Monofluorophosphate combined with hormone replacement therapy induces a synergistic effect on bone mass by dissociating bone formation and resorptionin postmenopausal women: A randomized study

Sodium fluoride stimulates bone formation and has been used to treat osteop orosis for decades despite debate about the antifracture efficacy. Hormone replacement therapy (HRT) results in only modest increases in bone mineral density (BMD). However, for women with low bone mass, the ideal therapy sho uld not only inhibit bone resorption but simultaneously stimulate bone form ation to increase bone mass above the fracture threshold. We thus performed a randomized, double-blind, placebo-controlled intervention study to prosp ectively investigate the effect of a low dose of fluoride, in combination w ith HRT, on BMD and biochemical markers of bone turnover. One hundred healthy postmenopausal women (60-70 yr old) were thus randomly assigned to: 1) HRT [transdermal 17 beta-estradiol, releasing 50 mu g/day; plus oral norethisterone acetate (NETA), 1 mg/ day]; or 2) oral monofluorop hosphate (MFP; equivalent to fluoride, 20 mg/day); or 3) HRT+MFP; or 4) pla cebo, for 96 weeks. All participants received a calcium supplement of 1000 mg/day. Sixty-eight women completed the study. We found a pronounced, linear increase in spinal BMD during treatment with HRT+MFP [11.8% (1.7% SEM)I, which was significantly greater than the increa se in the HRT group [4.0% (0.5% per yr); P < 0.05]. MFP produced a smaller increase [2.4% (0.6% per yr)], whereas there was no change in the placebo g roup [0.0% (0.5% SEM)I. Similar changes were found at the other skeletal si tes (distal forearm, hip, and total body). Markers of bone formation showed a fall in the HRT group, which was significantly more pronounced than in t he combined HRT+MFP group. A nonsignificant increase was found in the MFP g roup, whereas the placebo group showed a decrease caused by calcium treatme nt. The marker of bone resorption decreased significantly more in the HRT a nd the HRT+MFP groups than in the placebo group but tended to increase in t he MFP group. In conclusion, this study shows, by use of biochemical markers of bone turn over, that bone resorption and formation may be dissociated, as a result of actions of two compounds with diverging effects on bone turnover. Furtherm ore, the synergistic effects of relatively low doses of the compounds sugge sted statistically and clinically significant increases in trabecular and p robably also cortical bone. Adverse effects were relatively rare and mild.