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

Abstract

Intermittent administration of parathyroid hormone (PTH) stimulates skeletal remodeling and is a potent anabolic agent in bone. PTH‐related protein (PTHrP) is anabolic acting on the same PTH1 receptor and is in therapeutic use for osteoporosis. The body of literature for PTH actions in fracture healing is emerging with promising yet not entirely consistent results. The objective of this review was to perform a literature analysis to extract up‐to‐date knowledge on the effects of intermittent PTH and PTHrP therapy in bone fracture healing. A literature search of the PubMed database was performed. Clinical case studies and articles related to “regeneration,” “implant,” and “distraction osteogenesis” were excluded. A narrative review was performed to deliberate the therapeutic potential of intermittent PTH administration on fracture healing. A smaller number of studies centered on the use of PTHrP or a PTHrP analog were also reviewed. Animal studies clearly show that intermittent PTH therapy promotes fracture healing and revealed the strong therapeutic potential of PTH. Human subject studies were fewer and not as consistent as the animal studies yet provide insight into the potential of intermittent PTH administration on fracture healing. Differences in outcomes for animal and human studies appear to be attributed partly to variable doses, fracture sites, age, remodeling patterns, and bone architectures, although other factors are involved. Future studies to examine the dose, timing, and duration of PTH administration will be necessary to further delineate the therapeutic potential of PTH for fracture healing in humans. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Intramedullary injury combined with osteoporosis therapeutics regulates targeted local osteogenesis

“…Thus, callus formation is essential for fracture healing. The intermittent administration of PTH has been shown to increase callus volume by increasing numbers of chondro- and osteo-progenitors at the bone fracture site in rats 22 , resulting in enhanced fracture healing 14 . While ALN does not enhance fracture healing, it also exerts no negative effect 23 , 24 .…”

“…We previously reported that intermittent administration of PTH promoted bone formation during osseous wound healing 11,12 and boosted bone anabolism when administered during growth 13 . Furthermore, intermittent administration of PTH greatly accelerates callus formation during fracture healing in animals 14 . The antiresorptive treatment by ALN has no negative effect on the healing of tibial osteotomies and hip fractures [15][16][17] .…”

Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice

“…In fact, osteoclast formation is essential for the anabolic activity of PTH in bone. 13 , 36 Interestingly, Kindlin-2 and PTH1R cooperatively regulate not only the osteoblast-mediated bone formation, but also the osteoclast formation in bone. While Kindlin-2 loss in osteoblastic cells increases the basal level osteoclast formation in bone, which is consistent with our previously published results, 30 it abolished the intermittent PTH stimulation of osteoclast formation in bone, which can be partially explained by the fact that intermittent PTH induces expression of RANKL in control but not cKO bones.…”

“…Intermittent administration of PTH, a treatment for severe osteoporosis approved by the United States Food and Drug Administration, increases the bone mass and bone mineral density (BMD) and improves bone microstructure in a number of animal models and in humans. 13 PTH exerts its anabolic activity in bone through the action of PTH1R that is primarily expressed in cells of the osteoblastic lineage. PTH promotes the mesenchymal stem cell (MSC) differentiation into osteoblasts and subsequent osteoblast proliferation and differentiation and inhibits osteoblast apoptosis.…”

Role of PTHrP nuclear localization and carboxyl terminus sequences in postnatal spinal cord development

“…Both PTHrP and PTH bind to type 1 PTH receptor (PTHR1). Unlike PTH generated from parathyroid glands, PTHrP is produced by mesenchymal stem cells, certain tumors (squamous cell cancer of the lung, breast cancer, renal carcinoma, and prostate cancer) (Martin & Johnson, 2019; R. Zhang et al., 2019), and many other cell lines (keratinocytes, vascular smooth muscle cells, neurons, astrocytes, schwann cells, osteocytes, chondrocytes, and beta cells of the pancreas) (Funk et al., 2001; Macica et al., 2006; Martin, 2016; Shepherd et al, 2018; Weir et al., 1990; Yamashita & McCauley, 2019). The PTHrP peptide fragments consist of an N‐terminal (amino acids 1–36), mid‐region (37–86), nuclear localization sequence (NLS) (87–107), and C‐terminal region (108–139).…”