狄诺塞麦有助于男性提高骨密度

休斯顿——Ⅲ期ADAMO试验的结果提示，对骨密度(BMD)偏低的男性给予狄诺塞麦(denosumab)治疗1年，可使腰椎和所有接受测定的其他骨骼部位的BMD显著增高。

Ugis Gruntmanis博士

达拉斯市退伍军人事务部医学中心和德克萨斯州立大学西南医学中心的Ugis Gruntmanis博士指出，在男性中，骨质疏松症和骨折仍是普遍认识不足和治疗不足的疾病。估计美国有200万男性患有骨质疏松症。全球范围内，所有骨质疏松性骨折中有39%发生于50岁以上男性。

ADAMO是一项多中心、双盲、随机、Ⅲ期临床试验，共纳入242例低BMD患者，患者随机接受每6个月狄诺塞麦60 mg或安慰剂皮下注射治疗，共治疗1年。主要终点为腰椎BMD自基线至治疗12个月时的变化。从12个月时起，所有患者继续接受开放标记的狄诺塞麦治疗1年；24个月的次要终点尚未得出结果。该研究要求参与者腰椎或股骨颈的BMD T评分介于-2.0~-3.5；或之前曾发生大型骨质疏松性骨折，同时腰椎或股骨颈的BMD T评分介于-1.0~-3.5。患者平均年龄为65岁，其中94%为白人，并且1/4有主要骨质疏松性骨折病史。所有受试者接受每日钙剂和维生素D补充治疗。

结果显示，6个月时，狄诺塞麦组和对照组的腰椎BMD分别较基线增加了4.3%和0.9%。1年时，狄诺塞麦组均值较基线增加了5.7%，而安慰剂组仍保持在增加0.9%的水平。12个月时，狄诺塞麦组和对照组的全髋BMD分别较基线增加了2.4%和0.3%，两组桡骨远端三分之一处的BMD分别较基线增加0.6%和减少0.3%；这些有利于狄诺塞麦的差异均具有统计学意义。此外，狄诺塞麦也诱导了股骨颈和转子处的BMD增加。亚组分析显示，无论患者年龄、基线睾酮水平、初始骨密度以及估计10年骨质疏松性骨折的风险如何，狄诺塞麦对BMD的影响相似。在基线血清睾酮低于250 ng/dl的男性中(占15%)，接受狄诺塞麦治疗者较安慰剂组腰椎BMD增加了4.4%；而在睾酮250 ng/dl的受试者中，两组腰椎BMD增加相似，均为净增加4.8%。

根据基线FRAX评分评定的10年内大型骨质疏松性骨折风险处于最低四分位(<6.4%)的男性中，狄诺塞麦组腰椎BMD较安慰剂组绝对增加5.1%；在风险介于6.4%~11.2%的男性中，狄诺塞麦组腰椎BMD净增5.3%；在风险＞11.2%的男性中，腰椎BMD较安慰剂组增加4.0%。在这3个骨折风险组中，从统计学意义上看，狄诺塞麦驱动的BMD增加程度相似。

ADAMO试验的次要终点之一为骨重吸收生物标志物CTX-1自基线至第15天的变化。结果第15天时狄诺塞麦组的CTX-1水平降低了81%，第12个月时有60%得到抑制。并且，狄诺塞麦组的不良事件谱与安慰剂组无差异。

Gruntmanis博士披露接受了安进、诺华、葛兰素史克和宝洁公司提供的研究基金资助。

爱思唯尔  版权所有

By: BRUCE JANCIN, Internal Medicine News Digital Network

HOUSTON – One year of denosumab for treatment of men with low bone mineral density resulted in significant increases in bone density at the lumbar spine and all other measured skeletal sites in the phase III ADAMO trial.

The drug’s effects on BMD were similar regardless of patient age, baseline testosterone level, initial BMD, and estimated 10-year osteoporotic fracture risk, according to Dr. Ugis Gruntmanis of the Dallas Veterans Affairs Medical Center and the University of Texas Southwestern Medical Center.
 
"The increases in bone mineral density in this population were similar to those observed in earlier trials in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy," he reported at the annual meeting of the Endocrine Society.

Moreover, the adverse event profile for denosumab (Prolia) in ADAMO was indistinguishable from that with placebo.

"There was no osteonecrosis of the jaw or atypical femur fractures in this study. You really wouldn’t expect to see that in a study of this size," the endocrinologist added.

ADAMO is a multicenter, double-blind, randomized, phase III clinical trial in which 242 men with low BMD were randomized to 60 mg of denosumab or to placebo given subcutaneously every 6 months for 1 year. The primary end point in ADAMO was change in BMD at the lumbar spine from baseline through 12 months. At the 12-month mark, all patients were placed on open-label denosumab for another year; the 24-month secondary outcomes are not in yet.

Participants had to have a BMD T-score of -2.0 or less and -3.5 or greater at the lumbar spine or femoral neck, or a prior major osteoporotic fracture along with a T-score of -1.0 or less and -3.5 at the lumbar spine or femoral neck. The men’s average age was 65 years, 94% were white, and one-quarter had a history of a major osteoporotic fracture. All subjects received daily calcium and vitamin D supplements.

At the 6-month mark, lumbar spine BMD had improved by 4.3% over baseline in the denosumab group compared with 0.9% in controls. At 1 year, the denosumab group averaged a 5.7% increase over baseline while the placebo group remained flat at a 0.9% gain.

Total hip BMD improved by 2.4% at 12 months in the denosumab group compared with 0.3% in controls, and by 0.6% at the distal one-third of the radius compared with a 0.3% loss with placebo; both of those differences favoring denosumab were statistically significant. So were the denosumab-induced BMD gains at the femoral neck and trochanter.

In subgroup analyses, the 15% of men with a baseline serum testosterone below 250 ng/dL had a 4.4% greater gain in lumbar spine BMD than with placebo, while those with a testosterone of 250 ng/dL or above had a similar 4.8% net gain.

Men with a baseline FRAX score placing them in the lowest tertile for 10-year major osteoporotic fracture risk, at less than 6.4%, had an absolute 5.1% greater gain in lumbar spine BMD than with placebo, while those with a 10-year risk of 6.4%-11.2% had a net 5.3% gain in lumbar spine BMD and men with a greater than 11.2% fracture risk had a net placebo-subtracted 4.0% gain; the denosumab-driven BMD gains in these three fracture risk groups were statistically similar, according to Dr. Gruntmanis.

One of the secondary end points in ADAMO was the change in the bone resorption biomarker CTX-1 between baseline and day 15 of the study. The CTX-1 level plunged by 81% in the denosumab group by day 15, with 60% suppression at 12 months.

Osteoporosis and fractures remain widely underrecognized and undertreated in men, Dr. Gruntmanis said. An estimated 2 million American men have osteoporosis. Worldwide, 39% of all osteoporotic fractures occur in men above age 50.

He reported receiving research grants from Amgen, Novartis, GlaxoSmithKline, and Procter & Gamble.