The Effect of Sodium Monofluorophosphate plus Calcium on Vertebral Fracture Rate in Postmenopausal Women with Moderate Osteoporosis

During the past 30 years, fluoride salts have been studied as agents for the treatment of osteoporosis in postmenopausal women with the expectation that stimulation of osteoblastic proliferation and activity and the subsequent increase in bone formation would be followed by a significant decrease in fracture rates [1-3]. It is widely accepted that fluoride is effective in increasing trabecular bone mass in the spine [4]. However, discrepant results have been obtained from studies evaluating the effects of fluoride salts on cortical bone mass and, more important, on the quality of the newly synthesized bone and on vertebral and nonvertebral fracture rates [5-9]. These differences are probably related to differences in fluoride dose, formulation, and regimen; duration of therapy; and treated populations. Because bone-forming agents such as fluoride are expected to work mainly by increasing bone mineral content without restoring disrupted bone tissue integrity, they may be particularly useful in patients with mild to moderate osteoporosis in whom the microarchitecture of the skeleton is not excessively damaged. To test this hypothesis, we studied the effect of low-dose fluoride (sodium monofluorophosphate [MFP]) plus calcium in a 4-year, randomized, double-blind, controlled clinical trial in postmenopausal women with moderately low bone mineral density (BMD) of the spine. Methods Patients Our study included white postmenopausal women with lumbar (L2 to L4) BMD of the spine below the 90th percentile of the distribution of BMD of the spine seen in Belgian women with osteoporosis [10, 11]. This degree of bone loss corresponded to a T-score of 2.5,in accordance with the operational definition of osteoporosis recently proposed by a World Health Organization study group [12]. Patients were included in the study regardless of whether they had previously had vertebral or nonvertebral fractures; most of the patients were thought to be free of vertebral fractures at enrollment. Previous hip fracture was an exclusion criterion. All patients were free of other causes of osteoporosis, such as diseases or medications known to interfere with bone metabolism; none had been treated with any drug for postmenopausal osteoporosis; and no such treatment was allowed during the study. Hormone replacement therapy was continued, for ethical reasons, in women for whom it had been prescribed before enrollment for purposes other than bone therapy. Randomization was not stratified with respect to hormone replacement therapy. Patients with bone diseases other than osteoporosis, renal insufficiency, hypochlorhydria, or severe chronic disorders that could have interfered with the study were excluded. Study Design Patients were randomly assigned in a blinded manner to one of two therapeutic groups. Every day for 4 years, they received either two chewable tablets that each contained 76 mg of MFP (10 mg of equivalent fluoride [fluoride ion]) and 1250 mg of calcium carbonate (500 mg of equivalent calcium) or two chewable tablets that each contained 1250 mg of calcium carbonate alone and were similar in appearance to the MFP-plus-calcium tablets. Total daily dosages, therefore, were 20 mg of equivalent fluoride plus 1000 mg of calcium in the MFP-plus-calcium group and 1000 mg of calcium in the calcium-only group. The two tablets were taken at different meals. We determined compliance at each study visit by asking each patient for the number of days on which she had not taken the tablets and by counting the unused tablets. Compliance was expressed as the percentage of tablets taken (100% if the patient had taken all of the tablets). Patients received randomization numbers sequentially. Randomization was computer generated in blocks of four according to a strict standard operating procedure by persons who had no contact with the persons in the center who assigned patients to study groups. The randomization code was kept at the study sponsor's facility under secure conditions that were detailed in writing. The clinical research center was given opaque, sealed envelopes, each of which contained the code for one patient. Treatment assignment and other relevant information were thus concealed and were to be revealed only in the case of a medical emergency. Blinding was achieved by using the following procedures. First, the persons who did the visual readings of the spine radiographs saw the codes only after the results were analyzed. Second, the data were analyzed under blinded conditions: that is, a first analysis was done with groups A and B; the analysts did not know which group had received which treatment. Efficacy Evaluation Criteria The primary end point was the number of patients with new vertebral fractures during the 4-year treatment period, in accordance with recently published guidelines for the evaluation of drugs to be registered in Europe for the prevention or treatment of osteoporosis [13]. Standardized lateral radiographs of the thoracic and lumbar spine were obtained at enrollment and at each year of follow-up, for up to 4 years, in a single radiology center. The radiographs were sent to an independent assessor. Films were digitized, and the anterior, middle, and posterior heights of each vertebral body from the fourth thoracic (T4) to the fifth lumbar (L5) were determined (accuracy of the digitizer, 0.025 mm) by a computer program. This was done by persons with no knowledge of treatment assignment or film sequence. A new vertebral fracture (incident fracture) was defined as a reduction of at least 20% and an absolute decrease of at least 4 mm in any height of at least one vertebral body between enrollment and the latest follow-up film. All fractures, including borderline cases, were confirmed by visual reading. This definition was applied to vertebrae that were not fractured at enrollment, whereas fractures present at enrollment were determined on the digitized enrollment radiographs by using the Melton-Riggs 25% unadjusted algorithm [14]. The possible progression of such baseline lesions was assessed with the Vertebral Deformity Index obtained for each vertebra (T5 through L5); these were then summed to obtain the Spine Deformity Index, a continuous measure of vertebral deformities [15]. The Spine Deformity Index was also used as a secondary variable in patients with incident or progressing vertebral deformities, in whom it was expressed as the mean change between the last observed value and baseline. Bone mineral density was measured by using dual-energy x-ray absorptiometry on the same densitometer (Hologic QDR 1000, Waltham, Massachusetts) at 6-month intervals at the lumbar spine (L2 to L4) and the nondominant hip (total hip) after previously described and validated procedures were performed [11, 16]. In our hands, the long-term coefficients of variation of dual-energy x-ray absorptiometry are 0.8% for BMD of the spine and 1.1% for BMD of the total hip [17]. Biochemical determinations of bone remodeling were made at 6-month intervals. Bone formation was assessed by radioimmunoassay of serum bone-specific alkaline phosphatase (Ostase, Hybritech, San Diego, California). For bone resorption, we measured the ratio of urinary hydroxyproline to creatinine on the second fasting urine spot (2-hour morning urine) (Hypronostikon kit, Organon Technika, Oss Boxtel, the Netherlands). All peripheral (nonvertebral) fractures that occurred during the study were recorded independently of the nature and severity of the trauma that may have determined them. Statistical Analysis All analyses were done according to the intention-to-treat approach: that is, all patients who had at least one valid measurement after randomization were considered in the analysis, whether they were still taking the study drug or not. In the case of drop-out and, thus, discontinuation of therapy with the study medication, the patient was invited to return to the clinic at annual intervals (for 4 years, if possible) so that the radiography necessary to record outcome could be done. An exact-significance chi-square test was done to compare the number of patients with new vertebral fractures in the two groups. We calculated 95% CIs for vertebral fracture rates in each study group and for the difference in rates between the two groups, along with the point estimates of these rates. These rates were also expressed in terms of the number needed to treat for 4 years to prevent one fracture, including values for the lower and upper bounds of the 95% CIs. Changes in the Spine Deformity Index in patients with incident or progressing vertebral deformities were compared by analysis of variance. Analysis of variance for repeated measurements was used to compare the absolute values for BMD of the spine over the course of the study in the two groups. Analysis of variance for repeated measurements was also done to compare BMD of the total hip and percentage changes in biochemical markers of bone remodeling throughout the study. All P values are two-tailed. All statistical analyses were done with the SPS/WIN 6.2 statistical package (SPS, Inc., Chicago, Illinois). Role of Study Sponsor The trial was approved by the Ethical Committee of Liege University (registration no. 90/43-1262 of 14 May 1990), and all patients gave full informed consent before inclusion. The Rotta Research Group, which markets MFP and calcium combinations in Germany, Italy, and other countries, provided the drugs and funding for the study. Scientists from the Rotta Research Group were directly involved in the design, monitoring, and data management of the study and agreed to be listed as authors. However, the Rotta Research Group as a corporate entity had no control over the decision to approve or submit the manuscript for publication. Results Two hundred patients were enrolled in the study. The characteristics of the entire patient sample (100 patients were assigned to each group) at enrollment are shown in Table 1. The