Open-label study of treatment with alendronate sodium plus vitamin D in men and women with osteoporosis in Thailand.

BACKGROUND: It is generally believed that Thai people do not suffer from hypovitaminosis D because there is abundant sunlight throughout the year, and that taking vitamin D supplements could result in abnormally high levels of vitamin D. This is a Thai FDA-driven study to investigate this risk over a period of 26 weeks of taking alendronate sodium/vitamin D3 combination tablets. METHODS: Osteoporosis patients in Thailand were recruited to a multicenter, open-label, 6-month trial of oral alendronate sodium 70 mg/vitamin D3 5600 IU. Patients received study medication once a week for 26 weeks. Serum 25-hydroxyvitamin D (25(OH)D) and Beta-CrossLaps (ß-CTx) levels were measured at baseline and 26 weeks. The primary endpoint was the proportion of patients with 25(OH)D ≥ 50 ng/mL at week 26; it was hypothesized that 26 weeks' treatment would not result in 25(OH)D serum levels ≥ 50 ng/mL in > 7% of osteoporosis patients. RESULTS: One hundred ninety-eight patients were recruited. At baseline, 67.2% of the patients had 25(OH)D < 30 ng/mL; this declined to 34.4% by week 26. The mean 25(OH)D level improved from 27.8 ng/mL at baseline to 33.6 ng/mL at week 26. Five patients (2.69% of the full analysis set) had 25(OH)D levels ≥ 50 ng/mL at 26 weeks. The highest 25(OH)D level, 64.3 ng/mL, was observed in a patient whose baseline level was 102.2 ng/mL. The majority (62.9%) of the patients had optimal 25(OH)D levels (30-50 ng/mL). ß-CTx levels were reduced by 57.7% after 26 weeks' treatment. No clinically significant cases of hypercalcemia which could be associated with hypervitaminosis D were identified during physical examination, in vital signs, or in laboratory results. Overall, 73 patients (36.9%) reported at least one adverse event (AE), with 13 (6.6%) reporting drug-related AEs. Four patients discontinued due to AEs, two of which were drug-related. Serious AEs were reported for four patients, of which one was considered drug-related. CONCLUSIONS: Oral alendronate sodium 70 mg plus vitamin D3 5600 IU once weekly had an acceptable safety profile in this study, and increased serum 25(OH)D and reduced ß-CTx levels in osteoporosis patients. This treatment improved 25(OH)D levels, without causing abnormally high levels, after 26 weeks' treatment. TRIAL REGISTRATION: Clinical Trials.gov NCT01437111 , Registered September 19, 2011.

Odanacatib, a cathepsin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density.

Cathepsin K, a cysteine protease expressed in osteoclasts, degrades type 1 collagen. Odanacatib selectively and reversibly inhibited cathepsin K and rapidly decreased bone resorption in preclinical and phase I studies. A 1-year dose-finding trial with a 1-year extension on the same treatment assignment was performed in postmenopausal women with low bone mineral density (BMD) to evaluate the safety and efficacy of weekly doses of placebo or 3, 10, 25, or 50 mg of odanacatib on BMD and biomarkers of skeletal remodeling. Women with BMD T-scores of -2.0 or less but not less than -3.5 at the lumbar spine or femoral sites were randomly assigned to receive placebo or one of four doses of odanacatib; all received vitamin D with calcium supplementation as needed. The primary endpoint was percentage change from baseline lumbar spine BMD. Other endpoints included percentage change in BMD at hip and forearm sites, as well as changes in biomarkers of skeletal remodeling. Twenty-four months of treatment produced progressive dose-related increases in BMD. With the 50-mg dose of odanacatib, lumbar spine and total-hip BMD increased 5.5% and 3.2%, respectively, whereas BMD at these sites was essentially unchanged with placebo (-0.2% and -0.9%). Biochemical markers of bone turnover exhibited dose-related changes. The safety and tolerability of odanacatib generally were similar to those of placebo, with no dose-related trends in any adverse experiences. In summary, 2 years of weekly odanacatib treatment was generally well-tolerated and increased lumbar spine and total-hip BMD in a dose-related manner in postmenopausal women with low BMD.

Alendronate/vitamin D3 70 mg/2800 IU with and without additional 2800 IU vitamin D3 for osteoporosis: results from the 24-week extension of a 15-week randomized, controlled trial.

Although vitamin D supplementation is a fundamental part of osteoporosis treatment, many patients do not regularly take adequate amounts. A once-weekly (OW) alendronate (ALN) preparation that includes 2800 IU of vitamin D3 in a single combination tablet (ALN+D2800) is available for treating patients and ensuring intake of vitamin D that is consistent with existing guidelines. This randomized, double-blind study extension was conducted to evaluate the safety and tolerability of ALN+D2800 and ALN+D2800 plus an additional 2800 IU vitamin D3 single tablet supplement (ALN+D5600) administered for 24 weeks in men and postmenopausal women with osteoporosis previously treated OW for 15 weeks with either ALN or ALN+D2800. The primary endpoint was the proportion of participants who developed hypercalciuria (defined as a 24-hour urine calcium >300 mg in women or >350 mg in men and an increase of >25% versus randomization baseline) at week 39. The key secondary endpoint was the proportion of participants with vitamin D insufficiency (serum 25(OH)D <15 ng/mL [37.4 nmol/L]) at the end of the study. Hypercalciuria incidence (4.2% [ALN+D5600] vs. 2.8% [ALN+D2800]), did not differ between groups (p = 0.354). No participants developed hypercalcemia. Among the participants with vitamin D insufficiency at the week 0 baseline, the prevalence of insufficiency at the end of the study was reduced by 92% in the ALN+D5600 group and by 86% in the ALN+D2800 group. The incidences of clinical adverse experiences, including drug-related adverse experiences, were similar in both groups. In subjects previously treated with ALN+D2800 for 15 weeks, the addition of 2800 IU D3 for 24 weeks did not produce hypercalcemia nor increase the risk of hypercalciuria.

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.

Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension.

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.