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• W2956018153 abstract "Future OncologyVol. 15, No. 20 EditorialFree AccessExcess of second tumors in denosumab-treated patients: a metabolic hypothesisValeria Tovazzi, Alberto Dalla Volta, Rebecca Pedersini, Vito Amoroso & Alfredo BerrutiValeria TovazziDepartment of Medical & Surgical Specialties, Radiological Sciences, & Public Health, Medical Oncology, University of Brescia at ASST Spedali Civili, Brescia, ItalySearch for more papers by this author, Alberto Dalla VoltaASST Spedali Civili of Brescia Medical Oncology, University of Verona, Verona, ItalySearch for more papers by this author, Rebecca PedersiniDepartment of Medical & Surgical Specialties, Radiological Sciences, & Public Health, Medical Oncology, University of Brescia at ASST Spedali Civili, Brescia, ItalySearch for more papers by this author, Vito AmorosoDepartment of Medical & Surgical Specialties, Radiological Sciences, & Public Health, Medical Oncology, University of Brescia at ASST Spedali Civili, Brescia, ItalySearch for more papers by this author & Alfredo Berruti *Author for correspondence: Tel.: 030 399 5410, Fax: 030 399 6035; E-mail Address: alfredo.berruti@gmail.comhttps://orcid.org/0000-0002-3956-0043Department of Medical & Surgical Specialties, Radiological Sciences, & Public Health, Medical Oncology, University of Brescia at ASST Spedali Civili, Brescia, ItalySearch for more papers by this authorPublished Online:25 Jun 2019https://doi.org/10.2217/fon-2019-0170AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: denosumabhyperparathyroidismhypocalcemiasecond malignanciesDenosumab and zoledronic acid are the most frequently used bone resorption inhibitors to prevent symptomatic skeletal events (SSE) in cancer patients with bone metastases. Denosumab is a fully human monoclonal antibody that binds to RANK-L and inhibits osteoclast maturation. Zoledronic acid is a bisphosphonate that induces apoptosis of mature osteoclasts.In May 2018, prescribers of these drugs were warned about the increased incidence of second tumors in denosumab-treated patients. This alert was based upon the results of four Phase III studies that compared the efficacy of denosumab and zoledronic acid in bone metastatic patients suffering from castration-resistant prostate cancer, breast cancer, different advanced cancers (mostly lung cancer) and multiple myeloma [1–4].In all these studies, denosumab, administered subcutaneously at the dose of 120 mg every month, was superior to zoledronic acid in terms of reduction of the risk of adverse skeletal-related events (defined as the occurrence of any among pathologic fracture, spinal cord compression, necessity for radiation or surgery to bone), due to a more potent inhibition of the osteoclast activity. However, in patients randomized to receive denosumab there was a small increased proportion of second malignancies (ranging from 0.5 and 2.2%) comparing to patients who received zoledronic acid (0.3–1%).Since the greater frequency of malignancies linked to denosumab therapy was observed in three out of four trials [1,3,4], this observation seems not to be casual. Therefore, we have wondered what could be the possible mechanisms responsible for this phenomenon.The onset of second neoplasms could be related to the denosumab dose & scheduleDenosumab induces RANK-L inhibition and blocks osteoclast maturation. It is unlikely, however, that this mechanism per se can favor progression and diffusion of cancer cells. Several preclinical in vivo and in vitro studies, in fact, demonstrated that RANK-L expression promotes tumor cell migration, invasion and angiogenesis [5,6]. Moreover, cytokines and growth factors, produced by tumors, stimulate RANK-L and may reduce osteoprotegerin and increase T-regulatory cells, thus favoring tumor growth in bone microenvironment [7]. By contrast, several RANK-L-targeting drugs, including denosumab, led to reduction in skeletal tumor growth, cell proliferation and increase cell apoptosis and survival in mice bearing different tumor types [8]. On these bases, RANK-L inhibition can exert a protective role against progression and diffusion of cancer cells.Noteworthy, denosumab, at the subcutaneous dose of 60 mg every 6 months, was also tested against placebo in women receiving adjuvant aromatase-inhibitor therapy for breast cancer [9] and in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer [10], with the aim to prevent bone mass loss and fractures. In these studies, denosumab administration was not associated to an excess of second neoplasms (proportion of second malignancies 1.5 vs 1.1% and 5 vs 5% in denosumab and placebo arms in the two studies, respectively).Although the settings are different, one hypothesis is that the dose and schedule of denosumab could have had a role in favoring second neoplasms, in other words the deeper and more prolonged was the osteoclast inhibition the greater was the risk of second malignancies. An early effect of bone resorption inhibition is hypocalcemia. So the lower and delayed dose of denosumab administration in the nonmetastatic studies led to a less proportion of hypocalcemia with respect to the higher dose adopted in metastatic patients [9,10].PTH elevation as a consequence of denosumab-induced hypocalcemia may promote the appearance of second tumorsSerum calcium level is a master regulator for PTH incretion, resulting in an increased release of the hormone in presence of hypocalcemia. PTH may have promotional activity of cancer progression [11]. PTH, in fact, has an amino-terminal sequence homology with PTHrP, a hormone that notoriously stimulates cell growth and inhibits apoptosis in different cell types, and both PTHrP and PTH bind to the same receptor (PTH1R) with similar affinity, resulting in equal responses in terms of quality and quantity. PTH1R belongs to the G-protein-coupled receptor family and is placed upstream of a signal cascade involved in cell survival, antiapoptotic activity and migration [11]. PTHrP stimulates angiogenesis, inflammation and Wnt pathway in osteosarcoma cells [12], it promotes cell cycle and migration of colon cancer cells [13] and confers antiapoptotic stimuli to renal cancer cells [14]. Furthermore, the stimulating effect of PTHrP on tumor proliferation and progression is not limited to these neoplasms, so the finding that many cancers express PTHR1 suggests a direct role of PTH in promoting the clonal growth of transformed neoplastic cells [15]. It is pertinent mentioning that in a post hoc analysis of the registrative trial of zoledronic acid versus placebo in bone metastatic prostate cancer patients, PTH elevation was a negative prognostic factor in zoledronic acid treated patients [16].Unfortunately, in the aforementioned Phase III studies of denosumab administration, both in nonmetastatic and metastatic setting, PTH was not measured. However, provided the strong inverse correlation between PTH and serum calcium concentrations, the rate of hypocalcemia could be considered a valid surrogate of PTH elevation.As mentioned before, it is interesting to note that in the nonmetastatic studies [9,10] no difference in hypocalcemia (all grades) between denosumab and placebo arms was observed (0.1 vs 0.1% [9] and 0.1 vs 0% [10]). Conversely in the metastatic studies, denosumab was more frequently associated to hypocalcemia than zoledronic acid due the higher doses administered and, intriguingly, in patients randomized to denosumab there was an increased proportion of second malignancies.Analyzing the data of single studies, it should be noted that in the three studies in which the frequency of severe hypocalcemia (grade 3–4) was considerably higher in the denosumab versus zoledronic acid arm (5 vs 1% [1], 2.3 vs 1% [3] and 4 vs 2.6% [4]) there was also an increased frequency of second malignancies (2 vs 1% [1], 0.6 vs 0.3% [3] and 2.2 vs 0.8% [4]). This was not the case in the study involving breast cancer [2] in which the similar frequency of severe hypocalcemia in both arms (1.6 vs 1.2%) was associated with a same proportion of second malignancies (0.5 vs 0.5%). The higher rates of hypocalcemia (and consequently second malignancies) were observed in the studies in which patients with prostate cancer and multiple myeloma were involved. This phenomenon could be explained by osteoblast nature of bone metastases from prostate cancer leading per se to calcium entrapment in bone (the so-called bone hunger syndrome) [17], and renal impairment that often follows multiple myeloma; both these conditions favor the occurrence of hypocalcemia after bone resorption inhibitors.ConclusionSince the increase in second malignancies observed in patients treated with denosumab compared with zoledronic acid seems to be proportional to the augmented rate of hypocalcemia, it is plausible to infer that secondary hyperparathyroidism could play a role in favoring the excess of second tumors seen in patients treated with denosumab. A post hoc analysis exploring the correlation between second malignancies and drug-induced hypocalcemia in the above-mentioned randomized clinical trials could provide support to this hypothesis. If confirmed, our assumption may imply that calcium and PTH should be regularly monitored during intravenous administration of denosumab and calcium and vitamin D supplementation should target PTH elevation [18].Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Papers of special note have been highlighted as: •• of considerable interestReferences1. Fizazi K, Carducci M, Smith M et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377, 813–822 (2011). •• Trial cited in Amgen warning for second cancer excess with denosumab.Crossref, Medline, CAS, Google Scholar2. Stopeck AT, Lipton A, Body J et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J. Clin. Oncol. 28, 5132–5139 (2010). •• Trial cited in Amgen warning for second cancer excess with denosumab.Crossref, Medline, CAS, Google Scholar3. Henry DH, Costa L, Goldwasser F et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J. Clin. Oncol. 29, 1125–1132 (2011). •• Trial cited in Amgen warning for second cancer excess with denosumab.Crossref, Medline, CAS, Google Scholar4. Raje N, Terpos E, Willenbacher W et al. Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma: an international, double-blind, double-dummy, randomised, controlled, Phase III study. Lancet Oncol. 19, 370–381 (2018). •• Trial cited in Amgen warning for second cancer excess with denosumab.Crossref, Medline, CAS, Google Scholar5. Schramek D, Leibbrandt A, Sigl V et al. Osteoclast differentiation factor RANKL controls development for progestin-driven mammary cancer. Nature 468, 98–102 (2010).Crossref, Medline, CAS, Google Scholar6. Armstrong AP, Miller RE, Jones JC et al. RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate 68, 92–104 (2008).Crossref, Medline, CAS, Google Scholar7. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2, 584–593 (2002).Crossref, Medline, CAS, Google Scholar8. Dougall WC. Molecular pathways: osteoclast-dependent and osteoclast-independent roles of RANKL/RANK/OPG pathway in tumorigenesis and metastasis. Clin. Cancer Res. 18, 326–335 (2012).Crossref, Medline, CAS, Google Scholar9. Gnant M, Pfeiler G, Dubsky PC et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet 386, 433–443 (2015). •• Trial showing no excess of second cancers with adjuvant schedule of denosumab.Crossref, Medline, CAS, Google Scholar10. Smith MR, Egerdie B, Hernandez Toriz N et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N. Engl. J. Med. 361, 745–755 (2009). •• Trial showing no excess of second cancers with adjuvant schedule of denosumab.Crossref, Medline, CAS, Google Scholar11. McCarty MF. Parathyroid hormone may be a cancer promoter – an explanation for the decrease in cancer risk associated with ultraviolet light, calcium and vitamin D. Med. Hypoth. 54(3), 475–482 (2000).Crossref, Medline, CAS, Google Scholar12. Li S, Dong Y, Wang K, Wang Z, Zhang X. Transcriptomic analyses reveal the underlying pro-malignant functions of PTHR1 for osteosarcoma via activation of Wnt and angiogenesis pathways. J. Orthop. Surg. Res. 12, 168 (2017).Crossref, Medline, Google Scholar13. Calvo N, Carriere P, Martin MJ, Gentili C. RSK activation via ERK modulates human colon cancer cells response to PTHrP. J. Mol. Endocrinol. 59, 13–27 (2017).Crossref, Medline, CAS, Google Scholar14. Sourbier C, Massfelder T. Parathyroid hormone-related protein in human renal cell carcinoma. Cancer Lett. 240, 170–182 (2006).Crossref, Medline, CAS, Google Scholar15. Lupp A, Klenk C, Rocken C, Evert M, Mawrin C, Schulz S. Immunohistochemical identification of the PTHR1 parathyroid hormone receptor in normal and neoplastic human tissues. Eur. J. Endocrinol. 162, 979–986 (2010).Crossref, Medline, CAS, Google Scholar16. Berruti A, Cook R, Saad F et al. Prognostic role of serum parathyroid hormone levels in advanced prostate cancer patients undergoing zoledronic acid administration. Oncologist 17, 645–652 (2012).•• Prospective evaluation of PTH levels as prognostic factor in prostate cancer patients treated with zoledronic acid. Crossref, Medline, CAS, Google Scholar17. Berruti A, Dogliotti L, Tucci M, Scarpa RM, Angeli A. Hyperparathyroidism due to the so-called bone hunger syndrome in prostate cancer patients. J. Clin. Endocrinol. Metab. 87(4), 1910–1911 (2002).Crossref, Medline, CAS, Google Scholar18. Berruti A, Tucci M, Generali D et al. Management of the side-effects of intravenous bisphosphonates: targeting the serum parathyroidhormone elevation. Ann. Oncol. 17(12), 1854–1855 (2006).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByBrust- und gynäkologische Tumoren – medikamentöse Therapie ossärer Metastasen13 February 2023 | Frauenheilkunde up2date, Vol. 17, No. 01Clinicopathologic and molecular features of denosumab-treated giant cell tumour of bone (GCTB): Analysis of 21 casesAnnals of Diagnostic Pathology, Vol. 57LONG-TERM USE OF DENOSUMAB IN GIANT CELL TUMORS AND VERTEBRAL ANEURYSMAL BONE CYSTS1 January 2022 | Coluna/Columna, Vol. 21, No. 1Osteosarcoma mechanobiology and therapeutic targets21 December 2021 | British Journal of Pharmacology, Vol. 179, No. 2The safety profile of denosumab in oncology beyond the safety of denosumab as an anti-osteoporotic agent: still more to learn31 December 2020 | Expert Opinion on Drug Safety, Vol. 20, No. 2Repurposing denosumab in lung cancer beyond counteracting the skeletal related events: an intriguing perspective13 July 2020 | Expert Opinion on Biological Therapy, Vol. 20, No. 11Repurposing denosumab in breast cancer beyond prevention of skeletal related events: Could nonclinical data be translated into clinical practice?4 November 2020 | Expert Review of Clinical Pharmacology, Vol. 13, No. 11MDA-9/Syntenin (SDCBP): Novel gene and therapeutic target for cancer metastasisPharmacological Research, Vol. 155Spectrum of histological features of Denosumab treated Giant Cell Tumor of Bone; potential pitfalls and diagnostic challenges for pathologistsAnnals of Diagnostic Pathology, Vol. 45Safety and efficacy of extended dosing intervals of denosumab in patients with solid cancers and bone metastases: a retrospective study23 December 2020 | Therapeutic Advances in Medical Oncology, Vol. 12 Vol. 15, No. 20 eToC Sign up Follow us on social media for the latest updates Metrics History Received 26 March 2019 Accepted 16 April 2019 Published online 25 June 2019 Published in print July 2019 Information© 2019 Future Medicine LtdKeywordsdenosumabhyperparathyroidismhypocalcemiasecond malignanciesFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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