Parathyroid hormone (PTH) is a major systemic regulator of calcium homeostatsis (Harada and Rodan 2003
). It is released from the parathyroid gland in response to hypocalcaemia, and increases serum calcium concentration by promoting osteoclast-mediated bone resorption, calcium reabsorption in the kidneys, and intestinal absorption of calcium through production of the active vitamin D metabolite (1,25-dihydroxy vitamin D). Therefore, continuous exposure to PTH leads to hypercalcaemia and a decrease in bone volume, which is referred to as its catabolic effect. However, it has long been known that intermittent (once daily) exogenous PTH administered leads to an anabolic effect on bone, and the cellular and molecular mechanisms involved have been reviewed (Jilka 2007
). As a result of this unique mechanism of action on bone, PTH has been approved as the only anabolic therapy for postmenopausal osteoporosis (Neer et al. 2001
). Considering that bone formation is critical for fracture healing, there is also a strong rationale for PTH therapy for skeletal repair.
To date, several forms of PTH, including full length human PTH (PTH1-84
) and the N-terminal 1-34 amino acid peptide of human PTH (PTH1-34
), have been developed for the treatment of metabolic bone diseases. Among them, PTH1-34
, generically referred to as teriparatide, has been extensively studied based on investigations of PTH fragment analogs that assigned the major determinants of receptor-binding affinity, and intracellular signaling through cAMP to this peptide. Although there have not been any head-to-head comparison studies between PTH1-34
and full-length native PTH1-84
, in terms of their effects on bone, the activity of PTH1-34
is considered to be equivalent to that of PTH1-84
. Another major consideration that led to the clinical development of PTH1-34
is that industrial scale production of the recombinant peptide can be most cost-effectively done by fermentation in E. coli
, followed by standard protein purification. As such, PTH1-34
was the first molecule to be approved for osteoporosis therapy, and is currently used worldwide. Therefore, most of the studies referred to in this review involve data on PTH1-34
. Since Andreassen et al first reported the efficacy of intermittent PTH1-34
therapy on rat tibial fracture healing in 1999 (Andreassen et al. 1999
), a number of studies have shown that this treatment enhances skeletal repair regardless of the skeletal site and mode of bone healing (Bukata and Puzas 2010
). These studies suggest that PTH1-34
enhances not only bone remodeling, but also osteogenesis and chondrogenesis during skeletal repair, thereby leading to dramatic effects on bone healing. Although local therapy using growth factors such as bone morphogenetic protein (BMP)-2 and BMP-7 is another attractive option as an adjuvant therapy for skeletal repair based on a success of these use in spine fusion surgery (Einhorn 2003
therapy has some advantages over the local growth factor therapy. Local growth factor therapy requires surgical implantation with a carrier material at the lesion site, and is only effective for maximum of a few days. In contrast, PTH1-34
therapy can be applied to any type of skeletal disorders including the cases that would be treated non-surgically (i.e. cervical spine fractures), and can be commenced at any time. In addition, PTH1-34
therapy can be continued through the entire healing period.
The aim of the present article is to provide an overview of the published studies that demonstrated the efficacy of PTH1-34 therapy in a variety of skeletal repair models, and to review our current knowledge of the mechanism of PTH1-34 action on bone healing. In addition, we will discuss the potential clinical application of the PTH1-34 therapy for skeletal repair, and highlight the remaining issues that must be resolved to achieve clinical success.