Metabolic bone disease

รศ. น.พ. ววัิฒน์ วจนะวศิษิฐ

ภาควิชาออร์โธปิดกิส์

คณะแพทยศาสตร์โรงพยาบาลรามาธิบดี

มหาวิทยาลัยมหดิล

Mineral Homeostasis

• Controlling intra- and extra-cellular levels of ions : Calcium, Phosphorus

others: pH, Na, K, Mg, Cl, HCO3, SO4

• Hormone : PTH; 1,25(OH)2D; FGF23 calcitonin, prolactin, glucocorticoid, GH, insulin, IGF & several cytokines • Target tissues : Bone, Intestine, Kidney

Mineral Homeostasis

• Controlling intra- and extra-cellular levels of ions : Calcium, Phosphorus,

others: pH, Na, K, Mg, Cl, HCO3, SO4

• Hormone : PTH; 1,25(OH)2D; FGF23 calcitonin, prolactin, glucocorticoid, GH, insulin, IGF & several cytokines • Target tissues : Bone, Intestine, Kidney

Magnesium

The players

Ca, P, Mg

Ca, P

PTH

FGF23

1,25(OH)2D

25(OH)D

Ca P

Regulation of ions

Ca, P

PTH

FGF23

1,25(OH)2D

25(OH)D

Ca P

Ca, P

PTH

FGF23

1,25(OH)2D

25(OH)D

Ca P

What is Metabolic Bone Disease?

Most commonly these metabolic bone disorders are caused by abnormalities of minerals such as calcium, phosphorus, magnesium or vitamin D leading to dramatic clinical disorders that are commonly reversible once the underlying defect has been treated.

These disorders are to be differentiated from a larger group of genetic bone disorders where there is a defect in a specific signaling system or cell type that causes the bone disorder.

4 most common causes of MBD in Thailand

1. Renal tubular acidosis type I, distal RTA 2. Systemic fluorosis 3. Thalassemia 4. Osteoporosis

Differential diagnosis

1. 1o HPT 2. Rickets/Osteomalacia 3. Renal Osteodystrophy 4. Osteoporosis 5. Bone Metastasis and Myeloma

Differential diagnosis

Loss of mineralization: osteomalacia/rickets Low bone mass: osteoporosis, OI High bone mass: osteopetrosis High bone turnover: Paget, HPT, Thyrotoxicosis Low bone turnover: adynamic bone,

hypophosphatasia

Primary hyperparathyroidism

• von Recklinghausen • Osteitis fibrosa cystica

Rickets/Osteomalacia

• Hyperosteoidosis

Rickets/Osteomalacia

1. Nutritional 2. Gastrointestinal-biliary 3. Renal tubular causes 4. Unusual causes 5. Renal osteodystrophy (CKD-MBD)

Rickets/Osteomalacia

1. Nutritional 2. Gastrointestinal-biliary 3. Renal tubular causes 4. Unusual causes 5. Renal osteodystrophy (CKD-MBD)

Renal rickets

1. Hypophosphatemic rickets (VDRR, Albright) 2. VDDR I 3. VDDR II 4. Fanconi 5. Renal tubular acidosis: I, dRTA : distal tubule

II, IV

Unusual causes

• Fibrous dysplasia/Neurofibromatosis • Oncogenic osteomalacia (TIO) • Anti-epileptic drug

CKD-MBD (renal osteodystrophy)

Pathogenesis

Renal injury: Loss of skeletal anabolism

2nd HPT : high turnover osteodystrophy If we suppress PTH : adynamic bone

Pathogenetic factors in 2nd HPT

• Hyperphosphatemia • Calcitriol deficiency • Hypocalcemia • PT gland hyperplasia • FGF23 elevated • Hypogonadism

• Others: Al, B2 microglobulin, acidosis, GFs

Problems in CKD

• Fracture • Cardiovascular disease vascular calcification • Mortality

Prevention & Treatment

CKD III • Regulate P and Ca: phosphate binder • Hypocalcemia: suppl only in symptomatic • Calcitriol • Cinacalcet • Parathyroidectomy

Primary hyperparathyroidism

Osteitis fibrosa cystica

• stone

• bone pain

• Groan

• throne

• psychiatric overtone

Classical 1ry HPT

Classical 1ry HPT

Skeletal • Subperiosteal resorption

of distal phalanx • Tapering distal clavicle • Salt & pepper skull • Bone cyst • Brown tumor

Renal • Nephrolithiasis • Nephrocalcinosis • Hypercalciuria (F: 250 mg, M: 300 mg) • CCr reduction

Classical 1ry HPT

Neuromuscular : myopathy, weakness, aging, cognitive, distinct psychiatric feature

GI : peptic ulcer, pancreatitis CV : valvular calcification, vascular

stiffness Others

Clinical forms of 1ry HPT

Most common presentation : Asymptomatic hypercalcemia : within 1mg/dl above upper limits Incidence: 1 in 500 to 1 in 1,000 (USA) F:M = 3:1 51-60 y.o. In children: MEN I, II Acute 1ry HPT or HPT crisis is rare.

Evaluation & diagnosis

History & PE Established by laboratory tests X-ray (bone survey) BMD (included distal forearm)

Biochemical Hallmarks

• Hypercalcemia • PTH elevated

Treatment

Natural history

• A decade after Dx Ca2+, inP, PTH, 25(OH)D, 1,2(OH)2D, u-Ca,

BMD : stable

• Afterwards : 25% progressive

• Age <50 yr : 65% progressive

Guideline for asymptomatic 1ry HPT

Surgery

>1 mg/dl above upper lim. >400 mg/d Reduced by 30% NA T-score <-2.5, any site <50 yr

Follow-up of non-surgery

Two times/ year Do not measure Do not measure Measure annually Annually 3 sites

Serum Ca++ Urinary Ca++

Renal function CCr serum Cr BMD Age

Adapted from NIH workshop on Asymptomatic 1ry HPT 2002

Medical treatment

• Adequate hydration & ambulation • Avoid Thiazide & Lithium

• Dietary calcium : moderate >1 g/d avoid in high 1,25(OH)2D low calcium: stim PTH secretion

Medical treatment

Drug • Oral phosphate • Estrogen • SERM • Bisphosphonate • Calcimimetic agent: Cinacalcet HCL

•Ectopic calcification •Elevate PTH •GI tolerance

Non-parathyroid Hypercalcemia

Non-parathyroid Hypercalcemia

Pathophysiology Total calcium 9.5 mg/dl ionized 4.2 mg/dl Ca complex 0.3 mg/dl bound to protein 4.5 mg/dl Hypercalcemia > 2 SD means 10.6 mg/dl

• Mild < 12 mg/dl • Moderate 12-14 mg/dl • Severe >14 mg/dl

Disorders lead to Hypercalcemia

• Cancer • Granulomatous diseases • Endocrine disorder • Milk-Alkali syndrome • TPN • Abnormal protein binding • Medication: Lithium, Estrogen, SERM, Foscarnet, 8-

chlorocyclicAMP

• Acute & CRF • Hypophosphatemia

Malignancy-associated hyperalcemia (MAHC)

• Hypercalcemia of malignancy (HHM) • Local osteolytic hypercalcemia (LOH) • 1,25(OH)2D Induced hypercalcemia • Authentic ectopic hypercalcemia

HHM

• Humoral nature • 1987: PTHrP • Uncoupling bone turnover • Decrease 1,25(OH)2D • Squamous CA

LOH

• CA breast • Myeloma, lymphoma, leukemia • Skeletal metastasis • IL-1, IL-6, PTHrP, MIP-1a

Granulomatous disease

• Sarcoidosis, Tuberculosis • 1a-hydroxylase • Inapp production 1,25(OH)2D

• Treatment Eradicate granuloma antiTB, glucocorticoid limit Ca, D intake, sun exposure

Osteoporosis

Osteoporosis

Severe Osteoporosis

Normal

Courtesy Dr. A. Boyde

Practical approach to MBD