Continuous infusion of PTH1–34 delayed fracture healing in mice

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.

Effects of Intermittent Administration of Parathyroid Hormone and Parathyroid Hormone‐Related Protein on Fracture Healing: A Narrative Review of Animal and Human Studies

“…Because bone is a target organ of PTH, continuously elevated serum PTH levels in PHPT patients likely affect bone fracture healing. A study showed that continuous teriparatide infusion to mice resulted in delayed healing of tibial fractures . Although the literature on fracture healing in PHPT patients is sparse, case reports may provide insight into the effect of PHPT on healing .…”

“…A study showed that continuous teriparatide infusion to mice resulted in delayed healing of tibial fractures. (93) Although the literature on fracture healing in PHPT patients is sparse, case reports may provide insight into the effect of PHPT on healing. (94)(95)(96)(97)(98) Lancourt and Hochberg reported 4 fracture cases with delayed healing or nonunion in PHPT patients.…”

Pthlha and mechanical force control early patterning of growth zones in the zebrafish craniofacial skeleton

“…We detected pthr1a pth1ra expression uniformly in the developing ch (data not shown), but pth1rb may play a role in this asymmetry. Moreover, Parathyroid Hormone 1 (Pth1) acts like Pthlh in cartilage and can be carried in the bloodstream in rodents Development • Accepted manuscript (Jee et al, 2018;Yukata et al, 2018). Finally, pth4 is an ancestral Pth found in zebrafish but lost in eutherian mammals, that is expressed in the central nervous system, activates Pth1r receptors, and represses mineralization in the skeleton at long range (Suarez-Bregua et al, 2017).…”

Efficacy of Teriparatide in Comminuted Fracture Healing in Lower Limb: A Retrospective Study

“…This is termed as "anabolic index" of the drug. Teriparatide acts by promoting proliferation and differentiation of chondro as well as osteo-progenitor mesenchymal origin stem cells, maturation of chondrocytes, bone matrix protein production and formation of osteoclasts or osteoclastogenesis [10,11].…”

“…Mishra et al in 2019 in their prospective study on use of teriparatide on delayed union of bone fracture demonstrated enhanced healing of fracture wound[9].Kim et al in 2019 in their study showed that teriparatide treatment caused significant increase in Harris Hip Score (p=0.02) and reduction in visual analogue pain scale score (p=0.0005). The mean post-operative time required for healing of fracture was found to decrease in patient treatment with teriparatide when compared to those who did not receive this therapy (i.e., 12.1 and 14.8 weeks, respectively)[10].Yukata et al in 2018 in their study showed that a continuous PTH 1-34 administration or infusion led to a delay in healing of a fracture wound due to delay in maturation of callus[11]. Saraf and Munot in 2017 demonstrated that fractures which were treated with 20 µg dosage of teriparatide demonstrated only signs of union associated with large amount of callus formation with significant reduction in radiographic union and early patient rehabilitation[12].…”