Changes in bone and mineral homeostasis after short-term androgen deprivation therapy with or without androgen receptor signalling inhibitor - substudy of a single-centre, double blind, randomised, placebo-controlled phase 2 trial.
Androgen deprivation therapy; Androgen receptor signalling inhibitor; Bone turnover marker; Prostate cancer; Stable calcium isotope; Androgen Antagonists; Androgens; Receptors, Androgen; Calcium; Androgen Receptor Antagonists; Minerals; Biomarkers; Male; Humans; Androgen Receptor Antagonists/adverse effects; Minerals/therapeutic use; Homeostasis; Androgen Antagonists/adverse effects; Prostatic Neoplasms/pathology; Prostatic Neoplasms; Biochemistry, Genetics and Molecular Biology (all); General Biochemistry, Genetics and Molecular Biology; General Medicine
Abstract :
[en] [en] BACKGROUND: Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) have an increased fracture risk. Exploring biomarkers for early bone loss detection is of great interest.
METHODS: Pre-planned substudy of the ARNEO-trial (NCT03080116): a double blind, randomised, placebo-controlled phase 2 trial performed in high-risk PCa patients without bone metastases between March 2019 and April 2021. Patients were 1:1 randomised to treatment with gonadotropin-releasing hormone antagonist (degarelix) + androgen receptor signalling inhibitor (ARSI; apalutamide) versus degarelix + matching placebo for 12 weeks prior to prostatectomy. Before and following ADT, serum and 24-h urinary samples were collected. Primary endpoints were changes in calcium-phosphate homeostasis and bone biomarkers.
FINDINGS: Of the 89 randomised patients, 43 in the degarelix + apalutamide and 44 patients in the degarelix + placebo group were included in this substudy. Serum corrected calcium levels increased similarly in both treatment arms (mean difference +0.04 mmol/L, 95% confidence interval, 0.02; 0.06), and parathyroid hormone and 1,25-dihydroxyvitamin D3 levels decreased. Bone resorption markers increased, and stable calcium isotope ratios reflecting net bone mineral balance decreased in serum and urine similarly in both groups.
INTERPRETATION: This exploratory substudy suggests that 12 weeks of ADT in non-metastatic PCa patients results in early bone loss. Additional treatment with ARSI does not seem to more negatively influence bone loss in the early phase. Future studies should address if these early biomarkers are able to predict fracture risk, and can be implemented in clinical practice for follow-up of bone health in PCa patients under ADT.
FUNDING: Research Foundation Flanders; KU Leuven; University-Hospitals-Leuven.
Disciplines :
Laboratory medicine & medical technology
Author, co-author :
David, Karel ; Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium
Devos, Gaëtan; Department of Urology, University Hospitals Leuven, Leuven, Belgium, Urogenital, Abdominal and Plastic Surgery, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Narinx, Nick; Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
Antonio, Leen ; Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium
Devlies, Wout; Department of Urology, University Hospitals Leuven, Leuven, Belgium, Urogenital, Abdominal and Plastic Surgery, Department of Development and Regeneration, KU Leuven, Leuven, Belgium, Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
Deboel, Ludo; Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
Schollaert, Dieter; Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
Eisenhauer, Anton; Geomar Helmholtz Centre for Ocean Research Kiel, Kiel, Germany, Osteolabs GmbH, Kiel, Germany
Cavalier, Etienne ; Centre Hospitalier Universitaire de Liège - CHU > > Service de chimie clinique
Vanderschueren, Dirk; Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium
Claessens, Frank; Molecular Endocrinology, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
Joniau, Steven; Department of Urology, University Hospitals Leuven, Leuven, Belgium, Urogenital, Abdominal and Plastic Surgery, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Decallonne, Brigitte ; Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium, Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium. Electronic address: brigitte.decallonne@uzleuven.be
Changes in bone and mineral homeostasis after short-term androgen deprivation therapy with or without androgen receptor signalling inhibitor - substudy of a single-centre, double blind, randomised, placebo-controlled phase 2 trial.
KD receives a PhD fellowship Fundamental Research from Flanders Research Foundation (FWO 1196522N). SJ received support from Janssen and Ferring for the study drugs. This work was funded by FWO research grant (G099518N), by KOOR grant University Hospitals Leuven (S63579) and by KU Leuven grant (C14/19/100).Research Foundation Flanders; KU Leuven; University-Hospitals-Leuven.KD receives a PhD fellowship Fundamental Research from Flanders Research Foundation (FWO 1196522N). SJ received support from Janssen and Ferring for the study drugs. This work was funded by FWO research grant (G099518N), by KOOR grant University Hospitals Leuven (S63579) and by KU Leuven grant (C14/19/100). We thank the clinical trial nurses of the department of Urology of the University Hospitals Leuven for their logistic support. We thank Annouschka Laenen for the statistical advice and support provided.
Sung, H., Ferlay, J., Siegel, R.L., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:3 (2021), 209–249.
Mottet, N., van den Bergh, R.C.N., Briers, E., et al. EAU-EANM-ESTRO-ESUR-SIOG guidelines on prostate cancer-2020 update. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol 79:2 (2021), 243–262.
Mitsiades, N., Kaochar, S., Androgen receptor signaling inhibitors: post-chemotherapy, pre-chemotherapy and now in castration-sensitive prostate cancer. Endocr Relat Cancer 28:8 (2021), T19–T38.
Devos, G., Devlies, W., De Meerleer, G., et al. Neoadjuvant hormonal therapy before radical prostatectomy in high-risk prostate cancer. Nat Rev Urol 18:12 (2021), 739–762.
Shahinian, V.B., Kuo, Y.F., Freeman, J.L., Goodwin, J.S., Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:2 (2005), 154–164.
Smith, M.R., Lee, W.C., Brandman, J., Wang, Q., Botteman, M., Pashos, C.L., Gonadotropin-releasing hormone agonists and fracture risk: a claims-based cohort study of men with nonmetastatic prostate cancer. J Clin Oncol 23:31 (2005), 7897–7903.
Wallander, M., Axelsson, K.F., Lundh, D., Lorentzon, M., Patients with prostate cancer and androgen deprivation therapy have increased risk of fractures-a study from the fractures and fall injuries in the elderly cohort (FRAILCO). Osteoporos Int 30:1 (2019), 115–125.
Hussain, A., Tripathi, A., Pieczonka, C., et al. Bone health effects of androgen-deprivation therapy and androgen receptor inhibitors in patients with nonmetastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis 24:2 (2020), 290–300.
Myint, Z.W., Momo, H.D., Otto, D.E., Yan, D., Wang, P., Kolesar, J.M., Evaluation of fall and fracture risk among men with prostate cancer treated with androgen receptor inhibitors: a systematic review and meta-analysis. JAMA Netw Open, 3(11), 2020, e2025826.
Bouleftour, W., Boussoualim, K., Sotton, S., et al. Second-generation hormonotherapy in prostate cancer and bone microenvironment. Endocr Relat Cancer 28:8 (2021), T39–T49.
Shao, Y.H., Moore, D.F., Shih, W., Lin, Y., Jang, T.L., Lu-Yao, G.L., Fracture after androgen deprivation therapy among men with a high baseline risk of skeletal complications. BJU Int 111:5 (2013), 745–752.
Watts, N.B., Adler, R.A., Bilezikian, J.P., et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 97:6 (2012), 1802–1822.
Cianferotti, L., Bertoldo, F., Carini, M., et al. The prevention of fragility fractures in patients with non-metastatic prostate cancer: a position statement by the international osteoporosis foundation. Oncotarget 8:43 (2017), 75646–75663.
https://www.sheffield.ac.uk/FRAX/index.aspx.
Ye, C., Morin, S.N., Lix, L.M., et al. Performance of FRAX in men with prostate cancer: a registry-based cohort study. J Bone Miner Res 38:5 (2023), 659–664.
Hu, J., Aprikian, A.G., Vanhuyse, M., Dragomir, A., Contemporary population-based analysis of bone mineral density testing in men initiating androgen deprivation therapy for prostate cancer. J Natl Compr Canc Netw 18:10 (2020), 1374–1381.
Holt, A., Khan, M.A., Gujja, S., Govindarajan, R., Utilization of bone densitometry for prediction and administration of bisphosphonates to prevent osteoporosis in patients with prostate cancer without bone metastases receiving antiandrogen therapy. Cancer Manag Res 7 (2015), 13–18.
Greenspan, S.L., Coates, P., Sereika, S.M., Nelson, J.B., Trump, D.L., Resnick, N.M., Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer. J Clin Endocrinol Metab 90:12 (2005), 6410–6417.
Kimura, T., Koike, Y., Aikawa, K., et al. Short-term impact of androgen deprivation therapy on bone strength in castration-sensitive prostate cancer. Int J Urol 26:10 (2019), 980–984.
Tosco, L., Laenen, A., Gevaert, T., et al. Neoadjuvant degarelix with or without apalutamide followed by radical prostatectomy for intermediate and high-risk prostate cancer: ARNEO, a randomized, double blind, placebo-controlled trial. BMC Cancer, 18(1), 2018, 354.
Devos, G., Tosco, L., Baldewijns, M., et al. ARNEO: a randomized phase II trial of neoadjuvant degarelix with or without apalutamide prior to radical prostatectomy for high-risk prostate cancer. Eur Urol 83:6 (2022), 508–518.
Von Korff, M., Wagner, E.H., Saunders, K., A chronic disease score from automated pharmacy data. J Clin Epidemiol 45:2 (1992), 197–203.
Antonio, L., Pauwels, S., Laurent, M.R., et al. Free testosterone reflects metabolic as well as ovarian disturbances in subfertile oligomenorrheic women. Int J Endocrinol, 2018, 2018, 7956951.
Pauwels, S., Antonio, L., Jans, I., et al. Sensitive routine liquid chromatography-tandem mass spectrometry method for serum estradiol and estrone without derivatization. Anal Bioanal Chem 405:26 (2013), 8569–8577.
Vermeulen, A., Verdonck, L., Kaufman, J.M., A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84:10 (1999), 3666–3672.
Levey, A.S., Stevens, L.A., Schmid, C.H., et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 150:9 (2009), 604–612.
Casetta, B., Jans, I., Billen, J., Vanderschueren, D., Bouillon, R., Development of a method for the quantification of 1alpha,25(OH)2-vitamin D3 in serum by liquid chromatography tandem mass spectrometry without derivatization. Eur J Mass Spectrom (Chichester) 16:1 (2010), 81–89.
Cools, M., Goemaere, S., Baetens, D., et al. Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: a cross-sectional study. Bone 81 (2015), 89–96.
Bouillon, R., Vandoren, G., Van Baelen, H., De Moor, P., Immunochemical measurement of the vitamin D-binding protein in rat serum. Endocrinology 102:6 (1978), 1710–1715.
Eisenhauer, A., Müller, M., Heuser, A., et al. Calcium isotope ratios in blood and urine: a new biomarker for the diagnosis of osteoporosis. Bone Rep, 10, 2019, 100200.
Shroff, R., Lalayiannis, A.D., Fewtrell, M., et al. Naturally occurring stable calcium isotope ratios are a novel biomarker of bone calcium balance in chronic kidney disease. Kidney Int 102:3 (2022), 613–623.
Shroff, R., Fewtrell, M., Heuser, A., et al. Naturally occurring stable calcium isotope ratios in body compartments provide a novel biomarker of bone mineral balance in children and young adults. J Bone Miner Res 36:1 (2021), 133–142.
Khalil, R., Antonio, L., Laurent, M.R., et al. Early effects of androgen deprivation on bone and mineral homeostasis in adult men: a prospective cohort study. Eur J Endocrinol 183:2 (2020), 181–189.
Riggs, B.L., Khosla, S., Melton, L.J., Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:3 (2002), 279–302.
Schini, M., Vilaca, T., Gossiel, F., Salam, S., Eastell, R., Bone turnover markers: basic biology to clinical applications. Endocr Rev 44:3 (2022), 417–473.
Almeida, M., Laurent, M.R., Dubois, V., et al. Estrogens and androgens in skeletal physiology and pathophysiology. Physiol Rev 97:1 (2017), 135–187.
Finkelstein, J.S., Lee, H., Leder, B.Z., et al. Gonadal steroid-dependent effects on bone turnover and bone mineral density in men. J Clin Invest 126:3 (2016), 1114–1125.
Falahati-Nini, A., Riggs, B.L., Atkinson, E.J., O'Fallon, W.M., Eastell, R., Khosla, S., Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest 106:12 (2000), 1553–1560.
Hamilton, E.J., Ghasem-Zadeh, A., Gianatti, E., et al. Structural decay of bone microarchitecture in men with prostate cancer treated with androgen deprivation therapy. J Clin Endocrinol Metab 95:12 (2010), E456–E463.
Huhtaniemi, I., Nikula, H., Rannikko, S., Pituitary-testicular function of prostatic cancer patients during treatment with a gonadotropin-releasing hormone agonist analog. I. Circulating hormone levels. J Androl 8:6 (1987), 355–362.
Palumbo, C., Dalla Volta, A., Zamboni, S., et al. Effect of degarelix administration on bone health in prostate cancer patients without bone metastases. The Blade Study. J Clin Endocrinol Metab 107:12 (2022), 3398–3407.
García-Fontana, B., Morales-Santana, S., Varsavsky, M., et al. Sclerostin serum levels in prostate cancer patients and their relationship with sex steroids. Osteoporos Int 25:2 (2014), 645–651.
Smith, M.R., Goode, M., Zietman, A.L., McGovern, F.J., Lee, H., Finkelstein, J.S., Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition. J Clin Oncol 22:13 (2004), 2546–2553.
Yamada, Y., Takahashi, S., Fujimura, T., et al. The effect of combined androgen blockade on bone turnover and bone mineral density in men with prostate cancer. Osteoporos Int 19:3 (2008), 321–327.
Ishizaki, F., Hara, N., Takizawa, I., et al. Deficiency in androgens and upregulation of insulin-like growth factor-1 are involved in high bone turnover in men receiving androgen deprivation therapy for prostate cancer. Growth Horm IGF Res 22:3-4 (2012), 122–128.
Tombal, B., Borre, M., Rathenborg, P., et al. Long-term efficacy and safety of enzalutamide monotherapy in hormone-naïve prostate cancer: 1- and 2-year open-label follow-up results. Eur Urol 68:5 (2015), 787–794.
Smith, M.R., Saad, F., Chowdhury, S., et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 378:15 (2018), 1408–1418.
Ramchand, S.K., Cheung, Y.M., Yeo, B., Grossmann, M., The effects of adjuvant endocrine therapy on bone health in women with breast cancer. J Endocrinol 241:3 (2019), R111–R124.
