Clinical And Bone Microstructural Characteristics Of Neoplastic Osteomalacia

Part 1 Clinical analysis of tumor induced osteomalacia[Introduction]Tumor induced osteomalacia(TIO)is a rare acquired paraneoplastic syndrome which is usually induced by mesenchymal tumors secreting excessive fibroblast growth factor 23(FGF23).Clinical manifestations includes bone pain,muscle weakness,difficulty in walking and skeletal deformities.The typical biochemical pattern of TIO is renal phosphate leaking,hypophosphatemia,inappropriately normal or low 1,25-dihydroxyvitamin D level.Complete resection of the causative neoplasm is usually curative for TIO.It is difficult to locate the responsible tumors in clinic practice as these tumors are usually small in size,slowly growing and locating at variable elusive sites.TIO was frequently misdiagnosed and missed diagnosed due to its rarity,nonspecific clinical manifestations,and clinicians’ poor recognition,and the initial misdiagnosis rate was 95.1%.Diagnostic and therapeutic delay lead to prolonged morbidity and poor prognosis of TIO patients.At present,most clinical studies on TIO are case reports and there are few researches with large sample size.[Objective]1.To summarize the clinical,biochemical and imaging features of TIO patients.2.To analyze the detection,pathology and distribution of TIO tumors.3.To investigate the changes of serum phosphorus and FGF23 levels before and after surgery.Subjects and Methods[Subjects and Methods]SubjectsPatients with confirmed diagnosis of TIO at Peking Union Medical College Hospital from January 1998 to March 2017 were included.They must meet any of the following criteria:patients who received surgical removal of the responsible tumor and the postoperative pathology was classified as phosphaturic mesenchymal tumor(PMT)or phosphaturic mesenchymal tumor mixed connective tissue variant(PMTMCT);patients who treated with resection of causative neoplasms and serum phosphorous increased after surgery.Methods1.Clinical data including gender,age of onset,past history and family history,clinical symptoms and signs,pathology and distribution of TIO tumors,and prognosis were collected.2.Biochemical and bone turnover markers were measured.Serum full-length FGF23 levels were measured by a two-site enzyme-linked immunosorbent assay(ELISA)before and after the surgery.3.Bone mineral density(BMD)of the lumbar spine and total hip was measured by dual energy X-ray absorptiometry(DXA).Plain X-ray of the pelvic and thoracolumbar spine was performed to detect typical osteomalacia changes.4.Tumor location:Ask the patient if she/he had local mass,and perform careful physical examination.After functional imaging examinations(somatostatin receptor scintigraphy,68Ga-DOTA-TATE PET/CT)had positive findings,anatomic imaging examinations(Ultrasound,CT,MRI)at the related sites could be performed for further confirmation of the tumor.[Results]1.A total of 225 TIO patients(male/female,126/99)were enrolled.Ten patients were childhood-onset or adolescent-onset,and the rest were all adult-onset with the average onset age being 37.4± 11.7years old.The average time from onset to a diagnosis of hypophosphatemia was 2.0 years while the mean duration from onset to tumor resection was 4.0 years.2.Clinical presentations of TIO mainly included bone pain,difficulty in walking,fractures,height loss,and muscle weakness.Physical examination showed signs of bone tenderness,bone deformities,tooth loss or loosening and local mass.3.The key biochemical changes in TIO patients were hypophosphatemia,increased urine loss of phosphorus,reduced tubular maximum for phosphorus/glomerular filtration rate(TMP/GFR),elevated serum alkaline phosphatase and inappropriately normal or low 1,25-dihydroxyvitamin D level.Preoperative FGF23 levels in TIO patients were significantly elevated,with a median level of 305.1pg/ml.Aminoaciduria(35.4%),positive urine glucose or decline in renal threshold for glucose(18.6%),proteinuria(5.3%),and metabolic acidosis(8.9%)could occur in TIO patients.4.TIO patients showed significantly low bone mineral density before treatment.Plain x-rays of TIO patients frequently exhibited decreased bone mineral density,followed by vertebral deformation,pelvic deformation,and pseudofractures.Biconcave deformation is the most common form of vertebral deformation(60.7%).5.Among the 225 TIO patients,the tumors of 166 cases(73.8%)were located by somatostatin receptor scintigraphy.And the tumors of 12 cases(5.3%)whose somatostatin receptor scintigraphy were false positive and 47 cases(20.9%)whose somatostatin receptor scintigraphy were negative were all detected by 68Ga-DOTA-TATE PET/CT.The tumors could occur all over the body,with lower extremities being the most common site(44.0%).And soft tissue originated tumors were more common.Tumor pathology was mainly classified as PMT or PMTMCT,accounting for 95.1%and malignant tumors accounted for 7.6%.6.Surgical treatment was an effective way in treating TIO patients.Postoperatively,84%of TIO patients got recovery of serum phosphorus.Serum phosphorus normalized within 5.1±2.6 days postsurgery.After successful tumor resection,serum FGF23 level decreased rapidly within 1 day and fell below the normal range(median level 7.9 pg/ml).The rates of recurrence and metastasis in TIO patients were 3.1%and 1.3%respectively.[Conclusions]1.TIO is mainly seen in adults,but it can also occur in children and adolescents.Diagnostic and therapeutic delay is common in TIO patients,thus clinicians should raise awareness of TIO.2.FGF23 is vital for the diagnosis of TIO and might have a predictive value of surgical prognosis.Bone mineral density and skeletal X-ray examinations are beneficial to TIO diagnosis and assessment.TIO tumors distributed all over the body with the lower extremities being the most common sites and a thorough examination is helpful to detect the pathogenic tumor.Somatostatin receptor scintigraphy is of great value in localizing tumors,and 68Ga-DOTA-TATE PET/CT is the best functional imaging for tumor localization.3.In clinical practice,attention should be paid to the assessment of other renal tubular function among TIO patients.4.Malignant TIO tumors accounted for 7.6%.And postoperative recurrence and metastasis do exist in TIO patients,thus follow-up is of key importance.Part 2 Bone micro architecture assessed by HR-pQCT in tumor induced osteomalacia patients[Introduction]Tumor induced osteomalacia(TIO)is a rare acquired paraneoplastic syndrome which is usually induced by mesenchymal tumors secreting excessive fibroblast growth factor 23(FGF23).Currently,bone mineral density(BMD)measured by dual energy X-ray absorptiometry(DXA)at the hip and lumbar spine is clinically used to evaluate skeletal situation and response to treatment amongTIO patients,however there might be some shortcomings.The second generation of high-resolution peripheral quantitative CT(HR-pQCT)allows noninvasive assessment of skeletal microstructure and volumetric bone mineral density(vBMD)of human limb with a relatively low radiation exposure.At present,there is no reported research using HR-pQCT to evaluate bone microstructure in TIO patients.Surgical treatment is the first choice for TIO patients,but surgery is restricted to some patients due to failure in localizing tumors,surgery risks or contraindications.These patients receive medical treatment instead.The effect of the two treatments on bone mineralization restoring,bone mineral density and bone microstructure recovery might be different.However,currently,there is no comparative study of surgical treatment and drug treatment among TIO patients.[Objective]1.The purpose of the cross-sectional study is to assess bone geometry,volumetric bone mineral density and bone microstructure in TIO patients by using DXA and second generation HR-pQCT.2.The purpose of the longitudinal cohort study is to use DXA and the second generation HR-pQCT to explore geometry,volumetric bone mineral density and bone microstructure changes before and after half-year of treatment among TIO patients as well as to compare between surgical treatment and drug treatment.[Subjects and Methods]SubjectsCross-sectional studyTIO group:TIO patients in Peking Union Medical College Hospital from May 2015 to March 2017 completing the HR-pQCT examinations were enrolled.A total of 70 persons were enrolled.Control group:210 sex and age matched healthy controls completing the HR-pQCT examinations were included.Females were matched for menopausal status.Longitudinal cohort studyParticipants:TIO in Peking Union Medical College Hospital from May 2015 to March 2017 who completed baseline and follow-up(half a year)HR-pQCT examinations were enrolled.A total of 13 persons were included.Those with surgical resection of the tumor and recovery of serum phosphorus after operation were included in the surgery group.The non operative group was included in the drug group.Methods1.Clinical data including gender,age,height,body mass index(BMI),female menopause status,family history,course of disease,treatment were collected.2.Biochemical and bone turnover markers were measured.Serum full-length FGF23 levels were measured by a two-site enzyme-linked immunosorbent assay(ELISA).3.Bone mineral density(BMD)of lumbar spine and total hip was measured by dual energy X-ray absorptiometry(DXA)(baseline and half year after treatment)4.HR-pQCT examination(baseline and half year after treatment)[Results](1)Cross-sectional study1.A total of 70 TIO patients(male/female,48/22)and 210 normal controls were included.There is no significant difference of gender,age,and BMI between the two groups.The heights of TIO patients were significantly shorter than that of normal subjects(P<0.01).2.TIO patients showed decreased bone mineral density,and the mean Z score of trochanter and total hip were both less than-2.0.3.At both tibia and radius,the vBMD parameters of TIO patients were significantly lower than those of normal subjects(P<0.01).The cortical area of TIO patients was significantly lower than that of normal subjects(P<0.01).The cortical thickness,trabecular bone volume fraction,trabecular number of TIO patients were significantly lower than those of normal controls(P<0.01)and cortical porosity was significantly higher than that of normal controls(P=0.04).Trabecular separation and trabecular network inhomogeneity of TIO patients were significantly higher than those of normal controls(P<0.01).Trabecular thickness had no significant difference between the two groups.Except for the percentage change of cortical porosity,the percentage of other parameters of tibia was higher than that of radius.Subgroup(the untreated group and the drug treated group)analysis showed that at both tibia and radius,there were no significant differences in bone geometric parameters,bone mineral density parameters,and bone microstructure parameters between the two groups.(2))Longitudinal cohort study1.The surgery group included 8 cases(male/female 5/3),and the drug group included 5 cases(male/female 4/1).There was no significant difference in sex,age,BMI and course of disease between the two groups.Before treatment,the two groups all had bone pain and difficulty in walking.2.Symptoms of surgery group were significantly improved than the drug group(P<0.01).In the surgery group,serum phosphorus increased significantly(P<0.01)and FGF23 level decreased significantly(P<0.01).In the drug group,there was no significant difference of serum phosphorus,FGF23 between baseline and after treatment.3.In the surgery group,the postsurgery total hip and lumbar spine BMD were significantly higher than baseline.Compared with the baseline,the total hip and lumbar spine BMD increased by 30.9%and 49.3%in the surgery groupand while in the drug group it was increased by 12.9%and 8.7%respectively.The percentage of lumbar spine BMD in the surgery group was significantly higher than that in the drug group.4.HR-pQCT examination showed that there were no significant differences in bone geometric parameters,vBMD parameters and bone microstructure parameters between the two groups before and after treatment.At the radius,compared with baseline,cortical area,total vBMD,trabecular vBMD,trabecular hone volume firaction and trabecular number decreasedreduced by 5.8%,10.6%,19.4%,15.9%,12.7%respectively while trabecular separation and trabecular network inhomogeneity increased by 17.9%and 33.2%.There was significant difference of these changes between surgery group and drug group.The cortical area and vBMD in the drug group did not reduce than those of baseline.At the tibia,there was no significant difference in the mean percentage change of HR-pQCT parameters between the two groups compared with baseline.[Conclusions]1.TIO patients not only exhibited significantly lower vBMD,but also compromised bone microarchitecture changes and bone geometric changes.The change at tibia is more obvious than radius.Evaluation of bone microstructure is necessary in clinical management of TIO patients.2.In TIO patients,after a short term(half a year)of treatment(tumor resection or drug treatment),the BMD of the axial skeleton was improved,however the vBMD and bone microstructure of the peripheral bone were not improved.DXA and HR-pQCT have different value for the evaluation of therapeutic effect among TIO patients.Combined application of the two can better guide clinical treatment.