Anastasia G. Daifotis

Esophagitis Associated with the Use of Alendronate

BACKGROUND Alendronate, an aminobisphosphonate and a selective inhibitor of osteoclast-mediated bone resorption, is used to treat osteoporosis in postmenopausal women and Pagets disease of bone. Aminobiphosphonates can irritate the upper gastrointestinal mucosa. METHODS We describe three patients who had severe esophagitis shortly after starting to take alendronate and also analyze adverse esophageal effects reported to Merck, the manufacturer, through postmarketing surveillance. RESULTS As of March 5, 1996, alendronate had been prescribed for an estimated 475,000 patients worldwide, and 1213 reports of adverse effects had been received. A total of 199 patients had adverse effects related to the esophagus; in 51 of these patients (26 percent), including the 3 we describe in case reports, adverse effects were categorized as serious or severe. Thirty-two patients (16 percent) were hospitalized, and two were temporarily disabled. Endoscopic findings generally indicated chemical esophagitis, with erosions or ulcerations and exudative inflammation accompanied by thickening of the esophageal wall. Bleeding was rare, and stomach or duodenal involvement unusual. In patients for whom adequate information was available, esophagitis seemed to be associated with swallowing alendronate with little or no water, lying down during or after ingestion of the tablet, lying down during or after ingestion of the tablet, continuing to take alendronate after the onset of symptoms, and having preexisting esophageal disorders. CONCLUSIONS Alendronate can cause chemical esophagitis, including severe ulcerations, in some patients. Recommendations to reduce the risk of esophagitis include swallowing alendronate with 180 to 240 ml (6 to 8 oz) of water on arising in the morning, remaining upright for at least 30 minutes after swallowing the tablet and until the first food of the day has been ingested, and discontinuing the drug promptly if esophageal symptoms develop.

Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: A randomized, double-blind, placebo-controlled extension trial

OBJECTIVE To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

Alendronate Prevents Postmenopausal Bone Loss in Women without Osteoporosis: A Double-Blind, Randomized, Controlled Trial

Osteoporosis is characterized by low bone mass and architectural changes in bone that render the skeleton brittle and susceptible to fracture [1]. As the elderly population grows, the worldwide annual incidence of hip fractures is projected to increase from 1.7 million in 1990 to 6.3 million by 2050, placing great economic strain on health care systems [2]. Currently, a 50-year-old woman is estimated to have a risk as high as 40% for sustaining a fracture related to osteoporosis at some point in the future [3]. The age-adjusted risk for fracture seems to be increasing, and this risk may be an underestimate for the future [4]. Bone loss after menopause, which results in low bone density, is an important determinant of risk for fracture, although other factors (such as advanced age, hip geometry, and falls and injuries) also contribute [5, 6]. Bone loss is most rapid during the first few years after menopause, but evidence suggests that the rate of loss also becomes accelerated in advanced old age [7, 8]. One strategy to reduce the number of fractures in postmenopausal women is to begin treatment for osteoporosis only in patients who are at high risk for fracture, including those with osteoporosis or previous fragility fractures. Pharmacologic therapy in women with osteoporosis with or without fractures reduces the incidence of fracture by about 50% [9, 10]. However, half of women who would have sustained fractures without treatment still do so with treatment. Thus, preventing rather than treating osteoporosis is a more appealing clinical objective because it can avoid the increased risk for fracture. There may also be an advantage in terms of preserving the normal microarchitecture of bone. Preventing bone loss associated with menopause and aging and maintaining normal microarchitecture provide important opportunities for the prevention of osteoporosis and fractures. Estrogen is effective in preventing bone loss in early and late postmenopausal women, but it must be taken over the long term to decrease the incidence of vertebral and hip fractures [11]. Estrogen also relieves menopausal symptoms and, in epidemiologic cohort studies, seemed to protect against cardiovascular disease. However, most women who begin estrogen therapy do not continue it for more than a year, in part because of such side effects as breast tenderness, headache, fluid retention, and withdrawal bleeding [12, 13]. Although the benefits of estrogen therapy outweigh the risks in most women, concern about risk for breast cancer is sufficiently great that many women avoid estrogen therapy [14, 15]. Alendronate sodium (monosodium 4-amino, 1-hydroxybutylidene-1, 1-bisphosphonate) is a potent and selective inhibitor of osteoclast-mediated bone resorption. Studies in animals with low bone mineral density have shown that alendronate therapy is associated with increased bone mass of normal quality and increased bone strength [16]. Alendronate treatment of osteoporosis in postmenopausal women induces progressive increases in bone density and a reduction in the incidence of new fractures of the vertebrae, hip, and forearm in osteoporotic women [9, 10]. We performed a 3-year randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the efficacy of alendronate therapy in preventing bone loss in healthy women who had recently experienced menopause. Methods Study Participants Healthy women aged 40 to 59 years who had experienced menopause 6 to 36 months before enrollment were eligible to participate in this study. Women were excluded if their spine bone mineral density was more than 2 SDs above or below normal peak bone mineral density or if they had a history of nontraumatic spine or hip fracture. Women with disorders of bone and mineral metabolism were also excluded, as were those with recent (within 1 year of study entry) major upper gastrointestinal diseases (such as peptic ulcer, esophageal disease, and malabsorption). Other exclusion criteria were previous treatment with bisphosphonates or fluoride (>1 mg/d) or treatment within the 12 months before enrollment with estrogen, progestin, calcitonin, glucocorticoids, anticonvulsant agents, phosphate-binding antacids, or excessive vitamin A or vitamin D. Women who regularly used (>four times per week) any medication that had the potential to cause gastrointestinal irritation (such as aspirin), who smoked more than 20 cigarettes per day, or who drank three or more alcoholic beverages per day were also excluded. Four hundred forty-seven women met the inclusion criteria and were enrolled at 15 centers throughout the world. The target sample size of 250 women completing the study was selected to detect a difference in bone density of 2.4% between an individual alendronate dosage and placebo at a P value of 0.05 or less, with 95% power using an SD of 3.3% that was obtained from 1-year bone density data in placebo recipients [17]. All centers conducted the study with appropriate approval from the institutional review boards, and all participants gave informed consent. Treatment Participants were randomly assigned (in allocation blocks of five) to one of five regimens: placebo for 3 years; alendronate at 1, 5, or 10 mg/d for 3 years; or alendronate at 20 mg/d for 2 years followed by placebo for 1 year (20/0 mg/d). In all groups, double-blinding was maintained for all 3 years. Alendronate and placebo tablets were identical in size, shape, and color. The women were instructed to take the study drug daily at least 1 hour before breakfast or, as a less desirable alternative, at least 2 hours after a meal and 1 hour before the next meal. All participants also received a daily supplement of calcium carbonate (Os-Cal 500, Smith-Kline Beecham Consumer Brands, LP, Pittsburgh, Pennsylvania, or the equivalent) unless dietary calcium intake exceeded 1000 mg/d. This supplement was usually taken with the evening meal. After beginning therapy, each participant was seen at months 1 and 3 and every 3 months thereafter. Eight participants (four in the placebo group and four in the 1-mg/d group) lost more than 6% of their spine bone density at 24 months relative to their baseline measurements and were therefore designated fast bone losers. Seven of these participants completed the study; from month 24 to the end of the study, they received 5 mg of open-label alendronate per day. The other patient discontinued therapy at month 24. Bone Mineral Density Bone mineral density of the spine, proximal femur, total body, and forearm was measured every 6 months by dual-energy x-ray absorptiometry with a Hologic QDR-1000, 1000/W, or 2000 densitometer (Waltham, Massachusetts) or a Lunar DPX-L densitometer (Madison, Wisconsin). One bone density quality assurance center (Oregon Osteoporosis Center) that remained blinded to treatment allocation was responsible for the quality control of all participant and phantom calibration scans [18]. Factors to correct for machine calibration drift were applied as necessary. The primary end point was bone mineral density of the lumbar spine; the other most important end points were bone mineral density of the femoral neck, trochanter, and total body. Bone mineral density of the total body, total hip, and forearm was measured at the centers that had densitometers capable of performing these measurements (11 centers measured bone mineral density of the total body; 10 centers measured bone mineral density of the total hip and forearm). Biochemical Markers and Indices of Mineral Metabolism Fasting serum and urine samples (second morning void) were obtained at all clinic visits except those in months 27 and 33. The resorption markers included urine deoxypyridinoline, measured by high-pressure liquid chromatography, and (in a subgroup of 268 participants) urine N-telopeptide cross-links of type I collagen (Ostex, Seattle, Washington). Each of these markers was expressed as a ratio to urine creatinine. Serum osteocalcin levels, measured by radioimmunoassay (INCSTAR, Stillwater, Nebraska), and serum bone-specific alkaline phosphatase levels were used to assess the rate of bone formation. Levels of serum calcium, phosphorus, intact parathyroid hormone (measured by immunoradiometric assay), and 1,25 dihydroxyvitamin D (measured by competitive binding assay) were also determined to assess the effects of treatment on mineral metabolism. N-telopeptide levels were measured by Medical Research Laboratories (Highland Heights, Kentucky). All other assays were done at Corning-Nichols Institute (San Juan Capistrano, California). Safety Evaluations At each visit, vital signs were measured and any new or worsening symptoms were recorded. Physical examinations were performed at the baseline, month 3, and yearly visits. Standard laboratory safety evaluations (including evaluations of hematologic, renal, and liver function) were performed at every visit. Investigators reported any unfavorable or unintended clinical or laboratory events as adverse experiences. After 3 years of therapy, biopsy specimens of transiliac bone were obtained for histologic and histomorphometric assessment from 55 women who provided specific informed consent for this procedure. These analyses were performed, as previously described, by a single investigator who was blinded to treatment groups [19]. Statistical Analysis The Tukey trend test [20] was used to assess the trend in response with increasing alendronate dosages. The 20/0-mg/d group was excluded from this test because of the change in dosage. This test uses the minimum P value, adjusted for multiplicity [21], that was obtained from tests of the regression sloped on three dosage scalings. The test is done in a stepwise manner, with the highest dosage eliminated, until the minimum P value exceeds 0.05. Dose-response relations were examined for the responses of the percentage change in bone density variables, natural logarithm (fraction of the baseline value) for biochemical variabl

Effects of Alendronate on Bone Quality and Remodeling in Glucocorticoid-Induced Osteoporosis: A Histomorphometric Analysis of Transiliac Biopsies

Effects of alendronate (ALN) on bone quality and turnover were assessed in 88 patients (52 women and 36 men aged 22–75 years) who received long‐term oral glucocorticoid exposure. Patients were randomized to receive oral placebo or alendronate 2.5, 5, or 10 mg/day for 1 year and stratified according to the duration of their prior glucocorticoid treatment. Transiliac bone biopsies were obtained for qualitative and quantitative analysis after tetracycline double‐labeling at the end of 1 year of treatment. As previously reported in glucocorticoid‐induced osteoporosis, low cancellous bone volume and wall thickness were noted in the placebo group as compared with normal values. Alendronate treatment was not associated with any qualitative abnormalities. Quantitative comparisons among the four treatment groups were performed after adjustment for age, gender, and steroid exposure. Alendronate did not impair mineralization at any dose as assessed by mineralization rate. Osteoid thickness (O.Th) and volume (OV/BV) were significantly lower in alendronate‐treated patients, irrespective of the dose (P = 0.0003 and 0.01, respectively, for O.Th and OV/BV); however, mineral apposition rate was not altered. As anticipated, significant decreases of mineralizing surfaces (76% pooled alendronate group; P = 0.006), activation frequency (–72%; P = 0.004), and bone formation rate (–71%; P = 0.005) were also noted with alendronate treatment. No significant difference was noted between the changes observed with each dose. Absence of tetracycline label in trabecular bone was noted in approximately 4% of biopsies in placebo and alendronate‐treated groups. Trabecular bone volume, parameters of microarchitecture, and resorption did not differ significantly between groups. In conclusion, alendronate treatment in patients on glucocorticoids decreased the rate of bone turnover, but did not completely suppress bone remodeling and maintained normal mineralization at all alendronate doses studied. Alendronate treatment did not influence the osteoblastic activity, which is already low in glucocorticoid‐induced osteoporosis.

Weekly administration of alendronate: Rationale and plan for clinical assessment

OBJECTIVE This paper describes the rationale and supporting data for once-weekly dosing of alendronate. BACKGROUND Alendronate sodium, a bisphosphonate that potently inhibits bone resorption, has been shown to increase bone mass and substantially reduce the incidence of osteoporotic fractures, including fractures of the hip. The standard regimen of daily administration has generally been well tolerated. However, weekly administration may provide greater convenience to patients without compromising efficacy or tolerability. The pharmacokinetics of alendronate and bone remodeling theory predict similar efficacy for weekly and daily administration if the cumulative dose is the same. Bone resorption in individual remodeling units normally proceeds for approximately 2 weeks; alendronate inhibits the rate and extent of resorption. Because the half-life of residence on bone surfaces is several weeks, weekly administration of alendronate should inhibit bone resorption to an overall extent similar to that of daily dosing, thereby producing similar effects on bone mass and strength. Animal studies demonstrate that both weekly and daily parenteral administration of alendronate effectively increase bone mass and strength, but confirmation of efficacy is needed for weekly oral dosing in humans. Although daily bisphosphonates (alendronate and risedronate) elicited esophageal irritation in a canine model of gastroesophageal reflux, weekly dosing with alendronate at a higher unit dose did not. Thus, the lower frequency of weekly dosing with a higher unit dose may actually reduce the risk of upper gastrointestinal irritation compared with daily administration of a lower dose. CONCLUSIONS Current safety and efficacy data justify further investigation of once-weekly dosing of alendronate. Two positive-control, double-blind, randomized trials of osteoporosis treatment and prevention are currently being performed to assess the comparability of weekly, biweekly, and daily dosing of alendronate with regard to effects on bone density, safety, and tolerability.

The upper GI safety and tolerability of oral alendronate at a dose of 70 milligrams once weekly: a placebo-controlled endoscopy study

OBJECTIVE:Alendronate (10 mg daily) has been shown in long term clinical trials to be an effective treatment for postmenopausal osteoporosis. A weekly dosing regimen of alendronate is preferred by both patients and physicians, as it has the potential to provide greater convenience and enhance compliance. In a 1-yr clinical trial, alendronate (70 mg once weekly) was equally efficacious and at least as well tolerated as the 10-mg daily dose in the treatment of postmenopausal osteoporosis, despite the higher unit dosage required. We conducted a randomized, double blind, placebo- and active-controlled endoscopy study to confirm the results of this clinical trial. We hypothesized that mean endoscopic gastric erosion scores would be similar in subjects receiving alendronate (70 mg once weekly) and those receiving a placebo.METHODS:Two hundred seventy-seven subjects (90 men and 187 women) were randomized to one of three treatment groups: 1) alendronate (70 mg once weekly) for 10 wk (N = 126), 2) placebo (once weekly) for 10 wk (N = 126), or 3) placebo (once weekly) for 10 wk followed by aspirin (650 mg q.i.d.) for the last week as the positive control (N = 25). Esophagogastroduodenoscopy was performed 5 to 7 days after the last dose of alendronate or matching placebo.RESULTS:The mean gastric erosion scores (Lanza scale) were similar in subjects given alendronate (70 mg once weekly) and those given a placebo (0.32 vs 0.35, respectively; 95% CI for difference =− 0.22–0.16, p = 0.75), whereas scores in both groups were significantly lower than in those given aspirin (3.09; p < 0.001). Endoscopic gastroduodenal ulcers occurred in no alendronate (0%), two placebo (1.7%), and five aspirin (23.8%) subjects. The mean erosion scores in the esophagus and duodenum of alendronate and placebo subjects were also similar. The incidences of upper GI symptoms were similar in the alendronate and placebo subjects and did not suggest a relationship with endoscopic lesions.CONCLUSIONS:Alendronate (70 mg once weekly) was not associated with any increase in endoscopic lesions in the upper GI tract relative to a placebo.

Pharmacokinetic considerations in determining the terminal elimination half-lives of bisphosphonates.

AbstractBackground and objective: Bisphosphonates are commonly used to treat and prevent osteoporosis. These compounds have unusual pharmacokinetic characteristics because they bind strongly to bone, and a portion becomes buried under newly formed bone. Once incorporated into bone tissue, the subsequent release during bone remodeling is probably the rate-limiting step in the terminal elimination of bisphosphonates. Because of this unique property of bisphosphonates, pharmacokinetic studies with insufficient lengths of follow-up might entirely miss the true terminal elimination phase. A terminal half-life (t1/2γ) of approximately 11 years, similar to that of calcium and other minerals in bone, was reported from an 18-month study of alendronic acid in postmenopausal women with osteoporosis. We are not aware of any other published reports in which the elimination of a bisphosphonate has been followed for more than a few weeks post-dose. The purpose of the present study was to reanalyse the alendronic acid data to examine the effect of truncating the length of follow-up on the calculated t1/2γ. Patients and methods: Twenty-one postmenopausal women with osteoporosis (mean age 66 years) received intravenous alendronic acid 30mg over 4 consecutive days (7.5 mg/day), and urinary excretion of alendronic acid was monitored over the following 18–24 months. Terminal elimination half-life was originally calculated by log-linear regression of the percentage retained versus time curve between days 240 and 540 and substituting the slope of the regression line into the equation, t1/2γ = −log 2/slope. These data were reanalysed based on the period up to 30 days. Results: Data were sufficient for analysis of pharmacokinetics in 11 patients. A mean t1/2γ of approximately 11 years was reported previously, based on analysis of data between days 240 and 540. Recalculating the ‘terminal’ half-life of alendronic acid using only data from the first 30 days resulted in an ‘observed’ half-life of only 11 days. Conclusion: This analysis illustrates the importance of sufficient length of follow-up to accurately characterise the true terminal elimination half-life of bisphosphonates. The relatively short (expressed in units of days rather than years) terminal elimination half-lives reported for some bisphosphonates based on only 30 days of follow-up or less are likely to substantially underestimate the true terminal elimination half-lives.

Treatment of Male Osteoporosis: Recent Advances with Alendronate

Overall, the data from the two alendronate studies clearly document the efficacy and safety of alendronate in osteoporotic men. The positive effects of alendronate on BMD, markers and fractures are very consistent between studies. Importantly, they are also very consistent with the results of multiple clinical studies conducted in postmenopausal women with osteoporosis. Treatment with 10 mg alendronate for 2 years produced significant and clinically meaningful increases in BMD, similar to those previously observed in postmenopausal women. Data from studies including men and women confirm the similarity of response suggested by single-gender studies. Consistent with much larger studies in postmenopausal women, alendronate 10 mg/day also reduced the incidence of new vertebral fracture and, correspondingly, reduced height loss. The safety and tolerability of alendronate in men was favorable and consistent with the safety profile previously observed in postmenopausal women. Alendronate represents an important and needed therapeutic advancement in the management of osteoporosis in men.

Therapeutic equivalence of alendronate 35 milligrams once weekly and 5 milligrams daily in the prevention of postmenopausal osteoporosis

OBJECTIVE To evaluate the efficacy and safety of alendronate 35 mg once weekly compared with alendronate 5 mg daily in the prevention of osteoporosis. METHODS We compared the efficacy and safety of treatment with alendronate 35 mg once weekly (n = 362) and alendronate 5 mg daily (n = 361) in a 1-year, double-blind, multicenter study of postmenopausal women (6 months or greater), aged 40–70 years, with lumbar spine and femoral neck bone mineral density T-scores between −2.5 and 1. The primary efficacy end point was the comparability of lumbar spine bone mineral density increases, defined by strict prespecified criteria. RESULTS Mean increases in lumbar spine bone mineral density at 12 months were equivalent (difference between the alendronate 35-mg once-weekly group and the alendronate 5-mg daily group [90% confidence interval] at month 12 was −0.3% [−0.6, 0.1], well within the prespecified bounds of ±1.0%). Bone mineral density increases at other skeletal sites and effects on bone turnover were also virtually identical for the two dosing regimens. Both treatment regimens were well tolerated, and the larger weekly unit dose was not associated with an increased frequency of upper gastrointestinal events. CONCLUSION Alendronate 35 mg once weekly is therapeutically equivalent to alendronate 5 mg daily and provides patients with greater dosing convenience, in addition to the proven efficacy of alendronate and good tolerability.

Weekly Oral Alendronic Acid in Male Osteoporosis

AbstractObjective: To evaluate the efficacy and tolerability of alendronic acid 70mg once weekly for the treatment of male osteoporosis. Patients and methods: This randomised, double-blind, placebo-controlled, 12-month trial compared the effect of alendronic acid 70mg once weekly or placebo (randomised 2: 1) on bone mineral density (BMD) in 167 men with spine or hip BMD at least 2 standard deviations (SD) below the mean for young normal white males or nontraumatic fracture. All patients received calcium and vitamin D (colecalciferol). We measured lumbar spine, hip and total body BMD, and biochemical markers of bone turnover. Fractures were collected as adverse events. Results: Alendronic acid 70mg once weekly produced significant BMD increases from baseline of 4.3% at the spine, 2.1% at the femoral neck, 2.4% at the trochanter, and 1.4% at the total body, which were all significantly greater than placebo (p < 0.05). The increase at the lumbar spine was significant relative to baseline and placebo after 6 months of treatment (p < 0.001). The treatment effect was consistent regardless of BMD, age, height, weight, body mass index (BMI) and hypogonadal status at baseline. Alendronic acid significantly decreased biochemical markers of bone turnover relative to baseline and placebo. Alendronic acid was generally well tolerated, with an incidence of gastrointestinal adverse events similar to placebo. Conclusion: Alendronic acid 70mg administered once weekly is an effective and convenient alternative to daily dosing for the treatment of male osteoporosis.