1. Bone Metabolism 3 rd Department of Orthopaedic Surgery University of Athens KAT Hospital

2. Schematic bone mass balance 3. Inhibition of withdrawal Weight-bearing activity Estrogen Testosterone Calcitonin Adequate vitamin D intake Adequate calcium intake (mg/day) Child: 400–700 Adolescent: 1000–1500 Adult: 750–1000 Pregnancy: 1500 Lactation: 2000 Postmenopause: 1500 1. Stimulation of deposition Weight-bearing activity Growth Fluoride Electricity More (or more active) osteoblasts (B) 2. Inhibition of deposition Lack of weight-bearing activity Chronic malnutrition Alcoholism Chronic disease Normal aging Hypercortisolism 4. Stimulation of withdrawal More (or more active) osteoclast Lack of weight-bearing activity Space travel (weightlessness) Hyperparathyroidism Hypercortisolism Hyperthyroidism Estrogen deficiency (menopause) Testosterone deficiency Acidosis Myeloma Lymphoma Inadequate calcium intake Normal aging Net increase in bone massNet decrease in bone mass

3. Parameters affecting Bone Mineral Density & Bone Viability

4. Normal bone metabolism Calcium Important in muscle and nerve function, clotting, >99% of the body’s calcium in bones. Plasma calcium: equally free and bound (usually to albumin). Approximately 400mg of calcium is released from bone daily. Absorbed in the duodenum by active transport & jejunum by passive diffusion Regulated by 1,25(OH)2-vitamin D3 The kidney reabsorbs 98% of calcium (60% in the proximal tubule).. Primary homeostatic regulators of serum calcium are PTH & 1,25(OH)2-vitamin D3 Dietary requirement of elemental calcium: approximately 750mg/day for adults

5. Normal bone metabolism Phosphate A key component of bone mineral Approximately 85% of the body’s phosphate stores are in bone. Plasma phosphate is mostly unbound. Also important in enzyme systems and molecular interactions Dietary intake of phosphate is usually adequate. Daily requirement is 1000 to 1500mg. Reabsorbed by the kidney (proximal tubule) Phosphate may be excreted in urine.

6. Normal bone metabolism Parathyroid hormone PTH is an 84–AA peptide, synthesized in and secreted from the (four) parathyroid glands. Teriparatide, the synthetic form of PTH, contains this active sequence. The effect of PTH is mediated by the cAMP second messenger mechanism. PTH helps regulate plasma calcium. Decreased Ca levels: stimulate receptors to release PTH at intestines, kidneys, bones PTH directly activates osteoblasts. PTH modulates renal phosphate filtration. PTH-related protein and its receptor have been implicated in metaphyseal dysplasia.

7. Normal bone metabolism Vitamin D Naturally occurring steroid Activated by ultraviolet radiation from sunlight or utilized from dietary intake Hydroxylated to 25(OH)-vitamin D3 (liver) and hydroxylated a second time (kidney) to: - 1,25(OH)2-vitamin D3, the active hormone - 4,25(OH)2-vitamin D3, the inactive form 1,25(OH)2-vitamin D3 works at the intestines, kidneys, and bones (see Table 1-13). Phenytoin impair metabolism of vitamin D.

8. Normal bone metabolism Calcitonin A 32–amino acid peptide hormone Produced by clear cells in the parafollicles of the thyroid gland Limited role in calcium regulation Increased extracellular calcium levels cause secretion of calcitonin Inhibits osteoclastic bone resorption Osteoclasts have calcitonin receptors. Calcitonin decreases osteoclast number and activity. Decreases serum calcium level May have a role: - fracture healing - reduces vertebral compression fractures in high-turnover osteoporosis

9. Normal bone metabolism Estrogens Estrogen prevents bone loss by inhibiting bone resorption. Decrease in urinary pyridinoline cross-links Since bone formation and resorption are coupled, estrogen also decreases bone formation. Supplementation: in pm women only if started within 5/10 years after menopause. Risk of endometrial cancer: reduced when estrogens is combined with cyclic progestin Hormone replacement therapy may increase risk of heart disease and breast cancer. Other pharmacologic interventions (alendronate, raloxifene) should be considered.

10. Normal bone metabolism Corticosteroids Increase bone loss Decrease gut absorption of calcium by decreasing binding proteins Decrease bone formation (more cancellous / cortical) by inhibiting collagen synthesis and osteoblast productivity Do not affect mineralization Alternate-day therapy may reduce the effects

11. Normal bone metabolism Thyroid hormones Affect bone resorption more than bone formation Large doses of thyroxine can lead to osteoporosis Regulates skeletal growth at the physis Stimulates: - chondrocyte growth - type X collagen synthesis - alkaline phosphatase activity

12. Normal bone metabolism Growth hormone Causes positive calcium balance Increases gut absorption of calcium more thanurinary excretion Insulin and somatomedins participate in this effect

13. Normal bone metabolism Growth factors Transforming growth factor β (TGF-β) PDGF Monokines Lymphokines different roles in bone and cartilage repair

14. Calcium homeostasis Hypercalcemia Familial hypocalciuric hypercalcemia Autosomal dominant (100%) Hypercalcemia Hypocalciuria Normal or high levels of blood Mg Normal or high levels of PTH

15. Calcium homeostasis Hypercalcemia Hypercalcemia of Malignancy Poor prognosis ( death within 30d) Four types: (i) local osteolysis (ii) hypercalcemia of PTHrP (iii) hypercalcemia of vit D (iv) hypercalcemia of PTH

16. Calcium homeostasis Hypercalcemia Primary Hyperparathyroidism Cancer / hyperplasia Hypercalcemia, hypercalciuria, high vitD, hyprphosphatemia, high urine pH Kidney stones Kidney calcification Myocardial calcification Increases activity of osteoblasts in spongeous bone (pepper) Increases activity of osteoclasts in cancelous bone (fracture)

17. Calcium homeostasis Hypercalcemia Multiple Endocrine Neoplasia (MEN) Werner syndrome (I): parathyroids, pancreas, hypophysis Sipple syndrome (II): parathyroids, medullary thyroid carcinoma, kidney tumors

18. Calcium homeostasis Hypocalcemia Hypoparathyroidism Surgical, hereditary, autoimmune, functional( low PTH) Hypocalcemia, hyperphosphatemia, low PTH, normal urine Ca ++ Neuromuscular deficiency (Chvostek-Trousseau), bronchial-spasm, ECG (QT), depression, Parkinson-like disorders Urgent: i.v. Ca 90-180mg within 5-10min (200ml 5%D/W) & 0.5-2mg/Kg/h under ECG

19. Calcium homeostasis Hypocalcemia Pseudohypoparathyroidism G-proteins mutations: PTH intolerance Autosomal dominant Normal PTH levels Hyperphosphatemia, low vitD, hypocalcemia Propable intolerance in TSH, GnRH

20. Rickets Poor metallosis of osteoid Children Vit D deficiency Bone bending Osteomalacia Poor metallosis of osteoid Adults Vit D deficiency Looser zones Fish-like vertebral bodies

21. Osteoporosis Decreased bone density Decreased mechanical strength Osteoporotic fractures “quantitative but not qualitative disorder” (collagen/hydroxyapatite crystals)

22. Osteoporosis Factors Age Low force fracture > 45 years Famillial history of osteoporosis Low bone density Corticosteroids High bone turnover BMI < 18 Osteoporosis>2

23. Osteoporosis Balance Osteoclast / Osteoblast (+) RANKL M-CSF PGE 2 IL-1,6 PTH 1,25 vitD 2 T 3, T 4 (-) OPG TGF-b Estrogens

24. Osteoporosis RANK - OPG

25. Osteoporosis ILs – Estrogens - RANK

26. Osteoporosis Diagnosis Ro DEXA Blood tests: Cr, Ca, Albs, P, Mg, ALP, TSH, T3, T4, FT3, FT4, FSH, LH, E2 Electrophoresis !!!!!!!!!!!!!!! Markers: CTX, NTX, P1NP Urine: Cr24h, Ca24h, P24h, NTX

27. Osteoporosis Therapy Ca ++ & vit D Estrogens SERMs PTH - Teriparatide Strontium ranelate Biphosphonates (anticancer effect) Anti-TNF-a