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Emerging data support anabolic-first regimens for severe osteoporosis


 

EXPERT ANALYSIS FROM AACE 2019

– In the opinion of Felicia Cosman, MD, the current state of osteoporosis treatment is fraught with clinical challenges.

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First, most patients at highest risk for future fractures are not being treated. “In fact, fewer than 25% of patients with new clinical fractures are treated for their underlying disease,” Dr. Cosman, professor of medicine at Columbia University, New York, said at the annual scientific and clinical congress of the American Association of Clinical Endocrinologists (AACE).

“One of the reasons doctors are not treating these patients is that many of them do not have a T-score in the osteoporosis range. There’s a misunderstanding here. A fracture that occurs in people with low bone mass in the setting of minimal trauma – such as a fall from standing height – meets the criteria for the clinical diagnosis of osteoporosis and qualifies a person for being at high risk of more fractures. This is likely because bone weakness or fragility is related not just to quantitative aspects, but also to structural and qualitative aspects that cannot be measured as easily.”

Another problem is that some of the highest-risk patients are those with a vertebral fracture. “However, vertebral fractures are particularly difficult to find and treat because they’re often asymptomatic and we’re not [identifying] these patients,” she said. “Targeted screening [with] spine imaging to find vertebral fractures is probably as important as BMD [bone mineral density] testing.”

To complicate matters, Dr. Cosman said that clinicians and patients “misunderstand the balance between benefits and risks of osteoporosis medications and they don’t consider the risk of not treating the underlying disease. Lastly, there’s little evidence to help guide long-term strategies. Guidelines across medical specialties are incredibly inconsistent. With the exception of guidelines from AACE, the one thing that they’re very consistent about is underrecognizing the value of anabolic therapy for people with severe osteoporosis.”

It is well known that previous bone fracture is the most important risk factor for a future fracture, but the recency of the fracture is also important. In a recent study, researchers followed 377,561 female Medicare beneficiaries with a first fracture for up to 5 years (Osteoporos Int. 2019;30[1]:79-92). They found that at 1 year, the risk of another fracture was 10%. The fracture risk rose to 18% at 2 years, and to 31% at 5 years. “I like to think of this as the osteoporosis emergency,” said Dr. Cosman, co–editor-in-chief of Osteoporosis International. “We need to treat these people right away to prevent more fractures and related disability, morbidity, and mortality.”

According to data from pivotal trials, the anabolic agents teriparatide, abaloparatide, and romosozumab appear to produce more rapid and larger effects against all fractures, compared with even the best antiresorptive agents. “However, comparing across studies can be problematic, because the different populations have varying baseline characteristics and different underlying risk,” Dr. Cosman said. “The protocols and the outcome definitions might be different. It’s better to compare anabolic agents with antiresorptive agents in head-to-head trials, and we now have a few of these.”

Two trials are older studies in which fracture outcomes were not the primary endpoints. One study evaluated a population of patients with glucocorticoid-induced osteoporosis and found that over 18 months, teriparatide reduced vertebral fractures by 90%, compared with alendronate (N Engl J Med. 2007;357[20]:2028-39). The other trial focused on a population of patients with acute, painful vertebral fractures. It found that over 1 year, teriparatide reduced vertebral fractures by 50%, compared with risedronate (Osteoporos Int. 2012;23[8]:2141-50). Two more recent studies compared anabolic and antiresorptive therapies on fracture outcomes as primary endpoints in patients with prevalent fractures. The VERO trial compared teriparatide with risedronate (Lancet. 2018;391[10117]:230-40), and ARCH compared romosozumab with alendronate (N Engl J Med. 2017;377[15]:1417-27).

In VERO, 1,360 patients with a prevalent vertebral fracture were randomized to receive teriparatide or risedronate for 2 years. At 12 months, the proportion of patients with a new vertebral fracture was 3.1% and 6% in the teriparatide and risedronate groups, respectively, a pattern that held true at 24 months (6.4% vs. 12%). The study also showed that the number of nonvertebral fractures was significantly lower in teriparatide-treated patients, compared with those on risedronate. In ARCH, 4,093 postmenopausal women at high risk of fracture were randomized to receive romosozumab or alendronate for 1 year and then followed for a median period of 33 months. At 12 months, the proportion of patients with a new vertebral fracture was 4% and 6.3% in the romosozumab and alendronate groups, respectively, a pattern that held true at 24 months (6.2% vs. 11.9%).

“These trials showed that the antifracture effects are faster and larger with anabolic agents, compared with antiresorptive agents,” Dr. Cosman said. “They also showed that antifracture effects are sustained after transition to antiresorptive therapy.” In ARCH, both nonvertebral and hip fracture incidences were lower in the romosozumab group, compared with the alendronate group.

The trials demonstrated that improving total hip BMD is associated with improved bone strength and resistance to fracture, yet treatment sequence matters. “The greatest BMD gains of the hip are seen when anabolic agents are used first-line, followed by a potent antiresorptive agent,” she said.

Dr. Cosman offered a strategy for patients on potent antiresorptive agents who need anabolic medication. In patients on bisphosphonates, especially with an incident hip fracture or very low hip BMD, consider combination therapy with initiation of teriparatide or abaloparatide, along with an antiresorptive agent. “There are very little data addressing patients on denosumab, but I would suggest perhaps adding teriparatide or abaloparatide in this population, and continuing denosumab,” she said. “That could lead to BMD gain. Switching to romosozumab might also be an option. But, if possible, use an anabolic agent first. The role of anabolic medication for osteoporosis is evolving as evidence continues to suggest superior benefit of anabolic-first regimens for high-risk patients.”

Dr. Cosman disclosed that she has received advising, consulting, and speaking fees from Amgen and Radius. She has received consulting fees from Tarsa and research grants and medication from Amgen.

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