BONE MINERAL METABOLISM

1. BONE MINERAL METABOLISM
GUIDE – Dr. Yogendra Jamra
Candidate – Dr.Shivshankar

2. Calcium Metabolism
Percentage distribution of total body calcium
1 ECF - 0.1%
2 Intracellular – 1%
3 Bones – Rest (Serve as Reservoirs)

4. Calculation of Corrected Calcium
• Because calcium binds to albumin and
only the unbound calcium is biologically
active ,the serum level must be adjusted
as follows
Corrected Ca2+ = [4.5 - Plasma Albumin]*0.8
+ measured S. Calcium

5. Factors affecting Calcium
Concentration
1) Changes in Plasma Protein concentration
- Increased [protein] Increased total [Ca2+]
2) Changes in Anion concentration
- Increased [anion] Increased fraction of Ca2+
that is complexed Decreased ionized [Ca2+]
3)Acid base abnormality

7. Blood calcium is tightly regulated by:
1) Principle organ systems:
Intestine
Bone
 Kidney
2) Hormones:
Parathyroid hormone (PTH)
Vitamin D
Calcitonin

8. Role Of PTH in Calcium Homeostasis

9. HYPERCALCEMIA
• Normal Serum calcium: 8.5 mg/dl – 10.5 mg/dl
• Serum Calcium > 10.5 mg/dl (>2.5 mmol/l)
• Ionized Calcium > 5.3 mg/dl (1.3 mmol/L)
• Mild: Total Ca 10.5-11.9 mg/dl (2.5-3 mmol/l)
Ionised 5.6-8 mg/dl (1.4-2 mmol/l)
• Moderate: Total Ca 12-13.9 mg/dl (3-3.5mmol/l)
Ionised Ca 8-10 mg/dl (2-2.5 mmol/l)
• Severe: Total Ca 14-16 mg/dl (3.5-4 mmol/l)
Ionised Ca 10-12 mg/dl (2.5-3 mmol/l)

10. Clinical Manifestations of
Hypercalcemia
Renal
 Nephrolithiasis
 Nephrogenic diabetes insipidus
 Dehydration
 Nephrocalcinosis
Skeleton
 Bone pain
 Arthritis
 Osteoporosis
 Osteitis fibrosa cystica in hyperparathyroidism (subperiosteal
resorption, bone cysts)

11. Gastrointestinal
 Nausea, vomiting
 Anorexia, weight loss
 Constipation
 Abdominal pain
 Pancreatitis
 Peptic ulcer disease
Cardiovascular
 Hypertension
 Shortened QT interval on ECG
 Cardiac arrhythmias
 Vascular calcification

12. Neuromuscular
Impaired concentration and memory
Confusion, stupor, coma
Lethargy and fatigue
Muscle weakness
Other
Itching
Keratitis, conjunctivitis
Corneal calcification (band keratopathy)

13. Etiology
I. Parathyroid Related
A. Primary Hyperparathyroidism
B. Lithium Therapy
C. Familial Hypocalciuric Hypercalcemia
II. Malignancy related
A. Solid Tumor (Breast, Lung, Kidney)
B. Hematologic malignancy (Lymphoma, Leukemia)
III. Vitamin D Related
A. Vitamin D Intoxication
B. Increased 1,25(OH)2D (Sarcoidosis)

14. I. Associated with high bone turnover
A. Hyperthyroidism
B. Immobilization
C. Thiazides
D. Vitamin A Intoxication
E. Fat Necrosis
II. Associated with Renal failure
A. Severe Secondary Hyperparathyroidism
B. Aluminium Intoxication
C. Milk-Alkali syndrome

15. APPROACH TO
HYPERCALCEMIA

16. Serum Calcium must be corrected for serum
Albumin before labelling it as hypercalcemia.
Among all cases of hypercalcemia, Primary
Hyperparathyroidism and Malignancy are the
most common causes accounting for more
than 90% cases.
Therefore diagnostic approach to
hypercalcemia typically involves
distinguishing between the two.

19. Treatment according to
Calcium Levels
Calcium level <12 mg/dl
 Oral Hydration
 High salt Diet
 Avoid medications that cause hypercalcemia
 No treatment at all may be a option

20. Calcium level > 12mg/dl
(Severe or Symptomatic)
 Normal Saline: Initially 200-300ml/hr until patient is
euvolemic, then adjust to maintain urine output of 100-
150 ml/hr
 Loop diuretics only after volume repletion in patients
with CHF & CKD.
 Calcitonin, 4 IU/kg – subcutaneously or intramuscularly;
repeat every 6-12 hours only if patient is responsive
 IV Bisphosphonates
 Zoledronic acid: 4 mg over 15 minutes; 8 mg if
second dose is required (not FDA approved)
 Pamidronate: Given over 2-24 hours, either as 60mg
(Ca level, 12-13.5mg/dl) or 90 mg (Ca level,
>13.5mg/dl)

21. Indications For Hemodialysis
 Neurologic Symptoms
Calcium level > 18mg dl
Acute or Chronic Kidney Disease
Congestive Heart Failure

22. Primary Hyperparathyroidism
F:M 3:1
 Annual Incidence is 0.2% in patients >60
Includes
a. Adenoma
b. MEN
c. Carcinoma
Presentation:
– Asymptomatic hypercalcemia (>50%)
– Renal stones (20%)
– Decreased bone density
– Symptoms of hypercalcemia (<5%)

23. Images show Subperiosteal Bone Resorption
along the radial aspects of the middle phalanges.
Bone Manifestations in Hyperparathyroidism

24. Image demonstrates subperiosteal resorption
that has resulted in severe tuftal resorption.

25. Osteitis Fibrosa Cystica
(Brown Tumour)
 Manifestated in hyperparathyroidism
 Represents a reparative cellular process
rather than a neoplastic process.
Histologically identical to giant cell tumour so
it needs to be differentiated.
 Commonly seen with Secondary
Hyperparathyroidism.

26. Pathology
In CKD lower serum Ca level lead to a rise in PTH
secretion resulting in mobilisation of skeletal
calcium through rapid osteoclastic turnover of
bone to maintain normal serum calcium levels.
In localised regions where bone loss is
particularly rapid normal marrow contents may
be replaced by haemorrhage, and reparative
granulation tissue, with active, vascular,
proliferating fibrous tissue, resulting in a brown
tumour.
Haemosiderin imparts the brown colour

28. Asymptomatic Primary
Hyperparathyroidism
 Most prevalent form of disease
 Defined as biochemically confirmed
hyperparathyroidism with the absence of
signs and symptoms typically associated with
more severe hyperparathyroidism such as
features of renal or bone disease.

29. Guidelines for surgery in Asymptomatic
Primary hyperparathyroidism
 Serum Calcium >1mg/dl
(above Normal)
 24hr Urinary Calcium No Indication
Creatinine Clearance If <60ml/min
 Bone Density T score <2.5 at any
of 3 sites (Spine,
distal radius, hip)
Age <50 years

30. FAMILIAL HYPOCALCIURIC
HYPERCALCEMIA
 Inherited as Autosomal Dominant Trait
Caused by inactivating Mutation in CaSR leading
to inappropriate secretion of PTH and excessive
reabsorption of Ca in DCT
Patients with primary Hyperparathyroidism have
<99% Ca reabsorption whereas most patients
with FHH have > 99% absorption
Differentiating with Primary hyperparathyroidism
is important as there is no role of surgery in FHH

31.  Calcium/creatinine clearance ratio of <0.01 is
suggestive of FHH.
Sequence Analysis of CaSR is commonly
performed for Definitive Diagnosis.
Generally no treatment is required.

32. Secondary Hyperparathyroidism due
to Chronic Renal Failure
 Impaired production of 1,25(OH)2D is now thought to be the
principal factor that causes Calcium Deficiency, Secondary
Hyperparathyroidism and bone disease.
 Resistance to PTH also contributes to Hypocalcemia.
 Recent findings have indicated that increase in FGF23
production by osteocyte occurs in CKD.
 FGF23 is potent inhibitor of renal-1alpha hydroxylase so FGF23
dependent reduction in 1,25(OH)2D is important stimulus for
development of secondary hyperparathyroidism.

33. Management of Secondary
Hyperparathyroidism due to CKD
 Restriction of phosphate in diet.
 Avoidance of Aluminium containing phosphate
binding antacids to prevent problem of aluminium
intoxication.
 Adequate Calcium intake by mouth usually 1-2g/day
and supplementation with 0.25-1mcg/d calcitriol.
 It is usually recommended to maintain PTH levels
between 150-300pg/ml as high PTH may lead to
progression to Tertiary Hyperparathyroidism and low
PTH levels may lead to Adynamic Bone disease.

34. Tertiary Hyperparathyroidism
 Tertiary hyperparathyroidism is a state of excessive
secretion of PTH after a long period of secondary
hyperparathyroidism and resulting in a high blood
calcium level.
 It reflects development of autonomous
(unregulated) parathyroid function following a period
of persistent parathyroid stimulation.
• The basis of treatment is still prevention in
chronic kidney failure starting medication and dietary
restrictions long before dialysis treatment is initiated.
• The treatment of choice is surgical removal of three
and one half parathyroid glands.

35. HYPOCALCEMIA

36. DEFINITION
• Normal Serum calcium: 8.5 mg/dl –
10.5 mg/dl
• A decrease in the calcium levels
below 8.5mg/dl is termed
hypocalcemia

37. LOW PARATHYROID HORMONE LEVELS
1. Parathyroid agenesis
a) Isolated
b)DiGeorge Syndrome
2. Parathyroid destruction
a) Surgical
b)Radiation
c) Infiltration by metastases or systemic diseases
d)Autoimmune
3. Reduced Parathyroid function
a) Hypomagnesemia
b)Activating CaSR mutations

38. HIGH PARATHYROID HORMONE LEVELS ( Secondary Hyperparathyroidism)
1. Vitamin D deficiency or impaired 1,25(OH)2*D production/action
a) Nutritional vitamin D deficiency
b) Renal insufficiency with impaired 1,25(OH)2*D
production
c) Vitamin D resistance
2. Parathyroid hormone resistance syndromes
a) PTH receptor mutations
b) Pseudohypoparathyroidism
3. Drugs
a) Calcium chelators
b) Inhibitors of bone resorption
c) Altered vitamin D metabolism (Phenytoin, Ketoconazole)
4. Miscellaneous
a) Acute Pancreatitis
b) Acute Rhabdomyolysis
c) Hungry bone syndrome

39. Hypocalcemia: Clinical signs
Paresthesias
Tetany (carpopedal spasm)
Trousseau’s, Chvostek’s signs
Seizures
Laryngospasm
Arrythmia
Cataracts, Basal Ganglia Calcification

40. Trousseau’s sign
Carpal Spasm may be induced by inflation of BP cuff to
20 mm Hg above the patient’s Systolic BP for 3 minutes.

41. Chvostek Sign
Twitching of circumoral muscles in response to gentle
tapping of the facial nerve just anterior to the ear.

42. Differential Diagnosis of Hypocalcemia

43. Treatment
• Acute, symptomatic hypocalcemia:
– Calcium gluconate, 90 mg or 2.2 mmol IV, diluted in
50 mL of 5% dextrose or 0.9% sodium chloride,
given IV over 5 min
• Continuing hypocalcemia : constant IV infusion
(10 ampules of ca or 900 mg of ca in 1 L of 5%
dextrose or 0.9% sodium chloride administered
over 24 h)

44. Treatment
• Hypomagnesemia: magnesium supplementation
• Chronic hypocalcemia due to
hypoparathyroidism:
– calcium supplements (1000–1500 mg/d elemental
calcium in divided doses) AND
– either vitamin D2 or D3 (25,000–100,000 U daily) OR
calcitriol [1,25(OH)2D, 0.25–2 g/d]

45. Treatment
• Vitamin D deficiency - vitamin D supplementation
• Nutritional vitamin D deficiency:
– low doses of vitamin D (50,000 U, 2–3 times per week
for several months)
• Vitamin D deficiency due to malabsorption:
– higher doses (100,000 U/d or more)
• Goal is to bring serum calcium into the low
normal range and to avoid hypercalciuria, which
may lead to nephrolithiasis

47. VITAMIN D
• major steroid hormone involved in mineral ion
homeostasis regulation.

49. • The 25-hydroxyvitamin D-1α-hydroxylase -
expressed in the proximal convoluted tubule
cells of the kidney.
• PTH and hypophosphatemia are the major
inducers
• Calcium, FGF23, and the enzyme’s product
1,25(OH)2D, repress it

50. • 1α-hydroxylase is produced by macrophages
associated with granulomas and lymphomas.
• Activity of the enzyme is induced by interferon
γ and TNF-α but is not regulated by calcium or
1,25(OH)2D;
• Hypercalcemia,associated with elevated levels
of 1,25(OH)2D, may be observed.

51. CAUSES OF IMPAIRED VITAMIN D ACTION

52. Clinical manifestations
• Mild to moderate vitamin D deficiency is
asymptomatic
• Long-standing vitamin D deficiency results in
-Hypocalcemia
-Secondary hyperparathyroidism,
-Impaired mineralization of the skeleton
-Proximal myopathy

53. • RICKETS - In children, before epiphyseal
fusion, vitamin D deficiency results in growth
retardation associated with an expansion of
the growth plate.
• OSTEOMALACIA - The hypocalcemia and
hypophosphatemia that accompany vitamin D
deficiency result in impaired mineralization of
bone matrix proteins.

54. DIAGNOSIS
• Although the normal ranges vary, levels of
25(OH)D <37 nmol/L (<15 ng/mL) are
associated with increasing PTH levels and
lower bone density.

55. • Prolonged vitamin D deficiency results in
hypocalcemia .
• PTH is a major stimulus for the renal 25(OH)D 1α-
hydroxylase, there is increased synthesis of the
active hormone, 1,25(OH)2D.
• Paradoxically, levels of this hormone are often
normal in severe vitamin D deficiency.
• Therefore, measurements of 1,25(OH)2D are not
accurate reflections of vitamin D stores and
should not be used to diagnose vitamin D
deficiency in patients with normal renal function.

56. TREATMENT
• Recommended daily intake –
600 IU from 1 to 70 years of age, and
800 IU for those over 70.
• Toxicity usually is observed only in patients
taking doses in the range of 40,000 IU daily.

57. • Intact activation of vitamin D
– initially (50,000 IU weekly for 3–12 weeks),
followed by maintenance therapy (800 IU daily).
• In patients in whom 1α-hydroxylation is
impaired
– 1,25(OH)2D3 (calcitriol,0.25–0.5 μg/d) and
– 1α-hydroxyvitamin D2 (2.5–5 μg/d).

58. • Pharmacologic doses may be required for
maintenance therapy in patients who are
taking medications, such as barbiturates or
phenytoin,(accelerate metabolism of or cause
resistance to 1,25(OH)2D).
• Calcium supplementation should include 1.5–
2 g/d of elemental calcium.
• 24-h urinary calcium excretion should be in
the range of 100–250 mg/24 h.