Black DM, Thompson DE, Bauer DC et al, for the FIT Research Group. Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial. J Clin Endocrinol Metab 2000;85 (11):4118-4124.

A multicenter, randomized, placebo-controlled trial. The purpose of the study was to assess the effect of alendronate treatment on fracture risk reduction in women with vertebral fracture with that in women without existing vertebral fracture (with BMD T-score of less than –2.5), and to assess the effect of alendronate in these two groups combined. Secondarily, the effect of alendronate on clinical fracture risk with regard to time was also evaluated.

A total of 6459 women aged 55 to 80 years were randomly assigned to treatment, 2027 in the Vertebral Fracture Arm and 4432 in the Clinical Fracture Arm (women without vertebral fracture and femoral neck T-score <–2.5). Dosage of alendronate was initially 5 mg/day for 2 years, but was increased to 10 mg/day at the second annual visit. Women with existing vertebral fracture received alendronate for 3 years; those without vertebral fracture received alendronate for 4 years. Clinical fracture was defined as a fracture diagnosed by a community physician and confirmed by written reports of radiographs or other tests. Lateral spine radiographs were obtained according to published guidelines at baseline and at year 2 and 3 (Vertebral Fracture Arm), and again at year 4 for those in the Clinical Fracture Arm. A new radiographic vertebral fracture was defined as a decrease of 20% and at least 4 mm in the height of any vertebral body from baseline to end of the study. BMD was measured annually at the hip and posterior-anterior spine in all participants.

Baseline BMD:

• Mean total hip BMD: 0.66 g/cm² in the Vertebral Fracture Arm and
  0.64 g/cm² in the Clinical Fracture Arm.
• Mean lumbar spine BMD: 0.79 g/cm² in the Vertebral Fracture Arm and
  0.78 g/cm² in the Clinical Fracture Arm.

Bone HG, Hosking D, Devogelaer J-P, et al. Ten years’ experience with alendronate for the treatment of osteoporosis in postmenopausal women. N Engl J Med 2004;350:1189–1199.

Two identical, concurrent multicenter, double-blind, randomized, placebo controlled phase 3 studies (designed to permit pooling of results), enrolled 994 postmenopausal women to evaluate the efficacy and tolerability of alendronate.Women enrolled in the original study were randomly assigned to receive alendronate 5 mg, 10 mg, 20 mg, or placebo daily. In the original study, women assigned to 20 mg were switched (blindly) to 5 mg at year 3 and continued on 5 mg through years 4 and 5. In study extensions for years 6 to 7 and years 8 to 10, all women previously assigned to the 20 mg/5 mg group were switched to placebo.

Cranney A, Guyatt G, Griffith L et al. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23(4):570-578.

Systematic review of meta-analyses of available data for alendronate 5–40 mg, risedronate, etidronate, calcitonin, raloxifene, HRT, calcium, vitamin D, and fluoride to provide the best current estimate of the impact of osteoporosis treatments. Only randomized, controlled trials were included.

To understand the relative effectiveness of different osteoporosis treatments, head-to-head studies must be conducted. This systematic review of meta-analyses may not reliably show the relative impact of treatment effects for the following reasons: 1. Treatment response across patient populations may differ due to differences in bone density, fracture status, postmenopausal status, cointerventions, and comorbidity. 2. In some cases, confidence intervals around the magnitude of effect overlapped; therefore, apparent differences in point estimates may not indicate true differences in the magnitude of effect.
3. Dosage and administration across therapies may not be comparable.
4. Methodological differences, as opposed to relative treatment potency, may explain differences in treatment effects.

Hosking D, Adami S, Felsenberg D et al. Once weekly alendronate produces a greater decrease in bone resorption than daily risedronate. Poster presented at: World Congress on Osteoporosis (WCO); May 10-14, 2002; Lisbon, Portugal.

Hosking D, Adami S, Felsenberg D et al. Comparison of change in bone resorption and bone mineral density with once weekly alendronate and daily risedronate: a randomized, placebo-controlled study. Cur Med Res Opin 2003;19(5):preprint 1-12.

A 3-month randomized, double-blind, placebo-controlled, multicenter, multinational study with double-blind extensions to 12 months from the onset of therapy. The study objective was to compare the efficacy of alendronate
70 mg and risedronate 5 mg by evaluating the rate of bone turnover and BMD changes. Safety profile and tolerability were also assessed.

Five hundred forty-nine healthy women aged 60 to 90 years, and at least
2 years postmenopausal, were randomized to initiate treatment with alendronate 70 mg once weekly (n=219), risedronate 5 mg daily (n=222), or placebo (n=108). In the once-weekly arm, patients took alendronate 70 mg or placebo once weekly with a full glass of plain water upon rising for the day and waited at least 30 minutes before food, drink (other than water), or other medication. In the daily arm, patients took risedronate 5 mg or placebo daily
2 hours before or after any food or drink (except water) or other medication, and/or at least 30 minutes before bedtime.

Levis S, Quandt SA, Thompson D et al, for the FIT Research Group. Alendronate reduces the risk of multiple symptomatic fractures: Results from the Fracture Intervention Trial. J Am Geriatr Soc 2002;50(3):409-415.

Primary analysis of data from a randomized, placebo-controlled, double-blind study. The objective of the analysis was to evaluate the effect of alendronate on the occurrence rate of multiple symptomatic fractures among women with osteoporosis. The study reports women’s total symptomatic fracture experience over a 3- to 4-year follow-up period.

Analysis of fracture-event data was based on a subset of participants from the Fracture Intervention Trial (FIT). Of a total of 3658 women, 2027 were from the Vertebral Fracture Study and 1631 patients were from the Clinical Fracture Study. The primary endpoint was multiple symptomatic fractures that occurred during the postrandomization period. Data were examined by intent-to-treat analysis. Only within stratum-comparison contributed to the relative risk estimation. A stratified proportional hazards model was used to estimate relative risk and calculate 95% confidence interval. A stratified log-rank test was used to assess the difference between the cumulative incidence curves. A stratified Andersen-Gill model was used to compare the occurrence rate of symptomatic fracture in both treatment groups.

Patient Characteristics:

• Women aged 55 to 80 years, postmenopausal for at least 2 years.
• Femoral neck BMD: 0.68 g/cm² or less, corresponding to a BMD cutoff of about –1.6 SD below the mean for normal, young adult Caucasian women.

Lewiecki EM, Rosen C, Bockman RS et al. Alendronate 70 mg once weekly and alendronate 10 mg once daily preference study in postmenopausal women with osteoporosis. Poster presented at: American Society for Bone and Mineral Research (ASBMR) 23rd Annual Meeting; October 12-16, 2001; Phoenix, Arizona, USA.

A 9-week US multicenter, randomized, open-label, crossover study designed to assess patient preference, convenience, and overall expected compliance with once-weekly alendronate and with once-daily alendronate.

A total of 279 treatment-naive, postmenopausal women with osteoporosis were randomized in a 1:1 ratio to receive either alendronate 10 mg once daily or alendronate 70 mg once weekly for study weeks 1 through 4. After study week 4, there was an off-drug interval (week 5), following which patients were crossed over to receive the other dosage form for study weeks 6 through 9. Following completion of the study (week 9), subject outcomes were determined by a questionnaire that quantified whether alendronate weekly or daily is preferred, which treatment is considered the more convenient, and which treatment would provide greater overall long-term compliance.

Pols HAP, Felsenberg D, Hanley DA et al, for the Fosamax International Trial Study Group. Multinational, placebo-controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: Results of the FOSIT study. Osteoporos Int 1999;9(5):461-468.

A multinational, multicenter, randomized, doublemasked, placebo-controlled study. The study objective was to evaluate the efficacy and tolerability of alendronate in a large and diverse multinational population of postmenopausal women with low bone mass.

Following a 2- to 4-week baseline period, 1908 women, aged 39 to 84 years, were randomized to receive either alendronate 10 mg (n=950) or placebo (n=958) once daily for 12 months. All participants had been postmenopausal for at least 3 years and had a lumbar spine BMD T-score of at least 2 SD below the mean for mature, premenopausal women. Bone densitometry was performed at baseline and at months 3, 6, and 12. BMD was measured using Hologic QDR or Lunar DPX densitometers at the lumbar spine (primary endpoint), femoral neck, trochanter, and total hip. The occurrence of clinical fractures was captured as adverse events. An electrocardiogram and complete physical were performed at screening and at 12 months. Limited physical exams were performed at subsequent visits, and clinical laboratory tests were performed at each visit.

Baseline BMD:

• Using Hologic QDR densitometers, the mean lumbar spine BMD was
  0.72 g/cm² (SD=0.08) in both the alendronate and placebo groups.
• Using Lunar DPX densitometers, the mean lumbar spine BMD was
  0.84 g/cm² (SD=0.08) in the alendronate group and 0.83 g/cm² (SD=0.09) in the placebo group.

Yates AJ, Rodan GA. Alendronate and osteoporosis. DDT 1998;3(2):69-78.

A review of the alendronate development program, including pharmacological properties, mode of action information, and preclinical safety and efficacy data. Phase III clinical studies that demonstrated effect on bone density and fracture risk reduction were also reviewed.