We evaluated the biochemical and histomorphometric effects of a modified ADFR regimen in postmenopausal osteoporosis. Twenty women received oral phosphate (1500mg/day) for 6 months and 5 single infusions of clodronate (300mg each month) (n=10) or 5 single infusions of clodronate alone (300mg each month) (n=10).Clodronate alone significantly decreased serum alkaline phosphatase activity (-11%, p<0.05) whereas activity was maintained during combined treatment. Combined treatment decreased serum calcium with a slow progressive increase in PTH to 120% of pretreatment values by the fifth month (p<0.05). Clodronate alone decreased histological indices of both bone resorption and formation with significant reductions in active eroded surface (1.01±0.63 vs 0.12±0.10, p<0.02) and osteoid volume (0.35±0.23 vs 0.19±0.14, p<0.03). In contrast, combined treatment showed no significant effects on these indices. Both treatments were associated with reductions in resorption depth (-18.4±8.8, p<0.01 vs -9.5±18.2 μm in the clodronate and combined treatment groups) and non-significant increases in wall thickness were also observed (+19.9±18.7 vs +23.3±8 μm respectively).We conclude that intermittent low dose intravenous clodronate can suppress bone turnover at the tissue level. Concomitant phosphate maintains bone turnover but still appears to alter the balance between resorption and formation within the BMU. Studies are required to confirm these findings and to determine how they translate into increments in bone mass.