| Part 1.Health-related quality of life in patients with osteogenesis imperfectaIntroduction Osteogenesis imperfecta(OI)is an inheritable disease characterized by low bone mineral density(BMD)and increased fracture rates.OI is a collagen-related disorder,of which 85%-90%cases are due to dominantly inherited mutations in COL1A1 or COL1A2.Mutations in type I collagen can be divided into haploinsufficiency,with the synthesis of structurally normal collagen at about half the normal amount,and glycine substisution,that result in synthesis and secretion of abnormal collagen molecules.Patients with OI not only suffer from recurrent fractures and bone deformities,but also demonstrate muscle weakness and hearing impairment,which may remarkably affect health-related quality of life(QoL)in these patients.However,life quality of OI patients has not been investigated in detail.Therefore,we aim to assess the quality of life in a large cohort of Chinese children and adults with OI,investigate the differences of QoL in different phenotype and genotype,and analyse the correlating factors that may affect QoL.Methods1.In this cross-sectional study,we included 138 children and adolescents,38 adult patients with 01 at Department of endocrinology of PUMCH between Dec,2016 and Dec,2017.Moreover,138 healthy children and 50 healthy adults were also admitted as control group,matched in age and sex.Data of demographic information,clinical presentation and pathogenic mutations of 01 were collected.Serum levels ofβ-isomerized carboxy-telopeptide of type I collagen(β-CTX),alkaline phosphatase(ALP)and 25-hydroxyvitamin D(250HD)were also measured.Areal BMD at the lumbar spine 2-4(LS),femoral neck(FN)and total hip(TH)was measured by dual-energy X-ray absorptiometry(DXA)(Lunar,GE Healthcare,USA).We used a NGS-based panel for targeted sequencing of all exons of 19 genes related to OI,and performed diagnostic gene sequencing for 01 patients.Mutations identified by NGS were further confirmed by Sanger sequencing and co-segregation analysis.2.Then we used validated questionnaire,Pediatric Quality of Life Inventory(PedsQL version 4.0)and WHOQOL-BREF,to evaluate HRQoL of children and adults with OI separately.Both of questionnaires included physical function,emotional function,social function and school/environmental function.The items were scored from 0 to 100,and higher scores indicated better QoL.3.Furthermore,we compared QoL of OI patients with healthy controls.The differences in QoL were also evaluated among patients with OI type Ⅰ,Ⅲ and IV.Sillence nomenclature by clinical presentation was as follows:non-deforming(type Ⅰ),perinatally lethal(type Ⅱ),progressively deforming(type Ⅲ),and moderate severity(type Ⅳ).4.We compared differences of QoL in different genotypes,including autosomal dominant inheritance and autosomal ressesive inheritance,mutations of COL1A1 and COL1A2,haploinsufficiency and glycine substitution.5.We compared differences of QoL between patients with BPs treatment and without BPs treatment.6.Then we analyzed the possible influencing factors to QoL in OI patients by Spearman correlation coefficient test.Results1.A total of 138 children with OI,138 healthy children as control,38 adults with OI and 50 healthy adults were enrolled in this study.The average age of children with OI was 10.0 ±4.4 years old,total fracture was 4.6 ±4.2 times,BMD Z-score at LS and FN were 0.5±2.4 and-0.6±2.7(after treatment).The average age of adults with OI was 31.8±10.6 years old,total fracture was 10.0±12.4 times,BMD Z-score at LS and FN were-1.1± 1.7 and-1.1 ±1.3.In children,31 patients had never taken drug treatment,and 105 patients were undergoing BPs administration with an average duration of 2.5 ±3.1 years,including alendronate,zolendronate and both of them.In adults,25 patients were undergoing BPs administration with an average duration of 2.0± 1.2 years,3 patients were injecting teriparatide 20IU/d,and 10 patients had never taken drug treatment.As for age-and sex-matched control group,the average age were 10.5±3.6 and 34.1 ±6.9 years old for children and adults,separately.2.(1)The QoL score of OI children were 64.4±30.0、71.9122.2.75.7±24.8、63.7±24.5、68.9±22.0 in social functioning,emotional functioning,social functioning,school functioning and total score,all of which were lower than healthy children(86.5± 12.7、83.3±16.0、92.1 ± 11.8、87.5± 11.8.87.3±10.7,allP＜0.01).(2)Total score of QoL in OI type I/III/IV were 76.8± 18.7、58.5±21.9、61.6±22.7,and OI type I showed higher QoL than type III/IV.QoL of OI type I(74.9±22.1)in physical functioning was higher than type Ⅲ/Ⅳ(48.6±36.3、56.0±30.7).However,there were no difference between OI type Ⅲ and type IV in total score and physical functioning(all,P＞0.05).(3)The relationship between QoL and genotype was further investigated.Gene mutations inducing haploinsufficiency had higher QoL scores in all domains,except for emotional function,than those with mutations leading to glycine substitution(75.8±23.3 vs.63.2±30.8 in physical domain,78.1 ±19.5 vs.70.7±23.4 in emotional domain,86.9+20.1 vs.70.6±28.1 in social domain,74.7±24.7 vs.58.0±25.1 in school domain and 78.9± 19.4 vs.65.6±23.8 in total score,P=0.047,0.194,0.008,0.011,0.023,respectively).(4)QoL scores did not significantl,y differ between children with and without BPs treatment(all P＞0.05).3.Total score of QoL of children were positively correlated with economic income(R=0.240,P=0.020),Z score of height(R=0.319,P =0.001),LS BMD(R=0.272,P=0.002),LS BMD Z-score(R=0.260,P=0.004)，FN BMD(R=0.378,P<0.001),FN BMD Z-score(R=0.351,P<0.001);and negatively correlated with disease severity(R=-0.390,P＜0.001)and times of fractures(R=-0.284,P=0.001).4.The QoL of adults with OI were 52.5± 18.1、59.0± 16.7、63.66±13.7.57.7±16.2、58.2± 13.4 in physical domain,emotional domain,social domain,environment domain and total score.Of them,QoL of physical domain was lower than healthy control(P＜0.01)，but there were no difference in other domains.QoL of OI type I(58.5±16.0)in physical domain was higher than type III/IV(46.4±19.2、50.7±20.8),(P<0.05).However,there were no difference between OI type III and type IV in physical domain.5.Disease severity,times of fractures and educational status were correlated with QoL in adults with OI,and there was no correlationship between BMD and QoL of adults.Conclusion Children with OI had significantly lower scores in four domains of PedsQL 4.0 than healthy controls.More severe forms of OI patients(type III and IV)had more impaired QoL.For the first time,we found that children with haploinsufficiency in type I collagen had lower QoL in than those with glycine substitution in type I collagen.Adults with OI had lower QoL in physical domain than healthy control,however,it was comparable with controls in other domains.Total score of children’s QoL was correlated to many variables,including economic income,Z score of height,LS BMD,LS BMD Z-score,FN BMD,FN BMD Z-score,disease severity and times of fractures.We demonstrated that quality of life in OI were correlated with pathogenic gene mutation and severity of skeletal demonstration,which may contribute to enhancing QoL in OI patients.Part 2.Analysis of the course of bisphosphonates treatment for patients with osteogenesis imperfectaObjective:Osteogenesis imperfecta(OI)is a group of hereditary skeletal disorders characterized by low bone mass,increased bone fragility and recurrent fractures.It has a heterogeneous phenotype which was divided into four subtypes by Sillence nomenclature:non-deforming(type Ⅰ),perinatally lethal(type Ⅱ),progressively deforming(type Ⅲ),and moderate severity(type Ⅳ).Bisphosphonates(BPs)treatment remains the first-line medical management.However,there are still debates on many aspects of BPs treatment,such as its appropriate course of treatment,effectiveness and safety of long-term use,and effects in different subtypes.This study was to retrospectively analyze the difference between patients with OI who entered drug holiday when their bone mineral density(BMD)achieved normal range after the treatment of BPs,and those who continued BPs treatment because of low BMD.The aim of this study is to discuss the appropriate course of BPs treatment in different subtypes,and the safety and effectiveness of long-term application.Materials and methods:We retrospectively analyzed OI patients who received BPs treatment in Peking Union Medical College Hospital(PUMCH)from January 2004 to December 2015.Thrity-five children with OI who achieved normal BMD after BPs treatment were included as drug-discontinuation group.The other 35 children with OI acted as control group,who continued BPs treatment because of low BMD.These two groups matched in age,gender and treatment duration.All patients were administered oral calcium 500mg and vitamin D3 200IU/d.Before and after treatment,BMD were measured by dual energy X-ray absorptiometry,and serum levels of alkaline phosphatase(ALP)and β-cross linked C-telopeptide of type I collagen(β-CTX)were also tested.Moreover,height,fracture rate,BMD and bone turnover biomarkers were compared between the two groups.All adverse events were recorded.Results:A total of 70 OI patients were enrolled in this study,including 46 boys and 24 girls.There were 35 children both in drug-discontinuation group and control group,with the average age 9.1 ±4.6 and 9.1 ±4.5 years separately.1.At baseline,BMD at lumbar spine,femoral neck and total hip in drug-discontinuation group(543 mg/cm2,513 mg/m2,573mg/cm2)were higher than those in control group(419 mg/cm2,300 mg/cm2,328mg/cm2),and its annual fracture incidence were less than that in control group[(1.3±2.6)vs.(2.1 ±3.5)](P=0.035).2.It took an average of 4 years(range:1-8 years)to achieve normal BMD for drug-discontinuation group.At 1,2,3,4 years,Z score of height in drug-discontinuation group had no difference compared with baseline;but in control group,height Z-score were lower than baseline from the second year.During 4 years of treatment,there were no differences in increasing rate of BMD(138.0%vs.161.4%at LS,126.7%vs.113.5%at FN,79.1%vs.87.1%),decreasing rate of annual fracture incidence and bone turnover biomarkers between two groups(24.1%vs.30.9%in[p-CTX.26.1%vs.32.2%inALP,all P＞0.05).3.When BPs was discontinuated,the average age were 13.2 ± 4.0 years in drug-discontinuation group and 12.8 ± 4.6 years in control group.BMD at lumbar spine,femoral neck and total hip in drug-discontinuation group(1065 mg/cm2,944 mg/cm2,941mg/cm2)were higher than those in control group(803mg/cm2,674mg/cm2,687mg/cm2)(all P<0.01).Fracture rate were significantly lower than baseline in both groups(0.2±0.2,0.4±0.7/y,P=0.677).There were also no significance in decreasing rate of p-CTX and ALP in two groups(P=0.749、P=0.558).4.Acute-phase reaction was more frequent in patients taken zoledronic acid treatment(17%),and gastrointestinal adverse effects were more frequent in patients treated with alendronate(4%).Atypical femur fractures,osteonecrosis of the mandible and other serious adverse events were not observed in this study.During treatment,the hepatic and renal function were always in normal range,suggesting that long-term treatment was safe.Conclusion:BPs could significantly increase BMD,reduce fracture incidence and bone turnover biomarkers in patients with OI.Mild OI patients may have a chance to achieve normal level of BMD and enter the drug holiday after 4 years of BPs treatment.Severe 01 patients need to receive longer period treatment of BPs.This study took a meaningful exploration of BPs treatment for 01 patients in the appropriate course,safety and effectiveness of long-term application,which provide strenghthful evidence for long-term treatment in 01 children. |
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