Greenspan S L, Holland S, Maitland-Ramsey L, Poku M, Freeman A, Yuan W, Kher U, Gertz B
Thorndike and Charles A. Dana Research Laboratory, Department of Medicine, Beth Israel Hospital, Boston, MA 02215, USA.
Proc Assoc Am Physicians. 1996 May;108(3):230-8.
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.
目前可用的抗骨质疏松吸收疗法的主要作用是减缓或阻止骨质流失。尽管抗吸收疗法能使骨矿物质密度增加，但这种效果通常是短暂的，骨矿物质密度通常在1年后趋于平稳。抗吸收药物阿仑膦酸盐治疗有一个独特且无法解释的特点，即在第2年和第3年骨矿物质密度持续稳步提高。我们推测，这种意外效果的潜在机制可能是甲状旁腺激素（PTH）夜间分泌异常增加，而PTH可起到合成代谢剂的作用。我们在一个随机抽取的38名女性亚组中，检测了她们24小时内PTH、血清钙、离子钙以及骨形成标志物（骨钙素）和骨吸收标志物（N-端肽交联物）的昼夜水平及日变化情况。这些女性完成了一项规模更大（N = 120）的、随机、双盲、安慰剂对照的阿仑膦酸盐试验（5毫克/天），为期12至15个月。到第12个月时，与安慰剂组相比，阿仑膦酸盐治疗组的脊柱骨密度增加了4.6%，股骨颈骨密度增加了2.7%（脊柱，安慰剂组增加2.2%，p = 0.05；股骨颈，安慰剂组降低0.2%，p≤0.05）。与安慰剂组相比，阿仑膦酸盐组夜间平均PTH水平高21%（39对32皮克/毫升），夜间血清钙平均低3%（8.7对9.0毫克/分升）（两者p≤0.05）。两组日间（上午8点至晚上10点）PTH水平无显著差异。我们观察到阿仑膦酸盐组骨形成（骨钙素降低38%，p≤0.01）和骨吸收（N-端肽交联物降低50%，p≤0.01）的相关标志物随之下降。两组中PTH、血清钙和骨钙素均存在显著的昼夜变化。我们得出结论，在接受阿仑膦酸盐治疗1年后，女性的骨矿物质密度和夜间PTH水平显著增加，同时夜间血清钙和骨转换标志物下降，且昼夜变化得以维持。夜间PTH的增加可能模拟了低剂量间歇性给予PTH刺激骨形成的合成代谢作用。因此，这种增加可能是解释阿仑膦酸盐治疗1年以上后骨密度持续改善的潜在机制。
