Slow-Release Sodium Fluoride in the Management of Postmenopausal Osteoporosis

Although fluoride can cause osteoblastic proliferation [1, 2] and stimulate new bone formation [3], its use in managing osteoporosis has been associated with frequent and sometimes serious complications, including gastric bleeding and microfractures [3]. Excessive exposure may lead to fluorosis [4], characterized by a formation of abnormal bone that may be poorly mineralized and mechanically defective. Further, in a placebo-controlled randomized trial [3], continuous treatment with plain (nonsustained release) sodium fluoride and calcium carbonate supplementation did not produce a statistically significant decrease in the spinal fracture rate despite a substantial increase in the lumbar vertebral bone mass. We previously reported [5, 6] a nonrandomized trial in which intermittent slow-release sodium fluoride with continuous calcium citrate supplementation stimulated the formation of normally mineralized bone and decreased the spinal fracture rate without serious complications. In 1986, we initiated a randomized trial using slow-release sodium fluoride plus calcium citrate compared with placebo plus calcium citrate in 99 patients with postmenopausal osteoporosis. The trial is ongoing, with an average duration of treatment in the two study groups of 2.44 and 2.14 cycles (14 mo/cycle) and with 15 patients completing the intended 4 cycles of treatment. Although the study is not expected to be completed until August 1996, this interim analysis was done in response to a request for an update at the Fourth International Symposium on Osteoporosis [7]. The trial will be completed in order to determine if the treatment effect is sustained. We believe that the interim analysis will not affect the conduct of the remainder of the trial. Methods Clinical Data Recruited into the trial were 110 fully ambulatory white women with postmenopausal osteoporosis, all of whom were referred for symptomatic osteoporosis by practicing physicians because of an inadequate response to conventional therapy or the unwillingness of physicians to care for them. No other ethnic groups were enrolled, probably because of the rarity of postmenopausal osteoporosis and the nature of the referred patients in the study areas. The entry criteria were as follows: postmenopausal state, radiographic evidence of osteoporosis, and one or more vertebral fractures believed to be nontraumatic. Exclusion criteria were as follows: the presence of conditions causing bone loss such as hyperparathyroidism, adrenocorticosteroid excess, thyrotoxicosis, chronic diarrheal state or malabsorption, renal tubular acidosis, renal impairment (endogenous creatinine clearance less than 0.7 mL/min per kg); previous treatment with diphosphonate, calcitonin, or fluoride; active peptic ulcer disease; and skeletal fractures that could not be quantified for anatomic or technical reasons. Those taking pharmacologic doses of vitamin D preparations were accepted if they had discontinued the drug for at least 6 months. At recruitment, 31 patients were taking estrogen (treatment initiated after osteoporosis was diagnosed). Thirteen patients had documented recurrent spinal fractures while receiving estrogen. The total duration of estrogen therapy represented about a third of their postmenopausal state (mean, 8 years). This treatment, usually consisting of conjugated estrogen, 0.625 mg/d given continuously or intermittently (25 d/mo), and intermittent progesterone (5 mg/d for 10 d/mo), was continued during the trial. Patients receiving estrogen had similar baseline demographic characteristics as patients not receiving estrogen and were considered at increased risk for further fractures. Randomization and Treatment Scheme Participants were randomly assigned to the two treatment groups, stratified according to estrogen treatment (untreated or estrogen-treated). Patients in the treatment group received slow-release sodium fluoride (Slow Fluoride; Mission Pharmacal Company, San Antonio, Texas), 25 mg twice daily given orally before breakfast and at bedtime intermittently in repeated cycles of 14 months (12 months receiving treatment, followed by 2 months off treatment) and calcium citrate (Citracal, Mission Pharmacal Company) as 400 mg of calcium twice daily before breakfast and at bedtime. In the placebo group, medication identical in appearance to Slow Fluoride that was devoid of sodium fluoride was given on the same time schedule along with calcium citrate at the same dose and schedule. Study Protocol Patients were evaluated in an outpatient setting before treatment and at 3, 6, 9, 12, and 14 months of each cycle. At each visit, a careful history was taken for gastrointestinal and musculoskeletal side effects defined as symptoms that newly appeared or increased from baseline without apparent cause and persisted more than a month during treatment or disappeared during withdrawal. Where severe lower-extremity pain lasted more than 2 weeks, the protocol required a bone scan followed by radiographs for detection of microfracture; however, none was required. In addition, systematic multichannel analysis of venous blood, complete peripheral blood count, and 24-hour urinary calcium were determined at each visit; serum parathyroid hormone, reticulocyte count, and 24-hour urinary hydroxyproline were measured before and at 6 and 12 months of each cycle. Serum fluoride was measured before the morning dose of slow-release sodium fluoride at 0, 6, and 12 months of each cycle. Before treatment and at 12 months of each cycle, a lateral spinal radiograph was obtained to detect spinal fractures; moreover, bone mineral content of the L2 to L4 vertebrae, bone density of the distal third of the radius of the nondominant forearm, and bone density of the femoral neck were measured. Quantitation of Spinal Fractures Lateral spinal films taken before treatment and at 12 months of the first cycle were compared in order to determine new and recurrent fractures occurring during the first cycle of treatment. For each vertebra from T3 to L5, landmarks (anterior and posterior corners and midpoints) were recorded using an electrostatic digitizing board (Scriptel Corporation, Columbus, Ohio) with a coefficient of variation of 1.5%. A computer software program developed by one of the authors was used to compute changes in vertebral heights and area, and to calculate the magnification error between the two sets of radiographs. After correction for the magnification error, if any, a decrease in height of more than 20% of anterior, middle, or posterior height, accompanied by a decrease in area of more than 10% in a previously unaffected vertebra, was considered a new fracture [8], or if the decrease was in a previously fractured vertebra, it was considered to be a recurrent fracture. Identical criteria were used to identify new and recurrent fractures occurring during the second cycle (by comparing 26 months with 12 months), during the third cycle (by comparing 40 months with 26 months), and during the fourth cycle (by comparing 54 months with 40 months). Moreover, spinal films taken after the last cycle of follow-up were compared not only with the immediately preceding films but also with earlier radiographs. The same procedure was followed for the identification of new and recurrent fractures. Thus, it was possible to detect fractures occurring during two or more cycles (cumulative fractures) that escaped disclosure by previous cycle-to-cycle analysis. Bone Mass Measurement During the course of this study, two instruments were used to measure the L2 to L4 bone mineral content and the femoral neck bone density. A dual-photon x-ray absorptiometer (1.5 version, Lunar Radiation, Madison, Wisconsin) was used initially. It was replaced by quantitative digital radiography (Hologic, Waltham, Massachusetts) that yielded different absolute values for bone mass. The following procedures were adopted to accommodate problems imposed by the measurement of bone mass by two different densitometers. First, in estimating the extent of spinal bone loss at baseline, a given patient's L2 to L4 bone density obtained by either method was compared with the mean value for a normal 30-year-old woman established for the corresponding instrument. Second, in quantifying changes in the L2 to L4 bone mineral content and the femoral neck bone density produced by treatment, results were expressed as a percentage change for each cycle rather than as absolute values. When the same densitometer was used at the beginning and the end of a given cycle, the experimentally derived values were used to calculate the percentage change in bone mineral content or bone density. For a given cycle with the initial bone mass obtained by the Lunar method and the final bone mass measured by the Hologic technique, a correction factor was applied to convert the Lunar-derived value to the latter value. In patients who initially had bone mass determined by the Lunar method, a concurrent analysis by the Hologic instrument was done before converting to the latter technique for subsequent follow-up measurements. Thus, a correction factor could be calculated. The radial shaft bone density was obtained throughout the study by a single-photon absorptiometer (Norland, Ft. Atkinson, Wisconsin) [9]. For follow-up measurements, actual experimentally derived bone densities were used to calculate the percentage change in bone density for each cycle. The coefficient of variation for the L2 to L4 bone mineral content using the Lunar or Hologic method was 1%, whereas that for the femoral neck bone density and the radial shaft bone density was 1% to 2%. Biochemical Analysis The blood screen was done as SMA-20 (Smith-Kline Laboratory, Dallas, Texas). The serum parathyroid hormone level was analyzed by the whole-molecule, immunoradiometric assay (using a kit from Nichols Institute, San Juan Capistrano, California). The serum fluoride level was measured using an ion-specific electrode. The urinary