Endocrinol Metab.  2023 Dec;38(6):690-700. 10.3803/EnM.2023.1782.

Increased Risk of Hip Fracture in Patients with Acromegaly: A Nationwide Cohort Study in Korea

• Kim J
• Hong N
• Choi J
• Moon JH
• Kim EH
• Lee EJ
• Kim SG
• Ku CR

• KMID: 2549262
• DOI: http://doi.org/10.3803/EnM.2023.1782

Abstract

Background
Acromegaly leads to various skeletal complications, and fragility fractures are emerging as a new concern in patients with acromegaly. Therefore, this study investigated the risk of fractures in Korean patients with acromegaly.
Methods
We used the Korean nationwide claims database from 2009 to 2019. A total of 931 patients with acromegaly who had never used an osteoporosis drug before and were treated with surgery alone were selected as study participants, and a 1:29 ratio of 26,999 age- and sex-matched osteoporosis drug-naïve controls without acromegaly were randomly selected from the database.
Results
The mean age was 46.2 years, and 50.0% were male. During a median follow-up of 54.1 months, there was no difference in the risks of all, vertebral, and non-vertebral fractures between the acromegaly and control groups. However, hip fracture risk was significantly higher (hazard ratio [HR], 2.73; 95% confidence interval [CI], 1.32 to 5.65), and non-hip and non-vertebral fractures risk was significantly lower (HR, 0.40; 95% CI, 0.17 to 0.98) in patients with acromegaly than in controls; these results remained robust even after adjustment for socioeconomic status and baseline comorbidities. Age, type 2 diabetes mellitus, cardio-cerebrovascular disease, fracture history, recent use of acid-suppressant medication, psychotropic medication, and opioids were risk factors for all fractures in patients with acromegaly (all P<0.05).
Conclusion
Compared with controls, patients surgically treated for acromegaly had a higher risk of hip fractures. The risk factors for fracture in patients with acromegaly were consistent with widely accepted risk factors in the general population.

Keyword

Acromegaly; Hip fractures; Nationwide; Korea

Figure

• 

  Fig. 1. Flow chart of the study design. ICD-10, International Classification of Disease, 10th Revision.

• 

  Fig. 2. The Kaplan-Meier curve of site-specific fractures. (A) All fracture. (B) Vertebral fracture. (C) Non-vertebral fracture. (D) Hip fracture.

Reference

1. Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev. 2008; 29:535–59.

2. Courtland HW, Sun H, Beth-On M, Wu Y, Elis S, Rosen CJ, et al. Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production. J Bone Miner Res. 2011; 26:761–8.

3. Mirza F, Canalis E. Management of endocrine disease: secondary osteoporosis: pathophysiology and management. Eur J Endocrinol. 2015; 173:R131–51.

4. Colao A, Grasso LF, Giustina A, Melmed S, Chanson P, Pereira AM, et al. Acromegaly. Nat Rev Dis Primers. 2019; 5:20.

5. Hong JW, Ku CR, Kim SH, Lee EJ. Characteristics of acromegaly in Korea with a literature review. Endocrinol Metab (Seoul). 2013; 28:164–8.

6. Mazziotti G, Maffezzoni F, Frara S, Giustina A. Acromegalic osteopathy. Pituitary. 2017; 20:63–9.

7. Mazziotti G, Chiavistelli S, Giustina A. Pituitary diseases and bone. Endocrinol Metab Clin North Am. 2015; 44:171–80.

8. Bonadonna S, Mazziotti G, Nuzzo M, Bianchi A, Fusco A, De Marinis L, et al. Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women. J Bone Miner Res. 2005; 20:1837–44.

9. Stepan J, Marek J, Havranek T, Dolezal V, Pacovsky V. Bone isoenzyme of serum alkaline phosphatase in acromegaly. Clin Chim Acta. 1979; 93:355–63.

10. Scillitani A, Chiodini I, Carnevale V, Giannatempo GM, Frusciante V, Villella M, et al. Skeletal involvement in female acromegalic subjects: the effects of growth hormone excess in amenorrheal and menstruating patients. J Bone Miner Res. 1997; 12:1729–36.

11. Ueland T, Bollerslev J, Godang K, Muller F, Froland SS, Aukrust P. Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess: possible role in bone homeostasis. Eur J Endocrinol. 2001; 145:685–90.

12. Mazziotti G, Bianchi A, Porcelli T, Mormando M, Maffezzoni F, Cristiano A, et al. Vertebral fractures in patients with acromegaly: a 3-year prospective study. J Clin Endocrinol Metab. 2013; 98:3402–10.

13. Mazziotti G, Lania AGA, Canalis E. Management of endocrine disease: bone disorders associated with acromegaly: mechanisms and treatment. Eur J Endocrinol. 2019; 181:R45–56.

14. Song SO, Jung CH, Song YD, Park CY, Kwon HS, Cha BS, et al. Background and data configuration process of a nationwide population-based study using the Korean National Health Insurance system. Diabetes Metab J. 2014; 38:395–403.

15. Lee J, Lee JS, Park SH, Shin SA, Kim K. Cohort profile: the National Health Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int J Epidemiol. 2017; 46:e15.

16. Park KH, Lee EJ, Seo GH, Ku CR. Risk for acromegaly-related comorbidities by sex in Korean acromegaly. J Clin Endocrinol Metab. 2020; 105:dgz317.

17. Cho SW, Kim JH, Choi HS, Ahn HY, Kim MK, Rhee EJ. Big data research in the field of endocrine diseases using the Korean National Health Information Database. Endocrinol Metab (Seoul). 2023; 38:10–24.

18. Panday K, Gona A, Humphrey MB. Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis. 2014; 6:185–202.

19. Dalle Carbonare L, Micheletti V, Cosaro E, Valenti MT, Mottes M, Francia G, et al. Bone histomorphometry in acromegaly patients with fragility vertebral fractures. Pituitary. 2018; 21:56–64.

20. Cassidy JT, Laxer RM, Petty RE, Lindsley B. Textbook of pediatric rheumatology. 6th ed. Philadelphia: Saunders;2011.

21. Kuzma M, Vanuga P, Sagova I, Pavai D, Jackuliak P, Killinger Z, et al. Non-invasive DXA-derived bone structure assessment of acromegaly patients: a cross-sectional study. Eur J Endocrinol. 2019; 180:201–11.

22. Godang K, Lekva T, Normann KR, Olarescu NC, Oystese KA, Kolnes A, et al. Hip structure analyses in acromegaly: decrease of cortical bone thickness after treatment: a longitudinal cohort study. JBMR Plus. 2019; 3:e10240.

23. Kanis JA, Borgstrom F, De Laet C, Johansson H, Johnell O, Jonsson B, et al. Assessment of fracture risk. Osteoporos Int. 2005; 16:581–9.

24. Pouresmaeili F, Kamalidehghan B, Kamarehei M, Goh YM. A comprehensive overview on osteoporosis and its risk factors. Ther Clin Risk Manag. 2018; 14:2029–49.

25. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006; 296:2947–53.

26. Ramnemark A, Nyberg L, Borssen B, Olsson T, Gustafson Y. Fractures after stroke. Osteoporos Int. 1998; 8:92–5.

27. den Uyl D, Nurmohamed MT, van Tuyl LH, Raterman HG, Lems WF. (Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis. Arthritis Res Ther. 2011; 13:R5.

28. Claessen KM, Kroon HM, Pereira AM, Appelman-Dijkstra NM, Verstegen MJ, Kloppenburg M, et al. Progression of vertebral fractures despite long-term biochemical control of acromegaly: a prospective follow-up study. J Clin Endocrinol Metab. 2013; 98:4808–15.

29. Pelsma IC, Biermasz NR, Pereira AM, van Furth WR, Appelman-Dijkstra NM, Kloppenburg M, et al. Progression of vertebral fractures in long-term controlled acromegaly: a 9-year follow-up study. Eur J Endocrinol. 2020; 183:427–37.

30. Ross PD. Clinical consequences of vertebral fractures. Am J Med. 1997; 103(2A):30S–43S.

31. Mazziotti G, Bianchi A, Bonadonna S, Cimino V, Patelli I, Fusco A, et al. Prevalence of vertebral fractures in men with acromegaly. J Clin Endocrinol Metab. 2008; 93:4649–55.

32. Mazziotti G, Biagioli E, Maffezzoni F, Spinello M, Serra V, Maroldi R, et al. Bone turnover, bone mineral density, and fracture risk in acromegaly: a meta-analysis. J Clin Endocrinol Metab. 2015; 100:384–94.

33. Kim J, Hong N, Choi J, Moon JH, Kim EH, Hong JW, et al. Sex differences in mortality in patients with acromegaly: a nationwide cohort study in Korea. Eur J Endocrinol. 2023; 189:225–34.