Effect of ADT and ARPI on Bone Loss of Patients with Prostate Cancer

NCT ID: NCT06838520

Last Updated: 2025-02-20

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Total Enrollment: 200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2025-04-01
• Study Completion Date: 2030-12-31

Brief Summary

This study aims to assess the impact of Androgen Deprivation Therapy (ADT) and Androgen Receptor Pathway Inhibitors (ARPI) on bone quality in patients with prostate cancer. Patients undergoing ADT for prostate cancer often experience adverse effects such as decreased bone density and increased fracture risk. While ARPIs are emerging as novel therapeutic agents, their effects on bone quality remain unclear. This study will compare patients receiving combined ADT and ARPI therapy with those receiving ADT alone, evaluating changes in bone density, bone microarchitecture, and bone metabolic markers. The findings will help optimize treatment strategies for prostate cancer patients, reduce the risk of osteoporosis, and improve overall quality of life.

Detailed Description

Prostate cancer is the second most common malignancy in men worldwide and ranks fifth in cancer mortality among men. In developed countries in Europe and America, it has the highest incidence rate. In recent years, with the development of the social economy, increased life expectancy, changes in lifestyle, and improvements in the level of medical and health care, the incidence of prostate cancer in China is gradually rising, posing a serious threat to the life safety of men. In China, more than half of the patients with newly diagnosed prostate cancer have advanced metastatic disease. The skeleton is the most common site of metastasis in these patients. Metastatic lesions may cause pathological fractures and spinal cord compression. Patients with extensive bone metastasis are prone to fatigue, weight loss, anemia, and in severe cases, even systemic organ failure. Hormonal therapy based on ADT remains the main treatment for advanced prostate cancer, with the goal of reducing or eliminating the promoting effect of androgens on cancer cell growth.

While ADT treatment benefits patients with metastatic prostate cancer, it also leads to numerous side effects, such as cardiovascular diseases, changes in body composition, decreased bone mineral density (BMD), hot flashes, gynecomastia, cognitive decline, fatigue, anemia, and sexual dysfunction. ADT treatment can affect the number and function of osteoblasts and osteoclasts through various pathways, disrupting the balance of bone remodeling and leading to cancer treatment-induced bone loss. Under normal conditions, testosterone can be converted to estradiol via aromatase and bind to the estrogen receptors on the surface of osteoclasts, indirectly regulating these cells. With increasing age, the bioactivity of both testosterone and estrogen declines in normal men, resulting in low-turnover bone metabolic changes and a bone loss rate of 0.5% to 1% per year. In patients undergoing ADT, the levels of testosterone and estrogen decrease more significantly, and the number of osteoclasts increases markedly. Moreover, ADT treatment can reduce muscle mass and increase fat, leading to sarcopenic obesity, which is accompanied by chronic low-grade inflammation throughout the body and disrupts bone homeostasis. ADT may also lower the levels of circulating vitamin D, which not only affects bone mineralization but also has adverse effects on skeletal muscle and prostate cancer itself. Studies have shown that after 12 months of ADT treatment, the median lumbar spine BMD in patients decreased by an average of 3.6%, higher than that in untreated elderly men (0.5% to 1%). The BLADE study (NCT03202381) confirmed that long-term ADT treatment with either Gonadotropin-releasing hormone (GnRH) receptor agonists or antagonists significantly reduces bone quality. In fact, bone loss caused by ADT treatment can also lead to skeletal-related events (SREs), represented by pathological fractures, bone radiotherapy, bone surgery, and spinal cord compression.

ARPIs play a crucial role in the treatment of prostate cancer. Prostate cancer cells often rely on androgens for growth, and ARPIs work by blocking the androgen receptor pathway, thereby inhibiting the proliferation of cancer cells. These inhibitors, such as abiraterone, enzalutamide, and apalutamide, have significantly improved outcomes for patients with advanced prostate cancer, including those with metastatic castration-resistant prostate cancer (mCRPC). By reducing the levels of androgens or blocking their effects, ARPIs may also negatively impact bone quality in patients with prostate cancer. These agents, by reducing androgen levels, may lead to decreased BMD and increased fracture risk.

The impact of combining ADT with ARPIs on bone quality remains unclear. While clinical trial data on ARPIs in nonmetastatic castration-resistant prostate cancer (nmCRPC) have shown mixed results regarding bone health. Further research is needed to fully understand the combined effects of ADT and ARPIs on bone quality. It is essential to gain a deeper understanding of the patterns of osteoporosis to provide most effective bone-protective therapies to prevent the occurrence of SREs.

Conditions

Prostate Cancer (Adenocarcinoma)

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

Group A: ADT alone

Men with locally advanced prostate cancer or metastatic hormone-sensitive prostate cancer, about to start treatment.

ADT including LHRH agonist and antagonist.

Bone health assessment

Intervention Type: OTHER

Assessments of physical function, DXA scan

Group B: ADT + ARPIs

Men with locally advanced prostate cancer or metastatic hormone-sensitive prostate cancer, about to start treatment.

ADT including LHRH agonist and antagonist. ARPIs including Abiraterone Acetate, Enzalutamide, Apalutamide, Darolutamide or Rezvilutamide.

Bone health assessment

Intervention Type: OTHER

Assessments of physical function, DXA scan

Interventions

Bone health assessment

Assessments of physical function, DXA scan

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

1. Age ≥ 18 years, male gender;

2. Histologically or cytologically confirmed prostate cancer;

3. Clinical stage of metastatic hormone-sensitive prostate cancer (mHSPC);

4. Eastern Cooperative Oncology Group (ECOG) performance status score ≤ 2;

5. Life expectancy ≥ 12 months;

6. Willing and able to provide written informed consent.

Exclusion Criteria

1. Suffering from double primary malignancies.

2. Having previously received androgen deprivation therapy (ADT) or other pharmacological treatments (e.g., denosumab, bisphosphonates, or corticosteroids).

3. Having osteoporosis at baseline (T-score ≤ -2.5).

4. Having known bone diseases.

5. Having spinal metastases confirmed by imaging (e.g., ECT, MRI, CT, or PSMA PET-CT).

6. Having poor general condition (i.e., ECOG ≥ 4).

7. Having a life expectancy of less than 12 months.

8. Having elevated serum PSA levels (≥4 ng/dL) or testosterone levels (≥50 ng/dL) after 6 months of ADT.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

The First Affiliated Hospital with Nanjing Medical University

OTHER

Sponsor Role: lead

Responsible Party

Bianjiang Liu

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

The Third Affiliated Hospital of Soochow University

Changzhou, Jiangsu, China

The First Affiliated Hospital of Nanjing Medical University

Nanjing, Jiangsu, China

The First Affiliated Hospital of Soochow University

Suzhou, Jiangsu, China

Northern Jiangsu People's Hospital

Yangzhou, Jiangsu, China

Countries

China

Central Contacts

Bianjiang Liu, MD

Role: CONTACT

bjliu@njmu.edu.cn

+8613851493417

Ruizhe Zhao, MD

Role: CONTACT

drzrzurology@njmu.edu.cn

+8615251840611

Facility Contacts

Dong Xue, MD

Role: primary

xuedongdx@163.com

+8615251840611

Bianjiang Liu, MD

Role: primary

bjliu@njmu.edu.cn

+8613851493417

Xuedong Wei, MD

Role: primary

wxd0422@163.com

+8615251840611

Xuefei Ding

Role: primary

xuefeid@126.com

+8615251840611

References

Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, Lips P, Munns CF, Lazaretti-Castro M, Giustina A, Bilezikian J. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019 Aug 1;40(4):1109-1151. doi: 10.1210/er.2018-00126.

Reference Type: BACKGROUND

PMID: 30321335 (View on PubMed)

D'Andrea S, Martorella A, Coccia F, Castellini C, Minaldi E, Totaro M, Parisi A, Francavilla F, Francavilla S, Barbonetti A. Relationship of Vitamin D status with testosterone levels: a systematic review and meta-analysis. Endocrine. 2021 Apr;72(1):49-61. doi: 10.1007/s12020-020-02482-3. Epub 2020 Sep 3.

Reference Type: BACKGROUND

PMID: 32880851 (View on PubMed)

Feng W, Guo J, Li M. RANKL-independent modulation of osteoclastogenesis. J Oral Biosci. 2019 Mar;61(1):16-21. doi: 10.1016/j.job.2019.01.001. Epub 2019 Jan 11.

Reference Type: BACKGROUND

PMID: 30929797 (View on PubMed)

Kokorovic A, So AI, Serag H, French C, Hamilton RJ, Izard JP, Nayak JG, Pouliot F, Saad F, Shayegan B, Aprikian A, Rendon RA. Canadian Urological Association guideline on androgen deprivation therapy: Adverse events and management strategies. Can Urol Assoc J. 2021 Jun;15(6):E307-E322. doi: 10.5489/cuaj.7355. No abstract available.

Reference Type: BACKGROUND

PMID: 34127184 (View on PubMed)

Bhowmik D, Song X, Intorcia M, Gray S, Shi N. Examination of burden of skeletal-related events in patients naive to denosumab and intravenous bisphosphonate therapy in bone metastases from solid tumors population. Curr Med Res Opin. 2019 Mar;35(3):513-523. doi: 10.1080/03007995.2018.1532884. Epub 2018 Nov 20.

Reference Type: BACKGROUND

PMID: 30286662 (View on PubMed)

Other Identifiers

2024-SR-999

Identifier Type: -

Identifier Source: org_study_id