VIDEO: Romosozumab bested teriparatide in hip BMD transitioning from bisphosphonates

LONDON – Bone mineral density (BMD) and estimated bone strength in the hip significantly increased during 1 year of treatment with the investigational monoclonal antibody romosozumab in comparison with teriparatide in women with postmenopausal osteoporosis who had previous fracture history and had been taking bisphosphonates for at least the previous 3 years in an open-label, randomized trial.

The investigators in the phase III, international, multicenter STRUCTURE trial sought to compare the monoclonal anti-sclerostin antibody romosozumab, which works dually to increase bone formation and decrease bone resorption, against the bone-forming agent teriparatide (Forteo) to see if it would increase total hip bone mineral density to a significantly greater extent by 12 months. Teriparatide is known to take longer to build bone at the hip following bisphosphonate use.

“These results in our minds suggest that romosozumab may offer a unique benefit to patients at high risk for fracture, transitioning from bisphosphonates,” first author Bente L. Langdahl, Ph.D., of Aarhus (Denmark) University Hospital said at the European Congress of Rheumatology. She discussed the study results in this video interview.

When Dr. Langdahl was asked after her presentation about the foreseen role of the drug in clinical practice, she noted that ongoing phase III trials looking at fracture endpoints should indicate whether it works faster at preventing fractures. Because there does not seem to be a restriction to the repeated use of romosozumab, she suggested it might be given initially for 12 months to build bone, followed by bisphosphonates to stabilize gains made, and then it could be used again if needed in a treat-to-target fashion.

The trial randomized 436 patients to receive either subcutaneous romosozumab 210 mg once monthly or subcutaneous teriparatide 20 mcg once daily for 12 months. All patients received a loading dose of 50,000-60,000 IU vitamin D3 to make sure they were vitamin D replete. The patients were postmenopausal, aged 55-90 years, and required to have taken oral bisphosphonate therapy at a dose equivalent to 70 mg weekly of alendronate for at least 3 years before enrollment (with at least 1 year of alendronate therapy prior to enrollment). They had a T score of –2.5 or less in total hip, lumbar spine, or femoral neck BMD and a history of a nonvertebral fracture after 50 years of age or a vertebral fracture at any age.

At 12 months, the primary endpoint of total hip BMD percentage change from baseline, which was calculated by averaging dual-energy x-ray absorptiometry (DXA) measurements at 6 and 12 months, increased significantly by 2.6% in the romosozumab group, compared with a loss of –1.6% in the teriparatide group.

“Why did we choose this rather unusual endpoint? It’s because we wanted to capture what happened throughout the first year,” Dr. Langdahl said.

The respective changes from baseline total hip BMD at month 12 were 2.9% vs. –0.5%; in the femoral neck, the 12-month change was 3.2% vs. –0.2%; and in the lumbar spine, the change was 9.8% vs. 5.4%.

The trial participants had a mean age of about 71 years, and T scores ranging from –2.87 to –2.83 in the lumbar spine, –2.27 to –2.21 in total hip, and –2.49 to –2.43 in the femoral neck.

Secondary endpoints of volumetric BMD measured by quantitative CT at 12 months supported the results for DXA measurements at the total hip: integral BMD changed 3.4% with romosozumab vs. –0.2% with teriparatide, cortical BMD changed 1.1% with romosozumab vs. –3.6% with teriparatide, and trabecular BMD increased 15.6% vs. 9.9%, respectively. Total hip strength at 12 months as estimated by finite element analysis rose by 2.5% with romosozumab, compared with a loss of –0.7% with teriparatide. The loss in estimated bone strength at the hip occurred mainly in the first 6 months of treatment with teriparatide and had started to recover by 12 months.

The main difference between the two treatments in total hip BMD came from romosozumab’s bone-building effect on cortical bone, Dr. Langdahl said. The significant loss of total hip cortical BMD observed with teriparatide matches what has been seen in other studies, and it occurs “because the way that teriparatide works initially on cortical bone is to open up the remodeling space; therefore, a decrease in BMD is seen.”

While romosozumab’s speed in increasing BMD and building bone strength is likely to be clinically meaningful for patients at high risk of fracture, the short duration of the trial likely left out the possibility of seeing the same sort of late increases in hip BMD and bone strength during the second year of treatment with teriparatide that have been observed in other studies. Dr. Langdahl suggested that the decline in total hip cortical bone volumetric BMD may have increased had there been more time for measurement in the study; after bisphosphonate treatment, teriparatide’s mechanism of action is thought to open up the bone remodeling space by stimulating bone resorption and formation, particularly in cortical bone.

“You will see an increased porosity in the cortical bone, and I think that is what explains the initial decrease. You’ll also see that it’s kind of catching up [to romosozumab]. This is only a 12-month study, unfortunately. I’m sure if it had been continued for 24 months, there would be an increase in strength because that has been demonstrated in other studies.”

The trial’s comparison of romosozumab versus teriparatide alone also leaves open the question of whether adding teriparatide to bisphosphonate or switching to a combination of teriparatide plus denosumab or teriparatide plus zoledronic acid might have yielded results comparable with romosozumab alone.

Furthermore, The study is not large enough to determine the overall side-effect profile of romosozumab and will have to wait until the larger, ongoing phase III studies are completed, Dr. Langdahl said. In the STRUCTURE study, the overall side effect profile was well balanced between the two groups. More women who received teriparatide developed hypercalcemia, and patients who received romosozumab developed antibodies, although they did not neutralize the agent’s effects.

The study was sponsored by UCB Pharma and Amgen. One investigator is an employee of UCB, and one is an employee of Amgen. Dr. Langdahl reported receiving research grants, consulting fees, and/or honoraria from Amgen, UCB, Eli Lilly, Merck, and Orkla. Most other investigators also reported financial relationships to Amgen and other pharmaceutical companies.

jevans@frontlinemedcom.com

LONDON – Bone mineral density (BMD) and estimated bone strength in the hip significantly increased during 1 year of treatment with the investigational monoclonal antibody romosozumab in comparison with teriparatide in women with postmenopausal osteoporosis who had previous fracture history and had been taking bisphosphonates for at least the previous 3 years in an open-label, randomized trial.

The investigators in the phase III, international, multicenter STRUCTURE trial sought to compare the monoclonal anti-sclerostin antibody romosozumab, which works dually to increase bone formation and decrease bone resorption, against the bone-forming agent teriparatide (Forteo) to see if it would increase total hip bone mineral density to a significantly greater extent by 12 months. Teriparatide is known to take longer to build bone at the hip following bisphosphonate use.

“These results in our minds suggest that romosozumab may offer a unique benefit to patients at high risk for fracture, transitioning from bisphosphonates,” first author Bente L. Langdahl, Ph.D., of Aarhus (Denmark) University Hospital said at the European Congress of Rheumatology. She discussed the study results in this video interview.

When Dr. Langdahl was asked after her presentation about the foreseen role of the drug in clinical practice, she noted that ongoing phase III trials looking at fracture endpoints should indicate whether it works faster at preventing fractures. Because there does not seem to be a restriction to the repeated use of romosozumab, she suggested it might be given initially for 12 months to build bone, followed by bisphosphonates to stabilize gains made, and then it could be used again if needed in a treat-to-target fashion.

The trial randomized 436 patients to receive either subcutaneous romosozumab 210 mg once monthly or subcutaneous teriparatide 20 mcg once daily for 12 months. All patients received a loading dose of 50,000-60,000 IU vitamin D3 to make sure they were vitamin D replete. The patients were postmenopausal, aged 55-90 years, and required to have taken oral bisphosphonate therapy at a dose equivalent to 70 mg weekly of alendronate for at least 3 years before enrollment (with at least 1 year of alendronate therapy prior to enrollment). They had a T score of –2.5 or less in total hip, lumbar spine, or femoral neck BMD and a history of a nonvertebral fracture after 50 years of age or a vertebral fracture at any age.

At 12 months, the primary endpoint of total hip BMD percentage change from baseline, which was calculated by averaging dual-energy x-ray absorptiometry (DXA) measurements at 6 and 12 months, increased significantly by 2.6% in the romosozumab group, compared with a loss of –1.6% in the teriparatide group.

“Why did we choose this rather unusual endpoint? It’s because we wanted to capture what happened throughout the first year,” Dr. Langdahl said.

The respective changes from baseline total hip BMD at month 12 were 2.9% vs. –0.5%; in the femoral neck, the 12-month change was 3.2% vs. –0.2%; and in the lumbar spine, the change was 9.8% vs. 5.4%.

The trial participants had a mean age of about 71 years, and T scores ranging from –2.87 to –2.83 in the lumbar spine, –2.27 to –2.21 in total hip, and –2.49 to –2.43 in the femoral neck.

Secondary endpoints of volumetric BMD measured by quantitative CT at 12 months supported the results for DXA measurements at the total hip: integral BMD changed 3.4% with romosozumab vs. –0.2% with teriparatide, cortical BMD changed 1.1% with romosozumab vs. –3.6% with teriparatide, and trabecular BMD increased 15.6% vs. 9.9%, respectively. Total hip strength at 12 months as estimated by finite element analysis rose by 2.5% with romosozumab, compared with a loss of –0.7% with teriparatide. The loss in estimated bone strength at the hip occurred mainly in the first 6 months of treatment with teriparatide and had started to recover by 12 months.

The main difference between the two treatments in total hip BMD came from romosozumab’s bone-building effect on cortical bone, Dr. Langdahl said. The significant loss of total hip cortical BMD observed with teriparatide matches what has been seen in other studies, and it occurs “because the way that teriparatide works initially on cortical bone is to open up the remodeling space; therefore, a decrease in BMD is seen.”

While romosozumab’s speed in increasing BMD and building bone strength is likely to be clinically meaningful for patients at high risk of fracture, the short duration of the trial likely left out the possibility of seeing the same sort of late increases in hip BMD and bone strength during the second year of treatment with teriparatide that have been observed in other studies. Dr. Langdahl suggested that the decline in total hip cortical bone volumetric BMD may have increased had there been more time for measurement in the study; after bisphosphonate treatment, teriparatide’s mechanism of action is thought to open up the bone remodeling space by stimulating bone resorption and formation, particularly in cortical bone.

“You will see an increased porosity in the cortical bone, and I think that is what explains the initial decrease. You’ll also see that it’s kind of catching up [to romosozumab]. This is only a 12-month study, unfortunately. I’m sure if it had been continued for 24 months, there would be an increase in strength because that has been demonstrated in other studies.”

The trial’s comparison of romosozumab versus teriparatide alone also leaves open the question of whether adding teriparatide to bisphosphonate or switching to a combination of teriparatide plus denosumab or teriparatide plus zoledronic acid might have yielded results comparable with romosozumab alone.

Furthermore, The study is not large enough to determine the overall side-effect profile of romosozumab and will have to wait until the larger, ongoing phase III studies are completed, Dr. Langdahl said. In the STRUCTURE study, the overall side effect profile was well balanced between the two groups. More women who received teriparatide developed hypercalcemia, and patients who received romosozumab developed antibodies, although they did not neutralize the agent’s effects.

The study was sponsored by UCB Pharma and Amgen. One investigator is an employee of UCB, and one is an employee of Amgen. Dr. Langdahl reported receiving research grants, consulting fees, and/or honoraria from Amgen, UCB, Eli Lilly, Merck, and Orkla. Most other investigators also reported financial relationships to Amgen and other pharmaceutical companies.

jevans@frontlinemedcom.com

LONDON – Bone mineral density (BMD) and estimated bone strength in the hip significantly increased during 1 year of treatment with the investigational monoclonal antibody romosozumab in comparison with teriparatide in women with postmenopausal osteoporosis who had previous fracture history and had been taking bisphosphonates for at least the previous 3 years in an open-label, randomized trial.

The investigators in the phase III, international, multicenter STRUCTURE trial sought to compare the monoclonal anti-sclerostin antibody romosozumab, which works dually to increase bone formation and decrease bone resorption, against the bone-forming agent teriparatide (Forteo) to see if it would increase total hip bone mineral density to a significantly greater extent by 12 months. Teriparatide is known to take longer to build bone at the hip following bisphosphonate use.

“These results in our minds suggest that romosozumab may offer a unique benefit to patients at high risk for fracture, transitioning from bisphosphonates,” first author Bente L. Langdahl, Ph.D., of Aarhus (Denmark) University Hospital said at the European Congress of Rheumatology. She discussed the study results in this video interview.

When Dr. Langdahl was asked after her presentation about the foreseen role of the drug in clinical practice, she noted that ongoing phase III trials looking at fracture endpoints should indicate whether it works faster at preventing fractures. Because there does not seem to be a restriction to the repeated use of romosozumab, she suggested it might be given initially for 12 months to build bone, followed by bisphosphonates to stabilize gains made, and then it could be used again if needed in a treat-to-target fashion.

The trial randomized 436 patients to receive either subcutaneous romosozumab 210 mg once monthly or subcutaneous teriparatide 20 mcg once daily for 12 months. All patients received a loading dose of 50,000-60,000 IU vitamin D3 to make sure they were vitamin D replete. The patients were postmenopausal, aged 55-90 years, and required to have taken oral bisphosphonate therapy at a dose equivalent to 70 mg weekly of alendronate for at least 3 years before enrollment (with at least 1 year of alendronate therapy prior to enrollment). They had a T score of –2.5 or less in total hip, lumbar spine, or femoral neck BMD and a history of a nonvertebral fracture after 50 years of age or a vertebral fracture at any age.

At 12 months, the primary endpoint of total hip BMD percentage change from baseline, which was calculated by averaging dual-energy x-ray absorptiometry (DXA) measurements at 6 and 12 months, increased significantly by 2.6% in the romosozumab group, compared with a loss of –1.6% in the teriparatide group.

“Why did we choose this rather unusual endpoint? It’s because we wanted to capture what happened throughout the first year,” Dr. Langdahl said.

The respective changes from baseline total hip BMD at month 12 were 2.9% vs. –0.5%; in the femoral neck, the 12-month change was 3.2% vs. –0.2%; and in the lumbar spine, the change was 9.8% vs. 5.4%.

The trial participants had a mean age of about 71 years, and T scores ranging from –2.87 to –2.83 in the lumbar spine, –2.27 to –2.21 in total hip, and –2.49 to –2.43 in the femoral neck.

Secondary endpoints of volumetric BMD measured by quantitative CT at 12 months supported the results for DXA measurements at the total hip: integral BMD changed 3.4% with romosozumab vs. –0.2% with teriparatide, cortical BMD changed 1.1% with romosozumab vs. –3.6% with teriparatide, and trabecular BMD increased 15.6% vs. 9.9%, respectively. Total hip strength at 12 months as estimated by finite element analysis rose by 2.5% with romosozumab, compared with a loss of –0.7% with teriparatide. The loss in estimated bone strength at the hip occurred mainly in the first 6 months of treatment with teriparatide and had started to recover by 12 months.

The main difference between the two treatments in total hip BMD came from romosozumab’s bone-building effect on cortical bone, Dr. Langdahl said. The significant loss of total hip cortical BMD observed with teriparatide matches what has been seen in other studies, and it occurs “because the way that teriparatide works initially on cortical bone is to open up the remodeling space; therefore, a decrease in BMD is seen.”

While romosozumab’s speed in increasing BMD and building bone strength is likely to be clinically meaningful for patients at high risk of fracture, the short duration of the trial likely left out the possibility of seeing the same sort of late increases in hip BMD and bone strength during the second year of treatment with teriparatide that have been observed in other studies. Dr. Langdahl suggested that the decline in total hip cortical bone volumetric BMD may have increased had there been more time for measurement in the study; after bisphosphonate treatment, teriparatide’s mechanism of action is thought to open up the bone remodeling space by stimulating bone resorption and formation, particularly in cortical bone.

“You will see an increased porosity in the cortical bone, and I think that is what explains the initial decrease. You’ll also see that it’s kind of catching up [to romosozumab]. This is only a 12-month study, unfortunately. I’m sure if it had been continued for 24 months, there would be an increase in strength because that has been demonstrated in other studies.”

The trial’s comparison of romosozumab versus teriparatide alone also leaves open the question of whether adding teriparatide to bisphosphonate or switching to a combination of teriparatide plus denosumab or teriparatide plus zoledronic acid might have yielded results comparable with romosozumab alone.

Furthermore, The study is not large enough to determine the overall side-effect profile of romosozumab and will have to wait until the larger, ongoing phase III studies are completed, Dr. Langdahl said. In the STRUCTURE study, the overall side effect profile was well balanced between the two groups. More women who received teriparatide developed hypercalcemia, and patients who received romosozumab developed antibodies, although they did not neutralize the agent’s effects.

The study was sponsored by UCB Pharma and Amgen. One investigator is an employee of UCB, and one is an employee of Amgen. Dr. Langdahl reported receiving research grants, consulting fees, and/or honoraria from Amgen, UCB, Eli Lilly, Merck, and Orkla. Most other investigators also reported financial relationships to Amgen and other pharmaceutical companies.

jevans@frontlinemedcom.com