SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
UNLABELLED: To determine the effects of continuation versus discontinuation of alendronate on BMD and markers of bone turnover, we conducted an extension trial in which 1099 older women who received alendronate in the FIT were re-randomized to alendronate or placebo. Compared with women who stopped alendronate, those continuing alendronate for 3 years maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued treatment. However, among women who discontinued alendronate and took placebo in the extension, BMD remained higher, and reduction in bone turnover was greater than values at FIT baseline, showing persistence of alendronate's effects on bone. INTRODUCTION: Prior trials including the Fracture Intervention Trial (FIT) have found that therapy with alendronate increases BMD and decreases fracture risk for up to 4 years in postmenopausal women with low BMD. However, it is uncertain whether further therapy with alendronate results in preservation or further gains in BMD and if skeletal effects of alendronate continue after treatment is stopped. MATERIALS AND METHODS: We conducted a follow-up placebo-controlled extension trial to FIT (FIT long-term extension [FLEX]) in which 1099 women 60-86 years of age who were assigned to alendronate in FIT with an average duration of use of 5 years were re-randomized for an additional 5 years to alendronate or placebo. The results of a preplanned interim analysis at 3 years are reported herein. Participants were re-randomized to alendronate 10 mg/day (30%), alendronate 5 mg/day (30%), or placebo (40%). All participants were encouraged to take a calcium (500 mg/day) and vitamin D (250 IU/day) supplement. The primary outcome was change in total hip BMD. Secondary endpoints included change in lumbar spine BMD and change in markers of bone turnover (bone-specific alkaline phosphatase and urinary type I collagen cross-linked N-telopeptide). RESULTS: Among the women who had prior alendronate therapy in FIT, further therapy with alendronate (5 and 10 mg groups combined) for 3 years compared with placebo maintained BMD at the hip (2.0% difference; 95% CI, 1.6-2.5%) and further increased BMD at the spine (2.5% difference; 95% CI, 1.9-3. 1%). Markers of bone turnover increased among women discontinuing alendronate, whereas they remained stable in women continuing alendronate. Cumulative increases in BMD at the hip and spine and reductions in bone turnover from 8.6 years earlier at FIT baseline were greater for women continuing alendronate compared with those discontinuing alendronate. However, among women discontinuing alendronate and taking placebo in the extension, BMD remained higher and reduction in bone turnover was greater than values at FIT baseline. CONCLUSIONS: Compared with women who stopped alendronate after an average of 5 years, those continuing alendronate maintained a higher BMD and greater reduction of bone turnover, showing benefit of continued alendronate treatment on BMD and bone turnover. On discontinuation of alendronate therapy, rates of change in BMD at the hip and spine resumed at the background rate, but discontinuation did not result in either accelerated bone loss or a marked increase in bone turnover, showing persistence of alendronate's effects on bone. Data on the effect of continuation versus discontinuation on fracture risk are needed before making definitive recommendations regarding the optimal length of alendronate treatment.
Alendronate is a potent bisphosphonate that is effective in preventing osteoporotic fractures. Clinical trial data involving over 17,000 women provide a large, placebo-controlled experience from which alendronate has been demonstrated to be safe and well tolerated. We review the safety profile of alendronate in the context of its pharmacology, preclinical information and published literature on bisphosphonates. The clinical data include information from 1) the two primary Phase III osteoporosis treatment studies involving 994 women with postmenopausal osteoporosis treated with alendronate for up to 3 years; 2) upper gastrointestinal (GI) tolerability data (including special subgroup analyses) from the Fracture Intervention Trial (FIT), involving 2027 women with prior vertebral fractures; 3) an endoscopy study, and 4) postmarketing experience. Because all bisphosphonates have the potential to irritate the upper GI mucosa, we specifically investigated the safety and tolerability profile with respect to the upper GI tract. In the Phase III trials, alendronate 5 or 10 mg/day was well tolerated, with no increase relative to placebo in the incidence of overall adverse experiences (ie, inclusive of all events, not just those related to the GI tract). In the Phase III trials, alendronate 5 mg/day or 10 mg/day was well tolerated, with no increase relative to placebo in the incidence of overall adverse experiences. The incidence of upper gastrointestinal adverse experiences, overall, was similar among alendronate 5 mg or 10 mg and placebo, with abdominal pain and dysphagia being the only individual adverse experiences that were significantly increased (with alendronate 10 mg). Esophageal adverse experiences were uncommon, being reported in 8 (2.0%) patients receiving placebo and 9 (4.6%) patients taking alendronate 10 mg. None of the events occuring on alendronate therapy were serious or resulted in discontinuation. Tolerability was not affected by a wide range of concomitant medications including nonsteroidal anti-inflammatory drugs. Additional analyses of the 2027 postmenopausal women with vertebral fractures enrolled in FIT demonstrated that alendronate use was not associated with a significant increase in upper GI events, esophageal events, or gastroduodenal adverse events, even among women at high risk for upper GI complications (those older than 75 yr, those with previous upper GI disease, or those using NSAIDs). Esophageal adverse experiences (including esophagitis and esophageal ulcers) have been reported with alendronate in postmarketed use. A high proportion of these reports involved patients who did not follow the dosing instructions and probably relate to the irritant potential of refluxed gastric acid containing alendronate. Consistent with the antiresorptive mechanism of action of alendronate, asymptomatic decreases in serum calcium and phosphate were observed with alendronate treatment in the clinical trials. There were no other laboratory changes noted with alendronate. Now marketed in 78 countries and used by over 3 million women, the safety profile of alendronate, when dosed appropriately, has been consistent with that of the clinical trial experience. In view of the increased morbidity and mortality associated with fractures, and the proven efficacy of alendronate to reduce fracture risk, the benefit/risk ratio of alendronate remains highly favourable.
GH increases bone turnover and stimulates osteoblast activity. We hypothesized that administration of MK-677, an orally active GH secretagogue, together with alendronate, a potent inhibitor of bone resorption, would maintain a higher bone formation rate relative to that seen with alendronate alone, thereby generating greater enhancement of bone mineral density (BMD) in women with postmenopausal osteoporosis. We determined the individual and combined effects of MK-677 and alendronate administration on insulin-like growth factor I levels and biochemical markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) and resorption [urinary N-telopeptide cross-links (NTx)] for 12 months and BMD for 18 months. In a multicenter, randomized, double blind, placebo-controlled, 18-month study, 292 women (64-85 yr old) with low femoral neck BMD were randomly assigned in a 3:3:1:1 ratio to 1 of 4 daily treatment groups for 12 months: MK-677 (25 mg) plus alendronate (10 mg); alendronate (10 mg); MK-677 (25 mg); or a double dummy placebo. Patients who received MK-677 alone or placebo through month 12 received MK-677 (25 mg) plus alendronate (10 mg) from months 12-18. All other patients remained on their assigned therapy. All patients received 500 mg/day calcium. The primary results, except for BMD, are provided for month 12. MK-677, with or without alendronate, increased insulin-like growth factor I levels from baseline (39% and 45%; P < 0.05 vs. placebo). MK-677 increased osteocalcin and urinary NTx by 22% and 41%, on the average, respectively (P < 0.05 vs. placebo). MK-677 and alendronate mitigated the reduction in bone formation compared with alendronate alone based on mean relative changes in serum osteocalcin (-40% vs. -54%; P < 0.05, combination vs. alendronate) and reduced the effect of alendronate on resorption (NTx) as well (-52% vs. -61%; P < 0.05, combination vs. alendronate). MK-677 plus alendronate increased BMD at the femoral neck (4.2% vs. 2.5% for alendronate; P < 0.05). However, similar enhancement was not seen with MK-677 plus alendronate in BMD of the lumbar spine, total hip, or total body compared with alendronate alone. GH-mediated side effects were noted in the groups receiving MK-677, although adverse events resulting in discontinuation from the study were relatively infrequent. In conclusion, the anabolic effect of GH, as produced through the GH secretagogue MK-677, attenuated the indirect suppressive effect of alendronate on bone formation, but did not translate into significant increases in BMD at sites other than the femoral neck. Although the femoral neck is an important site for fracture prevention, the lack of enhancement in bone mass at other sites compared with that seen with alendronate alone is a concern when weighed against the potential side effects of enhanced GH secretion.
BACKGROUND AND AIMS: Osteoporosis is a chronic condition requiring long-term treatment, for which compliance is not easy to achieve. 70 mg of alendronate once weekly (alendronate OW) provides equivalent efficacy to treatment with 10 mg of alendronate once a day (alendronate OD); however, there are relatively few data regarding patient and physician preferences for once-weekly vs daily dosing. The aim of this study was to measure compliance, convenience, tolerance and relative preference of alendronate OW treatment among post-menopausal women with osteoporosis and physician satisfaction, compared with previous treatment with alendronate OD. METHODS: This open-label, prospective multi-center trial was conducted at 14 hospitals and 150 primary-care community clinics in Israel. Post-menopausal osteoporotic women (n = 3710), who had been treated for at least 1 month with alendronate OD during the preceding year, were treated with alendronate OW for 12 weeks. Convenience, satisfaction, tolerance and relative preference of alendronate OW during the trial, compared with past experience with alendronate OD, were recorded. RESULTS: Overall, 96% of the patients preferred the alendronate OW regimen to the 10-mg daily dosage. Nearly all (98%) the patients who completed 12 weeks of treatment, including 77% of patients who had previously discontinued daily treatment due to intolerance, were willing to continue the alendronate OW regimen. Patient-reported compliance with dosing instructions was over 98%. Alendronate OW was well tolerated; only 2.8% of patients discontinued, due to adverse events. Physicians were highly satisfied with the once-weekly dosing regimen, and recommended continued treatment with alendronate OW for 99% of the patients. CONCLUSIONS: The majority of post-menopausal women with osteoporosis, including those who were previously intolerant to alendronate OD, preferred alendronate OW to the once-daily dosing regimen. It is important to consider patient preference when selecting the appropriate treatment for osteoporosis.
Alendronate and etidronate are bisphosphonates used clinically to treat diseases associated with increased bone resorption. Etidronate is less potent and was reported to cause osteomalacia. This study examines if differences in distribution of alendronate and etidronate in the skeleton can explain differences in efficacy and in effects on mineralization between the two drugs. Eight-day old rat pups were injected s.c. with 3H-alendronate or 3H-etidronate both at either 1.3 mumol/kg or at their respective pharmacological effective doses in the growing rat of 0.12 mumol/kg for alendronate and 72.8 mumol/kg for etidronate. Twelve hours after administration at 1.3 mumol/kg both drugs showed a three- to fourfold higher localization on osteoclast vs. osteoblast surface. At the pharmacologically effective doses, 3H-alendronate labeled eightfold more osteoclast surface than osteoblast surface. In contrast, 3H-etidronate labeled approximately equal fractions of osteoclast and osteoblast surface. When similar doses of 3H-etidronate and 3H-alendronate (0.24 mumol/kg 3H-etidronate vs. 0.20 mumol/kg 3H-alendronate; 1.5 mumol/kg 3H-etidronate vs. 1.2 mumol/kg 3H-alendronate; and 14.6 mumol/kg 3H-etidronate vs. 12.0 mumol/kg 3 H-alendronate) were injected intravenously into adult mice at similar specific activities, 3H-etidronate labeled 1.5-2.5 times more osteoclast surface than 3-H-alendronate, but 3 to 15 times more osteoblast surface. Consequently, the ratio between the fraction of labeled osteoclast surface and the fraction of labeled osteoblast surface ranged for 3H-alendronate from 9 to 24, whereas for 3H-etidronate the range was from 4 to 7, due to more extensive labeling of osteoblast surface by 3H-etidronate. In a third experiment, we confirmed in adult mice the previous observation made in rat pups that normal bone formation occurs over alendronate-covered bone surfaces, and found that it occurred over etidronate-covered surfaces as well. Forty nine days after s.c. administration of alendronate at 0.12 mumol/kg or etidronate at 1.3 mumol/kg or 55.3 mumol/kg into adult mice bone formed over drug label. The distance from incorporated label to bone surface for both drugs (12.7 microns for alendronate and 8.7 and 9.2 microns for etidronate) was similar to wall width (defined by cement line) in controls (10.6 microns). In conclusion, alendronate, especially at pharmacologically active doses, shows higher uptake on resorption vs. formation surfaces than etidronate. The extent of bone formation on surfaces containing alendronate or etidronate is similar and is comparable to the "wall width" in controls.
Male hypogonadism is associated with low bone mineral density (BMD) and an increased risk of fractures. Testosterone replacement therapy improves BMD in young hypogonadal men. This effect is milder in older patients, who are at greater risk for fractures. We studied the effects of alendronate or placebo on BMD in 22 osteoporotic men, 29-69 years of age (mean, 50.2+/-11.2 years) with long-standing hypogonadism, receiving standard testosterone replacement treatment. Alendronate 10 mg daily (n=11) increased lumbar-spine BMD by 6.0 and 8.4% at 6 and 12 months, respectively, compared with -0.5% at 6 months and +3.3% at 12 months in the placebo group (n=11; P<0.005). Alendronate also increased mean femoral-neck BMD by 1.9% after 1 year, compared to a 1.4% decrease with placebo (P<0.005), and increased the total body bone mineral content by 4.4%, compared to a 0.6% decrease with placebo (P=0.07). After 6 months alendronate suppressed urinary deoxypyridinoline by 50% (P<0.005), compared to a 24% decrease in the placebo group. Both the alendronate and placebo groups continued with alendronate 70 mg once weekly for the following 2 years. Lumbar-spine BMD during this open-label study phase did not change significantly in the group originally treated with alendronate, but continued to increase in the placebo-alendronate group by 5.4, 6.5, and 6.2% after 18 (6 months of alendronate), 24 and 36 months, respectively (P<0.05). Femoral-neck BMD continued to increase in both groups receiving active therapy; in the alendronate-alendronate group by 3.7, 2.7, and 5.2% after 18, 24, and 36 months, respectively (P=0.01), and in the placebo-alendronate group by 0.7 and 1.9% at 24 (first 12 months of alendronate) and 36 months, respectively (P<0.05). Our results support the long-term administration of alendronate along with testosterone replacement to men with hypogonadism-induced osteoporosis.
The bisphosphonate alendronate and conjugated equine estrogens are both widely used for the treatment of postmenopausal osteoporosis. Acting by different mechanisms, these two agents decrease bone resorption and thereby increase or preserve bone mineral density (BMD). The comparative and combined effects of these medications have not been rigorously studied. This prospective, double blind, placebo-controlled, randomized clinical trial examined the effects of oral alendronate and conjugated estrogen, in combination and separately, on BMD, biochemical markers of bone turnover, safety, and tolerability in 425 hysterectomized postmenopausal women with low bone mass. In addition, bone biopsy with histomorphometry was performed in a subset of subjects. Treatment included placebo, alendronate (10 mg daily), conjugated equine estrogen (CEE; 0.625 mg daily), or alendronate (10 mg daily) plus CEE (0.625 mg daily) for 2 yr. All of the women received a supplement of 500 mg calcium daily. At 2 yr, placebo-treated patients showed a mean 0.6% loss in lumbar spine BMD, compared with mean increases in women receiving alendronate, CEE, and alendronate plus CEE of 6.0% (P < 0.001 vs. placebo), 6.0% (P < 0.001 vs. placebo), and 8.3% (P < 0.001 vs. placebo and CEE; P = 0.022 vs. alendronate), respectively. The corresponding changes in total proximal femur bone mineral density were +4.0%, +3.4%, +4.7%, and +0.3% for the alendronate, estrogen, alendronate plus estrogen, and placebo groups, respectively. Both alendronate and CEE significantly decreased biochemical markers of bone turnover, specifically urinary N-telopeptide of type I collagen and serum bone-specific alkaline phosphatase. The alendronate plus CEE combination produced slightly greater decreases in these markers than either treatment alone, but the mean absolute values remained within the normal premenopausal range. Alendronate, alone or in combination with CEE, was well tolerated. In the subset of patients who underwent bone biopsies, histomorphometry showed normal bone histology with the expected decrease in bone turnover, which was somewhat more pronounced in the combination group. Thus, alendronate and estrogen produced favorable effects on BMD. Combined use of alendronate and estrogen produced somewhat larger increases in BMD than either agent alone and was well tolerated.
Alendronate is an aminobisphosphonate that inhibits bone resorption in osteoporotic humans and rats but does not induce osteomalacia. Several bisphosphonates, including alendronate, also have direct positive actions on osteoblasts, bone formation, and mineralization. We studied the effects of alendronate on skeletal development in adolescent male rats during chronic alcohol intake. Four groups of age- and weight-matched male Sprague-Dawley rats (35 days of age) were fed the Lieber-DeCarli diet containing 36% of calories as EtOH (E), the EtOH diet plus 60 mg/kg alendronate (EA) every other day intraperitoneally (ip), an isocaloric diet (I), or the isocaloric diet plus 60 mg/kg alendronate (IA) every other day ip. Body weight, femur length, serum levels of osteocalcin (OC), insulin-like growth factor 1 (IGF-1), testosterone, and luteinizing hormone (LH); femur distal metaphyseal and middiaphyseal bone mineral density (BMD) and tibial metaphyseal gene expression for alpha-1-type I collagen (Col I), OC, and bone alkaline phosphatase (AP); and femur strength by four-point bending to failure were measured after 28 days of feeding and alendronate injections. Serum alcohol levels at death were 156 +/- 13 mg/dl (E) and 203 +/- 40 mg/dl (EA). Alendronate given to alcohol-fed rats increased metaphyseal BMD by more than 3-fold over rats fed alcohol alone. Alendronate given to isocaloric pair-fed rats increased metaphyseal BMD by more than 2.5-fold over rats fed the isocaloric diet alone. Cortical BMD was reduced by alcohol but was increased by alendronate. Alcohol consumption reduced serum IGF-1 levels, and alendronate increased IGF-1 levels in alcohol-fed rats. Serum OC, testosterone, and LH were unaffected by alcohol and alendronate. Quantitative dot blot hybridization using rat complementary DNA (cDNA) probes and normalization against 18S subunit ribosomal RNA (rRNA) levels revealed no changes in tibial metaphyseal gene expression for type I collagen, osteocalcin, or alkaline phosphatase. Alcohol significantly reduced the biomechanical properties of the femurs that were partially compensated by alendronate. Chronic alcohol consumption uncouples formation from ongoing resorption, and resorption is inhibited by alendronate. However, alendronate's positive effects on osteoblast-mediated mineralization during chronic alcohol consumption point to the potential use of bisphosphonates in the treatment of decreased bone formation secondary to alcohol-induced diminished osteoblast function.
CONTEXT: The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. OBJECTIVE: To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. DESIGN AND SETTING: Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT). PARTICIPANTS: One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. INTERVENTION: Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). MAIN OUTCOME MEASURES: The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. RESULTS: Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. CONCLUSIONS: Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT 00398931.
OBJECTIVES: To compare the efficacy and safety of etidronate and alendronate in patients with postmenopausal osteoporosis and to assess the efficacy of either bisphosphonate in combination with hormone replacement therapy (HRT). PATIENTS AND METHODS: In this pragmatic study, the main efficacy criterion was the mean annual change in bone mineral density (BMD). Patients who had a past or current history of etidronate or alendronate treatment for postmenopausal osteoporosis with at least 18 months follow-up and an evaluation in 1999 were eligible. Recruitment was in an outpatient clinic with a special focus on metabolic bone diseases. Osteoporosis was defined as at least one low-energy fracture or as a lumbar spine or femoral neck BMD decrease to at least 2.5 SD below the mean in young women. HRT was not an exclusion criterion provided treatment duration was longer than 1 year. Etidronate was given cyclically (14-day courses in a dosage of 400 mg/d separated by 76-day intervals with calcium and vitamin D supplementation) and alendronate was given daily in a dosage of 10 mg/d. RESULTS: Of the 99 patients who met our inclusion criteria, 53 received etidronate (including 23 on HRT) and 46 alendronate (18 on HRT). Repeat BMD measurements were obtained in 88 patients, including 11 who stopped their bisphosphonate therapy within the first year of use because of adverse events. Lumbar spine BMD (mean +/- SD) increased significantly both in the etidronate group (+2.1% +/- 0.7%/year) and in the alendronate group (+5.3% +/- 0.9%/year). The increase was significantly greater with alendronate (P< 0.01). The lumbar spine BMD increase was largest in the patients on alendronate and HRT (+6.5% +/- 1.4%/year) and was smallest (and nonsignificant) in the patients on etidronate without HRT (+ 1.2% +/- 0.8%). Femoral neck BMD showed no significant changes in any group. In the intention-to-treat analysis, fractures occurred in 12 etidronate patients (22.6%) and six (13.0%) alendronate patients (nonsignificant). Adverse events requiring bisphosphonate discontinuation before the scheduled date of the follow-up BMD measurement occurred in one patient (1.9%) in the etidronate group (generalized osteomalacia) and in ten patients (21.7%) in the alendronate group (upper or lower gastrointestinal tract symptoms in six and four patients, respectively; P < 0.01). CONCLUSION: Both etidronate and alendronate significantly increased lumbar BMD, but the effect was significantly more marked with alendronate. Conversely, adverse effects, most notably gastrointestinal symptoms, were more common with alendronate, so that premature treatment discontinuation because of adverse events were more common in the alendronate group. Both differences should be taken into account when selecting the best drug for a patient with postmenopausal osteoporosis.
UNLABELLED: A 3-year, randomized, double-blind, placebo-controlled trial evaluated the effect of oral alendronate on the BMD of 64 adult patients with osteogenesis imperfecta. The mean increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Oral alendronate increases BMD in adult patients with osteogenesis imperfecta. INTRODUCTION: This study evaluated the effect of oral alendronate on the BMD of adult patients with osteogenesis imperfecta. MATERIALS AND METHODS: We carried out a 3-year, randomized, double-blind, placebo-controlled trial of oral alendronate in 64 adult patients with osteogenesis imperfecta. The primary endpoint was the difference between the groups in the mean percent change in lumbar spine BMD at 3 years. Secondary outcomes included changes in BMD of total hip, vertebral and peripheral fracture incidence, pain, hearing loss, and bone turnover biochemical markers. Patients were treated daily with either placebo or 10 mg alendronate. All received 1 g of calcium and 800 IU of vitamin D daily. RESULTS: The mean +/- SD increases in the lumbar spine BMD were 10.1 +/- 9.8% (p < 0.001) and 0.7 +/- 5.7% in the alendronate and placebo groups, respectively. Hip BMD increased in the alendronate group by 3.3 +/- 0.5% (p = 0.001) and decreased in the placebo group by 0.3 +/- 0.6%. The sample size was not sufficient to determine an effect of alendronate on fracture rate. A significant increase of the pain score was noted in the alendronate group (p = 0.04) in the intent-to-treat analysis but not in the per protocol analysis. There was no change in hearing in either group. Bone resorption and formation biochemical markers were significantly decreased in the alendronate group (p < 0.001). There were no differences in severe adverse effects between the groups, but there was an increase in nonsevere upper gastrointestinal effects in the alendronate group (p = 0.003). CONCLUSIONS: Oral alendronate increases BMD and increase nonsevere gastrointestinal adverse effects but does not modify the hearing loss in adult patients with osteogenesis imperfecta. More studies are needed to evaluate an effect on the fracture rate.
OBJECTIVE: Recent randomized clinical trials have shown that risedronate reduces the risk of nonvertebral fractures and clinical vertebral fractures within 6 months of initiating treatment. The objective of the current study was to determine whether this early antifracture effect could be demonstrated in nonvertebral fractures for risedronate and other osteoporosis therapies in an observational administrative claims database. METHODS: A proprietary administrative claims database was used to identify managed care members who received a new prescription for risedronate, alendronate, or nasal calcitonin from July 1, 2000, to December 31, 2001. Patient records were analyzed for the incidence of nonvertebral fractures (clavicle, humerus, wrist, pelvis, hip, and leg) in the first 6 and 12 months following initiation of treatment. A Cox proportional hazards regression model was used to estimate relative risk (RR) of fracture at 6 and 12 months. RESULTS: In the 6-month analysis, 774 patients (11%) received calcitonin, 5,307 (75%) received alendronate, and 1,000 (14%) received risedronate. Twelve-month data were available for a subset (71%) of patients (656 calcitonin [13%], 3,716 alendronate [74%], and 652 risedronate [13%]). Most were women (93%); mean age was similar for alendronate and risedronate, and nasal calcitonin patients were about 3 years older, on average. Risedronate and alendronate patients were more likely to have used estrogen, while nasal calcitonin patients were more likely to have been hospitalized and had higher use of concomitant medications and more physician visits. Relative risks were adjusted for these differences. Risedronate and alendronate patients were similar with respect to these indicators of general health status. In the 6-month analysis, nonvertebral fractures were observed in 2.2% of patients receiving nasal calcitonin, 1.4% of patients receiving alendronate, and 0.6% of patients receiving risedronate. The adjusted RR reduction was 69% for risedronate versus calcitonin (RR = 0.31; 95% CI, 0.12 to 0.81; P = 0.02), 54% for risedronate versus alendronate (RR = 0.46; 95% CI, 0.20 to 1.06; P = 0.07), and 26% for alendronate versus calcitonin (RR = 0.74; 95% CI, 0.43 to 1.27; P = 0.28). In the 12-month analysis, nonvertebral fracture rates were 2.9% for nasal calcitonin, 2.4% for alendronate, and 0.9% for risedronate patients. The adjusted RR reduction was 75% for risedronate versus calcitonin (RR = 0.25; 95% CI, 0.10 to 0.64; P<0.01), 59% for risedronate versus alendronate (RR = 0.41; 95% CI, 0.18 to 0.94; P = 0.04), and 25% for alendronate versus calcitonin (RR = 0.75; 95% CI, 0.45 to 1.25; P = 0.27). CONCLUSIONS: This analysis of medical and pharmacy claims contained in an administrative database confirms the early fracture reduction with risedronate that was shown in randomized clinical trials. Risedronate was more effective than calcitonin in reducing the risk of nonvertebral fractures within the first 6 months of treatment. Risedronate was more effective than either calcitonin or alendronate in reducing the risk of nonvertebral fractures within 12 months of treatment.
UNLABELLED: Alendronate (alendronic acid) is a nitrogen-containing bisphosphonate which binds to bone surfaces and inhibits bone resorption by osteoclasts. Oral alendronate 5 or 10 mg/day produces sustained increases in bone mineral density (BMD) in postmenopausal women with or without osteoporosis, in men with primary osteoporosis and in both men and women with or without osteoporosis receiving systemic corticosteroid therapy. Histomorphometric analyses have found that alendronate does not appear to impair bone quality. Alendronate reduced the risk of radiographic vertebral fracture, clinical vertebral fracture or hip fracture by 47 to 56% in postmenopausal women who had > or = 1 existing vertebral fracture and in those with no existing vertebral fractures but who had osteoporosis. In a number of comparative trials in postmenopausal women with osteoporosis, alendronate 10 mg/day was found to be more effective at inducing sustained increases in BMD than intranasal calcitonin, and at least as effective as conjugated estrogens and raloxifene. Alendronate 70 mg administered once weekly and 35 mg twice weekly are as effective at increasing BMD as 10 mg/day in this patient group. In clinical trials, alendronate was generally well tolerated when taken as recommended. Adverse events tended to be transient and associated with the upper GI tract, most commonly including abdominal pain, nausea, dyspepsia, acid regurgitation and musculoskeletal pain. No statistically significant differences between alendronate 10 mg/day and placebo have been found in the incidence of upper GI adverse events in large clinical trials. However, postmarketing surveillance reported a low incidence of adverse events related to the oesophagus. Specific instructions aimed at reducing the risk of upper GI adverse events have been provided by the manufacturer. CONCLUSIONS: Alendronate is effective and generally well tolerated in the treatment of women or men with primary (including postmenopausal) or corticosteroid-induced osteoporosis and in the prevention of osteoporosis in postmenopausal women. The drug has been associated with upper GI tract adverse events, although the extent to which alendronate is responsible for these events has not been clearly established. Alendronate should be considered a treatment of choice in postmenopausal women with osteoporosis. Alendronate is also a suitable treatment option for primary osteoporosis in men and for corticosteroid-induced osteoporosis in both men and women.
BACKGROUND: Up to 3 years of treatment with alendronate, 5 mg/d, prevents postmenopausal bone loss. OBJECTIVE: To determine whether the effect of alendronate is sustained at 4 years of treatment and persists after treatment is discontinued. DESIGN: Randomized, controlled trial. SETTING: United States and Europe. PARTICIPANTS: 1609 postmenopausal women 45 to 59 years of age. INTERVENTION: Participants were randomly assigned to receive oral alendronate, 5 mg/d or 2.5 mg/d; placebo; or open-label estrogen-progestin. Women in the alendronate groups received alendronate for the first 2 years of the study. Treatment was then continued without change or replaced with placebo for the last 2 years of the study. MEASUREMENTS: Annual measurement of bone mineral density. RESULTS: By year 4, the bone mineral density of participants in the placebo group had decreased by 1% to 6% (P < 0.001). Four years of treatment with 5 mg of alendronate per day increased bone mineral density at the spine (mean change [+/-SE], 3.8%+/-0.3%), hip (mean, 2.9%+/-0.2%), and total body (mean, 0.9%+/-0.2%) (P < 0.001 overall). By year 4, bone mineral density at most skeletal sites was greater in participants who switched from alendronate to placebo than in those who continuously received placebo. In years 3 and 4, bone loss in participants who switched from alendronate to placebo was similar to that seen during years 1 and 2 in those who continuously received placebo. Compared with 5 mg of alendronate per day, estrogen-medroxyprogesterone acetate produced similar increases in bone mineral density and estradiol-norethisterone acetate produced increases that were substantially greater. CONCLUSIONS: Four years of treatment with alendronate or estrogen-progestin prevented postmenopausal bone loss. A residual effect was seen 2 years after alendronate therapy was stopped; however, continuous alendronate treatment was more effective in preventing postmenopausal bone loss than 2 years of alendronate followed by 2 years of placebo.
Previously we showed a loss of bone and a concomitant decrease in mechanical properties in the first 21 days after flexor tendon insertion site injury and repair in a canine model. The goal of this short-term study was to suppress bone loss after insertion site repair using alendronate in an attempt to prevent the reduction in biomechanical properties. Flexor tendons of the second and fifth digits of the right forelimbs of canines were injured and repaired. Dogs received a daily oral dose of alendronate (2 mg/kg). One digit in each dog also received a local dose of alendronate in the bone tunnel at the time of surgery. The repair was evaluated for bone mineral density (BMD) and biomechanical properties and compared to data from a previous study in which no alendronate was used. Alendronate was effective in protecting the distal phalanx from resorption during tendon-to-bone healing (BMD was 94 and 104% of control for systemic alendronate and for systemic plus local alendronate, respectively). Alendronate treatment prevented much of the decrease in ultimate load that occurs in the first 21 days. Without treatment, ultimate load was 42% of control. With systemic alendronate treatment and systemic plus local alendronate treatment, ultimate load was 78 and 69% of control, respectively. Failure mode was significantly different when comparing alendronate treatment to repair alone. A lower incidence of suture pull through was found in alendronate treated dogs, suggesting less tendon degeneration. Ultimate load can be improved in association with preventing the bone loss that normally occurs during the early period following tendon-to-bone repair. These initial short-term data demonstrate the potential for a clinical treatment that could enhance tendon-to-bone healing.
INTRODUCTION: Alendronate has been described to have a bone-sparing effect in patients treated with moderate and high dosages of prednisone for heterogeneous diseases, however no data are available on groups of patients with the same underlying diseases who receive chronic low-dose prednisone treatment. The objective of the investigation reported here was, therefore, to study the effect of alendronate on bone mineral density (BMD) of the lumbar spine and hips in patients with rheumatoid arthritis (RA) who are on chronic low-dose prednisone treatment. METHODS: A total of 163 patients with RA, according to the ACR-criteria, were enrolled in a double-blind, placebo-controlled trial. The patients were treated with low-dose prednisone (<or=10 mg/day) for at least 3 months. The patients were randomized to receive daily doses of alendronate or placebo: men and premenopausal women received 5 mg alendronate (or placebo) daily; postmenopausal women received 10 mg alendronate (or placebo) daily. All patients received daily calcium (500 mg, or 1000 mg, depending on baseline dietary calcium intake) and vitamin D3 (400 IU) supplementation. BMD of the lumbar spine (L1-L4) and the (total) hip was measured at baseline and after 6 and 12 months. The primary endpoint was change in BMD of the lumbar spine after 12 months (ITT). At baseline and after 3 and 12 months, serum bone-specific alkaline phosphatase (BAP) and urinary excretion of N-telopeptide (NTX) were measured. Radiographs of the thoracic and lumbar spine were made at baseline and after 12 months and subsequently scored for vertebral deformities. RESULTS: The groups were comparable at baseline in age, gender, daily dosage of prednisone, BMD at the spine and the hip and markers of bone turnover, while the number of patients with prevalent vertebral deformities was slightly higher in the alendronate-treated patients (54% versus 39%, not significant). After 12 months, BMD at the lumbar spine had increased by 3.7% in the alendronate-treated patients and decreased by -1.0% in the placebo-treated patients (p<0.0001); at the hip, the changes were +1.0% and -0.1%, respectively (not significant). After 3 months, serum BAP had decreased by 16.9% in the alendronate group versus 3.3% in the placebo group (p=0.0005), while urinary NTX had decreased by 46.4% in the alendronate group versus 12.1% in the placebo group (p<0.0001). After 12 months, no statistically significant difference was found between the groups with respect to number of patients with incident vertebral or non-vertebral fractures. Adverse effects were relatively common in these patients with severe RA: adverse effects were observed in 68% of the alendronate-treated patients and in 73% of the placebo patients (not significant), while serious adverse events were observed in 13% and 17%, respectively (not significant). CONCLUSION: We observed a favourable effect of alendronate on the BMD of the lumbar spine and on the markers of bone turnover in patients with RA treated with low-dose prednisone. These data support the conclusion that the prescribing of alendronate is not only beneficial in patients treated with high-dose prednisone but also in RA patients chronically treated with low-dose prednisone.