Parathormone
Hormones

Potential Role of Parathyroid Hormone (PTH) in Fracture Repair

Stimulation of Fracture-Healing with Systemic Intermittent Parathyroid Hormone Treatment 2008

PTH is a major systemic regulator of the concentrations of calcium, phosphate, and active vitamin-D metabolites in blood and cellular activity in bone. PTH is naturally produced as an 84 amino-acid peptide. However, it has been determined that the N-terminal fragment, PTH 1-34 (teriparatide), can reproduce the major biological actions attributed to full-length PTH, including activation of adenylyl cyclase in bone and kidney cells, increased urinary excretion of cyclic adenosine monophosphate and phosphate in rats, and elevation of blood calcium in rats, dogs. Intermittently administered PTH and amino-terminal PTH peptide fragments or analogs also augment bone mass and currently are being introduced into clinical practice as therapies for osteoporosis.
There are two primary areas of PTH research with regard to fractures — fracture prevention and the use of PTH to enhance bone repair after fracture.
In a study, 270 male rats underwent standard closed femoral fractures, were divided into three groups that were administered daily subcutaneous injections of 5 mg/kg or 30 mg/kg of PTH (1-34) or vehicle (saline solution). Fractured bones were harvested twenty-one, thirty-five, or eighty-four days after fracture and analyzed with use of microquantitative computed tomography and mechanical testing (Enhancement of Experimental Fracture-Healing by Systemic Administration of Recombinant Human Parathyroid Hormone (PTH 1-34) 2005)

Fig. 1

Representative microquantitative computed tomographic images of fracture calluses from the three experimental groups on days 21, 35, and 84 after fracture. Radiodensity is increased in both the 5-mg/kg and the 30-mg/kg groups at each of the three time-points.
Older animals would respond to PTH as robustly as younger animals?
PTH treatment of healing fractures in these older rats led to both increased callus formation and increased mechanical strength by twenty-one days after fracture. The primary difference noted between fracture repair in old and young control rats was the rate at which maximum callus volume was achieved. Younger rats reached maximum callus volume by twenty days after fracture, while older control rats had little callus volume at twenty-one days and continued to accrue callus volume until finally peaking at fifty-six days after fracture. In contrast, both old and young PTH-treated animals had achieved maximum callus volumes by day 21 after fracture, demonstrating that PTH was able to enhance the rate of callus formation in older rats. PTH treatment also enhanced the ultimate load of the fractures by 160% at twenty-one days of healing and by 270% at fifty-six days in comparison with controls. These results demonstrate that PTH treatment can increase the rate of callus formation and restore bone strength even in older animals with diminished callus formation.
Cellular Mechanisms of PTH Action
The current consensus in this area is that PTH treatment increases bone mineral density and reduces fracture risk through the induction of an overall increase in coupled remodelling.
Several studies have noted that both osteoclas mediated bone resorption and osteoblast-mediated new bone formation are enhanced in response to intermittent PTH treatment. One crucial observation consistent among all of the fracture studies on PTH, is the increased callus volume.
PTH preferentially enhances chondrocyte recruitment and the rate of chondrocyte maturation in the fracture callus of mice. Both high-resolution radiographs (Faxitron X-Ray, Wheeling, Illinois) and microquantitative computed tomographic imaging demonstrate that PTH-treated fractures generate larger total callus volumes in this murine closed femoral fracture model (Fig. 2)

Fig. 2

A: Faxitron high-resolution radiographic images showing vehicle-treated versus PTH (1-34)-treated fractures at fourteen and twenty-one days after fracture.
B: Histological images of vehicle-treated versus PTH (1-34)-treated fractures at five and ten days after fracture (original magnification, •4). All sections were stained with safranin-O and fast green, which stains chondrogenic cells red. Note the increased cartilage volume at day 5 and day 10.
C through F: Graphic presentations of selected quantitative data from the microquantitative computed tomographic analysis of
fracture-healing. The results of a two-factor analysis of variance with a Tukey post hoc assessment are given on each plot. (If no differences were found, then there are no letter annotations or footnotes.)
C: Total callus volume, effect of treatment (p = 0.0016) and time (day 14 > day 28, p = 0.0043).
D: Callus length a not equal to b, effect of treatment (p = 0. 0001).
E: Bone volume, effect of treatment (p = 0.0318) and time (day 14, day 21 > day 10, p = 0.0001).
F: Average mineral density; groups not connected by the same horizontal line are significantly different. Effect over time (day 28 > day 21 > day 14 > day 10, p < 0.0001). Each group contains n = 5 bones. (Enhanced chondrogenesis and Wnt-signaling in parathyroid hormone treated fractures. J Bone Miner Res., published online August 6, 2007; doi10.1359/JBMR.070724.)

The actions of PTH and PTHrP are mediated by a G protein coupled receptor, referred to as PTH receptor 1 (PTHR1). Ligand binding to PTHR1 stimulates Gαs-mediated activation of adenylyl cyclase which stimulates cAMP production, and subsequent activation of protein kinase (PKA). PTHR1 also stimulates Gαq-mediated activation of protein kinase C (PKC). In addition, PTH activates β-arrestin-mediated activation of extracellular regulated kinase (ERK) signaling. β-arrestin A is also involved in desensitization of cAMP signaling by PTHR1 (Distinct β-Arrestin- and G Protein-dependent Pathways for Parathyroid Hormone Receptor-stimulated ERK1/2 Activation 2006).
In vitro and in vivo evidence indicates that transient activation of the PTHR1 activates multiple interconnected pathways leading to increased survival signaling, decreased replication of osteoblast progenitors, increased differentiation, and the production and/or activation of osteogenic growth factors. The result of these actions is an increase in osteoblast number beyond that needed to refill the resorption cavity created by osteoclasts. The relative importance of prodifferentiating and pro-survival pathways to the ability of intermittent PTH to increase osteoblast number remains to be determined, as does the potential contribution of pro-survival signaling in osteoblast progenitors, in both animals and humans.
All current research clearly demonstrates that systemic PTH treatment can enhance both endochondral and intramembranous bone repair. The published studies demonstrate that systemic PTH treatment leads to increased callus volumes, rates of new bone formation, and restoration of mechanical competence in models of both normal and impaired fracture repair. These studies also show that PTH affects both chondrogenic and osteogenic events during bone repair, suggesting that PTH treatment may be effective in a number of different defect sites and fracture types.

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