In women with postmenopausal osteoporosis (PMO), response to therapy with bisphosphonates is conventionally monitored using central-site (hip and spine) bone mineral density (BMD), but more convenient alternatives are desirable. During a randomized parallel-group study of the efficacy of once-weekly (80 mg vs 160 mg) oral alendronate in the treatment of PMO, 81 women (mean age 70.2 years +/- 4.6 SD) had BMD measurements of total hip (TH) and lumbar spine (LS) (L1-L4, Hologic); and of the middle phalanx of the middle digit of the non-dominant hand (accuDXA) at baseline and after 6 and 12 months of therapy with alendronate. At the same timepoints, subjects also had measurements of speed of sound (SOS) through bone at four sites (distal 1/3 radius, proximal phalanx of the third finger, midshaft of the tibia and fifth metatarsal) using the Sunlight Omnisense Ultrasound Bone Sonometer. Data from both patient groups were pooled for this analysis. Mean TH BMD at baseline was 0.705 g/cm2 +/- 0.093 (SD) and increased by 1.7% +/- 2.3% and 2.5% +/- 2.3% at 6 and 12 months respectively (p = 0.09 and p<0.0001). Mean LS BMD at baseline was 0.718 +/- 0.076 g/cm2 and increased by 3.9% +/- 3.6% and 6.1% +/- 3.5% at 6 and 12 months respectively (both p<0.0001). There was no statistically significant change from baseline in mean BMD by accuDXA at either 6 or 12 months. The only statistically significant changes in SOS were at the radius (decrease in SOS at 12 months, p= 0.04) and tibia (increase at 6 months, p<0.01, but no change between baseline and 12 months). Baseline correlation coefficients between accuDXA and LS and TH DXA were 0.22 (p = 0.05) and 0.27 (p = 0.02) respectively. Correlation coefficients between SOS and LS DXA ranged from 0.05 to 0.22; and between SOS and TH DXA ranged from -0.08 to 0.10 (all p = NS). These data suggest that the response to alendronate therapy over this time period cannot be measured by accuDXA or Sunlight SOS at the sites studied.