Bone Metabolism

and
Osteoporosis

Deske Muhadi
Rheumatology - Internal Medicine
University of Sumatera Utara
Fungsi tulang

1. Fungsi mekanik
2.Fungsi protektif
3.Fungsi metabolik
4.Fungsi hemopoetik
 KOMPOSISI TULANG

• BAHAN ORGANIK (30 %)

» Matriks (98 %)
- Kolagen (95 %)
- Non Kolagen protein
Osteocalcin; osteonectin; proteoglycan, proteolipid, dll
» Sel- sel
Osteoblas; Osteoklas; Osteosit; (Bone lining cells)

• MINERAL (70 %)
- Hidroksiapatit, [Ca10(PO4)6(OH)2], (95 %)
- Mg, K, F, Cl
 Bone Composition

matrix Cell

Organic inorganic

collagen mucopolyshacarida Ca P
Non colagenus protein

Osteoprogenitor osteocyte Osteoblast osteoclast

 Distribution of Cortical and Trabecular Bone

Thoracic and 75% trabecular

Lumbar Spine 25% cortical

1/3 Radius
>95% Cortical

Femoral Neck 25% trabecular

75% cortical
Ultradistal Radius
25% trabecular
75% cortical
Hip Intertrochanteric Region
50% trabecular
50% cortical
Cortical and Trabecular Bone
Cortical Bone
• 80% of all the bone in the body
• 20% of bone turnover

Trabecular Bone

• 20% of all bone in the body

• 80% of bone turnover
 CORTICAL VS CANCELLOUS BONE

CORTICAL CANCELLOUS

• Porosity < 15% • Porosity 30-90%

• 80% of skeletal mass • 20% of skeletal mass
• Function : structural, • Function : metabolic
protection, locomotion (high surface area, 6-8
times more metabo-
lically active)
• Transmits loads from
joint surface to cortex
 OSTEOBLAS
• “Bone forming” cells
• Originate from mesenchymal cell lineage
• Synthhesize bone matrix prpteins and secrete
osteoid
• Receptors for many hormones and growth
factors
• Play important role in cross-talk between
osteoblasts and osteoclasts
 OSTEOKLAS
• “Bone resorbing” cells
• Originate from hematopoetc cell lineage
• Multinucleated, large cells
• Highly specialized cytoskeletal
structures, sealing zone & ruffled border
• Attach to bone, dissolve organic and
inorganic components of bone matrix
 OSTEOSIT
• Former osteoblasts that become
embedded in matrix
• Encased in lacunae
• May play key role as mechanoreceptor
(long projections [canaliculi] from cell
body to surface and to other osteocytes)
• Difficult to isolate and study
 m
eb
oo
ks
fre fre
e. e.
co co
m m
m
eb
oo
ks
fre fre
e. e.
co co
m m
m
eb
oo
ks
fre fre
e. e.
co co
m m
m
eb
oo
ks
fre fre
e. e.
co co
m m
 BONE MODELING & REMODELING

Bone modeling Bone remodeling

• Formation and • Coupled resorption and
resorption independent formation at same site
• Prominent during • Maintain mineral
growth and fracture homeostasis
healing • Preserve skeletal
• Shapes the skeleton integrity (respond to
according to altered mechanical
mechanical demands loading; repair of
accumulated damage)
 Bone Remodeling Process
Osteoclasts
Resorption
Cavities
Lining Cells

Bone

Lining Cells Osteoblasts

Mineralized Osteoid
Bone
 Bone Remodeling Phase
Quiescence
Activation

Resorption

Reversal

Formation

Quiescence
Osteocytes as orchestrators of bone (re)modeling
osteoporosis
Low bone mass
(BMD)
Microarchitectural
disruption
Skeletal fragility
— ê
— ¯bone strength ­ Risk of fracture

— ­ risk of fracture

normal Osteoporotic
Incidences of Osteoporosis
 Risk factor for osteoporosis
• Female
• Post maunoposal
• In a men , low colesterol level
• Caucasian or asian ethnicity
• Family history osteoporosis
• Thinnes or small frame
• Phisical inactivity
• Nutrition factor
Risk of Fracture
 Increased fracture risk in RA
Study Study cohort Follow-up Relative risk (RR) Most marked
duration increase
Britain 30,262 (male and Median 7.6 All osteoporotic #: 1.5 (1.4-1.6) Hip and spine
1
(GPRD) female) years Men: 1.4 (1.2-1.7)
Female: 1.5 (1.4-1.6)
US (Mayo 388 (female) 25 years Pelvic#: 2.56 (1.32-4.47) Pelvis and
2
clinic) Proximal femur #: 1.51 (1.01-2.17) proximal femur
Distal forearm #: 1.39 (0.88-2.09)

3
US (HIRD) 47,034 (male and 1.63 years Hip #: 1.62 (1.43-1.84) Pelvis and hip
female) Pelvis #: 2.02 (1.77-2.30)
Wrist #: 1.15 (1.00-1.32)
Humerus #: 1.51 (1.27-1.84)
4
Finland 517 (male and - Hip #: 3.26 (2.26-4.70) -
female)

1 van Staa TP et al Arthritis Rheum 2006, 54:3104-12;

2 Hooyman JR et al Arthritis Rheum 1984, 27:1353-61;
3 Kim SY et al Arthritis Res Ther 2010, 12:R154;
4 Huusko TM Ann Rheum Dis 2001, 60:521-2
Systemic lupus erythematosus (SLE)
— Increased prevalence of bone loss and
osteoporosis (4 – 23%)
— Increased prevalence of fracture (9-
29%)

Li EK, Tam LS, et al. J Rheumatol 2009;36:1646-52.

Mok CC et al. Lupus. 2005;14(2):106-12
Bultink IE, et al. Arthritis Rheum 2005;52:2044-50.
Borba VZ, et al. Lupus 2005;14:529-33.
Naganathan V, et al. Arch Intern Med 2000;160:2917-22.
Almed K, et al. Arthritis Res Ther. 2010;12(4):R153.
Li EK, Tam LS et al. Br J Rheumatol. 1998 Apr;37(4):405-10
Fracture Index
Site Fracture Osteoporosis
fracture of the right femoral shaft
Effect of fracture
Asymptomatic Fracture Osteoporosis
(micro damage of bone)
 Estrogens:
mechanism of action in bone

Precursor Cytokines Precursor

IL-1, TNF-a
(Osteoblast) IL-6, TGF-b,.... (Osteoclast)

Estrogens apoptosis
apoptosis TNF-α
TGF-β +
Cytokines
RANK-L

osteoblast osteoclast
Estrogen Osteoporosis

1.Estrogen Defeciency
! ↑ IL-1, IL-6, TNFα,
M-CSF RANKL !
osteoclast ↑
2.OPG ↓ : blocking
RANK and RANKL ↓,
osteoclastogenesis ↑
(Deficiency Estrogen ! OPG ↓)

x
 Pathophysiology of CIO:
Bone Formation and Resorption

Corticosteroids

Osteoblast bone formation GI calcium absorption

estrogen urinary calcium excretion
apoptosis testosterone
life span adrenal androgens
function calcium

Osteoclast bone resorption PTH

Osteoporosis
 Prednisone Dosage Ranges in Usual
Clinical Practice
Physiologic
Replacement Dose Pharmacologic Doses

Increasing Risk of GIOP

2.5 5 7.5 10 15 20 25 1
mg mg mg mg mg mg mg g

Low Dose Moderate Dose High Dose “Pulse”

Physiologic Cutoff

GIOP = glucocorticoid-induced osteoporosis.

Saag KG. Am J Med. 1997;103(Suppl 6A):31S-39S.

 Which Skeletal Sites Should Be
Measured?

Every Patient Some Patients

• Spine • Forearm (33% Radius)
L1-L4 If hip or spine cannot be
• Hip measured
Total Proximal Femur Hyperparathyroidism
Femoral Neck Very obese
Trochanter

Use lowest T-score of these sites

 Tehnik Densitometri

-Tehnik Radiografi
-Single Energy Absorptiomatry
-Dual Energy Absorptiometry (DXA)
-Quantitative CT
-Quantitative US
 Indications For Bone Density Testing

• All women age 65 and older

• All men age 70 and older
• Adults with a fragility fracture
• Adults with a disease or condition associated
with low bone density
• Adults taking medication associated with low
bone density
• Anyone being treated for low bone density to
monitor treatment effect
• Anyone not receiving therapy, in whom
evidence of bone loss would lead to treatment
ISCD Position Development Conference 2003
11
 DXA
• “Gold-standard” for BMD measurement
• Measures “central” or “axial” skeletal sites:
spine and hip
• May measure other sites: total body and
forearm
• Extensive epidemiologic data
• Correlation with bone strength in-vitro
• Validated in many clinical trials
• Widely available (about 10,000 DXA machines
in USA)
 DXA Technology

Detector (detects 2 tissue types - bone and soft

tissue)

Very low radiation to patient.

Very little scatter radiation to
Patient technologist

Photon Collimator
(pinhole for pencil beam, slit for fan
s beam)

X-ray Source
(produces 2 photon energies with different attenuation
profiles)
Assessment of fracture risk- DXA

— A normal BMD T-score cannot exclude the

possibility of osteoporosis

- 56% and 79% of non-vertebral fractures occurred in

women and men, respectively, with a DXA femoral neck
T-score >-2.5 (Rotterdam study)1
- vertebral fracture2 in15% SLE with T-score >-2.5
1. Schuit SC. Bone 34:195-202;
2. 2. Li EK et al. J Rheum 36:1646-52;
 DXA Nomenclature
Decimal digits

Digits Example
BMD 3 0.927 g/cm2

T-score 1 −2.3
Z-score 1 1.7
BMC 2 31.76 g
Area 2 43.25 cm2
% reference integer 82%
C
database
The Writing Group for the ISCD Position Development Conference.
J Clin Densitom. 2004;7:45.
 BMD and T-score

T-score is still considered to be major determinant

for treatment decision
 Why T-score And Not Z-score?

• T-score is related to bone strength

• T-score is related to fracture risk
• Using Z-scores would result in many
“normal” patients having fragility
fractures, and suggest that osteoporosis
does not increase with age
 Diagnostic Classification

Classification T-score

Normal -1 or greater

Osteopenia Between -1 and -2.5

Osteoporosis -2.5 or less

-2.5 or less and fragility

Severe Osteoporosis
fracture

28
 Diagnosis Caveats

• T-score -2.5 or less does not always mean

osteoporosis
Example: osteomalacia
• Clinical diagnosis of osteoporosis may be
made with T-score greater than -2.5
Example: atraumatic vertebral fracture with
T-score equals -1.9
• Low T-score does not identify the cause
Medical evaluation should be considered
Example: celiac disease with malabsorption
Common artifacts on
DXA scan images

• Degenerative disease
• Fractures
 Assessment of fracture risk

Limitations of DXA:
- Does not measure true
volumetric BMD
- Cannot distinguish between
cortical and trabecular bone
compartments
- Does not have an adequate
resolution to measure cortical and
trabecular architecture

Sornay-Rendu E et al Journal of bone and mineral research 22:425-433

Risk fracture assessment
 Bone strength
Bone
density
Mineralization

Bone Material Crystallinity

strength properties
Remodeling
Organic phase of bone

Cortical and trabecular

microstructure
Structural
design
Microdamage
Bone architecture
normal osteoporotic

thinning of the horizontal trabeculae

Perfect continuous and some loss of continuity
trabecular network
Dempster 2000
Assessment of bone
microarchitecture
— Histomorphometric assessment of bone
biopsies
— High resolution micro-computed tomography
(μCT)
— MRI
— High resolution peripheral quantitative
computed tomography (HR-pQCT)
High-resolution peripheral quantitative
computed tomography (HR-pQCT)
— Xtreme CT, Scanco Medical AG

Images courtesy of Qin L

High-resolution peripheral quantitative
computed tomography (HR-pQCT)
— Dedicated extremity imaging system designed
for trabecular-scale imaging
— Significantly higher SNR and spatial resolution
compared with multi-detector CT and MRI
(nominal isotropic voxel of 82μm)
— Low radiation (3-4 μSv) and short scan time
(3 minutes)

1.Burghardt AJ et al Clin Orthop Relat Res Epub 23 Feb 2011; 2.Rubin CD. Current medical Research and Opinion 21:1049-1056
 Parameters measured by HR-pQCT and FEA

Geometry

•Total area
•Cortical area
•Trabecular area
•Cross-sectional
area (CSA)
Volumetric BMD (vBMD) Microarchitecture Biomechanical
Properties
•Average density (D100) •Cortical thickness (Ct.Th)
•Trabecular bone volume •Stress
•Cortical density (Dcomp)
fraction (BV/TV) •Stiffness
•Trabecular density (Dtrab) •Trabecular number (Tb.N)
•Failure load
•Trabecular thickness (Tb.Th)
•Meta trabecular density (Dmeta) •Apparent modulus
•Trabecular separation (Tb.Sp)
•Inner trabecular density (Dinn) •Structure model index (SMI)
Distal radius Distal tibia

9.02mm, 110 slices

Krug, R et al. Radio Clin N Am 48: 601-621.
 High-resolution peripheral quantitative
computed tomography (HR-pQCT)

Distal radius

Distal tibia

Distal-most Proximal-most 3D reconstruction

Krug, R et al Radio Clin N Am 48: 601-621.
 High-resolution peripheral quantitative
computed tomography (HR-pQCT)

Medullary/inner
trabecular bone -
marrow
environment

Peripheral/meta
trabecular bone –
endocortical
resorptive activity
Cortex

Image courtesy of Qin L

Osteoporosis Therapy
 General Recommendation

Recommendation : Grade A : evidence levels Ia and Ib

Grade B : evidence levels IIa, IIb, and III
Grade C : evidence level IV

National Osteoporosis Guideline Group,2000

 Current treatment
• Calcium
• Vitamin D

Anti-resorptive Anabolic agent

• Alendronate • Fluoride
• Risedronate • Parathyroid hormon
• Ibandronate • Strontium
• Zoledronate
• Raloxifene
• Calcitonin
• Hormonal replacement therapy

Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocrine Reviews,

2002
 Treatment Guidelines
Summary of recommendations for pharmacologic therapy according to
T-score from the National Osteoporosis Foundation (NOF) and the American
Association of Clinical Endocrinologists (AACE)

Patient Profile T-score

NOF AACE

No Risk Factors Less than -2.0 -2.5 or less

Risk Factors† Less than -1.5 -1.5 or less

† Fragility fracture, family history of fracture, cigarette smoking, low body

weight (<127 lbs.), etc.
National Osteoporosis Foundation 1998.
American Association of Clinical Endocrinologists 2001.
 Distribusi kalsium didalam plasma
Ca2+

pH
Ca2+ Albumin 80%
Globulin 20% Ca 2+ Anion Ca2+

pH
HCO3-
H2PO4-
HPO42-
Ca2+ Sulfat
Sitrat
Laktat

Ca-terikat Ca ion bebas Calsium kompleks

Protein (40%) (50%) (10%)

Corrected Ca (mg/dL) =
total Ca serum (mg/dL) + 0,8(4 – albumin serum [gr/dL])
 KEBUTUHAN KALSIUM
(rekomendasi US National Academy of Sciences)

• 1-3 thn 500 mg/hari

• 4-8 thn 800 mg/hari
• 9-18 thn 1300 mg/hari
• 19-50 thn 1000 mg/hari
• > 51 thn 1200 mg/hari
 SUPLEMENTASI KALSIUM
• Ca glukonat 10% Ca elemen
Ca karbonat 40% Ca elemen
Ca sitrat 21% Ca elemen
• Ca karbonat absorpsi paling baik bila
diberikan bersamaan dengan waktu makan
• Bila kebutuhan Ca > 500 mg/hari
berikan dalam dosis terbagi
 HIPERKALSEMIA

• Hiperparatiroidisme primer
• Keganasan
• Penyakit granulomatosa
 Gambaran klinik hiperkalsemia
• Timbul bila kadar Ca > 14 mg/dl
• Gangguan gastrointestinal, ulkus peptikum dan
pankreatitis, terutama pada hiperparatiroidisme
primer.
• Poliuria akibat gangguan mengkonsentrasikan urin di
tubulus distal, sehingga timbul dehidrasi.
• Interval QT memendek,
• Pada penderita yang mendapat terapi digitalis,
keadaan hiperkalsemia harus dicegah karena akan
meningkatkan sensitifitas terhadp obat tersebut.
HIPERKALSEMIA PD OSTEOPOROSIS
Ny. JH, 56 tahun
Dx : Osteoporosis
Ca tot 10 mg/dl (8-11)
Ion Ca 1,30 mMol/L (1,14-1,28)
Alk fosf 119 U/L (35-135)
Osteokalsin 13,7 g/L (<10,5)
iPTH 1,1 pMol/L (1,0-5,5)
25(OH)D 108 ng/ml (Jun-Nop
30-120, Des-Mei 30-160)
DPD/Crurin 40 Mol/Mol (5-
27)
Nn. LM, 31 th
Dx : High bone turnover OP,
Tirotoksikosis
Ca tot 11,2 mg/dl (8-11)
Ion Ca 1,31 mMol/L (1,14-1,28)
Alk fosf 201 U/L (35-135)
Osteokalsin 33,7 g/L (<10,5)
iPTH 0,8 pMol/L (1,0-5,5)
25(OH)D - ng/ml (Jun-Nop 30-120,
Des-Mei 30-160)
DPD/Crurin 68,3 Mol/Mol (5-27)
 Penatalaksanaan Hiperkalsemia
• Pada kadar Ca < 12 mg/dl, biasanya tidak diperlukan
tindakan terapetik, kecuali bila ada gejala klinik
hiperkalsemia.
• Pada kadar kalsium 12-14 mg/dl, terapi agresif harus
diberikan bila terdapat gejala klinik hiperkalsemia.
• Pada kadar > 14 mg/dl, terapi harus diberikan walaupun
tidak ada gejalan klinik.

PENATALAKSANAAN :
• Rehidrasi NaCl 0,9%, 6 liter/hari
• Furosemid (!! Bukan HCT)
• Bisfosfonat parenteral
• Paratiroidektomi
 HIPERPARATIROIDISME
• Primer (ion Ca meningkat, PTH meningkat
atau normal tinggi)

• Sekunder (ion Ca menurun, PTH meningkat)

• Sekunder refrakter (2O HPT, PTH tetap

meningkat, walaupun Ca sudah dibuat normal)

• Tertier (2o HPT berubah menjadi 1o HPT)

 HIPERPARATIROIDISME O
1 &
2 O

Ny. PM, 69 tahun Tn VH, 55 tahun

Dx: Osteoporosis, 1o HPT Dx : 2o HPT, hipokalsemia

Ca tot 11 mg/dl (8-11) Ca tot 7,6 mg/dl (8-11)

Ion Ca 1,42 mMol/L (1,14-1,28)
Alk fosf 159 U/L (35-135)
Osteokalsin 6,7 g/L (<10,5)
iPTH 4,1 pMol/L (1,0-5,5)
25(OH)D - ng/ml (Jun-Nop
30-120, Des-Mei 30-160)
DPD/Cr urin 36,7 Mol/Mol (5-27)
Ion Ca 1,16 mMol/L (1,14-1,28)
Alk fosf 51 U/L (35-135)
Osteokalsin 5,7 g/L (<10,5)
iPTH 9,1 pMol/L (1,0-5,5)
25(OH)D 82 ng/ml (Jun-Nop
30-120, Des-Mei 30-160)
DPD/Cr urin 5,1 Mol/Mol (5-27)
Hiperkalsiuria
Ca serum ? Tinggi?
Rendah ?
Asupan protein ? Na ?
Obat : Glukokortikoid ?
Furosemid ?
(>< tiazid)
Asidosis ?
Tx : HCT 25 mg/hari
 HIPOKALSEMIA
• Hipoparatiroidisme
• Hiperparatiroidisme sekunder (deff vit D,
resistensi vit D, resistensi PTH
[pseudohipoparatiroidisme,
hipomagnesemia], obat-obatan dll)
 GEJALA HIPOKALSEMIA
• Parestesia, terutama pada jari-jari
• Tetani, spasme karpopedal, kramp otot
• Chovstek’s sign; Trousseau’s sign
• Kejang
• QT interval memanjang
• Laringospasme, bronkospasme
 Terapi Hipokalsemia
• Ca glukonat 10%, bolus dan/atau drip
• Ca oral Ca-carbonat (40% Ca elemen)
Ca-sitrat (21% Ca elemen)
• Koreksi hipomagnesemia
• Vitamin D kolekalsiferol, ergokalsiferol
alfa-kalsidol; kalsitriol
• Monitoring kadar Ca serum dan urin setiap
3 bulan
 HIPOPARATIROIDISME
Hipoparatiroidisme adalah produksi hormon PTH yang tidak
mencukupi untuk mempertahankan kadar kalsium ekstraseluler dalam
batas normal.
Penyebab :
- Kelenjar paratiroid yang tidak berkembang,
- Destruksi kelenjar paratiroid,
- Penurunan fungsi kelenjar paratiroid,
- Aksi PTH yang terganggu.
Gambaran klinis, biokimia & radiologik
- Gejala-gejala hipokalsemia pada berbagai tingkatan
- Secara biokimia, akan tampak hipokalsemia, hiperfosfatemia, PTH yang
rendah atau tidak terdeteksi, dan kadar 1,25(OH)2D yang rendah.
- Pada gambaran radiologik dan CT-scan kepala, akan tampak kalsifikasi
basal ganglia
 PSEUDOHIPOPARATIROIDISME

• Pseudohipoparatiroidisme (PHP) adalah keadaan

klinik yang secara biokimia ditandai oleh
gambaran hipoparatiroidisme, yaitu hipokalsemia
dan hiperfosfatemia, tetapi sekresi PTH meningkat
dan jaringan target tidak berespons terhadap
aktifitas biologik PTH.
- Untuk membedakan dengan PTH yang resisten,
dapat dilakukan tes Ellsworth-Howard, yaitu
dengan pemberian PTH bioaktif, pada
hipoparatiroidisme akan tampak peningkatan
ekskresi cAMP urin dan fosfat urin.
OSTEOMALASIA & RIKETS
• Osteomalasia adalah kelainan pada mineralisasi dan
pertumbuhan tulang akibat aktifitas vitamin D yang
inadekuat, baik akibat defisiensi, maupun resistensi. Bila
timbul pada anak-anak sebelum epiphyseal plate menutup
disebut rikets.
• Gejala klinik yang paling sering terlihat adalah nyeri
tulang yang difus dan kelemahan otot.
• Pada anak-anak, akan didapatkan kelemahan otot, tetani,
kaki yang bengkok (bowing legs), sendi kostokondral yang
prominen yang disebut rachitic rosary. Pada kepala akan
didapatkan kalvarium yang melunak yang disebut
kraniotabes, dan keterlambatan pertumbuhan gigi yang
permanen.
 Etiologi osteomalasia & rikets

Vitamin D-related rickets/ Hypophosphatemic rickets/

osteomalacia osteomalasia
• Nutrisional • X-linked hypophosphatemic
• Malabsorbsi rickets
• Gangguan hidroksilasi di hati • ADHR
• MBD-CKD • Osteomalasia onkogenik
• Peningkatan katabolisme : anti- • RTA tipe I & II
konvulsan
Lain-lain
• VDDR tipe I & II
• Intoksikasi alumunim
Defisiensi kalsium • Intoksikasi kadmium
• Overdosis etidronat
• Hipofosfatasia
 Assessment of bone formation by using sequential
tetracycline labeling

1st tetracycline labeling 2nd tetracycline labeling

2 days (1) 2 days (2)

Off-period
10 days
Biopsy

Chavassieux P, Brixen K, Zerbini C, et al. Osteoporos Int. 2011;22(Suppl.1):S104 (Abstract OC16)

 FIBROBLAST GROWTH FACTOR
23
(FGF23)
• FGF23 regulasi renal phosphate handling
( reabs Pi di ginjal PTH)
homeostasis vitamin D
( 1,25(OH2vit D >< PTH)
• FGF23 hipofosfatemia,
1,25(OH)2vit D rendah/normal
ADHR, TIO, XLH, ARHR
• FGF23 hiperfosfatemia,
1,25(OH)2vit D tinggi,
kalsinosis tumoral familial, CKD
 EFEK FGF23
Aktifitas FGF23 di ginjal 1 (OH)ase;
24(OH)ase
ekspresi NPT2a &
NPT2c produksi PTH

reabsorpsi Pi di
tub.prox.ginjal

Hipofosfatemia
Regulatory Mechanism of 1α-hydroxylase and 24-
hydroxylase in the Proximal Tubular Cells (PTC)

FGF23 Osteoblast Hypocalcemia

Parathyroid Cell
1 ,25(OH)2 D3 (Calcium Receptor)

ATP CaR
1α-hydroxylase Acceleration
Suppression AC PTH
25(OH)D3 cAMP Acceleration of
Acceleration PTH secretion
24-hydroxylase
Suppression

24,25(OH)2D3

Proximal Tubular Cells (PTC) in the Kidney

 Discovery of FGF-23 as a Common Cause of
Three Distinct Hypophosphatemic Diseases
Hypophosphatemic diseases
Synthesis & Fragmentation
of FGF-23 TIO ADHR XLH
Tumor-Induced Autosomal- X-Linked
1 25 251 Osteomalacia Dominant Hypophospha-
Hypophospha- temic rickets
Deletion of /osteomalacia
temic Rickets
signal-peptide
25 251 Resistance against
Overproduction Malfunction of
of FGF-23 by RXXR protease due PHEX
tumor cells to FGF-23 gene RXXR protease
Active fragment mutation
Breakage Protease having ability ＊ＸＸ＊Ｓ
to recognize RXXR
Activator
sequence (PHEX)
Ｑ Ｑ
25 179 180 251 Ｗ

ＲＸＸＲ Ｓ

Inactive fragment Inactive fragment Excessive production of FGF-23

T Yamashita, S Fukumoto, The Bone 17: 445-448(2003)

 A New Concept on the Regulation of 1α,25(OH)2D3
Production in the Kidney
Traditional Concept : PTH is a key factor
Production of 1α,25(OH)2D3
Increase of Induction by 1α-
Hypocalcemia
PTH levels hydroxylase Acceleration

Hypophosphatemia
Overproduction of 1α,25(OH)2D3 Suppression

New Concept : Metabolism of Vitamin D may be regulated by PTH

and FGF-23 independently.

Symptoms of FGF-23 knockout mice

Normal or Hypercalcemia
Hyperphosphatemia Although each factor suppresses production of
1α,25(OH)2D3, 1α-hydroxylase is induced in FGF-
High level of plasma 1α,25(OH)2D3
23 knockout mice
Low level of plasma PTH
MINERAL BONE DISORDER
IN CKD

- Lesi high turnover

- Lesi low turnover

* Adinamik
* Osteomalasia

- Osteodistrofi renal campuran

- Osteoartropati dialisis
 PATOGENESIS MBD-CKD
• Hiperfosfatemia
• Defisiensi kalsitriol
• Hipokalsemia
• Hiperparatiroidisme
• FGF23
• Hipogonadisme
MINERAL & BONE DISORDER IN CKD
Calcium, Vitamin D

Low Turnover High Turnover

PTH

Adynamic Mild
Normal Osteoitis
Bone Formation Fibrosa
Osteomalacia

Al+3

Mixed Lesion
 MBD-CKD TIPE HIGH BONE TURNOVER

Kerusakan ginjal progresif

GFR menurun Massa sel korteks

ginjal menurun
Retensi fosfat

Hipokalsemia 1,25(OH)2D menurun

2o HPTX

Osteodistrofi renal
Ostoartropati dialisis

ESRD dalam dialisis > 10-15 tahun;

jarang < 5 tahun
Amiloidosis 2-mikroglobulin
deposisi di osteoartikular
Carpal Tunnel Syndrome
Artritis erosif, terutama skapulohumeral
Kista tulang
 FGF23 & CKD
CKD Hiperfosfatemia
FGF23 1 (OH)ase 1,25(OH)2D
hipokalsemia & 2o hiperparatiroidisme
FGFR & rec Klotho di kel paratiroid
2o hiperparatiroidisme

FGF23 pada CKD non DM

prediktor progresi penyakit ginjal

FGF23 pada ESRD on dialisis berhubungan dg ggn metab

tlg, LVH, kalsifikasi vask, mortalitas
 PENATALAKSANAAN MBD-
CKD
• Mengontrol kadar P dan Ca serum
• Terapi vitamin D (kalsitriol, analog vit D)
• Kalsimimetik
• Paratiroidektomi
Pengaturan Diet

Diet rendah protein

Diet rendah fosfat

Pengikat fosfat

⃟ Ca-karbonat
⃟ Ca-asetat
⃟ Sevelamer
⃟ Lantanum karbonat

Hindari !!!
⃟ Al-hidroksida
⃟ Ca-sitrat
Kalsitriol
Menghambat transkripsi gen PTH
Mengurangi nyeri tulang, menambah
kekuatan otot, kadang-kadang mem-
perbaiki osteitis fibrosa
Dosis 0,25-1,5 g/hari, mulai dosis kecil,
dinaikkan bertahap
Large intermittent dose :
0,5-4 g/hari, 3x/mgg atau 2-5 g/hari
2x/mgg; Oral (CAPD) atau IV (HD)
Paratiroidektomi

Indikasi :
-Hiperkalsemia persisten (Ca > 11 mg/dl)
-Pruritus yang menetap yang tidak mem-
baik dengan dialisis atau terapi lain
-Kalsifikasi ekstraskeletal
-Hiperfosfatemia persisten
-Nyeri tulang hebat atau fraktur
Paratiroidektomi
Kontra-indikasi
- Aluminium bone disease
- Penyebab hiperkalsemia yang lain
(sarkoidosis, keganasan, asupan Ca dan
vitamin D yang berlebihan)
OSTEONEKROSIS

Putusnya vaskularisasi arteri ke tulang

Penyakit infiltratif, glukokortikoid, emboli

Ujung tulang panjang

OSTEONEKROSIS

Stadium 0 : klinis(-), radiologik (-), MRI (+)

Stadium I : klinis (+), radiologik (-), MRI (+)
Stadium II : osteopenia/osteosklerosis
Stadium III : crescent sign
Stadium IV : kolaps kaput femoris
OSTEONEKROSIS AKIBAT RADIASI
 SCLEROSING BONE DISORDERS
• Osteosklerosis peningkatan massa tulang trabekular
• Hiperostosis peningkatan massa tulang kortikal

Etiologi :
• Osteokondrodisplasia (herediter)
• Kelainan metabolik & endokrinologik
• Kelainan hematologik & keganasan
• Infeksi
• dll
 OSTEOPETROSIS
(Marble bone disease)
Etiopatogenesis deaktifasi gen yang mengkode RANKL
jumlah osteoklas sedikit resorpsi tulang terganggu
Klasifikasi :
1. Autosomal dominant adult osteopetrosis (benigna)
2. Autosomal recesive infantile osteopetrosis (maligna)
Gambaran klinik :
• Infantil : sinus aparanasal dan mastoid tidak berkembang, foramina
kranial tidak melebar, buta dan tuli, tulang lebih padat tapi rapuh
• Adult : tulang panjang rapuh, paralisis Nn kranial, penglihatan dan
pendengaran menurun, keterlambatan psikomotor
Penatalaksanaan :
• Transplantasi sumsum tulang
• Diet dan terapi hormonal (suplementasi Ca, kalsitriol,
glukokortikoid)
• Suportif (dekompresi kanal optik, saraf kranial dan auditorius)