Calcium and Vitamin D

Question 1

Calcium Homeostasis

Answer 1

• Goal is to have constant level of ionized calcium is extracellular fluid while still providing enough calcium to cells, bones, and for renal excretion.
• Hormones involved in calcium homeostasus are able to act on the gut, bone, and renal tubules.
  
  • PTH and 1,25(OH)₂D

Question 2

Secretion of PTH

Answer 2

• Secreted by parathryoid glands
• PTH is under tight control of serum calcium. In order to release PTH, parathyroid cells use calcium sensing receptors (CaSR) to determine Ca²⁺ levels in the body. In parathryoid glands activation of CaSR leads to inhibition of PTH secretion.

Question 3

Biological Effects of PTH

Answer 3

• Regulates serum ionized calcium levels by working on 3 main targets.

1. Bone - increase bone reabsorption to release calcium (also results in release on phosphate. It is important that phosphate secretion increases at kindey, because phosphate can also stimulate PTH via increase RANKL and decreased OPG secretion by osteoblasts.
2. Intestinal muscosa - indirect. Results from increase production of active vitamin D metabolite
3. Kidney - direct effect on tubular reabosorption of calcium, phosphate, and bicarbonate. See increase in calcium reabsorption and decrease in phosphate reabsorption.

Question 4

Calcitonin

Answer 4

• Main function is to inhibit osteoclast mediated bone resorption. Also inhibits calcium uptake/reabsorption in the kidneys and intestine.
• Secreted by parafollicular C cells of the thyroid - use CaSR to sense changes in calcium levels in the body (release in response to increasing calcium).
• Calcitonin does not likely play an essential role in homeostasis.

Question 5

Function of Vitamin D

Answer 5

• To be biologically active, vitamin D must be metabolized further. The live is the main organ capable of metabolizing vitamin D to 25(OH)D. The kidney then converts it to 1,25(OH)₂D
• Vitamin D functions in the regulation of calcium and phosphate homeostasis in conjuction with PTH.
• Intestines - regulates calcium transport through intestinal epithelium (increase Ca²⁺ and phosphate absorption).
• Bone - Stimuates osteoblasts to secrete RANKL, thereby activating osteoclasts to resorb bone to raise serum calcium levels.
• Kidney - Plays role in stimulating calcium and phosphate reabsorption.

Question 6

Function of Bone

Answer 6

• Provides rigit support to extremities and body cavities containing vital organs
• Locomotion - provides levers and sites of attachment for muscles
• Provide large reservoir of ions critical for life
• House hematopoietic elements

Question 7

1. RANKL
2. OPG

Answer 7

1. RANKL - Expressed on osteoblasts. Binding of RANKL to RANK stimualtes osteoclasts formation, differentiation, and activation
2. OPG - Release by osteoblasts. Inhibits RANK by binding RANKL, thereby preventing its interaction with RANK.

Question 8

Osteoporosis

Primary and Secondary

Answer 8

• Condition of low bone mass and microarchitectural disruption that results in fractures with minimal trauma.
• Primary osteoporsis - reduced bone mass and fractures in postmenopausal women or in older men and women due to age-related factors.
• A bone loss resulting from specific clinical disorders. EX. thryrotoxicosis or hyperadenocorticism.

Question 9

Fragility-related fractures

Answer 9

• Due to trauma equal to or less than a fall from standing position.
• Common sites - vertebral bodies, distal forearm, and proximal femur
• Vertebral compressur factures are the most common.

Question 10

Risk Factors for Osteoporosis

Answer 10

• Hereditary factors resulting in low peak bone mass
• Circulating gonadal steriods - estrogen acts on multiple cells via estrogen receptors. Thus, decreased estrogen increases bone resorption caused by increased osteoclast. Bone cells dont have receptors for testosterone, but it has an affect indirectly through local aromatization to estrogen.
• Physical activity - activity impses strain on skeletal system, resulting in microtrauma and appropriate bone remodelling and strengthening.
• Nutrient intake - insufficient calcium intake, vitamin D, deficiency (leads to secondary hyerparthryodisims and accerlated bone loss).
• Smoking - have direct toxic effects on osteoblasts; alters estrogen metabolism leadig to ealier menopause.
• Certain illness are associated with osteoporosis
  
  • GI diseases that result in impaired absorption of bone minerals and vitamin D (i.e., celiacs and crohns)
  • Hypogondal states
  • Endocrine disorders - cushings, hyperparathryoidism
• Certain medications are associated with osteoporosis
  
  • Glucocoticoids
  • Aromatase inhibitors
  • Thyroid hormones

Question 11

Bone loss and estrogen deficiency

Answer 11

• Estrogen is important for bone mass, and low levels are associated with bone loss with estrogen deficiency OPG secretion is low. This allows strong response of osteoclast precursors with RANKL and increases bone resorption. Furthermore, increased bone resorption will result in incease extracellular calcium -> decreased PTH -> increase calciuria, decreased renal production of 1,25(OH)₂D and decrease intestinal calcium.
• Thus, you see a net loss of calcium

Question 12

Bone loss and age

Answer 12

• Deficits in renal and intestinal function impact body calcium levels. With advancing age we see:
  
  • Decreased efficiency in vitamin D production by the skin
  • Decreased ability of the kidney to convert vitamin D to active form
    
    • Intestinal absorption of calcium becomes less efficient
    • Hypersecretion of PTH resulting in increase bone remodelling and accelerated bone loss.

Question 13

Diagnosis of Osteoporosis

Answer 13

• Patient sustained fragility fracture
• Bone densitometry - all women >65, all men >70, and men and women with increase risk factors for fractures should be screened with bone densitometry to osteoporosis.
  
  • BMD more than 2.5SD below the age-matched normal reference population indicate osteoporosis. Values between -1.0 and -2.5SD are categorized as low bone density.

Question 14

Treatment of osteoporosis

Answer 14

• Medications are used to treat or prevent act either by decreasing rate of bone resorption or by increasing bone formation.
• Antiresorptive agents:
  
  • Calcium
  • Vitamin D and calcitriol
  • Estrogen
  • Selective estrogen receptor modulators
  • Calcitonin
  • Bisphosphonates
  • RANKL inhibition
• Bone-forming agents:
  
  • Fluoride
  • Androgens
  • Parathyroid hormone
  • Strontium ranelate

Question 15

Antiresporitve agents osteoporosis

Answer 15

• Calcium supplementation of 1000-2000mg/day in doses of ≤ 600mg to maximize absorption is recommended.
• Vitamin D and Calcitriol - Vitamin D supplementation in individuals with marginal or deficiency vitamin D status improves intestinal calcium absorption, suppresses PTH and bone remodeling, increases bone mass, and reduced fracture risk. Used of vitamin D metabolties, such as calcitriol, may increase ability to interact with parathyroid cells and suppress PTH secretion directly.
• Estrogen - Increases BMD, however, protective effects dissipates within a few years of cessation. With balance with increase risk of breast cancer, CVD, and VTE (not considered as a first line therapy because of risks).
• Oral bisphosphonates - first -line therapy. Binds avidly to hydroxyapatite crystals, particulary at sites of active remodeling. They interfere with protein prenylation in osteoclast, impairing osteoclast bone resorption and enhancing osteoclast apoptosis. Reduce vertebral fracture by 50-60% and also reduce risk of non-vertebral fractures.
  
  • Contraindications - patients with esophageal disorders, patients who are unable to follow dosing requirements (stay upright for 30-60mins), patients with eGFR<30
• RANKL inhibition - inhibits osteoclast formation, decreases bone resorption, increases BMD, and reduced risk of fracture. Binds to RANKL to block the binding of RANKL to RANK reducing the function and survival of osteoclasts which results in decrease bone resorption and increase bone density. Not considered an initial therapy, can be used in those where oral bisphosphonates are contraindicated.
  *

Question 16

Bone forming agents

Answer 16

• Parathyroid hormone - generally fractures, skeletal deformity, and bone parin are manifestations of high PTH. Howeverem administration of PTH does improve BMD and reduces fracture risk. Effects of PTH depend on its concentration. If PTH levels are constantly elevated you see reduced BMD; but, if levels are intermittently elevated you see increase BMD. Treatment is limited to 18-24 months.
• Androgen - testosterone increases bone mass in hypogonadal men and improve bone mass in osteoporotic women. Therapy is oftem limited by virilizing side effects.

Question 17

Osteomalacia and Rickets

Answer 17

• Osteomalacia and rickets are caused by abnormal mineralization of bone and cartilage. Normal bone growth and mineralization require adequate calcium and phosphate, the two major constituents of the crystalline component of bone. Deficient mineralization can result in rickets and/or osteomalacia.
• Abnormal mineralization in growing bone affects the transformation of cartilage into bone at the zone of provisional calcification - results in enormous profusion of disorganized, nonmineralized, degenerating cartilage appears in region, leading to widening of the epiphyseal plate. Growth is retarded by the failure to make new bones.
• Osteomalacia - refers to impaired mineralization of the bone matrix.
• Rickets - refers to deficient mineralization at the growth plate, as well as architectural disruption of this structure.

Question 18

Pathogenesis of Osteomalacia and Rickets

Answer 18

• Hypophosphatemia, due to vitamin D deficiency and secondary hyperparathyroidism or primary renal tubular defects with phosphate wasting, is the most common cause of osteomalacia. Vitamin D ensures that calcium and phosphate concentrations are adequate for mineralization.
• May also develop with adequate levels if bone matrix cannot undergo normal mineralization as a reult on enzyme deficiencies.

Question 19

Signs and Symptoms Rickets

Answer 19

• Child may be apathetic, listless, weal, hypotonic, and growing poorly. May see soft, misshapen head, with wideded sutures and frontal bossing. Teeth eruption may be delayed, and teeth that do grow may be poorly mineralized.
• Rachitic Rosry on Thorax - enlargment and cupping of costochindral junctions.
• Harrisons groove - tug of diaphragm against softened lower ribs may produce indentation at point of insertion
• Muscle hypotonia can result in potbelly and waddling gait.
• Limbs may bow and joints may swell
• Pathologic fractures

Question 20

Signs and Symptoms of osteomalacia

Answer 20

• Signs are subtle and cannot be relied on to make diagnosis
• Bone pain and proximal muscle weakness
• Difficulty climbing stairs or rising from chairs
• History of fractures
• Difficulty walking and waddling gait

Question 21

Laboratory Findings Osteomalacia and Rickets

Answer 21

• Vitamin D deficiency reults in: decrease intestinal absorption of calcium and phosphate; increase urinary phosphate; decrease urinary calcium, increase bone resorption
• Results in:
  
  • Low 25(OH)D
  • Low-normal serum calcium
  • Low serum phosphate
  • Elevated serum alkaline phosphatase
  • Increase PTH
  • Decrease urinary calcium (the hypocalciumia stimulates PTH secretion, which increases calcium reabsorption)
  • Increased urinary phosphate

Question 22

How can vitamin D deficiency or resistance result in osteomalacia

Answer 22

• Impaired availability of vitamin D, secondary to inadequate dietary vitamin D, fat malabsorptive disorders, and/or lack of photoisomerization
• Impaired ability to convert it to its active form
• End-organ insensitivity to vitamin D metabolites (hereditary vitamin D-resistant rickets)

Question 23

Bone biopsy Osteomalacia

Answer 23

• Transcortical bone biopsy is most definitive means of making a diagnosis of osteomalacia, but it is rarely done. We see
  
  • Prolonged mineralization lag time
  • Widened osteoid seams
  • Increased osteoid volume

Question 24

Radiographic featues osteomalacia

Answer 24

• Radiographic abnormalities are not as stricking as those seen in rickets. May find
  
  • Reduced BMD
  • Changes in vertebral bodies - Inadequate mineralization of osteoid and loss of secondary trabeculae lead to a loss of radiologic distinctness of vertebral body trabeculae, making the radiograph appear of poor quality
  • Looser zones - pseudofactures, most often found along concave sie of femoral neck, pubic rami, ribs, calvicles, and lateral aspect on scapula.

Question 25

Treatment of osteomalacia

Answer 25

• Weakly administration of 50,000IU of vitamin D2 or D₃ for 6-8weeks followed by 800IU of D₃ afterwards.
• Calitriol and its analogs are not appropriate because patients likely require metabolites other than 1,25(OH)₂D and there is advantage if tissues are able to produce their own.
• Vitamin D therapy should be supplemented with calcium

Question 26

Function of Vertebral Colum

Answer 26

• Protection - encloses and protects spinal cord
• Support - carries the weight of the body above the pelvis
• Axis - forms the central axis of the body
• Movement and posture

Question 27

Structure of Vertebra

Answer 27

All vertebra share a basic common structure. They each consist of an anterior vertebral body and a posterior vertebral arch.

• Vertebral body - forms anterior part of each vertebra. They are the weight bearing component. Vertebra in lower portion of he column have larger bodies than those in the upper portion in order to better support the increased weight.
  
  • Superior and inferior aspects of the vertebral body are lined with hyaline cartilage.
  • Adjacent vertebral bodies are separated by fibrocartilaginous intervertebral discs.
• Vertebral Arch - forms lateral and posterior aspect of each vertebra. Together with the vertebral body the vertebral arch froms the vertebral foramen. The foramen of all vertebra line up to form the vertebral canal, which encloses the spinal cord.
  
  • The vertebral arches have several bony prominences, which act as attachment sites for muscles and ligaments.

Question 28

Anatomy of Vertebral Arch

Answer 28

Question 29

Types of vertebra

Answer 29

• Cervical - have three main distinguishing featues
  
  1. Bifid spinous process - spinous process bifurcates at distal end except for C₁ which does not have a spinous process and C₇ which has a longer spinous process and may not bifurcate.
  2. Transverse foramine - an opening in each transverse process, allows vertebral arteries travel to the brain.
  3. Trangular vertebral foramen
• Thoracic vertebra
  
  • Function to articulate with the ribs
  • Has 2 demi facets placced superior and inferiorly on each side which articulate with the heads of 2 different ribs.
  • Have costal facets for articulation with the shaft of a single rib on the transverse processes.
• Lumbar vertebra
  
  • Structurally specialized to support the weight of the torso. Lack transverse foramina, costal facets, or bifid spinous processes.
• Sacrun
  
  • collection of 5 fused vertebra
• Coccyx
  
  • Small bones that articulate at the end of the sacrum. Lacks vertebral arches and thus has no vertebral canal.