A Lot of Progress, With More to Be Done: A Response to NIH Pathways to Prevention Report “Research Gaps for Long-Term Drug Therapies for Osteoporotic Fracture Prevention”

Abstract

The public health implications of osteoporosis are enormous but the disease remains underdiagnosed and undertreated. In October 2018, the National Institutes of Health (NIH) convened a Pathways to Prevention (P2P) Workshop entitled “Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention” designed to identify research gaps, suggest future research opportunities, and advance the field through an evidence-based assessment. By design, the P2P report focused on “gaps” in our knowledge base. Unfortunately, however, the report did not sufficiently acknowledge the current evidence that unequivocally demonstrates the therapeutic efficacy of existing pharmacologic therapies for osteoporosis, which has the potential to exacerbate the current crises in osteoporosis diagnosis and treatment.

The public health implications of osteoporosis are enormous. In the United States alone, it has been estimated that more than 10 million men and women over the age of 50 years have osteoporosis and this number continues to rise as our population ages.⁽¹⁾ Each year more than 300,000 US women and men experience a hip fracture, an event that is accompanied by a 6-month mortality of 15% to 25% and an estimated health-care expenditure that will exceed $25 billion by 2025.^(2,3) Fortunately, however, although osteoporosis cannot be cured, there are effective therapies that can reduce the risk of fragility fractures considerably, including hip fracture.⁽⁴⁾ Nonetheless, over the past decade the utilization of these effective medications, which has always been distressingly suboptimal, has decreased further, and the overall incidence of hip fracture in the US, which had been declining, has leveled off.^(5–7) The reasons for this decline in medication use are likely multifactorial but no doubt include the well-publicized concerns regarding the rare but serious adverse effects associated with osteoporosis medications, particularly the most commonly used and most affordable class of medications, the nitrogen-containing bisphosphonates.

In this setting, on October 30–31, 2018, the National Institutes of Health (NIH) convened the Pathways to Prevention (P2P) Workshop entitled “Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention.” P2P workshops are designed to identify research gaps in a clinical area involving a complex public health issue, suggest future research opportunities, and advance the field through an evidence-based assessment. The goal of this specific workshop was to evaluate the current evidence concerning the potential risks and benefits of the available pharmacologic agents used to treat osteoporosis, with a specific focus on long-term therapy. The workshop, which was co-sponsored by the NIH Office of Disease Prevention (ODP), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the National Institute on Aging (NIA) brought together numerous experts for an in-depth discussion of the issues. The ODP also commissioned a systematic review of the efficacy and safety of long-term drug therapies. The results of the P2P workshop were recently published in the Annals of Internal Medicine in a report entitled “Research Gaps for Long-Term Drug Therapies for Osteoporotic Fracture Prevention.”⁽⁸⁾ Although this report identifies future research needs, by primarily empha-sizing the “gaps” in our understanding of the efficacy and safety of osteoporosis medications over the long term, we are concerned that this effort has the potential to further reduce enthusiasm to prescribe medications to treat a condition that is already massively underdiagnosed and undertreated.⁽⁹⁾ For this reason, we consider it crucial to emphasize that the deficits in our current knowledge base identified by the P2P report must be appreciated within the context of the established efficacy of osteoporosis drug therapy to prevent fractures.

The last two decades have seen great advances in osteoporosis pharmacotherapy as numerous effective medications have been introduced, including drugs that target osteoclastic bone resorption and those that target osteoblastic bone formation as well as drugs that are taken orally or parenterally as infrequently as every 6 to 12 months. Importantly, despite the diverse mechanisms of action, all of these agents are unequivocally effective, reducing the risk of extremely common fragility fractures by 40% to 80% in postmenopausal osteoporotic women (depending on the anatomic site and the specific agent) while being associated with only rare serious side effects.⁽⁴⁾ That said, the use of effective and safe drugs to treat osteoporosis has not been sufficient to reverse the current negative trends in osteoporosis care. And these negative trends, in turn, have stimulated renewed efforts by professional societies and patient-advocacy groups worldwide to support initiatives to address the ongoing crisis.⁽¹⁰⁾ In this setting, then, focusing on the few areas where there is a perceived lack of clarity could be unintentionally counterproductive if the benefits of short-term drug therapy are not highlighted.

Specifically, the P2P report raises several examples of current knowledge deficits, including the lack of robust data in non-white postmenopausal women, the fact that few osteoporosis trials continue beyond 5 years, the uncertainty that remains regarding “drug holidays,” and our current inability to initiate programs that will increase the utilization of osteoporosis screening tools and drug interventions. It also proposes some recommendations as to how to address these gaps with new clinical trials or new analyses. And while the authors of this report have identified important issues, it should be noted that several of their recommendations may not be realistic in the current environment. For example, they suggest that future osteoporosis drug trials utilize preference and sequential intervention designs with fracture as the preferred endpoint. They also suggest that trials be initiated that include men, the spectrum of races and ethnicities, people with diverse residential situations, and those with high fracture risk who do not meet criteria for osteoporosis. Notwithstanding, some of these issues have already been addressed, including a large study in osteoporotic men with fracture as the endpoint and multiple studies performed in Asian populations.^(11–14) What must be appreciated is that essentially all studies sufficiently robust to include fracture reduction as the primary endpoint (with the notable exception of the Women’s Health Initiative) have been industry-sponsored and designed to meet the specific FDA criteria for drug approval. And looking to the near and medium-term future, it is clear that we can expect less rather than more investment from private sources. Currently, in fact, there are no ongoing phase 2 or 3 clinical trials involving new osteoporosis drugs listed on clinicaltrials.gov. Thus, in the absence of a major public-sector effort to dramatically increase resources in order to initiate new clinical trials in osteoporosis, we are left with our current, admittedly somewhat incomplete, understanding of how to best manage each of our complex patients at high risk of fragility fracture and the associated loss of independence, quality of life, and increased mortality over the long term.

The American Society for Bone and Mineral Research has helped establish a coalition of multiple national and international scientific and medical societies focused on the treatment gap in osteoporosis care, with an initial focus on secondary fracture prevention where there is little doubt or debate. Since 2016, this group has worked on the establishment of treatment recommendations for the care of women and men over the age of 65 years experiencing hip or vertebral fractures. The coalition is near to establishment of consensus management recommendations designed to help reduce the risk of future fractures after initial osteoporotic fracture. These recommendations will balance concerns in the orthopedic community about starting antiresorptive medications too soon after fracture repair with the concerns of the medical community about missed opportunities to begin therapy shortly after fractures have occurred and will include the perspectives of osteoporosis experts in addition to those of primary care, physical medicine, nursing, and other providers. Once consensus has been achieved regarding secondary fracture prevention, the coalition will extend its efforts to the primary prevention of fragility fractures as well as to fractures occurring in specific high-risk populations.

Osteoporosis is a disease that is increasing in frequency while being progressively ignored. To reverse this trend, we must simultaneously address “gaps” in our knowledge yet recognize that some of these gaps are unlikely ever to be filled. Furthermore, we must emphasize just how effective osteoporosis therapy can be when used appropriately. And it is this latter message, if communicated effectively, that we believe has the greatest potential to reverse the discouraging trends in osteoporosis care.