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根据一项新研究指出，Teriparatide预防长期服用类固醇药物病患，例如prednisone，骨质流失与增加骨质密度（BMD）的效果比Alendronate佳；在另一项研究中，denosumab增加停经后妇女的骨质质量。这两篇研究都发表在美国风湿医学会2008年会上。
这项比较Teriparatide（Forteo）与Alendronate（Fosamx）使用于长期服用类固醇病患效果的随机分派研究，是第一个将Teriparatide使用时间延长到36个月的研究。研究团队随机分派214位病患接受Teriparatide每天20 μg或Alendronate每天10 mg。
虽然这两组的骨质质量都有增加，但研究团队发现，使用Teriparatide相较于使用Alendronate的病患，在腰椎（11%相较于5.3%）与股骨（6.3%相较于3.4%）BMD平均增加百分比达显著差异，这两个都是服用类固醇病患最常发生骨折的位置；他们也发现使用Teriparatide的病患，发生脊椎骨折的比例比使用Alendronate的低（1.7%相较于7.7%）。
伯明罕阿拉巴马大学医学与流行病学教授，同时也是这项研究的主要作者Kenneth Saag医师表示，Teriparatide刺激成骨细胞的活性，与抑制破骨细胞的细胞凋亡，因此使用在这个状况下是合理的；这是个可以考虑使用于因类固醇引起之骨质疏松的治疗策略。
然而，这两组的非脊椎骨折数目相差不多，这两个药物的耐受性都很好；在Teriparatide组仅有一位病患出现有症状的高血钙，但并没有任何一位Alendronate组的病患发生这个不良反应。
就像其他使用类固醇的病患，这项研究中的受试者发生骨折的风险显著较高；所有病患服用5 mg的Prednisone至少3个月以上，大部分病患的骨质质量介于骨质低下范围，且有些病患被诊断罹患骨质疏松症，超过40%病患过去发生过非脊椎性骨折。
Saag医师表示，这是个处于风险的族群，这些研究结果显示，Teriparatide可以是这些病患的另一个选择；他告诉听众，这些长期使用类固醇病患发生骨折的机率，据估计达50%。
在第二个双盲随机分派研究中，研究团队比较denosumab与alendronate对停经后女性骨质质量的影响；Denosumab是一个对抗RANKL的全人类化单株抗体，RANKL则是一个对成骨细胞存活与发育非常重要的配位子。
研究团队追踪1,189位骨质密度过低的停经后女性，这些病患被随机分派每6个月接受denosumab 60 mg，以及每周一次的口服安慰剂，或是每6个月接受安慰剂注射，与每周一次的alendronate 70 mg，受试者的平均腰椎T指数为-2.6。
结果显示，在12个月后，Denosumab组髋骨BMD（62%比上39%）与腰椎BMD（77%比上65%）增加超过3%的病患数目比Alendronate组高。Denosumab在5个骨质评估位置上，增加BMD的效果都比较好，这些位置包括髋骨、腰椎、股骨颈部、转子以及尺骨远端。
Denosumab也会在1个月的治疗内显著降低骨质更替的血清指标，例如血中第一型碳端多胜与原胶原蛋白第一型氮端多胜，且这个效应可以持续长达12个月。两组之间的不良反应发生率相差不多。
主要作者、俄亥俄州克里夫兰诊所骨质疏松症与代谢性骨骼疾病中心的主任Chad Deal医师在一项记者会上表示，这两个药物另一个显著差异是它们的半衰期，Fosamax对于骨骼的残留效应很长，特别是对使用超过5年以上的病患，但是Denosumab的效果比较快发生，也比较快结束。
同样的，研究团队在美国骨骼与矿物质研究学会于9月召开的年会上报告，在一项收纳7,868位骨质疏松妇女的临床研究中，Denosumab也可以显著地降低非脊椎与髋骨骨折发生率。
荷兰阿姆斯特丹自由大学的风湿学教授Willem Lems医师指出，研究结果显示，这些药物对于类固醇引起的骨质疏松是有效的，这对骨质疏松的停经后妇女来说，是个非常严重的问题；未参与这两个发表会的Lems医师表示，这两项研究的研究数据非常吸引人。
Lems医师表示，Denosumab具有增加骨质疏松病患顺应性的潜力，我们现在听到的研究显示许多病患偏好每6个月注射一次药物，而非每个星期口服一次。
Teriparatide的研究是由礼来公司赞助。Saag医师表示接受来自Amgen、Eli Lilly、Merck、Novartis、Roche Savient与Tap药厂的顾问费。Denosumab研究则由Amgen药厂赞助。Deal 医师表示接受Amgen、Eli Lily、GlaxoSmithKline、Merck Human Health、Merck、Novartis、Proctor & Gamble与Roche Pharmaceuticals的顾问费。Lems医师表示没有相关资金上的往来。
Two New Osteoporosis Drugs Increase BMD More Than Alendronate
By Barbara Boughton
Medscape Medical News
Teriparatide prevents bone loss and increases bone mineral density (BMD) over the long term in patients taking glucocorticoids, such as prednisone, compared with alendronate, according to a new study. In a second study, denosumab increased bone mass in postmenopausal women. Both papers were presented here at the American College of Rheumatology 2008 Annual Scientific Meeting.
The double-blind randomized controlled trial that compared the effects of teriparatide (Forteo) and alendronate (Fosamax) in patients taking glucorticoids was the first to extend teriparatide use to 36 months. The researchers randomized 214 patients to either teriparatide 20?μg per day or alendronate 10?mg per day.
Although both groups experienced increases in bone mass, the researchers found that the mean percent increase in BMD was significantly greater in patients taking teriparatide than in those taking alendronate at the lumbar spine (11% vs 5.3%) and femoral neck (6.3% vs 3.4%), both frequent fracture sites for patients taking glucocorticoids. They also noted that fewer patients taking teriparatide than taking alendronate experienced vertebral fractures (1.7% vs 7.7%).
“Teriparatide stimulates osteoblastic activity and inhibits osteblast apoptosis, so there’s a rationale for its use in this condition. It’s a therapeutic strategy that could be considered for glucocorticoid-induced osteoporosis, particularly those at high risk for fracture,” said Kenneth Saag, MD, professor of medicine and epidemiology at the University of Alabama, in Birmingham, and lead investigator in the study.
However, the number of nonvertebral fractures was similar in both groups, although both drugs were well tolerated. One patient exhibited symptomatic hypercalcemia in the teriparatide group, but no patient in the alendronate group experienced this adverse event.
Like many patients taking glucorticoids, the population in the study was at significantly increased risk for fracture. All had been taking at least 5?mg of prednisone for at least 3 months. Most had bone mass within the osteopenic range, and some had been diagnosed with osteoporosis. More than 40% had experienced a previous nonvertebral fracture.
“This was an at-risk population,” Dr. Saag said. “The results show that teriparatide can be another alternative for these patients. Many such patients have an estimated rate of fractures approaching 50% with chronic glucocorticoid use,” he told the attendees.
In the second double-blind randomized controlled trial, the researchers compared the effects of denosumab and alendronate on bone mass in postmenopausal women. Denosumab is a fully humanized monoclonal antibody against RANKL, a ligand that is critical for osteoclast survival and development.
The researchers followed 1189 postmenopausal women with low bone mass who were randomly assigned to receive either a 60-mg injection of denosumab every 6 months and a weekly oral placebo, or an injection of placebo every 6 months and a weekly 70-mg dose of alendronate. The subjects had a mean lumbar spine T-score of –2.6.
Results showed that a greater number of patients in the denosumab group gained more than 3% of BMD than those in the alendronate group at the total hip (62% vs 39%) and at the lumbar spine (77% vs 65%) after 12 months. Denosumab also caused superior gains in BMD at all 5 skeletal sites evaluated: the total hip, lumbar spine, femoral neck, trochanter, and distal third of the radius.
Denosumab also suppressed serum markers of bone turnover, such as serum type?1 C-telopeptide and procollagen type?1 N-propeptide within 1 month of treatment, and this effect was sustained over 12 months. Adverse events were similar in both groups.
Another significant difference between the drugs is their half-lives. “Fosamax has a long residual effect on bone, particularly for patients who take it for 5 years or more. But denosumab has both a quicker onset and a quicker offset,” said lead investigator Chad Deal, MD, head of the Center for Osteoporosis and Metabolic Bone Disease at the Cleveland Clinic, in Ohio, at a press conference.
In a trial of 7868 women with osteoporosis, reported by the same researchers at the American Society for Bone and Mineral Research meeting in September, denosumab also significantly decreased the risk for nonvertebral and hip fractures.
“The results show that both these medications are effective for glucocorticoid-induced osteoporosis, a very serious problem, and for postmenopausal women with osteoporosis,” said Willem Lems, MD, professor of rheumatology at Free University Hospital in Amsterdam, the Netherlands. “Together, they are very attractive data,” said Dr. Lems, who attended both presentations.
Dr. Lems noted that denosumab has the potential to increase patient compliance in those with osteoporosis. “The research we’re hearing now shows us that many patients prefer to take an injection every 6 months than weekly oral medications,” he said.
The teriparatide study was funded by Eli Lilly. Dr. Saag has reported consulting fees from Amgen, Eli Lilly, Merck, Novartis, Roche Savient, and Tap Pharmaceuticals. The denosumab study was funded by Amgen. Dr. Deal has reported receiving consulting fees from Amgen, Eli Lily, GlaxoSmithKline, Merck Human Health, Merck, Novartis, Proctor & Gamble, and Roche Pharmaceuticals. Dr. Lems has disclosed no relevant financial relationships.
American College of Rheumatology (ACR) 2008 Annual Scientific Meeting: Abstracts 2101 and 2102. Presented October 29, 2008.