Will BMD as sole endpoint be a competitive disadvantage for new osteoporosis drugs?
Yes. Physicians, patients and academics will still want evidence of fracture reduction.
Recent research from Dennis M. Black, PhD, makes a good case that the antifracture efficacy of antiresorptive osteoporosis medications can be reliably predicted from their effects on bone mineral density. This opens up the possibility of smaller and less expensive studies to determine the effectiveness of novel bone agents. However, there are a number of cautions that need to be borne in mind.
The experience with fluoride made clear that increased BMD does not result in reduced fractures when the mineralization of bone is compromised. Therefore, good data on bone histology is a prerequisite for accepting BMD as a surrogate for fracture. Strontium increases BMD substantially, but this is significantly contributed to by the heavier strontium atoms replacing calcium in bone mineral. Thus, the increase in BMD does not reflect an increase in bone tissue volume, again dissociating BMD from bone strength.
The Black study is substantially based on antiresorptive agents, such as bisphosphonates and denosumab (Prolia, Amgen). Whether antiresorptives with a novel mechanism of action, anabolics, or agents with multiple mechanisms of action would show the same relationship needs more extensive exploration.
All therapeutic agents have the potential to produce adverse effects, some of which are very uncommon. Therefore, an important function of large, phase 3, fracture trials is to provide a substantial safety database. The difficulty already experienced in assessing post-marketing data on the safety of bone and other drugs highlights the difficulties of doing this simply using observational data. Large randomized controlled trials are more compelling in establishing the safety and risks of interventions.
Finally, will physicians and their patients be as confident in using medicines that have not been subject to extensive trial evaluation? This is a significant concern. An agent shown to prevent hip fracture is more appealing than one that might not have this benefit. While marketing is likely to overcome this problem to a substantial extent, academic leaders are likely to cling to the tenets of evidence-based medicine and wish to see studies that have clinical events as their primary endpoints rather than whole-heartedly endorsing a move to BMD alone as the basis for the registration of novel medications.
Ian Reid, MD, FRACP, FRCP, is distinguished professor of medicine and head of the department of medicine at the University of Auckland, New Zealand.
No, but convincing providers will take time.
After 20 years of entrenched thinking of “you must show fracture reduction” for any osteoporosis treatment, the new thinking is that demonstrating change in BMD as a surrogate for fracture is OK again. Still, there is a substantial group of people who will always argue to keep that endpoint when evaluating any osteoporosis intervention.
That said, a requirement for fracture endpoints has had a substantial chilling effect on new drug development. This change, if accepted by the FDA, will dramatically lower the cost of drug development and allow smaller trials with a shorter duration. It will take less investment, from a pharmaceutical company’s perspective, to get a drug to market if they do not have to show a fracture endpoint. On the other hand, there may be less revenue from that drug. It requires a balancing act, and a change to BMD as a surrogate is not a panacea.
It may be a challenge to convince general internists and primary care physicians. It is one thing for an endocrinologist or a trialist to say, “This is the right thing to do,” but as a generalist or internist, you must balance competing priorities. Patients are often prescribed many different medications for several different diseases. Primary care physicians want to make sure that any medication they prescribe gives that patient the best shot at improving their life. There may be a tendency to prescribe the familiar drug, especially if there are data showing fracture prevention, unless there is a very good reason to go with a new drug.
This is a little like turning an ocean liner around in the middle of the Atlantic. It is not going to turn on a dime. Changing minds will take time, but it is still worth doing. Otherwise, there will be no new efforts in this field.
We also need options for people who are losing bone rapidly but have not yet reached the bone density threshold for osteoporosis. It is deeply unsatisfying to watch people’s bone density deteriorate over time and then wait to intervene. We need an agent for women who are immediately postmenopausal and are losing bone so we can prevent their bone microarchitecture and strength deteriorating unabated.
Elizabeth Shane, MD, is professor of medicine and senior associate dean for student research at Columbia University, College of Physicians and Surgeons in New York City and an attending physician at NewYork-Presbyterian Hospital/Columbia University Medical Center.