Describe the biochemical composition of bone and the cells involved in its remodelling. Discuss the biochemical findings in the common bone disorders.

Composition of Bone

• Mineral gives compressive strength; collagen gives tensile strength
• Loss of mineral → osteomalacia; loss of both → osteoporosis; abnormal collagen → osteogenesis imperfecta

Cells of Bone

Osteoblast expresses RANKL → Binds rank on the osteoclast precursor → Osteoclast differentiation and activation → resorption → Osteoblast also secretes osteoprotegerin (OPG) → OPG is a decoy receptor that mops up RANKL → The RANKL : OPG ratio determines net bone turnover

• PTH and cytokines raise RANKL; oestrogen raises OPG — which is exactly why bone is lost after the menopause
• Denosumab is a monoclonal antibody against RANKL, a treatment derived directly from this pathway

Biochemical Markers of Bone Turnover

Biochemistry of Common Bone Disorders

Connective Tissue Matrix

• Collagen — tensile strength; type I in bone and skin, II in cartilage, III in reticulin, IV in basement membrane
• Elastin — recoil; cross-linked by desmosine; not hydroxylated and not glycosylated, unlike collagen
• Proteoglycans — hydrated gel resisting compression; aggrecan in cartilage
• Fibronectin and laminin — adhesion glycoproteins linking cells to matrix
• Matrix metalloproteinases degrade the matrix in remodelling, and in tumour invasion; opposed by TIMPs

Mineralisation and its Control

Osteoblast secretes osteoid (type I collagen + non-collagenous proteins) → Matrix vesicles bud from the osteoblast membrane → Concentrate Ca2+ and PO43− → alkaline phosphatase raises local phosphate by hydrolysing pyrophosphate → Pyrophosphate is a natural inhibitor of mineralisation — removing it permits crystal growth → Hydroxyapatite crystals nucleate and grow along the collagen fibrils

• This is why alkaline phosphatase rises whenever bone formation increases — in growing children, in rickets, in Paget disease and around healing fractures
• Bisphosphonates are stable analogues of pyrophosphate, which is exactly why they inhibit resorption and bind so avidly to bone
• Requires adequate calcium, phosphate, vitamin D, vitamin C and vitamin K

Applied Aspects

• Bisphosphonates bind hydroxyapatite and are taken up by osteoclasts, inhibiting them — first-line in osteoporosis and Paget disease
• Osteocalcin is vitamin K dependent, which is one reason warfarin and vitamin K deficiency affect bone
• Fluoride forms fluoroapatite, which is more acid-resistant — the basis of caries prevention; in excess it causes brittle, mottled bone and teeth
• Alkaline phosphatase is the single most useful screening test in bone disease, but it also rises in liver disease — check GGT to distinguish
• Bone turnover markers guide treatment response long before bone density changes, since density takes a year or more to shift measurably
• Cathepsin K, the osteoclast protease that degrades collagen, has been a drug target; its deficiency causes pycnodysostosis, with dense but brittle bone
• Fluoride stimulates osteoblasts and increases bone density, but the bone formed is of poor quality — which is why it failed as an osteoporosis treatment
• Bone is a metabolically active reservoir, not an inert scaffold: about 10% of the adult skeleton is remodelled each year
• Osteoporosis after the menopause follows loss of oestrogen, which normally raises osteoprotegerin and restrains osteoclasts
• Glucocorticoids cause osteoporosis by inhibiting osteoblasts, reducing calcium absorption and increasing urinary loss — the commonest drug-induced cause
• Immobilisation causes rapid bone loss, since mechanical loading sensed by osteocytes is the stimulus for formation
• Hydroxyproline and pyridinoline in urine come almost entirely from collagen breakdown, and rise in Paget disease and bone metastases
• Vitamin C deficiency affects bone as well as skin — the osteoid cannot be laid down, giving the subperiosteal haemorrhages of infantile scurvy
• Denosumab and teriparatide are derived directly from this biology — one blocks RANKL, the other is recombinant PTH given intermittently, which paradoxically stimulates formation