing analgesic effect are close to those inducing toxicity.  (+info)

Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Fracture Intervention Trial Research Group. (4/413)

OBJECTIVE: To investigate whether the incidence of vertebral fractures is related to the magnitude of change in bone mineral density (BMD) during alendronate treatment. METHODS: Women in this study were age 55-81 years (n = 2,984). While participating in the Fracture Intervention Trial, they received 5 mg/day of alendronate for 2 years followed by 10 mg/day for the remaining 12-30 months of the study. Their BMD was measured at baseline and at 12 and 24 months, and spine radiographs were obtained at baseline and again at 36 or 48 months to identify new vertebral fractures. RESULTS: After 12 months of alendronate treatment, 35% of participants had increases of > or =3% in total hip BMD, and 21% had either decreased total hip BMD or no change. Women who had larger increases in total hip BMD during the first 12 months had a lower incidence of new vertebral fractures during the entire followup period. Only 3.2% of women with increases of > or =3% in total hip BMD experienced new vertebral fractures, whereas twice as many women (6.3%) whose BMD declined or stayed the same experienced new fractures (adjusted odds ratio 0.45, 95% confidence interval 0.27-0.72). Similar patterns were observed for spine BMD at 12 months, and for both sites using change in BMD at 24 months. CONCLUSION: Women with increases of > or =3% in BMD during the first 1 or 2 years of alendronate treatment had the lowest incidence of new vertebral fractures. These findings suggest that, among women taking antiresorptive agents, greater increases in BMD are associated with lower risk of new vertebral fractures.  (+info)

Farnesol and geranylgeraniol prevent activation of caspases by aminobisphosphonates: biochemical evidence for two distinct pharmacological classes of bisphosphonate drugs. (5/413)

Recently, advances have been made in understanding the molecular mechanisms by which bisphosphonate drugs inhibit bone resorption. Studies with the macrophage-like cell line J774 have suggested that alendronate, an amino-containing bisphosphonate, causes apoptosis by preventing post-translational modification of GTP-binding proteins with isoprenoid lipids. However, clodronate, a nonaminobisphosphonate, does not inhibit protein isoprenylation but can be metabolized intracellularly to a cytotoxic, beta-gamma-methylene (AppCp-type) analog of ATP. These observations raise the possibility that bisphosphonates can be divided into two groups with distinct molecular mechanisms of action depending on the nature of the R2 side chain. We addressed this question by directly comparing the ability of three aminobisphosphonates (alendronate, ibandronate, and pamidronate) and three nonaminobisphosphonates (clodronate, etidronate, and tiludronate) to inhibit protein isoprenylation and activate caspase-3-like proteases or to be metabolized to AppCp-type nucleotides by J774 cells. All three aminobisphosphonates inhibited protein isoprenylation and activated caspase-3-like proteases. Apoptosis and caspase activation after 24-h treatment with the aminobisphosphonates could be prevented by addition of farnesol or geranylgeraniol, confirming that these bisphosphonates inhibit the metabolic mevalonate pathway. No AppCp-type metabolites of the aminobisphosphonates could be detected by mass spectrometry. The three nonaminobisphosphonates did not inhibit protein isoprenylation or cause activation of caspase-3-like proteases, but were incorporated into AppCp-type nucleotides. Taken together, these observations clearly demonstrate that bisphosphonate drugs can be divided into two pharmacological classes: the aminobisphosphonates, which act by inhibiting protein isoprenylation, and the less potent nonaminobisphosphonates, which act through the intracellular accumulation of AppCp-type metabolites.  (+info)

Use of bone alkaline phosphatase to monitor alendronate therapy in individual postmenopausal osteoporotic women. (6/413)

BACKGROUND: Biochemical bone markers are sensitive to the changes in bone turnover that result from treatment of postmenopausal osteoporotic women with antiresorptive therapies. Although information is available on the use of bone markers in monitoring therapy in groups of subjects, less is known regarding how these markers perform in individual patients. METHODS: Serum bone alkaline phosphatase (bone ALP) concentrations, measured with the Tandem(R) Ostase(R) assay, were used to monitor the biochemical response of bone in postmenopausal women with osteoporosis receiving either 10 mg/day alendronate therapy (n = 74) or calcium supplementation (n = 148) for 24 months. RESULTS: Bone ALP decreased significantly from baseline at 3 months (P +info)

Prevention of osteoporosis and fractures. (7/413)

Osteoporosis and low bone density are associated with a risk of fracture as a result of even minimally traumatic events. The estimated lifetime risk of osteoporotic fracture is as high as 50 percent, especially in white and Asian women. The use of caffeine, tobacco and steroids is associated with a decrease in bone density. Cognitive impairment, vision problems and postural instability increase the risk of falling and sustaining a fracture. Medications such as long-acting sedative hypnotics, anticonvulsants and tricyclic antidepressants also increase this risk. Combinations of clinical and radiographic findings can predict fracture risk more effectively than bone densitometry, but often only after the first fracture has occurred. The addition of dietary calcium and/or vitamin D is clearly both cost-effective and significant in reducing the likelihood of fractures. Bisphosphonates reduce fracture risk but at a cost that may be prohibitive for some patients. Estrogen and estrogen-receptor modulators have not been well studied in randomized trials evaluating the reduction of fractures, but they are known to increase bone density. Pharmacologic therapy and the reduction of sensory and environmental hazards can prevent osteoporotic fractures in some patients.  (+info)

Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. (8/413)

Glucocorticoid-induced osteoporosis may be due, in part, to increased apoptosis of osteocytes and osteoblasts, and bisphosphonates (BPs) are effective in the management of this condition. We have tested the hypothesis that BPs suppress apoptosis in these cell types. Etidronate, alendronate, pamidronate, olpadronate, or amino-olpadronate (IG9402, a bisphosphonate that lacks antiresorptive activity) at 10(-9) to 10(-6) M prevented apoptosis of murine osteocytic MLO-Y4 cells, whether it was induced by etoposide, TNF-alpha, or the synthetic glucocorticoid dexamethasone. BPs also inhibited apoptosis of primary murine osteoblastic cells isolated from calvaria. Similar antiapoptotic effects on MLO-Y4 and osteoblastic cells were seen with nanomolar concentrations of the peptide hormone calcitonin. The antiapoptotic effect of BPs and calcitonin was associated with a rapid increase in the phosphorylated fraction of extracellular signal regulated kinases (ERKs) and was blocked by specific inhibitors of ERK activation. Consistent with these in vitro results, alendronate abolished the increased prevalence of apoptosis in vertebral cancellous bone osteocytes and osteoblasts that follows prednisolone administration to mice. These results suggest that the therapeutic efficacy of BPs or calcitonin in diseases such as glucocorticoid-induced osteoporosis may be due, in part, to their ability to prevent osteocyte and osteoblast apoptosis.  (+info)

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