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Although the antiresorptive agent alendronate has been shown to increase bone mineral density (BMD) at the hip and spine and decrease the incidence of osteoporotic fractures in older women, few data are available regarding early prediction of long-term response to therapy, particularly with regard to increases in hip BMD. Examining short-term changes in biochemical markers incorporates physiologic response with therapeutic compliance and should provide useful prognostic information for patients. The objective of this study was to examine whether early changes in biochemical markers of bone turnover predict long-term changes in hip BMD in elderly women. The study was a double-blind, placebo-controlled, randomized clinical trial which took place in a community-based academic hospital. One hundred and twenty community-dwelling, ambulatory women 65 years of age and older participated in the study. Intervention consisted of alendronate versus placebo for 2.5 years. All patients received appropriate calcium and vitamin D supplementation. The principal outcome measures included BMD of the hip (total hip, femoral neck, trochanter, and intertrochanter), spine (posteroanterior [PA] and lateral), total body, and radius. Biochemical markers of bone resorption included urinary N-telopeptide cross-linked collagen type I and free deoxypyridinoline; markers of bone formation included serum osteocalcin and bone-specific alkaline phosphatase. Long-term alendronate therapy was associated with increased BMD at the total hip (4.0%), femoral neck (3.1%), trochanter (5.5%), intertrochanter (3.8%), PA spine (7.8%), lateral spine (10.6%), total body (2.2%), and one-third distal radius (1.3%) in elderly women (all p< 0.01). In the placebo group, bone density increased 1.9-2.1% at the spine (p < 0.05) and remained stable at all other sites. At 6 months, there were significant decreases in all markers of bone turnover (−10% to −53%,p < 0.01) in women on alendronate. The changes in urinary cross-linked collagen at 6 months correlated with long-term bone density changes at the hip (r = −0.35, p < 0.01), trochanter (r = −0.36,p < 0.01), PA spine (r = −0.41, p < 0.01), and total body (r = −0.34, p < 0.05). At 6 months, patients with the greatest drop in urinary cross-linked collagen (65% or more) demonstrated the greatest gains in total hip, trochanteric, and vertebral bone density (all p < 0.05). A 30% decrease in urinary cross-linked collagen at 6 months predicted a bone density increase of 2.8-4.1% for the hip regions and 5.8-6.9% for the spine views at the 2.5-year time point (p < 0.05). There were no substantive associations between changes in biochemical markers and bone density in the placebo group. Alendronate therapy was associated with significant long-term gains in BMD at all clinically relevant sites, including the hip, in elderly women. Moreover, these improvements were associated with early decreases in biochemical markers of bone turnover. Early dynamic decreases in urinary cross-linked collagen can be used to monitor and predict long-term response to bisphosphonate therapy in elderly women. Future studies are needed to determine if early assessment improves long-term patient compliance or uncovers poor compliance, thereby aiding the physician in maximizing the benefits of therapy.