내분비 대사 내과 전임의 이윤정 Hypophosphatemic & Osteomalacia disorders – FGF 23(Fibroblast Growth Factor 23) <Review>

Definition Osteoporosis 1. Osteoclast > Osteoblast Decreased Bone mass 2. Bx: Wt / Volume ↓ Normal Amount of matrix / Wt Osteomalacia 1.Defect of mineralization in Osteoid(bone matrix) 2. Ca X P ↓, Phosphaturia, Hypophosphatemia 3. Pathologic finding : 1) Osteoid surface > 80% 2) Osteoid thickness > 14 μm 3) Mineralization lag time > 100 days

Schematic representation of cellular transport of bone minerals Prim Care June ; 35(2)

J. Clin. Invest. 116:2062–2072 (2006)

Phosphate Homeostasis Humoral Factor 1. Reduction of Renal P- Reabsorption 2. Active Vit D Synthetic Defect Candidate of Phosphatoin FGF23(Fibroblast Growth Factor 23) MEPE(Matrix extracellular phophoglycoprotein) FRP4(Frizzled related protein 4) Dentin Matrix Protein 1 (DMP1), Fibroblast Growth Factor 7 (FGF7),Klotho

J. Clin. Invest. 116:2062–2072 (2006)

Inherited hypophosphatemic disorders Autosomal dominant hypophosphatemic rickets (ADHR) X-linked hypophosphatemia rickets (m/c) Autosomal recessive hypophosphatemic rickets (ARHR) Etiologic factors  Circulating phosphaturic factor Regulates phosphate homeostasis and skeletal mineralization Am J Physiol Endocrinol Metab 285: E1–E9, 2003

X-linked hypophosphatemic rickets(XLH) ; Clinical features Hypophosphatemia, slow growth, and rickets or osteomalacia Enthesopathy (calcification of tendons, ligaments, and joint capsules) is a common finding, particularly in adults Defects in dentin may cause dental abscesses and early tooth decay in young adults Normal serum levels of calcium, normal-to-high parathyroid hormone levels, increased (or normal) alkaline phosphatase activity, normal plasma calcidiol concentration, and normal or slightly reduced plasma calcitriol concentration Determination of the PHEX mutation may be useful to confirm the diagnosis Some of the other clinical manifestations of XLH (such as enthesiopathy and dental abnormalities) also may be mediated by mechanisms other than FGF23 Adult goal of therapy is simply to manage generalized bone pain, if it occurs, and to cure any non-union fractures Endocrinology 2008; 149:1757

A MORE COMPLEX MODEL TO EXPLAIN THE PATHOGENESIS Similarities between ADHR, ARHR,XLH, and TIO suggest a model to explain the common pathogenesis of renal phosphate wasting and defective mineralization FGF23 elevations in ADHR are due to mutations of FGF23 that block its degradation XLH from indirect actions of inactivating mutations of PHEX to modify the expression and/or degradation of FGF23 and MEPE TIO increased production of FGF23 and MEPE Am J Physiol Endocrinol Metab 285: E1–E9, 2003

Am J Physiol Endocrinol Metab 285: E1–E9, 2003, Pediatr Nephrol,august,2009

31 세 여자, 심한 골변형, 저인산 혈증, 고인산뇨증,1,25- dihydroxyvitamin D 3 의 감소 종양의 수술적 제거 후 임상 증 상의 현저한 호전 수술 전 후의 혈장을 확보하여 미국, 영국 및 일본 의 연구자들과 함께 공동 연구를 진행 FGF-23 이 종양원성 골연화증의 원인 물질임을 밝힘

N Eng J Med 2003;348: Department of Internal Medicine, Kuyunghee University, Seoul, Korea (I M Y)

N Eng J Med 2003;348:

‡ With the exception of Patient 37, all the patients with X-linked hypophosphatemia received treatment with phosphate and 1,25 -dihydroxyvitamin D

PHEX Gene Mutations and Genotype-Phenotype Analysis of Korean Patients with Hypophosphatemic Rickets J Korean Med Sci 2007; 22: 981-6

Subjects This study included 15 patients and five of their family members, aged from 20 months to 60 yr (average, 22 yr) Five had a family history of XLH, four were sporadic cases, and the other six were unknown Diagnoses were made based on clinical, radiological, and laboratory findings by specialists at the Korea University Guro Hospital

Table 2. Genotype and phenotype data for patients and family members with a PHEX gene mutation

Autosomal recessive hypophosphatemic rickets DMP1 is a member of the ‘SIBLING’ (Small Integrin Binding Ligand N-linked Glycoprotein) family, which is a group of non- collagenous extracellular matrix proteins involved in bone mineralization Localized to human chromosome 4q21–25 DMP1 is coupled to renal phosphate handling and vitamin D metabolism through a DMP1-dependent regulation of FGF23 production by osteocytes Manifest ; rickets and osteomalacia with isolated renal phosphate wasting associated with elevated FGF23 levels and normocalciuria Bone 44 (2009) 287–294

Inter Med 47: , 2008

Treatment Oral phosphate administration, typically 250–500 mg up to 5 times a day, as well as twice daily oral delivery of 0.5–1.0 μ g of 1,25(OH) 2 D3 Side effect : transient increase in serum phosphate causes a decrease in ionized calcium and an increase in PTH level and causes parathyroid glands to become hyperplastic and autonomous, which leads to secondary or tertiary hyperparathyroidism, moderate nephrocalcinosis Recent studies ; both dietary phosphate loading and administration of vitamin D can increase FGF23 levels and has the potential to stimulate PTH Clin J Am Soc Nephrol 3: , 2008