GH receptor polymorphisms guide second-line therapies to prevent acromegaly skeletal fragility: preliminary results of a pilot study

Front Endocrinol (Lausanne). 2024 Aug 30:15:1414101. doi: 10.3389/fendo.2024.1414101. eCollection 2024.

Abstract

Background: Skeletal fragility is characterized by increased frequency of vertebral fractures (VFs) in acromegaly. Several trials were conducted to identify modifiable risk factors and predictors of VFs, with limited data on the prognostic role of GH receptor (GHR) isoforms. In this study, we investigated the potential role of GHR polymorphism on the occurrence of incidental VFs (i-VFs), in patients treated with second-line medical therapies.

Methods: A longitudinal, retrospective, observational study was conducted on a cohort of 45 acromegalic patients not-responsive to first-generation somatostatin receptor ligands (fg-SRLs) and treated with GHR antagonist (Pegvisomant) or with the second-generation SRLs (Pasireotide long-acting release).

Results: Second line treatments were Pegvisomant plus fg-SRLs in 26 patients and Pasireotide LAR in 19 patients. From the group treated with fg-SRLs+Peg-V, the fl-GHR isoform was identified in 18 patients (69.2%) and the d3-GHR isoform in 8 patients (30.8%). I-VFs arose exclusively in fl-GHR isoform carriers (p=0.039). From the group treated with Pasireotide LAR, the fl-GHR isoform was identified in 11 patients (57.9%), and the d3-GHR isoform in 8 patients (42.1%). I-VFs arose exclusively in d3-GHR isoform carriers (p=0.018). Patients with fl-GHR isoform had a higher risk for i-VFs if treated with fg-SRL+Peg-V (OR: 1.6 95%IC: 1.1-2.3, p=0.04), and a lower risk if treated with Pasi-LAR (OR: 0.26 IC95%: 0.11-0.66, p=0.038).

Conclusions: Our data support a predictive role of the GHR isoforms for the occurrence of i-VFs in acromegalic patients treated with second-line drugs, tailored to the individual patient. The knowledge of the GHR polymorphism may facilitate the choice of second-line therapies, improving the therapeutic approach, in the context of personalized medicine.

Keywords: GH receptor; acromegaly; fracture; osteopenia; osteoporosis; pasireotide; pegvisomant; somatostatin receptor ligands.

Publication types

  • Observational Study

MeSH terms

  • Acromegaly* / drug therapy
  • Adult
  • Aged
  • Female
  • Human Growth Hormone* / analogs & derivatives
  • Human Growth Hormone* / metabolism
  • Human Growth Hormone* / therapeutic use
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Pilot Projects
  • Polymorphism, Genetic
  • Receptors, Somatotropin* / antagonists & inhibitors
  • Receptors, Somatotropin* / genetics
  • Receptors, Somatotropin* / metabolism
  • Retrospective Studies
  • Somatostatin* / analogs & derivatives
  • Somatostatin* / therapeutic use

Substances

  • pegvisomant
  • Receptors, Somatotropin
  • Somatostatin
  • Human Growth Hormone
  • pasireotide

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study was supported by the Pfizer Research Grant 56843615. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.