AACE 28th Annual Scientific & Clinical Congress:

Anabolic Agents Superior as First-Line Therapy in Patients at Highest Risk

With Felicia Cosman, MD, and Michael R. McClung, MD

The prescribing sequence of osteoporosis medications for high-risk patients matters greatly.  

Evolving evidence strongly suggests that using anabolic medication as first-line therapy provides superior benefit, 1  said Felicia Cosman, MD, professor of medicine at Columbia University School of Medicine, during a plenary session at the 28th annual American Association of Clinical Endocrinologists (AACE) Scientific & Clinical Congress in Los Angeles, California.  

"It's exciting to see the strong data on the newer agents in the past 10 years, specifically how effective the anabolic medicines are," said Dr. Cosman, who is also co-editor-in-chief of Osteoporosis International.

Bone mineral density of hip on imaging is predictive of fracture risk.

Anabolic Drugs Are Better Bone-Builders for Highest Risk Patients

In high-risk patients, making one of the anabolic agents the initial treatment will assure women the fastest and largest fracture risk reduction, she said, and then clinicians will be able to transition patients with osteoporosis to antiresorptive therapy to sustain the achieved fracture risk reduction.1

''Deciding the right treatment is one of the biggest challenges in the field today," she said. Complicating the issue of bone loss management, the guidelines across various medical organizations are inconsistent,2-5 she said, calling out those published by AACE as the best availalbe.5

"All the guidelines except those from AACE undervalued the use of medications in high-risk patients," she told EndocrineWeb during a preconference interview.

In the plenary presentation, Dr. Cosman addressed four key points regarding best practices in the clinical management of osteoporosis:1

  • Need to identify high-risk patients.
  • The rationale for using anabolic medicines as first-line therapy.  
  • Summary of pivotal clinical trial results for anabolic therapy and head-to-head comparative data between anabolic and antiresorptive agents.
  • Provide road map regarding which treatment strategies would be optimal for high-risk patients.

Evalating Patients to Determine Fracture Risk

"We need to be better at recognizing who the really high-risk patients are," Dr. Cosman told EndocrineWeb, and then initiating treatment unhesitantly.

At present, the majority of patients at high risk—upwards of 75%— with new clinical fractures are not being treated for their underlying disease,1 she said. Many of these individuals with recent fractures have had a T-score greater than -2.5; and most vertebral fractures typically are not identified.

"More over, striking the right balance between the benefits and risks in osteoporosis medicine has been highly misunderstood because the risks of not treating osteoporosis were not the primary consideration," said Dr. Cosman.

While most clinicians understand that prior fracture is the most important risk factor for future fractures, Dr. Cosman cited the FREEDOM trial that followed 377,561 women with an initial fracture for up to five years. The researchers demonstrated that 31% of these patients had had recurrent fractures, including 10% who had expereinced hip fractures.6

A radiographically diagnosed vertebral fracture increased the risk of more such fractures, she said, citing a study of 2,725 women with osteoporosis from placebo groups of 4 clinical trials.  Incident vertebral fracture was associated with a 20% risk of recurrent ones in the next year.7

Although these fractures predict the risk of recurrent ones, 75% of vertebral fractures do not come to clinical attention when they happen, Dr. Cosman said; half are thoracic; half lumbar.8

She urged clinicians to consider spine imaging, calling it at least as important as bone density testing in patients at high risk, but not commonly done.1 Then, Dr. Cosman reminded attendees that the National Osteoporosis Foundation recommendation is to screen with spine imaging: 8

  • Oldest group: women age 70 and up and men age 80 and up if the T-score is less than 1.0 at spine, total hip, or femoral neck.
  • Older patients: women who are 65-69 years of age, and men who are 70-79 years of age with a T-score less than -1.5 at the spine, total hip or femoral neck.

Other factors that may be indicative of patients at high risk, Dr. Cosman said,1, include:

  • Indication of multiple fractures
  • Very low bone mass, with T-score less than -3
  • Family history of osteoporosis and/or significant bone loss
  • Evidence of underlying disease
  • Presence of other medical indications such as type 2 diabetes
  • Lifestyle issues: low vitamin D, inadequate calcium intake, sedentary, other relevant nutrient deficiencies, other drugs that are bone disrupting  (ie, glucocorticoids)

Assessing Treatment Options—Order and Timing Are Critical

Among the pharmacologic treatment options, Dr. Cosman reminded attendees, are:1

  • Anabolic agents which stimulate bone formation, including pro-remodeling medications teriparatide (Forteo) and abaloparatide (Tymos)and anti-remodeling medicines romosozumab (sclerostin antibody).
  • Antiresorptive drugs that slow the bone remodeling rate, such as: estrogen, selective estrogen receptor modulators (raloxifene/Evista), bisphosphonates including oral (alendronate/Fosamax, risedronate/Actonel, Ibandronate/Boniva) and intravenous (zoledronic adid) and, finally, denosumab/Prolia.

We know that antiresorptive agents reduced vertebral fracture risk by 60 to 70% at one year, Dr. Cosman said, but nonvertebral fracture risk reduction was not achieved until closer to three years of treatment, and, at best, offers a 20-25% reduction in risk.1,9,10

Next she focused on the role of anabolic drugs, which have been demonstrated to achieve quicker, superior fracture protections throughout the skeleton. To summarize:

Teriparitide: Compared to placebo, teriparatide at 20 ug produced an absolute risk reduction of 2.9% and a relative risk reduction of 53% (p<.05).10

Teriparatide vs. abalopartide (Effect of Abaloparatide vs. Placebo on New Vertebral Fractures in Postmenopausal Women with Osteoporosis [ACTIVE trial]): Looking at Looking at new vertebral fractures over 18 months, abaloparatide produces a relative risk reduction of 86% and teriparatide 80%.11

Romosozumab, Then Denosumab (FRAME): In FRAME, romosozumab was compared with placebo for one year, then followed by denosumab treatment. At the end of month 12, the relative risk reduction in new vertebral fractures in those on romosozumab was 73% (< 0.001). The relative risk reduction was 36% when researchers looked at time to first clinical fracture through month 12 (P < 0.008).12

After the switch to denosumab, among the key fracture endpoints through month 36 were a 66% relative risk reduction in new vertebral fractures (P < 0.001), 21% risk  reduction in nonvertebral (P < 0.039).13

Teriparatide vs. Risedronate (VERO): This comparison of the two medications tracked 1360 patients with new vertebral fractures over 24 months, finding 6% of risedronate patients and 3.1% of teriparatide patients with a new vertebral fracture at 12 months (ARR 2.9%; RRR, 48%, 95% CI, 0.30, 0.91, P < 0.019). At 24 months, 12% of those on risedronate and 5.4% of those on teriparatide did (ARR 6.6%, RRR 56%; 95% CI: 0.29, 0.68, P < 0.0001).14

"A lot of times when I am looking at this, I think I am looking at drug versus placebo," Dr. Cosman said.1

Romosozumab vs. Alendronate (ARCH): With 4,093 subjects enrolled, researchers looked at the incidence of nonvertebral and hip fractures at the primary analysis. Over 24 months, a 48% lower risk of new vertebral fractures as observed in the romosozumab-to-alendronate group, 6.2%, than in the alendronate-to-alendronate group, 11.9%. Clinical fractures occurred in 9.7% of the romosozumab-to-alendronate group versus 13% in the alendronate-to-alendroante group, representing a 27% lower risk with romosozumab (P < 0.001).15

Osteoporosis Management—Applying Evidence in the Clinical Setting

For the recognized high-risk group, the data are clear—starting with an anabolic agent will provide the fastest and most significant fracture risk reduction, said Dr. Cosman. And that bone protection will be sustained after transitioning to antiresorptive therapy.

On evaluating patients under consideration for treatment, rely on hip BMD as a major predictor of future fracture risk, and begin first-line treatment with an anabolic medication to provide the best chance of attaining the target hip BMD levels, she said.

Michael McClung, MD, founding director of the Oregon Osteoporosis Center, endorsed this approach, speaking in favor of advancing osteoporosis treatment with anabolic drugs first in high-risk patients in speaking with EndocrineWeb after the session.

"For many years, osteoporosis experts have believed that beginning treatment with a bone-forming agent was needed to induce a large, rapid gain in bone mass, to be followed by an anti-remodeling drug to maintain or even improve upon those large gains, would be a more effective way to prevent fractures than starting therapy with the anti-remodeling agent," he said.

However, the evidence needed to advance this treatment approach was lacking for this sequence, Dr. McClung said, until recently. Dr. Cosman provided a solid review of the recent trials, which offers strong evidence in favor of beginning with an anabolic agent as this resulted in larger gain in bone mineral density and more rapid declines in fracture risk than did starting treatment with an anti-remodeling drug.

It's also important, he added, that the data indicated that the fracture protection achieved with anabolic therapiy persisted once the patients were transitioned to an anti-remodeling agent.

"Those data alone are sufficient to support the use of anabolic agents as initial therapy in patients at very high risk of fracture," Dr. McClung said.

The other important clinical take-home, he said, is that the level of hip BMD, measured by DXA and known to predict fracture risk in postmenopausal women not on therapy, is effective in illuminating current fracture risk when on any of several treatments.

"Patients who experience large and rapid gains in BMD are at lower risk of fracture sooner than those with smaller, slower gains in BMD," Dr. McClung told EndocrineWeb. The new anabolic therapies are the most effective way to achieve that, he said.

While the past approach of starting with a bisphosphonate is appropriate for many patients at moderately high fracture risk, he added, the sequence outlined in this plenary presentation is appropriate for those at very high risk. The emerging research, he said, ''is redefining our thinking about how best to treat patients with severe osteoporosis and very high risk of fracture."

Dr. Cosman reports financial support from Amgen, Radius Health, and Tarsa Therapeutics. Dr. McClung reports receiving fees from Amgen and Radius Health. 

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