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Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial.
Gómez-Barrena, E, Rosset, P, Gebhard, F, Hernigou, P, Baldini, N, Rouard, H, Sensebé, L, Gonzalo-Daganzo, RM, Giordano, R, Padilla-Eguiluz, N, et al
Biomaterials. 2019;:100-108
Abstract
BACKGROUND ORTHO-1 is a European, multicentric, first in human clinical trial to prove safety and feasibility after surgical implantation of commercially available biphasic calcium phosphate bioceramic granules associated during surgery with autologous mesenchymal stromal cells expanded from bone marrow (BM-hMSC) under good manufacturing practices, in patients with long bone pseudarthrosis. METHODS Twenty-eight patients with femur, tibia or humerus diaphyseal or metaphyso-diaphyseal non-unions were recruited and surgically treated in France, Germany, Italy and Spain with 100 or 200 million BM-hMSC/mL associated with 5-10 cc of bioceramic granules. Patients were followed up during one year. The investigational advanced therapy medicinal product (ATMP) was expanded under the same protocol in all four countries, and approved by each National Competent Authority. FINDINGS With safety as primary end-point, no severe adverse event was reported as related to the BM-hMSC. With feasibility as secondary end-point, the participating production centres manufactured the BM-hMSC as planned. The ATMP combined to the bioceramic was surgically delivered to the non-unions, and 26/28 treated patients were found radiologically healed at one year (3 out of 4 cortices with bone bridging). INTERPRETATION Safety and feasibility were clinically proven for surgical implantation of expanded autologous BM-hMSC with bioceramic. FUNDING EU-FP7-HEALTH-2009, REBORNE Project (GA: 241876).
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Population-Wide Impact of Non-Hip Non-Vertebral Fractures on Mortality.
Tran, T, Bliuc, D, van Geel, T, Adachi, JD, Berger, C, van den Bergh, J, Eisman, JA, Geusens, P, Goltzman, D, Hanley, DA, et al
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2017;(9):1802-1810
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Abstract
Data on long-term consequences of non-hip non-vertebral (NHNV) fractures, accounting for approximately two-thirds of all fragility fractures, are scanty. Our study aimed to quantify the population-wide impact of NHNV fractures on mortality. The national population-based prospective cohort study (Canadian Multicentre Osteoporosis Study) included 5526 community dwelling women and 2163 men aged 50 years or older followed from July 1995 to September 2013. Population impact number was used to quantify the average number of people for whom one death would be attributable to fracture and case impact number to quantify the number of deaths out of which one would be attributable to a fracture. There were 1370 fragility fractures followed by 296 deaths in women (mortality rate: 3.49; 95% CI, 3.11 to 3.91), and 302 fractures with 92 deaths in men (5.05; 95% CI, 4.12 to 6.20). NHNV fractures accounted for three-quarters of fractures. In women, the population-wide impact of NHNV fractures on mortality was greater than that of hip and vertebral fractures because of the greater number of NHNV fractures. Out of 800 women, one death was estimated to be attributable to a NHNV fracture, compared with one death in 2000 women attributable to hip or vertebral fracture. Similarly, out of 15 deaths in women, one was estimated to be attributable to a NHNV fracture, compared with one in over 40 deaths for hip or vertebral fracture. The impact of forearm fractures (ie, one death in 2400 women and one out of 42 deaths in women attributable to forearm fracture) was similar to that of hip, vertebral, or rib fractures. Similar, albeit not significant, results were noted for men. The study highlights the important contribution of NHNV fractures on mortality because many NHNV fracture types, except for the most distal fractures, have serious adverse consequences that affect a significant proportion of the population. © 2017 American Society for Bone and Mineral Research.
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Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus.
Watts, NB, Bilezikian, JP, Usiskin, K, Edwards, R, Desai, M, Law, G, Meininger, G
The Journal of clinical endocrinology and metabolism. 2016;(1):157-66
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CONTEXT Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed to treat type 2 diabetes mellitus (T2DM). OBJECTIVE The purpose of this study was to describe the effects of canagliflozin on bone fracture risk. DESIGN AND SETTING This was a randomized phase 3 study in patients with T2DM. PATIENTS AND INTERVENTIONS Canagliflozin doses of 100 and 300 mg were evaluated in the overall population of patients from 9 placebo- and active-controlled studies (N = 10 194), as well as in separate analyses of a single trial enriched with patients with a prior history/risk of cardiovascular disease (ie, the CANagliflozin cardioVascular Assessment Study [CANVAS]; N = 4327) and a pooled population of 8 non-CANVAS studies (N = 5867). OUTCOME MEASURES The incidence of adjudicated fracture adverse events (AEs), fall-related AEs, and volume depletion-related AEs was assessed. RESULTS The incidence of fractures was similar with canagliflozin (1.7%) and noncanagliflozin (1.5%) in the pooled non-CANVAS studies. In CANVAS, a significant increase in fractures was seen with canagliflozin (4.0%) vs placebo (2.6%) that was balanced between the upper and lower limbs. The incidence of fractures was higher with canagliflozin (2.7%) vs noncanagliflozin (1.9%) in the overall population, which was driven by the increase of fractures in CANVAS. The incidence of reported fall-related AEs was low, but significantly higher with canagliflozin in CANVAS, potentially related to volume depletion-related AEs, but not significantly different in the pooled non-CANVAS studies and the overall population. CONCLUSIONS Fracture risk was increased with canagliflozin treatment, driven by CANVAS patients, who were older, with a prior history/risk of cardiovascular disease, and with lower baseline estimated glomerular filtration rate and higher baseline diuretic use. The increase in fractures may be mediated by falls; however, the cause of increased fracture risk with canagliflozin is unknown.
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Low bone mineral density and fragility fractures in permanent vegetative state patients.
Oppl, B, Michitsch, G, Misof, B, Kudlacek, S, Donis, J, Klaushofer, K, Zwerina, J, Zwettler, E
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;(5):1096-100
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Disuse of the musculoskeletal system causes bone loss. Whether patients in vegetative state, a dramatic example of immobilization after severe brain injury, suffer from bone loss and fractures is currently unknown. Serum markers of bone turnover, bone mineral density (BMD) measurements, and clinical data were cross-sectionally analyzed in 30 consecutive vegetative state patients of a dedicated apallic care unit between 2003 and 2007 and compared with age- and sex-matched healthy individuals. Vegetative state patients showed low calcium levels and vitamin D deficiency compared with healthy controls. Serum bone turnover markers revealed high turnover as evidenced by markedly elevated carboxy-terminal telopeptide of type I collagen (β-crosslaps) and increased levels of alkaline phosphatase. BMD measured by dual-energy X-ray absorptiometry (DXA) scanning showed strongly decreased T- and Z-scores for hip and spine. Over a period of 5 years, 8 fragility fractures occurred at peripheral sites in 6 of 30 patients (n = 3 femur, n = 2 tibia, n = 2 fibula, n = 1 humerus). In conclusion, high bone turnover and low BMD is highly prevalent in vegetative state patients, translating into a clinically relevant problem as shown by fragility fractures in 20% of patients over a time period of 5 years. .
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Effect of bisphosphonates on bone mineral density and fracture prevention in gastric cancer patients after gastrectomy.
Lim, JS, Jin, SH, Kim, SB, Lee, JI
Journal of clinical gastroenterology. 2012;(8):669-74
Abstract
GOAL: To evaluate the effectiveness of bisphosphonates in preventing fractures in gastric cancer patients by increasing bone mineral density (BMD). BACKGROUND The effectiveness of bisphosphonates is questionable in gastric cancer patients who have undergone gastrectomy, although they display a high prevalence of osteoporosis. STUDY Forty-seven gastric cancer patients with osteoporosis were retrospectively analyzed. All patients were supplemented with calcium and vitamin D. Twenty-four patients were treated with bisphosphonate (bisphosphonate group) and 23 patients were untreated (control group). Fractures, severe bone pain, and adverse effects of bisphosphonates were monitored. BMD of the lumbar spine and femoral neck were measured before and 1-year treatment with bisphosphonates by dual-energy X-ray absorptiometry. RESULTS During a 1-year follow-up, 7 of the 47 (15%) patients developed new fractures. The bisphosphonate-treated group had a significantly lower fracture rate than the control group (n=1 vs. 6, P<0.05). Lumbar spine BMD increased in both groups (0.047 ± 0.03 vs. 0.021 ± 0.03 g/cm², respectively), whereas femoral neck BMD increased only in the bisphosphonate group (0.032 ± 0.03 vs. -0.004 ± 0.02 g/cm², respectively). Furthermore, the bisphosphonate group showed greater increases in lumbar spine and femoral neck BMDs than the controls (P<0.05). No difference was found between alendronate and risedronate in terms of BMD at follow-up. CONCLUSIONS Therapy using bisphosphonates might be effective at increasing BMD and reducing fracture risk in gastric cancer patients after gastrectomy. Further well-designed randomized controlled trials are needed for confirmation.
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Prevention of falls and fractures in old people by administration of calcium and vitamin D, randomized clinical trial.
López-Torres Hidalgo, J, ,
BMC public health. 2011;:910
Abstract
BACKGROUND There are many studies that associate vitamin D serum levels in older persons with muscle strength, physical performance and risk of fractures and falls. However, current evidence is insufficient to make a general recommendation for administrating calcium and vitamin D to older persons. The objective of this study is to determine the effectiveness of calcium and vitamin D supplementation in improving musculoskeletal function and decreasing the number of falls in person aged over 65 years. METHODS/DESIGN Phase III, randomized, double blind, placebo-controlled trial to evaluate the efficacy of already marketed drugs in a new indication. It will be performed at Primary Care doctor visits at several Healthcare Centers in different Spanish Health Areas. A total of 704 non-institutionalized subjects aged 65 years or older will be studied (sample size calculated for a statistical power of 80%, alpha error 0.05, annual incidence of falls 30% and expected reduction of 30% to 20% and expected loss to follow up of 20%). The test drug containing 800 IU of vitamin D and 1000 mg of calcium will be administered daily. The control group will receive a placebo. The subjects will be followed up over two years. The primary variable will be the incidence of spontaneous falls. The secondary variables will include: consequences of the falls (fractures, need for hospitalization), change in calcidiol plasma levels and other analytical determinations (transaminases, PTH, calcium/phosphorous, albumin, creatinine, etc.), change in bone mass by densitometry, change in muscle strength in the dominant hand and change in musculoskeletal strength, risk factors for falls, treatment compliance, adverse effects and socio-demographic data. DISCUSSION The following principles have been considered in the development of this Project: the product data are sufficient to ensure that the risks assumed by the study participants are acceptable, the study objectives will probably provide further knowledge on the problem studied and the available information justifies the performance of the study and its possible risk for the participants.If calcium and vitamin D supplementation is effective in the prevention of falls and fractures in the elderly population, a recommendation may be issued with the aim of preventing some of the consequences of falls that affect quality of life and the ensuing personal, health and social costs. TRIAL REGISTRATION ClinicalTrials.gov: NCT01452243
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[Free vascularized iliac bone graft for the treatment of scaphoid nonunion with avascular proximal fragment].
Gabl, M, Pechlaner, S, Zimmermann, R
Operative Orthopadie und Traumatologie. 2009;(4-5):386-95
Abstract
OBJECTIVE The goal of the procedure is osseous healing of the scaphoid in an anatomic position and replacement of necrotic bone at the site of the scaphoid nonunion by a vascularized iliac bone graft. INDICATIONS Scaphoid nonunion with necrotic fragment in SNAC (scaphoid nonunion advanced collapse) < 1. Nonunion following previous surgery. CONTRAINDICATIONS Pattern of advanced carpal collapse (SNAC > 1). Malformation, disease or previous injury of the vascular system. Poor compliance. Reduced general health. SURGICAL TECHNIQUE Principles of the surgical technique according to Pechlaner et al.: harvesting of a corticocancellous bone graft from the anterior iliac crest with a nutrient vascular bundle from the deep circumflex iliac artery, debridement of the necrotic scaphoid, press-fit fixation of the tailored graft, pin fixation, and microvascular anastomosis to the radial artery. POSTOPERATIVE MANAGEMENT Fixation in an upper-arm cast for 4 weeks, followed by lower-arm cast fixation including the thumb to the interphalangeal joint until week 12. Physiotherapy. Wrist splinting in patients enforced to heavy manual load. RESULTS The described procedure has been practiced at the own institution since 1985 and evaluated in different studies. Using a free vascularized iliac bone graft, union could be achieved in 85% of patients with avascular scaphoid nonunion and in 80% with avascular proximal pole nonunion. The nonunion can be bridged in 93% following failed previous scaphoid screw fixation.
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[Patella fracture].
Dietz, SO, Hessmann, MH, Gercek, E, Rommens, PM
Operative Orthopadie und Traumatologie. 2009;(2):206-20
Abstract
OBJECTIVE Reconstruction of the extensor apparatus of the knee joint. Open reduction and stable internal fixation of patella fractures. Exact reconstruction of the articular surface of the patellofemoral joint. INDICATIONS Open and closed fractures. Fractures with an intraarticular incongruity (> 2 mm). Incapability of extension of the knee also in nondisplaced fractures of the patella. In the context of internal fixations of additional periarticular fractures of the knee joint. CONTRAINDICATIONS Compromised general health status or associated injuries. Compromised local soft-tissue situation (contamination, poor soft-tissue cover). Relative: nondisplaced transverse fractures (no displacement in 40 degrees of flexion). Relative: nondisplaced longitudinal fractures(3). Relative: nondisplaced radiating fractures(3). Relative: nondisplaced fractures of the distal pole without involvement of the joint surface and intact extensor apparatus(3). SURGICAL TECHNIQUE Longitudinal parapatellar incision. Tension band wiring. Lag screw osteosynthesis. Combination of tension band wiring and lag screws. Patellectomy (partial/complete). POSTOPERATIVE MANAGEMENT Thrombosis prophylaxis. Early physiotherapy. Knee brace. RESULTS 70% good to excellent results. 30% chronic pain and posttraumatic arthritis. Loss of motion (limited extension).
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Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover.
Delmas, PD, Licata, AA, Reginster, JY, Crans, GG, Chen, P, Misurski, DA, Wagman, RB, Mitlak, BH
Bone. 2006;(2):237-43
Abstract
INTRODUCTION Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk. METHODS The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX). RESULTS Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk. CONCLUSION Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.
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The effect of demineralized bone matrix-calcium sulfate with vancomycin on calcaneal fracture healing and infection rates: a prospective study.
Bibbo, C, Patel, DV
Foot & ankle international. 2006;(7):487-93
Abstract
BACKGROUND Displaced intra-articular calcaneal fractures may have a central cancellous bone defect area. We hypothesized that human demineralized bone matrix (DBM) calcium sulfate (CaSO(4)) might act as a reasonable alternative to autograft in calcaneal fractures. When combined with antibiotic powder, this bone graft substitute also may act as a local antibiotic delivery device. This is the first clinical study evaluating bone healing and complications associated with DBM-calcium sulfate bone graft substitute in the treatment of displaced intra-articular calcaneal fractures with a central cancellous bone defect. METHODS Over a 29-month period, 33 displaced intra-articular calcaneal fractures with central cancellous defects were treated with open reduction and internal fixation (ORIF) and grafting with vancomycin/DBM-calcium sulfate bone graft substitute. Eleven fractures without bone defects were treated with ORIF only. Patient demographics, medical history, and CT fracture classification were recorded. Postoperatively, fractures were monitored every 2 weeks for healing and complications. RESULTS The mean time to union was 8.2 weeks in the grafted, while the control group mean time to union was 10.4 weeks (p = 0.0117). Wound problems occurred in five (15%) of the 33 patients with grafting, all in type III fractures with severe soft-tissue swelling, and included two minor wound healing delays, and three serious wound problems. At a mean followup time of 22.4 months, no DBM-calcium sulfate grafted calcaneus demonstrated evidence of osteomyelitis. CONCLUSIONS This is the first study examining human DBM-calcium sulfate bone graft substitute to treat displaced intra-articular calcaneal fractures. Based on these initial data, human DBM-calcium sulfate acted as an acceptable and safe autograft alternative in displaced intra-articular calcaneal fractures with moderate (5 cc to 10 cc) central cancellous bone defects.