With Felicia Cosman, MD, Steven R. Cummings, MD, Malachi McKenna, MD,John T. Schousboe MD, PhD, E. Michael Lewiecki, MD, and Kenneth G. Saag, MD
Establishing a more individualized, goal-directed approach to managing osteoporosis may foster better drug therapy selection, improve patient follow-up, and anticipate use of new treatments,1 according to a panel convened at Clinical Osteoporosis 2017—a joint symposium of the National Osteoporosis Foundation and the American Society for Bone and Mineral Research—held in Orlando, Florida.
This treat-to-target approach to care focuses on well-defined outcomes, a model that has been very effective in improving management of diabetes and cardiovascular disease.2-4
"Ultimately, osteoporosis goals can help patients achieve maximal benefits while minimizing the risk of rare side effects, possibly associated with long-term, uninterrupted antiresorptive exposure," session moderator, Felicia Cosman, MD, professor of medicine at Columbia University College of Physicians and Surgeons in New York, New York, told EndocrineWeb.
Bone Density Represents a Treat-to-Target Strategy
The current practice for osteoporosis treatment is to start with a first-line medication, typically a bisphosphonate (BP). If the patient is responsive after a year or 2, the therapy is continued,1 said Steven R. Cummings MD, in an effort to frame the standard of care currently followed for osteoporosis.
However, the patient who does not appear responsive in that time frame may be switched to another anti-resorptive medication, or parathyroid hormone (PTH); 3 to 5 years in, patients might be advised to take a drug holiday, said Dr. Cummings, director of the San Francisco Coordinating Center, research scientist at the California Pacific Medical Center Research Institute, and professor emeritus of the University of California, San Francisco School of Medicine.
The disadvantage of this approach, said Dr. Cummings, is that while a patient may be responding biologically, she can still have very low bone mineral density (BMD) and a high risk of fracture. Rather, he suggested treatment goals should be dictated by an individual’s circumstances, with periodic checks for progress toward the goals.1 If for example, the main reason for treatment was a high fracture risk, then the treatment goal would be an acceptable low fracture risk, such as being free of fractures for 3 to 5 years.
“Clinicians face multiple challenges with insufficient tools for assessment of risk of fracture during treatment, and lack potent treatments to reduce the risk of hip and other major fractures besides vertebral fracture,” he said, and additional risk factors that could warrant a change to treatment include “poor patient compliance and fracture during treatment.”
“The goal is to improve the selection of initial drug therapy based on severity, improve follow-up of patients on treatment, and anticipate how to use new treatments that have a very potent effect on BMD and perhaps greater reductions in risk,” Dr. Cummings said.
At present, treatments are not potent enough to enable some patients with severe osteoporosis to reach target BMD goals, or for patients with high fracture risk to sufficiently achieve their fracture risk goals.1
While patient screening for height against a baseline level plus spine imaging may be helpful now, he said, clinicians need better evidence of anti-fracture efficacy, algorithms for estimating fracture risk in patients undergoing treatment, and data that compare the value of starting or switching to alternative treatments for BMD goals.
In considering the treat-to-target approach for osteoporosis, a patient could technically respond to treatment while still having an unacceptably high fracture risk,1 said E. Michael Lewiecki, MD, of the University of New Mexico School of Medicine in Albuquerque, New Mexico.
“The current paradigm is—we’re happy with the response to therapy; but, in treat-to-target—we’re not so happy because we believe fracture risk is high. So why do we treat osteoporosis different from other diseases like blood pressure?” Dr. Lewiecki said. “Treatment may be fully effective, even as fracture risk remains unacceptably high.”
He agreed that not enough data exists to definitively compare effectiveness, or assess the risk of specific treatment protocols.1 Cost-effectiveness is also unclear, leading to resistance from insurers.
Dr. Lewiecki said a T-score of more than -2.5 is a practical and intuitive treatment target since dual-energy X-ray absorptiometry (DXA) is widely available and BMD is modifiable with treatment.1 However, when a experiences a recent fracture, risk of future fractures increases and becomes a
“T-score target spoiler.”
For patients who have been on oral BP for 10 years and achieve a T-score greater than or equal to -2.5, he said, it’s time to consider a drug holiday, extended dosing schedule, or switch to an anabolic agent, according to Dr. Lewiecki.1 Other 10-year treatments also call for a change to maximize benefits and curb side effects.
John T. Schousboe MD, PhD, director of the of the Park Nicollete Clinic Osteoporosis Center, discussed how measuring bone turnover markers (BTMs) might aid in treat-to-target strategies.1 He said resorption markers and formation markers each have potential utility in assessing change and potential efficacy of a therapy within months of the treatment start, but not as a long-term goal.
“We use BTMs to identify responders,” he said.
More data is needed to know whether BTMs are effective in identifying patients whose fracture risk rises during drug holidays. The value of BTM data is limited by variations in reference ranges, circadian variations, food consumption, kidney disease, and fracture history, Dr. Schousboe said, so right now, BTMs are most useful for identifying poor patient adherence and non-responders to oral BPs and teriparatide therapy.1
Safety surveillance is critical for osteoporosis therapeutics, said Kenneth G. Saag, MD, MSc, vice chair of the Department of Medicine and director of the Center for Outcomes, Effectiveness Research, and Education in the Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.
“Our patients are very fearful of rare side effects from these drugs,” said Dr. Saag. While estrogen use (daily, pill or patch) and calcitonin nasal spray usage rates have held steady, oral BP use has dropped since the 1990s, a trend reflected in a New York Times article, “Fearing Drugs’ Rare Side Effects, Millions Take Their Chances With Osteoporosis.”5
Despite a good safety profile, tolerability concerns documented during clinical trials for BPs included osteonecrosis of the jaw (ONJ), atypical fractures, hypocalcemia, acute phase reactions, acute kidney injury, esophageal cancer, atrial fibrillation, fracture non-union, and uveitis.6
Dr. Saag said, “patients most at risk for ONJ include those who have taken anti-resorptive agents for more than 2 years, are over age 65, have an invasive dental procedure or dentures, smoke, or have diabetes.”
ONJ risk can be reduced by frequent surveillance, removing oral infections and pathology, deferring anti-resorptive treatments until oral health is stabilized and, he noted, pre-treatment bone turnover markers such as CTX/NTX generally have not been helpful.1
“Turnover markers don’t help us to identify who will get into problems with these drugs,” said Dr. Saag.
Dr. Saag asked how many clinicians had seen atypical femur fractures (AFF), and nearly three-quarters of the attendees raised their hands.1 The longer BPs are used, the higher the risk of AFF, “so we increase risk of AFF and reduce risk of typical fractures,” he said.
To prevent AFF, Dr. Saag recommended4 avoiding BPs in high-risk patient such as those with:1
Similarly, he suggested using biomarkers judiciously to define very low turnover risk group.1 After 5 years of oral BP, or 3 years of IV therapy, consideration should be given to having patients take a BP drug sabbatical.
Clinicians can detect AFF by examining for pain and tenderness in hip or thigh, and screening with radiographs, NM imaging, MRI, or DXA,1 said Dr. Saag. If AFF is detected, BPs should be stopped immediately and possible prophylactic rodding or anabolic medication may be considered. Single energy absorptiometry has some screening advantages, including faster image acquisition, he said, and to prevent hypocalcemia, particularly with IV BPs, calcium and vitamin D levels should be checked. Alternatively, prophylactic ergocalciferol 100K IU peri-infusions may be given.1
“While clinical trials of IV BPs show acute phase reactions in up to 10% of patients, actual clinical practice may approach 30%,” he said. Postmenopausal women taking denosumab are at risk of serious skin infections, and should be encouraged to report skin lesions and monitored accordingly.4 “Less serious side effects are often preventable through careful patient selection and monitoring,” Dr. Saag said. More serious side effects are rare.
Panelists and audience members debated the importance of screening tools, research data, and clinical intuition. Repeated comments included “we’re in a data-free zone here” and “we don’t have a fracture risk assessment tool that is sufficient,” particularly for patients who will be treated for 10 or 20 more years.1
“The panelists got me thinking about what happens after 5 years of treatment,” Malachi McKenna, MD, an endocrinologist at St. Vincent’s University Hospital in Dublin, Ireland, told EndocrineWeb, “It involves assessing [patients] response to therapy and assessing if they have reached what we consider a good target with respect to better bone density and lower fracture risk, then we have to temper that with our concerns about using some of these meds long term. We’ll have some individuals who have spells of treatment, then a drug holiday and come back to treatment at a later stage.”
"In general, osteoporosis treatment goals are the inverse of the indications to initiate treatment: patients with a history of fracture and those with a bone density levels in the osteoporosis range," said Dr. Cosman, coeditor-in-chief of Osteoporosis International.
"Treatment targets, therefore, should include attaining bone density levels (in hip and spine) above osteoporosis level and maintaining patients for about 5 years. Choosing the most potent therapies for these patients, such as anabolic bone-building medication, is most likely to reduce risk of further fractures quickly and prominently," she told EndocrineWeb, and "for those patients with very low BMD (even without fracture), having a BMD treatment target is more likely to result in use of an optimal treatment sequence to attain a BMD above -2.5, often starting with anabolic therapy and then using the most potent antiresorptive therapy."
"Following this paradigm, there may even be an opportunity to convert to a maintenance regimen (such as intermittent bisphosphonate treatment) once treatment goals are achieved," Dr. Cosman concluded.
The session was supported by the American Society for Bone and Mineral Research and the National Osteoporosis Foundation, with funding from Amgen and Radius, both companies have treatments that could benefit from goal-directed treatment.