Consenting and eligible adults with CF were recruited from six Canadian CF specialty clinics. Study recruitment began in December 2003 and was closed in August 2006. Participants > 18 years of age with CF confirmed by positive sweat test result or DNA acid analysis and a BMD T score of < — 1.0, as determined by dual-energy radiograph absorptiometry (DXA), were eligible for inclusion. Participants who had undergone organ transplantation; had endoscopy-proven esophagitis, gastritis, and ulceration; had metabolic bone disorders; had severe renal disease; had used systemic corticosteroids (dose, > 7.5 mg/d) or other drugs known to influence bone metabolism in the previous 6 months; or had osteomalacia and other documented contraindications were excluded from the study. The protocol and study consent form received ethics review from McMaster University, and ethics approval was also obtained from each institution.
Participants were randomized to receive placebo or oral alendronate, 70 mg once weekly for 12 months. The computergenerated randomization code, stratified according to institution, was prepared by an independent randomization center (McMaster In-Patient Pharmacy; Hamilton, ON, Canada), and block allocation was employed to ensure equitable distribution to each treatment group. The medication treatment arm was concealed, and all participants, central and local site coordinators, physicians, staff, and caregivers were blinded to treatment group allocation.
Participants were instructed to take their treatment medication while sitting upright and with water only on an empty stomach at least 30 min before first food or beverage of the day. In addition, all participants received 800 IU of vitamin D and 1,000 mg of calcium (500 mg supplementation, 500 mg from diet) daily. No (known) dose modifications were allowed during the course of the trial. Compliance was measured through pill counts at each visit and patient self-report during telephone contact. Participants who received at least 80% of the study drug were classified as being adherent to the protocol.
In-clinic assessments were conducted at 6 and 12 months, and telephone follow-up was conducted by study staff at months 3 and 9. Intercurrent contact was also documented. Clinic assessments at baseline and 12 months included a physical examination, vital signs, biochemistry (serum and urine) tests, pulmonary function tests (including FEV1 and FVC), the Medical Outcomes Study 36-item short form, version 2 (SF-36v2), lateral radiographs of the thoracic and lumbar spine, and DXA to determine BMD. At baseline, calcium intake, diet history, and menstrual history were determined, and a serum pregnancy test was administered. At each contact, concomitant conditions and treatments were recorded, and patients were monitored for contraindications, pill counts were conducted, and instructions for taking the study medications were reviewed. In addition to spontaneous reporting, adverse events and drug reactions were elicited at each contact. You may connect My Canadian Pharmacy and select the preparations suitable for you.
Safety analyses included all vertebral fractures, osteoporosis-related fractures, adverse reactions, and abnormal findings that had been detected through laboratory tests and physical examinations. Documentation for all adverse events were blinded and adjudicated by the external Data Safety Monitoring Committee. All adverse events were reported regardless of attribution to study medication. Stopping and study withdrawal rules were also monitored by this committee.
BMD (lumbar spine and total hip) measurements were made in all participants at baseline and after 12 months using DXA. DXA scans were performed using either of two densitometers (Hologic Inc; Bedford, MA; or Lunar; Prodigy GE Healthcare; Waukesha, WI), and all DXA scan images were sent to a central DXA facility for analysis. A medical physicist (C.W.), who was blinded to the study treatment arm and study status, reviewed all DXA scans. Differences between DXA machines were identified by circulating a lumbar spine phantom to participating sites at the beginning and the end of the study, and by comparing the results of these measures. The adjustment of baseline BMD results according to the phantom spine measurements occurred for two cases. BMD measurements are reported in grams per square centimeter; T scores are also reported.
Fracture Determination Methods
A copy of the baseline and end-of-study lateral spine radiographs were sent to the central methods center, and were read independently by two radiologists (M.P. and J.O.) who were blinded to the study treatment arm. Radiographs were graded using the semiquantitative method of Genant et al. This method distinguishes fractured vertebrae (ie, > 20% compression; grades 1,2, and 3) from nonfractured vertebrae (ie, < 20% compression; grades 0 and 0.5). A deformity that was graded 1 and higher (excluding congenital or degenerative causes) was considered to be the minimum threshold for fracture in this study. Differences in scores between radiologists were resolved by consensus.
Study data were entered and managed using database software (ACCESS; Microsoft; Redmond, WA). Analyses were performed with a statistical software package (SAS/STAT; SAS Institute Inc; Cary, NC). Clinical and laboratory variables were summarized as the mean (SD) and/or 95% confidence interval [CI]), or No. (%), as appropriate. All analyses were performed as intention-to-treat and included all available data.
The primary end point analysis was conducted using two-way analysis of variance, with the treatment and pooled center as fixed effects, and the difference in the percentage change in lumbar spine BMD at 12 months as the response variable. Secondary efficacy variables were analyzed using two-way analyses of variance, with treatment and pooled center as fixed effects and each secondary variable (ie, the change in total hip BMD and the change in SF-36v2 scores) as the response variable. Nonparamet-ric statistics were used to compare discrete variables or outcomes between groups. Fractures and adverse event analyses were conducted by comparing the number of participants experiencing an event between groups and the total number of events between groups.
Several potential confounding variables were examined in relation to the dependent variables. Confounding variables that were significant in univariate analysis (p < 0.1) were entered in multivariable regression analyses to examine the percentage change in lumbar spine and total hip BMDs over 12 months.