Effects of different regimens of sodium fluoride treatment for osteoporosis on the structure, remodeling and mineralization of bone

We compared initial and final bone histomorphometric findings in 66 osteopo rotic patients treated with sodium fluoride (NaF) according to three regime ns, and in 7 osteoporotic patients who did not receive NaF. Fourteen patien ts received continuous NaF 75 mg/day (high-dose) with calcium 1500 mg/day f or a mean of 11 months. Twenty-six patients received continuous NaF 50 mg/d ay (low-dose) with calcium 2000 mg/day for a mean of 15 months, either with (10 patients) or without (16 patients) vitamin D. Twenty-six patients rece ived cyclical low-dose NaF, alternating with vitamin D, for a mean of 15 mo nths and a total treatment duration of 28 months, of whom 14 were and 12 we re not on NaF at the time of the second biopsy. Disregarding differences be tween regimens, there were significant increases in total and mineralized b one volume and trabecular thickness and nonsignificant decreases in these m easurements in the control group. Fluoride-induced bone formation was exclu sively appositional with no evidence for the creation of new trabeculae. Th e effect of low-dose NaF on bone structure was the same when the same total dose was given continuously or intermittently, and when the patient was or was not taking vitamin D. The increases in total and mineralized bone volu me but not trabecular thickness were greater with high-dose than with low-d ose NaF. Low-dose NaF caused modest but significant increases in all osteoi d indices, and modest but significant declines in adjusted apposition rate and osteoid maturation rate and no change in bone formation rate. With high -dose NaF, the increase in BV/TV was greater but all indices of osteoid acc umulation were much higher and all indices of impaired osteoblast function and mineralization were much lower, and 12 of 14 patients had some form of osteomalacia. This occurred also in 3 of 30 patients treated with few-dose NaF who were not taking vitamin D; the mean increase in osteoid thickness w as significantly greater in these patients than in 22 low-dose patients who were taking vitamin D. We conclude: (1) The inconsistent effect of NaF in increasing bone strength is partly due to failure to restore connectivity i n patients with severe bone loss and partly due to substantial osteoid accu mulation. (7) Even low-dose NaF causes impaired osteoblast function, but th is is much greater with high-dose prolonged therapy. (3) There is an unexpl ained discrepancy between the increase in bone formation implied by increas es in spinal bone mineral and the lack of increase in bone formation measur ed histomorphometrically. ( I) Defective mineralization is more closely rel ated to the total cumulative dose of NaF than to the duration of treatment, and with low-dose treatment may be preventable by vitamin D. (5) Future cl inical trials should be carried out with smaller doses of NaF and before th ere has been substantial loss of horizontal trabeculae in the spine.