Will BMD as the sole endpoint be a competitive disadvantage for new osteoporosis drugs?

Yes. Doctors, patients and academics will always want evidence of reduced fractures.

Recent research by Dennis M. Black, PhD, shows that the anti-fracture efficacy of anti-resorptive drugs against osteoporosis can be reliably predicted from their effects on bone mineral density. This opens up the possibility of smaller, less expensive studies to determine the effectiveness of new bone agents. However, there are a number of caveats to keep in mind.

Experience with fluoride has clearly shown that increasing BMD does not lead to reduced fractures when bone mineralization is compromised. Therefore, good bone histology data is a prerequisite for accepting BMD as a fracture surrogate. Strontium greatly increases BMD, but this is significantly contributed by the heavier strontium atoms replacing calcium in the bone mineral. Thus, the increase in BMD does not reflect an increase in the volume of bone tissue, again dissociating BMD from bone strength.

The Black study is essentially based on anti-resorptive agents, such as bisphosphonates and denosumab (Prolia, Amgen). Whether antiresorptives with a new mechanism of action, anabolics, or agents with multiple mechanisms of action would show that the same relationship requires further exploration.

All therapeutic agents have the potential to produce side effects, some of which are very rare. Therefore, an important function of the large Phase 3 fracture trials is to provide a substantial safety database. The difficulty already encountered in evaluating post-marketing data on the safety of bones and other drugs highlights the difficulties of doing so simply by using observational data. Large randomized controlled trials are more convincing in establishing the safety and risks of interventions.

Finally, will physicians and their patients be as confident in using drugs that have not been thoroughly tested? It is an important concern. An agent that prevents hip fractures is more attractive than one that might not have this benefit. While marketing is likely to overcome this problem to a large extent, academic leaders are likely to cling to the principles of evidence-based medicine and wish to see studies in which clinical events are their primary endpoints rather than wholeheartedly approve the move to BMD. as the basis for the approval of new drugs.

Ian Reid, MD, FRACP, FRCP, is Professor Emeritus of Medicine and Head of the Department of Medicine at the University of Auckland, New Zealand.

No, but convincing suppliers will take time.

Elizabeth shane

After 20 years of ingrained thinking about “you have to show fracture reduction” for any treatment for osteoporosis, the new way of thinking is that demonstrating BMD change as a fracture surrogate is once again acceptable. Yet there is a significant group of people who will always advocate for keeping this endpoint when evaluating any osteoporosis intervention.

That said, the requirement for fracture criteria has had a substantial deterrent effect on the development of new drugs. This change, if accepted by the FDA, will significantly reduce the cost of drug development and allow smaller trials with shorter duration. It will take less investment, from a pharmaceutical company’s perspective, to bring a drug to market if there is no need to show an end point of fracture. On the other hand, this drug can generate less income. It requires balancing act and a change in BMD as a surrogate is not a panacea.

It can be difficult to convince general internists and primary care physicians. It’s one thing for an endocrinologist or a trialist to say, “It’s the right thing to do,” but as a generalist or internist you have to balance competing priorities. Patients are often prescribed many different medications for several different conditions. Primary care physicians want to make sure that any medication they prescribe gives this patient the best chance of improving their life. There may be a tendency to prescribe the familiar drug, especially if there is data showing prevention of fractures, unless there is a very good reason to switch to a new drug.

It’s a bit like spinning an ocean liner in the middle of the Atlantic. It won’t work in no time. Changing mindsets will take time, but it is worth it. Otherwise, there will be no further efforts in this area.

We also need options for people who are losing bone quickly 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 going through menopause and are losing bone so that we can prevent their bone microarchitecture and resistance from deteriorating relentlessly.

Elizabeth Shane, MD, is Professor of Medicine and Senior Associate Dean for Student Research at Columbia University, College of Physicians and Surgeons of New York, and attending physician at NewYork-Presbyterian Hospital / Columbia University Medical Center.