Sustained-release sodium fluoride in the management of established postmenopausal osteoporosis

A unique treatment format for established postmenopausal osteoporosis was developed. SR-NaF administered with Ca citrate restricted fluoride bioavailability, attenuated circadian fluctuation in serum fluoride (40 ng/mL to 60 ng/mL), and prolonged T(1/2). It maintained peak and basal levels of serum fluoride within the narrow therapeutic window (95 ng/mL to 190 ng/mL), and it kept the skeletal fluoride well below the toxic threshold during the recommended 4 years of treatment. In the completed randomized trial in established postmenopausal osteoporosis, SR-NaF decreased the spinal fracture rate by approximately 70%. From pooled data derived from the study of 233 patients who were treated with SR-NaF and from 83 patients who were administered a placebo, it was concluded that SR-NaF eliminated virtually all spinal fractures among patients with mild to moderate bone loss. The decline in the spinal fracture rate was approximately 91%, with fractures developing in only 2.7% of the patients. In severe bone loss, SR- NaF produced a modest but significant decline of 40% in the fracture rate. In the SR-NaF group, L2-L4 bone mass increased by approximately 5% per cycle through four cycles; femoral neck BD increased by 1% per cycle to 2% per cycle during the first two cycles. Radial shaft BD did not change. In the placebo groups, L2-L4 BD rose significantly by 1.5% during the first cycle but not in remaining cycles. Femoral neck BD and radial shaft BD did not change. The above effects of SR-NaF on spinal fractures and bone mass, disclosed in established postmenopausal osteoporosis, were just as marked in idiopathic osteoporosis, but they were less prominent in steroid-induced osteoporosis. Histomorphometrically, SR-NaF stimulated bone formation and inhibited resorption (probably from administered Ca citrate) without altering mineralization. Results of a back-scattered electron imaging of mineralized structures and the results of a transmission electron microscopy were normal. Trabecular connectivity improved, especially in mild to moderate bone loss. This accounted for the marked anti-fracture efficacy for SR-NaF. Functionally, SR-NaF improved cancellous bone quality while it maintained the quality of cortical bone. No gastric ulcers developed. Microfractures developed only in patients treated with steroids. The hip fracture rate and other appendicular fracture rates of the SR-NaF group did not differ from rates of the placebo group. Minor side effects were the same as in the group treated with a placebo. In conclusion, SR-NaF plus Ca citrate maintained serum fluoride within the therapeutic window, kept skeletal fluoride below the toxic threshold, augmented spinal bone mass by 5% per cycle for four cycles, inhibited spinal fractures by 70% to 80%, and was safe to use in established postmenopausal osteoporosis. In contrast, MFP, EC-NaF, and plan NaF were reported to have either no effect or a marginal effect on spinal fracture occurrence, despite a marked augmentation of spinal bone mass. Thus, the response to fluoride treatment is dependent on the fluoride formulations and the treatment format.