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 ost eoporosis is to slow or arrest bone loss. Although antiresorptive ther apies demonstrate increases in bone mineral density, the effect is usu ally transient, and a plateau in bone mineral density usually emerges at 1 year. A unique and unexplained feature of treatment with the anti resorptive agent alendronate is continued, and steady improvement in b one mineral density occurs in years 2 and 3. We postulated that a pote ntial mechanism for this unanticipated effect might be an exaggerated nocturnal increase in parathyroid hormone (PTH), which can act as an a nabolic agent. We examined day-night levels and diurnal variation of P TH, serum calcium, ionized calcium, and markers of bone formation (ost eocalcin) 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 yea rs) who had completed 12 to 15 months of a larger (N = 120), randomize d, double-blind, placebo-controlled trial with alendronate, 5 mg/day. By month 12, increases in the bone density of the spine (4.6%) and fem oral neck (2.7%) were observed in the group treated with alendronate c ompared with placebo, (spine, 2.2%, p =.05; femoral neck, -0.2%, p les s than or equal to.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 less than or equal to.05). Daytime levels (8 AM-10 PM) of PTH did nor differ significantly between groups. We observed accompanying decrease s in coupled markers of bone formation (osteocalcin, 38% lower, p less than or equal to.01) and resorption (N-telopeptide cross-links, 50% l ower, p less than or equal to.01) in the alendronate group. Significan t diurnal variations of PTH, serum calcium, and osteocalcin were prese nt in both groups.We conclude that following 1 year of alendronate the rapy, women have significant increases in bone mineral density and in nocturnal PTH levels, associated with decreases in nocturnal serum cal cium and markers of bone turnover with maintenance of the diurnal vari ation. 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 al endronate therapy.