Mechanisms for the bone anabolic effect of parathyroid hormone treatment in humans

Scand J Clin Lab Invest. 2012 Feb;72(1):14-22. doi: 10.3109/00365513.2011.624631. Epub 2011 Nov 16.

Abstract

Intermittent low-dose treatment with parathyroid hormone (PTH) analogues has become widely used in the treatment of severe osteoporosis. During normal physiological conditions, PTH stimulates both bone formation and resorption, and in patients with primary hyperparathyroidism, bone loss is frequent. However, development of the biochemical measurement of PTH in the 1980s led us to understand the regulation of PTH secretion and calcium metabolism which subsequently paved the way for the use of PTH as an anabolic treatment of osteoporosis as, when given intermittently, it has strong anabolic effects in bone. This could not have taken place without the basic understanding achieved by the biochemical measurements of PTH. The stimulatory effects of PTH on bone formation have been explained by the so-called 'anabolic window', which means that during PTH treatment, bone formation is in excess over bone resorption during the first 6-18 months. This is due to the following: (1) PTH up-regulates c-fos expression in bone cells, (2) IGF is essential for PTH's anabolic effect, (3) bone lining cells are driven to differentiate into osteoblasts, (4) mesenchymal stem cells adhesion to bone surface is enhanced, (5) PTH has a direct antiapoptotic effect on osteoblasts and (6) when PTH interferes with remodelling, the osteoblasts over-compensate, and (7) PTH also decreases sclerostin levels, thereby removing inhibition of Wnt signalling which is required for PTH's anabolic actions. Thus, the net formative effect of PTH given in intermittent treatment emerges through a complex network of pathways. In summary, the effects of PTH on bone turnover are dependent on the mode and dose of administration and studies investigating the mechanisms underlying this effect are reviewed in this article.

Publication types

  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Anabolic Agents / pharmacology*
  • Anabolic Agents / therapeutic use
  • Animals
  • Apoptosis / drug effects
  • Bone Morphogenetic Proteins / genetics
  • Bone Morphogenetic Proteins / metabolism
  • Bone Regeneration / drug effects
  • Bone and Bones / drug effects*
  • Bone and Bones / metabolism
  • Bone and Bones / pathology
  • Cell Differentiation
  • Gene Expression / drug effects
  • Genetic Markers / genetics
  • Humans
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / physiology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteoblasts / physiology
  • Osteoporosis / drug therapy*
  • Parathyroid Hormone / pharmacology*
  • Parathyroid Hormone / physiology
  • Parathyroid Hormone / therapeutic use
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Somatomedins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Anabolic Agents
  • Bone Morphogenetic Proteins
  • Genetic Markers
  • Parathyroid Hormone
  • Proto-Oncogene Proteins c-fos
  • SOST protein, human
  • Somatomedins