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PubMed2005

The use of alendronate to prevent early collapse of the femoral head in patients with nontraumatic osteonecrosis. A randomized clinical study.

BACKGROUND: Osteonecrosis of the femoral head is the most common diagnosis leading to total hip arthroplasty in young adults. Joint-preserving treatment options have been mainly surgical, with inconsistent results. Alendronate (a bisphosphonate agent) has been shown to lower the prevalence of vertebral compression fractures and could potentially retard the collapse of an osteonecrotic femoral head. The purpose of this study was to test the effect of alendronate in preventing early collapse of the femoral head in patients with nontraumatic osteonecrosis. METHODS: Forty patients with Steinberg stage-II or III nontraumatic osteonecrosis of the femoral head and a necrotic area of >30% (class C) were randomly divided into alendronate and control groups of twenty patients each. Patients in the alendronate group took 70 mg of alendronate orally per week for twenty-five weeks, while the patients in the control group did not receive this medication or a placebo. The patients were observed for a minimum of twenty-four months. Harris hip scores, plain radiographs, and magnetic resonance imaging scans were obtained. RESULTS: During the study period, only two of twenty-nine femoral heads in the alendronate group collapsed, whereas nineteen of twenty-five femoral heads in the control group collapsed (p < 0.001). One hip in the alendronate group underwent total hip arthroplasty, whereas sixteen hips in the control group underwent total hip arthroplasty (p < 0.001). CONCLUSIONS: Alendronate appeared to prevent early collapse of the femoral head in the hips with Steinberg stage-II or IIIC nontraumatic osteonecrosis. A longer duration of follow-up is needed to confirm whether alendronate prevents or only retards collapse. LEVEL OF EVIDENCE: Therapeutic Level I.

Adult↗
PubMed1997

Alendronate. A review of its pharmacological properties and therapeutic efficacy in postmenopausal osteoporosis.

Alendronate is an aminobisphosphonate which appears to attenuate, rather than completely inhibiting bone turnover, by suppressing the activity of osteoclasts. Clinical trials have established that 10 mg/day orally administered alendronate is the optimum dosage. Despite its poor bioavailability after oral administration, alendronate is highly effective at preventing bone loss associated with the absence of endogenous estrogen. A sustained increase in bone mass was observed during alendronate therapy without accelerated loss after withdrawal of the drug. Increased bone mass was associated with a reduction in the risk and rate of occurrence of vertebral fractures. A recent study demonstrated a 47% reduction in the risk of developing new radiographic vertebral fractures over 3 years in women with low bone mass and pre-existing vertebral fractures. There have been few direct comparisons in clinical trials. However, when compared with calcium or low dosages of salmon calcitonin (salcatonin) therapy in women with postmenopausal osteoporosis, alendronate induced a sustained increase in bone mass during therapy that was not seen with the comparator. In clinical trials alendronate was generally well tolerated when taken as recommended. Adverse events tended to be transient and usually associated with the upper gastrointestinal tract; the most common events included abdominal pain, nausea, dyspepsia, constipation and diarrhoea, which are also common with other bisphosphonates. Of potential concern are the small number of reports of patients developing oesophageal ulceration; however, this adverse event was attributed to noncompliance with the manufacturer's recommendations for administration of the drug. In addition, alendronate has not been associated with osteomalacia. Studies are still required to establish the long term efficacy of alendronate, particularly with regard to other available therapies. Although estrogen replacement therapy is generally considered the treatment of choice for the management of postmenopausal osteoporosis, many women are unable or unwilling to receive estrogens on a long term basis. Thus, alendronate, with its demonstrated beneficial effects and its good tolerability profile (when taken as recommended), is a promising alternative treatment option for the management of postmenopausal osteoporosis.

Alendronate↗
PubMed1999

Alendronate in the treatment of Paget's disease of bone.

This review reports the results of 2 recently completed long-term, randomised, double-blind, multicentre, controlled studies in which men and women with moderate to severe Paget's disease received oral alendronate 40 mg daily for 6 months One study conducted in the United States, compared the effects of alendronate 60 mg/day (n=41) with those of oral etidronate 400 mg/day (n=47); the other, conducted in the United Kingdom, Australia, and New Zealand, compared the effects of alendronate (n=27) with those of placebo (n=28). In both studies alendronate significantly reduced serum concentrations of alkaline phosphatase by more than 70%, which was significant in comparison with baseline (P < 0.001) and the comparator regimens (P < 0.001). Response to treatment (i.e. a > 60% decrease in or normalisation of serum alkaline phosphatase) was seen in more than three-quarters of patients treated with alendronate in both trials, compared with less than one-third of patients treated with etidronate and no patients treated with placebo. Radiologic scores, reflecting the status of osteolytic lesions, improved in a greater proportion of patients receiving alendronate than in those receiving etidronate or placebo. Histomorphometric analysis performed at 6 months showed that bone formed during alendronate treatment was of normal quality, without evidence of impaired mineralisation or other abnormalities. Alendronate was well tolerated, with an adverse event profile comparable with those of etidronate and placebo. These studies therefore showed that 6 months of treatment with oral alendronate suppresses disease activity in patients with Paget's disease of bone, with beneficial effects on biochemical, radiologic, and histomorphometric indices superior to those of etidronate and placebo.

Alendronate↗
PubMedDate not supplied

Effect of administration of alendronate sodium and retinol on the mechanical properties of the femur in ovariectomized rats.

Alendronate sodium, an aminobisphosphonate with potent antiresorptive activity, is used in the treatment of postmenopausal osteoporosis. Retinol, as a component of multivitamin preparations, is frequently used especially by elderly people. There are no reports on the interaction of alendronate sodium and retinol. The aim of the present study was to investigate the effect of administration of alendronate sodium and retinol on mechanical properties of the femoral bone in bilaterally ovariectomized rats. The experiments were carried out on 3-month-old Wistar rats, divided into 7 groups: I - sham-operated control rats, II - ovariectomized control rats, III - ovariectomy + alendronate sodium 3 mg/kg po, IV - ovariectomy + retinol 700 IU/kg po, V - ovariectomy + retinol 3500 IU/kg po, VI - ovariectomy + alendronate sodium 3 mg/kg po + retinol 700 IU/kg po, VII - ovariectomy + alendronate sodium 3 mg/kg po + retinol 3500 IU/kg po. The drugs were administered to the rats daily by oral gavage for 28 days. Body mass gain, bone mass, bone mineral content and calcium content in the femur and L-4 vertebra and mechanical properties of the whole femur (extrinsic stiffness, ultimate load, breaking load, deformation caused by the ultimate load) and the neck of the femur (load at fracture), were examined. Bilateral ovariectomy induced osteopenic changes in the rat skeletal system. Alendronate sodium (3 mg/kg po) counteracted the development of osteopenia induced by ovariectomy. Retinol at both used doses unfavorably affected the examined bone parameters of ovariectomized rats. Retinol administered with alendronate sodium lessened the preventive action of alendronate on the development of osteopenic changes in the skeletal system of ovariectomized rats.

Alendronate↗
PubMed2005

Benefit period using alendronate to increase bone mineral density in women with osteoporosis?

BACKGROUND: Alendronate, a nitrogen-containing bisphosphonate is a specific inhibitor of bone resorption and now in the forefront of treatment of osteoporosis. In this study, we reported a significant increase in bone mineral density (BMD) of the spine and the hip in postmenopausal women taking alendronate at 10 mg/d for 1, 2 and 3 years. METHODS: Participants had received daily, oral, 10 mg dose of alendronate for one to three years and placed into one of three groups according to alendronate treatment duration: 41 women received alendronate for 1 year (group I), 46 received alendronate for 2 years (group II), and 30 received alendronate for 3 years (group III). Measurements of bone density had been made by dual energy X-ray absorbtiometry once each year. RESULTS: The differences in L2-L4, L2, L4, femoral neck and trochanter BMD values before and after treatment for first group were significantly different. In second group, significant differences between initial and after treatment were found at the other sites except at the Ward's triangle. In the third group, only a significant increase in the L2-L4, L2, L3, L4, trochanter BMD values between before treatment and at the end of third year was found. Comparisons between groups were performed with Student's t test. ANOVA was used to test the age, menopause age, menopause duration and initial BMD values between the three groups. Calculated P values of less than 0.05 were considered statistically significant. CONCLUSIONS: Alendronate had increased BMD significantly at the spine and hip in postmenopausal women over three years. Increases of BMD in third group were significant during the first and second years. However, continued therapy with alendronate had been required to maintain the gain in BMD over the third year.

Absorptiometry, Photon↗
PubMed2006

[The effect of alendronate on arterial calcification in rat model].

OBJECTIVE: To study the effect of alendronate on artery calcification in rats. METHODS: (1) 4-week SD male rats were randomly divided into 3 groups: alendronate group (AL, n = 6), calcification group (CA, n = 6) and normal group (N, n = 6). In AL and CA group, artery calcification of rat was established by subcutaneous injection of vitamin D3 (300,000 U x kg(-1) x d(-1) for 3 days) and Warfarin (15 mg x 100 g(-1) x 12 h(-1) for 4 days); In AL group, at 4 days before establishment of artery calcification, alendronate (1 mg x kg(-1) x 24 h(-1)) was administered with subcutaneous injection and continued to be given to the end of the study. Abdominal aortae were collected for paraffin section and stained with von Kossa staining to observe the area of calcification. (2) Rat aortic vascular smooth muscle cells (VSMC) were cultured in vitro with tissue explant. All cells were divided into 5 groups: normal group, calcification group (control group), and alendronate 10(-9), 10(-7) and 10(-5) mol/L group. Before inducing calcification, alendronate 10(-9), 10(-7) and 10(-5) mol/L group were individually pre-treated with final concentrations of 10(-9), 10(-7) and 10(-5) mol/L alendronate for 24 hours. Beta-glycerophosphate were then added in the calcification group and in all the alendronate groups to induce VSMC calcification. All cells were cultured for 14 days. Cell crawling slice was applied to Alizarin red S staining to observe VSMC calcification. Colorimetric method was applied to measure the contents of Ca2+, cell proteins, and ALP activity. The ratio of contents of Ca2+ and cell proteins was cell calcium deposits. Cell proliferation was measured with tetrazolium salt (MTT) method. RESULTS: (1) With von Kossa staining the black deeply stained structure was found to be decreased in AL group. (2) As compared with the control group, in all the alendronate groups, showed that the number of calcium nodules [(6.8 +/- 2.7, 6.2 +/- 4.2, 5.3 +/- 2.4) % vs (7.4 +/- 3.8)%], and cell calcium depositions [(5.2 +/- 1.2, 4.8 +/- 1.7, 3.5 +/- 1.8)% vs (5.6 +/- 1.6)%], cell ALP activity and cell proliferation decreased significantly and dose-dependently. CONCLUSION: Alendronate can inhibit the artery calcification in rats.

Alendronate↗
PubMed1993

Role of calcium in plasma protein binding and renal handling of alendronate in hypo- and hypercalcemic rats.

Alendronate (4-amino-1-hydroxybutylidine-1,1-bisphosphonate), an antiosteolytic agent, is currently under investigation for the treatment of osteoporosis. Earlier studies in animals from this laboratory disclosed that systemically administered alendronate is rapidly taken up by bone tissues to the extent of 60% to 70% of the dose and excreted by the kidney, 30% to 40% in 24 hr, and that renal excretion is the only route of elimination. This study was designed to explore the effect of calcium on plasma protein binding and the renal handling of alendronate. The binding of alendronate to rat plasma was concentration, pH and calcium dependent. The fraction of unbound drug in rat plasma increased from about 3% to 9% over a drug concentration range of 0.2 to 10 micrograms/ml. Supplementation of calcium strongly augmented the binding to serum albumin. The binding of alendronate in plasma increased with increasing pH from about 50% at pH 6.6 to 98% at pH 8.6. The effects of pH on the binding of calcium and of alendronate to serum albumin were qualitatively similar. Under steady-state conditions, the binding of alendronate was substantially lower in hypocalcemic rats but unchanged in hypercalcemic rats. Although hypocalcemia caused a significant decrease in the renal secretion of alendronate, there was no effect on the renal secretion of tetraethylammonium bromide and p-aminohippuric acid. The differential effect of hypocalcemia suggests that calcium may play an important role in the renal handling of alendronate. However, hypercalcemia resulted in a substantial decrease of renal secretion of all three compounds and the decreased renal secretion was associated with a marked decrease in the glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Alendronate↗
PubMed1997

Primary amino-bisphosphonates: a new class of gastrotoxic drugs--comparison of alendronate and aspirin.

BACKGROUND: Alendronate and pamidronate are primary amino-bisphosphonates used in the treatment of metabolic bone disease. Both drugs have been associated with reversible erosive esophagitis and as a result pamidronate is approved in the United States only for parenteral use. In rats, alendronate causes acute gastric mucosal damage similar to that seen with aspirin or nonsteroidal anti-inflammatory drugs. METHODS: We performed a blinded, crossover, randomized, single-center, placebo-controlled, endoscopic comparison of alendronate (40 mg/day), aspirin (1, 300 mg/day), and placebo to evaluate the presence and degree of mucosal damage to the esophagus, stomach, and duodenal bulb. RESULTS: Twelve normal healthy volunteers were studied both before and after 4 days of drug therapy. Placebo caused no visible endoscopic damage. In contrast, both aspirin and alendronate were associated with visible gastric mucosal injury in the majority of those studied (75 and 58%, respectively) and both were significantly greater than placebo (p < 0.001). The gastric mucosal injury was deemed severe in 50% of those receiving alendronate or aspirin; one alendronate-associated gastric ulcer was seen. Esophageal and duodenal bulb injury was seen once each, and both were associated with alendronate. CONCLUSIONS: The primary amino-bisphosphonate alendronate causes mucosal injury to the upper gastrointestinal tract similar to aspirin. Even when used according to manufacturer's dosing instructions alendronate should probably be used with caution.

Adult↗
PubMedDate not supplied

Effect of alendronate treatment on bone mineral density in male patients with osteoporosis.

OBJECTIVE: To assess the efficacy of alendronate therapy on bone mineral density (BMD) at the lumbar spine and hip in men with osteoporosis. METHODS: Medical records of male patients with osteoporosis, who had undergone follow-up in the Endocrinology Clinic at the National Naval Medical Center, were reviewed, and nine patients treated with alendronate for at least 1 year were identified. Patients were excluded from analysis if they had evidence of osteomalacia or if baseline and follow-up BMD results on the same dual-energy x-ray absorptiometry (DEXA) densitometer, at least 10 months apart, were not available. DEXA BMD results at the lumbar spine and hip, before and after at least 10 months of alendronate treatment, were analyzed for significant differences. Patients were also receiving calcium supplementation (1,000 to 1,500 mg/day), and all but one patient received vitamin D (400 to 800 U/day). RESULTS: Lumbar spine BMD increased by 6.4 +/- 1.8% per year with alendronate treatment (P = 0.008). A mean absolute gain of 0.052 +/- 0.010 g/cm 2 (P = 0.005) in lumbar spine BMD was noted for the entire study group (N = 9), after a mean duration of treatment of 14 +/- 1 months. The mean lumbar spine BMD Z score improved by 0.40 +/- 0.09 (P = 0.002) with alendronate therapy. The femoral neck BMD also increased by 4.5 +/- 1.4% per year with alendronate treatment (P = 0.013). The mean absolute gain in femoral neck BMD was 0.028 +/- 0.009 g/cm 2 (P = 0.013) for the study group (N = 9) after 14 +/- 1 months of therapy. The mean femoral neck BMD Z score improved 0.30 +/- 0.08 (P = 0.005) with treatment. BMD gains at the greater trochanter of 3.2 +/- 1.5% per year (P = 0.067) and at Ward's triangle of 9.1 +/- 4.2% per year (P = 0.061) were not statistically significant. Two patients discontinued alendronate treatment after 1 year because of epigastric or retrosternal pain. CONCLUSION: Oral alendronate treatment, given in combination with calcium supplementation and physiologic doses of vitamin D, resulted in significant improvements in lumbar spine and femoral neck BMD after a 14-month period in this small group of men with osteoporosis. Although controlled, prospective trials involving larger numbers of male patients with fracture incidence data are needed before definitive conclusions can be made, alendronate treatment seems to be effective in improving BMD in men with osteoporosis, similar to its efficacy in women.

Journal Article↗
PubMed2003

Alendronate prevents loss of bone density associated with discontinuation of hormone replacement therapy: a randomized controlled trial.

BACKGROUND: Many women using hormone replacement therapy (HRT) will discontinue HRT and lose its bone-protective effect. Methods to preserve bone density in these women need to be explored. This multicenter, international, randomized, blinded, 12-month study was conducted to assess the effect of alendronate sodium on bone density in women who had recently discontinued HRT. METHODS: The 144 postmenopausal women included in the study were diagnosed as having low bone mineral density (BMD) and had recently discontinued HRT. They were randomized to receive either a daily dose of 10 mg of alendronate sodium or matching placebo. The main outcome measures were spine, hip, and total body BMD; biochemical markers of bone turnover; and tolerability. RESULTS: Alendronate treatment was associated with a 2.3% mean increase (95% confidence interval [CI], 1.7%-3.0%) in spine BMD compared with a mean loss of 3.2% (95% CI, - 4.6% to - 1.7%) in patients receiving placebo, for a difference of 5.5% (95% CI, 4.2%-6.8%) between alendronate and placebo. Greater hip and total body BMD preservation was also observed with alendronate use. Bone turnover decreased significantly with alendronate (bone-specific alkaline phosphatase levels decreased by 20% and urinary N-telopeptide/creatinine ratio by 47%), but increased in the placebo group (by 18% and 36%, respectively). Alendronate was well tolerated, with no increase in adverse events compared with placebo. CONCLUSIONS: A high rate of bone loss was observed in the first 12 to 15 months after discontinuation of HRT in postmenopausal women with low BMD. Treatment with alendronate increased or maintained both spine and hip BMD and prevented the increase in bone resorption seen with withdrawal of HRT in this population.

Alendronate↗
PubMed1995

Prevention of hypercalciuria and stone-forming propensity during prolonged bedrest by alendronate.

The bone loss and hypercalciuria induced by immobilization or the decreased gravitational forces of space are well described. Using a model of bedrest immobilization, the ability of a potent aminobisphosphonate, alendronate, to avert hypercalciuria and stone-forming propensity was tested. Sixteen male subjects participated in a randomized, placebo-controlled trial in which they received either 20 mg of alendronate or placebo 2 weeks prior to and during 3 weeks of strict bedrest. Parameters of bone and calcium metabolism and urinary crystallization of stone-forming salts were measured before and at the end of bedrest. In the placebo group, bedrest increased urinary calcium (209 +/- 47 to 267 +/- 60 mg/day, p < 0.01) and the saturation of calcium phosphate. Before bedrest, the alendronate group had a significantly lower serum calcium (8.8 +/- 0.4 vs. 9.6 +/- 0.5 mg/dl, p < 0.01) and higher serum PTH (62.4 +/- 33.1 vs. 23.1 +/- 7.5 pg/ml, p < 0.01) compared with the placebo group. Moreover, the alendronate group had a lower urinary calcium (75 +/- 41 mg/day) and saturation of calcium oxalate and calcium phosphate. These effects of alendronate were sustained during bedrest. Following bedrest in the alendronate group, urinary calcium rose to 121 +/- 50 mg/day, a value less than that in the placebo group before or during bedrest. Similarly, urinary saturation of calcium oxalate and calcium phosphate rose with bedrest in the alendronate-treated patients but remained lower than values obtained in placebo-treated patients before or during bedrest. Alendronate inhibits bone mineral loss and averts the hypercalciuria and increased propensity for the crystallization of stone-forming calcium salts which occurs during 3 weeks of strict bedrest.

Adult↗
PubMed2006

Alendronate and vitamin D2 for prevention of hip fracture in Parkinson's disease: a randomized controlled trial.

Incidence of a fracture, particularly in the hip joint, is high in elderly women with Parkinson's disease (PD), and this is due to the immobilization-induced bone resorption and vitamin D deficiency with reduced bone mineral density (BMD). The objective of this study was to address the possibility that treatment with alendronate and vitamin D2 may reduce the incidence of hip fractures in elderly women with PD. PD patients were randomly assigned to daily treatment with 5 mg alendronate (n = 144) or a placebo combined with 1,000 IU of vitamin D2 (n = 144) and followed for 2 years. Incidence of hip fractures in the two patient groups during the 2-year follow-up period was studied. At baseline, both groups of patients had low BMD with high levels of serum-ionized calcium and urinary deoxypyridinoline (D-Pyr). Hip fractures occurred in 14 patients in the placebo group and 4 in the alendronate group. The relative risk for hip fractures in the alendronate group as compared with the placebo group was 0.29 (95% CI, 0.10-0.85). The number of hip fracture per 1,000 patient-years was 14 and 49 for the alendronate and placebo groups, respectively. In the alendronate group, serum calcium and urinary D-Pyr levels decreased significantly during the follow-up period, while the levels in the placebo group were increased. BMD increased by 3.1% in the alendronate group and decreased by 2.8% in the placebo group (P < 0.01). Treatment with alendronate and vitamin D2 increases BMD in elderly women with PD and leads to the prevention of hip fractures.

Aged↗
PubMed2000

Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase.

Alendronate, a nitrogen-containing bisphosphonate, is a potent inhibitor of bone resorption used for the treatment and prevention of osteoporosis. Recent findings suggest that alendronate and other N-containing bisphosphonates inhibit the isoprenoid biosynthesis pathway and interfere with protein prenylation, as a result of reduced geranylgeranyl diphosphate levels. This study identified farnesyl disphosphate synthase as the mevalonate pathway enzyme inhibited by bisphosphonates. HPLC analysis of products from a liver cytosolic extract narrowed the potential targets for alendronate inhibition (IC(50) = 1700 nM) to isopentenyl diphosphate isomerase and farnesyl diphosphate synthase. Recombinant human farnesyl diphosphate synthase was inhibited by alendronate with an IC(50) of 460 nM (following 15 min preincubation). Alendronate did not inhibit isopentenyl diphosphate isomerase or GGPP synthase, partially purified from liver cytosol. Recombinant farnesyl diphosphate synthase was also inhibited by pamidronate (IC(50) = 500 nM) and risedronate (IC(50) = 3.9 nM), negligibly by etidronate (IC50 = 80 microM), and not at all by clodronate. In osteoclasts, alendronate inhibited the incorporation of [(3)H]mevalonolactone into proteins of 18-25 kDa and into nonsaponifiable lipids, including sterols. These findings (i) identify farnesyl diphosphate synthase as the selective target of alendronate in the mevalonate pathway, (ii) show that this enzyme is inhibited by other N-containing bisphosphonates, such as risendronate, but not by clodronate, supporting a different mechanism of action for different bisphosphonates, and (iii) document in purified osteoclasts alendronate inhibition of prenylation and sterol biosynthesis.

Alendronate↗
PubMed1993

Clinical pharmacology of alendronate sodium.

Clinical studies have been performed to investigate the pharmacokinetics and pharmacodynamics of alendronate, an inhibitor of bone resorption for the treatment of osteoporosis. Alendronate is one of the most potent bisphosphonates currently undergoing clinical investigation (> 100-fold more potent than etidronate in vivo). The pharmacokinetics of alendronate are similar to those of other bisphosphonates. After a 2-h intravenous infusion, plasma concentrations of alendronate decline rapidly to approximately 5% of initial values within 6 h. About 50% of a systemic dose is excreted unchanged in the urine in the 72 h following administration. By analogy to its behavior in animals the remainder is assumed to be taken up by the skeleton. After sequestration into bone, the elimination of alendronate is very prolonged. The terminal half-life was estimated to be greater than 10 years. Despite prolonged skeletal residence, the biological effects of alendronate begin to diminish post-treatment, since the duration of effect reflects factors besides dose and cumulative drug exposure. When taken after an overnight fast, 2 h before breakfast, the oral bioavailability of alendronate averages approximately 0.75% of dose with substantial variability (coefficient of variation 55%-75%) both between and within subjects. Reducing the wait before food from 2 h to 1 h, or even 30 min, produces a mean reduction in absorption of 40%. Since the clinical efficacy of alendronate is indistinguishable whether it is given 30 min, 1h, or 3 h before a meal, the observed variability in bioavailability within this range is of little consequence. Dosing up to at least 2 h after a meal dramatically reduces absorption (80%-90%).

Alendronate↗
PubMed2005

Effectiveness of alendronate and etidronate in the treatment of osteoporosis in men: a prospective observational study.

The prevalence of osteoporosis in men is higher than previously assumed; consequently, numerous therapies are being investigated to treat these patients. The Canadian Database of Osteoporosis and Osteopenia patients (CANDOO) was analyzed to examine changes in bone mineral density (BMD) in consecutively seen osteoporotic men administered alendronate, etidronate or no bone-active drugs (control) over 1 year. A total of 244 men attending six Canadian osteoporosis clinics were included in the study (42 alendronate, 102 etidronate and 100 control). Multiple imputation was used to model missing data to provide a more robust statistical model. The imputed datasets (five) were analyzed using multivariable linear regression to determine differences between groups in the percent change of lumbar spine (LS) and femoral neck (FN) BMD from baseline to 1 year. Differences in the percent change in BMD from baseline were most notable at the LS in favor of alendronate (4.3%; 95% CI: 2.1, 6.6 ) and etidronate (2.1%; 95% CI: 0.3, 4.0) therapy when compared with controls. At the LS, alendronate therapy led to significantly greater (2.2%; 95% CI: 0.2, 4.2) gains in BMD as compared to etidronate therapy. Compared to controls, there were no significant differences in FN BMD with alendronate (2.1%; 95% CI: -0.4, 4.7) or etidronate therapy (0.9%; 95% CI: -1.1, 2.8), nor were there significant differences between bisphosphonate groups (1.3%; 95% CI: -1.1, 3.6, in favor of alendronate). While both alendronate and etidronate significantly increased LS BMD in osteoporotic men after 1 year in real-world settings, alendronate therapy resulted in significantly superior gains in LS BMD. The effect of these two bisphosphonates on fractures and FN BMD in osteoporotic men is likely positive, but requires further study.

Alendronate↗
PubMed2001

Comparison of bone and total alkaline phosphatase and bone mineral density in postmenopausal osteoporotic women treated with alendronate.

Alendronate therapy in osteoporotic women decreases bone turnover and increases bone mineral density (BMD). Optimal patient management should include verification that each patient is responding to therapy. Markers of bone turnover and BMD have both been proposed for this purpose. We have investigated changes resulting from alendronate therapy with an enzyme immunoassay for bone alkaline phosphatase (BAP) and compared it with total alkaline phosphatase (TAP) and BMD of the lumbar spine, hip, and total body. Subjects were drawn from a multicenter randomized, placebo-controlled trial of alendronate in postmenopausal women with osteoporosis. BAP and TAP levels were measured at baseline and following 3, 6 and 12 months of therapy with either placebo (n = 180) or alendronate 10 mg/day (n = 134). All subjects also received 500 mg/day supplemental calcium. BMD was measured at baseline and following 3, 6, 12, 18, 24 and 36 months of therapy. To compare BAP, TAP and BMD at each site for identifying women that experienced a skeletal effect of alendronate, we calculated least significant change (LSC) values from the long-term intraindividual variability in each placebo-treated woman. Median levels of BAP decreased by 34%, 44% and 43% at 3, 6 and 12 months, respectively, in alendronate-treated women (p < 0.0001 compared with baseline and with placebo). These changes were significantly greater (p < 0.0001) than changes observed for TAP. Following 6 months of alendronate therapy, 90% of the women had experienced a decrease in BAP exceeding the LSC compared with only 71% for TAP. The greatest number of women similarly identified with BMD at any site (i.e. a gain in BMD exceeding the LSC) was 81% for spinal BMD at 36 months. All other sites were less than 70% at 36 months. Short-term changes in BAP and TAP were modestly associated with subsequent changes in BMD at all sites (Spearman's rho -0.22 to -0.52, p < 0.05). Compared with TAP and BMD, BAP testing rapidly and sensitively identified skeletal effects of alendronate thus enabling appropriate drug monitoring of osteoporotic women. Though BAP and TAP changes were modestly predictive of BMD changes, the value of the bone marker tests is their ability to detect rapidly a skeletal effect of therapy.

Aged↗
PubMed1998

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

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.

Alendronate↗
PubMed2004

Effect of discontinuation of alendronate treatment and exercise on bone mass and physical fitness: 15-month follow-up of a randomized, controlled trial.

The purpose of this study was to evaluate the remaining effects of 12-month intervention of alendronate and exercise on selected risk factors of fragility fractures in 15-month follow-up after withdrawal of intervention among early postmenopausal women. The trial consisted four experimental groups: (1) 5 mg of alendronate daily + exercise (Al+Ex+), (2) 5 mg alendronate daily (Al+Ex-), (3) placebo + exercise (Al-Ex+), and (4) placebo (Al-Ex-). At the follow-up measurements, bone mass and physical fitness of 102 women (mean age 53.5 +/- 2.5 years) out of initial 150 subjects could be evaluated. Alendronate increased bone mass significantly [mean; 95% confidence interval (CI)] during the intervention at the lumbar spine (3.9%; 2.2% to 5.7%) and femoral neck (2.1%; 0.9% to 3.4%). After withdrawal of alendronate, bone loss resumed to the rate comparable to that evident in the placebo group. Despite the declining bone mass, the between-group mean difference (3.2%; 1.0% to 5.4%) remained at the lumbar spine. However, the benefits at the femoral neck had disappeared 15 months after the withdrawal of alendronate. The 12-month exercise training resulted in significant increases in muscle power, dynamic balance, and aerobic capacity with no benefits on bone mass. Fifteen months later, these performance variables had declined among both the exercisers and nonexercisers. Although the between-group differences were no longer statistically significant, muscle power, dynamic balance, and aerobic capacity of those who exercised still remained above the pretraining levels. In conclusion, 12-month treatment with alendronate prevented postmenopausal bone loss, and residual effect was seen 15 months after withdrawal of the drug at the lumbar spine. Similarly, exercise improved muscle power, agility, and aerobic capacity during the intervention, but the improvement was lost after the cessation of the exercise program. Based on these results, it was evident that to maintain the benefits of alendronate or exercise, therapy should be continued.

Alendronate↗