PHYSIOLOGY OF CALCIUM AND VITAMIN D METABOLISM PPT DR NAV.pptx

BONE METABOLISM

1. PHYSIOLOGY OF CALCIUM AND VITAMIN D METABOLISM markers of bone formation and bone resorption BY DR. MOHAMMED ABDUL NAVEED 2 ND YR ORTHOPAEDIC PG GANDHI MEDICAL COLLEGE

2. BONE COMPOSITION

3. Calcium Calcium is essential for normal cell function and physiological processes such as blood coagulation, nerve conduction and muscle contraction . The main sources of calcium are dairy products , green vegetables and soya (or fortified foods). The recommended daily intake for adults is 800–1000  mg and 1200   mg during pregnancy and lactation. Children need less, about 200–400  mg per day. About 50% of the dietary calcium is absorbed (mainly in the upper gut) but much of that is secreted back into the bowel and only about 200 mg enters the circulation. The normal concentration in plasma and extracellular fluid is ( 8.8–10.4  mg/ dL ). Much of this is bound to albumin as well as other proteins; about half is ionized and effective in cell metabolism and the regulation of calcium homoeostasis .

4. PHOSPHORUS Phosphorus is needed for many important metabolic processes, including energy transport and intracellular cell signalling . It is abundantly available in the diet and is absorbed in the small intestine, more or less in proportion to the amount ingested ; Absorption is reduced in the presence of antacids such as aluminium hydroxide, which binds phosphorus in the gut. Phosphate excretion is extremely efficient, but 90% is reabsorbed in the proximal tubules. Plasma concentration – almost entirely in the form of ionized inorganic phosphate (Pi) – is normally maintained at (2.8–4.0 mg/ dL ). The solubility product of calcium and phosphate is held at a fairly constant level ; any increase in the one will cause the other to fall.

5. HORMONE REGULATION REGULATORS OF CALCIUM VIT D3 PTH CALCITONIN REGULATORS OF PHOSPHORUS VIT D3 PTH FGF23

6. Vitamin D There are two main forms: vitamin D2 ( ergocalciferol ) , which s synthetic, and vitamin D3 ( cholecalciferol ), which is naturally occurring .

7. VITAMIN D METABOLISM The active vitamin D metabolites are derived either from the diet or by conversion of precursors when the skin is exposed to sunlight. The inactive ‘vitamin’ is hydroxylated , first in the liver and then in the kidney, to form the active metabolites 25-HCC and 1,25-DHCC.

8. VITAMIN D Although the concentration of active metabolites can be measured in serum samples, the best indicator of vitamin D status is 25-OHD concentration ( serum 1,25-(OH)2D has a half-life of only 15 hours and is therefore not as good an indicator). Generally, 25-OHD levels of >50  nmol /L are considered sufficient.

9. Parathyroid hormone (PTH) PTH is produced by the parathyroid glands. ( PTH) is the major regulator of extracellular calcium concentration. Secretion is regulated by plasma ionized calcium. This regulation is mediated by the calcium-sensing receptor ( CaSR ), which is activated by decreased ionized calcium, leading to suppression of PTH secretion.

10. 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

11. FGF23(PHOPHATURIC HORMONE) FGF23 is produced by osteocytes , and acts to lower serum Pi by promoting renal Pi excretion through suppression of renal tubular Pi reabsorption. FGF23 levels are influenced by dietary Pi intake, and by calcitriol levels; the latter reduces serum Pi by increasing Pi excretion via stimulation of FGF23 release, leading to a reciprocal increase in serum calcium. Altered circulating levels of FGF23, which can be readily measured, are associated with a variety of genetic and acquired disorders. In many of these cases, the clinical manifestations reflect reduced skel-etal mineralization as a result of a reduction in the calcium × phosphate product due to excess FGF23 activity, giving a clinical picture of hypophospha-temia and vitamin D-resistant osteomalacia .

12. BONE REMODELLING CYCLE BONE REMODELLING =BONE RESORPTION +BONE FORMATION. Bone formation and resorption continue as a lifelong process contributing to bone growth and modelling . These two processes are carefully which serves to maintain bone integrity. They are also activated during repair following injury, for example after a fracture.

13. BONE REMODELLING CYCLE

14. BONE RESORPTION Bone resorption is carried out by the osteoclasts under the influence of stromal cells (including osteoblasts) and both local and systemic activators . Though it has long been known that parathyroid hormone (PTH) promotes bone resorption , osteoclasts have no receptor for PTH. The hormone acts indirectly through its effect on 1,25- (OH)2D3 and osteoblasts. Proliferation of osteoclastic progenitor cells requires the presence of an osteoclast differentiating factor produced by the stromal osteoblasts after stimulation by, for example, PTH, glucocorticoids or pro-inflammatory cytokines.

15. BONE FORMATION carried out by teams of osteoblasts , which are recruited to a bone surface and secrete osteoid, composed of type I collagen fibrils, which becomes deposited on the adjacent bone surface. Bone mineral, hydroxyapatite crystals, subsequently become deposited in spaces between collagen fibrils . Whereas osteoid is rapidly mineralized following its synthesis, a process of secondary mineralization takes place after bone formation is complete. Skeletal maturity also influences the degree of collagen cross-link formation, a process whereby adjacent type I collagen fibrils undergo fur- ther protein binding to enhance tensile strength. The amino acid sequence where these cross-links occur, termed N-terminal telopeptide , are largely specific to bone, and their level in plasma following release into the circulation following bone resorption forms the basis of clinical measurement of bone turnover .

16. BONE FORMATION Like bone resorption , bone formation is regulated by a combination of systemic and locally produced factors acting to promote osteoblast differentiation. most important local factors in regulating osteoblast differentiation are the bone morphoge-netic proteins (BMPs) and the Wnt signalling system, both of which comprise complex systems of multiple ligands, cell surface receptors, intracellular signalling pathways and endogenous inhibitors.

17. BONE REMODELLING Osteoblast and osteoclast activity are coordinated during bone remodelling . This process, which determines the internal architecture of bone, occurs not only during growth but throughout life. Bone remodelling serves several crucial purposes: ‘old bone’ is continually replaced by ‘new bone’ and in this way the skeleton is protected from the excess accumulation of fatigue damage and the risk of stress failure; B one turnover is sensitive to the demands of function, and trabec-ulae are fashioned in accordance with the stresses imposed upon the bone, the thicker and stronger trabeculae following the trajectories of compressive stress and the finer trabeculae lying in the planes of tensile stress .

18. 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 The annual rate of bone turnover in healthy adults has been esti -mated as 4% for cortical bone and 25% for trabecular bone .

19. BIOCHEMICAL MARKERS OF BONE FORMATION AND RESORPTION AND THEIR UTILITY IN ORTHOPAEDICS Chemicals in serum and urine can serve as markers for monitoring bone loss, bone reformation, and the effectiveness of therapy in patients with osteoporosis.

20. 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.

21. Formation Markers(serum) Total ALP Bone ALP Osteocalcin (OC) C-terminal propeptide of protocollagen type I (PICP) N-terminal propeptide of protocollagen type I (PINP)

22. Resorption Markers(serum ) Tartrate resistant acid phosphatase (TRAP) C-terminal telopeptide of collagen type I(ICTP) N-terminal telopeptide of collagen type I (NTX) β- CrossLaps ( β- CTX)

23. URINE MARKERS Urinary excretion of calcium Hydroxyproline Pirydinolin ( Pir ) Deoxypirydinolin ( Dpir ) C-terminal telopeptide of collagen type I (ICTP) N-terminal telopeptide of collagen type I (NTX) α- CrossLaps ( α- CTX)

24. FORMATION MARKERS ALKALINE POHOSPHATASE Alkaline phosphatase activity is derived from various tissues such as the liver, bone, placenta, etc. Bone and liver isoforms are the most common (90%). Both are found in the same proportion in the healthy individual . Normal range: 20 – 140 IU/L

25. SERUM OSTEOCALCIN Osteocalcin is a small protein (49 amino acids) . Synthesized by mature osteoblasts , odontoblasts , and hypertrophic chondrocytes . Major advantages – considered a specific marker of osteoblast function as its levels correlate with the bone formation rate.

26. PRO COLLAGEN TYPE 1 Procollagen type 1 contains N- and C-terminal extensions, which are removed by specific proteases during conversion of procollagen to collagen. Antibodies are used to detect the P1CP and P1NP by ELISA or radioimmunoassay. Measurement of P1NP appears to be a more sensitive marker of bone formation rate in osteoporosis. Because type I collagen is the main product of synthesis of the osteoblast, the amino- termina carboxy propeptides would, theoretically, be the ideal marker of bone formation.

27. RESORPTION MARKERS Historically , urinary calcium was the first test used to assess bone resorption . However , the fact that it is influenced by various factors, such as calcium intake, intestinal absorption and renal threshold of excretion of calcium, makes its determination a test with low sensitivity and specificity, and is currently unused.

28. Carboxyterminal (ICTP, CTX) and amino-terminal (NTX) telopeptides of collagen They have shown a significant correlation with BMD in postmenopausal women. considered the most clinically useful markers of bone resorption currently available . Tartrate-resistant acid phosphatase(TRAP) Is a lysosomal enzyme not only involved in osteoclast bone degradation but is also present in other tissues. It is poorly specific, and together with the methodological difficulty in identifying it, currently makes it of little use.

29. Clinical Utility of Biomarkers in Osteoporosis assessment of therapeutic response. Predicting risk of fracture and bone loss and their correlation with BMD. Prediction of bone mass.

30. Disease with markers Disease S. Ca S. PO 4 S.PTH S. ALP Recent biomarker Osteoporosis N N N N/high Cathepsin K C- telopeptide Rickets/Osetmalacia Low low high high Osteocalcin Paget’s disease N N N high --------

31. Limitations on the Use of Markers However , one cannot ignore the fact that markers of bone turnover show a marked variability, both analytical and biological. The causes of variability : age, sex, ethnicity, fracture repair, renal and hepatic function, other associated diseases, and so on. It is important to determine the time of sample collection according to the circadian rhythm of each marker. Some markers in particular are heavily influenced by food, as is the case with serum CTX.

32. APPLIED PHYSIOLOGY

33. METABOLIC BONE DISEASES OSTEOPOROSIS(MOST COMMON) RICKETS OSTEOMALACIA HYPERPARATHYROIDISM RENAL OSTEODYSTROPHY(CHRONIC KIDNEY DISEASE-BONE MINERAL DISEASE) PAGETS DISEASE(OSTEITITS DEFORMANS) OSTEOPETROSIS(MARBLE BONE DISEASE) HYPERCALCAEMIA OF MALIGNANCY

34. Rickets & Osteomalacia Rickets 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.

35. Rickets & Osteomalacia Lab investigations include : S. ALP ↑ Ca low in Vitamin D deficiency Phosphate may be normal or low PTH may ↑

36. osteoporosis DEF-Osteoporosis as a clinical disorder is characterized by an abnormally low bone mass and defects in bone structure, a combination which renders the bone unusually fragile and at greater than normal risk of fracture in a person of that age, sex and race.

37. 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

38. OSTEOPOROSIS Pathophysiology Inadequate bone formation during growth Pathophysiological process impairing osteoblastic bone formation Increase in bone resorption

39. Factors involved in causation of osteoporosis Hormones Poor diet Genetic factors Cytokines Prostaglandins Growth factors Low physical activity and low exposure to sunlight

40. osteoporosis Risk Factors Early menopause family history Sedentary life Low calcium intake Cigarette smoking Excessive alcohol Excessive caffeine steroid therapy -

41. Clinical presentations Back pain Fractures Investigations Routine X-rays Bone scan Investigations for secondary causes

42. Osteoporosis (management) Exercise Calcium Vit D Bisphosponates Oestrogen replacement Androgens

43. Pagets Disease Disease of bone remodelling osteoclast mediated bone resorption followed by new bone formation Cause unknown ?virus (paramyxovirus) More common in caucasian

44. 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

45. RENAL OSTEODYSTROPHY Associated with CRF ↓excretion of PO4 ---> ↑ PO4 Inability of kidney to synthesise 1,25 (OH) 2 D (↓ renal mass & ↑ PO 4 ) ↓ intestinal absorption of Ca ---> hypocalcemia Results in hyper parathyroidism

46. LAB INVESTIGATIONS: ↑ PO4 HYPOCALCEMIA ↑ PTH ↓ 1,25 (OH)2 D ↑ ALP Mg ↑

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