Abstract
Hyperparathyroidism, which is increased parathyroid hormone (PTH) levels in the blood, could cause delayed or non-union of bone fractures. But, no study has yet demonstrated the effects of excess continuous PTH exposure, such as that seen in hyperparathyroidism, for fracture healing. Continuous human PTH1–34 (teriparatide) infusion using an osmotic pump was performed for stabilized tibial fractures in eight-week-old male mice to determine the relative bone healing process compared with saline treatment. Radiographs and micro-computed tomography showed delayed but increased calcified callus formation in the continuous PTH1–34 infusion group compared with the controls. Histology and quantitative histomorphometry confirmed that continuous PTH1–34 treatment significantly increased the bone callus area at a later time point after fracture, since delayed endochondral ossification occurred. Gene expression analyses showed that PTH1–34 resulted in sustained Col2a1 and reduced Col10a1 expression, consistent with delayed maturation of the cartilage tissue during fracture healing. In contrast, continuous PTH1–34 infusion stimulated the expression of both Bglap and Acp5 through the healing process, in accordance with bone callus formation and remodeling. Mechanical testing showed that continuously administered PTH1–34 increased the maximum load on Day 21 compared with control mice. We concluded that continuous PTH1–34 infusion resulted in a delayed fracture healing process due to delayed callus cell maturation but ultimately increased biomechanical properties.
Highlights
Hyperparathyroidism, which is increased parathyroid hormone (PTH) levels in the blood, could cause delayed or non-union of bone fractures
Evaluations for the contralateral tibiae demonstrated that continuous PTH1–34 infusion for two weeks caused osteopenia, and intermittent administration increased the bone mass, bone formation and resorption were enhanced in both PTH-treated groups (Supplemental Tables 1 and 2)
The Bglap expression peaked at 10 days in both PTH-treated and vehicle-treated mice and was significantly increased at 14, 21, and 35 days compared to the baseline. This increase in Bglap expression is consistent with an increased mineralized callus and delayed maturation of the osteoid matrix. These findings suggest that the delayed increase in bone callus by the continuous administration of PTH1–34 is primarily due to the delayed ossification of the increased cartilage and pre-mature bone callus
Summary
Hyperparathyroidism, which is increased parathyroid hormone (PTH) levels in the blood, could cause delayed or non-union of bone fractures. In 1970, Kalu et al demonstrated the anabolic effect on the bone of 20-day daily subcutaneous injection of low doses of both parathyroid extracts and pure PTH, resulting in an increased bone mineral density (BMD) in the rat femoral metaphysis[8]. These data suggested that intermittent low doses of human PTH might increase the BMD for patients with osteoporosis. Some clinical reports suggested that hyperparathyroidism, which is increased parathyroid hormone (PTH) levels in the blood, could cause delayed or non-union of bone fractures[22,23,24]. The effects of continuous PTH exposure for bone fracture healing have not been yet elucidated
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