Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial.

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.

Classification of osteoporosis in the elderly is dependent on site-specific analysis.

Vertebral osteoporosis accounts for over 500,000 spinal fractures annually, the majority of which occur in older women. Despite these statistics, data regarding the rate of spinal bone loss in this population are conflicting. Moreover, the site of skeletal evaluation may significantly alter classification of osteoporosis in this age group. To examine trabecular-rich spinal bone loss with a measurement less affected by age-related artifacts than the AP spine, we measured lateral lumbar spine bone density (BMD) using dual-energy X-ray absorptiometry in 120 healthy, ambulatory, community-dwelling women 65 years of age and older (mean 70 +/- 5 years, range 65-88). We also examined cortical-rich sites in the forearm and total body along with AP spine and femoral BMD to assess the impact of site specificity using the World Health Organization (WHO) classification of osteoporosis. Significant losses in BMD were observed at the lateral spine (-1.1%/year, P < 0.01), forearm (-0. 77%/year, P

Alendronate stimulation of nocturnal parathyroid hormone secretion: a mechanism to explain the continued improvement in bone mineral density accompanying alendronate therapy.

The major effect of currently available antiresorptive therapy for osteoporosis is to slow or arrest bone loss. Although antiresorptive therapies demonstrate increases in bone mineral density, the effect is usually transient, and a plateau in bone mineral density usually emerges at 1 year. A unique and unexplained feature of treatment with the antiresorptive agent alendronate is continued, and steady improvement in bone mineral density occurs in years 2 and 3. We postulated that a potential mechanism for this unanticipated effect might be an exaggerated nocturnal increase in parathyroid hormone (PTH), which can act as an anabolic agent. We examined day-night levels and diurnal variation of PTH, serum calcium, ionized calcium, and markers of bone formation (osteocalcin) and resorption (N-telopeptide cross-links) over 24 hours in a randomly selected subset of 38 women (placebo: N = 13; mean age +/- SD, 69 +/- 3 years; alendronate: N = 25; mean age +/- SD, 69 +/- 3 years) who had completed 12 to 15 months of a larger (N = 120), randomized, double-blind, placebo-controlled trial with alendronate, 5 mg/day. By month 12, increases in the bone density of the spine (4.6%) and femoral neck (2.7%) were observed in the group treated with alendronate compared with placebo, (spine, 2.2%, p = .05; femoral neck, -0.2%, p < or = .05). Mean nocturnal PTH (10 PM-8 AM) was 21% higher (39 versus 32 pg/ml), and nocturnal serum calcium averaged 3% lower (8.7 versus 9.0 mg/dL) in the alendronate-versus-placebo group (both p < or = .05). Daytime levels (8 AM-10 PM) of PTH did not differ significantly between groups. We observed accompanying decreases in coupled markers of bone formation (osteocalcin, 38% lower, p < or = .01) and resorption (N-telopeptide cross-links, 50% lower, p < or = .01) in the alendronate group. Significant diurnal variations of PTH, serum calcium, and osteocalcin were present in both groups. We conclude that following 1 year of alendronate therapy, women have significant increases in bone mineral density and in nocturnal PTH levels, associated with decreases in nocturnal serum calcium and markers of bone turnover with maintenance of the diurnal variation. The nocturnal increase in PTH may mimic the anabolic effect of low-dose intermittent PTH administration to stimulate bone formation. Therefore, the increase might be a potential mechanism to explain the continued improvement in bone density following more than 1 year of alendronate therapy.