Osteoporosis Canada
Our team works directly with Osteoporosis Canada to identify and fill critical knowledge gaps in osteoporosis drug therapy. Much of our work aims to provide evidence to inform long-term oral bisphosphonate therapy and drug holidays, utilization of second-line therapies like denosumab and zoledronic acid, and the impact of switching between osteoporosis medications.
Trends in bisphosphonate use
We identified major changes in how oral bisphosphonate therapy has been initiated over the past 20 years in Ontario, including identifying risedronate prescribing patterns unique to our region, identifying a 10-times increase in the proportion of men starting therapy, and major changes in co-medication use: Hayes KN, Ban JK, Athanasiadis G, Burden AM, Cadarette SM. Time-trends in oral bisphosphonate initiation in Ontario, Canada over 20 years reflect drug policy and healthcare delivery changes. Osteoporos Int. 2019;30(11):2311-2319.
We also were the first to identify that 60% of patients starting oral bisphosphonate treatment received 3 or more years of continuous exposure after accounting for initial gaps in therapy: Hayes KN, He N, Brown KA, Cheung AM, Juurlink DN, Cadarette SM. Over half of seniors who start oral bisphosphonate therapy are exposed for 3 or more years: novel rolling window approach and patterns of use. Published online ahead of print, Osteoporos Int, Jan 7, 2021.
Previous work that focused on initial treatment only estimated 3-year exposure to be as low as 25%. Upcoming work compares the duration of benefits of alendronate and risedronate during oral bisphosphonate drug holidays. Risedronate’s half-life in bone is much shorter than alendronate and thus fracture protection after therapy discontinuation may also be shorter.
Relationship between frequency of zoledronic acid dosing and fracture risk
Zoledronic acid is an attractive second-line treatment for patients who are intolerant to first-line therapies (oral bisphosphonates), and is currently administered once yearly for the prevention of fractures. Zoledronic acid, like all bisphosphonates, persists in bone and may provide antifracture benefits after treatment cessation. Evidence from clinical trials shows antifracture benefits for zoledronic acid with 3 annual doses, yet minimal benefits of continued therapy beyond 3 years. Instead, the benefits of therapy persist, and treatment beyond 3 years may pose serious risks. Emerging evidence from re-analysis of clinical trials is also encouraging, suggesting that less frequent dosing of zoledronic acid may be safe and effective. However, patients that participate in clinical trials are often younger and healthier than the average patient. Consequently, real-world evidence is thus critical to evaluating drug safety and effectiveness. There is no real-world evidence that considers the effectiveness of zoledronic acid’s dosing frequency, particularly in the context of prior oral bisphosphonate treatment that also persists in bone. A better understanding of the benefits and harms on fracture risk of less frequent zoledronic acid dosing is needed. We are working directly with Osteoporosis Canada to fill gaps in knowledge and answer this important clinical question to inform future clinical practice guidelines.
Benefits and harms of denosumab therapy after bisphosphonate exposure
Denosumab is a semi-annual injectable osteoporosis medication recommended for patients with past bisphosphonate exposure. While denosumab effectively reduces risk of fracture during therapy, patients experience a rapid decline in bone mineral density and an increased risk of multiple vertebral fractures at denosumab discontinuation. A current priority in osteoporosis research is determining effective strategies for preventing bone loss and spontaneous fracture risk after denosumab discontinuation. Our group is leveraging administrative healthcare data to study the benefits and harms of denosumab therapy after bisphosphonate exposure, including whether length of bisphosphonate exposure prior to denosumab impacts fracture risk at denosumab discontinuation. Evidence from these investigations will address key knowledge gaps that have been identified by Osteoporosis Canada regarding long-term osteoporosis therapy.