Use of Teriparatide to improve fracture healing: What is the evidence?

Teriparatide is a recombinant form of the biologically active component of Parathyroid hormone. It has been shown to increase bone mass and prevent fractures in osteoporotic bone. It is licensed by the Food and Drug Administration for the treatment of Osteoporosis. Over the last decade, a growing body of evidence has accumulated suggesting a role for Teriparatide in the management of fractures. Studies in both normal and delayed healing models have shown improvement in callus volume and mineralisation, bone mineral content, rate of successful union and strength at fracture sites. However most of these results have been derived from animal studies. The majority of this research on humans has comprised low level evidence, with few randomised controlled trials, many case reports and case series. Nevertheless, the results from these studies seem to support research from animal models. This has led to a growing number of clinicians using Teriparatide “off license” to treat fractures and non-unions in their patients. This review presents a critical appraisal of the current evidence supporting the use of Teriparatide for fracture healing, delayed unions and non unions and in the setting of osteoporotic fractures, the studies producing this evidence and their transferability to human beings.     

The use of bone morphogenetic protein 7 in fracture non‐unions

Objective: To assess the rate of clinical and radiological union with the use of bone morphogenetic protein 7 (BMP‐7) in a range of fractures. Methods: This case series retrospectively reviews a series of 16 fracture non‐unions in 13 patients. These patients were treated with the commercially available BMP‐7. Time to radiological and clinical union was assessed by serial out‐patient follow‐up. Results: At nine months post‐surgery in which BMP‐7 was added, 12 of 16 non‐unions had achieved clinical and radiographic union. Three patients required repeat grafting. The mean time to union was 5.1 ± 1.6 months after the application of BMP‐7. Conclusion: The use of the osteo‐inductive agent, BMP‐7 results in good clinical and radiological outcomes which are not restricted to tibial non‐unions.     

Use of bone morphogenetic proteins in traumatology

An estimated 5–10% of all fractures show impaired healing, leading to delayed union, or non-union. Chemical, or physical methods to accelerate bone healing are of great interest to the orthopaedic and trauma community. Research over the last 20 years has established that successful fracture healing is steered by specific growth factors. Of these, the bone morphogenetic proteins (BMPs) are probably the most important. The signalling pathway of these proteins is tightly regulated, overseeing a finely orchestrated cascade of events that occur after a fracture. The promising results of BMPs in preclinical studies have recently cleared the way for their use in specific fractures, or non-unions in clinical practice. The purpose of this work is to give a brief overview of BMPs and to review the clinical data currently available on the use of BMPs in fracture healing.     

The challenges of promoting osteogenesis in segmental bone defects and osteoporosis

Conventional clinical management of complex bone healing scenarios continues to result in 5–10% of fractures forming non‐unions. Additionally, the aging population and prevalence of osteoporosis‐related fractures necessitate the further exploration of novel ways to augment osteogenesis in this special population. This review focuses on the current clinical modalities available, and the ongoing clinical and pre‐clinical research to promote osteogenesis in segmental bone defects, delayed unions, and osteoporosis. In summary, animal models of fracture repair are often small animals as historically significant large animal models, like the dog, continue to gain favor as companion animals. Small rodents have well‐documented limitations in comparing to fracture repair in humans, and few similarities exist. Study design, number of studies, and availability of funding continue to limit large animal studies. Osteoinduction with rhBMP‐2 results in robust bone formation, although long‐term quality is scrutinized due to poor bone mineral quality. PTH 1‐34 is the only FDA approved osteo‐anabolic treatment to prevent osteoporotic fractures. Limited to 2 years of clinical use, PTH 1‐34 has further been plagued by dose‐related ambiguities and inconsistent results when applied to pathologic fractures in systematic human clinical studies. There is limited animal data of PTH 1‐34 applied locally to bone defects. Gene therapy continues to gain popularity among researchers to augment bone healing. Non‐integrating viral vectors and targeted apoptosis of genetically modified therapeutic cells is an ongoing area of research. Finally, progenitor cell therapies and the content variation of patient‐side treatments (e.g., PRP and BMAC) are being studied. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1559–1572, 2018.     

A prospective comparison for suspected scaphoid fractures: bone scintigraphy versus clinical outcome

Early diagnosis and treatment of scaphoid fractures limits the number of delayed and non-unions. Bone scintigraphy proved to be a sensitive diagnostic tool for the detection of occult scaphoid fractures. However, the results have to be interpreted with care. OBJECTIVE: To prospectively correlate the results of bone scintigraphy with clinical outcome. METHODS: In a prospective study, we analysed 50 consecutive patients with signs of a scaphoid fracture at physical examination but no evidence of a scaphoid fracture on scaphoid radiographs. All patients had a protocolised follow up at fixed intervals. The clinical outcome was defined according to a standardised algorithm. MAIN RESULTS: Bone scintigraphy revealed 32% (16/50) occult scaphoid fractures and 40% (20/50) occult other fractures. Clinical outcome proved that bone scintigraphy was false positive in five patients and in one case false negative for a scaphoid fracture. CONCLUSION: Bone scintigraphy in combination with protocolised physical examination is the gold standard for patients with signs of a scaphoid fracture that cannot be proven on scaphoid radiographs.     

Use of bone morphogenetic proteins for treatment of non-unions and future perspectives

Still a major problem in orthopedic and trauma surgery is the delayed healing or the non-union of long bone fractures. Demographic data reveal that due to the steadily rising age of the population, complications with the musculoskeletal system will increase during the next years. Bone morphogenetic proteins (BMPs) have successfully been applied in clinic for the treatment of delayed healing and non-unions. The broad difference concerning the indication, timing of treatment, dosage and application technique of BMPs calls for the need to perform further prospective studies in order to standardize the treatment and furthermore optimize the procedures or even develop new therapeutic strategies. For example, the application technique may be improved and in some cases injectable BMP preparations could be of use. Also the coating of implants with growth factors might be valuable in order to stimulate bone healing and to prevent delayed healing or non-union. This article tries to discuss some of the open questions, however can and will not reflect the absolute standard of care. To make the BMP treatment a standard of care, more clinical data and long time experiences are necessary. The intramedullary application of BMP in combination with autologous or allogenic bone grafts or bone substitutes after debridement and stabilization with implants seems to be an adequate procedure for treatment of atrophic non-unions. However, the total number of patients is too small to draw final conclusions. Further clinical studies need to be performed in the future.     

Wachstumshormone und BMP

BMP (bone morphogenetic proteins) belong to the TGFβ superfamily and appear to play a central role in fracture healing. Two growth factors have been in use since 2001 as an approved therapy option for the delayed healing of fractures or open lower leg fractures: BMP-7 for delayed fracture healing and BMP-2 for open lower leg fractures. The aim of the present study was to examine the effectiveness of the BMP in fracture healing and compare fracture healing without the use of bone growth factors. Patients who were treated with BMP-7 following repeated attempts to treat atrophic pseudoarthrosis of the tibia were compared with a large standardized collective of patients with first-time spongiosa plastic. Patients receiving BMP-7 showed significantly better bone fusion in the fracture area at radiological examination at four months. In order to prove the advantages of this procedure, as well as to be able to recommend it as a treatment modality, further studies on larger patient collectives and prospective control groups are needed.     

Low-intensity pulsed ultrasound increases bone volume, osteoid thickness and mineral apposition rate in the area of fracture healing in patients with a delayed union of the osteotomized fibula

INTRODUCTION: Low-intensity pulsed ultrasound (LIPUS) accelerates impaired fracture healing, but the exact mechanism is unknown. The aim of this study was to investigate how LIPUS affects bone healing at the tissue level in patients with a delayed union of the osteotomized fibula, by using histology and histomorphometric analysis to determine bone formation and bone resorption parameters. MATERIALS AND METHODS: Biopsies were obtained from 13 patients (9 female, 4 male; age 42-63) with a delayed union of the osteotomized fibula after a high tibial osteotomy, treated for 2-4 months with or without LIPUS in a randomized prospective double-blind placebo-controlled trial. In the histological sections of the delayed union biopsies, 3 areas of interest were distinguished, i.e. 1) area of new bone formation at the fracture ends, 2) area of cancellous bone, and 3) area of cortical bone. Histomorphometrical analysis was performed to determine bone formation and bone resorption parameters (as well as angiogenesis). RESULTS: In LIPUS-treated delayed unions, endosteal callus formation by direct bone formation without a cartilage intermediate as well as indirect bone formation was observed, while in untreated controls only indirect bone formation was observed. In the area of new bone formation, LIPUS significantly increased osteoid thickness by 47%, mineral apposition rate by 27%, and bone volume by 33%. No increase in the number of blood vessels was seen in the newly formed bony callus. In the area of cancellous bone, bone volume was significantly increased by 17% whereas no effect on osteoid thickness and mineral apposition rate was seen. LIPUS did not affect osteoid volume, osteoid maturation time, number of osteocytes, osteocyte lacunae, or osteoclast-like cells in any of the areas of interest. CONCLUSIONS: Our results suggest that LIPUS accelerates clinical fracture healing of delayed unions of the fibula by increasing osteoid thickness, mineral apposition rate, and bone volume, indicating increased osteoblast activity, at the front of new bony callus formation. Improved stability and/or increased blood flow, but probably not increased angiogenesis, might explain the differences in ossification modes between LIPUS-treated delayed unions and untreated controls.     

Extracorporeal shockwave therapy: A systematic review of its use in fracture management

Extracorporeal shockwave therapy is increasingly used as an adjuvant therapy in the management of nonunions, delayed unions and more recently fresh fractures. This is in an effort to increase union rates or obtain unions when fractures have proven recalcitrant to healing. In this report we have systematically reviewed the English language literature to attempt to determine the potential clinical efficacy of extracorporeal shockwave therapy in fracture management. Of 32 potentially eligible studies identified, 10 were included that assessed the extracorporeal shockwave therapy use for healing nonunions or delayed unions, and one trial was included that assessed its use for acute high-energy fractures. From the included, studies'' overall union rates were in favor of extracorporeal shockwave therapy (72% union rate overall for nonunions or delayed unions, and a 46% relative risk reduction in nonunions when it is used for acute high-energy fractures). However, the methodologic quality of included studies was weak and any clinical inferences made from these data should be interpreted with caution. Further research in this area in the form of a large-scale randomized trial is necessary to better answer the question of the effectiveness of extracorporeal shockwave therapy on union rates for both nonunions and acute fractures.     

Low-intensity pulsed ultrasound for bone healing: an overview

Low-intensity ultrasound is a biophysical form of intervention in the fracture-repair process, which through several mechanisms accelerates healing of fresh fractures and enhances callus formation in delayed unions and nonunions. The goal of this review is to present the current knowledge obtained from basic science and animal studies, as well as existing evidence from clinical trials and case series with the different applications of ultrasound in the management of fractures, delayed unions, nonunions and distraction osteogenesis. Low-intensity pulsed ultrasound is currently applied transcutaneously, although recent experimental studies have proven the efficacy of a trans-osseous application for both enhancement and monitoring of the bone healing process with modern smart implant technologies.     

Effect of repeated irrigation and debridement on fracture healing in an animal model.

The initial management of open fractures often requires repeated irrigation and debridement of the open wound and stabilization of the fracture. However, washing out the fracture hematoma could delay the early healing process of stable fractures. Because delayed union and non-union are serious complications, the effect of repeated irrigation and debridement on the fracture healing process was investigated. Twenty-four rabbits received unilateral, transverse. mid-tibial open osteotomies with a 3 mm gap. The osteotomy site was thoroughly irrigated and stabilized with double-bar external fixators. The osteotomy sites in the study groups underwent repeat irrigation and debridement on either the third day (Group II), the fourth day (Group III), or consecutively on the first and second days (Group IV) after the index procedure. The bone healing was assessed with weekly radiographs and peripheral quantitative computerized tomographs. In Group I (control), all osteotomies healed radiographically before the tenth week. In Group II, five out of six osteotomies healed radiographically before the tenth week. In Group III, only two of five osteotomies healed before the tenth week. In Group IV, none of the osteotomies had healed by week fifteen. All of the non-healed osteotomies exhibited atrophic non-unions at fifteen weeks. Compared to the control group at the tenth week, the average bone mineral content at the osteotomy site and the area of high mineral density callus (> or = 890 mg/cm3) were significantly lower in Groups III (63%, p = 0.002 and 95%, p = 0.05, respectively) and IV (99%, p < 0.001 and 100%, p = 0.05, respectively). The results of this study suggest that repeated irrigation and debridement, associated with persistent rigid immobilization, may contribute to the development of delayed unions or atrophic non-unions.     

Low-intensity pulsed ultrasound affects RUNX2 immunopositive osteogenic cells in delayed clinical fracture healing

IntroductionOsteogenic cell proliferation and differentiation play an important role in adequate fracture healing, and is target for osteoinductive therapies in delayed fracture healing. The aim of this study was to investigate whether low-intensity pulsed ultrasound enhances fracture healing at the tissue level in patients with a delayed union of the osteotomized fibula through an effect on the presence of RUNX2 immunopositive osteogenic cells. The effect was studied in both atrophic and hypertrophic delayed unions.Materials and methodsBiopsies were obtained from 6 female and 1 male patient (age 43–63) with a delayed union of the osteotomized fibula after a high tibial osteotomy treated for 2–4 months with or without low-intensity pulsed ultrasound in a randomized prospective double-blind placebo-controlled trial. Immunolocalization of RUNX2 protein was performed to identify osteogenic cells. Histomorphometrical analysis was performed to determine the number of cells expressing RUNX2 located within and around the newly formed woven bone at the fracture end (area of new bone formation), and up to 3 mm distant from the fracture end.ResultsCells expressing RUNX2 were present in all histological sections of control and low-intensity pulsed ultrasound-treated bone evaluated. Within the area of new bone formation, RUNX2 immunopositive cells were found in the undifferentiated soft connective tissue, at the bone surface (presumably osteoblasts), and within the newly formed woven bone. Low-intensity pulsed ultrasound treatment of fibula delayed unions significantly reduced the number of RUNX2 immunopositive cells within the soft connective tissue at the fracture ends, whereas the number of RUNX2 immunopositive cells at the bone surface was not affected. The number of RUNX2 immunopositive cells was similar for the atrophic and hypertrophic delayed unions.ConclusionsImmunolocalization of RUNX2 positive cells in delayed unions of the fibula reveals that delayed clinical fracture healing does not result in impairment of osteogenic cell proliferation and/or differentiation at the tissue level, even if delayed unions are clinically regarded as atrophic. Reduced number of osteogenic RUNX2 immunopositive cells within the soft connective tissue, and unchanged number of RUNX2 immunopositive cells at the bone surface, implicate that low-intensity pulsed ultrasound does not increase osteogenic cell presence, but likely affects osteogenic cell differentiation.     

Longitudinal in vivo monitoring of callus remodeling in BMP-7- and Zoledronate-treated fractures

Pharmacological interventions that combine pro-anabolic and anti-catabolic drugs to treat recalcitrant fractures have shown remarkable efficacy in augmenting the regenerative response. Specifically, in rodent models of fracture repair, treatment with BMP-7 and Zoledronate (ZA) has almost uniformally resulted in complete union. However, delayed remodeling may be problematic for ZA-treated fractures. The increase in newly formed bone is substantial but if translated in humans, delayed remodeling may delay functional recovery. Our objective was to determine if, and to what extent, bone morphogenetic protein (BMP) (in synergistically administered BMP-7 + ZA) can modulate the delayed hard callus remodeling caused by ZA. Callus remodeling in BMP-7-only and BMP-7 + ZA-treated osteotomies were monitored using in vivo µCT to follow the progression of healing at 6-week intervals over 24 weeks in an open femoral fracture rat model. None of the groups recovered baseline cortical bone volumes within 24 weeks post-osteotomy. Treatment prolonged the remodeling phase but the kinetics of remodeling appeared to differ between BMP and BMP + ZA groups. However, the mechanical characteristics were largely restored. Callus/bone volumes in BMP-only treated fractures peaked as early as week 3 suggesting that remodeling is stimulated prematurely. However, this rate of remodeling was not maintained as BMP-7 was found to exhibit negligible changes in callus/bone volumes between weeks 6 and 18, whereas declines in callus/bone volumes were present at these time points in the BMP-7 + ZA group. Our findings suggest that inclusion of ZA as an anti-catabolic agent may not be detrimental to the regenerative process despite a prolonged remodeling phase.     

P-15 small peptide bone graft substitute in the treatment of non-unions and delayed union. A pilot clinical trial

Treatment of non-unions and delayed unions often requires osteogenic material. Recently, a biomimetic bone matrix that simulates the cellular environment of hard tissue, identified as P-15, was introduced to the orthopaedic community. A total of 22 patients with mal-union or delayed union fractures was treated from June 2000 to October 2003 with P15- bone graft substitute (P15-BGS) in the site of fracture and mostly with internal fixation. Patients were examined by independent radiographic analysis. Assessment criteria included time elapsed until bone bridging and time to full consolidation. In addition, histological assessment of the callus was done at the time of recovery of metal implants in five patients. Full consolidation was achieved in 90% (20 out of 22) of the patients treated with P15-BGS. The average time for full consolidation was 4.2 months. Histological assessment of the fracture callus in five of the patients confirmed the positive clinical and radiographic results. P15-BGS appears to offer a safe, economical and clinically useful alternative to autograft in the repair of ununited fractures. These results compare favourably with those in the published literature as an alternative to autograft.     

Bone morphogenetic proteins in clinical applications

The role of bone morphogenetic proteins (BMPs) in bone healing has been shown in numerous animal models. To date, at least 20 BMPs have been identified, some of which have been shown in vitro to stimulate the process of stem cell differentiation into osteoblasts in human and animal models. Having realized the osteoinductive properties of BMPs and having identified their genetic sequences, recombinant gene technology has been used to produce BMPs for clinical application - most commonly, as alternatives or adjuncts in the treatment of cases in which fracture healing is compromised. BMP-2 and BMP-7 are approved for clinical use in open fractures of long bones, non-unions and spinal fusion. However, despite significant evidence of their potential benefit to bone repair and regeneration in animal and preclinical studies, there is, to date, a dearth of convincing clinical trials. The purpose of this paper is to give a brief overview of BMPs and to critically review the clinical data currently available on the use of BMP-2 and BMP-7 in fracture healing.     

Co-expression of BMPs and BMP-inhibitors in human fractures and non-unions

Bone morphogenetic proteins (BMPs) are increasingly being used clinically to enhance fracture repair and healing of non-unions. However, the potential efficacy of supraphysiological dosing for clinical results warrants further clarification of the BMP signaling pathway in human fracture healing. As BMP signaling can be fine-tuned at numerous levels, the role of BMP-inhibitors has become a major focus. The aim of the present study was to document co-expression of BMPs, pSmad 1/5/8, and BMP-inhibitors in human fracture callus and human non-unions. Using human tissue of fracture callus (n=14) and non-unions (n=4) we documented expression of BMPs (BMP2, BMP3 and BMP7), pSmad 1/5/8 and the BMP-inhibitors noggin, gremlin, chordin, Smad-6, Smad-7 and BAMBI. Co-expression of pSmad 1/5/8, BMPs and BMP-inhibitors was noted in the osteoblasts of fracture callus as well as of non-unions. Expression of BMP-inhibitors was generally stronger in non-unions than in fracture callus. The most pertinent differences were noted in the cartilaginous tissue components. Expression of BMP2 in chondrocytes was markedly decreased in non-unions compared to fracture callus and that of BMP7 was almost completely absent. Expression of BMP-inhibitors was almost the same in osteoblasts, chondrocytes and fibroblasts of fracture callus and well as in non-unions. Interestingly, although BMP ligands were present in the chondrocytes and fibroblasts of non-unions, they did not co-express pSmad 1/5/8 suggesting that BMP signaling may have been inhibited at some point before Smad 1/5/8 phosphorylation. These results suggest co-expression of BMP, pSmad 1/5/8 and BMP-inhibitors occurs in human fracture callus as well as non-unions but the relative expression of BMPs vs. BMP-inhibitors was different between these two tissue types. In contrast to our expectations, the expression of BMP inhibitors was comparable between fracture callus and non-unions, whereas the expression of BMPs was notably lower in the cartilaginous component of the non-unions in comparison to fracture callus. Based on these results, we believe that aberrations in the BMP-signaling pathway in the cartilaginous component of fracture healing could influence clinical fracture healing. An imbalance between the local presence of BMP and BMP-inhibitors may switch the direction towards healing or non-healing of a fracture.     

Management of fractures of the humerus in patients who have an injury of the ipsilateral brachial plexus

Twenty-one adults who had a fracture of the middle of the humeral shaft and an injury of the ipsilateral brachial plexus were followed for an average of twenty-eight months. Only two of these patients showed evidence of neurological improvement. Of the eleven patients who had an associated traumatic injury to the brain, eight were treated non-operatively and three, operatively. The presence of a fracture of the humerus in a flail extremity has been found to delay rehabilitation markedly and to result in prolonged hospitalization. Eleven fractures were treated non-operatively with a brace or cast, and there were five non-unions, two delayed unions, and two malunions. Of the ten fractures that were treated operatively, three that were treated by compression-plating all united. Two fractures were treated by external fixation; one had a delayed union and one, a malunion. In the remaining five patients, who were treated with an intramedullary rod, there were two non-unions, one delayed union, and one malunion.     

Notwendigkeit von „bone morphogenetic proteins“ in der Frakturbehandlung

Bone morphogenetic proteins (BMP) are bone growth factors. They are released locally following a fracture event and stimulate the healing process right through to bone remodelling. Since 2001 it has been possible to use BMP2 and BMP7 as medications for genetic engineering; BMP2 is indicated for open fractures of the lower leg and BMP7, for nonunion in the tibia. Delayed fracture healing and nonunion are common, being observed in up to 10% of all cases (up to 30% in risk groups). Quite apart from the personal, sometimes disastrous, consequences for the individual patient, they also represent a considerable loss to the national economy. The conventional treatments for nonunion (including autologous and allogeneic bone transplantation, dynamisation of the nail or a strained plate fixation) are not always successful. The success rate of initial cancellous bone transplantation in the lower leg for delayed fracture healing is only 60–70%. In our patient population (26 tibial fractures treated with BMP7; average of 3 previous operations) healing was achieved with no further surgery in 89% of cases. In view of the high economic costs of delayed healing and the decidedly higher success rate of BMP implantation, this medication should be used at an early stage despite its high cost.     

The clinical use of bone morphogenetic proteins revisited: a novel biocompatible carrier device OSTEOGROW for bone healing

Purpose

The purpose of this study was to revise the clinical use of commercial BMP2 (Infuse) and BMP7 (Osigraft) based bone devices and explore the mechanism of action and efficacy of low BMP6 doses in a novel whole blood biocompatible device OSTEOGROW.

Methods

Complications from the clinical use of BMP2 and BMP7 have been systemically reviewed in light of their role in bone remodeling. BMP6 function has been assessed in Bmp6-/- mice by μCT and skeletal histology, and has also been examined in mesenchymal stem cells (MSC), hematopoietic stem cells (HSC) and osteoclasts. Safety and efficacy of OSTEOGROW have been assessed in rats and rabbits.

Results

Clinical use issues of BMP2 and BMP7 have been ascribed to the limited understanding of their role in bone remodeling at the time of device development for clinical trials. BMP2 and BMP7 in bone devices significantly promote bone resorption leading to osteolysis at the endosteal surfaces, while in parallel stimulating exuberant bone formation in surrounding tissues. Unbound BMP2 and BMP7 in bone devices precipitate on the bovine collagen and cause inflammation and swelling. OSTEOGROW required small amounts of BMP6, applied in a biocompatible blood coagulum carrier, for stimulating differentiation of MSCs and accelerated healing of critical size bone defects in animals, without bone resorption and inflammation. BMP6 decreased the number of osteoclasts derived from HSC, while BMP2 and BMP7 increased their number.

Conclusions

Current issues and challenges with commercial bone devices may be resolved by using novel BMP6 biocompatible device OSTEOGROW, which will be clinically tested in metaphyseal bone fractures, compartments where BMP2 and BMP7 have not been effective.