Molecular enhancement of fracture healing - Is there a role for Bone Morphogenetic Protein-2, parathyroid hormone, statins, or sclerostin-antibodies?

Abstract

Enhancement of fracture healing has been a hot topic over the last two decades. This narrative review article is aimed to provide an update on current clinical use and evidence on four clinically available agents in the treatment of fracture healing: bone morphogenetic proteins-2 (BMP-2), parathyroid hormone, statins and sclerostin-antibodies. After first promising results from animal and clinical studies in the early 2000s, BMP-2 was studied mainly in open tibia shaft fractures treated with intramedullary nailing. There are conflicting results from different randomized clinical trials (RCTs) regarding fracture healing time and complications compared to BMP-2 free control treatment in open tibia fractures, as BMP-2 could not show significant differences in patients treated with reamed nails compared to BMP-2 free control treatment with reamed nailing only. Given that fact, its official use was limited in Europe to open tibia shaft fractures treated with unreamed tibial nailing by the European Medical Agency (EMA). Another more recent RCT failed to show equivalence of BMP- 2 together with allograft versus autograft for the treatment of tibia fractures with critical size defects. Recombinant human parathyroid hormone has proven anabolic effects on bone metabolism and is commonly used in treatment of severe osteoporosis. Different animal trials suggested an enhancement effect in fracture healing by PTH. In several clinical trials, PTH seems to have a stimulative effect for lower limb fractures. Statins, commonly used in treatment of dyslipidemia, could also enhance fracture healing in animal trials, especially when they were applied locally at the fracture site. For statins, there is only one RCT that failed to show significant effects for the oral administration of statins in undisplaced distal radius fractures. The role of sclerostin in fracture healing has more and more been understood. Application of sclerostin antibodies has been shown to be beneficial for fracture healing in animal trials. However, no RCTs on the effect of sclerostin antibodies on fracture healing have been performed yet. In conclusion, the "magic bullet" for molecular enhancement of fracture healing has not been identified yet, at least not with its optimal dosage and delivery method.

Keywords: BMP; Enhancement; Fracture healing; PTH; Sclerostin; Statin; Teriparatide.