Understanding Metabolic Bone Diseases: Bone Health & Calcium Regulation

1. ENDOCRINEPATHOPHYSIOLOGY 5., Metabolic Bone Diseases Calcium and Bone Metabolism

2. Calcium Pools and Balance

3. Distribution of Calcium in Plasma Calculation of Serum Total Calcium Concentration Albumin < 40 g/L Cacorr=[Ca]T+0.02(40-[Alb]) Albumin > 40 g/L Cacorr=[Ca]T-0.02([Alb]-45) w. HCO3-, citrate, phosphate pH  [Ca2+]

4. Action of Major Calcium-regulating Hormones Bone Kidney Intestine Parathhyroid hormone (PTH) Calcitonin (CT) Vitamin D (1,25(OH)2D3) Ca2+, PO43- reabsorption Ca2+, PO43- reabsorption Maintains Ca2+ transport system Ca2+ reabsorption PO43- reabsorption HCO3- reabsorption, 1-OH-ase act. Ca2+, PO43- reabsorption Ca2+reabsorption No direct effect No direct effect Ca2+, PO43- reabsorption

5. Parathyroid Glands

6. Formation of Active Vitamin D

7. Hypoparathyroidism Etiology • Surgical Hypoparathyroidism • Idiopathic Hypoparathyroidism multi endocrine deficiency-autoimmune-candidiasis (MEDAC) • Functional Hypoparathyroidism (low magnesium intake, malabsorption)

8. Clinical Features • Neuromusclar Manifestation • Paresthesias (numbness, tingling) • Hyperventilation • Adrenergic symptoms (increased epinephrine) • Signs of latent tetany Chvostek`s sign Trousseau`s sign • Other Clinical Manifestation • Posterior lenticular cataract • Cardiac manifestation • Dental manifestation • Malabsorption syndrome

9. Hypocalcemic States

10. Pseudohypoparathyroidism Resistance of Target Hormone to PTH Type I PTH stimulation  no cAMP or phosphate Type II PTH stimulation  cAMP normal, no phosphate • Same as in hypoparathyroidism • Mental retardation, short and stocky, obese with rounded faces • Short metacarpal or metatarsal bones short fingers • Delayed dentations, defective enamel and absence of teeth Clinical Features

11. Pseudohypoparathyroidism

12. Primary Hyperparathyroidism • Hyperplastic (about 20%), adenomatous (80%) or malignant parathyroid gland • Increased resorption of bone surfaces Increased number of osteoclasts, osteocytic osteolysis • Nephrolithiasis (20-30%), frequently complicated with pyelonephritis • Soft tissue calcification (lung, heart) • Myopathy, neuropathic atrophy

13. Primary Hyperparathyroidism • Features • Uncontrolled secretion of PTH of the parathyroid gland • Hypercalcemia fails to inhibit gland activity • Nephrolithiasis, osteitis fibrosa, soft tissue calcification (rare today) • Etiology(unknown) • Genetic factor may be involved (autosomal dominant trait) • Failure of feedback regulation

14. Primary Hyperparathyroidism Hypercalcemia and Associated Hypercalciuria Clinical Features • Central nervous system • impaired mentation • loss of memory for recent events • emotional labiality • depression etc. • Neuromusclar • weakness (proximal musculature) • Rheumatologic • joint pain • Renal • polyuria • nocturia • nephrocalcinosis • renal colic due to lithiasis • Gastrointestinal • anorexia • nausea • vomiting • dyspepsia • Dermatologic • pruritus

15. Primary Hyperparathyroidism

16. Secondary Hyperparathyroidism Chronic hypocalcemia  secondary hyperparathyroidism • Chronic renal failure (most important) • Dietary deficiency of vitamin D or calcium • Decreased intestinal absorption of vitamin D • Drugs that cause rickets or osteomalacia (phenytoin, phenobarbital etc.) • Excessive intake of inorganic phosphate compound • Pseudohypoparathyroidism • Severe hypomagnesemia

17. Secondary Hyperparathyroidism

18. Disorders of Calcitonin Secretion No disorders has been reported to date in which hypocalcitoninemia plays a definitive role • Medullary carcinoma of the thyroid gland • Excess secretion of CT • Multi Endocrine Neoplasia Syndrome (MEN) • Clinical symptoms vary • asymptomatic thyroid mass • paraneoplastic syndromes (eg. Cushing`s syndrome) • diarrhea • flushing • family history Hypercalcitoninema

19. ENDOCRINEPATHOPHYSIOLOGY Metabolic Bone Diseases

20. Metabolic Bone Disease I. Function of Bone • Provide rigid support to extremities and body cavities containing vital organs • Crucial to locomotion and provide efficient levers and sites of attachment for muscle • Large reservoir of ions such as calcium, phosphorus, magnesium etc. Structure of Bone • Cortical bone (densely packed) Disorders lead to fractures of the long bones • Trabecular (cancellous) bone (spongy) Disorders lead to vertebral fractures

21. Metabolic Bone Disease II. Bone minerals • Hydroxyapatite • Amorphous calcium phosphate Dynamics of Bone • “Modeling”  formation of macroscopic skeleton • “remodeling”  process occurring at bone surface before and after adult development Required to maintain the structure and integrity of bone Abnormality of “remodeling” are responsible for metabolic bone disease

22. Bone Remodeling Cycle

23. Regulation of Bone Mass

24. Attainment of Maximal Bone Mass

25. Loss of Bone Mass by Age

26. Model of Risk Factors Age-related factors Initial bone mass low bone mass Menopause BONE LOSS FRACTURES Sporadic factors Propensity to fall trauma Decreased resistance to trauma

27. ENDOCRINEPATHOPHYSIOLOGY Osteoporosis

28. Osteoporosis A generalized bone disorder. Characterized by a decrease in the quantity of bone but no change in its quality Classification • Primary • Idiopathic juvenile osteoporosis • Idiopathic osteoporosis in young adults • Involutional osteoporosis Type I “postmenopausal” osteoporosis Type II “senile” osteoporosis Type III osteoporosis associated with increased parathyroid function • Secondary • Hypercortisolism • Hypogonadism • Hyperthyroidism • Diabetes mellitus • Malabsorption syndrome • Connective tissue disease etc.

29. Risk Factors and complicating Factors in osteoporosis • Nutritional deficiency • calcium, phosphate • vitamin D, vitamin C protein • Smoking • Renal disease • Gastrointestinal disease • Genetic factors • non-black race • Northern European stock • small bone mass • Hypogonadism • Drugs • alcohol • corticosteroids • thyroid hormones • caffeine

30. Characterization of Involutional Osteoporosis Type I Type II Age (yr) 51-75 >70 Sex ratio (F:M) 6:1 2:1 Type of bone trabecular trabecular and cortical Rate of bone lossaccelerated not accelerated Fracture site vertebrae (crush) vertebrae and hip and distal radius Parathyroid function decreased increased Calcium absorption decreased decreased 25(OH)D  1,25(OH)2D3secondary primary Conversion decrease decrease

31. Pathogenesis of Type I osteoporosis Other factors Estrogen deficiency Bone loss Decreased PTH secretion Decreased 1,25(OH)2D3 formation Decreased calcium absorption

32. Pathogenesis of Type II osteoporosis Aging Decreased Bone function (cellular level) Decreased 1 OH-ase activity Decreased Ca absorption Secondary Hyperparathyroidism BONE LOSS

33. ENDOCRINEPATHOPHYSIOLOGY Osteomalatia and Rickets

34. Osteomalacia Etiology • Vitamin D deficiency • inadequate sunlight w/o supplementation • gastrointestinal disease • impaired synthesis of 1,25(OH) D3 by the kidney • target cell resistance to vitamin D3 • Phosphate deficiency • dietary • impaired renal tubular reabsorption • Primary mineralization defects • osteopetrosis • fibrogenesis imperfecta ossis • Systemic acidosis • chronic renal failure • distal renal tubular acidosis • Drug induced osteomalacia • excessive fluoride • Toxin induced osteomalacia • Aluminum, lead, cadmium etc.

35. Osteomalacia Laboratory Findings • Depend upon the stages of disease • Low level of 25(OH) D3 • Increased serum level of alkaline phosphatase • Increased PTH Differetial Diagnosis • Hypophosphatemia • normal Ca, PTH, 25(OH)D3 • Hypoparathyroidism • hypophosphatemia, low level of PTH • Tumor

36. Osteomalacia

37. Osteomalacia

38. Milk-Alkaline Syndrome

39. ENDOCRINE PATHOPHYSIOLOGY Disturbances in Sexual Function

40. Sexual Differentiation Gametes Gametes Zygote X+22 + X+22 X+22 + Y+22 Gonad Bipotential Bipotential XX XY Normal ovary Normal testes Sertoli cells Leyding cells Testosterone DHT Mullerian duct inhibitory factor Phenotypic sex Female sex differentiation External genitalia Male sex differentiation

41. Disorders of Gonadal Differentation • Seminiferous tubule dysgenesis (Klinefelter`s syndrome) • Gonadal dysgenesis and its variants (Turner`s syndrome) • Complete and incomplete form to XX and XY gonadal dysgenesis • True hermaphroditism

42. Seminiferous Tubule Dysgenesis(Klinefelter`s syndrome) Commonest forms pf primary hypogonadism and infertility in male Karyotype: XXY (XY/XXY; XXYY; XXXY and XXXYY) (XXXXY, XX male H-Y antigen positive) Clinical symptoms: • Gynecomastia • Diminished facial and body hair • Small phallus, poor muscular development • Eunochoid tall body habits • Increased incidence of: • mild diabetes mellitus • varicose veins • chronic pulmonary disease • carcinoma of breast • Progressive testicular lesion

43. Seminiferous Tubule Dysgenesis(Klinefelter`s syndrome)

44. Syndrome of Gonadal Dysgenesis(Turner`s syndrome) • Karyotype: XO (XY/XO mosaicism; XO/XY; XO/XXY; XO/XY/XYY) • Clinical features: • Sexual infantilism • Short stature • Lymphedema of the extremities • Typical face • Short neck, shieldlike chest • Coarctation of the aorta • Hypertension, renal abnormalities • Obesity, diabetes mellitus, Hashimoto`s thyroiditis, rheumatoid arthiritis etc.

45. Syndrome of Gonadal Dysgenesis(Turner`s syndrome)

46. Pseudohermaphroidism Female Normal ovaries, extragonadal hypersecretion of androgen Masculinization, clitoral hypertrophy Male Testes, genital ducts or extragenitalias are not completely masculinized Deficient testosterone secretion • failure of testicular differentiation • failure of secretion of testosterone or Mullerian duct inhibitory factors • failure of target tissue response to testosterone or DHT • Failure of conversion of testosterone to DHT

47. True Hermaphroditism Clinical features • uterus  breast development • ovotestis  menses (50 %) • karyotype 60 % XX 20 % XY 20 % XX/XY Cause of true hermaphroditism • sexchromatin mosaicism or chimerism • Y to autosome; Y to X chromosome translocation or exchange • autosomal mutant gene