During the past decade, relative utilization of alendronate and zoledronic acid have slightly increased as measured by percent of all patients treated with bone-directed therapy, while other bisphosphonates and raloxifene have declined. Meanwhile, the relative share of patients receiving denosumab as bone-directed therapy has increased since its introduction in 2010, overtaking use of every other medication except alendronate by early 2017. Use of PTH/PTHrP analogs and romosozumab remains low but increased slightly in the fracture cohort. Importantly, treatment of any kind for those with recent fractures at common osteoporotic sites remains very low (<15%) and has declined over the past decade, indicating a significant gap in the care of patients with osteoporotic fractures.
During the study period, osteoporosis treatment guidelines recommended the use of bisphosphonates as first-line therapy, with consideration of denosumab as an acceptable “alternative initial treatment.” 20,21,22 Recently, there has also been increasing consideration of PTH/PTHrP analogs as initial therapy, especially in cases of advanced bone loss or high risk of fracture,20,23 due to their osteoanabolic characteristics, significant fracture prevention, and concern that their benefit may be blunted after use of anti-resorptive agents.23,24 In accordance with the guidelines, alendronate and zoledronic acid relative use increased slightly over time, although denosumab use increased to a greater degree. Use of other bisphosphonates declined, possibly related to patent expirations or meta-analyses and observational data suggesting inferior fracture prevention compared to alendronate and zoledronic acid.25,26 Uptake of PTH analogs and romosozumab remained low, despite randomized controlled trials demonstrating the superiority of teriparatide (a PTH analog)27 and romosozumab28 versus bisphosphonates for reducing vertebral, non-vertebral, and clinical fractures. This lower uptake may be related to higher medication costs (Appendix Table 1 in the Supplementary information), concerns regarding serious side effects (osteosarcoma for teriparatide, cardiovascular events for romosozumab), or debate surrounding these medications’ relative efficacy in prevention of hip fractures. Additionally, the later approval years of abaloparatide and romosozumab (2017 and 2019, respectively) may limit their adoption and guideline recommendations, as well as our ability to detect uptake during the study period.
Regarding the rise in use of denosumab, there were several major studies which may have influenced physician prescribing during this period. Between 2010 and 2012, denosumab was found to be superior to zoledronic acid for prevention of skeletal-related events in patients treated for bone metastases from a variety of solid organ malignancies.19,29,30,31 For the treatment of postmenopausal osteoporosis, a randomized trial published in 2016 found that denosumab resulted in greater increases in bone mineral density than zoledronic acid.32,33 No difference in fracture rates was seen in this study, although data suggest that greater improvements in bone density are associated with greater reduction in fracture rates.34 A meta-analysis of 10 randomized controlled trials confirmed that denosumab resulted in greater increases in bone mineral density than bisphosphonates including alendronate (n=7), risedronate (n=1), and zoledronic acid (n=2), although only one trial showed reduction in osteoporotic fractures with denosumab versus alendronate.35 However, in 2017–2018, numerous studies documented an increase in vertebral fractures following abrupt discontinuation of denosumab, 36,37,38,39 such that recent guideline updates recommend starting an alternate bone-directed therapy, generally a bisphosphonate, upon discontinuation of denosumab.40 However, results from early trials to prevent rebound fracture after denosumab discontinuation are conflicting, suggesting that even following denosumab with a bisphosphonate may not completely negate the risk of rebound vertebral fractures,41,42,43,44,45 and questions remain regarding the ideal type, timing, and duration of alternate therapy after denosumab discontinuation.
Our results demonstrate growth in use of denosumab, outpacing other bone-directed therapies, with neither clear jumps in prescribing following positive studies nor clear declines in prescribing following reports of safety concerns (Appendix Table 2 in the Supplementary information). Similarly, data suggesting decreased all-cause mortality in men and women treated with zoledronic acid after hip fracture46 and improved disease-free survival with zoledronic acid in select patients with breast cancer18 did not associate with clear rises in zoledronic acid use in the osteoporosis or malignancy subgroups, respectively. In the malignancy subgroup as in the osteoporosis subgroup, there was a dramatic uptake of denosumab, reaching 18% by 2012 and 46% by 2020, following regulatory approval for this indication in 2011 and the publication of evidence for equivalent or superior prevention of skeletal-related events, relative to bisphosphonates, in breast cancer, prostate cancer, and lung cancer.17,18,19 Similarly, Gupta et al. observed a rapid rise in denosumab use for multiple myeloma in Medicare claims after the approval of denosumab for prevention of skeletal-related events in multiple myeloma in 201847. The rapid rise in denosumab uptake may be influenced by many factors, such as advertising, physician or pharmacy incentives,48,49 improved medication adherence, patient or insurance plan preferences, ease of biannual subcutaneous administration in a clinic setting, or better tolerability (i.e., no flu-like symptoms, unlike those observed after zoledronic acid administration). However, denosumab was more expensive than many options available during this period, with estimated annual median standard drug-related costs per patient for bone-directed therapies ranging from $3082 for denosumab to $368 for zoledronic acid to $113 for alendronate in the Optum data set in 2020 (prior to accounting for drug administration costs; Appendix Table 1 in the Supplementary information). Further to this, other parenteral medications, such as zoledronic acid, share many of the benefits of denosumab (e.g., convenience of annual infusions, non-reliance on adherence to oral therapy) and did not see as steep a rise in use during this period.
Given the already very low rates of treatment of osteoporosis, the decline in treatment rates for patients with a recent fracture in this study and others11,12,13 is especially concerning. An older, widely publicized study showed that after years of rising rates of hip fracture, these rates stabilized and then began to decline starting in approximately 1995,50 the year alendronate was approved in the US. However, more recent studies have found either plateauing or increasing fracture rates, especially at the hip, beginning in approximately 201351,52,53 and declines in femoral neck bone density in US adults over age 50 beginning in approximately 2007.2 It is possible that the decline in treatment for osteoporosis has contributed to rising rates of hip fractures in recent years. Further to this, our study shows that 92% of individuals receiving bone-directed therapy in the primary cohort were women, possibly reflecting that osteoporosis is both underdiagnosed and undertreated in men.54,55
There are several strengths to this study, including large sample size, availability of pharmacy dispensing and medication administration claims data, and generalizability to commercially insured patients in the US. However, our results must be interpreted in light of the study design. As we examined medication use by calendar quarter, patients receiving medications with administration less frequently than every 3 months (denosumab biannually, zoledronic acid annually) will be relatively undercounted. However, we conducted a sensitivity analysis counting treatment effect of denosumab for 2 quarters and zoledronic acid for 4 quarters and found similar results to our primary analysis. In the fracture cohort, in which individuals receiving treatment greater than 6 months prior to fracture (e.g., with zoledronic acid given annually) but not in the quarters immediately following the fracture will be counted as untreated. Individuals in the fracture cohort may also have a variable look-back period (at least 90 and up to 180 days) depending on the exact timing of their fracture within a calendar quarter. Although this may affect reported relative rates of medication use, it should not significantly affect trends over time. Finally, the method used to identify fractures has not been previously validated, although we systematically collected ICD-9, ICD-10, and procedure codes for fractures at common osteoporotic sites, allowing for comprehensive fracture identification.
Our study demonstrates that alendronate is the most commonly used bone-directed therapy, with low but stable use of zoledronic acid, PTH/PTHrP analogs, and romosozumab and declines in use of other bisphosphonates and raloxifene over the past decade. Conversely, denosumab use has increased in the treatment of both osteoporosis and malignancy despite concerns about cost and rebound vertebral fractures. Finally, overall rates of treatment for secondary fracture prevention are dismally low (<15%) and have declined in the past decade. Ongoing efforts by clinicians, patient advocacy groups, and public health entities should focus on efforts to improve fracture prevention and treatment in at-risk populations, with attention to risk-benefit and cost-effectiveness analyses in the choice of medications used.