Genetic approaches to metabolic bone diseases

Br J Clin Pharmacol. 2019 Jun;85(6):1147-1160. doi: 10.1111/bcp.13803. Epub 2018 Nov 28.


Metabolic bone diseases comprise a diverse group of disorders characterized by alterations in skeletal homeostasis, and are often associated with abnormal circulating concentrations of calcium, phosphate or vitamin D metabolites. These diseases commonly have a genetic basis and represent either a monogenic disorder due to a germline or somatic single gene mutation, or an oligogenic or polygenic disorder that involves variants in more than one gene. Germline single gene mutations causing Mendelian diseases typically have a high penetrance, whereas the genetic variations causing oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. Recognition of familial monogenic disorders is of clinical importance to facilitate timely investigations and management of the patient and any affected relatives. The diagnosis of monogenic metabolic bone disease requires careful clinical evaluation of the large diversity of symptoms and signs associated with these disorders. Thus, the clinician must pursue a systematic approach beginning with a detailed history and physical examination, followed by appropriate laboratory and skeletal imaging evaluations. Finally, the clinician must understand the increasing number and complexity of molecular genetic tests available to ensure their appropriate use and interpretation.

Keywords: genetic diseases; genetics and pharmacogenetics; molecular biology; osteoporosis; rheumatology.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Bone Diseases, Metabolic / diagnosis
  • Bone Diseases, Metabolic / genetics*
  • Bone Diseases, Metabolic / physiopathology
  • Bone Diseases, Metabolic / therapy
  • Bone Remodeling / genetics*
  • Genetic Predisposition to Disease
  • Genetic Therapy
  • Germ-Line Mutation*
  • Heredity
  • Humans
  • Medical History Taking
  • Molecular Diagnostic Techniques
  • Pedigree
  • Penetrance
  • Phenotype
  • Physical Examination
  • Predictive Value of Tests
  • Prognosis
  • Risk Factors