Not all osteoporosis medications work the same, and that's especially true for the small class of osteoanabolic agents.
Only three approved drugs belong to this category -- teriparatide, abaloparatide (Tymlos), and romosozumab (Evenity) -- and they work by stimulating bone formation instead of by only preventing bone resorption like other classes of osteoporosis drugs like bisphosphonates or denosumab (Prolia, Xgeva).
"What's important to note here is that there's both an increase in bone mineral density (BMD), as well as an improvement in microarchitecture [with these agents]," said Laila Tabatabai, MD, of Houston Methodist's Bone Health Initiative.
"All three of these agents are highly efficacious, [and] have different safety profiles and different administration. It's important to keep all this in mind as you approach your patient," she said at the 2025 American Association of Clinical Endocrinology (AACE) annual meeting.
There's an increasing body of evidence documenting the superiority of anabolic agents, according to AACE's 2020 osteoporosis clinical practice guidelines.
"It is intuitive that agents which stimulate bone formation (anabolic treatment) and restore degraded bone microarchitecture could be expected to have greater effects on BMD and fracture reduction than those that inhibit bone breakdown (antiresorptive therapies)," the guidelines noted.
It's best to start treatment with an osteoanabolic agent for patients at imminent risk for fracture, said Tabatabai, but prescribers should also understand the unique safety and efficacy profiles of each agent and know which agents should come next in the treatment sequence.
Teriparatide, the First Approved Osteoanabolic
Teriparatide was approved by the FDA in 2002. It's a synthetic form of the natural human parathyroid hormone (PTH) that stimulates osteoblasts by intermittent PTH receptor activation. Given as a 20-mcg daily injectable, it's recommended for no longer than 2 years, unless a patient remains at or has returned to having a high risk for fracture.
In a randomized trial of postmenopausal women with osteoporosis, teriparatide reduced the risk of one or more new vertebral fractures by 65% compared with placebo, and reduced the risk of nonvertebral fractures by 35%. It also yielded a 10% increase in BMD at the spine and a 3% increase at the hip.
While it carries a neutral risk for cardiac safety, teriparatide has been linked to a risk for osteosarcoma in animal studies.
Then Came Abaloparatide
Teriparatide stood alone as the only osteoanabolic agent for 15 years until abaloparatide was approved in 2017. It's a synthetic peptide analog of PTH-related protein that's also taken as a once-daily injectable (80 mcg) for a maximum of 2 years throughout the patient's life.
Similar to its predecessor, abaloparatide carries a neutral cardiac safety profile, but a warning for risk of osteosarcoma.
In the ACTIVE trial, it was tied to an 86% reduction in vertebral fractures and a 43% reduction in nonvertebral fractures in postmenopausal women with osteoporosis.
Abaloparatide also yielded larger BMD gains at the total hip, femoral neck, and lumbar spine compared with teriparatide.
Romosozumab, Newest Addition
Romosozumab was approved in 2019. Acting as a sclerostin inhibitor, it works differently than the other two drugs in this class.
In the phase III FRAME study of postmenopausal women with osteoporosis, there was a 73% relative risk reduction in new vertebral fractures among those receiving romosozumab for 12 months compared with those given placebo, with incidences of 0.5% versus 1.8%, respectively (P<0.001).
BMD increased rapidly in the spine and hip with romosozumab, with significant changes by month 6. By 12 months, BMD had increased by 13.3% at the spine and 6.8% at the total hip.
As the only monthly osteoanabolic injectable, romosozumab is dosed at 210 mg once per month over 12 months.
However, caution should be used in patients at high cardiovascular risk. The drug's label carries a boxed warning about a potential increased risk of myocardial infarction, stroke, and cardiovascular-related death.
Treatment Sequence
An osteoanabolic agent should be the first choice treatment for patients at high or imminent risk for fracture, but once their use has been maxed out after a year or two, prescribers should reach next for an antiresorptive agent.
"Typically, the best treatment sequence to achieve that would be osteoanabolic first followed by antiresorptive. This type of strategy would be the treatment that you would want for patients at imminent risk of fracture," said Tabatabai.
"If you're doing a bone-builder first, you're switching to either bisphosphonates or denosumab [and] the patient will do very well. Denosumab does lead to further increases -- slightly larger than with bisphosphonates so that's something to keep in mind," she added.
The reverse order of antiresorptive to osteoanabolic will also boost BMD, but will yield "blunted" results compared with a de novo osteoanabolic, she pointed out.
One treatment sequence -- denosumab to teriparatide -- should be "truly avoided," warned Tabatabai.
In the 2015 DATA-Switch study, patients who switched from denosumab to teriparatide had a sharp drop-off in BMD after switching, especially at the total hip, which quickly fell back to baseline levels.
Antiresorptive to antiresorptive will "occasionally happen in clinical practice," Tabatabai said, but cautioned that both bisphosphonates and denosumab carry risks of osteoporosis in the jaw and atypical femur fracture. "If you're going from one treatment to another, you should consider the cumulative amount of time that the patient's been on the antiresorptive treatment," she added.
Disclosures
Tabatabai reported relationships with Amgen and Kyowa Kirin.
https://www.medpagetoday.com/spotlight/aace-osteoporosis/115923
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