Issue: May 2022
Disclosures: Cosman, Cusano, Lane, Lewiecki and Rosen report no relevant financial disclosures.
May 19, 2022
10 min read

Treatment sequence key for optimal management of osteoporosis

Issue: May 2022
Disclosures: Cosman, Cusano, Lane, Lewiecki and Rosen report no relevant financial disclosures.
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Osteoporosis is a common disease that remains significantly underdiagnosed and undertreated.

There is no lack of treatment options, as several new therapies have been approved during the past few years that have added to the arsenal of therapeutic options for osteoporosis. Research has explored whether combinations of these agents or different sequences of drug classes are more effective than others, and it is now well recognized that the sequence of therapy for osteoporosis is key.

However, several groups have varying treatment guidelines, leaving clinicians without clear direction.

“The American Association of Clinical Endocrinology [AACE] and the Endocrine Society guidelines recommend treatment with osteoanabolic medications for patients who are at very high risk for fracture based on data showing strong efficacy against vertebral and nonvertebral fractures as a class, including hip fractures. However, the American College of Physicians guidelines recommend treatment with alendronate and risedronate, zoledronic acid or denosumab [Prolia, Amgen], and they recommend against teriparatide [Forteo, Eli Lilly; Bonsity, Alvogen] because there has been no direct evidence specifically for hip fracture efficacy — these are the major distinctions between the guidelines,” Natalie Cusano, MD, MS, associate professor of medicine at the Zucker School of Medicine at Hofstra/Northwell and director of the bone metabolism program in the division of endocrinology at Lenox Hill Hospital in New York, told Endocrine Today.

Improved physician and patient education regarding recommendations for bone density screening and risks and benefits of treatment are also needed, Cusano added.

“Osteoporosis is known as a ‘silent disease’ because people do not feel symptoms of having low bone density — it does not cause pain unless they break a bone,” she said. “Additionally, many individuals who qualify for bone mineral density screening never undergo testing, especially men, so osteoporosis is often underdiagnosed, unfortunately.”

Treatment options

Two broad classes of agents are recommended for osteoporosis treatment.

The first are antiresorptive agents, which stop bone from breaking down, and include the bisphosphonates alendronate, risedronate, zoledronic acid and ibandronate.

“Denosumab works in a different way but is also an antiresorptive agent,” Cusano said. “Bone is always breaking down and building back up, so by stopping bone from breaking down, these medications give the bone more time to build back up. Bone density improves and the risk for fracture decreases.”

The other class of agents, osteoanabolics, builds new bone. These include teriparatide, abaloparatide (Tymlos, Radius Health) and romosozumab-aqqg (Evenity, Amgen).

“These medications directly build new bone and decrease fracture risk,” Cusano said. “They are generally considered for individuals at very high risk for fracture, such as those with a history of fracture, or who have very low bone density, including individuals with a T-score below –3.5.”

E. Michael Lewiecki

The currently available therapeutic options for the prevention and treatment of osteoporosis are vast, according to E. Michael Lewiecki, MD, FACE, FACP, director of the New Mexico Clinical Research & Osteoporosis Center and director of Bone Health TeleECHO at the University of New Mexico Health Sciences Center in Albuquerque.

“The mainstay of treatment that have been around the longest are bisphosphonates,” Lewiecki told Endocrine Today. “Other than the bisphosphonates, we have estrogen, which is approved for prevention of osteoporosis, but not treatment. We also have raloxifene, which is a selective estrogen receptor modulator that is approved for prevention and treatment of osteoporosis. Then there are three osteoanabolic agents that are approved for postmenopausal women who are at high risk for fracture. Of these, teriparatide has been around the longest and is also approved for the treatment of glucocorticoid-induced osteoporosis and osteoporosis in men.”

Within the past couple of years, the field of osteoporosis has been fortunate to gain more osteoanabolic therapies, according to Nancy E. Lane, MD, distinguished professor of medicine and rheumatology at the University of California, Davis School of Medicine.

Nancy E. Lane

“All osteoanabolic agents have been shown to reduce fractures and to increase bone mass and calculated hip bone strength. However, after they are used, both bone mass and bone strength rapidly deteriorate unless an antiresorptive agent is administered,” Lane told Endocrine Today. “The antiresorptive agent can be a bisphosphonate, or injectable denosumab may be a better choice because it does continue to increase bone mass through unique properties throughout time. It is important to note that once a decision is made to stop treatment with denosumab, an antiresorptive agent needs to be instituted immediately, otherwise the bone mass and bone strength will be rapidly lost. Professional societies have generated new guidelines to help guide treatment with some of these newer agents.”

Differing guidelines

The Endocrine Society and AACE published new guidelines in 2020 to help endocrinologists and other clinicians guide the treatment course for osteoporosis.

“The current guidelines suggest that we stratify risk, and the general theme of this is that the higher the risk, the more aggressive the therapy should be,” Lewiecki said. “For patients who are at very low risk, a nonpharmacological agent may be perfectly appropriate, whereas for high-risk patients, perhaps a bisphosphonate is more appropriate.”

The Endocrine Society and AACE have examples of what constitutes a very high-risk patient, Lewiecki added.

“They are not actual definitions of high risk, just examples, but the general gist of it is that bone mineral density that is in the osteoporosis range or lower, and in patients with fractures, especially recent fractures and multiple fractures, these individuals are at very high risk,” he said.

Although guidelines are consistent across societies for the most part, some are more aggressive than others, according to Clifford J. Rosen, MD, faculty scientist and director of the Center for Clinical & Translational Research at Maine Medical Center Research Institute.

Clifford J. Rosen

“Some guidelines recommend treating osteopenia or at least consider treatment once the T-score threshold is met. Others, like the Endocrine Society, are a bit more conservative in the risk for osteopenia — if a patient has had fractures, then that is a signal to commence therapy,” Rosen told Endocrine Today. “The most recent changes during the past 2 years have been the recommended use of osteoanabolic agents to build bone in individuals who have multiple fractures and low bone density, and we should use these agents as first-line therapy as opposed to bisphosphonates.”

A 2021 position statement of the North American Menopause Society affirms that BMD measured while on current treatment correlates with a patient’s current risk for fracture and justifies use of the T-score at the hip as an appropriate clinical target guiding treatment choices.

Additionally, the position statement recommends those who are at very high risk for fracture should follow a new paradigm of beginning treatment with an osteoanabolic agent followed by an antiresorptive agent.

“The bottom line is guidelines are now matching the appropriate patient to the appropriate therapy,” Felicia Cosman, MD, professor of medicine at Columbia University College of Physicians and Surgeons and co-editor-in-chief of Osteoporosis International told Endocrine Today. “Guidelines help us appropriately tailor therapy and nonpharmacologic approaches for patients at different stages of disease and give us a better long-term view of how we can manage a patient over her entire postmenopausal life span, which could be 40 to 50 years for many women who are included in an at-risk category.”

More on treatment sequence

Recent research indicates that the sequence of osteoporosis treatment is key.

“For example, when an osteoanabolic agent is administered after an antiresorptive agent, there may be a delay or attenuation of the anabolic effect,” Lewiecki said. “This is particularly pronounced when teriparatide is given after denosumab. It has been shown that there is a decline in bone density at the hip throughout the following year, then bone mass begins to recover after the second year in that transition, but it may still not get quite up to where it was when the transition first started.”

In a 2020 study by Cosman and colleagues, researchers found that the osteoanabolic agent romosozumab was most effective at increasing gains in bone formation when the drug was administered before antiresorptive therapy. They examined data from the phase 3 ARCH trial and phase 3 FRAME trial, in which participants received romosozumab before a switch to antiresorptive therapy, compared with the phase 3 STRUCTURE trial and a phase 2 trial, in which romosozumab was administered after participants received antiresorptive treatment with alendronate or denosumab, respectively.

Felicia Cosman

Findings from the ARCH trial showed the largest BMD gains after 1 year of romosozumab, with a mean total hip BMD gain of 6.2% and mean spine BMD gain of 13.7%. Data from the FRAME trial showed similar mean BMD gains of 6% at the total hip and 13.1% at the spine. In the STRUCTURE trial, in which romosozumab was administered after alendronate, mean 1-year BMD gains were 2.9% at the total hip and 9.8% at the lumbar spine. The phase 2 trial in which denosumab was administered before romosozumab showed the lowest mean 1-year BMD gains at 0.9% at the total hip and 5.3% at the lumbar spine.

“The evolving concepts of osteoanabolic therapy in the first-line setting are based on a few observations within the past 5 years that anabolic agents have a superior effect against fractures compared with antiresorptive therapies, which has been shown in head-to-head studies,” Cosman said. “These head-to-head studies have shown that osteoanabolic therapies are superior, and this is where the guidelines agree — these agents should be considered first-line in very high-risk patients.”

Challenges and practical considerations

Despite these advances, challenges and practical considerations associated with osteoporosis treatment remain. For one, patients often hesitant to start treatment due to concerns about adverse events, which is why patients must be counseled properly about the risks and benefits, according to Cusano.

“For patients with osteoporosis, the benefits of medication to reduce high risk for fracture outweigh the possible risks from treatment,” Cusano said. “The AACE Osteoporosis Clinical Practice Guidelines have good resources for patient counseling. The guidelines explain information in different ways so that we can personalize our conversation with each patient.”

Rosen said there are major issues that are not talked about enough.

“Many times, patients are looking for new therapies because either they failed or couldn’t tolerate the treatment, or certain treatments are difficult to get insurance approval for — especially some of the newer osteoanabolic agents that cost a lot more money and are administered subcutaneously,” Rosen said. “In individuals with severe osteoporosis, the Endocrine Society guidelines recommend starting with an osteoanabolic agent, but a lot of insurance companies will not allow us to start a parathyroid hormone [such as teriparatide], for example, unless we first try a bisphosphonate, even though it is probably just as efficacious, if not more so. These issues are underappreciated by academicians but are so important.”

Although the approval of bisphosphonates was a dramatic step forward for the field of osteoporosis, data indicate an increased risk for adverse events associated with the therapy, according to Lane.

“Atypical femoral fractures and osteonecrosis of the jaw are rare but occur more often in individuals who are receiving high doses of IV bisphosphonates for prevention of skeletal metastases in cancer, and they also occur in patients on treatment with bisphosphonates,” Lane said. “Also, while the risk for atypical femoral fractures is dramatically reduced upon stopping the bisphosphonate, we still have a gap in our knowledge of understanding the duration of a ‘drug holiday’ [when treatment is suspended for some period] that will be safe and prevent these patients from fracturing in the future. In fact, there is evidence that shows that patients do fracture once they are on a ‘drug holiday,’ and there is ongoing research focused now on trying to identify these patients at risk and the best duration to safely pause treatment.”

Lewiecki said every patient has unique issues that need to be addressed.

“We have to consider that each patient has had their own prior experience with treatments, their own bias from talking with their friends and neighbors, their own insurance coverage and their own personal comorbidities,” Lewiecki said. “This is where shared decision-making comes in. ... Hopefully, in the end, we come up with something that is medically reasonable and acceptable to the patient and affordable at the same time.”

Continued education needed

Experts agreed that continued education on osteoporosis treatment and management is needed for both physicians and patients.

“A previous study found that for a 50-year-old woman, her estimated lifetime risk of death from a hip fracture is 2.8%, which is equal to the risk for death from breast cancer. We focus on risk of the things we hear most about, such as breast cancer or cardiovascular disease, but there isn’t a focus on the risk for morbidity and mortality from fractures, which is a major issue,” Cusano said. “It is important to educate primary care providers and other clinicians who prescribe medications that are associated with bone health, such as steroids or hormone therapies for breast cancer, as well as educate our patients more on bone health.”

Cosman said there needs to be a focus on the treatment of the underlying osteoporosis.

“Patients and health care providers tend to focus on the management of the fracture itself and not on the treatment of underlying disease,” Cosman said. “Now that we have wonderful treatment options with rapid effects to build up bone tissue and reduce fracture risk quickly, we need to ensure that we are treating patients appropriately to prevent more fractures in the future while also treating the pain and disability from the fracture.”

Lewiecki agreed.

“It is now incorporated into many practice guidelines that we should consider osteoporosis a lifelong disease, and just as with any other lifelong chronic disease, there is no temporary treatment,” Lewiecki said. “There is a myth that we can treat someone with osteoporosis for 3 to 5 years and then stop treatment, which is not the case. If we can do a better job at educating patients on the fact that osteoporosis is a lifelong disease that requires lifelong care, then we will all do a lot better.”

Better physician education is also needed, Lewiecki added.

“I am involved with Bone Health TeleECHO, which is an online community practice where experts in the field connect through video conferencing once weekly, and we have been doing this since 2015,” Lewiecki said. “We discuss osteoporosis cases and gain opinions from each other on those cases, and we all learn from one another. ... The ongoing, case-based discussions recapitulate the way that we learn during our postgraduate medical training, and we can all elevate our level of knowledge and take better care of our patients. Any treatment for osteoporosis is better than none, but we need to recognize that some treatments are better than others, and we now know that the sequence of therapy is so important.”

Click here to read the point/counter, “Should a prior fracture be a requirement for initiating osteoporosis treatment with an anabolic agent?”