Update on vertebral fractures in pituitary diseases: from research to clinical practice

Abstract

Derangement of pituitary hormone axes can induce changes in bone remodeling and metabolism with possible alterations in bone microarchitectural structure and increased susceptibility to fractures. Vertebral fractures (VFs), which are a hallmark of skeletal fragility, have been described in a very large number of patients with pituitary diseases. These fractures are clinically relevant, since they predispose to further fractures and may negatively impact on patients’ quality of life. However, the management of skeletal fragility and VFs in the specific setting of pituitary diseases is a challenge, since the awareness for this disease is still low, prediction of VFs is uncertain, the diagnosis of VFs cannot be solely based on a clinical approach and also needs a radiological and morphometric approach, the risk of fractures may not be decreased via treatment of pituitary hormone disorders, and the effectiveness of bone-active drugs in this setting is not always evidence-based. This review is an update on skeletal fragility in patients with pituitary diseases, with a focus on clinical and therapeutic aspects concerning the management of VFs.

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References

  1. 1.

    Mazziotti G, Frara S, Giustina A (2018) Pituitary Diseases and Bone. Endocr Rev 39(4):440–488. https://doi.org/10.1210/er.2018-00005

    Article  PubMed  Google Scholar 

  2. 2.

    Cooper C, Atkinson EJ, O'Fallon WM, Melton LJ 3rd (1992) Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985-1989. J Bone Miner Res 7(2):221–227. https://doi.org/10.1002/jbmr.5650070214

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Melton LJ 3rd (2003) Adverse outcomes of osteoporotic fractures in the general population. J Bone Miner Res 18(6):1139–1141. https://doi.org/10.1359/jbmr.2003.18.6.1139

    Article  PubMed  Google Scholar 

  4. 4.

    Vasikaran SD, Chubb SA (2016) The use of biochemical markers of bone turnover in the clinical management of primary and secondary osteoporosis. Endocrine 52(2):222–225. https://doi.org/10.1007/s12020-016-0900-2

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Schousboe JT, Shepherd JA, Bilezikian JP, Baim S (2013) Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry. J Clin Densitom 16(4):455–466. https://doi.org/10.1016/j.jocd.2013.08.004

    Article  PubMed  Google Scholar 

  6. 6.

    Stone KL, Seeley DG, Lui LY, Cauley JA, Ensrud K, Browner WS, Nevitt MC, Cummings SR (2003) BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res 18(11):1947–1954. https://doi.org/10.1359/jbmr.2003.18.11.1947

    Article  PubMed  Google Scholar 

  7. 7.

    Griffith JF, Genant HK (2012) New advances in imaging osteoporosis and its complications. Endocrine 42(1):39–51. https://doi.org/10.1007/s12020-012-9691-2

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Trementino L, Appolloni G, Ceccoli L, Marcelli G, Concettoni C, Boscaro M, Arnaldi G (2014) Bone complications in patients with Cushing's syndrome: looking for clinical, biochemical, and genetic determinants. Osteoporos Int 25(3):913–921. https://doi.org/10.1007/s00198-013-2520-5

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Valassi E, Santos A, Yaneva M, Toth M, Strasburger CJ, Chanson P, Wass JA, Chabre O, Pfeifer M, Feelders RA, Tsagarakis S, Trainer PJ, Franz H, Zopf K, Zacharieva S, Lamberts SW, Tabarin A, Webb SM (2011) The European Registry on Cushing's syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur J Endocrinol 165(3):383–392. https://doi.org/10.1530/eje-11-0272

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Tauchmanova L, Pivonello R, Di Somma C, Rossi R, De Martino MC, Camera L, Klain M, Salvatore M, Lombardi G, Colao A (2006) Bone demineralization and vertebral fractures in endogenous cortisol excess: role of disease etiology and gonadal status. J Clin Endocrinol Metab 91(5):1779–1784. https://doi.org/10.1210/jc.2005-0582

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Belaya ZE, Hans D, Rozhinskaya LY, Dragunova NV, Sasonova NI, Solodovnikov AG, Tsoriev TT, Dzeranova LK, Melnichenko GA, Dedov II (2015) The risk factors for fractures and trabecular bone-score value in patients with endogenous Cushing's syndrome. Arch Osteoporos 10:44. https://doi.org/10.1007/s11657-015-0244-1

    Article  PubMed  Google Scholar 

  12. 12.

    Mazziotti G, Biagioli E, Maffezzoni F, Spinello M, Serra V, Maroldi R, Floriani I, Giustina A (2015) Bone turnover, bone mineral density, and fracture risk in acromegaly: a meta-analysis. J Clin Endocrinol Metab 100(2):384–394. https://doi.org/10.1210/jc.2014-2937

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Mazziotti G, Bianchi A, Bonadonna S, Nuzzo M, Cimino V, Fusco A, De Marinis L, Giustina A (2006) Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy. J Bone Miner Res 21(4):520–528. https://doi.org/10.1359/jbmr.060112

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Marques A, Ferreira RJ, Santos E, Loza E, Carmona L, da Silva JA (2015) The accuracy of osteoporotic fracture risk prediction tools: a systematic review and meta-analysis. Ann Rheum Dis 74(11):1958–1967. https://doi.org/10.1136/annrheumdis-2015-207907

    Article  PubMed  Google Scholar 

  15. 15.

    Mikolajewicz N, Bishop N, Burghardt AJ, Folkestad L, Hall A, Kozloff KM, Lukey PT, Molloy-Bland M, Morin SN, Offiah AC, Shapiro J, van Rietbergen B, Wager K, Willie BM, Komarova SV, Glorieux FH (2020) HR-pQCT Measures of bone microarchitecture predict fracture: systematic review and meta-analysis. J Bone Miner Res 35(3):446–459. https://doi.org/10.1002/jbmr.3901

    Article  PubMed  Google Scholar 

  16. 16.

    McCloskey EV, Odén A, Harvey NC, Leslie WD, Hans D, Johansson H, Barkmann R, Boutroy S, Brown J, Chapurlat R, Elders PJM, Fujita Y, Glüer CC, Goltzman D, Iki M, Karlsson M, Kindmark A, Kotowicz M, Kurumatani N, Kwok T, Lamy O, Leung J, Lippuner K, Ljunggren Ö, Lorentzon M, Mellström D, Merlijn T, Oei L, Ohlsson C, Pasco JA, Rivadeneira F, Rosengren B, Sornay-Rendu E, Szulc P, Tamaki J, Kanis JA (2016) A Meta-Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX. J Bone Miner Res 31(5):940–948. https://doi.org/10.1002/jbmr.2734

    Article  PubMed  Google Scholar 

  17. 17.

    Ulivieri FM, Silva BC, Sardanelli F, Hans D, Bilezikian JP, Caudarella R (2014) Utility of the trabecular bone score (TBS) in secondary osteoporosis. Endocrine 47(2):435–448. https://doi.org/10.1007/s12020-014-0280-4

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Prince RL, Lewis JR, Lim WH, Wong G, Wilson KE, Khoo BC, Zhu K, Kiel DP, Schousboe JT (2019) Adding Lateral Spine Imaging for Vertebral Fractures to Densitometric Screening: Improving Ascertainment of Patients at High Risk of Incident Osteoporotic Fractures. J Bone Miner Res 34(2):282–289. https://doi.org/10.1002/jbmr.3595

    Article  PubMed  Google Scholar 

  19. 19.

    Lindsay R, Silverman SL, Cooper C, Hanley DA, Barton I, Broy SB, Licata A, Benhamou L, Geusens P, Flowers K, Stracke H, Seeman E (2001) Risk of new vertebral fracture in the year following a fracture. Jama 285(3):320–323. https://doi.org/10.1001/jama.285.3.320

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Kanis JA, McCloskey EV, Johansson H, Cooper C, Rizzoli R, Reginster JY (2013) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 24(1):23–57. https://doi.org/10.1007/s00198-012-2074-y

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Clark EM, Carter L, Gould VC, Morrison L, Tobias JH (2014) Vertebral fracture assessment (VFA) by lateral DXA scanning may be cost-effective when used as part of fracture liaison services or primary care screening. Osteoporos Int 25(3):953–964. https://doi.org/10.1007/s00198-013-2567-3

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Cellini M, Biamonte E, Mazza M, Trenti N, Ragucci P, Milani D, Ferrante E, Rossini Z, Lavezzi E, Sala E, Mantovani G, Arosio M, Fornari M, Balzarini L, Lania AG, Mazziotti G (2020) Vertebral fractures associated with spinal sagittal imbalance and quality of life in acromegaly: a radiographic study with eos 2d/3d technology. Neuroendocrinology. https://doi.org/10.1159/000511811

  23. 23.

    Jensen GF, McNair P, Boesen J, Hegedüs V (1984) Validity in diagnosing osteoporosis. Observer variation in interpreting spinal radiographs. Eur J Radiol 4(1):1–3

    CAS  PubMed  Google Scholar 

  24. 24.

    Lentle B, Koromani F, Brown JP, Oei L, Ward L, Goltzman D, Rivadeneira F, Leslie WD, Probyn L, Prior J, Hammond I, Cheung AM, Oei EH (2019) The Radiology of Osteoporotic Vertebral Fractures Revisited. J Bone Miner Res 34(3):409–418. https://doi.org/10.1002/jbmr.3669

    Article  PubMed  Google Scholar 

  25. 25.

    Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RS, Black D, Cummings SR (1996) Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis The Study of Osteoporotic Fractures Research Group. J Bone Miner Res 11(7):984–996. https://doi.org/10.1002/jbmr.5650110716

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Jiang G, Eastell R, Barrington NA, Ferrar L (2004) Comparison of methods for the visual identification of prevalent vertebral fracture in osteoporosis. Osteoporos Int 15(11):887–896. https://doi.org/10.1007/s00198-004-1626-1

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Delmas PD, van de Langerijt L, Watts NB, Eastell R, Genant H, Grauer A, Cahall DL (2005) Underdiagnosis of vertebral fractures is a worldwide problem: the IMPACT study. J Bone Miner Res 20(4):557–563. https://doi.org/10.1359/jbmr.041214

    Article  PubMed  Google Scholar 

  28. 28.

    Szulc P (2018) Vertebral Fracture: Diagnostic Difficulties of a Major Medical Problem. J Bone Miner Res 33(4):553–559. https://doi.org/10.1002/jbmr.3404

    Article  PubMed  Google Scholar 

  29. 29.

    Ahmadi SA, Takahashi S, Hoshino M, Takayama K, Sasaoka R, Tsujio T, Yasuda H, Kanematsu F, Kono H, Toyoda H, Nakamura H (2019) Association between MRI findings and back pain after osteoporotic vertebral fractures: a multicenter prospective cohort study. Spine J 19(7):1186–1193. https://doi.org/10.1016/j.spinee.2019.02.007

    Article  PubMed  Google Scholar 

  30. 30.

    Mazziotti G, Lania A, Canalis E (2019) MANAGEMENT OF ENDOCRINE DISEASE: Bone disorders associated with acromegaly: mechanisms and treatment. Eur J Endocrinol. https://doi.org/10.1530/eje-19-0184

  31. 31.

    Lim SV, Marenzana M, Hopkinson M, List EO, Kopchick JJ, Pereira M, Javaheri B, Roux JP, Chavassieux P, Korbonits M, Chenu C (2015) Excessive growth hormone expression in male GH transgenic mice adversely alters bone architecture and mechanical strength. Endocrinology 156(4):1362–1371. https://doi.org/10.1210/en.2014-1572

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Dalle Carbonare L, Micheletti V, Cosaro E, Valenti MT, Mottes M, Francia G, Davi MV (2018) Bone histomorphometry in acromegaly patients with fragility vertebral fractures. Pituitary 21(1):56–64. https://doi.org/10.1007/s11102-017-0847-1

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Maffezzoni F, Maddalo M, Frara S, Mezzone M, Zorza I, Baruffaldi F, Doglietto F, Mazziotti G, Maroldi R, Giustina A (2016) High-resolution-cone beam tomography analysis of bone microarchitecture in patients with acromegaly and radiological vertebral fractures. Endocrine 54(2):532–542. https://doi.org/10.1007/s12020-016-1078-3

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Malgo F, Hamdy NA, Rabelink TJ, Kroon HM, Claessen KM, Pereira AM, Biermasz NR, Appelman-Dijkstra NM (2017) Bone material strength index as measured by impact microindentation is altered in patients with acromegaly. Eur J Endocrinol 176(3):339–347. https://doi.org/10.1530/eje-16-0808

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Kuzma M, Killinger Z, Jackuliak P, Vanuga P, Hans D, Binkley N, Payer J (2019) Pathophysiology of growth hormone secretion disorders and their impact on bone microstructure as measured by trabecular bone score. Physiol Res 68(Suppl 2):S121–s129. https://doi.org/10.33549/physiolres.934303

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Bonadonna S, Mazziotti G, Nuzzo M, Bianchi A, Fusco A, De Marinis L, Giustina A (2005) Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women. J Bone Miner Res 20(10):1837–1844. https://doi.org/10.1359/jbmr.050603

    Article  PubMed  Google Scholar 

  37. 37.

    Mazziotti G, Bianchi A, Bonadonna S, Cimino V, Patelli I, Fusco A, Pontecorvi A, De Marinis L, Giustina A (2008) Prevalence of vertebral fractures in men with acromegaly. J Clin Endocrinol Metab 93(12):4649–4655. https://doi.org/10.1210/jc.2008-0791

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Battista C, Chiodini I, Muscarella S, Guglielmi G, Mascia ML, Carnevale V, Scillitani A (2009) Spinal volumetric trabecular bone mass in acromegalic patients: a longitudinal study. Clin Endocrinol 70(3):378–382. https://doi.org/10.1111/j.1365-2265.2008.03322.x

    Article  Google Scholar 

  39. 39.

    Padova G, Borzì G, Incorvaia L, Siciliano G, Migliorino V, Vetri M, Tita P (2011) Prevalence of osteoporosis and vertebral fractures in acromegalic patients. Clin Cases Min Bone Metab 8(3):37–43

    Google Scholar 

  40. 40.

    Wassenaar MJ, Biermasz NR, Hamdy NA, Zillikens MC, van Meurs JB, Rivadeneira F, Hofman A, Uitterlinden AG, Stokkel MP, Roelfsema F, Kloppenburg M, Kroon HM, Romijn JA, Pereira AM (2011) High prevalence of vertebral fractures despite normal bone mineral density in patients with long-term controlled acromegaly. Eur J Endocrinol 164(4):475–483. https://doi.org/10.1530/eje-10-1005

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Mazziotti G, Gola M, Bianchi A, Porcelli T, Giampietro A, Cimino V, Doga M, Gazzaruso C, De Marinis L, Giustina A (2011) Influence of diabetes mellitus on vertebral fractures in men with acromegaly. Endocrine 40(1):102–108. https://doi.org/10.1007/s12020-011-9486-x

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Madeira M, Neto LV, Torres CH, de Mendonça LM, Gadelha MR, de Farias ML (2013) Vertebral fracture assessment in acromegaly. J Clin Densitom 16(2):238–243. https://doi.org/10.1016/j.jocd.2012.06.002

    Article  PubMed  Google Scholar 

  43. 43.

    Claessen KM, Kroon HM, Pereira AM, Appelman-Dijkstra NM, Verstegen MJ, Kloppenburg M, Hamdy NA, Biermasz NR (2013) Progression of vertebral fractures despite long-term biochemical control of acromegaly: a prospective follow-up study. J Clin Endocrinol Metab 98(12):4808–4815. https://doi.org/10.1210/jc.2013-2695

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Mazziotti G, Bianchi A, Porcelli T, Mormando M, Maffezzoni F, Cristiano A, Giampietro A, De Marinis L, Giustina A (2013) Vertebral fractures in patients with acromegaly: a 3-year prospective study. J Clin Endocrinol Metab 98(8):3402–3410. https://doi.org/10.1210/jc.2013-1460

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Brzana J, Yedinak CG, Hameed N, Fleseriu M (2014) FRAX score in acromegaly: does it tell the whole story? Clin Endocrinol 80(4):614–616. https://doi.org/10.1111/cen.12262

    Article  Google Scholar 

  46. 46.

    Mormando M, Nasto LA, Bianchi A, Mazziotti G, Giampietro A, Pola E, Pontecorvi A, Giustina A, De Marinis L (2014) GH receptor isoforms and skeletal fragility in acromegaly. Eur J Endocrinol 171(2):237–245. https://doi.org/10.1530/eje-14-0205

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Chiloiro S, Mormando M, Bianchi A, Giampietro A, Milardi D, Bima C, Grande G, Formenti AM, Mazziotti G, Pontecorvi A, Giustina A, De Marinis L (2018) Prevalence of morphometric vertebral fractures in "difficult" patients with acromegaly with different biochemical outcomes after multimodal treatment. Endocrine 59(2):449–453. https://doi.org/10.1007/s12020-017-1391-5

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Chiloiro S, Mazziotti G, Giampietro A, Bianchi A, Frara S, Mormando M, Pontecorvi A, Giustina A, De Marinis L (2018) Effects of pegvisomant and somatostatin receptor ligands on incidence of vertebral fractures in patients with acromegaly. Pituitary 21(3):302–308. https://doi.org/10.1007/s11102-018-0873-7

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Pelsma ICM, Biermasz NR, Pereira AM, van Furth WR, Appelman-Dijkstra NM, Kloppenburg M, Kroon HM, Claessen K (2020) Progression of vertebral fractures in long-term controlled acromegaly: a 9-year follow-up study. Eur J Endocrinol 183(4):427–437. https://doi.org/10.1530/eje-20-0415

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Mazziotti G, Battista C, Maffezzoni F, Chiloiro S, Ferrante E, Prencipe N, Grasso L, Gatto F, Olivetti R, Arosio M, Barale M, Bianchi A, Cellini M, Chiodini I, De Marinis L, Del Sindaco G, Di Somma C, Ferlin A, Ghigo E, Giampietro A, Grottoli S, Lavezzi E, Mantovani G, Morenghi E, Pivonello R, Porcelli T, Procopio M, Pugliese F, Scillitani A, Lania AG (2020) Treatment of Acromegalic Osteopathy in Real-Life Clinical Practice: The BAAC (Bone Active drugs in ACromegaly) Study. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgaa363

  51. 51.

    Plard C, Hochman C, Hadjadj S, Goff BL, Maugars Y, Cariou B, Drui D, Guillot P (2020) Acromegaly is associated with vertebral deformations but not vertebral fractures: results of a cross-sectional monocentric study. Joint Bone Spine. https://doi.org/10.1016/j.jbspin.2020.04.020

  52. 52.

    Chiloiro S, Giampietro A, Frara S, Bima C, Donfrancesco F, Fleseriu CM, Pontecorvi A, Giustina A, Fleseriu M, De Marinis L, Bianchi A (2020) Effects of Pegvisomant and Pasireotide LAR on Vertebral Fractures in Acromegaly Resistant to First-generation SRLs. J Clin Endocrinol Metab 105(3). https://doi.org/10.1210/clinem/dgz054

  53. 53.

    de Azevedo Oliveira B, Araujo B, Dos Santos TM, Ongaratti BR, Rech C, Ferreira NP, Pereira-Lima JFS, da Costa Oliveira M (2019) The acromegalic spine: fractures, deformities and spinopelvic balance. Pituitary 22(6):601–606. https://doi.org/10.1007/s11102-019-00991-7

    Article  PubMed  Google Scholar 

  54. 54.

    Kuzma M, Vanuga P, Sagova I, Pavai D, Jackuliak P, Killinger Z, Binkley NC, Winzenrieth R, Genant HK, Payer J (2019) Non-invasive DXA-derived bone structure assessment of acromegaly patients: a cross-sectional study. Eur J Endocrinol 180(3):201–211. https://doi.org/10.1530/eje-18-0881

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Godang K, Lekva T, Normann KR, Olarescu NC, Oystese KAB, Kolnes A, Ueland T, Bollerslev J, Heck A (2019) Hip Structure Analyses in Acromegaly: Decrease of Cortical Bone Thickness After Treatment: A Longitudinal Cohort Study. JBMR Plus 3(12):e10240. https://doi.org/10.1002/jbm4.10240

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Valenti MT, Mottes M, Cheri S, Deiana M, Micheletti V, Cosaro E, Davi MV, Francia G, Dalle Carbonare L (2018) Runx2 overexpression compromises bone quality in acromegalic patients. Endocr Relat Cancer 25(3):269–277. https://doi.org/10.1530/erc-17-0523

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Briggs AM, Greig AM, Wark JD (2007) The vertebral fracture cascade in osteoporosis: a review of aetiopathogenesis. Osteoporos Int 18(5):575–584. https://doi.org/10.1007/s00198-006-0304-x

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Hu Z, Man GCW, Kwok AKL, Law SW, Chu WWC, Cheung WH, Qiu Y, Cheng JCY (2018) Global sagittal alignment in elderly patients with osteoporosis and its relationship with severity of vertebral fracture and quality of life. Arch Osteoporos 13(1):95. https://doi.org/10.1007/s11657-018-0512-y

    Article  PubMed  Google Scholar 

  59. 59.

    Giustina A, Barkan A, Beckers A, Biermasz N, Biller BMK, Boguszewski C, Bolanowski M, Bonert V, Bronstein MD, Casanueva FF, Clemmons D, Colao A, Ferone D, Fleseriu M, Frara S, Gadelha MR, Ghigo E, Gurnell M, Heaney AP, Ho K, Ioachimescu A, Katznelson L, Kelestimur F, Kopchick J, Krsek M, Lamberts S, Losa M, Luger A, Maffei P, Marazuela M, Mazziotti G, Mercado M, Mortini P, Neggers S, Pereira AM, Petersenn S, Puig-Domingo M, Salvatori R, Shimon I, Strasburger C, Tsagarakis S, van der Lely AJ, Wass J, Zatelli MC, Melmed S (2020) A Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities: An Update. J Clin Endocrinol Metab 105(4). https://doi.org/10.1210/clinem/dgz096

  60. 60.

    Fleseriu M, Biller BMK, Freda PU, Gadelha MR, Giustina A, Katznelson L, Molitch ME, Samson SL, Strasburger CJ, van der Lely AJ, Melmed S (2020) A Pituitary Society update to acromegaly management guidelines. Pituitary. https://doi.org/10.1007/s11102-020-01091-7

  61. 61.

    Chiodini I, Carnevale V, Torlontano M, Fusilli S, Guglielmi G, Pileri M, Modoni S, Di Giorgio A, Liuzzi A, Minisola S, Cammisa M, Trischitta V, Scillitani A (1998) Alterations of bone turnover and bone mass at different skeletal sites due to pure glucocorticoid excess: study in eumenorrheic patients with Cushing's syndrome. J Clin Endocrinol Metab 83(6):1863–1867. https://doi.org/10.1210/jcem.83.6.4880

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Di Somma C, Pivonello R, Loche S, Faggiano A, Klain M, Salvatore M, Lombardi G, Colao A (2003) Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing's disease: a prospective study. Clin Endocrinol 58(3):302–308

    Article  Google Scholar 

  63. 63.

    Vinolas H, Grouthier V, Mehsen-Cetre N, Boisson A, Winzenrieth R, Schaeverbeke T, Mesguich C, Bordenave L, Tabarin A (2018) Assessment of vertebral microarchitecture in overt and mild Cushing's syndrome using trabecular bone score. Clin Endocrinol 89(2):148–154. https://doi.org/10.1111/cen.13743

    Article  Google Scholar 

  64. 64.

    Ferraù F, Giovinazzo S, Messina E, Tessitore A, Vinci S, Mazziotti G, Lania A, Granata F, Cannavò S (2020) High bone marrow fat in patients with Cushing's syndrome and vertebral fractures. Endocrine 67(1):172–179. https://doi.org/10.1007/s12020-019-02034-4

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    dos Santos CV, Vieira Neto L, Madeira M, Alves Coelho MC, de Mendonca LM, Paranhos-Neto Fde P, Lima IC, Gadelha MR, Farias ML (2015) Bone density and microarchitecture in endogenous hypercortisolism. Clin Endocrinol 83(4):468–474. https://doi.org/10.1111/cen.12812

    CAS  Article  Google Scholar 

  66. 66.

    Vestergaard P, Lindholm J, Jorgensen JO, Hagen C, Hoeck HC, Laurberg P, Rejnmark L, Brixen K, Kristensen LO, Feldt-Rasmussen U, Mosekilde L (2002) Increased risk of osteoporotic fractures in patients with Cushing's syndrome. Eur J Endocrinol 146(1):51–56

    CAS  Article  Google Scholar 

  67. 67.

    Faggiano A, Pivonello R, Filippella M, Di Somma C, Orio F Jr, Lombard G, Colao A (2001) Spine abnormalities and damage in patients cured from Cushing's disease. Pituitary 4(3):153–161

    CAS  Article  Google Scholar 

  68. 68.

    Tauchmanova L, Pivonello R, De Martino MC, Rusciano A, De Leo M, Ruosi C, Mainolfi C, Lombardi G, Salvatore M, Colao A (2007) Effects of sex steroids on bone in women with subclinical or overt endogenous hypercortisolism. Eur J Endocrinol 157(3):359–366. https://doi.org/10.1530/eje-07-0137

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Braun LT, Fazel J, Zopp S, Benedix S, Osswald-Kopp A, Riester A, Rubinstein G, Seidensticker M, Beuschlein F, Drey M, Bidlingmaier M, Schmidmaier R, Reincke M (2020) The Effect of Biochemical Remission on Bone Metabolism in Cushing's Syndrome: A 2-Year Follow-Up Study. J Bone Miner Res 35(9):1711–1717. https://doi.org/10.1002/jbmr.4033

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Kristo C, Jemtland R, Ueland T, Godang K, Bollerslev J (2006) Restoration of the coupling process and normalization of bone mass following successful treatment of endogenous Cushing's syndrome: a prospective, long-term study. Eur J Endocrinol 154(1):109–118. https://doi.org/10.1530/eje.1.02067

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Randazzo ME, Grossrubatscher E, Dalino Ciaramella P, Vanzulli A, Loli P (2012) Spontaneous recovery of bone mass after cure of endogenous hypercortisolism. Pituitary 15(2):193–201. https://doi.org/10.1007/s11102-011-0306-3

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Scillitani A, Mazziotti G, Di Somma C, Moretti S, Stigliano A, Pivonello R, Giustina A, Colao A (2014) Treatment of skeletal impairment in patients with endogenous hypercortisolism: when and how? Osteoporos Int 25(2):441–446. https://doi.org/10.1007/s00198-013-2588-y

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Klibanski A, Biller BM, Rosenthal DI, Schoenfeld DA, Saxe V (1988) Effects of prolactin and estrogen deficiency in amenorrheic bone loss. J Clin Endocrinol Metab 67(1):124–130. https://doi.org/10.1210/jcem-67-1-124

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Clement-Lacroix P, Ormandy C, Lepescheux L, Ammann P, Damotte D, Goffin V, Bouchard B, Amling M, Gaillard-Kelly M, Binart N, Baron R, Kelly PA (1999) Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice. Endocrinology 140(1):96–105. https://doi.org/10.1210/endo.140.1.6436

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Di Somma C, Colao A, Di Sarno A, Klain M, Landi ML, Facciolli G, Pivonello R, Panza N, Salvatore M, Lombardi G (1998) Bone marker and bone density responses to dopamine agonist therapy in hyperprolactinemic males. J Clin Endocrinol Metab 83(3):807–813. https://doi.org/10.1210/jcem.83.3.4674

    Article  PubMed  Google Scholar 

  76. 76.

    Naliato EC, Farias ML, Braucks GR, Costa FS, Zylberberg D, Violante AH (2005) Prevalence of osteopenia in men with prolactinoma. J Endocrinol Investig 28(1):12–17

    CAS  Article  Google Scholar 

  77. 77.

    Vestergaard P, Jorgensen JO, Hagen C, Hoeck HC, Laurberg P, Rejnmark L, Brixen K, Weeke J, Andersen M, Conceicao FL, Nielsen TL, Mosekilde L (2002) Fracture risk is increased in patients with GH deficiency or untreated prolactinomas--a case-control study. Clin Endocrinol 56(2):159–167

    Article  Google Scholar 

  78. 78.

    Soto-Pedre E, Newey PJ, Bevan JS, Leese GP (2017) Morbidity and mortality in patients with hyperprolactinaemia: the PROLEARS study. Endocrine Connect 6(8):580–588. https://doi.org/10.1530/ec-17-0171

    CAS  Article  Google Scholar 

  79. 79.

    Mazziotti G, Mancini T, Mormando M, De Menis E, Bianchi A, Doga M, Porcelli T, Vescovi PP, De Marinis L, Giustina A (2011) High prevalence of radiological vertebral fractures in women with prolactin-secreting pituitary adenomas. Pituitary 14(4):299–306. https://doi.org/10.1007/s11102-011-0293-4

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Mazziotti G, Porcelli T, Mormando M, De Menis E, Bianchi A, Mejia C, Mancini T, De Marinis L, Giustina A (2011) Vertebral fractures in males with prolactinoma. Endocrine 39(3):288–293. https://doi.org/10.1007/s12020-011-9462-5

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Klibanski A, Greenspan SL (1986) Increase in bone mass after treatment of hyperprolactinemic amenorrhea. N Engl J Med 315(9):542–546. https://doi.org/10.1056/nejm198608283150903

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    D'Sylva C, Khan T, Van Uum S, Fraser LA (2015) Osteoporotic fractures in patients with untreated hyperprolactinemia vs. those taking dopamine agonists: A systematic review and meta-analysis. Neuro Endocrinol Lett 36(8):745–749

    CAS  PubMed  Google Scholar 

  83. 83.

    Faje AT, Klibanski A (2015) The treatment of hyperprolactinemia in postmenopausal women with prolactin-secreting microadenomas: cons. Endocrine 48(1):79–82. https://doi.org/10.1007/s12020-014-0308-9

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Pekić S, Medic Stojanoska M, Popovic V (2019) Hyperprolactinemia/Prolactinomas in the Postmenopausal Period: Challenges in Diagnosis and Management. Neuroendocrinology 109(1):28–33. https://doi.org/10.1159/000494725

    CAS  Article  PubMed  Google Scholar 

  85. 85.

    Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JA (2011) Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(2):273–288. https://doi.org/10.1210/jc.2010-1692

    CAS  Article  PubMed  Google Scholar 

  86. 86.

    Beck-Peccoz P, Giavoli C, Lania A (2019) A 2019 update on TSH-secreting pituitary adenomas. J Endocrinol Investig 42(12):1401–1406. https://doi.org/10.1007/s40618-019-01066-x

    CAS  Article  Google Scholar 

  87. 87.

    Biondi B, Cooper DS (2008) The clinical significance of subclinical thyroid dysfunction. Endocr Rev 29(1):76–131. https://doi.org/10.1210/er.2006-0043

    CAS  Article  PubMed  Google Scholar 

  88. 88.

    Cellini M, Rotondi M, Tanda ML, Piantanida E, Chiovato L, Beck-Peccoz P, Lania A, Mazziotti G (2020) Skeletal health in patients with differentiated thyroid carcinoma. J Endocrinol Investig. https://doi.org/10.1007/s40618-020-01359-6

  89. 89.

    Bassett JH, Williams GR (2016) Role of Thyroid Hormones in Skeletal Development and Bone Maintenance. Endocr Rev 37(2):135–187. https://doi.org/10.1210/er.2015-1106

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Williams GR, Bassett JHD (2018) Thyroid diseases and bone health. J Endocrinol Investig 41(1):99–109. https://doi.org/10.1007/s40618-017-0753-4

    CAS  Article  Google Scholar 

  91. 91.

    Frara S, Losa M, Doga M, Formenti AM, Mortini P, Mazziotti G, Giustina A (2018) High Prevalence of Radiological Vertebral Fractures in Patients With TSH-Secreting Pituitary Adenoma. J Endocrine Soc 2(9):1089–1099. https://doi.org/10.1210/js.2018-00091

    CAS  Article  Google Scholar 

  92. 92.

    Mazziotti G, Sorvillo F, Piscopo M, Cioffi M, Pilla P, Biondi B, Iorio S, Giustina A, Amato G, Carella C (2005) 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(3):480–486. https://doi.org/10.1359/jbmr.041126

    CAS  Article  PubMed  Google Scholar 

  93. 93.

    Sampath TK, Simic P, Sendak R, Draca N, Bowe AE, O'Brien S, Schiavi SC, McPherson JM, Vukicevic S (2007) Thyroid-stimulating hormone restores bone volume, microarchitecture, and strength in aged ovariectomized rats. J Bone Miner Res 22(6):849–859. https://doi.org/10.1359/jbmr.070302

    CAS  Article  PubMed  Google Scholar 

  94. 94.

    Abe E, Marians RC, Yu W, Wu XB, Ando T, Li Y, Iqbal J, Eldeiry L, Rajendren G, Blair HC, Davies TF, Zaidi M (2003) TSH is a negative regulator of skeletal remodeling. Cell 115(2):151–162. https://doi.org/10.1016/s0092-8674(03)00771-2

    CAS  Article  PubMed  Google Scholar 

  95. 95.

    Mousiolis AC, Rapti E, Grammatiki M, Yavropoulou M, Efstathiou M, Foroglou N, Daniilidis M, Kotsa K (2016) Somatostatin Analogue Treatment of a TSH-Secreting Adenoma Presenting With Accelerated Bone Metabolism and a Pericardial Effusion: A Case Report. Medicine 95(2):e2358. https://doi.org/10.1097/md.0000000000002358

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Mazziotti G, Formenti AM, Frara S, Olivetti R, Banfi G, Memo M, Maroldi R, Giubbini R, Giustina A (2018) High Prevalence of Radiological Vertebral Fractures in Women on Thyroid-Stimulating Hormone-Suppressive Therapy for Thyroid Carcinoma. J Clin Endocrinol Metab 103(3):956–964. https://doi.org/10.1210/jc.2017-01986

    Article  PubMed  Google Scholar 

  97. 97.

    Vestergaard P, Mosekilde L (2003) Hyperthyroidism, bone mineral, and fracture risk--a meta-analysis. Thyroid 13(6):585–593. https://doi.org/10.1089/105072503322238854

    Article  PubMed  Google Scholar 

  98. 98.

    Higham CE, Johannsson G, Shalet SM (2016) Hypopituitarism. Lancet 388(10058):2403–2415. https://doi.org/10.1016/s0140-6736(16)30053-8

    CAS  Article  Google Scholar 

  99. 99.

    Molitch ME, Clemmons DR, Malozowski S, Merriam GR, Vance ML (2011) Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(6):1587–1609. https://doi.org/10.1210/jc.2011-0179

    CAS  Article  PubMed  Google Scholar 

  100. 100.

    Toogood AA, Adams JE, O'Neill PA, Shalet SM (1997) Elderly patients with adult-onset growth hormone deficiency are not osteopenic. J Clin Endocrinol Metab 82(5):1462–1466. https://doi.org/10.1210/jcem.82.5.3932

    CAS  Article  PubMed  Google Scholar 

  101. 101.

    Yang H, Yan K, Yuping X, Zhang Q, Wang L, Gong F, Zhu H, Xia W, Pan H (2019) Bone microarchitecture and volumetric bone density impairment in young male adults with childhood-onset growth hormone deficiency. Eur J Endocrinol 180(2):145–153. https://doi.org/10.1530/eje-18-0711

    CAS  Article  PubMed  Google Scholar 

  102. 102.

    Wuster C, Abs R, Bengtsson BA, Bennmarker H, Feldt-Rasmussen U, Hernberg-Stahl E, Monson JP, Westberg B, Wilton P (2001) The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. J Bone Miner Res 16(2):398–405. https://doi.org/10.1359/jbmr.2001.16.2.398

    CAS  Article  PubMed  Google Scholar 

  103. 103.

    Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson BA (1997) Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. Eur J Endocrinol 137(3):240–245

    CAS  Article  Google Scholar 

  104. 104.

    Mazziotti G, Bianchi A, Cimino V, Bonadonna S, Martini P, Fusco A, De Marinis L, Giustina A (2008) Effect of gonadal status on bone mineral density and radiological spinal deformities in adult patients with growth hormone deficiency. Pituitary 11(1):55–61. https://doi.org/10.1007/s11102-007-0069-z

    CAS  Article  PubMed  Google Scholar 

  105. 105.

    Mazziotti G, Porcelli T, Bianchi A, Cimino V, Patelli I, Mejia C, Fusco A, Giampietro A, De Marinis L, Giustina A (2010) Glucocorticoid replacement therapy and vertebral fractures in hypopituitary adult males with GH deficiency. Eur J Endocrinol 163(1):15–20. https://doi.org/10.1530/eje-10-0125

    CAS  Article  PubMed  Google Scholar 

  106. 106.

    Mazziotti G, Mormando M, Cristiano A, Bianchi A, Porcelli T, Giampietro A, Maffezzoni F, Serra V, De Marinis L, Giustina A (2014) Association between l-thyroxine treatment, GH deficiency, and radiological vertebral fractures in patients with adult-onset hypopituitarism. Eur J Endocrinol 170(6):893–899. https://doi.org/10.1530/eje-14-0097

    CAS  Article  PubMed  Google Scholar 

  107. 107.

    Mormando M, Chiloiro S, Bianchi A, Giampietro A, Angelini F, Tartaglione L, Nasto L, Milardi D, Formenti AM, Giustina A, De Marinis L (2016) Growth hormone receptor isoforms and fracture risk in adult-onset growth hormone-deficient patients. Clin Endocrinol 85(5):717–724. https://doi.org/10.1111/cen.13161

    CAS  Article  Google Scholar 

  108. 108.

    Mazziotti G, Doga M, Frara S, Maffezzoni F, Porcelli T, Cerri L, Maroldi R, Giustina A (2016) Incidence of morphometric vertebral fractures in adult patients with growth hormone deficiency. Endocrine 52(1):103–110. https://doi.org/10.1007/s12020-015-0738-z

    CAS  Article  PubMed  Google Scholar 

  109. 109.

    Tritos NA, Greenspan SL, King D, Hamrahian A, Cook DM, Jonsson PJ, Wajnrajch MP, Koltowska-Haggstrom M, Biller BM (2011) Unreplaced sex steroid deficiency, corticotropin deficiency, and lower IGF-I are associated with lower bone mineral density in adults with growth hormone deficiency: a KIMS database analysis. J Clin Endocrinol Metab 96(5):1516–1523. https://doi.org/10.1210/jc.2010-2662

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Bex M, Abs R, Maiter D, Beckers A, Lamberigts G, Bouillon R (2002) The effects of growth hormone replacement therapy on bone metabolism in adult-onset growth hormone deficiency: a 2-year open randomized controlled multicenter trial. J Bone Miner Res 17(6):1081–1094. https://doi.org/10.1359/jbmr.2002.17.6.1081

    CAS  Article  PubMed  Google Scholar 

  111. 111.

    Ueland T, Olarescu NC, Jorgensen AP, Otterdal K, Aukrust P, Godang K, Lekva T, Bollerslev J (2015) Increased serum and bone matrix levels of the secreted Wnt antagonist DKK-1 in patients with growth hormone deficiency in response to growth hormone treatment. J Clin Endocrinol Metab 100(2):736–743. https://doi.org/10.1210/jc.2014-2912

    CAS  Article  PubMed  Google Scholar 

  112. 112.

    Davidson P, Milne R, Chase D, Cooper C (2004) Growth hormone replacement in adults and bone mineral density: a systematic review and meta-analysis. Clin Endocrinol 60(1):92–98. https://doi.org/10.1111/j.1365-2265.2004.01935.x

    CAS  Article  Google Scholar 

  113. 113.

    Barake M, Klibanski A, Tritos NA (2014) Effects of recombinant human growth hormone therapy on bone mineral density in adults with growth hormone deficiency: a meta-analysis. J Clin Endocrinol Metab 99(3):852–860. https://doi.org/10.1210/jc.2013-3921

    CAS  Article  PubMed  Google Scholar 

  114. 114.

    Barake M, Arabi A, Nakhoul N, El-Hajj Fuleihan G, El Ghandour S, Klibanski A, Tritos NA (2018) Effects of growth hormone therapy on bone density and fracture risk in age-related osteoporosis in the absence of growth hormone deficiency: a systematic review and meta-analysis. Endocrine 59(1):39–49. https://doi.org/10.1007/s12020-017-1440-0

    CAS  Article  PubMed  Google Scholar 

  115. 115.

    Fleseriu M, Hashim IA, Karavitaki N, Melmed S, Murad MH, Salvatori R, Samuels MH (2016) Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 101(11):3888–3921. https://doi.org/10.1210/jc.2016-2118

    CAS  Article  PubMed  Google Scholar 

  116. 116.

    Hansen TB, Brixen K, Vahl N, Jorgensen JO, Christiansen JS, Mosekilde L, Hagen C (1996) Effects of 12 months of growth hormone (GH) treatment on calciotropic hormones, calcium homeostasis, and bone metabolism in adults with acquired GH deficiency: a double blind, randomized, placebo-controlled study. J Clin Endocrinol Metab 81(9):3352–3359. https://doi.org/10.1210/jcem.81.9.8784096

    CAS  Article  PubMed  Google Scholar 

  117. 117.

    Cosman F, Eriksen EF, Recknor C, Miller PD, Guañabens N, Kasperk C, Papanastasiou P, Readie A, Rao H, Gasser JA, Bucci-Rechtweg C, Boonen S (2011) Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis. J Bone Miner Res 26(3):503–511. https://doi.org/10.1002/jbmr.238

    CAS  Article  PubMed  Google Scholar 

  118. 118.

    White HD, Ahmad AM, Durham BH, Joshi AA, Fraser WD, Vora JP (2011) Effect of oral phosphate and alendronate on bone mineral density when given as adjunctive therapy to growth hormone replacement in adult growth hormone deficiency. J Clin Endocrinol Metab 96(3):726–736. https://doi.org/10.1210/jc.2010-1929

    CAS  Article  PubMed  Google Scholar 

  119. 119.

    Valk NK, Erdtsieck RJ, Algra D, Lamberts SW, Pols HA (1995) Combined treatment of growth hormone and the bisphosphonate pamidronate, versus treatment with GH alone, in GH-deficient adults: the effects on renal phosphate handling, bone turnover and bone mineral mass. Clin Endocrinol 43(3):317–324. https://doi.org/10.1111/j.1365-2265.1995.tb02038.x

    CAS  Article  Google Scholar 

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Correspondence to Andrea Gerardo Lania or Gherardo Mazziotti.

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Carrone, F., Ariano, S., Piccini, S. et al. Update on vertebral fractures in pituitary diseases: from research to clinical practice. Hormones (2021). https://doi.org/10.1007/s42000-021-00275-5

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Keywords

  • Vertebral fractures
  • Pituitary diseases
  • Acromegaly
  • GH deficiency
  • Cushing’s disease
  • Prolactinoma
  • Hypogonadism
  • Osteoporosis