RESUMO
To study the effects of low-density lipoprotein receptor-related protein 5 (LRP5) gene mutations on bone, and to open up our view of LRP5 and Wnt pathways on bone mass regulation. Three patients with increased bone mineral density or thickened bone cortex were included, who were 30-year-old, 22-year-old and 50-year-old men, respectively. The latter two patients were son and father of a same family. The characteristics of bone X-rays were evaluated in detail. Bone turnover markers were detected, such as procollagen type 1 amino-terminal peptide (P1NP), alkaline phosphatase (ALP), and type 1 collagen carboxyl terminal peptide (ß-CTX). Dual energy X-ray absorptiometry (DXA) was used to measure the bone mineral density (BMD) at lumbar spine and proximal femur of the patients. The targeted next-generation sequencing (NGS) technology was used to detect pathogenic gene mutations, which were further verified by Sanger sequencing. Moreover, the gene mutation spectrum and phenotypic characteristics of reported patients with LRP5 gain-of-function mutations were summarized by reviewing the literature. The main characteristics of the first patient were headache, facial paralysis, high BMD (lumbar vertebrae 1-4: 1.877 g/cm2, Z-score: 5.8; total hip: 1.705 g/cm2, Z-score: 5.7), slightly increased P1NP (87.0 ng/mL) and ß-CTX (0.761 ng/mL) level, and with thickened bone cortex, especially the cranial vault. The latter two patients showed enlargement of the mandible and enlarged osseous prominence of the tours palatinus. X-rays showed that the bone cortex of skull and long bones were thickened. The bone turnover markers and BMD were normal. All three cases carried novel missense mutations in LRP5 gene, which were mutation in exon 3 (c.586 T > G, p.Trp196Gly) of the first patient, and mutation in exon 20 (c.4240C > A, p.Arg1414Ser) of the latter two patients. Combined with the reported literature, a total of 19 gain-of-function mutations in LRP5 were detected in 113 patients from 33 families. Hotspot mutations included c.724G > A, c.512G > T and c.758C > T. Furthermore, mutations in the exon 3 of LRP5 may cause severe phenotypes. LRP5 gain-of-function mutations can lead to rare autosomal dominant osteosclerosis type Ι (ADO Ι), which was characterized by increased bone mass and thickened bone cortex. In-depth research on the Wnt pathway will be benefit for discovering important mechanisms of bone mass regulation.
Assuntos
Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Osteosclerose , Humanos , Osso e Ossos , Densidade Óssea/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Mutação , Osteosclerose/diagnóstico por imagem , Osteosclerose/genética , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Osteoporosis leads to more serious consequences in men than in women, but less is known about its impacts on health-related quality of life (HRQoL) of men, and whether the anti-osteoporosis treatment can improve HRQoL of men with osteopenia/osteoprosis. METHODS: We enrolled men with primary osteoporosis and age-matched healthy controls. We collected medical history, serum levels of carboxyl-terminal type I collagen telopeptide, procollagen type I propeptides, and bone mineral density of patients. All patients and controls completed the short-form 36 (SF-36) questionnaires. Changes in HRQoL of osteopenia/osteoporosis men were prospectively evaluated after alendronate or zoledronic acid treatment. RESULTS: A total of 100 men with primary osteoporosis or osteopenia and 100 healthy men were included. The patients were divided into three subgroups: osteopenia (n = 35), osteoporosis (n = 39) and severe osteoporosis (n = 26). Men with osteoporosis or severe osteoporosis had impaired HRQoL in domains of physical health compared to healthy controls. HRQoL scores in physical health related domains of patients with severe osteoporosis were significantly lower compared to healthy controls, and were the poorest among the three subgroups of patients. Fragility fracture history was correlated with lower SF-36 scores about physical health. In 34 men with newly diagnosed osteoporosis receiving bisphosphonates treatment, HRQoL scores were significantly improved in domains of physical health after treatments. CONCLUSIONS: The HRQoL is significantly impaired in men with osteoporosis, and the more severe the osteoporosis, the poorer the HRQoL. Fragility fracture is an important influencing factor of deteriorated HRQoL. Bisphosphonates treatment is beneficial to improve HRQoL of osteopenia/osteoporosis men.
Assuntos
Doenças Ósseas Metabólicas , Fraturas Ósseas , Osteoporose , Masculino , Humanos , Feminino , Difosfonatos/uso terapêutico , Qualidade de Vida , Osteoporose/tratamento farmacológico , Doenças Ósseas Metabólicas/tratamento farmacológico , Densidade ÓsseaRESUMO
OBJECTIVE: Osteoporosis in men has been neglected despite its association with disability and mortality. We evaluated the effect of bisphosphonates (BPs) on bone mineral density (BMD) and bone turnover biomarkers of osteoporotic men with different androgen levels. METHODS: This case-control study included 136 osteoporotic men who were divided into normal group (n = 75) and hypogonadism group (n = 61) (patients treated with testosterone were excluded) according to their serum testosterone levels (cutoff value, 350 ng/dL). BMD, serum testosterone, total alkaline phosphatase, and cross-linked C-telopeptide of type I collagen were detected. The relationship between testosterone levels and BMD at baseline was evaluated. All patients were treated with BPs for 2 years. We compared the effects of BPs on BMD and bone turnover biomarkers between the 2 groups. RESULTS: At baseline, there were no significant differences in BMD and bone turnover biomarkers between the 2 groups. Testosterone levels were positively correlated with BMD in the hypogonadism group. After treatment, the lumbar BMD increased by 7.65% ± 1.54% and 7.47% ± 1.88% in normal and hypogonadism groups, respectively (both P < .01 vs baseline) and hip BMD increased without significant differences between the 2 groups. Serum cross-linked C-telopeptide of type I collagen and alkaline phosphatase levels decreased without significant differences between the 2 groups (all P < .01 vs baseline). CONCLUSION: Testosterone level is positively correlated with BMD in men with hypogonadism. In osteoporotic men, BPs significantly increase spine and hip BMD and decrease bone resorption. The efficacy of BPs is similar in men with or without hypogonadism.
Assuntos
Androgênios , Hipogonadismo , Biomarcadores , Densidade Óssea , Remodelação Óssea , Estudos de Casos e Controles , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Humanos , Hipogonadismo/tratamento farmacológico , Masculino , TestosteronaRESUMO
BACKGROUND: The reduction in androgen level gives rise to a decrease in bone mineral density (BMD) and muscle strength, but the exact mechanisms are unclear. We investigated the roles of novel cytokines of sclerostin and irisin on bone and muscle of orchiectomized rats. METHODS: Twenty 3-month-old male rats were randomized to receive sham or orchiectomy (ORX) operation. Rats were euthanized after 8 weeks of surgery, and serum levels of sclerostin and irisin were measured by enzyme-linked immunosorbent assay at baseline and execution. Grip strength was measured by a grip strength tester at baseline and before execution. BMD and bone microarchitecture were measured by microcomputed tomography. The samples of bone and muscle were harvested at execution. Bone biomechanics were measured by three-point bending tests and vertebral body indentation tests. Bone and muscle histological features were analyzed by hematoxylin and eosin stain, Von Kossa's stain and tartrate resistant acid phosphatase stain. Simple linear regression analyses were used to analyze the relationships between serum levels of sclerostin, irisin and grip strength and BMD of ORX rats. RESULTS: Serum sclerostin level increased from 279 ± 44 pg/mL to 586 ± 57 pg/mL since baseline to 8 weeks after ORX (P = 0.002), which was significantly higher than that in sham rats (406 ± 20 pg/mL at execution) (P = 0.012). Serum irisin level decreased from 4.12 ± 0.20 ng/mL to 3.55 ± 0.29 ng/mL since baseline to 8 weeks of ORX (P = 0.048), which was significantly lower than sham rats (4.84 ± 0.37 pg/mL at execution) (P = 0.013). Trabecular BMD, parameters of bone microarchitecture, bone strength, grip strength and the myofibers size of soleus muscles were significantly lower in ORX rats than in sham group. Grip strength was positively correlated with femoral trabecular BMD (r = 0.713, P < 0.001) and bone volume/total volume (r = 0.712, P < 0.001) in all rats. The serum sclerostin level was negatively correlated to femoral trabecular BMD (r = -0.508, P = 0.022) and grip strength (r = -0.492, P = 0.028). Serum irisin level was positively correlated with femoral trabecular BMD (r = 0.597, P = 0.005), but no obvious correlation was found between irisin level and muscle strength in all rats. CONCLUSIONS: Reduced BMD, impaired bone microarchitecture, weak strength of bone and muscle, and thin myofibers were induced by androgen deficiency of ORX rats. Serum sclerostin and irisin levels were significantly changed after ORX, which might be closely correlated with the occurrence of osteoporosis and sarcopenia in ORX rats.
Assuntos
Androgênios , Fibronectinas , Animais , Masculino , Ratos , Densidade Óssea , Músculos , Microtomografia por Raio-XRESUMO
OBJECTIVE: To detect the genetic variant of a child with cleidocranial dysplasia (CCD) and to find out the causation of the illness. METHODS: Gene variant was identified by the second generation targeted sequencing and Sanger sequencing. RESULTS: The gene sequencing revealed that the RUNX2 gene had c.196C>T(p.Glu66*) nonsense variant, which was predicted to be a pathogenic variant according to the ACMG guidelines(PVS1+PS2). CONCLUSION: The variant of c.196C > T in the RUNX2 gene may be the cause of the child with CCD, and the novel variant enriches the RUNX2 gene variant spectrum.
Assuntos
Displasia Cleidocraniana , Subunidade alfa 1 de Fator de Ligação ao Core , Povo Asiático/genética , Criança , China , Displasia Cleidocraniana/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Humanos , MutaçãoRESUMO
OBJECTIVE: Deficiency of cartilage-associated protein (CRTAP) can cause extremely rare autosomal recessive osteogenesis imperfecta (OI) type VII. We investigated the pathogenic mechanisms of CRTAP variants through functional studies on bones of patients with OI. METHODS: Two nonconsanguineous families with CRTAP mutations were included and their phenotypes and genotypes were evaluated. Bone specimens were obtained from 1 patient with OI and a normal control during orthopedic surgery. The impacts of the novel variant on the CRTAP transcript were confirmed. The expression levels of CRTAP mRNA and CRTAP protein were analyzed. The quantification of prolyl 3-hydroxylation in the α1 chain of type I collagen was evaluated. RESULTS: Patients with OI type VII had early-onset recurrent fractures, severe osteoporosis, and bone deformities. The c.621 + 1G > A and c.1153-3C > G mutations were identified in CRTAP in the patients with OI. The c.621 + 1G > A variant was a novel mutation that could impair mRNA transcription, leading to a truncated CRTAP protein. In a patient with c.621 + 1G > A and c.1153-3C > G mutations in CRTAP, the mRNA and protein levels of CRTAP in osteoblasts were significantly decreased and the osteoid volume and osteoblast numbers were markedly reduced compared with those in the normal control individual. This was simultaneously accompanied by significantly reduced prolyl 3-hydroxylation at Pro986 in the α1 chain of type I collagen and invisible active bone formation in bone. CONCLUSION: The novel c.621 + 1G > A mutation in CRTAP expands the genotypic spectrum of type VII OI. Biallelic mutations of c.621 + 1G > A and c.1153-3C > G in CRTAP can lead to reduced CRTAP mRNA and deficient CRTAP protein in osteoblasts, which reduces 3-hydroxylation in Pro986 of the α1 chain of type I collagen and impairs bone formation, thus contributing to severe OI type VII.
Assuntos
Proteínas da Matriz Extracelular , Chaperonas Moleculares , Osteogênese Imperfeita , Fenótipo , Humanos , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/patologia , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Masculino , Feminino , Chaperonas Moleculares/genética , Mutação , Criança , Linhagem , Pré-Escolar , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Genótipo , Osteoblastos/metabolismo , Osteoblastos/patologia , Cadeia alfa 1 do Colágeno Tipo I , Adulto , AdolescenteRESUMO
CONTEXT: The comparative effectiveness of denosumab and zoledronic acid for adult patients with osteogenesis imperfecta (OI) has not been established. OBJECTIVE: To evaluate the efficacy and safety of denosumab and zoledronic acid in adult patients with OI. METHODS: This was a prospective, open-label study. Patients were randomized to receive denosumab 60â mg every 6 months or zoledronic acid 5â mg once for 12 months. Pathogenic mutations of OI were identified by next-generation sequencing and confirmed by Sanger sequencing. Percentage changes in the areal bone mineral density (aBMD), trabecular bone score (TBS), and bone turnover biomarkers (BTMs) from baseline to 6 and 12 months of treatment, as well as safety, were evaluated. RESULTS: A total of 51 adults with OI (denosumab: 25, zoledronic acid: 26) were included, of whom 49 patients had identified pathogenic mutations. At 12 months, aBMD at the lumbar spine and total hip significantly increased by 4.34% (P = .005) and 1.45% (P = .023) in the denosumab group and by 4.92% (P = .006) and 2.02% (P = .016) in the zoledronic acid group, respectively. TBS showed an increasing trend by 1.39% and 2.70% in denosumab and zoledronic acid groups, respectively. Serum levels of ß-isomerized carboxy-telopeptide of type I collagen and alkaline phosphatase markedly decreased after denosumab treatment. Percentage changes in aBMD, TBS, and BTMs during the treatment were similar between the 2 groups. Patients with OI with milder phenotypes showed a significantly higher increase in the TBS after 12 months of denosumab treatment than those with more severe phenotypes (P = .030). During the study period, the denosumab group had fewer adverse events than the zoledronic acid group. CONCLUSION: Denosumab effectively increases aBMD in adults with OI, with similar efficacy to zoledronic acid. Long-term and large-sample studies are needed to confirm the antifracture efficacy and safety of denosumab in adult patients with OI.
Assuntos
Conservadores da Densidade Óssea , Densidade Óssea , Denosumab , Osteogênese Imperfeita , Ácido Zoledrônico , Humanos , Denosumab/uso terapêutico , Denosumab/efeitos adversos , Denosumab/administração & dosagem , Ácido Zoledrônico/uso terapêutico , Ácido Zoledrônico/administração & dosagem , Ácido Zoledrônico/efeitos adversos , Feminino , Masculino , Adulto , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/efeitos adversos , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , Densidade Óssea/efeitos dos fármacos , Estudos Prospectivos , Resultado do Tratamento , Remodelação Óssea/efeitos dos fármacos , Adulto Jovem , Pessoa de Meia-IdadeRESUMO
Background: Alzheimer's disease (AD) is a neurodegenerative disorder that is the major cause of dementia in the aged population. Recent researches indicate that patients with AD have a significantly increased fracture risk, but the pathological mechanisms are still unclear. Objective: We systematically reviewed studies regarding bone fracture risk in AD to uncover links between the pathologies of osteoporosis and AD. Methods: We searched the literature using the databases of PubMed, Web of Science, Embase and Cochrane Library. Studies were included if they evaluated bone fracture risk in AD patients and if they explored the pathogenesis and prevention of bone fractures in these patients. Results: AD patients had a significantly higher risk of bone fractures than age-matched controls. Multiple factors contributed to the increased risk of bone fractures in AD patients, including the direct effects of amyloid pathology on bone cells, abnormal brain-bone interconnection, Wnt/ß-catenin signalling deficits, reduced activity, high risk of falls and frailty, and chronic immune activity. Exercise, prevention of falls and fortified nutrition were beneficial for reducing the fracture risk in AD patients. However, the efficacy of anti-osteoporotic agents in preventing bone fractures should be further evaluated in AD patients as corresponding clinical studies are very scarce. Conclusion: Alzheimer's disease patients have increased bone fracture risk and decreased bone mineral density owing to multiple factors. Assessment of anti-osteoporotic agents' efficacy in preventing bone fractures of AD patients is urgently needed.
Assuntos
Doença de Alzheimer , Fraturas Ósseas , Osteoporose , Humanos , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/epidemiologia , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Osteoporose/complicações , Proteínas Amiloidogênicas , EncéfaloRESUMO
CONTEXT: Mutations in WNT1 can cause rare inherited disorders such as osteogenesis imperfecta (OI) and early-onset osteoporosis (EOOP). Owing to its rarity, the clinical characteristics and pathogenic mechanism of WNT1 mutations remain unclear. OBJECTIVE: We aimed to explore the phenotypic and genotypic spectrum and treatment responses of a large cohort of patients with WNT1-related OI/OP and the molecular mechanisms of WNT1 variants. METHODS: The phenotypes and genotypes of patients and their responses to bisphosphonates or denosumab were evaluated. Western blot analysis, quantitative polymerase chain reaction, and immunofluorescence staining were used to evaluate the expression levels of WNT1, total ß-catenin, and type I collagen in the tibial bone or skin from one patient. RESULTS: We included 16 patients with 16 mutations identified in WNT1, including a novel mutation. The types of WNT1 mutations were related to skeletal phenotypes, and biallelic nonsense mutations or frameshift mutations could lead to an earlier occurrence of fragility fractures and more severe skeletal phenotypes. Some rare comorbidities were identified in this cohort, including cerebral abnormalities, hematologic diseases, and pituitary adenoma. Bisphosphonates and denosumab significantly increased the spine and proximal hip BMD of patients with WNT1 mutations and reshaped the compressed vertebrae. We report for the first time a decreased ß-catenin level in the bone of patient 10 with c.677C > T and c.502G > A compared to the healthy control, which revealed the potential mechanisms of WNT1-induced skeletal phenotypes. CONCLUSION: Biallelic nonsense mutations or frameshift mutations of WNT1 could lead to an earlier occurrence of fragility fractures and a more severe skeletal phenotype in OI and EOOP induced by WNT1 mutations. The reduced osteogenic activity caused by WNT pathway downregulation could be a potential pathogenic mechanism of WNT1-related OI and EOOP.
Assuntos
Fraturas Ósseas , Osteogênese Imperfeita , Osteoporose , Humanos , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/genética , beta Catenina/genética , Códon sem Sentido , Denosumab , Osteoporose/genética , Genótipo , FenótipoRESUMO
Plastin 3 (PLS3), a protein involved in formation of filamentous actin (F-actin) bundles, is important in human bone health. Recent studies identify PLS3 as a novel bone regulator and PLS3 mutations can lead to a rare monogenic early-onset osteoporosis. However, the mechanism of PLS3 mutation leading to osteoporosis is unknown, and its effective treatment strategies have not been established. Here, we have constructed a novel rat model with clinically relevant hemizygous E10-16del mutation in PLS3 (PLS3E10-16del/0) that recapitulates the osteoporotic phenotypes with obviously thinner cortical thickness, significant decreases in yield load, maximum load, and breaking load of femora at 3, 6, 9 months old compared to wild-type rats. Histomorphometric analysis indicates a significantly lower mineral apposition rate in PLS3E10-16del/0 rats. Treatment with alendronate (1.0 µg/kg/day) or teriparatide (40 µg/kg five times weekly) for 8 weeks significantly improves bone mass and bone microarchitecture, and bone strength is significantly increased after teriparatide treatment (pï¼0.05). Thus, our results indicate that PLS3 plays an important role in the regulation of bone microstructure and bone strength, and we provide a novel animal model for the study of X-linked early-onset osteoporosis. Alendronate and teriparatide treatment could be a potential treatment for early-onset osteoporosis induced by PLS3 mutation.
Assuntos
Osteoporose , Teriparatida , Humanos , Ratos , Animais , Lactente , Alendronato/farmacologia , Proteínas dos Microfilamentos/genética , Osteoporose/tratamento farmacológico , Osteoporose/genética , Densidade Óssea/genética , MutaçãoRESUMO
Objective: Osteoblasts are discovered to secrete hormones with endocrine effects on metabolism, and osteocalcin (OC) is the most abundant non-collagenous protein in bone. We investigate the relationship between serum OC levels and glycolipid metabolism and muscle function in children with osteogenesis imperfecta (OI). Methods: A total of 225 children with OI and 80 healthy controls matched in age and gender were included in this single center study. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated analyzers. Serum levels of fasting insulin (FINS) were measured using an automated electrochemiluminescence system. Serum levels of OC and undercarboxylated osteocalcin (ucOC) were measured by enzyme-linked immunosorbent assay. Grip strength and timed-up-and-go (TUG) test were measured. Bone mineral density (BMD) and body composition were measured using dual-energy X-ray absorptiometry. Results: OI patients had significantly higher body mass index (BMI), FBG, and HOMA-IR, but lower HDL-C levels, lower grip strength and longer TUG than control group (all P<0.05). Serum OC, ucOC levels, and ucOC/OC in OI type III patients were significantly lower than those in OI patients with type I and IV. Serum levels of OC, ucOC, and ucOC/OC were negatively correlated to BMI, FBG, insulin levels, and HOMA-IR (all P<0.05). The ratio of ucOC/OC was positively correlated to grip strength (r=0.512, P=0.036), lean mass percentage (%LM) of the total body and limbs, and negatively correlated to fat mass percentage (%FM) of the total body, %FM and fat mass index (FMI) of the trunk (all P<0.05). Conclusions: Obesity, glucolipid metabolic abnormalities, and reduced grip strength were common in children with OI. Circulating osteocalcin and ucOC may play an important role in the regulation of glucose metabolism, as well as the muscle function of children with OI.
Assuntos
Músculos , Osteocalcina , Osteogênese Imperfeita , Criança , Colesterol , Glicolipídeos/metabolismo , Humanos , Insulina/metabolismo , Músculos/fisiologia , Músculos/fisiopatologia , Osteocalcina/sangueRESUMO
PURPOSE: The increased social and economic burdens make osteoporosis in men an emerging public health issue. However, the quality of life among men with osteoporosis is still unclear. This systematic review and meta-analysis aimed to evaluate the health-related quality of life (HRQoL) among men with osteoporosis or osteoporotic fracture. METHODS: PubMed, EMBASE, and the Cochrane Library database were systematically searched from inception to May 2021. Studies were included if they used validated questionnaires to measure HRQoL among osteoporotic men. A meta-analysis was performed using a random-effects model or fixed-effects model to calculate the standard mean difference (SMD) or mean difference (MD) with 95% confidential interval (95% CI). RESULTS: 14 studies involving 6338 male participants were chosen for systematic review, of which 10 were included in the meta-analysis. Men with osteoporosis had poorer global HRQoL and multiple dimensions of HRQoL than men without osteoporosis. Hip fracture, vertebral fractures, or wrist fractures dramatically impaired HRQoL of men, and physical function was declined even before hip fracture (SMD = -0.60, 95% CI, -0.82 to -0.39). Femoral and lumbar BMD was positively correlated with HRQoL, and a number of fragility fractures and time since fracture had negative effects on HRQoL. Effective anti-osteoporotic drugs could improve HRQoL of men. CONCLUSION: The health-related life quality of men was significantly impaired by osteoporosis and fracture of the hip, vertebral, or wrist. We should pay more attention to the diagnosis and treatment of male osteoporosis to improve the life quality of men.