Growth hormone: does it have a therapeutic role in fracture healing?

BACKGROUND: The role of growth hormone (GH) in augmenting fracture healing has been postulated for over half a century. GH has been shown to play a role in bone metabolism and this can be mediated directly or indirectly through IGF-I. OBJECTIVES: The use of GH was evaluated as a possible therapeutic agent in augmenting fracture healing. METHOD: A literature search was undertaken on GH and its effect on bone fracture healing primarily using MEDLINE/OVID (1950 to January 2009). Key words and phrases including 'growth hormone', 'insulin like growth factor', 'insulin like growth factor binding protein', 'insulin like growth factor receptor', 'fracture repair', 'bone healing', 'bone fracture', 'bone metabolism', 'osteoblast' and 'osteoclast' were used in different combinations. Manual searches of the bibliography of key papers were also undertaken. RESULTS: Current evidence suggests a positive role of GH on fracture healing as demonstrated by in vitro studies on osteoblasts, osteoclasts and the crosstalk between the two. Animal studies have demonstrated a number of factors influencing the effect of GH in vivo such as dose, timing and method of administration. Application of this knowledge in humans is limited but clearly demonstrates a positive effect on fracture healing. Concern has been raised in the past regarding the safety profile of the pharmacological use of GH when used in critically ill patients. CONCLUSION: The optimal dose and method of administration is still to be determined, and the safety profile of this novel use of GH needs to be investigated prior to establishing its widespread use as a fracture-healing agent.

TGF-beta3: A potential biological therapy for enhancing chondrogenesis.

BACKGROUND: TGF-beta has been proposed to stimulate chondrogenesis through intracellular pathways involving small mothers against decapentaplegic proteins (Smads). OBJECTIVE: To examine the use of exogenous TGF-beta3 to promote new hyaline cartilage formation. METHODS: An overview of in vitro and in vivo evidence on the effects of TGF-beta3 on cartilage regeneration. RESULTS/CONCLUSION: There is robust in vitro evidence suggesting a positive dose- and time-dependent effect of TGF-beta3 on anabolic chondrogenic gene markers such as alpha1-collagen type II and cartilage oligomeric matrix protein in human mesenchymal stem cells. TGF-beta3 cultured with silk elastin-like polymer scaffold carrier exhibits significantly increased glycosaminoglycan and collagen content. In vivo data showed that TGF-beta3 cultured with ovine mesenchymal stem cells in a chitosan scaffold stimulated the growth of hyaline cartilage that was fully integrated into host cartilage tissue of sheep. We highlight the potential for the clinical enhancement of cartilage formation through the use of TGF-beta3 with a suitable dose and scaffold carrier.

Prostaglandin EP2 and EP4 receptor agonists in bone formation and bone healing: In vivo and in vitro evidence.

BACKGROUND: Using agonists that selectively stimulate PGE2 receptors, the adverse effects that have limited the clinical utility of PGE2 can be avoided and there may be potential for their use as therapeutic agents in the treatment of bone loss in humans. OBJECTIVE: A comprehensive review of the recent literature on the effect of prostaglandins and their agonists on bone mineral density and fracture healing. METHODS: In vitro and in vivo evidence was collected using medical search engines MEDLINE (1950 to March 2008) and EMBASE (1980 to March 2008) databases. RESULTS/CONCLUSION: EP4 receptors have been identified in human osteoblast cell lines and have also been shown to activate osteoblast directly and osteoclast indirectly via osteoblastic activation. Although there are strong in vitro and in vivo collective data indicating that EP2 receptors may have a role in mediating the anabolic effects of PGE2 on bone, to date no functional EP2 receptors have been identified on human osteoblasts or osteoclasts. This suggests that PGE2 effect on bone formation and resorption in humans may be governed by activation of the EP4 receptor on osteoblasts. Selective EP4 receptor agonists may therefore provide therapeutic potential for systemic use in the treatment of osteoporosis and fracture healing. Further studies need to be carried out in order fully elicit the role of EP2 receptor agonists in fracture healing and bone formation in humans.

Intraoperative anaphylaxis due to gelofusine in a patient undergoing intramedullary nailing of the femur: a case report.

BACKGROUND: Although uncommon, anaphylaxis due to a colloid plasma expander can occur peri-operatively CASE PRESENTATION: We present a case of an intra-operative cardiac arrest in a 72 year old Caucasian male patient who underwent prophylactic intramedullary nailing for a proximal femoral metastasis from prostate cancer. The patient was resuscitated successfully and the procedure was completed uneventfully. Elevated serum tryptase levels confirmed the diagnosis of an anaphylactic reaction and positive allergy skin prick testing identified gelofusine as the causative agent. CONCLUSION: A high index of suspicion, prompt diagnosis and rapid institution of treatment are essential for a safe outcome following such reactions. To our knowledge, this is the first published report of such a severe reaction to gelofusine infusion that occurs during an orthopaedic procedure.

Targeting bone morphogenetic protein antagonists: in vitro and in vivo evidence of their role in bone metabolism.

BACKGROUND: Bone morphogenetic proteins (BMPs) and their antagonists are involved in fracture healing. Antagonists regulate BMPs by blocking signal transduction or interfering with transcription factors at the nucleus. OBJECTIVE: To examine targeting of BMP antagonists to manipulate osteogenesis. METHODS: An overview of in vitro and in vivo evidence on effects of BMP antagonists on bone metabolism. RESULTS/CONCLUSION: There is in vitro evidence suggesting that overexpression of noggin and gremlin inhibits osteogenic differentiation, markedly decreases alkaline phosphatase (ALP) levels and impedes R-Smad (1/5/8) phosphorylation in murine cell lines. Knockdown of chordin results in a threefold increase in ALP activity in human mesenchymal stem cells. In vivo data shows that inhibition of noggin leads to increased bone regeneration in mice. Noggin and sclerostin can combine in a mutually inhibitory complex, neutralising their individual inhibitory effects. This allows BMP signalling to proceed to osteoinduction. We highlight the potential for clinical enhancement of bone formation through inhibition of BMP antagonists.

Statins: under investigation for increasing bone mineral density and augmenting fracture healing.

BACKGROUND: Statins are 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors and have been shown to possess anti-lipidaemic properties effective in lowering cholesterol. Recent evidence has suggested beneficial pleiotropic effects, including that of fracture healing, alongside its widely accepted ability to reduce the incidence of cardiovascular disease. OBJECTIVES: A comprehensive review of the recent literature on the effect of statins on bone mineral density and fracture healing. METHODS: Medline/Ovid and EMBASE search and manual search of bibliography of key papers, on the effects of statins on bone metabolism including in vitro and in vivo studies, as well as clinical trials on the effects of statins on bone mineral density and fracture risk. RESULTS/CONCLUSIONS: There is robust in vitro and in vivo evidence to suggest the anabolic effects of statins on bone metabolism. Although evidence in patients with osteoporosis is conflicting, several studies have shown that the use of statins is associated with increases in bone mass density and reduction in fracture risk. Conflicting studies identified may be due to different routes of administration, types of statins employed and low doses used. Taken together, there is strong evidence to suggest that statins have beneficial effects on fracture healing that would support further clinical trials investigating such properties.

The effect of beta-blockers on bone metabolism as potential drugs under investigation for osteoporosis and fracture healing.

BACKGROUND: beta-Adrenergic receptor antagonists (beta-blockers) have a well-recognised antihypertensive action that is mediated through a reduction in cardiac output and in the release of renin from the kidneys and inhibition of the action of endogenous catecholamines on beta-adrenergic receptors. This class of drugs has been shown to reduce the incidence of cardiovascular disease. Recent evidence suggests that beta-blockers may also have an effect on bone structure, metabolism and fracture healing. OBJECTIVE: This paper reviews in vitro and in vivo data that suggest beta-blockers have primarily an anabolic effect on bone metabolism. RESULTS: The sympathetic nervous system has a catabolic effect on bone, and in vitro studies have shown that adrenergic agonists stimulate bone resorption. The beta-blocker propranolol has been shown to increase bone formation in ovariectomised female rats. Also, recent observational clinical studies provide evidence to show that beta-blockers are associated with reduction in fracture risk in both men and women. CONCLUSION: Although there are some controversial studies, most research concludes that beta-blockers show promise in the treatment of osteoporosis and fracture healing.

The effect of anticoagulant pharmacotherapy on fracture healing.

BACKGROUND: There is in vitro and in vivo evidence that anticoagulants impair normal bone metabolism, and it is widely believed that this may impair fracture healing. However, there are only a few heterogeneous in vivo animal studies confirming this and the mechanisms are not fully understood. OBJECTIVE: To review the literature concerning the effects of anticoagulants on fracture healing, and to present current understanding of the mechanisms involved by reviewing in vivo studies of bone biology and in vitro studies of bone cells. METHODS: A systematic search of Medline and other databases was combined with manual searching of bibliographies of key papers to identify relevant studies in the English and German languages. CONCLUSION: There is strong evidence that warfarin, heparin and aspirin retard fracture healing. The preferential use of low molecular weight heparins is advocated to minimise this. Fondaparinux has not shown any impairment in vitro. Further studies of fondaparinux, the timing of anticoagulation therapy and the mechanisms of action of these agents are of paramount importance.