Date of Award
2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Pharmaceutical Sciences
Department
Biomedical and Pharmaceutical Sciences
First Advisor
Aisling Caffrey
Abstract
Osteoporosis is a condition characterized by the loss of bone mass, which increases the risk of fractures. In 2017-2018, the age-adjusted prevalence of osteoporosis among adults aged 50 and over was 12.6%, with 19.6% in women and 4.4% in men. Untreated osteoporosis can lead to a cycle of recurrent fractures that severely impact quality of life and place significant emotional, physical, and financial strain on patients, families, and healthcare resources. Approximately 50% of women and 20% of men will experience at least one fracture in their lifetime. In the United States, an estimated 1.5 million osteoporotic fractures occur each year, resulting in an economic burden of approximately $17.9 billion.
Current research on osteoporosis has predominantly focused on female populations. Most osteoporosis clinical trials have been conducted in women, with only a small proportion of trials involving men. These studies often have smaller sample sizes, shorter follow-up periods, and typically use bone mineral density as the primary endpoint, rather than fracture occurrence. Moreover, existing real-world studies have mostly involved women, and the comparative effectiveness of medications in men has not been thoroughly assessed. Furthermore, in cost-effectiveness analyses of osteoporosis drugs, essential transition probability parameters are often based on female data, and the economic implications for male patients remain unclear.
Osteoporosis is less common in men, yet men experience higher rates of underdiagnosis and undertreatment compared to women, with 90.5% of men versus 81.8% of women at high fracture risk remaining untreated. Men also have greater risks of subsequent fractures, morbidity, and mortality after an initial fracture. Research specifically addressing osteoporosis treatment in men is therefore essential. To address these gaps, we conducted three studies.
This dissertation is presented in a manuscript format and utilizes the data from the National Veterans Affairs Healthcare System.
Manuscript 1. This retrospective study included 33,387 Veterans who initiated osteoporosis treatment between 2018 and 2023 with alendronate (n=31,090), risedronate (n=712), zoledronic acid (n=97), denosumab (n=903), and teriparatide (n=585). Fracture rates (all, hip, vertebral, and other) were assessed in each treatment group defined by initiation of osteoporosis therapy during the study period, with no osteoporosis treatment in the prior 18 months. To assess longitudinal changes, fracture rates during the first three months after treatment initiation were compared to rates over the subsequent 12 months (months 4-15). None of the five medications assessed led to a significant reduction in fracture rates, as all incidence rate ratios (IRRs) included 1. In stratified analyses among alendronate users, significant fracture reductions were observed in patients younger than 75 years (all fractures IRR 0.82, 95% CI 0.71-0.94), patients without a prior fracture history (all fractures IRR 0.71, 95% CI 0.61-0.82; vertebral fractures IRR 0.47, 95% CI 0.38-0.60), patients who consumed alcohol (all fractures IRR 0.71, 95% CI 0.56-0.90; vertebral fractures IRR 0.69, 95% CI 0.48-0.99), and patients who smoked (all fractures IRR 0.86, 95% CI 0.75-0.98). In contrast to previous findings in women, where osteoporosis medications consistently reduced fracture risk, our results suggest that such benefits in men were limited to specific subgroups, namely, younger patients and those without a prior fracture history. This indicates that earlier initiation of alendronate, before a fracture occurs, may offer greater protective benefits. The observed effectiveness in smokers and alcohol users, both high-risk populations, also highlights the utility of alendronate in patients with lifestyle-related risk factors. These findings support a more personalized approach to osteoporosis treatment in men, emphasizing the need to identify and target those most likely to benefit. Conversely, the lack of significant benefit in older men and those with prior fractures suggests a need to investigate whether initiating treatment earlier in the disease course could improve outcomes in these higher-risk populations. Additionally, the potential role of combination therapy or earlier use of second-line treatments should be explored as alternative strategies to optimize fracture prevention in these groups.
Manuscript 2. In this retrospective cohort study, we used propensity score matching (greedy matching) and Cox regression models to evaluate the comparative effectiveness of three osteoporosis drugs, denosumab, teriparatide, and risedronate, each compared to alendronate, in reducing the risk of all fracture types, as well as hip, vertebral, and other fracture types. This study included 916 patients treated with denosumab, 600 with teriparatide, and 721 with risedronate, each matched to three alendronate users. For all drug comparisons with alendronate, hazard ratios for all outcomes included 1, indicating no significant differences in effectiveness. Sensitivity analyses using optimal propensity score matching and stabilized inverse probability weighting mostly confirmed the main results. In women, prior studies demonstrated greater effectiveness with denosumab, lower effectiveness with teriparatide, and comparable effectiveness with risedronate, relative to alendronate. In contrast, we observed no significant differences in fracture risk reduction between alendronate and denosumab, teriparatide, or risedronate in men. Clinically, these results suggest that alendronate may remain the preferred first-line treatment for osteoporosis in men, given its comparable effectiveness and lower cost relative to other therapies.
Manuscript 3. We conducted a Markov model cost-effectiveness analysis comparing denosumab and risedronate, each against alendronate, to inform the value of treatment among males with osteoporosis. The model included discrete health states for hip, vertebral, and other fractures, as well as post-fracture states, to estimate total costs and quality-adjusted life years (QALYs) for each treatment. Male-specific inputs for population characteristics, fracture incidence, and comparative effectiveness were derived from Study 2. The model employed a six-month cycle length and a five-year simulation duration. Compared to alendronate, denosumab resulted in an additional treatment cost of $14,442 and a loss of 0.02 QALYs, indicating it was dominated by alendronate. Risedronate was associated with an incremental cost of $1,498 and a gain of 0.03 QALYs relative to alendronate, yielding a cost-effectiveness ratio (ICER) of $46,433 per QALY, which falls below the $150,000 cost-effectiveness threshold. Both deterministic and probabilistic sensitivity analyses confirmed the robustness of the base-case analysis. One-way sensitivity analysis revealed that the primary factors influencing the ICER were the comparative effectiveness parameters and drug costs. Previous economic evaluations of osteoporosis treatment in men relied on data derived from female populations and concluded that denosumab was cost-effective, while risedronate was not. Our study found that risedronate was cost-effective relative to alendronate in men, whereas denosumab was not. These findings underscore the importance of generating sex-specific outcome evidence to inform treatment decisions. When selecting among osteoporosis therapies in men, risedronate may offer better economic value relative to alendronate, while denosumab does not appear to provide a cost-effective advantage.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Recommended Citation
Ren, Yu, "REAL-WORLD CLINICAL AND COST EFFECTIVENESS OF OSTEOPOROTIC TREATMENTS IN MEN" (2025). Open Access Dissertations. Paper 4505.
https://digitalcommons.uri.edu/oa_diss/4505