Teriparatide for Acceleration of Fracture Repair in Humans: A Prospective, Randomized, Double-Blind Study of 102 Postmenopausal Women With Distal Radial Fractures

Orthopaedics, Linköping University, Linköping, Sweden.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research (Impact Factor: 6.83). 08/2009; 25(2):404-14. DOI: 10.1359/jbmr.090731
Source: PubMed


Animal experiments show a dramatic improvement in skeletal repair by teriparatide. We tested the hypothesis that recombinant teriparatide, at the 20 microg dose normally used for osteoporosis treatment or higher, would accelerate fracture repair in humans. Postmenopausal women (45 to 85 years of age) who had sustained a dorsally angulated distal radial fracture in need of closed reduction but no surgery were randomly assigned to 8 weeks of once-daily injections of placebo (n = 34) or teriparatide 20 microg (n = 34) or teriparatide 40 microg (n = 34) within 10 days of fracture. Hypotheses were tested sequentially, beginning with the teriparatide 40 microg versus placebo comparison, using a gatekeeping strategy. The estimated median time from fracture to first radiographic evidence of complete cortical bridging in three of four cortices was 9.1, 7.4, and 8.8 weeks for placebo and teriparatide 20 microg and 40 microg, respectively (overall p = .015). There was no significant difference between the teriparatide 40 microg versus placebo groups (p = .523). In post hoc analyses, there was no significant difference between teriparatide 40 microg versus 20 microg (p = .053); however, the time to healing was shorter in teriparatide 20 microg than placebo (p = .006). The primary hypothesis that teriparatide 40 microg would shorten the time to cortical bridging was not supported. The shortened time to healing for teriparatide 20 microg compared with placebo still may suggest that fracture repair can be accelerated by teriparatide, but this result should be interpreted with caution and warrants further study.

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    • "These difficult fractures in individuals are a serious threat to the health of the workforce and to the economy. In 2008, a survey showed that 110 million adults in the US reported disabling musculoskeletal conditions, and a World Health Organization report showed that 50% of the 9 million osteoporotic fractures that had occurred worldwide had happened in the Americas and Europe.1,2 It is estimated that of the 7.9 million fractures sustained each year in the United States, 5% to 20% result in delayed or impaired healing.2 "
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    ABSTRACT: Antioxidants were implicated as potential reagents to enhance osteogenesis, and nano-fullerenes have been demonstrated to have a great antioxidative capacity by both in vitro and in vivo experiments. In this study, we assessed the impact of a polyhydroxylated fullerene, fullerol, on the osteogenic differentiation of human adipose-derived stem cells (ADSCs). Fullerol was not toxic against human ADSCs at concentrations up to 10 μM. At a concentration of 1 μM, fullerol reduced cellular reactive oxygen species after a 5-day incubation either in the presence or in the absence of osteogenic media. Pretreatment of fullerol for 7 days increased the osteogenic potential of human ADSCs. Furthermore, when incubated together with osteogenic medium, fullerol promoted osteogenic differentiation in a dose-dependent manner. Finally, fullerol proved to promote expression of FoxO1, a major functional isoform of forkhead box O transcription factors that defend against reactive oxygen species in bone. Although further clarification of related mechanisms is required, the findings may help further development of a novel approach for bone repair, using combined treatment of nano-fullerol with ADSCs.
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    • "Deficiencies in mesenchymal stem cells (MSCs) [1]–[2], angiogenesis induced by vascular endothelial growth factor (VEGF) [3]–[4] and bone morphogenetic proteins (BMPs) signaling [5]–[7] are associated with fractures that do not heal. It is estimated that of the 7.9 million fractures sustained each year in the United States, 5% to 20% result in delayed or impaired healing [8]. "
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    ABSTRACT: Clinical trials on fracture repair have challenged the effectiveness of bone morphogenetic proteins (BMPs) but suggest that delivery of mesenchymal stem cells (MSCs) might be beneficial. It has also been reported that BMPs could not increase mineralization in several MSCs populations, which adds ambiguity to the use of BMPs. However, an exogenous supply of MSCs combined with vascular endothelial growth factor (VEGF) and BMPs is reported to synergistically enhance fracture repair in animal models. To elucidate the mechanism of this synergy, we investigated the osteoblastic differentiation of cloned mouse bone marrow derived MSCs (D1 cells) in vitro in response to human recombinant proteins of VEGF, BMPs (-2, -4, -6, -9) and the combination of VEGF with BMP-6 (most potent BMP). We further investigated ectopic bone formation induced by MSCs pre-conditioned with VEGF, BMP-6 or both. No significant increase in mineralization, phosphorylation of Smads 1/5/8 and expression of the ALP, COL1A1 and osterix genes was observed upon addition of VEGF or BMPs alone to the cells in culture. The lack of CD105, Alk1 and Alk6 expression in D1 cells correlated with poor response to BMPs indicating that a greater care in the selection of MSCs is necessary. Interestingly, the combination of VEGF and BMP-6 significantly increased the expression of ALP, COL1A1 and osterix genes and D1 cells pre-conditioned with VEGF and BMP-6 induced greater bone formation in vivo than the non-conditioned control cells or the cells pre-conditioned with either VEGF or BMP-6 alone. This enhanced bone formation by MSCs correlated with higher CADM1 expression and OPG/RANKL ratio in the implants. Thus, combined action of VEGF and BMP on MSCs enhances osteoblastic differentiation of MSCs and increases their bone forming ability, which cannot be achieved through use of BMPs alone. This strategy can be effectively used for bone repair.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "The radiographic union and the active range of motion were assessed at each follow-up, and the Constant scores were measured at 3, 6, and 12 months postoperatively. The radiographic union was defined by bridging callus formation in at least three cortices on the radiographs made in two orthogonal projections.16,17,18) We defined the clinical union as an absence of tenderness or pain on the fracture site at rest. "
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    ABSTRACT: Background The minimally invasive plate osteosynthesis (MIPO) technique using periarticular locking plates may be a good option for the repair of displaced proximal humeral fractures. However, axillary nerve complications related to this technique may be underestimated. The purpose of this study is to evaluate the outcomes of the minimally invasive plating, focusing on the complications. Methods The records of 21 consecutive patients treated for proximal humerus fractures using the MIPO technique with locking plates were retrospectively reviewed. These patients were treated between March 2009 and March 2011 with a minimum one-year follow-up. The clinical function, complications, and radiological bony union were evaluated. Results All of the patients, with one exception, showed at least 90 degrees of flexion and abduction at the shoulder joint six months postoperatively. The average Constant scores at three months, six months, and one year follow-ups were 74.0 (range, 62 to 90), 79.4 (range, 64 to 91), and 82.7 (range, 66 to 92), respectively. All of the patients achieved bony union within the average of 3.2 months (range, 2 to 6 months). There was one case of delayed union, one case of intra-articular screw penetration, and one case of axillary nerve paresis (incomplete injury), which did not completely recover during the one year of follow-up. Conclusions The MIPO technique using periarticular locking plates is a useful option for the treatment of selected cases of displaced proximal humeral fractures. However, nerve complications such as axillary nerve paresis should be considered along with implant-related complications when choosing patients for minimally invasive plating.
    Full-text · Article · Jun 2014 · Clinics in orthopedic surgery
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