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We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated ß-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.
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Densidad Ósea/genética , Huesos/patología , Mutación/genética , Osteogénesis Imperfecta/genética , Osteoporosis/genética , Proteína Wnt1/genética , Animales , Secuencia de Bases , Células Cultivadas , Niño , Preescolar , Femenino , Heterocigoto , Humanos , Recién Nacido , Proteínas Relacionadas con Receptor de LDL/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Osteoblastos/metabolismo , Osteoblastos/patología , Osteogénesis Imperfecta/patología , Osteoporosis/patología , Linaje , Fenotipo , EmbarazoRESUMEN
PURPOSE: The purpose of this study was to investigate specific risk factors, common fracture locations and possible sex-specific differences in elderly patients with stress fractures. METHODS: This analysis enrolled 105 patients (83 women, 22 men) with stress fractures. For the analysis of possible risk factors related to increasing age, data from 82 patients (67 women, 15 men) aged 40 years and older (mean age of 57.4 ± 11.0 years) were compared with that from a younger control group [23 patients (16 women, seven men), mean age 28.4 ± 6.7 years]. Bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry bone densitometry (DXA) and blood samples were taken. RESULTS: A total of 211 stress fractures were found. Of these, 177 were found in the study group, of which 90.4 % were located in the lower limb. Lumbar and femoral BMD was significantly lower in elderly patients; however, the BMD of most patients was within the osteopenic or normal range. Within the study group, a total of 83.8 % had a vitamin D insufficiency (<30 µg/l); 75.5 % were not engaged in regular physical activity more than once a week. Overweight patients within the study group had significantly more stress fractures compared to normal weight patients (2.6 ± 1.7 vs. 1.9 ± 1.1, p<0.05). CONCLUSIONS: A similar contribution of risk factors has been found for stress fractures in elderly patients and younger controls of the general population. Stress fracture incidence seems to be rather multifactorial and not based on osteoporotic changes alone. A balanced calcium and vitamin D metabolism seems to be of paramount importance for stress fracture prevention in elderly patients.
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Fracturas por Estrés/epidemiología , Fracturas por Estrés/etiología , Absorciometría de Fotón , Adulto , Factores de Edad , Anciano , Densidad Ósea/fisiología , Estudios de Casos y Controles , Femenino , Fracturas por Estrés/fisiopatología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Actividad Motora/fisiología , Sobrepeso/complicaciones , Estudios Retrospectivos , Factores de Riesgo , Factores SexualesRESUMEN
PURPOSE: The use of inappropriate cementation techniques has been suggested as an adverse factor for the long-term survival of hip-resurfacing arthroplasty. Inadequate initial fixation, thermal osteonecrosis and interface biological reactions are possible causes of failure. We analysed morphological changes associated with the cementation technique in a large collection of retrieved femoral components. METHODS: One hundred and fifty femoral components (mean time to failure of 8.3 months±11.0) obtained at revision surgery were analysed morphometrically and histopathologically. Cement mantle and penetration were quantified in six different regions of interest. Histopathological analysis of the bone-cement interface was performed on undecalcified processed bone tissue. RESULTS: The vast majority of the cases differed substantially from laboratory-based cement-penetration depth recommendations. Fifty-nine cases had a fibrous membrane at the cement-bone interface. This membrane was significantly thicker in cases with osteonecrosis compared to cases viable bone. CONCLUSIONS: Our results demonstrate that most failures were cemented inappropriately. We suggest that poor cementation was an important adverse factor; however, the cause of the failures was obviously multifactorial. The thickness of the fibrous membrane at the cement-bone interface differed significantly between cases with osteonecrosis and specimens with viable bone tissue.
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Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Cadera/métodos , Cementación/efectos adversos , Falla de Prótesis/etiología , Artroplastia de Reemplazo de Cadera/estadística & datos numéricos , Cementación/métodos , Análisis de Falla de Equipo , Femenino , Fémur/patología , Necrosis de la Cabeza Femoral/etiología , Necrosis de la Cabeza Femoral/patología , Fibrosis/patología , Articulación de la Cadera/diagnóstico por imagen , Articulación de la Cadera/cirugía , Humanos , Masculino , Membranas/patología , Persona de Mediana Edad , Radiografía , Factores de TiempoRESUMEN
PURPOSE: The characteristics of tantalum augment osseointegration in human ex vivo specimens from re-revision procedures are unknown and limited data in this regard is available. The purpose of this study was to investigate the osseointegration pattern into porous tantalum augmentations harvested during re-revision procedures. METHODS: Between 2007 and 2010 a total of 324 hip and knee revisions with a tantalum augmentation were performed in our institution. Out of this cohort, seven patients (2.2 %) had to be re-revised. To analyse the status of trabecular ingrowth in the retrieved cases (four hips, three knees), all specimens were analysed by contact radiography, subjected to undecalcified processing, histology, thin-section analysis and backscattered electron imaging. RESULTS: Trabecular and vascular ingrowth could be found along the bone-augment-interface in two of seven revised specimens, respectively. The depth of bone ingrowth reached up to 2.6 mm. However, the analysis of the remaining cases revealed no bony ingrowth into trabecular metal. Rather, large parts of the implants were embedded in cement or pores were filled with autologous bone. CONCLUSIONS: Although the cause for the missing bony ingrowth seems to be multifactorial, some fundamental conditions, such as the provision of the greatest possible interface between the tantalum implant and the host bone, should be met and thus, bone cement and autologous bone grafts should be used with caution.
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Artroplastia de Reemplazo/métodos , Prótesis Articulares , Oseointegración/fisiología , Diseño de Prótesis , Falla de Prótesis , Tantalio , Anciano , Artroplastia de Reemplazo/efectos adversos , Artroplastia de Reemplazo/instrumentación , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Cadera/instrumentación , Artroplastia de Reemplazo de Cadera/métodos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Artroplastia de Reemplazo de Rodilla/instrumentación , Artroplastia de Reemplazo de Rodilla/métodos , Materiales Biocompatibles , Huesos/ultraestructura , Cementación , Remoción de Dispositivos , Análisis de Falla de Equipo , Femenino , Prótesis de Cadera , Humanos , Prótesis de la Rodilla , Masculino , Persona de Mediana Edad , ReoperaciónRESUMEN
BACKGROUND: We developed a quadriceps-tendon graft technique using a double-layered, partial-thickness, soft tissue quadriceps tendon graft (dlQUAD) for anterior cruciate ligament reconstruction (ACLR). This technique allows simple femoral loop button fixation and a limited harvest depth of the quadriceps tendon. PURPOSE: To evaluate the outcome of patients undergoing revision ACLR using the dlQUAD technique compared with a hamstring tendon graft (HT). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 114 patients who underwent revision ACLR between 2017 and 2018 were included in this retrospective case series. At a mean follow-up of 26.9 ± 3.7 months (range, 24-36), 89 patients (dlQUAD: n = 43, HT: n = 46) were clinically examined. In addition, patients completed the Lysholm score, Tegner activity scale, subjective International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score, and visual analog scale (VAS) for pain. Postoperative failure of the revision ACLR was defined as a side-to-side difference (SSD) in Rolimeter testing ≥5 mm or a pivot-shift grade of 2 or 3. RESULTS: Nine patients (10.1%) were identified with a failed revision ACLR. There was a significantly lower failure rate with dlQUAD versus the HT group (2.3% vs 17.4%; P = .031). The mean postoperative SSD was significantly less in the dlQUAD group (1.3 ± 1.3 mm [range, 0-5] vs 1.8 ± 2.2 mm [range, 0-9]; P = .043). At the latest follow-up, Tegner and IKDC scores significantly improved in the dlQUAD group compared with the HT group (Tegner: 5.8 ± 1.8 vs 5.6 ± 1.5; P = .043; IKDC: 83.8 ± 12.2 vs 78.6 ± 16.8; P = .037). The pain VAS score was also significantly reduced in the dlQUAD group compared with the HT group (0.9 ± 1.1 vs 1.6 ± 2.0; P = .014). CONCLUSION: The dlQUAD and HT techniques both demonstrated significant improvement of preoperative knee laxity and satisfactory patient-reported outcome measures after revision ACLR. Compared with the HT grafts, the dlQUAD technique showed lower failure rates and small increases in Tegner and IKDC scores.
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To identify a possible role of lymphocytic infiltrates in failure mechanism of the metal-on-metal hip resurfacing arthroplasty, the extent of lymphocytic infiltration was compared with reasons for prosthesis failure in a series of retrieval specimens. One hundred eighty-one femoral head and neck remnants were subjected to thorough analysis of histological findings and clinical data. Lymphocytic infiltrates were considered weak to moderate in 52 (28.7%) and excessive in ten (5.5%) cases. Six cases with excessive lymphocytic infiltrates belonged to the group of 33 (18.2%) revisions without obvious cause (periprosthetic fracture, component loosening, and infection) for prosthesis failure. Excessive lymphocytic infiltrates were strongly linked to the presence of proliferative desquamative synovitis (p < 0.0001). Both the excessive lymphocytic infiltrates and proliferative desquamative synovitis were associated with female gender (p < 0.05). We hypothesize that a specific cause of groin pain might be related to excessive intraosseous lymphocytic infiltrates and explained possibly by the hypersensitivity reaction of the delayed type after the hip resurfacing arthroplasty. Proliferative desquamative synovitis might constitute another morphologic feature associated with the delayed type hypersensitivity reaction.
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Artroplastia de Reemplazo de Cadera/efectos adversos , Materiales Biocompatibles/efectos adversos , Fémur/patología , Prótesis de Cadera/efectos adversos , Metales/efectos adversos , Linfocitos T/patología , Anciano , Femenino , Fémur/inmunología , Fémur/cirugía , Cabeza Femoral/inmunología , Cabeza Femoral/patología , Cabeza Femoral/cirugía , Cuello Femoral/inmunología , Cuello Femoral/patología , Cuello Femoral/cirugía , Humanos , Hipersensibilidad Tardía/etiología , Masculino , Persona de Mediana Edad , Diseño de Prótesis , Falla de Prótesis , ReoperaciónRESUMEN
OBJECTIVES: Screw fixation and fragment anchoring in osteoporotic bones is often difficult. Problems like the cut out phenomenon and implant migration in osteoporotic bones have been reported. One possibility of improving the anchoring force of screws is augmentation of the screw. Cement-augmented screws in spinal surgery could exhibit a better anchoring in osteoporotic bones. METHODS: The purpose of this study was to examine the effect of screw augmentation using a resorbable polymer. Ultrasound-activated biodegradable pins were used for the purpose of a resorbable augmentation technique. Cannulated screws were inserted into the femur of 12 sheep and augmented by an ultrasound-activated polylactic acid (PLDLA) pin. In a paired approach, four screws were implanted in each animal: 2× a 10-mm thread and 2× a 20-mm thread, both of which were augmented with polymer. Both screws, named A and B, were also applied without augmentation (control group) and implanted into the contralateral hind limb. After 4, 8, and 12 weeks, the sheep were euthanized and a macroscopical and histological examination followed. RESULTS: The polymer spread well out of the screws into the cancellous lacunae. Around the polymer, the peripheral bone showed signs of healthy and active bone tissue. No evidence of inflammation or infection was observed. The boneto-implant contact was significantly higher in the augmented screws. Biocompatibility was proven in histopathological examination. After 12 weeks, no pathological changes were found. CONCLUSION: Ultrasound-activated polymer augmentation of cannulated screws may improve the anchoring in osteoporotic bone. ARTICLE FOCUS: Can screw augmentation using a resorbable polymer improve the bone-to-implant contact in case of screw osteosynthesis? Is there any effect on the surrounding tissue by the induced temperature and liquefied polymer? Can biocompatibility be proven by this new osteosynthesis? KEY MESSAGES: Screw augmentation by ultrasound-activated biopolymer leads to a significant higher bone-to-implant contact than pure screw osteosynthesis. No tissue damage could be observed by the application of the SonicFusion™. STRENGTH AND LIMITATIONS OF THIS STUDY: The ovine in vivo study concept can simulate physiological conditions. First examination of screw augmentation by ultrasound-activated biopolymer. No biomechanical testing of the higher bone-to-implant contact by now.
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Tornillos Óseos , Fijación Interna de Fracturas/métodos , Poliésteres/uso terapéutico , Animales , Femenino , Ensayo de Materiales , Ovinos , Ondas UltrasónicasRESUMEN
INTRODUCTION: Due to inconsistent findings, the influence of vitamin D on postural body sway (PBS) is currently under debate. This study evaluated the impact of vitamin D on PBS with regards to different foot positions and eye opening states in community-dwelling older individuals. METHODS: In a cross-sectional study, we assessed PBS in 342 older individuals (264 females [average age (± SD): 68.3 ± 9.0 years], 78 males [65.7 ± 9.6 years]). A detailed medical history and vitamin D level were obtained for each individual. Fall risk was evaluated using the New York-Presbyterian Fall Risk Assessment Tool (NY PFRA). PBS parameters (area, distance, velocity, frequency) were evaluated on a pressure plate with feet in closed stance (CS) or hip-width stance (HWS), open eyes and closed eyes. Statistical analysis included logarithmic mixed models for repeated measures with the MIXED model procedure to test the influence of vitamin D (categorized in <10 µg/l, 10-20 µg/l, 21-30 µg/l, >30 µg/l), foot position, eye opening state, age, sex and frequency of physical activity on PBS. RESULTS: Vitamin D was not an independent risk factor for falls experienced in the last 12 months. Nonetheless, PBS was higher in patients with vitamin D deficiency (<10 µg/l) in HWS (A/P p=0.028 and area p=0.037). Additionally, vitamin D deficiency intensified the deleterious effects of male sex (distance p=0.002) and absence of vision (area p<0.001) on PBS. CONCLUSION: Independent risk factors for increased PBS like male sex and absence of vision are additionally compromised by vitamin D deficiency.
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Accidentes por Caídas/estadística & datos numéricos , Pie/fisiopatología , Equilibrio Postural/fisiología , Medición de Riesgo/métodos , Deficiencia de Vitamina D/complicaciones , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Trastornos de la Visión , Deficiencia de Vitamina D/epidemiología , Deficiencia de Vitamina D/fisiopatologíaRESUMEN
Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia and low calcitriol levels as well as clinical symptoms like diffuse bone and muscle pain, fatigue fractures or increased fracture risk. Conventional imaging methods, however, often fail to detect the small tumors. Lately, tumor localization clearly improved by somatostatin-receptor (SSTR) imaging, such as octreotide scintigraphy or octreotide SPECT/CT. However, recent studies revealed that still a large number of tumors remained undetected by octreotide imaging. Hence, studies focused on different SSTR imaging methods such as 68Ga DOTA-NOC, 68Ga DOTA-TOC and 68Ga DOTA-TATE PET/CT with promising first results. Studies comparing different SSTR imaging methods for tumor localization in TIO are rare and thus little is known about diagnostic alternatives once a particular method failed to detect a tumor in patients with TIO. Here, we report the data of 5 consecutive patients suffering from TIO, who underwent both 111Indium-octreotide scintigraphy (111In-OCT) SPECT/CT as well as 68Ga DOTA-TATE PET/CT for tumor detection. While 111In-OCT SPECT/CT allowed tumor detection in only 1 of 5 patients, 68Ga DOTA-TATE PET/CT was able to localize the tumor in all patients. Afterwards, anatomical imaging of the region of interest was performed with CT and MRI. Thus, successful surgical resection of the tumor was achieved in all patients. Serum phosphate levels returned to normal and all patients reported relief of symptoms within weeks. Moreover, an iliac crest biopsy was obtained from every patient and revealed marked osteomalacia in all cases. Follow-up DXA revealed an increase in BMD of up to 34.5% 1-year postoperative, indicating remineralization. No recurrence was observed. In conclusion our data indicates that 68Ga DOTA-TATE PET/CT is an effective and promising diagnostic tool in the diagnosis of TIO, even in patients in whom 111In-OCT prior failed to detect a tumor.
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Radioisótopos de Galio , Neoplasias/diagnóstico por imagen , Osteomalacia/etiología , Radiofármacos , Adulto , Estudios de Cohortes , Femenino , Factor-23 de Crecimiento de Fibroblastos , Humanos , Masculino , Persona de Mediana Edad , Imagen Multimodal , Neoplasias/complicaciones , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos XRESUMEN
The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.
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Calcitonina/metabolismo , Lisofosfolípidos/metabolismo , Osteoclastos/citología , Osteogénesis , Esfingosina/análogos & derivados , Alelos , Animales , Huesos/metabolismo , Colagenasas/metabolismo , Cruzamientos Genéticos , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Osteoblastos/citología , Osteoporosis/fisiopatología , Fenotipo , Porosidad , Receptores de Calcitonina/metabolismo , Transducción de Señal , Esfingosina/metabolismoRESUMEN
Retrieved hip resurfacing arthroplasties (HRA) revised for causes other than osteonecrosis enable further insights into bone-cement interactions within the interface with only minimal biomechanical stresses. Our primary objective was to investigate the mineralization changes at the trabecular bone interface in retrieved hips using bright field and polarized light microscopy and by quantitative backscattered electron imaging. Because superficial seams of non-mineralized bone tissue varied substantially, we defined hyperosteoidosis as an osteoid seam of more than 20 µm thickness. We hypothesized that interface hyperosteoidosis might be caused by the demineralization of previously mineralized bone tissue. One hundred and thirty-one retrieved HRAs with viable bone remnant tissue were analyzed. Bone mineral density distribution obtained from backscattered signal intensities of the trabecular bone at the bone-cement interface was assessed in cases with and without interface hyperosteoidosis. In cases with interface hyperosteoidosis, the degree of trabecular mineralization was also analyzed in deeper areas of the femoral remnants. Thirty-four cases showed hyperosteoidosis at the bone-cement interface, mostly in female patients. Bone trabeculae with hyperosteoidosis displayed a mineral density distribution pattern suggestive of the demineralization of a previously mineralized bone matrix. Our results demonstrate the localized disorder of the mineralization pattern of bone trabeculae at the bone-cement interface in a group of retrieved HRAs. In previously well-fixed femoral components, potential adverse effects on the load-bearing bone due to a decreased degree of mineralization at the bone-cement interface may affect the durability of the implant's function.
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Artroplastia de Reemplazo de Cadera/métodos , Resorción Ósea/fisiopatología , Calcificación Fisiológica/fisiología , Fémur/fisiopatología , Osteonecrosis/fisiopatología , Densidad Ósea/fisiología , Resorción Ósea/patología , Cartílago Articular/patología , Estudios de Cohortes , Femenino , Fémur/patología , Fibrosis/patología , Fibrosis/fisiopatología , Humanos , Macrófagos/patología , Masculino , Persona de Mediana Edad , Osteoblastos/patología , Osteonecrosis/patología , Falla de PrótesisRESUMEN
BACKGROUND: Periprosthetic fractures have long been recognized as one of the major complications of hip resurfacing arthroplasty. The objective of this study was to develop a systematic and morphologic classification of the fracture mode based on pathogenesis. METHODS: One hundred and seven retrieved specimens consisting of the femoral remnant and the femoral component of a total hip resurfacing arthroplasty that had failed as a result of a periprosthetic fracture were analyzed with regard to the morphologic failure mode. The location of the fracture line was used to differentiate the fractures. The fractures were also classified histopathologically as acute biomechanical, acute postnecrotic, or chronic biomechanical. RESULTS: Fifty-nine percent (sixty-three) of the fractures occurred within the bone inside the femoral component. Fifty-one percent (fifty-five) of the fractures were classified morphologically as acute postnecrotic; 40% (forty-three), as chronic biomechanical; and 8% (nine), as acute biomechanical. Acute biomechanical fractures were found exclusively in the femoral neck and occurred earlier (mean time [and standard deviation] between implantation and revision, 41 +/- 57 days) than acute postnecrotic fractures (mean time between implantation and revision, 149 +/- 168 days; p = 0.002) or chronic biomechanical fractures (mean time between implantation and revision, 179 +/- 165 days; p = 0.001). The latter two fracture types both occurred predominantly in the bone inside the femoral component. CONCLUSIONS: Three distinct fracture modes were characterized morphologically. Osteonecrosis was the most frequent cause of fracture-related failures. We suggest that an intraoperative mechanical injury of the femoral neck such as notching and/or malpositioning of the femoral component might lead to changes in the loading pattern or in the resistance to fracture of the femoral neck and may result in both acute and chronic biomechanical femoral neck fractures. These findings may serve as feedback information for the surgeon and possibly influence future therapeutic strategies.