BIOCHEMICAL MARKERS OF BONE

FORMATION AND RESORPTION

AND THEIR UTILITY IN

ORTHOPAEDICS

INTRODUCTION• Chemicals in serum and urine can serve as

markers for monitoring bone loss, bone reformation, and the effectiveness of therapy in patients with osteoporosis. Although not yet well recognized or readily available, tests for these markers may prove preferable to densitometry in some settings or for some patients. In the future, biochemical markers may provide important information on fracture risks as well.

HISTORY

• More than 50 years ago, Fuller Albright,the father of metabolic bone diseases, noted that postmenopausal women were losing excessive amounts of calcium in their urine.

• He is credited with introducing the use of biochemical markers into the clinical arena.

COThe BONE matrix– 40% organic • Type 1 collagen (tensile strength)• Proteoglycans (compressive strength)• Osteocalcin/Osteonectin• Growth factors/Cytokines/Osteoid

– 60% inorganic• Calcium hydroxyapatite

• The cells – osteo-clast/blast/cyte/progenitor

PHYSIOLOGY

• Bone is a reservoir of calcium, calcium En Masse being required to make &maintain the skeleton. To be an effective reservoir for the maintenance of normal blood calcium, calcium must be able to be incorporated into & liberated from the bone on short notice.

BONE REMODELLING• Characteristic of the adult skeleton, occurs most often

in skeletal sites rich in trabecular bone, e.g. proximal femur, calcaneus, and distal radius.

• Remodeling is essential to maintain skeletal homeostasis, to provide elasticity to bone, and to produce a steady source of extracellular calcium.

• Takes place in a cyclic fashion at specific sites or skeletal lacunae in a cycle lasting about 120 days .

REMODELLING PROCESS

• Osteoclasts induce bone degradation

• Activation of surface osteoblasts

BONE TURNOVER• It is a coupled process of bone formation and bone

resorption• Takes place throughout the life at different rates• Before 30yrs bone formation exceeds resorption• At 30 yrs the skeletal mass is at its peak and both

processes are matched• Later resorption goes on increasing for the rest of the

life

MEDIATORS

• Bone formation is mediated by osteoblasts.

• Bone resorption is mediated by osteoclasts

MARKERS

OSTEOBLASTIC MARKERS

MarkerMarker Type of Type of assayassay

Ease of use*Ease of use* Bone Bone specificityspecificity

VariabilityVariability

Total alkaline Total alkaline phosphatase phosphatase

Colorimetric Colorimetric ++++++++ -- ++++

Skeletal Skeletal alkaline alkaline phosphatase phosphatase

ELISA ELISA ++++ ++++++ ++

Procollagen-I Procollagen-I extension extension peptide peptide

RIA RIA ++++ ++++++ ++++

Osteocalcin Osteocalcin RIA, ELISA RIA, ELISA ++++++ ++++++ ++

OSTEOCLASTIC MARKERS

MarkerMarker Type of Type of assayassay

Ease of use*Ease of use* Bone Bone specificityspecificity

VariabilityVariability

Calcium Calcium AAAA ++++++ -- ++++++

Hydroxy Hydroxy proline proline

ColorimetricColorimetric ++++ ++ ++++++

Total Total pyridinolines pyridinolines

HPLC HPLC ++ ++++ ++++

Free deoxyFree deoxypyridinoline pyridinoline

ELISAELISA ++++++ ++++++ ++++

NN-telopeptide -telopeptide ELISAELISA ++++++ ++++++ ++to+++++to+++

CC-telopeptide -telopeptide ELISAELISA ++++ ++++ ++++

CALCIUM HOMEOSTASIS

DIETARY CALCIUM

INTESTINAL ABSORPTIONORGAN PHYSIOLOGY

ENDOCRINE PHYSIOLOGY

DIETARY HABITS,

SUPPLEMENTS BLOOD CALCIUM

BONE

KIDNEYS

URINE

THE ONLY “IN”

THE PRINCIPLE “OUT”

ORGAN PHYS.

ENDOCRINE PHYS.

ORGAN, ENDOCRINE

CALCIUM, PTH, AND VITAMIN D FEEDBACK LOOPS

NORMAL BLOOD Ca

RISING BLOOD Ca

FALLING BLOOD Ca

SUPPRESS PTH

STIMULATE PTH

BONE RESORPTION

URINARY LOSS

1,25(OH)2 D PRODUCTION

BONE RESORPTION

URINARY LOSS

1,25(OH)2 D PRODUCTION

ALKALINE PHOSPHATASE

• In intestinal mucosa, bone & kidney• Concentrated in epiphyseal area• Normal level : 4-13 units/dl (KA). • Composed of a group of isoenzymes- heat

labile and heat stable

HYDROXYPROLINE

• Hypro is an exclusive constituent of collagen• Excreted in urine in peptide bound form• Rate of excretion differs with age

FACTORS AFFECTING BONE TURNOVER

• Local factors• I-GF 1 (somatomedin C)– increased osteoblast proliferation

• TGF– increased osteoblast activity

• IL-1– increased osteoclast activity (myeloma)

• PG’s– increased bone turnover (#’s/inflammn)

• BMP– bone formation

FACTORS AFFECTING BONE TURNOVER

• Other hormones• Oestrogen– gut – increased ca absorption– bone - decreased re-sorption

• Glucocorticoids– gut - decrease ca absorption– bone - increased re-sorption/decreased formation

• Thyroxine– stimulates bone formation/resorption– net resorption

FACTORS AFFECTING BONE TURNOVER

• Other factors• Local stresses• Electrical stimulation• Environmental– temp– oxygen levels– acid/base balance

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