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Should we be using a treat-to-target paradigm in addressing skeletal fragility?
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Treat-to-target for osteoporosis is a clinically useful concept for individualizing treatment decisions in patients at high risk for fracture.
The prevailing paradigm for treating patients with osteoporosis is to begin with a generic oral bisphosphonate, such as alendronate, unless there is a contraindication for doing so. Patients are usually monitored for response to therapy with bone density testing. If the patient responds, treatment is continued, at least for a while. This is an effective strategy for some patients, but may not be appropriate for others, especially those at very high risk for fracture.
Treat-to-target takes a different, more individualized, approach. Before treatment is started, patients are stratified according to the level of fracture risk. A treatment target that represents an acceptable level of fracture risk is identified. Initial treatment is chosen according to the probability of reaching that target. A treated patient is monitored for response to therapy, achievement of the target, and occurrence of fractures, including screening for radiographic vertebral fractures, when indicated. For a patient who is not on a pathway to reach the treatment target, modification of the treatment plan is considered.
An American Society for Bone and Mineral Research/National Osteoporosis Foundation working group has suggested a target T-score greater than –2.5 for patients who are started on treatment because of T-score –2.5 or less; when DXA measurement error is considered, T-score greater than –2 may be preferable. When treatment is started because of high fracture probability by FRAX, the target should be a level of risk below the treatment threshold; however, there is currently no validated algorithm that fully captures the change in fracture risk with therapy. When treatment is started because of a recent fracture, the target, as with all patients, is avoidance of future fractures.
Treat-to-target for osteoporosis is a concept, not a guideline. Although more study is needed to fully validate its clinical utility and identify the most appropriate treatment targets, application of its principles can help us take better care of patients now.
E. Michael Lewiecki, MD, FACP, FACE, is director of the New Mexico Clinical Research and Osteoporosis Center and director of Bone Health TeleECHO Clinic at the University of New Mexico Health Sciences Center in Albuquerque. He is past president of the International Society for Clinical Densitometry (ISCD). Disclosure: Lewiecki reports he a consultant for Amgen and Radius, speaker for Radius and board member of the National Osteoporosis Foundation, Osteoporosis Foundation of New Mexico and ISCD.
There are three reasons I oppose treat-to-target.
First, there is no good target. Second, whatever the designated target may be, there are no proven strategies to get someone there. And third, assuming there were a good target and clear treatment options to get there, managing osteoporosis is a long-term proposal — benefits go away when drugs are stopped — so reaching a target might suggest it’s time to stop treatment, which would not be the right thing to do.
Fracture risk calculators, such as FRAX, are increasingly used to identify patients at high risk for fracture to be treated with medications that reduce fracture risk. However, these calculators are driven largely by age (birthdays will continue, regardless of treatment, and this component of fracture risk will go up), and change in BMD is not strongly predictive of fracture risk reduction, so these calculators, though useful for initial assessment, cannot be used to assess the response to treatment — therefore, not a good “target.”
BMD or T-scores have been proposed as targets. The current recommendation from the National Osteoporosis Foundation is to treat if the T-score is –2.5 or below; however, more fractures occur in patients with T-scores better than –2.5, so if –2.5 were the target, treatment might be stopped for patients still at high risk for fracture. Raising the T-score target to –1.5 or –1 would lead to many patients not at high risk being treated.
Several good treatments are available that reduce fracture risk. It’s important to choose one that has been shown to reduce not only vertebral fracture risk, but also nonvertebral and hip fracture risks. Patients present at different levels of fracture risk as well as at different points on the bone density deficit scale. For those further down on the bone density deficit scale, I often chose drugs that produce greater gains in BMD over the long term of treatment. My patients seem happy when I can tell them their BMD is increasing, but I am not aware of evidence that the greater gains in BMD result in better fracture risk reduction. To me, where one might wind up with a particular agent is useful to consider when deciding on initial treatment. However, there are no studies taking patients not responding well to one agent, changing them to a different agent and showing better outcomes. We often do this in practice, and it’s not necessarily wrong, but there is not good evidence that it’s better than just sticking with the initial choice.
Anabolic agents (teriparatide [Forteo, Lilly] and abaloparatide [Tymlos, Radius Health]) are limited to 2 years of treatment per label (I don’t think that’s medically sound, but we have to deal with that limit). Bisphosphonate holidays have clouded the issue: After a loading period, the drug can be held for a time, but eventually the surplus is depleted and treatment must be started again. After stopping denosumab or estrogen or raloxifene, BMD gains are lost within 6 to 12 months and probably fracture protection as well.
Selecting an agent for initial treatment that has the best chance of maximum benefit for each patient makes sense. A drug that prevents bone loss may be fine for a 75-year-old woman with a T-score of –2.5 (which is average for her age) and no other risk factors, but not adequate for a 60-year-old with a T-score of –3.5. If, for whatever reason, that initial choice is felt to be suboptimal, it’s art, not science, to move on from there.
Nelson B. Watts, MD, is the director of Mercy Health Osteoporosis and Bone Health Services in Cincinnati. Disclosure: Watts reports he is a speaker for Amgen and Radius and is a consultant for Amgen.