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Dr Cosman is an osteoporosis specialist, clinical scientist, and professor of medicine at Columbia University in New York City.
When identifying osteoporosis treatment strategies for postmenopausal women, I start by identifying those who are at higher risk for fracture. I don’t usually define the highest-risk patients by the Fracture Risk Assessment Tool (FRAX®) because it does not enable the separation of patients who are at very high risk from those who just need to be treated. That being said, I think the use of both fracture history and bone mineral density (BMD) can help clinicians determine who those “high-severity” patients are. The patients who I consider to be at highest risk are those who have had recent osteoporotic fractures (within the last 2 years) or those with a history of multiple fractures.
There is one very large database study of more than 377,000 women aged ≥65 years who had sustained a fracture. The study indicated that the cumulative risk of an individual experiencing a subsequent fracture was 10% in the very next year and almost 20% within the next 2 years. This showed that patients who have had a recent fracture need a treatment that reduces their fracture risk very quickly. Similarly, patients who have had multiple fractures, even if they occurred more remotely, are at very high near-term risk of more fractures and need to be treated urgently to minimize their risk for more fractures. Several studies show that for those patients, anabolic drugs reduce the risk of fracture faster and more effectively than antiresorptive drugs.
Additionally, people who have a very low T-score (eg, in the range of -3.00 or lower), especially if they have clinical risk factors, need a medication that can increase their BMD to the target range where we know that subsequent fracture risk is minimized. The sequence of beginning with an anabolic and then afterward switching to an antiresorptive drug is the best way to increase BMD. I believe we are starting to get to a consensus of opinion that a BMD T-score in the range of -2.00 to -2.50 is the target that we should be trying to achieve after starting treatment for most individuals. This target might be a bit higher for those with other major risk factors such as high falling risk, certain underlying chronic diseases, or advanced age.
Some data that my colleagues and I have prepared to be submitted to the American Society for Bone and Mineral Research this year showed that women who start with a T-score of -3.00 or below have a <50% probability of achieving the target BMD T-score (of -2.5 or higher) with bisphosphonate treatment alone; however, if you start with an anabolic agent and then move to an antiresorptive agent, the likelihood of achieving that target BMD target is quite high. So starting with anabolic therapy is the best approach in people who have severe osteoporosis as we have defined it with regard to both the goal of reducing future fracture risk quickly and attaining the target BMD level.
With regard to clinical monitoring of BMD after starting therapy, the ideal BMD monitoring interval for patients with osteoporosis would be at least once a year. If we could measure BMD every year in these patients, and not just the first year after starting osteoporosis treatment, it would help us make effective treatment decisions, in part because BMD assessments have an error associated with the test itself, just as any biologic or analytic measurement does. The more data points we have, the more accurate the slope-of-change line will be. As a result, we would have a better chance of knowing if BMD is indeed stable, declining, or increasing with more data points. So, measuring BMD once a year would be the best. But of course, we have restrictions on reimbursement, as not all insurance companies will cover annual BMD testing, so 2-year monitoring for patients on treatment is often the best we can do.
For patients who start out in the low-bone-mass category – not yet osteoporosis range and who are not going on therapy – I think that a repeat test every 1 or 2 years is appropriate: 1 year for people who are close to the osteoporosis range and perhaps 2 years for those who are closer to a T-score of -1.5. For people who are screened and have BMD that is normal, I think a repeat at 3 to 5 years is probably warranted. Again, that is a large range, but it would be based on how close the individual is to low bone mass, the age of the patient, how close the patient is to her last menstrual period, whether the patient has clinical risk factors, and so forth. For those people who are healthy and are aged 50, have a T-score of 0, and have no risk factors, then monitoring every 5 to 10 years might be enough.
Regarding the use of biochemical markers of bone turnover for monitoring response to therapy, I don’t think we have consensus in this area. Biochemical markers should not be considered an actual target of osteoporosis medication, but I think that biochemical markers can be extremely helpful in monitoring therapy. A baseline level is needed before starting treatment; then for antiresorptive agents, you expect to see a decline of approximately 50% in a bone turnover marker, such as the carboxy-terminal telopeptide (CTX) level, within about 6 months of starting your antiresorptive agent. If you don’t see that magnitude of decrease, it could be a sign of poor adherence to treatment or poor drug bioavailability, and certainly you need to discuss this with your patients to determine what the issue is. If they are taking the medication correctly and persistently, then switching to a different type of antiresorptive therapy is probably indicated.
If you start with an anabolic drug, it might make more sense to measure the bone formation markers rather than the bone resorption markers in that setting; I use a bone resorption marker when I start an antiresorptive drug and the bone formation marker when I start an anabolic drug. We want to see an increase of at least 50% in the bone formation markers within the first few months of anabolic therapy to be assured that the medication is working.
If patients are not doing well from a clinical perspective while on an antiresorptive agent, that would take precedence over what is happening with the biochemical markers. In other words, if a patient had a CTX level that was >50% below their baseline but they had a fracture, or if their BMD looks like it is declining beyond the least significant change, then you might want to a different medication, including consideration of an anabolic agent, even though the marker is doing what it is “supposed” to do.
One other area that I think is still being explored is the use of a marker like CTX to monitor the persistence of the effect of a medication, and here I am speaking specifically about bisphosphonates. As you know, we have often recommended that people can take a temporary holiday from bisphosphonates because they persist in bone and have residual effect for much longer than any of our other therapies. One of my clinical interests over the last few years is how we can use bisphosphonates to maintain BMD once we have attained the goal level (eg, T-score of -2.5). One of the best options for intermittent use in my view is zoledronic acid. We can use the CTX level to help determine when another zoledronic acid treatment needs to be given, because some patients might only need an infusion every 5 years whereas other patients may need an infusion every 1, 2, or 3 years. Using the biochemical marker to hone in on what parameters need to be considered can really be helpful for monitoring these patients.
When addressing approaches for postmenopausal patients who have started osteoporosis therapy but still present with new fractures, my approach depends on their therapeutic regimens. If a patient is already on anabolic therapy, I would try to make sure that the patient is taking the medication correctly, check a bone turnover marker to make sure that it is in the range of what is expected, and probably just stay the course. These patients have severe osteoporosis, which is why they are on an anabolic agent, so we are not going to be able to stop all fractures from occurring, and we have to postulate that we’re doing the best that we can, as long as they are tolerating and taking the medication correctly.
For patients who are on antiresorptive agents who don’t appear to be doing well from a clinical perspective and who are experiencing fractures or their BMD is declining, we have to look at it from 2 different clinical scenarios: the first is with patients on bisphosphonates and the second is with patients on denosumab. For patients on bisphosphonates, it is a little easier, and one option for those individuals is to switch to romosozumab. There is a specific study in women who were on alendronate for at least a year and who were randomly assigned to switch to romosozumab or teriparatide that showed a much better bone density response in both the hip and spine when they switched to romosozumab.2 So, that is a good option for those patients. Switching to abaloparatide probably is better than switching to teriparatide, particularly with respect to hip BMD, but we do not have a specific study to prove this. In patients who have very low total hip or femoral neck BMD, or a recent limb fracture and that is why anabolic therapy is being considered, I would probably suggest adding abaloparatide and continuing an antiresorptive agent rather than making the switch to teriparatide or abaloparatide. I think we can optimize effects on BMD and fracture risk reduction that way. This is based on some of my research from years ago where we randomized women on alendronate to switch to teriparatide or add teriparatide. Results were superior in those who received the combination than those who switched to teriparatide monotherapy.3,4
For patients who are on denosumab, we don’t want to consider making a switch to a PTH agonist drug, either abaloparatide or teriparatide, because hip BMD declines very prominently in those patients. Those patients may very well be better off adding abaloparatide or teriparatide, or switching to romosozumab may also be a decent option. We’re still trying to explore the optimal approach for using romosozumab in these patients. What we have seen in a very small study is that if you stop denosumab and switch to romosozumab, you’ll get a small increase in spine BMD and stable hip BMD.5 Although this is definitely better than what we see when we switch to teriparatide after stopping denosumab, it is still not optimal for the high-risk patient, where you would like to see an increase in both hip and spine BMD. So we’re trying to explore other options for those individuals.
In speaking about the risk-benefit profile of anabolic agents, I think we always need to mention the theoretical risk for osteosarcoma because it is in the label and there is a boxed warning for both abaloparatide and teriparatide. We feel pretty confident at this stage, however, that there is no risk to human use, and certainly not after a 2-year course of therapy, based on the long-term registries where we see absolutely no increased risk of osteosarcoma in humans.6 Of course, we are avoiding using both teriparatide and abaloparatide in people who are at particularly high risk for osteosarcoma. So I would recommend avoiding it in people who had an osteosarcoma as a child, who have a family history of osteosarcoma, people who have had radiation exposure to the skeleton and those with a Paget’s disease diagnosis. Even though I have no qualms using these PTH-agonist drugs in most patients, aside from those few clinical circumstances I just mentioned, it is important for people to realize that for romosozumab, there are no animal models showing an increased risk of osteosarcoma. So, romosozumab can even be used in people who have had radiation exposure to the skeleton. The Romosozumab label has a boxed warning for cardiovascular disease risk based on an imbalance in MACE (Major Adverse Cardiovascular Events) seen in one study (ARCH), where romosozumab was compared with alendronate but not seen in another large study (FRAME), where romosozumab was compared with placebo. It is recommended that women who have had heart attacks or strokes within the preceding year not be given romosozumab. Women with more remote CV history or risk factors for CV disease can still be candidates, based on a positive benefit to risk assessment.
Shifting gears to speak about management strategies for postmenopausal women with severe osteoporosis at high risk for fracture with comorbid chronic kidney disease, I don’t think we have a clear answer yet for these patients. One thing that is being theorized is that you can give bisphosphonate down to an estimated creatinine clearance of approximately 30 mL/min relatively safely, and if you are using an intravenously administered bisphosphonate such as zoledronic acid, a prudent approach is to administer it over a more prolonged period of time. In this situation, it is very unlikely that you will see any renal toxicity. However, once you have a patient with an estimated creatinine clearance of <30 mL/min, it is more difficult to know what to do because there is often a component of metabolic bone disease related to chronic kidney disease (MBD-CKD), and we don’t have any easy way to diagnose that mineral bone disorder because most centers are not doing trans-iliac crest bone biopsies with tetracycline labelling anymore. In addition, you need to have an expert reading the results of these specialized tests in order to understand what they mean.
We are in dire need of other biochemical markers that we can use to follow these patients and to determine who really needs therapy, and when it needs to be repeated, and we’re just not quite there yet. We know that denosumab can be used in people with fairly severe CKD, but they are at higher risk for hypocalcemia and other metabolic disturbances that can be quite severe. There is also a worry that when you use these potent antiresorptive therapies you could be precipitating aplastic bone disease, and that can have repercussions not just for bone but also perhaps for increasing the risk for vascular calcifications.
I am really in the dark, as many clinicians are, regarding how to treat patients in whom creatinine clearance is <30 mL/min. I hope that our renal colleagues and renal bone experts can help us over the next few years with a better paradigm for these patients. They are at very high risk for fracture, but they are also at very high risk for vascular events. We need to make sure that we can effectively reduce the risk of both of these conditions and not cause worsening of either.
In summary, this idea of imminent risk of fracture – the fact that patients who have had recent fractures, including those who have recently been diagnosed with a vertebral fracture, are at such high risk – is a key point. These fractures are often asymptomatic for months and perhaps even years, but they still carry the same predictive value for future risk of fracture. That is an extremely important concept. It means that not only do we have to treat these patients, we have to treat them urgently. We don’t want to wait. We want to offer them therapy as they are getting out of the hospital and they are starting to get back on their feet because if we wait too long, they are going to suffer more fractures and with more morbidity and, ultimately, disability associated with a progressive, domino-type effect of more and more fractures. This is where our biggest treatment gap is and where I really think that all of us need to direct our best efforts. In the United States, we are treating fewer than 10% of hip fractures and fewer than 20% of all osteoporosis-related fractures after the fracture occurs. That’s what we need to fix over this next year or two. We need fracture liaison programs and subspecialists to help achieve this goal, and a “fracture champion” at every institution would be a good step toward this. These clinicians need to come from not only in the hospital, but also the emergency department and orthopedic service, so that we can make sure we are preventing fractures in patients who are at highest risk.
Disclosure: Dr Cosman is a consultant, advisor and speaker for Amgen and Radius Health. She has received research grants from Amgen for investigator-initiated research studies.
1. Balasubramanian A, Zhang J, Chen L, et al. Risk of subsequent fracture after prior fracture among older women. Osteo Int. 2019;30(1):79-92. doi:10.1007/s00198-018-4732-1
2. Langdahl BL, Libanati C, Crittenden DB, et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet. 2017;390(10102):1585-1594.
3. Cosman F, Wermers RA, Recknor C, et al. Effects of teriparatide in postmenopausal women with osteoporosis on prior alendronate or raloxifene: differences between stopping and continuing the antiresorptive agent. J Clin Endocrinol Metab. 2009;94:3772-3780.
4. Cosman F, Keaveny TM, Kopperdahl D, et al. Hip and spine strength effects of adding versus switching to teriparatide in postmenopausal women with osteoporosis treated with prior alendronate or raloxifene. J Bone Miner Res. 2013;28:1328-1336.
5. Kendler DL, Bone HG, Massari F, et al. Retreatment with romosozumab after 12 months of placebo demonstrates similar BMD efficacy compared with initial romosozumab treatment. Presentation at: ENDO 2017; April 1-4, 2017; Orlando, FL.
6. Andrews EB, Gilsenan AW, Midkiff K, et al. The US postmarketing surveillance study of adult osteosarcoma and teriparatide: study design and findings from the first 7 years. J Bone Miner Res. 2012;27(12):2429-2437.
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