We have previously demonstrated that a treatment regimen of slow-release sodium fluoride (SRNaF) and continuous calcium citrate increases lumbar bone mass, improves cancellous bone material quality, and significantly reduces vertebral fracture rate in osteoporotic patients. In order to assess whether such treatment also improves trabecular structure, we quantitated cancellous bone connectivity before and following 2 years of therapy with SRNaF in 23 patients with osteoporosis and vertebral fractures. In addition, we performed bone histomorphometry on the same sections used for connectivity measurements. There was a significant increase in L2-L4 bone mineral density during therapy (0.827 +/- 0.176 g/cm2 SD to 0.872 +/- 0.166, p = 0.0004). Significant histomorphometric changes were represented by increases in mineral apposition rate (0.6 +/- 0.4 microns/d to 1.1 +/- 0.7, p = 0.0078) and adjusted apposition rate (0.4 +/- 0.3 microns/d to 0.6 +/- 0.4, p = 0.016). On the other hand, trabecular spacing significantly declined (from 1375 +/- 878 microns to 1052 +/- 541, p = 0.05). Two-dimensional quantitation of trabecular struts on iliac crest histological sections disclosed significant increases in mean node number per mm2 of cancellous tissue area (0.22 +/- 0.12 vs. 0.39 +/- 0.27, p = 0.0077), the mean node to free-end ratio (0.23 +/- 0.21 vs. 0.41 +/- 0.46, p < 0.05), and in the mean node to node strut length per mm2 of cancellous area (0.098 +/- 0.101 vs. 0.212 +/- 0.183, p < 0.01). There were no significant changes in any of the measurements associated with free-end number or free-end to free-end strut length. When patients were divided into those with severe and mild-modest spinal bone loss (based upon initial lumbar bone density) the significant changes in connectivity occurred in patients with mild-moderate bone loss, but not in those with severe bone loss, suggesting that fluoride’s effect is in part dependent on the presence of a certain critical amount of bone. This finding in combination with the previously reported increases in bone mass and bone material quality may explain the significant reduction in vertebral fracture rate observed with this particular fluoride regimen.