Endocrine

, Volume 59, Issue 1, pp 90–101 | Cite as

Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience

  • G. Mazziotti
  • A. M. Formenti
  • M. B. Panarotto
  • E. Arvat
  • A. Chiti
  • A. Cuocolo
  • M. E. Dottorini
  • C. Durante
  • L. Agate
  • S. Filetti
  • F. Felicetti
  • A. Filice
  • L. Pace
  • T. Pellegrino
  • M. Rodari
  • M. Salvatori
  • C. Tranfaglia
  • A. Versari
  • D. Viola
  • S. Frara
  • A. Berruti
  • A. Giustina
  • R. Giubbini
Clinical Management of Endocrine Diseases

Abstract

Purpose and Patients

The M.O.S.CA.TI. (Metastases of the Skeleton from CArcinoma of the ThyroId) is a multicenter, retrospective study investigating the real-life outcome and management of bone metastases (BM) in 143 patients (63 M, 80 F; median age 64 years, range 11–87) with differentiated thyroid carcinoma (DTC).

Results

Radio-active iodine (RAI) treatment was performed in 131 patients (91.6%), surgical approach and/or external radiotherapy in 68 patients (47.6%), and anti-resorptive bone-active drugs in 32 patients (22.4%; in 31 zoledronate and in one denosumab). At the start of treatment, 24 patients (75.0%) receiving anti-resorptive bone-active drugs had at least one clinical skeletal-related event (SRE) (p < 0.001). One or more clinical SREs (pathological fractures and/or malignant hypercalcemia and/or spinal cord compression) developed in 53 patients (37.1%). Development of SREs was significantly associated with metachronous BM (hazard ratio (HR) 2.04; p = 0.04), localization of BM to cervical spine (HR 3.89; p = 0.01), and lack of avid RAI uptake (HR 2.66; p = 0.02). Thirty-nine patients (27.3%) died in correlation with development of SREs (HR 6.97; p = 0.006) and localization of BM to the hip (HR 3.86; p = 0.02). Moreover, overall mortality was significantly decreased by RAI therapy (HR 0.10; p = 0.02), whereas no significant effects were induced by bone-active drugs (p = 0.36), external radiotherapy (p = 0.54), and surgery (p = 0.43) of BM.

Conclusions

SREs are very frequent in BM from DTC and they impact patient survival. In the real life, the use of bone-active drugs is currently limited to zoledronate in patients with pre-existing SREs. In this clinical setting, RAI therapy, but not zoledronate, decreased mortality.

Keywords

Thyroid carcinoma Bone metastases Zoledronate Denosumab-radioiodine 

Notes

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector. The study was partially supported by G.I.O.S.E.G. (Glucocorticoid-induced osteoporosis and Skeletal Endocrinology Group).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

12020_2017_1455_MOESM1_ESM.tif (55 kb)
Supplementary Figure

References

  1. 1.
    M.M. Muresan, P. Olivier, J. Leclère, F. Sirveaux, L. Brunaud, M. Klein, R. Zarnegar, G. Weryha, Bone metastases from differentiated thyroid carcinoma. Endocr. Relat. Cancer 15, 37–49 (2008)CrossRefPubMedGoogle Scholar
  2. 2.
    C. Durante, N. Haddy, E. Baudin, S. Leboulleux, D. Hartl, J.P. Travagli, B. Caillou, M. Ricard, J.D. Lumbroso, F. DeVathaire, M. Schlumberger, Long term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J. Clin. Endocrinol. Metab. 91, 2892–2899 (2006)CrossRefPubMedGoogle Scholar
  3. 3.
    J.D. Lin, M.J. Huang, J.H. Juang, T.C. Chao, B.Y. Huang, K.W. Chen, J.Y. Chen, K.L. Li, J.F. Chen, Y.S. Ho, Factors related to the survival of papillary and follicular thyroid carcinoma patients with distant metastases. Thyroid 9, 1227–1235 (1999)CrossRefPubMedGoogle Scholar
  4. 4.
    C. Marcocci, F. Pacini, R. Elisei, E. Schipani, C. Ceccarelli, P. Miccoli, M. Arganini, A. Pinchera, Clinical and biologic behavior of bone metastases from differentiated thyroid carcinoma. Surgery 106, 960–966 (1989)PubMedGoogle Scholar
  5. 5.
    A.G. Pittas, M. Adler, M. Fazzari, S. Tickoo, J. Rosai, S.M. Larson, R.J. Robbins, Bone metastases from thyroid carcinoma: clinical characteristics and prognostic variables in one hundred forty-six patients. Thyroid 10, 261–268 (2000)CrossRefPubMedGoogle Scholar
  6. 6.
    A. Farooki, V. Leung, H. Tala, R.M. Tuttle, Skeletal-related events due to bone metastases from differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 97, 2433–2439 (2012)CrossRefPubMedGoogle Scholar
  7. 7.
    M. Tucci, A. Mosca, G. Lamanna, F. Porpiglia, M. Terzolo, F. Vana, C. Cracco, L. Russo, G. Gorzegno, M. Tampellini, M. Torta, G. Reimondo, M. Poggio, R.M. Scarpa, A. Angeli, L. Dogliotti, A. Berruti, Prognostic significance of disordered calcium metabolism in hormone-refractory prostate cancer patients with metastatic bone disease. Prostate Cancer Prostatic Dis. 12, 94–99 (2009)CrossRefPubMedGoogle Scholar
  8. 8.
    D.S. Cooper, G.M. Doherty, B.R. Haugen, R.T. Kloos, S.L. Lee, S.J. Mandel, E.L. Mazzaferri, B. McIver, F. Pacini, M. Schlumberger, S.I. Sherman, D.L. Steward, R.M. Tuttle, Revised American Thyroid Association Management Guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19, 1167–1214 (2009)CrossRefPubMedGoogle Scholar
  9. 9.
    B.R. Haugen, E.K. Alexander, K.C. Bible, G.M. Doherty, S.J. Mandel, Y.E. Nikiforov, F. Pacini, G.W. Randolph, A.M. Sawka, M. Schlumberger, K.G. Schuff, S.I. Sherman, J.A. Sosa, D.L. Steward, R.M. Tuttle, L. Wartofsky, American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26, 1–133 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Y. Orita, I. Sugitani, K. Toda, J. Manabe, Y. Fujimoto, Zoledronic acid in the treatment of bone metastases from differentiated thyroid carcinoma. Thyroid 21, 31–35 (2011)CrossRefPubMedGoogle Scholar
  11. 11.
    G. Vitale, F. Fonderico, A. Martignetti, M. Caraglia, A. Ciccarelli, V. Nuzzo, A. Abbruzzese, G. Lupoli, Pamidronate improves the quality of life and induces clinical remission of bone metastases in patients with thyroid cancer. Br. J. Cancer 84, 1586–1590 (2001)CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    A. Lipton, K. Fizazi, A.T. Stopeck, D.H. Henry, M.R. Smith, N. Shore, M. Martin, S. Vadhan-Raj, J.E. Brown, G.E. Richardson, F. Saad, D.A. Yardley, K. Zhou, A. Balakumaran, A. Braun, Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics. Eur. J. Cancer 53, 75–83 (2016)CrossRefPubMedGoogle Scholar
  13. 13.
    J. Liu, W. Huang, R. Zhou, S. Jia, W. Tang, Y. Luo, J. Zhang Bisphosphonates in the treatment of patients with metastatic breast, lung, and prostate cancer: a meta-analysis. Medicine 94, e2014 (2015)Google Scholar
  14. 14.
    D. Santini, G. Procopio, C. Porta, T. Ibrahim, S. Barni, C. Mazzara, A. Fontana, A. Berruti, R. Berardi, B. Vincenzi, C. Ortega, D. Ottaviani, G. Carteni, G. Lanzetta, V. Virzì, M. Santoni, N. Silvestris, M.A. Satolli, E. Collovà, A. Russo, G. Badalamenti, S.L. Fedeli, F.M. Tanca, V. Adamo, E. Maiello, R. Sabbatini, A. Felici, S. Cinieri, G. Tonini, S. Bracarda, Natural history of malignant bone disease in renal cancer: final results of an Italian bone metastasis survey. PLoS ONE 30, e83026 (2013)CrossRefGoogle Scholar
  15. 15.
    W.H. Beierwaltes, R.H. Nishiyama, N.W. Thompson, J.E. Copp, A. Kubo, Survival time and “cure” in papillary and follicular thyroid carcinoma with distant metastases: statistics following University of Michigan therapy. J. Nucl. Med. 23, 561–568 (1982)PubMedGoogle Scholar
  16. 16.
    M. Schlumberger, C. Challeton, F. De Vathaire, J.P. Travagli, P. Gardet, J.D. Lumbroso, C. Francese, F. Fontaine, M. Ricard, C. Parmentier, Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J. Nucl. Med. 37, 598–605 (1996)PubMedGoogle Scholar
  17. 17.
    Y. Mizukami, T. Mishigishi, A. Nonomura, T. Hashimoto, S. Terahata, M. Noguchi, K. Hisada, F. Matsubara, Distant metastases in differentiated thyroid carcinomas: a clinical and pathologic study. Hum. Pathol. 21, 283–290 (1990)CrossRefPubMedGoogle Scholar
  18. 18.
    J.J. Ruegemer, I.D. Hay, E.J. Bergstralh, J.J. Ryan, K.P. Offord, C.A. Gorman, Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J. Clin. Endocrinol. Metab. 67, 501–508 (1988)CrossRefPubMedGoogle Scholar
  19. 19.
    S.K. Tickoo, A.G. Pittas, M. Adler, M. Fazzari, S.M. Larson, R.J. Robbins, J. Rosai, Bone metastases from thyroid carcinoma: a histopathologic study with clinical correlates. Arch. Pathol. Lab. Med. 124, 1440–1447 (2000)PubMedGoogle Scholar
  20. 20.
    Y.E. Nikiforov, R.R. Seethala, G. Tallini, Z.W. Baloch, F. Basolo, L.D. Thompson, J.A. Barletta, B.M. Wenig, A. Al Ghuzlan, K. Kakudo, T.J. Giordano, V.A. Alves, E. Khanafshar, S.L. Asa, A.K. El-Naggar, W.E. Gooding, S.P. Hodak, R.V. Lloyd, G. Maytal, O. Mete, M.N. Nikiforova, V. Nosé, M. Papotti, D.N. Poller, P.M. Sadow, A.S. Tischler, R.M. Tuttle, K.B. Wall, V.A. LiVolsi, G.W. Randolph, R.A. Ghossein, Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2, 1023–1029 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    E. Hindié, P. Zanotti-Fregonara, I. Keller, F. Duron, J.Y. Devaux, M. Calzada-Nocaudie, E. Sarfati, J.L. Moretti, P. Bouchard, M.E. Toubert, Bone metastases of differentiated thyroid cancer: impact of early 131I-based detection on outcome. Endocr. Rel. Cancer 14, 799–807 (2007)CrossRefGoogle Scholar
  22. 22.
    F.A. Verburg, C. Aktolun, A. Chiti, S. Frangos, L. Giovanella, M. Hoffmann, I. Iakovou, J. Mihailovic, B.J. Krause, W. Langsteger, M. Luster, Why the European Association of Nuclear Medicine has declined to endorse the 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Eur. J. Nucl. Med. Mol. Imaging 43, 1001–1005 (2016)CrossRefPubMedGoogle Scholar
  23. 23.
    R. Harel, L. Angelov, Spine metastases: current treatments and future directions. Eur. J. Cancer 46, 2696–2707 (2010)CrossRefPubMedGoogle Scholar
  24. 24.
    S. Bonadonna, G. Mazziotti, M. Nuzzo, A. Bianchi, A. Fusco, L. De Marinis, A. Giustina, Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women. J. Bone Miner. Res. 20, 1837–1844 (2005)CrossRefPubMedGoogle Scholar
  25. 25.
    T. Mancini, G. Mazziotti, M. Doga, R. Carpinteri, N. Simetovic, P.P. Vescovi, A. Giustina, Vertebral fractures in males with type 2 diabetes treated with rosiglitazone. Bone 45, 784–788 (2009)CrossRefPubMedGoogle Scholar
  26. 26.
    G. Mazziotti, T. Porcelli, M. Mormando, E. De Menis, A. Bianchi, C. Mejia, T. Mancini, L. De Marinis, A. Giustina, Vertebral fractures in males with prolactinoma. Endocrine 39, 288–293 (2011)CrossRefPubMedGoogle Scholar
  27. 27.
    G. Mazziotti, M. Baracca, M. Doga, T. Porcelli, P.P. Vescovi, A. Giustina, Prevalence of thoracic vertebral fractures in hospitalized elderly patients with heart failure. Eur. J. Endocrinol. 167, 865–872 (2012)CrossRefPubMedGoogle Scholar
  28. 28.
    C. Torti, G. Mazziotti, P.A. Soldini, E. Focà, R. Maroldi, D. Gotti, G. Carosi, A. Giustina, High prevalence of radiological vertebral fractures in HIV-infected males. Endocrine 41, 512–517 (2012)CrossRefPubMedGoogle Scholar
  29. 29.
    G. Mazziotti, A. Bianchi, T. Porcelli, M. Mormando, F. Maffezzoni, A. Cristiano, A. Giampietro, L. De Marinis, A. Giustina, Vertebral fractures in patients with acromegaly: a 3-year prospective study. J. Clin. Endocrinol. Metab. 98, 3402–3410 (2013)CrossRefPubMedGoogle Scholar
  30. 30.
    G. Mazziotti, M. Doga, S. Frara, F. Maffezzoni, T. Porcelli, L. Cerri, R. Maroldi, A. Giustina, Incidence of morphometric vertebral fractures in adult patients with growth hormone deficiency. Endocrine 52, 103–110 (2016)CrossRefPubMedGoogle Scholar
  31. 31.
    G. Mazziotti, C. Dordoni, M. Doga, F. Galderisi, M. Venturini, P. Calzavara-Pinton, R. Maroldi, A. Giustina, M. Colombi, High prevalence of radiological vertebral fractures in adult patients with Ehlers-Danlos syndrome. Bone 84, 88–92 (2016)CrossRefPubMedGoogle Scholar
  32. 32.
    R. Pedersini, S. Monteverdi, G. Mazziotti, V. Amoroso, E. Roca, F. Maffezzoni, L. Vassalli, F. Rodella, A.M. Formenti, S. Frara, R. Maroldi, A. Berruti, E. Simoncini, A. Giustina, Morphometric vertebral fractures in breast cancer patients treated with adjuvant aromatase inhibitor therapy: a cross-sectional study. Bone 97, 147–152 (2017)CrossRefPubMedGoogle Scholar
  33. 33.
    G. Mazziotti, F. Sorvillo, M. Piscopo, M. Cioffi, P. Pilla, B. Biondi, S. Iorio, A. Giustina, G. Amato, C. Carella, Recombinant human TSH modulates in vivo C-telopeptides of type-1 collagen and bone alkaline phosphatase, but not osteoprotegerin production in postmenopausal women monitored for differentiated thyroid carcinoma. J. Bone Miner. Res. 20, 480–486 (2005)CrossRefPubMedGoogle Scholar
  34. 34.
    G. Mazziotti, T. Porcelli, I. Patelli, P.P. Vescovi, A. Giustina, Serum TSH values and risk of vertebral fractures in euthyroid post-menopausal women with low bone mineral density. Bone 46, 747–751 (2010)CrossRefPubMedGoogle Scholar
  35. 35.
    G. Mazziotti, M. Mormando, A. Cristiano, A. Bianchi, T. Porcelli, A. Giampietro, F. Maffezzoni, V. Serra, L. De Marinis, A. Giustina, Association between l-thyroxine treatment, GH deficiency, and radiological vertebral fractures in patients with adult-onset hypopituitarism. Eur. J. Endocrinol. 170, 893–899 (2014)CrossRefPubMedGoogle Scholar
  36. 36.
    M.O. Bernier, L. Leenhardt, C. Hoang, A. Aurengo, J.Y. Mary, F. Menegaux, E. Enkaoua, G. Turpin, J. Chiras, G. Saillant, G. Hejblum, Survival and therapeutic modalities in patients with bone metastases of differentiated thyroid carcinomas. J. Clin. Endocrinol. Metab. 86, 1568–1573 (2001)CrossRefPubMedGoogle Scholar
  37. 37.
    G. Zettinig, B.J. Fueger, C. Passler, K. Kaserer, C. Pirich, R. Dudczak, B. Niederle, Long-term follow-up of patients with bone metastases from differentiated thyroid carcinoma—surgery or conventional therapy? Clin. Endocrinol. 56, 377–382 (2002)CrossRefGoogle Scholar
  38. 38.
    S. Ramadan, M.A. Ugas, R.J. Berwick, M. Notay, H. Cho, W. Jerjes, P.V. Giannoudis, Spinal metastasis in thyroid cancer. Head Neck Oncol. 4, 39 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    R.J. Weiss, W. Ekström, B.H. Hansen, J. Keller, M. Laitinen, C. Trovik, O. Zaikova, R. Wedin, Pathological subtrochanteric fractures in 194 patients: a comparison of outcome after surgical treatment of pathological and non-pathological fractures. J. Surg. Oncol. 107, 498–504 (2013)CrossRefPubMedGoogle Scholar
  40. 40.
    T. Smith, K. Pelpola, M. Ball, A. Ong, P.K. Myint, Pre-operative indicators for mortality following hip fracture surgery: a systematic review and meta-analysis. Age Ageing 43, 464–471 (2014)CrossRefPubMedGoogle Scholar
  41. 41.
    O. Kilci, C. Un, O. Sacan, M. Gamli, S. Baskan, M. Baydar, B. Ozkurt, Postoperative mortality after hip fracture surgery: a 3 years follow -up. PLoS ONE 27. 11, e0162097 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Y.M. Choi, W.G. Kim, H. Kwon, M.J. Jeon, J.J. Lee, J.S. Ryu, E.G. Hong, T.Y. Kim, Y.K. Shong, W.B. Kim, Early prognostic factors at the time of diagnosis of bone metastasis in patients with bone metastases of differentiated thyroid carcinoma. Eur. J. Endocrinol. 175, 165–172 (2016)CrossRefPubMedGoogle Scholar
  43. 43.
    Z.L. Qiu, H.J. Song, Y.H. Xu, Q.Y. Luo, Efficacy and survival analysis of 131I therapy for bone metastases from differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 96, 3078–3086 (2011)CrossRefPubMedGoogle Scholar
  44. 44.
    G.D. Roodman, Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004)CrossRefPubMedGoogle Scholar
  45. 45.
    K. Fizazi, A. Lipton, X. Mariette, J.J. Body, Y. Rahim, J.R. Gralow, G. Gao, L. Wu, W. Sohn, S. Jun, Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J. Clin. Oncol. 27, 1564–1571 (2009)CrossRefPubMedGoogle Scholar
  46. 46.
    G. Mazziotti, E. Canalis, A. Giustina, Drug-induced osteoporosis: mechanisms and clinical implications. Am. J. Med. 123, 877–884 (2010)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • G. Mazziotti
    • 1
  • A. M. Formenti
    • 2
    • 3
  • M. B. Panarotto
    • 3
    • 4
  • E. Arvat
    • 5
  • A. Chiti
    • 6
    • 7
  • A. Cuocolo
    • 8
  • M. E. Dottorini
    • 9
  • C. Durante
    • 10
  • L. Agate
    • 11
  • S. Filetti
    • 10
  • F. Felicetti
    • 5
  • A. Filice
    • 12
  • L. Pace
    • 13
  • T. Pellegrino
    • 14
  • M. Rodari
    • 6
  • M. Salvatori
    • 15
  • C. Tranfaglia
    • 9
  • A. Versari
    • 12
  • D. Viola
    • 11
  • S. Frara
    • 16
  • A. Berruti
    • 17
  • A. Giustina
    • 16
  • R. Giubbini
    • 3
    • 4
  1. 1.Endocrine Unit, ASST Carlo PomaMantuaItaly
  2. 2.Department of Molecular and Translational MedicineUniversity of BresciaBresciaItaly
  3. 3.Nuclear Medicine, ASST Spedali Civili of BresciaBresciaItaly
  4. 4.Nuclear Medicine, University of BresciaBresciaItaly
  5. 5.Oncological Endocrinology, University of TurinTorinoItaly
  6. 6.Nuclear Medicine, Humanitas Research Hospital and Humanitas UniversityMilanItaly
  7. 7.Humanitas UniversityMilanItaly
  8. 8.Nuclear Medicine, University of Naples Federico IINapoliItaly
  9. 9.Nuclear Medicine, “S. Maria della Misericordia” HospitalPerugiaItaly
  10. 10.Internal Medicine, University Sapienza of RomeRomaItaly
  11. 11.Endocrinology Unit, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  12. 12.Nuclear Medicine, Azienda Ospedaliera Santa Maria Nuova—IRCCS Reggio EmiliaReggio EmiliaItaly
  13. 13.Department of Medicine and SurgeryUniversity of SalernoFiscianoItaly
  14. 14.Institute of Biostructure and Bioimaging of the National Research Council of Italy—CNRNaplesItaly
  15. 15.Nuclear Medicine, Catholic University of Sacred HeartRomeItaly
  16. 16.San Raffaele Vita-Salute UniversityMilanItaly
  17. 17.Medical Oncology, Department of Medical and Surgical SpecialtiesRadiological Sciences, and Public Health, University of BresciaBresciaItaly

Personalised recommendations