Analysis Of Skeletal Characteristics And Clinical Correlation In Patients With Neoplastic Osteomalacia

BackgroundTumor induced osteomalacia(TIO)is a very rare paraneoplastic syndrome and a type of acquired osteomalacia caused by increased renal phosphorus excretion from the tumor.The responsible tumor usually affects patients' serum phosphorus level and other bone parameters through excess production of FGF23,which thus causes bone pain,movement difficulties and other symptoms,reducing patients' quality of life.The existing assessment of the bone structure among TIO patients is performed by Dual-energy X-ray absorbtiometry(DXA),which is a two-dimensional measurement that cannot assess the bone quality,and is easily affected by the patient's own disease status(e.g.,inflammation,fracture).Moreover,DXA results mainly reflect the bone mass of the patient's axis bone.The 2nd generation High Resolution Peripheral Quantitative CT(HR-pQCT)is a technique for the quantitative determination of peripheral bone structure using CT,which can fully reflect the microarchitecture characteristics of bone.The combination uses of DXA and HR-pQCT can thus offer a more accurate and comprehensive understanding on characteristics of bone changes among TIO patients.AND there is no study available on relations between clinical biochemical indicators and bone structures yet.Objectives1.To evaluate bone density and bone microarchitecture in TIO patients using DXA and HR-pQCT.2.To explore the correlation between clinical biochemical indicators and bone density and microarchitecture changes in patients,so as to improve the understanding of the disease,and to explore the clinical application of biochemical indicators to predict bone structure.MethodsA total of 99 patients with tumor induced osteomalacia from May 2015 to May 2018 diagnosed in the Endocrinology Department of Peking Union Medical College Hospital were enrolled for the study,and 198 normal controls were matched according to sex,age,and menopausal status.General information(gender,height,weight,medical history,etc.),laboratory tests(calcium and phosphorus levels,bone conversion index,phosphate profile index,FGF23 levels)and skeletal assessment results(DXA and HR-pQCT)and treatment were collected and recorded,and relevant statistical analysis was performed.Results1.A total of 99 persons were included in the study,of whom 68(68.7%)were men and 31(31.3%)were women.Compared with healthy controls,TIO patients had lower height and weight(P<0.05),but no other significant differences were seen.All patients had bone pain and mobility difficulties(73/73),45.2%had skeletal deformities at different sites(33/73),18.8%had loose teeth(13/69),84.1%had varying degrees of height loss(58/69),and 77.8%had a history of fracture(56/72).Of the patients with documented pathological findings,92.1%were benign PMT(58/63)and five patients returned malignant PMT;for tumor origin,56.9%were soft tissue sources(37/65)and 36.9%were bone tissue sources(24/65).In terms of distribution,the tumors were located in the head and neck(16/72),limbs(28/72),trunk(26/72)and multiple sites(2/72).2.The main clinical biochemical features of TIO patients were hypophosphatemia(0.51±0.13 mmol/L)with high levels of FGF23(383.8[168.4,572.0]pg/ml).1,25(OH)2D levels were within normal limits.3.There was a decrease in bone mass in TIO patients,with a mean Z-value of less than-2.0 for both the total hip and the great trochanter.And there,s a tendency for women to have a lower mean overall BMD compared to men.4.The results of HR-pQCT confirmed that the total volumertric BMD,cortical volumetric BMD,and trabecular volumetric BMD were significantly lower in TIO patients than in normal subjects(P<0.01),regardless of the tibial or radial.In addition,the microstructure of the bones in TIO patients was significantly impaired.The trabecular bone volume fraction,trabecular number and the cortical thickness were significantly lower in TIO patients(P<0.01),while the trabecular separation,inhomogeneity of trabecular network,and cortical bone porosity were higher(P<0.01).In terms of bone geometry,the total tibial bone areas,cortical bone areas and cortical perimeter of TIO patients were significantly lower than normal control(P<0.01)while trabecular bone areas was significantly higher(P<0.01).Also,the radial cortical bone areas of TIO patients was significantly reduced(P<0.01),and the total bone areas and trabecular bone areas showed an increasing tendency,while the difference was not significant(P>0.05).5.Correlation analysis showed that BMD and ALP levels were significantly negatively correlated in TIO patients,with lumbar L2-4 being the most strongly correlated(r=0.499,P<0.01);lumbar L2-4 BMD was also positively correlated with serum phosphorus level and ?-CTX level(P<0.05).In terms of volumetric BMD parameters,negative correlations(P<0.01)were found between trabecular bone volumetric BMD(Tb.vBMD)and total volumetric BMD(Tt.vBMD)with PTH levels,cortical bone volumetric BMD(Ct.vBMD)with ALP levels.In addition,tibial cortical bone volumetric BMD(Ct.vBMD)was negatively correlated with ?-CTX level(P<0.01),tibial total volumetric BMD(Tt.vBMD)was negatively correlated with ALP level(P<0.01),radial cortical bone volumetric BMD(Ct.vBMD)was negatively correlated with PTH level(P<0.05)and positively correlated with 25(OH)D level(P<0.05).In terms of bone geometry parameters,tibial cortical bone areas(Ct.Ar)was negatively correlated with ALP and?-CTX levels(P<0.01),total bone areas(Tt.Ar)and cortical bone perimeter(Ct.Pm)were negatively correlated with ?-CTX level(P<0.05),radial trabecular bone areas(Tb.Ar),total bone areas(Tt.Ar)and cortical bone perimeters(Ct.Pm)were negatively correlated with ?-CTX level(P<0.01)and radial cortical bone area(Ct.Ar)was negatively correlated with PTH level(P<0.05).In terms of bone microarchitecture parameters at tibia,the trabecular number(Tb.N)was negatively correlated with ALP,PTH,?-CTX levels(P<0.01),while inhomogeneity of trabecular network(Tb.l/N.SD)and trabecular separation(Tb.Sp)were positively correlated with the three(P<0.05).Trabecular bone volume fraction(Tb.BV/TV)was negatively correlated with PTH level(P<0.01),cortical thickness(Ct.Th)was negatively correlated with ?-CTX level(P<0.01).For parameters at radius,the trabecular number(Tb.N)was negatively correlated with PTH level(P<0.01)and positively correlated with blood calcium level.Trabecular separation(Tb.Sp)and inhomogeneity of trabecular network(Tb.1/N.SD)are positively correlated with PTH levels(P<0.05)and negatively correlated with blood calcium level(P<0.05).In addition,inhomogeneity of trabecular network(Tb.1/N.SD)was positively correlated with FGF23 level(P<0.05),trabecular bone volume fraction(Tb.BV/TV)is negatively correlated with PTH level(P<0.01),cortical porosity(Ct.Po)is positively correlated with ALP and ?-CTX levels(P<0.01),cortical thickness(Ct.Th)was negatively correlated with PTH level(P<0.01)and positively correlated with 25(OH)D level(P<0.05).No linear correlation with clinical biochemical indicators was seen for bone strength.Conclusion1.Patients with TIO have reduced bone volume and impaired bone microarchitecture,with reduced trabecular bone volume fraction,trabecular number,cortical bone thickness,and increased trabecular separation,inhomogeneity of trabecular network,cortical bone porosity.No significant difference in trabecular thickness compared with normal subjects was shown.In terms of bone geometry,we found significant decreases of cortical bone areas.No compensation of bone area increase was observed except for tibial trabecular bone areas.2.Elevated ALP and ?-CTX may be a risk factor for decreased bone density(especially in axis bone)and impaired bone microstructure at all sites in TIO patients,and elevated PTH may be risk factors for impaired bone microarchitecture in TIO patients,revealing the significance of close monitoring of ALP,PTH and ?-CTX in predicting impaired bone microstructure in TIO patients.