Efficacy and tolerability of once-monthly oral ibandronate (150 mg) and once-weekly oral alendronate (70 mg): additional results from the Monthly Oral Therapy With Ibandronate For Osteoporosis Intervention (MOTION) study.

BACKGROUND: The MOTION (Monthly Oral Therapy with Ibandronate for Osteoporosis Intervention) study reported that once-monthly ibandronate was noninferior to once-weekly alendronate in terms of increasing bone mineral density (BMD) at the lumbar spine and total hip over 12 months. On analysis of secondary and exploratory end points in MOTION, which included trochanter and femoral neck BMD, monthly ibandronate was found to be noninferior to weekly alendronate. The coprimary, secondary, and exploratory BMD end points from MOTION have been previously reported. OBJECTIVE: This report presents additional results from the MOTION study, including response rates in terms of lumbar spine and total hip BMD gains above baseline; findings from a comparison of serum concentrations of bone turnover markers; and tolerability analysis, including adverse events that led to withdrawal and gastrointestinal (GI) adverse events. METHODS: MOTION was a 12-month (with 15-day follow-up), randomized, multinational, multicenter, double-blind, double-dummy, parallel-group, noninferiority study in postmenopausal women aged 55 to <85 years with osteoporosis. Patients were randomly assigned to receive 150-mg-monthly oral ibandronate and weekly alendronate-matched placebo, or 70-mg-weekly oral alendronate and monthly ibandronate-matched placebo, for 12 months. At baseline, day 7 of treatment, 3 and 6 months, 6 months + 7 days, and 12 months, serum concentrations of markers of bone resorption (C-telopeptide of the a chain of type 1 collagen [sCTX]) and bone formation (serum N-terminal propeptides of type 1 collagen) were measured in a subset of the total trial population. At baseline and month 12, BMD was measured using dual-energy x-ray absorptiometry. Exploratory analyses of patients whose spine, total hip, and trochanter BMD at 12 months were above baseline (responders) were also performed. RESULTS: A total of 1760 women were enrolled (ibandronate, 887 patients; alendronate, 873). The median changes in the trough concentrations of sCTX were -75.5% with monthly ibandronate and -81.2% with weekly alendronate. The percentage of patients with mean lumbar spine and total hip BMD gains above baseline (responders) were 90% and 87%, respectively, for ibandronate and 92% and 90%, respectively, for alendronate. GI adverse events were reported in

Denosumab Versus Risedronate in Glucocorticoid-Induced Osteoporosis: Final Results of a Twenty-Four-Month Randomized, Double-Blind, Double-Dummy Trial.

OBJECTIVE: Clinical trial results have shown that, in glucocorticoid-treated patients, treatment with denosumab 60 mg subcutaneously once every 6 months (Q6M) increased spine and hip bone mineral density (BMD) at month 12 significantly more than treatment with risedronate 5 mg orally once daily (QD). The present analysis was performed to compare efficacy and characterize safety through month 24. METHODS: This phase III study enrolled men and women ≥18 years old who had received ≥7.5 mg daily prednisone or equivalent for <3 months (glucocorticoid-initiating) or for ≥3 months (glucocorticoid-continuing) before screening. All patients <50 years old had a history of osteoporotic fracture. Glucocorticoid-continuing patients ≥50 years old had T scores of -2.0 or less (or -1.0 or less with fracture history). Patients were randomized (1:1) to receive denosumab 60 mg subcutaneously Q6M or risedronate 5 mg orally QD for 24 months, with daily calcium and vitamin D. RESULTS: Of 795 patients, 590 (74.2%) completed the study (in the glucocorticoid-initiating group, 109 of 145 patients treated with denosumab and 117 of 145 patients treated with risedronate; in the glucocorticoid-continuing group, 186 of 253 patients treated with denosumab and 178 of 252 patients treated with risedronate). Denosumab was superior to risedronate in increasing lumbar spine and total hip BMD at all time points assessed, among glucocorticoid-initiating patients (24-month lumbar spine: BMD increase of 6.2% versus 1.7%, respectively [P < 0.001]; 24-month total hip: BMD increase of 3.1% versus 0.0% [P < 0.001]) and among glucocorticoid-continuing patients (24-month lumbar spine: BMD increase of 6.4% versus 3.2% [P < 0.001]; 24-month total hip: BMD increase of 2.9% versus 0.5% [P < 0.001]). Adverse events, serious adverse events (including infections), and fractures were similar between treatment groups. CONCLUSION: Denosumab was superior to risedronate in terms of increases in spine and hip BMD through month 24, and the safety profile was similar between treatment groups. Denosumab may offer a new osteoporosis treatment option for glucocorticoid-treated patients.

Denosumab versus risedronate in glucocorticoid-induced osteoporosis: a multicentre, randomised, double-blind, active-controlled, double-dummy, non-inferiority study.

BACKGROUND: Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis and is associated with an estimated annual fracture rate of 5%. We aimed to assess the efficacy and safety of denosumab compared with risedronate in glucocorticoid-induced osteoporosis. METHODS: We did a 24-month, double-blind, active-controlled, double-dummy, non-inferiority study at 79 centres in Europe, Latin America, Asia, and North America. Eligible patients were aged 18 years or older and were receiving glucocorticoids (≥7·5 mg prednisone daily, or equivalent) for at least 3 months (glucocorticoid continuing) or less than 3 months (glucocorticoid initiating) before screening. Patients younger than 50 years needed to have a history of osteoporosis-related fracture; glucocorticoid-continuing patients aged 50 years or older needed a lumbar spine, total hip, or femoral neck bone mineral density T score of -2·0 or less, or -1·0 or less if they had a history of osteoporosis-related fracture. Participants were randomly assigned (1:1) to either 60 mg subcutaneous denosumab every 6 months and oral placebo daily for 24 months, or 5 mg oral risedronate daily and subcutaneous placebo every 6 months for 24 months. Randomisation was stratified by sex within each subpopulation, and was done with an interactive voice-response system. Active drugs and corresponding placebos had identical packaging, labels, and appearance. The primary outcome was non-inferiority of denosumab to risedronate in terms of percentage change from baseline in lumbar spine bone mineral density at 12 months based on non-inferiority margins (-0·7 and -1·1 percentage points for the glucocorticoid-continuing and glucocorticoid-initiating subpopulations, respectively). Superiority was also assessed as a secondary outcome. The primary efficacy set included all randomly assigned participants who had a baseline and postbaseline lumbar spine bone mineral density measurement, and was analysed according to randomised treatment assignment. The safety analysis set included all randomly assigned participants who received at least one dose of investigational product, and was analysed by actual treatment received. This study is registered with ClinicalTrials.gov (NCT01575873) and is completed. FINDINGS: Between March 28, 2012, and June 30, 2015, 795 patients, 505 of whom were glucocorticoid continuing and 290 of whom were glucocorticoid initiating, were enrolled and randomly assigned (398 to denosumab, 397 to risedronate). Denosumab was both non-inferior and superior to risedronate at 12 months for effect on bone mineral density at the lumbar spine in both glucocorticoid-continuing (4·4% [95% CI 3·8-5·0] vs 2·3% [1·7-2·9]; p<0·0001) and glucocorticoid-initiating (3·8% [3·1-4·5] vs 0·8% [0·2-1·5]; p<0·0001) subpopulations. Incidence of adverse events, serious adverse events (including infections), and fractures was similar between treatment groups. The most common adverse events were back pain (17 [4%] patients in the risedronate group and 18 [5%] in the denosumab group) and arthralgia (21 [5%] patients in the risedronate group and 17 [4%] in the denosumab group). Serious infection occurred in 15 (4%) patients in the risedronate group and 17 (4%) patients in the denosumab group. INTERPRETATION: Denosumab could be a useful treatment option for patients newly initiating or continuing glucocorticoids who are at risk of fractures. FUNDING: Amgen.

Ten years' experience with alendronate for osteoporosis in postmenopausal women.

BACKGROUND: Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years. METHODS: The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study. RESULTS: Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit. CONCLUSIONS: The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects.

Safety considerations with bisphosphonates for the treatment of osteoporosis.

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although evidence supports a good safety profile for these agents, numerous tolerability issues have been associated with their use. This review provides an overview of the safety issues associated with the nitrogen-containing class of bisphosphonates and discusses the potential effect of these issues on adherence. The review specifically considers upper gastrointestinal (UGI) adverse events (AEs), renal toxicity, influenza-like illness, osteonecrosis of the jaw and evidence on how to treat or prevent these events. In clinical trials, UGI AEs, including severe events such as oesophageal ulcer, oesophagitis and erosive oesophagitis, have been reported at similar frequencies in placebo- and active-treatment arms. However, postmarketing studies have highlighted UGI AEs as a concern. These studies show that a significant portion of patients are less compliant with administration instructions outside strict clinical trial supervision, and when oral bisphosphonates are not administered as directed, patients are more likely to experience UGI AEs. Some clinical trials with oral bisphosphonates have suggested that a decrease in the frequency of administration may lead to improvement in gastrointestinal tolerability. In the authors' experience, the issue of UGI tolerability can be minimised by explaining to the patient and/or caregiver the importance of following administration instructions. Intravenous (IV) bisphosphonates have been recently approved for use in osteoporosis, offering an alternative regimen for patients with osteoporosis. Earlier generation IV bisphosphonates (e.g. etidronate) have been associated with acute renal failure. Alternatively, late-generation IV bisphosphonates (i.e. ibandronate) have shown a better safety profile in relation to renal toxicity. Influenza-like illness, often referred to as an acute-phase reaction, covers symptoms such as fatigue, fever, chills, myalgia and arthralgia. These symptoms are transitory and self-limiting and usually do not recur after subsequent drug administration. Symptoms of influenza-like illness have been associated with both IV and oral bisphosphonates. Osteonecrosis of the jaw has also been associated with IV bisphosphonate treatment, particularly in patients treated with high doses. A small number of patients with cancer and osteoporosis using oral bisphosphonates have also reported this AE. As osteonecrosis of the jaw is difficult to treat and is often associated with dental procedures and poor oral hygiene, preventive measures seem to be the best management option for patients taking bisphosphonates.Overall, the safety and tolerability profile of the nitrogen-containing bisphosphonates is good, and long-term treatment does not appear to carry a risk of serious AEs. By encouraging adherence to administration instructions physicians can minimise certain complications, such as UGI intolerability. By being aware of other potential safety issues, such as renal impairment, influenza-like illness and osteonecrosis of the jaw, physicians can detect these AEs early in the course of treatment.

Prevention of bone loss in postmenopausal women treated with lasofoxifene compared with raloxifene.

OBJECTIVE: Osteoporosis is a significant health problem in postmenopausal women. Consequently, new and effective therapies are being sought to preserve bone mass and prevent osteoporosis in this population of women. The objective of this study was to compare the effects of lasofoxifene with raloxifene and placebo on indices of bone health in postmenopausal women. DESIGN: A randomized, double-blind, placebo- and active treatment-controlled study of 2 years duration was conducted. Women included 410 postmenopausal women aged 47 to 74 years. The four treatment groups were: lasofoxifene 0.25 mg/day, or 1.0 mg/day, raloxifene 60 mg/day, or placebo daily. All women received daily calcium and vitamin D supplements. The primary endpoint was percent change from baseline to 2 years in lumbar spine bone mineral density (BMD) in all women having baseline and at least one follow-up bone density measurement. Total hip BMD, biochemical markers of bone turnover, low-density lipoprotein cholesterol, and safety were also evaluated in all women. RESULTS: Both doses of lasofoxifene significantly increased lumbar spine BMD compared with raloxifene (P < or = 0.05) and with placebo treatment (P < or = 0.05). Least squares mean increases (95% CI) from baseline in lumbar spine BMD, compared with placebo, were 3.6% (1.9, 5.2) for lasofoxifene 0.25 mg/day, 3.9% (2.4, 5.5) for lasofoxifene 1.0 mg/day, and 1.7% (0.3, 3.0) for raloxifene. The two doses of lasofoxifene and raloxifene were equally effective at increasing total hip BMD. Lasofoxifene and raloxifene significantly reduced the levels of biochemical markers of bone turnover compared with placebo. In general, the effects of lasofoxifene were greater than the responses to raloxifene. At 2 years, lasofoxifene significantly (P < or = 0.05) reduced low-density lipoprotein cholesterol levels by 20.6% and 19.7% with 0.25 mg/day and 1 mg/day, respectively, compared with raloxifene (12.1%) and placebo (3.2%). Lasofoxifene and raloxifene had a similar adverse event profile with low rate of discontinuations due to adverse events. CONCLUSIONS: Lasofoxifene may be an effective and well-tolerated treatment option for the prevention of bone loss in postmenopausal women.

Alendronate with and without cholecalciferol for osteoporosis: results of a 15-week randomized controlled trial.

OBJECTIVE: Many osteoporosis patients have low 25-hydroxyvitamin D (25OHD) and do not take recommended vitamin D amounts. A single tablet containing both cholecalciferol (vitamin D3) and alendronate would improve vitamin D status concurrently, with a drug shown to reduce fracture risk. This study assessed the efficacy, safety, and tolerability of a once-weekly tablet containing alendronate 70 mg and cholecalciferol 70 microg (2800 IU) (ALN + D) versus alendronate 70 mg alone (ALN). METHODS: This 15-week, randomized, double-blind, multi-center, active-controlled study was conducted during a season when 25OHD levels are declining, and patients were required to avoid sunlight and vitamin D supplements for the duration of the study. Men (n = 35) and postmenopausal women (n = 682) with osteoporosis and 25OHD >or= 9 ng/mL were randomized to ALN + D (n = 360) or ALN (n = 357). MAIN OUTCOME MEASURES: Serum 25OHD, parathyroid hormone, bone-specific alkaline phosphatase (BSAP), and urinary N-telopeptide collagen cross-links (NTX). RESULTS: Serum 25OHD declined from 22.2 to 18.6 ng/mL with ALN (adjusted mean change = -3.4; 95% confidence interval [CI]: -4.0 to -2.8), and increased from 22.1 to 23.1 ng/mL with ALN + D (adjusted mean change = 1.2; 95% CI: 0.6 to 1.8). At 15 weeks, adjusted mean 25OHD was 26% higher (p < 0.001, ALN + D versus ALN), the adjusted relative risk (RR) of 25OHD < 15 ng/mL (primary endpoint) was reduced by 64% (incidence 11% vs. 32%; RR = 0.36; 95% CI: 0.27 to 0.48 [p < 0.001]), and the RR of 25OHD < 9 ng/mL (a secondary endpoint) was reduced by 91% (1% vs. 13%; RR = 0.09; 95% CI: 0.03 to 0.23 [p < 0.001]). Antiresorptive efficacy was unaltered, as measured by reduction in bone turnover (BSAP and NTX). CONCLUSION: In osteoporosis patients who avoided sunlight and vitamin D supplements, this once-weekly tablet containing alendronate and cholecalciferol provided equivalent antiresorptive efficacy, reduced the risk of low serum 25OHD, improved vitamin D status over 15 weeks, and was not associated with hypercalcemia, hypercalciuria or other adverse findings, versus alendronate alone.

Oral ibandronate in the management of postmenopausal osteoporosis: review of upper gastrointestinal safety.

Oral daily bisphosphonates carry a potential for gastrointestinal (GI) adverse events, which has been partly addressed by introducing once-weekly regimens. Nevertheless, the need to follow inconvenient dosing instructions every week could still hinder long-term compliance and therapeutic outcome. In addition, survey data indicates that many patients would prefer a once-monthly rather than once-weekly bisphosphonate dosing regimen. Ibandronate is a potent, nitrogen-containing bisphosphonate specifically developed for less frequent administration. In a pivotal study in postmenopausal osteoporosis, oral ibandronate, administered daily or with a between-dose interval of >2 months, demonstrated robust antifracture efficacy and an overall incidence of upper GI adverse events similar to placebo, even in patients at increased risk of such events. This and other clinical studies conducted in postmenopausal women demonstrate that oral ibandronate has an excellent upper GI safety profile.

Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO).

OBJECTIVE: Ibandronate, a potent nitrogen-containing bisphosphonate, can be administered with extended interval dosing. Patient preferences were assessed for once-monthly versus once-weekly bisphosphonate treatment using a previously developed, open-label, cross-over trial design. RESEARCH DESIGN AND METHODS: This was a 6-month, prospective, randomized, open-label, multi-center study with a two-period and two-sequence cross-over treatment design. After screening, eligible patients (postmenopausal women with osteoporosis) were randomized to once-monthly ibandronate 150 mg followed by once-weekly alendronate 70 mg for a total of 6 months (Sequence A) or once-weekly alendronate followed by once-monthly ibandronate for a total of 6 months (Sequence B). The primary objective was to evaluate patient-reported preference for either the once-monthly ibandronate regimen or the once-weekly alendronate regimen based on responses to a preference questionnaire. RESULTS: A total of 342 patients were enrolled into this study (Sequence A, 170; Sequence B, 172). In the primary analysis of patient preference, 71.4% of women selected once-monthly ibandronate and 28.6% of women selected once-weekly alendronate. Overall, 66.1% preferred the once-monthly ibandronate regimen to the once-weekly alendronate regimen (26.5%) and 7.4% of participants stated no preference for either regimen. The preference rate for once-monthly ibandronate was statistically significant (p < 0.0001). 'Ease of following a treatment regimen for a long time' was the most common reason given for patient preference for both the once-monthly ibandronate (61%, 169/276) and once-weekly alendronate (25%, 70/276) regimens. Additionally, 17% (47/276) of patients who preferred once-monthly ibandronate chose 'it is easier to tolerate side effects' as did 4.3% (12/276) of patients who preferred alendronate. Significantly more women found once-monthly ibandronate to be more convenient (p < 0.0001). CONCLUSIONS: Significantly more women with postmenopausal osteoporosis preferred once-monthly ibandronate therapy to once-weekly alendronate therapy, and found the once-monthly regimen to be more convenient. Ease of following a treatment regimen for a long time was the most common reason given for the patients' preferences.

Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE.

OBJECTIVES: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2 months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here. PATIENTS AND METHODS: BONE was a randomized, double-blind, placebo-controlled, fractureprevention study in 2946 postmenopausal women (age 55 years-80 years; > or = 5 years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4-L4]). Participants received daily calcium (500 mg) and vitamin D (400 IU) plus either placebo, oral daily ibandronate (2.5 mg) or oral intermittent ibandronate (20 mg every other day for 12 doses every 3 months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations. RESULTS: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo. CONCLUSIONS: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients' geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.

Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Combination therapy with alendronate and estrogen for 2 years increases bone mineral density at the spine and hip more than does therapy with either agent alone. Changes in bone mineral density after discontinuation of therapy have not been compared directly. OBJECTIVE: To determine the rate of bone loss when therapy with alendronate, estrogen, or both agents is discontinued. DESIGN: Double-blind, placebo-controlled discontinuation trial. SETTING: 18 U.S. centers. PATIENTS: 244 postmenopausal, hysterectomized women 44 to 77 years of age. INTERVENTION: 2 years of therapy with alendronate, 10 mg/d (n = 92); conjugated estrogen, 0.625 mg/d (n = 143); alendronate and conjugated estrogen (n = 140); or placebo (n = 50). At year 3, women were allocated into five groups: Twenty-eight women continued to take placebo and 44 women continued to take combination therapy, but 50 women taking alendronate, 81 taking conjugated estrogen, and 41 taking combination therapy were switched to placebo. MEASUREMENTS: Bone mineral density and biochemical markers of bone turnover. RESULTS: Women taking alendronate or combination therapy who were switched to placebo for year 3 of the study maintained bone mass. Bone mineral density in these women was 4.1% (CI, 2.6% to 5.7%) and 6.6% (CI, 5.0% to 8.2%) higher, respectively, at the spine (P < 0.001 for both treatment comparisons) and 3.5% (CI, 2.3% to 4.6%) and 3.0% (CI, 1.8% to 4.2%) higher, respectively, at the trochanter (P < 0.001 for both treatment comparisons) than that in women previously taking estrogen who were switched to placebo. In contrast, women who were taking estrogen and were switched to placebo during year 3 experienced a 4.5% decrease at the spine (95% CI, -5.0% to -4.0%) and a 2.4% decrease at the trochanter (CI, -2.7% to -2.1%) (P < 0.001 for both changes). Compared with women who took placebo for 3 years, women who took estrogen for 2 years and were then switched to placebo had a bone mineral density that was 2.9% higher (CI, 1.2% to 4.6%) at the spine (P < 0.05) and 2.9% higher (CI, 1.6% to 4.2%) at the trochanter (P < 0.001). Changes in biochemical markers during year 3 did not differ among the groups that discontinued active treatment. CONCLUSIONS: Accelerated bone loss is seen after withdrawal of estrogen therapy but not after withdrawal of alendronate or combination therapy. The differential effects after withdrawal of therapy should be considered in the management of postmenopausal osteoporosis.

Efficacy and safety of oral weekly ibandronate in the treatment of postmenopausal osteoporosis.

Adherence to oral daily bisphosphonate regimens in postmenopausal osteoporosis is currently suboptimal. Less frequent dosing regimens are likely to improve patient adherence and thus, potentially, patient outcomes. A multicenter, randomized, double-blind, noninferiority study was conducted in 235 women (53-80 yr old; time since menopause >/==" BORDER="0"> 3 yr) with postmenopausal osteoporosis [lumbar spine (L1-L4) bone mineral density (BMD) T-score

Weekly oral alendronic Acid in male osteoporosis.

OBJECTIVE: 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.

Alendronate and risedronate for the treatment of postmenopausal osteoporosis: clinical profiles of the once-weekly and once-daily dosing formulations.

OBJECTIVE: The objective of this review is to present the clinical profiles of the once-weekly and once-daily dosing formulations of alendronate and risedronate, the 2 bisphosphonates currently available in the United States for the prevention and treatment of postmenopausal osteoporosis. DATA SOURCE/STUDY SELECTION: Data were obtained from a MEDLINE literature search of all English language articles published between January 1996 and April 2004 using generic names of the bisphosphonates alendronate and risedronate. Results were refined by incorporating terms such as "osteoporosis," "bone mineral density," "fracture risk," and "adverse events." Randomized, controlled trials of once-daily and once-weekly bisphosphonate therapies were selected. Also selected for review were post hoc analyses and extension studies of the original controlled trials, including more recent data from published abstracts from scientific meetings. DATA EXTRACTION: Relevant portions of articles obtained from the literature search were used to summarize the efficacy and tolerability of the 2 therapies. CONCLUSIONS: In prospective trials, both bisphosphonates were effective in reducing vertebral and hip fractures in women with postmenopausal osteoporosis. In the only prospective trial evaluating hip fracture risk reduction as the primary end point, risedronate was effective at reducing hip fracture vs placebo. Both alendronate and risedronate are available in once-weekly formulations that have efficacy and tolerability profiles similar to the once-daily doses. Clinicians should review all available data for both agents as well as the medical history of the patient to make the most appropriate treatment choice.

Calcium metabolism and correcting calcium deficiencies.

Calcium is the most abundant cation in the human body, of which approximately 99% occurs in bone, contributing to its rigidity and strength. Bone also functions as a reservoir of Ca for its role in multiple physiologic and biochemical processes. This article aims to provide a thorough understanding of the absorptive mechanisms and factors affecting these processes to enable one to better appreciate an individual's Ca needs, and to provide a rationale for correcting Ca deficiencies. An overview of Ca requirements and suggested dosing regimens is presented, with discussion of various Ca preparations and potential toxicities of Ca treatment.

Ibandronate dose response is associated with increases in bone mineral density and reductions in clinical fractures: results of a meta-analysis.

This meta-analysis pooled data from the four phase III clinical trials of ibandronate to assess the relationship between ibandronate dose, changes in bone mineral density, and rates of both clinical and non-vertebral fractures. Individual patient data from the intent-to-treat population of the BONE, IV fracture prevention, MOBILE, and DIVA studies were included for analysis. The relationship between ibandronate dose and bone mineral density at both the lumbar spine and at the total hip was assessed qualitatively. The relationship between lumbar spine bone mineral density and clinical fracture rate, and the relationship between total hip bone mineral density and non-vertebral fracture rate, were assessed both qualitatively and using mathematical models. A total of 8710 patients were included in this analysis. Both lumbar spine and total hip bone mineral density were observed to increase with increasing ibandronate dose. The incidence of all clinical fractures was observed to decrease as lumbar spine bone mineral density increased. A statistically significant inverse linear relationship was observed between percent change in lumbar spine bone mineral density and the rate of clinical fractures (P=0.005). A non-significant curvilinear relationship was observed between percent change in total hip bone mineral density and non-vertebral fracture rate. Increased ibandronate exposure is associated with increasing gains in the lumbar spine bone mineral density and decreasing clinical fracture rates. A non-linear relationship may exist between increases in the total hip bone mineral density and non-vertebral fracture rate.

Quarterly intravenous ibandronate for postmenopausal osteoporosis.

Osteoporosis is under-recognized and undertreated among postmenopausal women. Nitrogen-containing bisphosphonates are its first-line pharmacotherapy. Oral bisphosphonate treatment requires stringent dosing guidelines to minimize gastrointestinal irritation and enhance absorption. This paper reviews the efficacy, safety and tolerability of quarterly intravenous ibandronate 3 mg injection, approved in 2006 in the USA and Europe. Quarterly intravenous ibandronate injection has shown superior efficacy to daily oral ibandronate for bone mineral density increase and fracture prevention. No drug-related serious atrial fibrillation events have been reported with intravenous ibandronate. The regimen has a favorable renal safety profile. Quarterly intravenous ibandronate is administered as a simple 15-30-s intravenous injection in a physician's office and provides a beneficial option for patients who are unable to tolerate oral administration.

Double-blind trial of recombinant gamma-interferon versus placebo in the treatment of rheumatoid arthritis. 1989.

One hundred five patients were enrolled in a 12-week, randomized, prospective, double-blind, placebo-controlled trial of recombinant human gamma-interferon (rHu gamma-IFN) for the treatment of rheumatoid arthritis. Fifty-four patients received rHu gamma-IFN and 51 received placebo. Forty-two patients in each group completed the 12-week trial. Some clinical improvement occurred in both groups of patients. Although the improvement with rHu gamma-IFN was greater than that with placebo, the differences were generally not statistically significant.

Ibandronate: once-monthly and intravenous dosing options for osteoporosis treatment.

Ibandronate is a potent nitrogen-containing bisphosphonate that is currently available as a daily and once-monthly oral formulation for the treatment and prevention of osteoporosis. It has recently been approved for intermittent intravenous administration. The oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE), Monthly Oral iBandronate In LadiEs (MOBILE), and Dosing IntraVenous Administration (DIVA) trials demonstrated that long-term daily and intermittent administration of ibandronate was efficacious for increasing bone mineral density and reducing markers of bone turnover. BONE demonstrated that ibandronate reduced the risk of new vertebral fractures and reduced the relative risk of nonvertebral fractures in higher-risk patients. Histomorphometric evaluations in the BONE and DIVA trials have demonstrated that bone quality is maintained following treatment. Giving patients the option of choosing their dose regimen and route of administration may increase overall adherence to treatment, leading to enhanced fracture protection in patients with osteoporosis.

Improving compliance and persistence with bisphosphonate therapy for osteoporosis.

The successful treatment of patients at increased risk for fracture requires proper diagnosis and the development of a treatment plan that permits the patient to take medications in accordance with dosing guidelines and on the correct schedule. Data indicate that patients with osteoporosis who have good long-term medication compliance experience substantially lower risk of fracture. Persistence with therapy also correlates with better bone mineral density and improved suppression of bone turnover markers. Although bisphosphonates are the most potent currently approved antiresorptive agents, they have special dosing issues that can have a negative impact on long-term persistence. The inconvenience and complexity of some dosing requirements; the potential for adverse effects, especially when dosing recommendations are not followed; and very low absorption rates--even under ideal conditions--all contribute to poor outcomes. Extension of the dosing interval from a once-daily to a once-weekly regimen is associated with comparable efficacy, theoretically may improve gastrointestinal safety, and is associated with substantial improvement in persistence with therapy. However, compliance with weekly regimens remains suboptimal. Monthly dosing of ibandronate, a bisphosphonate, was recently approved by the US Food and Drug Administration (FDA). Although extending the dosing interval may improve compliance and persistence with bisphosphonate therapy, it is important to recognize that missed doses or improper dosing may have greater consequences with extended dosing intervals. This article highlights the importance of educating patients about their diagnosis and long-term treatment plan, including the importance of persistence with therapy and compliance with dosing recommendations.