Top

Published in:

Open Access 03-08-2022 | Acromegaly

Impact of the diagnostic delay of acromegaly on bone health: data from a real life and long term follow-up experience

Authors: Sabrina Chiloiro, Antonella Giampietro, Irene Gagliardi, Marta Bondanelli, Miriam Veleno, Maria Rosaria Ambrosio, Maria Chiara Zatelli, Alfredo Pontecorvi, Andrea Giustina, Laura De Marinis, Antonio Bianchi

Published in: Pituitary | Issue 6/2022

Abstract

Introduction

Acromegaly is a chronic disease with systemic complications. Disease onset is insidious and consequently typically burdened by diagnostic delay. A longer diagnostic delay induces more frequently cardiovascular, respiratory, metabolic, neuropsychiatric and musculoskeletal comorbidities. No data are available on the effect of diagnostic delay on skeletal fragility. We aimed to evaluate the effect of diagnostic delay on the frequency of incident and prevalent of vertebral fractures (i-VFs and p-VFs) in a large cohort of acromegaly patients.

Patients and methods

A longitudinal, retrospective and multicenter study was conducted on 172 acromegaly patients.

Results

Median diagnostic delay and duration of follow-up were respectively 10 years (IQR: 6) and 10 years (IQR: 8). P-VFs were observed in 18.6% and i-VFs occurred in 34.3% of patients. The median estimated diagnostic delay was longer in patients with i-VFs (median: 11 years, IQR: 3), in comparison to those without i-VFs (median: 8 years, IQR: 7; p = 0.02). Age at acromegaly diagnosis and at last follow-up were higher in patients with i-VFs, with respect to those without i-VFs. The age at acromegaly diagnosis was positively associated with the diagnostic delay (p < 0.001, r = 0.216). A longer history of active acromegaly was associated with a high frequency of i-VFs (p = 0.03). The logistic regression confirmed that patients with a diagnostic delay > 10 years had 1.5-folds increased risk of developing i-VFs (OR: 1.5; 95%CI: 1.1–2; p = 0.017).

Conclusion

Our data showed that the diagnostic delay in acromegaly has a significant impact on VF risk, further supporting the clinical relevance of an early acromegaly diagnosis.

Available only for authorised users

Kasuki L, Rocha PDS, Lamback EB, Gadelha MR (2019) Determinants of morbidities and mortality in acromegaly. Arch Endocrinol Metab 63(6):630–637. https://doi.org/10.20945/2359-3997000000193CrossRefPubMed

Chiloiro S, Mirra F, Federico D, Giampietro A, Visconti F, Rossi L, Pontecorvi A, De Marinis L, Bianchi A (2020) The role of growth hormone receptor isoforms and their effects in bone metabolism and skeletal fragility. Protein Pept Lett 27(12):1260–1267. https://doi.org/10.2174/0929866527666200616151105CrossRefPubMed

Kužma M, Killinger Z, Jackuliak P, Vaňuga 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(2):S121–S129. https://doi.org/10.33549/physiolres.934303CrossRefPubMed

Bima C, Chiloiro S, Mormando M, Piacentini S, Bracaccia E, Giampietro A, Tartaglione L, Bianchi A, De Marinis L (2016) Understanding the effect of acromegaly on the human skeleton. Expert Rev Endocrinol Metab 11(3):263–270. https://doi.org/10.1080/17446651.2016.1179108CrossRefPubMed

Giustina A (2020) Acromegaly and vertebral fractures: facts and questions. Trends Endocrinol Metab 31(4):274–275. https://doi.org/10.1016/j.tem.2020.01.011CrossRefPubMed

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):3402–3410CrossRefPubMed

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.2013-2695CrossRefPubMed

Frara S, Uygur MM, di Filippo L, Doga M, Losa M, Santoro S, Mortini P, Giustina A (2022) High Prevalence of Vertebral Fractures Associated with Preoperative GH Levels in Patients with recent Diagnosis of Acromegaly. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgac183CrossRefPubMed

Claessen KM, Mazziotti G, Biermasz NR, Giustina A (2016) Bone and joint disorders in acromegaly. Neuroendocrinology 103(1):86–95CrossRefPubMed

10.

Mazziotti G, Biagioli E, Maffezzoni F, Spinello M, Serra V, Maroldi R et al (2015) Bone turnover, bone mineral density, and fracture risk in acromegaly: a meta-analysis. J Clin Endocrinol Metab 100(2):384–394CrossRefPubMed

11.

Giustina A (2016) Acromegaly: reducing diagnostic delay. Recenti Progr Med 107(8):450–451. https://doi.org/10.1701/2332.25074CrossRefPubMed

12.

Petrossians P, Daly AF, Natchev E, Maione L, Blijdorp K, Sahnoun-Fathallah M, Auriemma R, Diallo AM, Hulting AL, Ferone D, Hana V Jr, Filipponi S, Sievers C, Nogueira C, Fajardo-Montañana C, Carvalho D, Hana V, Stalla GK, Jaffrain-Réa ML, Delemer B, Colao A, Brue T, Neggers SJCMM, Zacharieva S, Chanson P, Beckers A (2017) Acromegaly at diagnosis in 3173 patients from the Liege Acromegaly Survey (LAS) Database. Endocr Relat Cancer 24(10):505–518. https://doi.org/10.1530/ERC-17-0253CrossRefPubMedPubMedCentral

13.

Caron P, Brue T, Raverot G, Tabarin A, Cailleux A, Delemer B, Renoult PP, Houchard A, Elaraki F, Chanson P (2019) Signs and symptoms of acromegaly at diagnosis: the physician’s and the patient’s perspectives in the ACRO-POLIS study. Endocrine 63(1):120–129. https://doi.org/10.1007/s12020-018-1764-4CrossRefPubMed

14.

Esposito D, Ragnarsson O, Johannsson G, Olsson DS (2020) Prolonged diagnostic delay in acromegaly is associated with increased morbidity and mortality. Eur J Endocrinol 182(6):523–531. https://doi.org/10.1530/EJE-20-0019CrossRefPubMed

15.

Sisco J, van der Lely AJ (2021) Towards an Earlier Diagnosis of Acromegaly and Gigantism. J Clin Med 10(7):1363. https://doi.org/10.3390/jcm10071363CrossRefPubMedPubMedCentral

16.

Mazziotti G, Canalis E, Giustina A (2010) Drug-induced osteoporosis: mechanisms and clinical implications. Am J Med 123(10):877–884CrossRefPubMed

17.

Giustina A, Barkhoudarian G, Beckers A, Ben-Shlomo A, Biermasz N, Biller B, Boguszewski C, Bolanowski M, Bollerslev J, Bonert V, Bronstein MD, Buchfelder M, Casanueva F, Chanson P, Clemmons D, Fleseriu M, Formenti AM, Freda P, Gadelha M, Geer E, Gurnell M, Heaney AP, Ho KKY, Ioachimescu AG, Lamberts S, Laws E, Losa M, Maffei P, Mamelak A, Mercado M, Molitch M, Mortini P, Pereira AM, Petersenn S, Post K, Puig-Domingo M, Salvatori R, Samson SL, Shimon I, Strasburger C, Swearingen B, Trainer P, Vance ML, Wass J, Wierman ME, Yuen KCJ, Zatelli MC, Melmed S (2020) Multidisciplinary management of acromegaly: a consensus. Rev Endocr Metab Disord. https://doi.org/10.1007/s11154-020-09588-zCrossRefPubMedPubMedCentral

18.

Melmed S, Bronstein MD, Chanson P, Klibanski A, Casanuela FF, Wass JAH, Strasburger CJ, Luger A, Clemmons DR, Giustina A (2018) A Consensus Statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol 14(9):552–561CrossRefPubMedPubMedCentral

19.

Peixe C, Sánchez-García M, Grossman AB, Korbonits M, Marques P (2022) Elevated GH or IGF-1 levels do not always diagnose acromegaly. Growth Horm IGF Res 64:101467. https://doi.org/10.1016/j.ghir.2022.101467CrossRefPubMed

20.

Melmed S, Casanueva FF, Klibanski A, Bronstein MD, Chanson P, Lamberts SW, Strasburger CJ, Wass JAH, Giustina A (2013) A consensus on the diagnosis and treatment of acromegaly complications. Pituitary 16(3):294–302. https://doi.org/10.1007/s11102-012-0420-xCrossRefPubMed

21.

Detomas M, Reuter M, Deutschbein T (2021) New developments and perspectives in acromegaly. Dtsch Med Wochenschr 146(15):950–954. https://doi.org/10.1055/a-1495-2715CrossRefPubMed

22.

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

23.

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):dgz054. https://doi.org/10.1210/clinem/dgz054CrossRefPubMed

24.

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/s12020-017-1391-5CrossRefPubMed

25.

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 105(9):dgaa363. https://doi.org/10.1210/clinem/dgaa363CrossRefPubMed

26.

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/s11102-018-0873-7CrossRefPubMed

27.

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.2014-2937CrossRefPubMed

28.

Hubina E, Lakatos P, Kovacs L, Szabolcs I, Racz K, Toth M, Szucs N, Goth MI (2004) Effects of 24 months of growth hormone (GH) treatment on serum carboxylated and undercarboxylated osteocalcin levels in GH-deficient adults. Calcif Tissue Int 74:55–59CrossRefPubMed

29.

Sugiyama T, Kawai S (2001) Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. J Bone Miner Res 19:146–149CrossRef

30.

Canalis E, Rydziel S, Delany AM, Varghese S, Jeffrey JJ (1995) Insulin-like growth factors inhibit interstitial collagenase synthesis in bone cell cultures. Endocrinology 136:1348–1354CrossRefPubMed

31.

Playford MP, Bicknell D, Bodmer WF, Macaulay VM (2000) Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of β-catenin. Proc Natl Acad Sci 97:12103–12108CrossRefPubMedPubMedCentral

32.

Krishnan V, Bryant HU, MacDougald OA (2006) Regulation of bone mass by Wnt signaling. J Clin Invest 116:1202–1209CrossRefPubMedPubMedCentral

33.

Mochizuki H, Hakeda Y, Wakatsuki N, Usui N, Akashi S, Sato T, Tanaka K, Kumegawa M (1992) Insulin-like growth factor-I supports formation and activation of osteoclasts. Endocrinology 131:1075–1080CrossRefPubMed

34.

Niu T, Rosen CJ (2005) The insulin-like growth factor-I gene and osteoporosis: a critical appraisal. Gene 361:38–56CrossRefPubMed

35.

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 (2021) Vertebral fractures associated with spinal sagittal imbalance and quality of life in acromegaly: a radiographic study with EOS 2D/3D technology. Neuroendocrinology 111(8):775–785. https://doi.org/10.1159/000511811CrossRefPubMed

36.

Cangiano B, Giusti E, Premoli C, Soranna D, Vitale G, Grottoli S, Cambria V, Mantovani G, Mungari R, Maffei P, Dassie F, Giampietro A, Chiloiro S, Tanda ML, Ippolito S, Cannavò S, Ragonese M, Zambon A, Persani L, Fatti LM, Scacchi M, “PRO-ACRO” study group on Motor Disability in Acromegaly, of the Italian Society of Endocrinology (SIE) (2022) Psychological complications in patients with acromegaly: relationships with sex, arthropathy, and quality of life. Endocrine. https://doi.org/10.1007/s12020-022-03106-8CrossRefPubMedPubMedCentral

37.

di Filippo L, Formenti AM, Doga M, Pedone E, Rovere-Querini P, Giustina A (2021) Radiological thoracic vertebral fractures are highly prevalent in COVID-19 and predict disease outcomes. J Clin Endocrinol Metab 106(2):e602–e614. https://doi.org/10.1210/clinem/dgaa738CrossRefPubMed

38.

Kasuki L, Antunes X, Lamback EB, Gadelha MR (2020) Acromegaly: update on management and long-term morbidities. Endocrinol Metab Clin North Am 49(3):475–486. https://doi.org/10.1016/j.ecl.2020.05.007CrossRefPubMed

39.

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):dgz096. https://doi.org/10.1210/clinem/dgz096CrossRefPubMed

40.

Duan L, Yang S, Wang LJ, Zhang Y, Li R, Yang H, Zhao Y, Du H, Zhai X, Gong F, Pan H, Zhu H, Xia W (2021) The negative impacts of acromegaly on bone microstructure not fully reversible. Front Endocrinol (Lausanne) 12:738895. https://doi.org/10.3389/fendo.2021.738895.eCollection2021CrossRef

41.

Canalis E, Giustina A, Bilezikian JP (2007) Mechanisms of anabolic therapies for osteoporosis. N Engl J Med 357(9):905–916CrossRefPubMed

42.

Chiloiro S, Bianchi A, Giampietro A (2019) De Marinis L Somatotropic Axis in Human Aging. In: Huhtaniemi I, Martini L (eds) Encyclopedia of Endocrine Diseases, 2nd edn. Academic Press, Oxford, pp 700–707CrossRef

43.

Gagliardi I, Chiloiro S, Vallillo M, Bondanelli M, Volpato S, Giampietro A, Bianchi A, De Marinis L, Zarelli MC, Ambrosio MR (2021) Multidimensional geriatric evaluation in acromegaly: a comparative cross-sectional study. BMC Geriatr 21:598CrossRefPubMedPubMedCentral

44.

Salari N, Darvishi N, Bartina Y, Larti M, Kiaei A, Hemmati M, Shohaimi S, Mohammadi M (2021) Global prevalence of osteoporosis among the world older adults: a comprehensive systematic review and meta-analysis. J Orthop Surg Res 16(1):669. https://doi.org/10.1186/s13018-021-02821-8CrossRefPubMedPubMedCentral

45.

Bilezikian JP, Formenti AM, Adler RA, Binkley N, Bouillon R, Lararetti-Castro M, Marcocci C, Napoli N, Rizzoli R, Giustina A (2021) Vitamin D: dosing, levels, form, and route of administration: does one approach fit all? Rev Endocr Metab Dosord 22(4):1201–1218. https://doi.org/10.1007/s11154-021-09693-7CrossRef

46.

Hampson G, Elder GJ, Cohen-Solal M, Abrahamsen B (2021) A review and perspective on the assessment, management and prevention of fragility fractures in patients with osteoporosis and chronic kidney disease. Endocrine 73(3):509–529. https://doi.org/10.1007/s12020-021-02735-9CrossRefPubMedPubMedCentral

47.

Ambrosio MR, Gagliardi I, Chiloiro S, Ferreira AG, Bondanelli M, Giampietro A, Bianchi A, Marinis L, Fleseriu M, Zatelli MC (2020) Acromegaly in the elderly patients. Endocrine 68(1):16–31. https://doi.org/10.1007/s12020-020-02206-7CrossRefPubMed

48.

Colao A, Pivonello R, Spinelli L, Galderisi M, Auriemma RS, Galdiero M, Vitale G, De Leo M, Lombardi G (2007) A retrospective analysis on biochemical parameters, cardiovascular risk and cardiomyopathy in elderly acromegalic patients. J Endocrinol Invest 30(6):497–506CrossRefPubMed

49.

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-14-0205CrossRefPubMed

Title: Impact of the diagnostic delay of acromegaly on bone health: data from a real life and long term follow-up experience
Authors: Sabrina Chiloiro
Antonella Giampietro
Irene Gagliardi
Marta Bondanelli
Miriam Veleno
Maria Rosaria Ambrosio
Maria Chiara Zatelli
Alfredo Pontecorvi
Andrea Giustina
Laura De Marinis
Antonio Bianchi
Publication date: 03-08-2022
Publisher: Springer US
Keyword: Acromegaly
Published in: Pituitary / Issue 6/2022
Print ISSN: 1386-341X
Electronic ISSN: 1573-7403
DOI: https://doi.org/10.1007/s11102-022-01266-4

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Impact of the diagnostic delay of acromegaly on bone health: data from a real life and long term follow-up experience

Abstract

Introduction

Patients and methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Introduction

Patients and methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 6/2022

Long-term hepatic and cardiac health in patients diagnosed with Sheehan’s syndrome

Long-term efficacy and safety of osilodrostat in Cushing’s disease: final results from a Phase II study with an optional extension phase (LINC 2)

The role of stereotactic radiosurgery in the multidisciplinary management of pituitary metastases

Characterization of sporadic somatotropinomas with high GIP receptor expression

Development of a cost-effective diagnostic algorithm incorporating transcription factor immunohistochemistry in the evaluation of pituitary tumours

Idiopathic central diabetes insipidus in a large cohort of patients: the hypopituitarism ENEA rare observational (HEROS) study

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page