Postmenopausal Caucasian women aged less than 80 years (n = 99) with one or more atraumatic vertebral fracture and no hip fractures, were treated by cyclical administration of enteric coated sodium fluoride (NaF) or no NaF for 27 months, with precautions to prevent excessive stimulation of bone turnover. In the first study 65 women, unexposed to estrogen (-E study), age 70.8 +/- 0.8 years (mean +/- SEM) were all treated with calcium (Ca) 1.0-1.2 g daily and ergocalciferol (D) 0.25 mg per 25 kg once weekly and were randomly assigned to cyclical NaF (6 months on, 3 months off, initial dose 60 mg/day; group F CaD, n = 34) or no NaF (group CaD, n = 31). In the second study 34 patients, age 65.5 +/- 1.2 years, on hormone replacement therapy (E) at baseline, had this standardized, and were all treated with Ca and D and similarly randomized (FE CaD, n = 17; E CaD, n = 17) (+E study). The patients were stratified according to E status and subsequently assigned randomly to +/- NaF. Seventy-five patients completed the trial. Both groups treated with NaF showed an increase in lumbar spinal density (by DXA) above baseline by 27 months: FE CaD + 16.2% and F CaD +9.3% (both p = 0.0001). In neither group CaD nor E CaD did lumbar spinal density increase. Peripheral bone loss occurred at most sites in the F CaD group at 27 months: tibia/fibula shaft -7.3% (p = 0.005); femoral shaft -7.1% (p = 0.004); distal forearm -4.0% (p=0.004); total hip -4.1% (p = 0.003); and femoral neck -3.5% (p = 0.006). No significant loss occurred in group FE CaD. Differences between the two NaF groups were greatest at the total hip at 27 months but were not significant [p < 0.05; in view of the multiple bone mineral density (BMD) sites, an alpha of 0.01 was employed to denote significance in BMD changes throughout this paper]. Using Cox's proportional hazards model, in the -E study there were significantly more patients with first fresh vertebral fractures in those treated with NaF than in those not so treated (RR = 24.2, p = 0.008, 95% CI 2.3-255). Patients developing first fresh fractures in the first 9 months were markedly different between groups: -23% of F CaD, 0 of CaD, 29% of FE CaD and 0 of E CaD. The incidence of incomplete (stress) fractures was similar in the two NaF-treated groups. Complete nonvertebral fractures did not occur in the two +E groups; there were no differences between groups F CaD and CaD. Baseline BMD (spine and femoral neck) was related to incident vertebral fractures in the control groups (no NaF), but not in the two NaF groups. Our results and a literature review indicate that fluoride salts, if used, should be at low dosage, with pretreatment and co-treatment with a bone resorption inhibitor.

The future of sodium fluoride (NaF), the most potent osteoblast stimulator known to man, is in the balance. Of three recent randomized trials of continuous NaF only one found a significant in vertebral fractures in the NaF group. When data from the first year were excluded, two of the studies (those with the largest numbers) showed a significantly reduced risk of vertebral fracture on NaF. The effect of NaF on cortical bone is poorly documented. Two studies have shown reduced forearm cortical bone density with continuous NaF. A further two (histomorphometric) studies have shown the development of increased cortical porosity on continuous NaF treatment. In one, this was selectively at the external cortex and was linearly correlated with cancellous volume increase. Our pilot study using NaF administered cyclically has shown an encouraging (though non-significant) reduction in vertebral fracture rates (excluding year 1) and no fall in forearm cortical density. Another (US) cyclical study has shown no increase in cortical porosity. A current W. Australian randomized study of 50 patients is described where NaF dosage is varied proportional to the osteoblast response, and duration is dependent on densitometric and radiographic response. The future of NaF should involve cyclical administration, in cautious initial dosage (50-60 mg/day) of enteric-coated NaF, in conjunction with a potent inhibitor of resorption such as hormone replacement, bisphosphonates or calcitonin.