Abstract
Prostate cancer (PC) treatment, particularly androgen deprivation therapy (ADT), remains pivotal, albeit linked to increased fracture risk due to osteoporosis. The advent of novel hormonal agents (NHAs) has spurred inquiries into their influence on bone health. This study aimed to evaluate the impact of NHAs on bone health in patients receiving combination therapy. We conducted a retrospective analysis using Taiwan’s National Health Insurance Research Database, encompassing men aged 45 and above diagnosed with PC without bone metastasis and undergoing ADT between 2000 and 2018. The study involved 25,949 patients, categorized into those receiving standard ADT (n = 25,166) and those on NHA combination therapy (n = 783). Our analysis delved into fracture risk, comorbidities, and osteoporosis treatments. Patients on NHA combination therapy faced significantly higher risks of any osteoporotic fracture and major osteoporotic fracture than those on ADT alone (HR = 1.29, 95% CI 1.04–1.61; HR = 1.37, 95% CI 1.06–1.75, respectively). Notably, age emerged as a critical factor, with the highest risk observed in those aged 90 or above. The 5-year overall survival rates were lower for patients who experienced any osteoporotic fracture, major osteoporotic fracture, and hospitalization due to osteoporotic fracture compared to those who did not experience these fractures (51.5% vs. 56.5%, 47.1% vs. 56.7%, and 48.2% vs. 56.3%, respectively, p < 0.001). Furthermore, patients not using any bone-modifying agents had the highest risk for all fracture types. In conclusion, NHA combination therapy in PC patients potentially escalates the risk of osteoporotic fractures, especially in older individuals. Our findings underscore the pivotal role of osteoporosis treatments in preventing fractures, emphasizing the importance of evaluating fracture risk in patients undergoing NHA combination therapy.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-024-73598-z.
Subject terms: Cancer, Physiology, Diseases
Introduction
Prostate cancer (PC) accounts for 26% of all newly diagnosed cancers in men, projecting an estimated 248,530 new cases in the US in 20211. Androgen deprivation therapy (ADT) remains the cornerstone treatment for high-risk localized, locally advanced or metastatic PC2–4. Clinical guidelines recommend continuing ADT in metastatic PC patients until the end of life, even beyond the castration-resistant phase5. Consequently, ADT exposure can extend across multiple years, regardless of whether it’s employed for locally advanced or metastatic disease. However, ADT can accelerate osteoclastic bone resorption, leading to diminished bone mineral density (BMD) and an elevated susceptibility to fractures6,7.
A study analyzing data from the Surveillance, Epidemiology, and End Results (SEER)-linked Medicare database revealed that 19.4% of patients who underwent ADT experienced fractures within 12 to 60 months after diagnosis, compared to only 12.6% of patients who did not receive ADT8. Later reports confirmed a consistent rise in fracture rates, with a 2-fold higher mortality among affected men9. Our previous study, based on the Taiwan National Health Insurance Research Database (NHIRD), also showed a 1.55 and 1.95 times higher risk of fractures associated with medical and surgical castration, respectively, in advanced prostate cancer patients compared with a non-cancer matched control group10. These findings align with another study that further corroborates the concept of an augmented fracture risk associated with ADT11–13.
Prior studies have established a noteworthy correlation between the number of gonadotropin-releasing hormone doses administered within the first year following diagnosis and the subsequent fracture risk8, underscoring the potential influence of hormonal suppression intensity on subsequent fracture susceptibility. Moreover, in the era of novel hormonal agents (NHA), combination therapy with conventional ADT has become the standard of care for metastatic PC. However, it is imperative to recognize that although NHA combination therapy can yield improved outcomes for PC patients, it may also heighten the vulnerability to osteoporotic fractures. In clinical trials involving NHA combination therapy for patients with non-metastatic castration-resistant prostate cancer (nmCRPC), both apalutamide and enzalutamide were linked to greater fracture risks in comparison to the placebo group (11.7% vs. 6.5% and 9.8% vs. 4.9%, respectively)14,15. A recent meta-analysis of randomized controlled trials (RCTs) in men with advanced and metastatic prostate cancer (PCa) undergoing novel hormonal agent (NHA) combination therapy revealed a significantly increased risk of fractures and falls16. Additionally, current guidelines on assessing and managing treatment-induced bone loss in prostate cancer patients highlight the need for further research into the impact of NHA combination therapy on bone health17.
Nonetheless, fractures as adverse events of ADT are multifactorial results, not only related to osteoporosis but also encompassing falls and mental disturbances. Previous epidemiological studies have shown the potential role of ADT’s psychological impacts in augmenting fall-related risks. Notably, men undergoing ADT for PC exhibited an elevated susceptibility to dementia and/or Alzheimer’s disease, consequently heightening the propensity for falls. This phenomenon was evident across studies conducted in both eastern and western populations, underscoring their collective contribution to elevated fracture rates, resulting in increased mortality and morbidity18–21. Moreover, the increased fracture risk among PC patients can also be attributed to several additional factors, including age, disease advancement, the employment of bone-modifying agents, and comorbidities22,23.
In this study, we utilized the Taiwan National Health Insurance Research Database (NHIRD) to evaluate the risk of osteoporotic fractures in men with PC who underwent NHA combination therapy without bone involvement. Additionally, we investigated whether osteoporosis treatment agents could mitigate any potential adverse effects.
Results
Demographic characteristics of study population
A total of 25,949 newly diagnosed patients with PC (ICD9-CM code: 185/ ICD10-CM code: C61) holding a certificate of catastrophic illness between 2000 and 2019 met the primary inclusion criteria. The definition of catastrophic illness is determined by the regulations of the Ministry of Health and Welfare, Taiwan24,25. These patients were divided into two distinct groups: those receiving ADT alone (n = 25,166) and those with a combination of conventional ADT and NHA (n = 783). Notably, there were differences between the cohorts concerning age, comorbidities, fracture status, and osteonecrosis of the jaw during bone antiresorptive treatment, as outlined in Table 1.
Table 1.
Characteristics of patient with prostate cancer under androgen deprivation therapy(ADT) alone or novel hormonal agents(NHA) combination therapy.
| Characteristic | Total | Conventional ADT group | NHA combination group | P-value |
|---|---|---|---|---|
| n = 25,949 | n = 25,166 | n = 783 | ||
| n | n (%) | n (%) | ||
| Age | 0.005 | |||
| < 60 | 1230 | 1199 (4.8) | 31 (4) | |
| 60–69 | 5752 | 5556 (22.1) | 196 (25) | |
| 70–79 | 11,546 | 11,230 (44.6) | 316 (40.4) | |
| 80–89 | 6817 | 6607 (26.3) | 210 (26.8) | |
| ≥ 90 | 604 | 574 (2.3) | 30 (3.8) | |
| Comorbidity | ||||
| Myocardial infarction | 1030 | 1001 (4) | 29 (3.7) | 0.699 |
| Heart failure | 2775 | 2697 (10.7) | 78 (10) | 0.501 |
| Peripheral vascular disease | 1126 | 1090 (4.3) | 36 (4.6) | 0.719 |
| Cerebrovascular Disease | 6796 | 6615 (26.3) | 181 (23.1) | 0.047 |
| Dementia | 1427 | 1391 (5.5) | 36 (4.6) | 0.261 |
| Pulmonary disease | 11,895 | 11,586 (46) | 309 (39.5) | < 0.001 |
| Connective tissue disorder | 614 | 593 (2.4) | 21 (2.7) | 0.555 |
| Chronic liver disease | 5490 | 5325 (21.2) | 165 (21.1) | 0.953 |
| Diabetes mellitus | 9025 | 8675 (34.5) | 350 (44.7) | < 0.001 |
| Paraplegia | 567 | 543 (2.2) | 24 (3.1) | 0.087 |
| Chronic kidney disease | 4938 | 4747 (18.9) | 191 (24.4) | < 0.001 |
| Hyperthyroidism | 234 | 228 (0.9) | 6 (0.8) | 0.684 |
| Hyperparathyroidism | 30 | 30 (0.1) | 0 (0) | 0.334 |
| Steroid | < 0.001 | |||
| No | 8227 | 8146 (32.4) | 81 (10.3) | |
| Yes | 17,722 | 17,020 (67.6) | 702 (89.7) | |
| Outcome | ||||
| Any osteoporotic fracture | 3232 | 3148 (12.5) | 84 (10.7) | 0.137 |
| Major osteoporotic fracture | 2362 | 2298 (9.1) | 64 (8.2) | 0.359 |
| Hospitalization related to osteoporotic fracture | 1387 | 1355 (5.4) | 32 (4.1) | 0.112 |
| Osteonecrosis of the jaw during bone antiresorptive treatment | 46 | 26 (0.1) | 20 (2.6) | < 0.001 |
In terms of age distribution, the majority of patients fell within the 70–79 age group, while the group receiving NHA combination therapy exhibited a higher proportion of patients in the 60–69 age range (25% vs. 22.1%) and a lower proportion in the 70–79 age range (40.4% vs. 44.6%) compared to the group receiving ADT alone. Additionally, there was a higher percentage of long-term steroid usage in the NHA combination group (89.7% vs. 67.7%).
A total of 3,232 cases of any osteoporotic fracture, 2,362 cases of major osteoporotic fracture, and 1,387 cases of hospitalization due to osteoporotic fracture were observed in the study. Furthermore, the 5-year overall survival rates of patients who experienced any osteoporotic fracture, major osteoporotic fracture, and hospitalization due to osteoporotic fracture were lower compared to those who did not experience these fractures (51.5% vs. 56.5%, 47.1% vs. 56.7%, and 48.2% vs. 56.3% respectively, p < 0.001) (Fig. 1).
Fig. 1.
Overall survival curves of patients with or without any osteoporotic fracture (A), major osteoporotic fracture (B) and osteoporotic fracture related hospitalization (C) for 25,949 patients with prostate cancer undergoing androgen deprivation therapy.
In the group receiving conventional ADT alone, the frequency of all types of fracture-related outcomes was slightly higher than in the group receiving NHA combination therapy. Additionally, the group receiving NHA combination therapy exhibited a significantly higher incidence of osteonecrosis of the jaw during bone antiresorptive treatment.
Association of NHA combination and osteoporotic fracture
Figure 2 illustrates fracture-free survival following the initiation of hormonal therapy. We classified the patients in the fracture-free survival curve into three groups: those on medical ADT, those who received bilateral orchiectomy, and those on NHA combination therapy. Our analysis showed that patients receiving NHA combination therapy and those who underwent bilateral orchiectomy had a higher risk of fractures and fracture-related hospitalization compared to those on medical ADT. Notably, patients on NHA combination therapy exhibited an even greater risk of any osteoporotic fracture and major osteoporotic fracture compared to those who received surgical castration therapy. Subsequently, we conducted a multivariate regression analysis, which revealed that patients receiving NHA combination therapy had a significantly higher risk of any osteoporotic fracture and major osteoporotic fracture (HR = 1.29, p = 0.022; HR = 1.38, p = 0.012). Furthermore, the risk of fractures and fracture-related hospitalization increased with patient age, in comparison to those younger than 60 years old. Notably, patients aged 90 years or older exhibited the highest risk across all types of fractures (Table 2). Patients with cerebrovascular disease or pulmonary disease also had a higher risk of fractures and fracture-related hospitalization. However, no increased risk of fractures was found in patients with long-term steroid usage after analysis.
Fig. 2.
Survival curves for different types of fractures (any osteoporotic fracture (A), major osteoporotic fracture (B), and osteoporotic fracture-related hospitalization (C)) among 25,949 patients with prostate cancer, with or without novel hormonal agents combination therapy.
Table 2.
Multivariable analysis of factors associated osteoporotic fracture in patient with prostate cancer under androgen deprivation therapy.
| Characteristic | Any osteoporotic fracture | Major osteoporotic fracture | Hospitalization related to osteoporotic fracture | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HR | 95%CI | P-value | HR | 95%CI | P-value | HR | 95%CI | P-value | ||||
| NHA combination therapy | 1.29 | 1.04 | 1.61 | 0.022 | 1.38 | 1.07 | 1.77 | 0.012 | 1.14 | 0.80 | 1.62 | 0.464 |
| Age | ||||||||||||
| < 60 | 1.00 | 1.00 | 1.00 | |||||||||
| 60–69 | 1.10 | 0.88 | 1.37 | 0.399 | 1.20 | 0.90 | 1.58 | 0.211 | 1.69 | 1.10 | 2.61 | 0.017 |
| 70–79 | 1.51 | 1.22 | 1.86 | 0.000 | 1.75 | 1.34 | 2.29 | < 0.001 | 2.60 | 1.71 | 3.95 | < 0.001 |
| 80–89 | 2.13 | 1.72 | 2.63 | < 0.001 | 2.82 | 2.16 | 3.70 | < 0.001 | 4.00 | 2.62 | 6.10 | < 0.001 |
| ≥ 90 | 2.40 | 1.80 | 3.20 | < 0.001 | 3.33 | 2.37 | 4.68 | < 0.001 | 4.92 | 2.98 | 8.11 | < 0.001 |
| Comorbidity | ||||||||||||
| Myocardial infarction | 1.07 | 0.90 | 1.27 | 0.426 | 1.05 | 0.86 | 1.29 | 0.620 | 0.86 | 0.65 | 1.14 | 0.295 |
| Heart failure | 1.06 | 0.95 | 1.18 | 0.341 | 1.07 | 0.94 | 1.21 | 0.305 | 1.14 | 0.97 | 1.33 | 0.123 |
| Peripheral vascular disease | 1.05 | 0.90 | 1.23 | 0.542 | 0.98 | 0.81 | 1.19 | 0.856 | 1.10 | 0.87 | 1.38 | 0.447 |
| Cerebrovascular Disease | 1.13 | 1.04 | 1.22 | 0.004 | 1.13 | 1.03 | 1.24 | 0.011 | 1.24 | 1.10 | 1.39 | 0.001 |
| Dementia | 1.07 | 0.93 | 1.24 | 0.327 | 1.06 | 0.90 | 1.25 | 0.455 | 1.07 | 0.87 | 1.32 | 0.533 |
| Pulmonary disease | 1.26 | 1.17 | 1.36 | < 0.001 | 1.26 | 1.16 | 1.38 | < 0.001 | 1.18 | 1.05 | 1.32 | 0.004 |
| Connective tissue disorder | 1.16 | 0.95 | 1.43 | 0.154 | 1.15 | 0.91 | 1.47 | 0.241 | 0.92 | 0.66 | 1.30 | 0.650 |
| Chronic liver disease | 0.98 | 0.90 | 1.06 | 0.564 | 0.96 | 0.87 | 1.06 | 0.412 | 0.90 | 0.79 | 1.03 | 0.121 |
| Diabetes mellitus | 1.07 | 1.00 | 1.15 | 0.070 | 0.97 | 0.89 | 1.06 | 0.543 | 1.04 | 0.93 | 1.16 | 0.503 |
| Paraplegia | 1.15 | 0.92 | 1.43 | 0.234 | 1.31 | 1.02 | 1.67 | 0.036 | 1.14 | 0.82 | 1.60 | 0.432 |
| Chronic kidney disease | 1.00 | 0.92 | 1.09 | 0.990 | 0.99 | 0.89 | 1.10 | 0.847 | 1.00 | 0.87 | 1.14 | 0.948 |
| Hyperthyroidism | 1.06 | 0.75 | 1.49 | 0.742 | 1.07 | 0.72 | 1.61 | 0.727 | 1.03 | 0.61 | 1.75 | 0.901 |
| Hyperparathyroidism | 0.53 | 0.13 | 2.13 | 0.373 | 0.39 | 0.05 | 2.74 | 0.342 | 1.34 | 0.33 | 5.37 | 0.680 |
| Steroid | ||||||||||||
| No | 1.00 | 1.00 | 1.00 | |||||||||
| Yes | 1.00 | 0.92 | 1.08 | 0.924 | 0.96 | 0.87 | 1.05 | 0.340 | 1.00 | 0.89 | 1.13 | 0.967 |
Association of bone modifying agents and osteoporotic fractures
We conducted an analysis to evaluate the impact of bisphosphonates and denosumab in the prevention of fractures. Compared to patients who received denosumab, those who did not use any bone modifying agent had the highest risk of all types of fractures (any osteoporotic fracture, HR = 1.76, 95% CI 1.41 to 2.19, p < 0.001; major osteoporotic fracture, HR = 1.92, 95% CI 1.47 to 2.52, p < 0.001; hospitalizations related to osteoporotic fracture, HR = 2.11, 95% CI 1.47 to 3.01, p < 0.001).
Furthermore, patients who used bisphosphonates also had a higher risk of all types of fractures compared to those who received denosumab (any osteoporotic fracture, HR = 1.43, 95% CI 1.11 to 2.84, p = 0.006; major osteoporotic fracture, HR = 1.65, 95% CI 1.22 to 2.24, p = 0.001; hospitalizations related to osteoporotic fracture, HR = 1.70, 95% CI 1.14 to 2.53, p = 0.010). Interestingly, the risk of osteonecrosis related to medication was lower in the bisphosphonates group (HR = 0.13, 95% CI 0.06 to 0.26, p < 0.001) (Table 3). When considering the interaction between the osteoporotic effects of NHA and different bone-modifying agents, patients undergoing conventional ADT with denosumab prevention exhibited the lowest risk of all types of fractures, followed by patients undergoing NHA combination therapy with denosumab prevention.
Table 3.
Impact of novel hormonal agents combination therapy and bone modifying agents on osteoporotic fractures.
| Characteristic | Any osteoporotic fracture | Major osteoporotic fracture | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No, n(%) | Yes, n(%) | HR | 95%CI | P-value | No, n(%) | Yes, n(%) | HR | 95%CI | P-value | ||||
| Bone modifying agents | |||||||||||||
| Denosumab | 1153 (93.4) | 81 (6.6) | 1.00 | 1189 (95.7) | 54 (4.3) | 1.00 | |||||||
| BP | 2669 (91.9) | 236 (8.1) | 1.43 | 1.11 | 1.84 | 0.006 | 2748 (93.8) | 183 (6.2) | 1.65 | 1.22 | 2.24 | 0.001 | |
| No use | 18,895 (86.6) | 2915 (13.4) | 1.76 | 1.41 | 2.19 | <0.001 | 19,650 (90.2) | 2125 (9.8) | 1.92 | 1.47 | 2.52 | <0.001 | |
| Hormone therapy | Bone modifying agents | Any osteoporotic fracture | Major osteoporotic fracture | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No, n(%) | Yes, n(%) | HR | 95%CI | P-value | No, n(%) | Yes, n(%) | HR | 95%CI | P-value | ||||
| ADT alone | Denosumab | 858 (93.3) | 62 (6.7) | 1.00 | 889 (95.7) | 40 (4.3) | 1.00 | ||||||
| BP | 2555 (92.0) | 223 (8.0) | 1.50 | 1.13 | 1.99 | 0.005 | 2628 (93.7) | 176 (6.3) | 1.83 | 1.30 | 2.59 | 0.001 | |
| No use | 18,605 (86.7) | 2863 (13.3) | 1.88 | 1.46 | 2.41 | <0.001 | 19,351 (90.3) | 2082 (9.7) | 2.13 | 1.56 | 2.91 | <0.001 | |
| NHA combination | Denosumab | 295 (94.0) | 19 (6.1) | 1.42 | 0.85 | 2.37 | 0.182 | 300 (95.5) | 14 (4.5) | 1.68 | 0.92 | 3.09 | 0.094 |
| BP | 114 (89.8) | 13 (10.2) | 2.49 | 1.37 | 4.52 | 0.003 | 120 (94.5) | 7 (5.5) | 2.10 | 0.94 | 4.70 | 0.070 | |
| No use | 290 (84.8) | 52 (15.2) | 3.00 | 2.07 | 4.34 | <0.001 | 299 (87.4) | 43(12.6) | 3.87 | 2.51 | 5.95 | <0.001 | |
| Characteristic | Hospitalization related to osteoporotic fracture | Osteonecrosis due to drugs | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No, n(%) | Yes, n(%) | HR | 95%CI | P-value | No, n(%) | Yes, n(%) | HR | 95%CI | P-value | ||||
| Bone modifying agents | |||||||||||||
| Denosumab | 1283 (97.6) | 31 (2.4) | 1.00 | 1344 (97.3) | 37 (2.7) | 1.00 | |||||||
| BP | 2952 (96.5) | 107 (3.5) | 1.70 | 1.14 | 2.53 | 0.010 | 3158 (99.7) | 9 (0.3) | 0.14 | 0.07 | 0.28 | <0.001 | |
| No use | 20,327 (94.2) | 1249 (5.8) | 2.11 | 1.47 | 3.01 | <0.001 | 21,401 (100.0) | 0 (0.0) | - | ||||
| Hormone therapy | Bone modifying agents | Hospitalization related to osteoporotic fracture | Osteonecrosis due to drugs | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No, n(%) | Yes, n(%) | HR | 95%CI | P-value | No, n(%) | Yes, n(%) | HR | 95%CI | P-value | ||||
| ADT alone | Denosumab | 971 (97.6) | 24 (2.4) | 1.00 | 1035 (97.8) | 23(2.2) | 1.00 | ||||||
| BP | 2828 (96.5) | 102 (3.5) | 1.81 | 1.16 | 2.82 | 0.009 | 3034 (99.9) | 3 (0.1) | 0.06 | 0.02 | 0.19 | <0.0001 | |
| No use | 20,012 (94.2) | 1229 (5.8) | 2.26 | 1.51 | 3.39 | <0.001 | 21,071 (100.0) | 0 (0.0) | - | ||||
| NHA combination | Denosumab | 312 (97.8) | 7 (2.2) | 1.49 | 0.64 | 3.45 | 0.358 | 309 (95.7) | 14 (4.3) | 2.67 | 1.34 | 5.32 | 0.005 |
| BP | 124 (96.1) | 5 (3.9) | 2.47 | 0.94 | 6.49 | 0.065 | 124 (95.4) | 6 (4.6) | 2.84 | 1.14 | 7.10 | 0.025 | |
| No use | 315 (94.0) | 20 (6.0) | 3.22 | 1.78 | 5.84 | <0.001 | 330 (100.0) | 0 (0.0) | - | ||||
ADT, androgen deprivation therapy; BP, bisphosphonate; NHA, Novel hormonal agents.
Moreover, the clinical characteristics revealed that patients treated with denosumab had higher percentages of several fracture-predisposing factors compared to those treated with bisphosphonates. These factors include age over 80 years (31.4% vs. 26.5%), NHA combination therapy (17.1% vs. 3.3%, p < 0.001), cerebrovascular disease (27.2% vs. 22.7%, p < 0.001), pulmonary disease (47.3% vs. 43.2%, p = 0.003), and long-term steroid usage (76.9% vs. 62.6%, p < 0.001)(Table 4).
Table 4.
Characteristics of patient with prostate cancer under different bone modifying agents.
| Characteristic | Denosumab group | Bisphosphonate group | Total | P-value |
|---|---|---|---|---|
| (n=1904) | (n=3974) | |||
| n (%) | n (%) | n (%) | ||
| Age | <0.001 | |||
| <60 | 112 (5.9) | 254 (6.4) | 366 | |
| 60-69 | 415 (21.8) | 890 (22.4) | 1305 | |
| 70-79 | 778 (40.9) | 1779 (44.8) | 2557 | |
| 80-89 | 541 (28.4) | 992 (25) | 1533 | |
| ≥90 | 58 (3) | 59 (1.5) | 117 | |
| Hormone therapy | <0.001 | |||
| ADT alone | 1578 (82.9) | 3844 (96.7) | 5422 | |
| NHA combination | 326 (17.1) | 130 (3.3) | 456 | |
| Comorbidity | ||||
| Myocardial infarction | 71 (3.7) | 117 (2.9) | 188 | 0.110 |
| Heart failure | 194 (10.2) | 434 (10.9) | 628 | 0.395 |
| Peripheral vascular disease | 88 (4.6) | 153 (3.9) | 241 | 0.163 |
| Cerebrovascular Disease | 517 (27.2) | 901 (22.7) | 1418 | <0.001 |
| Dementia | 106 (5.6) | 160 (4) | 266 | 0.008 |
| Pulmonary disease | 901 (47.3) | 1718 (43.2) | 2619 | 0.003 |
| Connective tissue disorder | 51 (2.7) | 96 (2.4) | 147 | 0.546 |
| Chronic liver disease | 433 (22.7) | 715 (18) | 1148 | <0.001 |
| Diabetes mellitus | 738 (38.8) | 1078 (27.1) | 1816 | <0.001 |
| Paraplegia | 45 (2.4) | 67 (1.7) | 112 | 0.075 |
| Chronic kidney disease | 410 (21.5) | 568 (14.3) | 978 | <0.001 |
| Hyperthyroidism | 22 (1.2) | 25 (0.6) | 47 | 0.034 |
| Hyperparathyroidism | 0.829 | |||
| Steroid | <0.001 | |||
| No | 439 (23.1) | 1486 (37.4) | 1925 | |
| Yes | 1465 (76.9) | 2488 (62.6) | 3953 |
Discussion
To our knowledge, this study is the first population-based analysis to examine the osteoporotic fracture risk in patients with PC without bone metastasis undergoing NHA combination therapy. Our findings indicate that patients under NHA combination therapy face a 1.29-fold and 1.37-fold increased risk of any and major fractures, respectively. This elevated risk might result from the negative impact of androgen suppression on bone health.
In our study, where over 70% of patients were equal to or older than 70 years old, the multivariate analysis indicated that age remains a crucial factor influencing fracture risk. Despite the majority of patients with PC being over 70 years old and experiencing age-related bone loss and an increased risk of falls17, osteoporosis remains one of the most overlooked comorbidities of PC. Additionally, androgen deprivation therapy, the primary treatment for locally advanced or metastatic PC, has been shown to negatively impact bone health6. Notably, a substantial prevalence of up to 80.6% of osteoporosis has been reported in hormone-naive men with PC after 10 years of receiving ADT26. Indeed, specific guidelines have been released for the management of bone fragility in patients with prostate cancer27–29. However, in retrospective analyses of real-world databases up to 2015, only 8.4–23.4% of patients underwent BMD screening30,31. Thus, osteoporosis remains a commonly disregarded aspect of prostate cancer management in real-world clinical practice.
A study analyzing data from the SEER-Medicare database between 1992 and 1997 found that 19.4% of patients developed a fracture between 12 and 60 months after initiated ADT, whereas only 12.6% of patients who did not receive ADT experienced fractures8. Furthermore, this study also indicated a dose-related risk of sequential fractures in conventional ADT, and our findings further support this concept.
Moreover, The increased risk of fracture may also be a complication resulting from the adverse effects of NHA. The PROSPER and SPARTAN trials of nmCRPC setting with enzalutamide and apalutamide revealed a higher risk of falls, cognitive impairment, and memory/mental impairment compared to the placebo group14,15,32,33. On the other hand, darolutamide in the ARAMIS trial demonstrated a similar risk to the placebo arm in these aspects34,35. A possible explanation for this difference lies in the drug’s permeability across the blood-brain barrier and its impact on cerebral blood flow (CBF). Enzalutamide and apalutamide, as androgen receptor (AR) inhibitors, have higher brain: plasma ratios of 27% and 62%, respectively, in mice, while darolutamide’s ratio is only 1.9–3.9%.36–38 Additionally, a phase I trial using MRI imaging further investigated the effect of CBF of darolutamide and enzalutamide. It showed a significant reduction in CBF with enzalutamide, while darolutamide did not significantly alter CBF, aligning with its low blood-brain barrier penetration39. Nowadays, the early and extended use of second-generation AR inhibitors is recommended in metastatic PC and CRPC. Fracture prevention in these populations should no longer be overlooked.
The bone mineral density (BMD) screening is the primary tool for diagnosing osteoporosis. Over the past decades, the significance of fracture prevention in men with PC and the recommendation for BMD screening in guidelines have garnered increasing attention among physicians. However, the actual rates of BMD screening remained below expectations. A study analyzing the SEER-Medicare database showed that the BMD screening rate in men with nonmetastatic PC under ADT increased only from 6.8% in 2005 to 8.4% in 201530. Similarly, a study utilizing the Quebec public health care insurance database reported a modest rise in BMD testing rates from 4.1% in 2000 to 23.4% in 201531. These rates are still suboptimal, especially considering the era of NHA combination therapy, which was found to carry a higher risk of osteoporotic fractures in our study and is now the mainstay treatment for metastatic PC.
Limitations
Our study has several limitations to consider. Using claims data, we cannot rule out that some fractures may be due to metastatic processes instead of osteoporosis, despite our focus on patients without bone metastasis. Furthermore, NHA reimbursement in Taiwan is limited to high-risk and high-volume mCRPC or mHSPC patients, potentially introducing baseline differences between our patient groups. The inherent constraints of observational claims research also affect our analysis. Despite our efforts to control for confounding factors, some latent confounders may remain unaccounted for. Additionally, our use of Charlson scores to assess comorbidities may not capture all fracture-related risk factors.
Conclusion
In this cohort study, we revealed that PC patients, without bone metastasis, undergoing NHA combination therapy face a heightened risk of osteoporotic fractures. Age significantly influences this risk, particularly in older patients. Osteoporosis, an underrated comorbidity, remains a pressing concern. However, bone-modifying agents, especially denosumab, offer hope for fracture prevention. These findings emphasize the need to recognize osteoporosis in prostate cancer management and to implement proactive strategies, including bone density screening and the use of bone-modifying agents, to prevent deterioration in patients’ quality of life due to fractures.
Materials and methods
The study protocol (approved no. CE13151-1) has been approved by the institutional review board at Taichung Veterans General Hospital. As this study solely utilized deidentified data, the acquisition of informed consent has been waived. All methods were conducted in accordance with the Declaration of Helsinki, and relevant guidelines and regulations.
Data sources
The NHIRD encompasses comprehensive clinical and in-hospital data, including disease profiles, medical costs, and diagnostic codes, covering over 99% of Taiwan’s population. Furthermore, the Taiwan Cancer Registry (TCR) files provide comprehensive laboratory values and detailed clinical information on patients, ensuring the accuracy of cancer registration data. If any discrepancies were identified, they would collaborate with hospitals to verify and rectify the information.
Defining the target population
We conducted a retrospective study on a cohort of men aged 45 years and older who had a confirmed histological diagnosis of PC between January 1, 2000, and June 30, 2018. Data analysis was performed from May 1 to June 30, 2023, with data censored at the last enrollment in the NHIRD. The inclusion criteria encompassed patients who underwent conventional androgen deprivation therapy (ADT), either through bilateral orchiectomy or medical castration. These patients were then categorized into groups based on whether they received conventional ADT alone or in combination with novel hormonal agents (NHA). It’s important to note that the observation period was set for a minimum of 3 years to explore potential bone-related adverse effects. Worth mentioning is that Taiwan’s national health insurance began covering abiraterone payments in December 2014 and enzalutamide payments in September 2016. In this study design, we excluded patients previously diagnosed with bone metastasis, whether they had received an operation or not, to minimize the effect of pathologic fractures related to prostate cancer. Additionally, to clarify the osteoporotic effects of ADT and minimize underlying fragility issues, we excluded patients who experienced any fractures 12 months prior to or 6 months after the initiation of ADT. Patients who received any bone-modifying agent (BMA) were presumed to be due to concerns of osteoporosis rather than bone metastasis or previous fractures. Consequently, the prevalence rate of BMA use was relatively low, at only 16% (4319 out of 25,949 patients). All fracture episodes were recorded after 6 months of initiating ADT. An illustration of the study flow diagram, outlining the principles used for patient selection and sampling (Supplement Fig. 1).
Outcome of interest
The primary outcomes of interest were fractures (any fracture, major osteoporotic fracture, and hospitalization due to osteoporotic fracture), as well as overall survival (OS). We analyzed the frequency of any fracture and major osteoporotic fracture (in the spine, upper arm, lower arm, hip, and other femur), investigating the impact of comorbidities (including age, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disorder, chronic liver disease, diabetes mellitus, paraplegia, chronic kidney disease, hyperthyroidism, hyperparathyroidism and long-term steroid used, defined as regular prednisone usage of more than 5 mg per day for more than 3 months.) using the Charlson comorbidity index. Additionally, we examined the use of bone-modifying agents (bisphosphonates and denosumab) among a subset of participants and assessed their efficacy in reducing fracture risk. Fracture onset time was defined from the initial ADT claim to the first fracture, with censoring at the date of death or the last day of NHIRD coverage. Our data extended up to 2021, which was the last year included in our analysis. It’s essential to note that all fractures considered occurred after the initial ADT claim. Overall survival (OS) was measured from 6 months after the commencement of conventional ADT or NHA combination therapy to the date of death, with censoring at the last follow-up to ensure data accuracy.
Statistical analysis
The demographic characteristics of this study were compared using the chi-square test for categorical variables and the t-test for continuous variables. The association between the prevalence of fracture among the divided groups was assessed using multivariate Cox proportional hazard regression to estimate the hazard ratio (HR) and its 95% confidence interval (CI). The statistical significance of the cumulative incidence curves was examined using a log-rank test, and the curves were plotted using the Kaplan-Meier method. All statistical analysis were conducted using SAS software version 9.2 (SAS Institute Inc., Cary, NC, USA). Statistical significance was determined with a p-value less than 0.05.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Acknowledgements
This study was based in part on data obtained from the National Health Insurance Research Database which was provided by the Bureau of National Health Insurance, Department of Health, Taiwan, and managed by the National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health, or National Health Research Institutes, Taiwan.
Author contributions
Conception and design: C.Y.L., S.S.W.Acquisition of data: C.L.W, J.R.L.Analysis and interpretation of data: C.L.W. , C.S.C. Drafting of the manuscript: C.Y.L.Critical revision of the manuscript: C.K.Y., K.Y.C. Statistical analysis: C.H.L. Administrative, technical support: C.S.C., K.Y.C. Supervision: S.S.W.
Data availability
The data presented in this study are available on request from the corresponding author.
Declarations
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data presented in this study are available on request from the corresponding author.