METABOLIC BONE DISEASE

Dr. KAPIL DEV

Composition of Bone

The extracellular matrix

40% organic

Type 1 collagen

Proteoglycan

Osteocalcin/osteonectin

Growth factors/cytokines

60% inorganic

Calcium hydroxyapatite Ca10(PO4)6(OH)2

The cells

Osteo-clast/blast/cytes/progenitors

Bone Turn over

Calcium metabolism What is recommended daily intake?

Adult:1000 mg/day

Pregnancy,lactation,postmenopausal:1.3g/day

Children (1-18 yrs):0.5-1.3 g/day

Infant (<1 yr):300-500 mg/day

What is plasma concentration?

Total (mg/dL): 8.6-10.3

(mmol/L): 2.15-2.57

Ionized (mg/dL): 4.5-5.6

(mmol/L): 1.1-1.4

Ref: Harrison’s 18th edition

Phosphate Metabolism

What is recommended daily intake?

Infants (< 1yrs): 100-275 mg/day

Children (1-18 yrs): 460-1250 mg/day

Adults:700-1250 mg/day

Pregnancy/lactation: 700-1250 mg/day

What is plasma concentration?

Adult:2.5-4.5 mg/dL

Children:4-7 mg/dL

Ref: Harrison’s 18th edition

Parathyroid hormone (PTH)

• Synthesizes and secreted by chief cells of

parathyroid gland

• Synthesized as pre-pro-PTH, cleaved

enzymatically to intact PTH

• Plasma calcium: primary physiological

regulator of PTH synthesis and secretion

• Normal Reference Range: 10 -65 ng/L

Effect on serum levels: increase Ca, decrease P

Target organ Action

Kidney Increase reabsorption of Ca

Increase excretion of P

Bone Increase Ca/P mobilization

from bone

GIT Increase in Ca absorption

by stimulating activation of

Vitamin D

Vitamin D

• Sources of vitamin D?

Diet

UV light exposure on precursor in skin

• Daily requirement?

400 International units

Target organ Action

Bone Increase Ca mobilisation from bone

GIT Increase in Ca absorption

Effect on serum levels: increase Ca, decrease P

Calcitonin

• Secreted by parafollicular or C cells

distributed throughout thyroid gland

• Normal serum concentration

Men:<8.8 pg/mL

Women:<5.8 pg/mL

• Level Increases when serum Ca concentration

>2.25mmol/L

Ref: Harrison’s 18th edition

Effect on serum levels: decrease Ca, increase P

Target organ Action

Bone Supresses resorption

Kidney Increase excretion of Ca

Alkaline Phosphate

Present in all tissue, concentrated in liver,

intestins, kidney, bone and placenta

Normal range: 20 – 140 IU/L

Recent Markers

OsteoblastsOsteoid

Osteocyte

Bone matrix

Osteoclast

Markers of bone resorption (Urine)HydroxyprolineCollagen cross-linksPyridinolines (pyridinoline, deoxypyridinoline)Cross-linked telopeptides (NTx, CTx)Tartrate-Resistant Acid Posphate

Markers of bone formation (serum)Bone alkaline phosphataseOsteocalcinProcollagen type I propeptides (PINP, PICP)

Disease with markers

Disease S. Ca S. PO4 S.PTH S. ALP Recent biomarker

Osteoporosis N N N N/high Cathepsin KC- telopeptide

Rickets/Osetmalacia Low low high high Osteocalcin

Paget’s disease N N N high --------

Metabolic bone diseases

heterogeneous group of disorders characterized by abnormalities in

calciummetabolism and/or bone cell physiology. They lead to analtered serum

calcium concentration and/or skeletal failure. The most common type of metabolic

bone disease in developed countries is osteoporosis

• Osteoporosis

• Osteomalacia & Rickets

• Renal Osteodystrophy

Rickets & OsteomalaciaRickets is defective mineralization of bones

before epiphysial closure in immature mammals due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium ,potentially leading to fractures and deformity.

Osteomalacia is a similar condition occurring in adults, generally due to a deficiency of vitamin D but occurs after epiphyseal closure.

Rickets & Osteomalacia Vit D deficiency

low intake plus inadequate sunlight exposure

malabsorption

Abnormal vit D metabolism

Liver disease

Renal disease

Drugs(anticonvulsants)

Hypophosphatemia

Low intake

Hypophosphatemic Vitamin D resistant rickets(X-linked)

• Skeletal deformity

Toddlers: Bowed legs (genu varum)

Older children: Knock-knees (genu valgum) or "windswept knees"

Cranial deformity (such as skull bossing or delayed fontanelle closure)

Pelvic deformity

Spinal deformity (such as kyphoscoliosis or lumbar lordosis)

Rickets & Osteomalacia

• Lab investigations include :• S. ALP ↑

• Ca low in Vitamin D deficiency

• Phosphate may be normal or low

• PTH may ↑

OSTEOPOROSIS

Common in developed countries

Associated with advanced age

Associated with increased risk of fractures (hip, vertebrae, forearm)

Exercise & nutrition play an important role in attaining adequate skeletal mass

During early adult life bone formation = bone resorption

Aging increases bone resorption

OSTEOPOROSIS

• Pathophysiology

Inadequate bone formation during growth

Pathophysiological process impairing osteoblastic bone formation

Increase in bone resorption

Factors involved in causation of osteoporosis

Hormones

Poor diet

Genetic factors

Cytokines

Prostaglandins

Growth factors

Low physical activity and low exposure to sunlight

Osteoporosis• Risk Factors

- Early menopause

- family history

- Sedentary life

- Low calcium intake

- Cigarette smoking

- Excessive alcohol

- Excessive caffeine

- steroid therapy

- Most commonly encountered in post menopausal females

Clinical presentations

Back pain

Fractures

Investigations

Routine X-rays

Bone scan

Investigations for secondary causes

Osteoporosis (management)

Exercise

Calcium

Vit D

Bisphosponates

Oestrogen replacement

Androgens

Pagets Disease

Disease of bone remodelling

osteoclast mediated bone resorption followed by new bone formation

Cause unknown ?virus (paramyxovirus)

More common in caucasian

Pagets Disease (clinical manifestation)

Bone pain

Joint pain

Deformity

Spontaneous fractures

Pagets Disease (complications)Fractures

Deafness

Nerve entrapment

Spinal stenosis

Cardiac failure

Osteogenic sarcoma

Hypercalcemia

Pagets Disease (investigations)

↑ markers of bone formation

↑ ↑ Serum alk phosphatase

Urinary hydroxy proline and pyridinoline cross links

X-rays

cortical thikening

osteolytic, & osteiosclerotic

bone scan

RENAL OSTEODYSTROPHY

• Associated with CRFa) ↓excretion of PO4 ---> ↑ PO4

b) Inability of kidney to synthesise 1,25 (OH)2D (↓ renal

mass & ↑ PO4)

c) ↓ intestinal absorption of Ca ---> hypocalcemia

• Results in hyper parathyroidism

RENAL OSTEODYSTROPHY : CLINICAL MENIFESTATIONS

• BONE PAINS (WT BEARING)

• SKELETAL DEFORMITIES IN CHILD

• EXTRACELLULAR CALCIFICATION

• LAB INVESTIGATIONS: ↑ PO4

HYPOCALCEMIA

↑ PTH

↓1,25 (OH)2 D

↑ ALP

Mg ↑

THANK YOU