FREEDOM扩展试验显示狄诺塞麦疗效佳

休斯敦——FREEDOM扩展研究在使用狄诺塞麦6年的患者中持续观察到骨折发生率降低、骨密度(BMD)进行性增加和骨转换生物标志物持续降低。

FREEDOM是一项为期3年的关键性Ⅲ期、双盲、安慰剂对照、随机研究。正是基于该研究结果，狄诺塞麦(Prolia)这一新型RANKL(受体激活核因子-κB配体)抑制剂被批准上市用于治疗绝经后骨质疏松(60 mg, 皮下给药，每6个月1次)。FREEDOM扩展研究为期7年，目前已进行3年，目的是评价狄诺塞麦的长期安全性和疗效。因此，原研究中的活性治疗组患者将接受总共10年的狄诺塞麦治疗，而安慰剂对照组患者在接受3年安慰剂治疗后将交叉接受7年的狄诺塞麦治疗。

原研究中共有4,550例绝经后女性进入扩展研究，目前在扩展研究中已随访3年，加上原研究的3年随访，这些女性已被随访6年。

在原研究中，狄诺塞麦组患者在使用该药3年后，腰椎BMD相对基线增加10.1%。在额外3年开放标记治疗后，该数字增至15.1%。对照组患者在交叉接受开放标记狄诺塞麦治疗3年后，腰椎BMD相对基线增加9.4%，这一结果与狄诺塞麦组前3年的结果相似。

狄诺塞麦组治疗3年和6年后，全髋关节BMD分别相对基线增加5.7%和7.5%。对照组患者在交叉接受活性治疗3年后，全髋关节BMD相对基线增加4.8%。

在FREEDOM研究的前3年，狄诺塞麦组和安慰剂对照组的新椎体骨折发生率分别为2.3%和7.2%。在后续3年的开放标记治疗中，原狄诺塞麦组的新椎体骨折发生率为3.5%。由于在后续3年设置安慰剂组有违伦理，因此采用一种名为“虚拟双胞胎”的统计学方法来建模，预测原对照组患者如果仍继续接受安慰剂治疗的结局，预测得出的该组在扩展研究前3年内的新发椎体骨折发生率为6.3%。

在FREEDOM研究的3年双盲期内，狄诺塞麦组的非椎体骨折发生率显著低于安慰剂组(6.5% vs. 8.0%)。在第2个3年狄诺塞麦治疗期内，该发生率为3.8%。研究者表示，第2个3年内的非椎体骨折发生率低于第1个3年，表明狄诺塞麦长期治疗具有额外益处。“虚拟双胞胎”组第2个3年内的新发非椎体骨折的预测发生率为7.5%。

在安全性方面，狄诺塞麦组在6年治疗期间观察到2例确定的颌骨坏死病例，对照组在交叉至活性治疗后也观察到2例。狄诺塞麦组在6年治疗期间观察到1例非典型股骨骨折。对照组在交叉至3年狄诺塞麦治疗后观察到1例严重皮肤感染，狄诺塞麦组在第2个3年内观察到数例严重皮肤感染。

FREEDOM扩展研究由安进公司资助。研究者声明是该公司的顾问和讲师。

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By: BRUCE JANCIN, Internal Medicine News Digital Network

HOUSTON – Denosumab continued to achieve reduced fractures rates, progressively rising bone mineral density, and sustained reduction in bone turnover biomarkers through 6 years of continuous use in the ongoing 7-year extension of the landmark FREEDOM trial.

FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) was the pivotal phase III, double-blind, placebo-controlled, 3-year randomized trial that led to marketing approval of denosumab (Prolia) at 60 mg subcutaneously every 6 months for treatment of postmenopausal osteoporosis (N. Engl. J. Med. 2009;361:756-65).

The FREEDOM extension study is evaluating the long-term safety and efficacy of denosumab for an additional 7 years. Thus, participants who were in the active treatment arm of the original study will receive denosumab for a total of 10 years, whereas patients who crossed over to denosumab after 3 years on placebo will be on the novel RANKL (receptor-activated nuclear factor–kappaB ligand) inhibitor for 7 years.

At the conference, Dr. Henry G. Bone presented updated study results through 6 years. In all, 4,550 postmenopausal women from the original randomized trial were enrolled in the extension and have been followed for an additional 3 years.

In the original FREEDOM trial, 3 years of denosumab resulted in a 10.1% increase in BMD in the lumbar spine, compared with baseline. With an additional 3 years of open-label therapy, this figure has increased to 15.1%. The gain in the crossover group paralleled that seen with active therapy in the original trial; that is, after 6 years – the last 3 on open-label denosumab – those patients had a 9.4% increase over baseline in lumbar spine BMD, reported Dr. Bone, chief of the endocrinology department at St. John Hospital and Medical Center, Detroit, and director of the Michigan Bone and Mineral Clinic.

Total hip BMD rose from a 5.7% increase over baseline after 3 years of denosumab to a 7.5% increase after 6 years. The crossover group had a 4.8% increase at this site after 3 years of active therapy.

During the first 3 years of the FREEDOM trial, new vertebral fractures occurred in 2.3% of the denosumab group, compared with 7.2% of placebo-treated controls. During the subsequent 3 years of open-label therapy, the original denosumab cohort had a 3.5% incidence of new vertebral fractures. Because it would have been unethical to have a placebo arm during those second 3 years, statistical modeling using a method known as "virtual twins" was used to project outcomes had the original control group remained on placebo. Their expected rate of new vertebral fractures during the first 3 years of the extension study was 6.3%.

The incidence of nonvertebral fractures during the 3-year, double-blind phase of FREEDOM was 8.0% in the placebo arm and significantly lower, at 6.5%, in the denosumab group. During the second 3-year period of denosumab therapy, the incidence was 3.8%.

"It’s interesting that the nonvertebral fracture rate in the second 3 years is actually quite a bit lower than in the first 3 years, suggesting there may be an additional benefit of long treatment," Dr. Bone said.

The projected rate of new nonvertebral fractures during years 4-6 in the "virtual twins" was 7.5%.

Turning to safety issues, the endocrinologist said that there were two adjudicated cases of osteonecrosis of the jaw during 6 years of denosumab therapy, and two more in the control group that occurred after crossover to active treatment. There has been one documented case of atypical femoral fracture during 6 consecutive years on denosumab. There has been one serious skin infection in the control group after they were crossed to 3 years of denosumab, and several more during years 4-6 in the long-term extension group.

The FREEDOM study extension is sponsored by Amgen. The presenter is a consultant to and on the speakers bureau for the company.