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Ollier Disease (OD) and Maffucci syndrome (MS) is a rare bone disorder that affects the growth and development of the bones, with an estimated prevalence of 1 in 100,000 people. It is associated with somatic mosaicism of isocitrate dehydrogenase-1 (IDH1) or 2 (IDH2) pathogenic variants. Ivosidenib is indicated for the treatment of acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma and is currently investigated in low-grade glioma with a susceptible isocitrate dehydrogenase-1 (IDH1) pathogenic variant, but its effects in patients with OD or MS are unknown. We here report the first case of a patient with MS who was treated with Ivosidenib for recurrent IDH-1 mutated glioma. Besides the stabilization of the tumor size, the patient observed significant improvement in his enchondromas that became stiffer, with reduced pain, and significant modification of the mineralization of the enchondromas observed on X-rays. This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.
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X-linked Hypophosphatemia (XLH) is the most common type of inherited rickets. Although the clinical features are well characterized, bone structure, mineralization, and biomechanical properties are poorly known. Our aim was to analyze bone properties in the appendicular and axial skeleton of adults with XLH. In this observational case-control study, each affected patient (N = 14; 9 females; age 50 ± 15 years) was matched by sex, age and body mass index to a minimum of two healthy controls (N = 34). Dual-energy X-ray Absorptiometry (DXA) analyses revealed that areal bone mineral density (aBMD) was higher in XLH patients at the lumbar spine (Z score mean difference = +2.47 SD, P value = 1.4 × 10-3). Trabecular Bone Score was also higher at the lumbar spine (P value = 1.0 × 10-4). High Resolution peripheral Quantitative Computed Tomography (HRpQCT) demonstrated that bone cross-sectional area was larger at the distal radius (P value = 6 × 10-3). Total and trabecular volumetric BMD were lower at both sites. Trabecular bone volume fraction was also lower with fewer trabecular numbers at both sites. However, bone strength evaluated by micro-finite element analyzes revealed unaffected bone stiffness and maximum failure load. Evaluation of bone mineralization with aBMD by DXA at the distal radius correlated with vBMD by HRpQCT measurements at both sites. PTH levels were inversely correlated with trabecular vBMD and BV/TV at the tibia. We then followed a subset of nine patients (median follow-up of 4 years) and reassessed HRpQCT. At the tibia, we observed a greater decrease than expected from an age and sex standardized normal population in total and cortical vBMD as well as a trabecularization of the cortical compartment. In conclusion, in adult patients with XLH, bone mineral density is high at the axial skeleton but low at the appendicular skeleton. With time, microarchitectural alterations worsen. We propose that noninvasive evaluation methods of bone mineralization such as DXA including the radius should be part of the management of XLH patients. Larger studies are needed to evaluate the clinical significance of BMD changes in XLH patients under conventional or targeted therapies.
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Absorciometría de Fotón , Densidad Ósea , Raquitismo Hipofosfatémico Familiar , Humanos , Raquitismo Hipofosfatémico Familiar/diagnóstico por imagen , Raquitismo Hipofosfatémico Familiar/patología , Raquitismo Hipofosfatémico Familiar/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Proyectos Piloto , Adulto , Estudios de Casos y Controles , Estudios Longitudinales , Tomografía Computarizada por Rayos X , Hueso Esponjoso/diagnóstico por imagen , Hueso Esponjoso/patología , Hueso Esponjoso/fisiopatologíaRESUMEN
Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.
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Osteoclastos , Osteopetrosis , Osteopetrosis/genética , Osteopetrosis/patología , Humanos , Osteoclastos/patología , Adulto , Canales de Cloruro/genética , MutaciónRESUMEN
INTRODUCTION: Osteoporosis in candidates for liver transplantation (LT) is often underdiagnosed despite the important consequences of morbidity. METHODS: We included 376 patients with cirrhosis evaluated for LT with available computed tomography (CT) scans. Prevalent vertebral fractures (VFs) were identified on CT reconstructions, and bone density was assessed by measuring CT attenuation of the L1 vertebra (L1-CT). RESULTS: We identified 139 VFs in 55 patients (14.6%). Logistic regression models showed that low L1-CT was the only independent determinant of VF. DISCUSSION: In patients with cirrhosis evaluated for LT, CT scans identified persons with severe osteoporosis without additional costs.
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Trasplante de Hígado , Osteoporosis , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Humanos , Fracturas Osteoporóticas/diagnóstico por imagen , Fracturas Osteoporóticas/epidemiología , Fracturas Osteoporóticas/cirugía , Absorciometría de Fotón/métodos , Estudios Retrospectivos , Osteoporosis/complicaciones , Osteoporosis/diagnóstico por imagen , Osteoporosis/epidemiología , Densidad Ósea , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiología , Fracturas de la Columna Vertebral/cirugía , Tomografía Computarizada por Rayos X/métodos , Vértebras Lumbares , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico por imagenRESUMEN
BACKGROUNDSlow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODSThe Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTSThirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3-4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSIONSirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATIONClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDINGThe Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR grant 21CVD03), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.
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Sirolimus , Malformaciones Vasculares , Adulto , Niño , Humanos , Europa (Continente) , Fosfatidilinositol 3-Quinasas , Estudios Prospectivos , Sirolimus/efectos adversos , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/genéticaRESUMEN
Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
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Antebrazo , Fracturas Óseas , Animales , Ratones , Estudio de Asociación del Genoma Completo , Fracturas Óseas/genética , Densidad Ósea/genética , Factores de RiesgoRESUMEN
Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by heterotopic ossification (HO) in connective tissues and painful flare-ups. In the phase 2 LUMINA-1 trial, adult patients with FOP were randomized to garetosmab, an activin A-blocking antibody (n = 20) or placebo (n = 24) in period 1 (28 weeks), followed by an open-label period 2 (28 weeks; n = 43). The primary end points were safety and for period 1, the activity and size of HO lesions. All patients experienced at least one treatment-emergent adverse event during period 1, notably epistaxis, madarosis and skin abscesses. Five deaths (5 of 44; 11.4%) occurred in the open-label period and, while considered unlikely to be related, causality cannot be ruled out. The primary efficacy end point in period 1 (total lesion activity by PET-CT) was not met (P = 0.0741). As the development of new HO lesions was suppressed in period 1, the primary efficacy end point in period 2 was prospectively changed to the number of new HO lesions versus period 1. No placebo patients crossing over to garetosmab developed new HO lesions (0% in period 2 versus 40.9% in period 1; P = 0.0027). Further investigation of garetosmab in FOP is ongoing. ClinicalTrials.gov identifier NCT03188666 .
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Miositis Osificante , Osificación Heterotópica , Adulto , Humanos , Miositis Osificante/tratamiento farmacológico , Miositis Osificante/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Osificación Heterotópica/patologíaRESUMEN
Early-onset osteoporosis (EOOP) has been associated with several genes, including LRP5, coding for a coreceptor in the Wnt pathway. Variants in LRP5 were also described in osteoporosis pseudoglioma syndrome, combining severe osteoporosis and eye abnormalities. Genomewide-association studies (GWAS) showed that LRP5 p.Val667Met (V667M) variant is associated with low bone mineral density (BMD) and increased fractures. However, despite association with a bone phenotype in humans and knockout mice, the impact of the variant in bone and eye remains to be investigated. Here, we aimed to evaluate the bone and ocular impact of the V667M variant. We recruited 11 patients carrying the V667M variant or other loss-of-function variants of LRP5 and generated an Lrp5 V667M mutated mice. Patients had low lumbar and hip BMD Z-score and altered bone microarchitecture evaluated by HR-pQCT compared with an age-matched reference population. Murine primary osteoblasts from Lrp5 V667M mice showed lower differentiation capacity, alkaline phosphatase activity, and mineralization capacity in vitro. Ex vivo, mRNA expression of Osx, Col1, and osteocalcin was lower in Lrp5 V667M bones than controls (all p < 0.01). Lrp5 V667M 3-month-old mice, compared with control (CTL) mice, had decreased BMD at the femur (p < 0.01) and lumbar spine (p < 0.01) with normal microarchitecture and bone biomarkers. However, Lrp5 V667M mice revealed a trend toward a lower femoral and vertebral stiffness (p = 0.14) and had a lower hydroxyproline/proline ratio compared with CTL, (p = 0.01), showing altered composition and quality of the bone matrix. Finally, higher tortuosity of retinal vessels was found in the Lrp5 V667M mice and unspecific vascular tortuosity in two patients only. In conclusion, Lrp5 V667M variant is associated with low BMD and impaired bone matrix quality. Retinal vascularization abnormalities were observed in mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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OBJECTIVE: Numerous studies have confirmed a strong association between progestins and meningiomas and the regression and/or stabilization of meningiomas after discontinuation of treatment. Osteomeningiomas represent a small subgroup of meningiomas that appear to be more common among progestin-related meningiomas. However, the specificity of the behavior of this subset of meningiomas after discontinuation of progestin has not yet been assessed. METHODS: Thirty-six patients (mean age 49.5 years) who presented with at least one progestin-related osteomeningioma (48 tumors total) were identified from a prospectively collected database of patients and had been referred to our department for meningioma and had documented use of cyproterone acetate, nomegestrol acetate, and/or chlormadinone acetate. Hormonal treatment was stopped at the time of diagnosis for all the patients, and the clinical and radiological evolution of this subgroup of tumors was evaluated. RESULTS: For half of the 36 patients, treatment was prescribed for signs of hyperandrogenism, such as hirsutism, alopecia, or acne. Most lesions were spheno-orbital (35.4%) or frontal (31.2%). Although the tissular part of the meningioma shrank in 77.1% of cases, the osseous part exhibited discordant behavior with 81.3% showing volume progression. The combination of estrogens, as well as the prolonged duration of progestin treatment, seems to increase the risk of progression of the osseous part after treatment discontinuation (p = 0.02 and p = 0.028, respectively). No patient required surgical treatment at diagnosis or during the study. CONCLUSIONS: These results show that while the soft intracranial part of progestin-related osteomeningioma tumor is the most likely to regress after treatment discontinuation, the bony part is more likely to increase in volume. These findings suggest the need for careful follow-up of these patients, especially those with tumors near the optical apparatus.
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Neoplasias Meníngeas , Meningioma , Humanos , Persona de Mediana Edad , Progestinas/efectos adversos , Meningioma/inducido químicamente , Meningioma/diagnóstico por imagen , Meningioma/patología , Acetato de Ciproterona/efectos adversos , Neoplasias Meníngeas/patologíaRESUMEN
Osteoporosis is a common non-communicable disease with enormous societal costs. Antiosteoporosis medications have been proven efficacious in reducing the refracture rate and mortality; moreover, we have now convincing evidence about the cost-effectiveness of antiosteoporotic medications. However, albeit preventable and treatable, osteoporosis has been somehow neglected by health authorities. Drugs approval has been unnecessarily lengthy, especially when compared with other non-communicable diseases. Herein, we discuss the issue of procrastinating drug approval in osteoporosis and future implications.
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Aprobación de Drogas , Osteoporosis , Humanos , Osteoporosis/tratamiento farmacológicoRESUMEN
Hip fracture is the clinically most important fracture, but the genetic architecture of hip fracture is unclear. Here, we perform a large-scale hip fracture genome-wide association study meta-analysis and Mendelian randomization study using five cohorts from European biobanks. The results show that five genetic signals associate with hip fractures. Among these, one signal associates with falls, but not with bone mineral density (BMD), while four signals are in loci known to be involved in bone biology. Mendelian randomization analyses demonstrate a strong causal effect of decreased femoral neck BMD and moderate causal effects of Alzheimer's disease and having ever smoked regularly on risk of hip fractures. The substantial causal effect of decreased femoral neck BMD on hip fractures in both young and old subjects and in both men and women supports the use of change in femoral neck BMD as a surrogate outcome for hip fractures in clinical trials.
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Estudio de Asociación del Genoma Completo , Fracturas de Cadera , Masculino , Femenino , Humanos , Análisis de la Aleatorización Mendeliana , Densidad Ósea/genética , Fracturas de Cadera/epidemiología , Cuello FemoralRESUMEN
Several drugs are able to reduce fracture risk in osteoporotic patients. Incident fractures occur despite good adherence to treatment. Inadequate response has been found related to high serum bone biomarkers of bone turnover. We here aimed to analyze bone microarchitecture and cellular profiles of inadequate responders. We retrospectively analyzed bone biopsies from patients with major fractures despite long-term treatment (inadequate responder [IR] n = 31) in comparison to patients with untreated osteoporosis (U-OP, n = 31) and controls without osteoporosis (Ctrl, n = 16). Bone samples were analyzed by histomorphometry and micro-computed tomography. Clinical and bone turnover markers and bone mineral density were assessed. As compared with U-OP patients, IRs were older (mean age 69.7 ± 8.8 vs 63.3 ± 9.3 years, p = 0.007) and had lower mean hip bone mineral density (0.685 ± 0.116 vs 0.786 ± 0.093 g/cm2), p = 0.019 and T-score (-2.3 ± 0.769 vs -1.6 ± 0.900, p = 0.032). BV/TV was lower for IRs than U-OP patients and Ctrls (13.9 ± 3.8% vs 15.2 ± 5.1 and 17.6 ± 5.2%, p = 0.044) as was trabecular thickness (145.6 ± 23.1 vs 160.5 ± 22.7 and 153.7 ± 21.4 µm, p = 0.033). Mean structure model index was lower for IRs than U-OP patients (1.9 ± 0.806 vs 2.4 ± 0.687, p = 0.042) and osteoclast number was higher for IRs than U-OP patients and Ctrls (0.721 ± 0.611 vs 0.394 ± 0.393 and 0.199 ± 0.071 mm-2, p < 0.001). The mean Obl.S/BS was lower for IRs than U-OP patients and Ctrls (1.2 ± 1.3 vs 1.9 ± 1.4 and 3.0 ± 0.638 mm-2, p < 0.0001), and the mean number of labelled surfaces was lower for IRs than U-OP patients (51.6% vs 87%, p = 0.002). Cortical parameters did not significantly differ. We show an imbalance of bone remodeling in favor of bone resorption in IRs. The persistence of high bone resorption suggests insufficient inhibition of bone resorption that could explain the incident fractures with anti-osteoporotic drug use. Adaptation to treatment should be considered to inhibit bone resorption and prevent further fractures.
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Resorción Ósea , Osteoporosis , Fracturas Osteoporóticas , Anciano , Densidad Ósea , Humanos , Persona de Mediana Edad , Osteoclastos , Osteoporosis/tratamiento farmacológico , Estudios Retrospectivos , Microtomografía por Rayos XRESUMEN
BACKGROUND: Early-onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low-density lipoprotein receptor-related protein 5 (LRP5) are associated with EOOP. This study aimed to investigate the genetic profile in patients with EOOP to better understand the variation in phenotype severity by using a targeted gene sequencing panel associated with bone fragility. METHOD AND RESULTS: We used a sequencing panel with 17 genes reported to be related to bone fragility for analysis of 68 patients with EOOP. We found a high positivity rate of EOOP with LRP5 variants (14 patients, 20.6%). The remaining 79.4% of patients with EOOP but without LRP5 variants showed variable disease severity, as observed in patients with at least one variant in this gene. One patient, with multiple fractures and spine L1-L4 BMD Z-score -2.9, carried a novel pathogenic homozygous variant, c.2918T>C, p.(Leu973Pro), without any pseudoglioma. In addition to carrying the LRP5 variant, 2 other patients carried a heterozygous variant in Wnt signaling pathway genes: dickkopf WNT signaling pathway inhibitor 1 (DKK1) [NM_012242.4: c.359G>T, p.(Arg120Leu)] and Wnt family member 3A (WNT3A) [NM_033131.3: c.377G>A, p. (Arg126His)]. As compared with single-variant LRP5 carriers, double-variant carriers had a significantly lower BMD Z-score (-4.1 ± 0.8) and higher mean number of fractures (6.0 ± 2.8 vs. 2.2 ± 1.9). Analysis of the family segregation suggests the inheritance of BMD trait. CONCLUSION: Severe forms of EOOP may occur with carriage of 2 pathogenic variants in genes encoding regulators of the Wnt signaling pathway. Two-variant carriers of Wnt pathway genes had severe EOOP. Moreover, DKK1 and WNT3A genes should be included in next-generation sequence analyses of bone fragility.
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Péptidos y Proteínas de Señalización Intercelular/genética , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Osteoporosis/genética , Fenotipo , Proteína Wnt3A/genética , Adolescente , Adulto , Edad de Inicio , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/patologíaAsunto(s)
Densidad Ósea , Hueso Esponjoso/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Hueso Cortical/diagnóstico por imagen , Fémur/diagnóstico por imagen , Osteoporosis/epidemiología , Vértebras Torácicas/diagnóstico por imagen , Calcificación Vascular/epidemiología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoporosis/diagnóstico por imagen , Proyectos Piloto , Suecia/epidemiología , Tomografía Computarizada por Rayos X , Calcificación Vascular/diagnóstico por imagenRESUMEN
The Wnt pathway is a key element of bone remodeling; its activation stimulates bone formation and inhibits bone resorption. The discovery of sclerostin, a natural antagonist of the Wnt pathway, promoted the development of romosozumab, a human monoclonal antibody directed against sclerostin, as well as other anti-sclerostin antibodies. Phase 3 studies have shown the efficacy of romosozumab in the prevention of fractures in postmenopausal women, against placebo but also against alendronate or teriparatide and this treatment also allows bone mineral density (BMD) increase in men. Romosozumab induces the uncoupling of bone remodeling, leading to both an increase in bone formation and a decrease in bone resorption during the first months of treatment. The effect is attenuated over time and reversible when stopped but transition with anti-resorbing agents allows the maintenance or reinforcement of BMD improvements. Some concerns were raised about cardiovascular events. Therefore, romosozumab was recently approved in several countries for the treatment of severe osteoporosis in postmenopausal women with high fracture risk and without a history of heart attack, myocardial infarction or stroke. This review aims to outline the role of sclerostin, the efficacy and safety of anti-sclerostin therapies and in particular romosozumab and their place in therapeutic strategies against osteoporosis or other bone diseases.
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Epidemiological studies have shown that high bone mineral density (BMD) is associated with an increased risk of osteoarthritis (OA), but the causality of this relationship remains unclear. Both bone mass and OA have been associated with the WNT signaling pathway in genetic studies, there is thus an interest in studying molecular partners of the WNT signaling pathway and OA. Female mice overexpressing WNT16 in osteoblasts (Obl-Wnt16 mice) have an increased bone mass. We aimed to evaluate if the high bone mass in Obl-Wnt16 mice leads to a more severe experimental OA development than in WT control mice. We induced experimental OA in female Obl-Wnt16 and WT control mice by destabilizing the medial meniscus (DMM). The Obl-Wnt16 mice displayed thicker medial and lateral subchondral bone plates as well as increased subchondral trabecular bone volume/tissue volume (BV/TV) but un-altered thickness of articular cartilage compared to WT mice. After DMM surgery, there was no difference in OA severity in the articular cartilage in the knee joint between the Obl-Wnt16 and WT mice. Both the Obl-Wnt16 and WT mice developed osteophytes in the DMM-operated tibia to a similar extent. We conclude that although the Obl-Wnt16 female mice have a high subchondral bone mass due to increased WNT signaling, they do not exhibit a more severe OA phenotype than their WT controls. This demonstrates that high bone mass does not result in an increased risk of OA per se.
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Densidad Ósea , Osteoartritis/metabolismo , Osteoblastos/metabolismo , Proteínas Wnt/metabolismo , Animales , Cartílago Articular , Femenino , Ratones , TibiaRESUMEN
Mineral and bone diseases (MBD) are predominant in patients with chronic kidney disease (CKD) and lead to several bone manifestations, from pain to skeletal fractures. Cumulative traditional clinical risk factors, such as age and gender, in addition to those related to CKD, enhance the risk of comorbidity and mortality related to fractures. Despite great advances in understanding MBD in CKD, clinical and biological targets are lacking, which leads to under-management of fractures. Optimal PTH control results in a net improvement in defining the levels of bone remodeling. In addition, circulating biomarkers such as bone-specific alkaline phosphatase and cross-linked collagen type I peptide will also provide additional information about remodeling rate, bone mineralization and the evaluation of fracture risk. Imaging techniques identify patients at risk by measurement of bone mineral density by DEXA or by high peripheral QCT, which allow the discrimination of trabecular and cortical bone. Here, we have reviewed the literature related to epidemiology and the pathophysiological role of mineral and biochemical factors involved in CKD-MBD with a special focus on fracture risk. We also provide an algorithm that could be used for the management of bone diseases and to guide treatment decisions. Finally, the combined expertise of clinicians from various disciplines is crucial for the best prevention of fractures.