Week 2 - Bones, Calcium, and Obesity Flashcards
What is cortical bone?
Dense bone which is laid down in layers; cortical bone is found primarily in the long bones.
What is matrix? What does it consist of?
The unmineralized part of bone which provides the protein structure upon which mineralization occurs. It consists of organic and inorganic components in a roughly 1:1 ratio. The organic component is made of collagen (90%) and proteoglycans. The inorganic component consists of hydroxyapatite.
What do the organic and inorganic components of bone confer in terms of structural strength?
The organic component (collagen and proteoglycans) provide tensile strength.
The inorganic component (hydroxyapatite) provides rigidity and compressive strength.
What is MEN-1?
Multiple Endocrine Neoplasia - 1
Rare syndrome caused by mutations in the RET gene resulting in adenomata of several endocrine glands, the parathyroid glands being the most commonly affected.
What is an osteoclast?
Multinucleated bone marrow-derived bone cell which resorbs bone.
What cell likely controls calcium flux into and out of bones?
Osteocytes
What are three jobs of osteocytes?
- Control calcium flux into and out of bone.
- Sense mechanical strain and microfractures.
- Control osteoblasts through production of sclerostin.
What does sclerostin do?
Inhibits osteoblasts. It is secreted by osteocytes.
What is osteomalacia, and what does it cause problems with?
Osteomalacia is a condition found in adults in which excess amounts of uncalcified osteoid are present. This causes problem with proper bone formation.
What is Rickets?
Childhood osteomalacia characterized by bone deformities. Also a term referring to the results of any form of vitamin D deficiency.
What is osteopenia and how is it defined?
Decreased total amount of bone mineral content. The WHO defines osteopenia as bone mineral density (BMD) between -1 and -2.5 SD the young adult mean.
What is osteoporosis and how is it defined?
Decreased total amount of bone mineral content.
The WHO defines osteoporosis as BMD < -2.5 SD the young adult mean PLUS micro architectural deterioration in bone structure.
How is severe osteoporosis defined by the WHO?
BMD < -2.5 SD the young adult mean and micro architectural deterioration in bone structure. {Osteoporosis}
PLUS the presence of fragility fractures.
{Severe osteoporosis}
How is the ratio between unmineralized bone (osteoid) and mineralized bone changed in osteoporosis?
It is normal (unchanged). Osteoporosis and Osteopenia are results of total bone mineral content loss.
What is the periosteum?
A fibrous sheath of dense connective tissue covering bone. Mesenchymal cells in the periosteum can differentiate into osteoblasts.
What are pseudofracture and what is thought to cause them?
Radiolucent lines (aka Looser’s Lines) seen with osteomalacia. They are areas of reabsorbed bone along side penetrating arteries; it is thought that the mechanical pulsating force of the arteries nearby cause bone resorption.
What causes tetany?
Low serum calcium results in muscle spasms. {Different from tetanus which is caused by toxins from C. tetani}.
What is trabecular (spongy) bone?
Bone found in the axial skeleton consisting of an interconnected latticework of bone.
What is woven bone?
Bone laid down in a disorganized fashion; structurally weaker than lamellar bone. It is found in immature bone and fracture callus.
Woven bone is also seen in conditions such as Paget’s disease and Osteogenesis imperfecta.
What is Paget’s disease?
A chronic metabolic disease characterized by excessive bone destruction and repair. The “repaired” bone is abnormal and fragile (woven bone).
What is the rate of bone turnover per year?
50% in young children decreasing to 3% in adults.
When is the critical period for acquiring peak bone mass?
It starts in the early teenage years ending at age 25.
At what age is there an increase in resorption compared to formation of bone?
40
How long is the bone resorption phase? The bone formation phase?
Resorption: Less than 1 month.
Formation: ~3 months.
The _________ controls ________ development and function through cytokines CSF-1 and RANKL.
Osteoblast, Osteoclast
What triggers the resorption-formation cycle?
Microfractures
Osteocytes signal osteoblast activation by decreasing the cytokine?
Sclerostin
How do gonadal steroids and calcitonin increase relative bone formation?
They inhibit osteoclast activation leading to the prevention of resorption.
What does PTH do in physiological amounts? In excess?
In physiological amounts PTH promotes bone formation and stimulates osteoblasts. In excess it results in excess resorption and bone loss.
What does excess thyroxine do?
Increases the turnover and resorption of bone.
What cell(s) do PTH, Calcitriol, Thyroxine, Gonadal Steroids, and Calcitonin act on?
Osteoblasts
Where are osteoblast precursor cells found?
In the bone mesenchyme and the periosteum.
What two things are required for bone formation?
- Vitamin D (calcium absorption).
- Alkaline Phosphatase (secreted by osteoblasts).
What two treatments can be used to treat osteoporosis?
- Monoclonal antibodies to inhibit RANKL.
- Recombinant osteoprotegerin to inhibit bone resorption.
Which cells make RANKL?
Osteoblasts and Marrow Stromal cells.
How can cancer result in bone loss?
Cancer cells sometimes make PTH-RP and other substances, like RANKL, that activate osteoclasts and stimulate bone resorption.
How much calcium is typically bound to serum proteins. What protein is it mainly bound to?
40%, Albumin
What two factors affect the severity of hypercalcemia symptoms?
Both the degree and rate of the increase.
What is nephrocalcinosis?
Deposition of calcium in the renal parenchyma.
What is the major symptom of hypercalcemia to be concerned with?
Arrhythmias - major mortality risk.
What are the two major causes of hypercalcemia?
- Hyperparathyroidism: PTH excess from autonomous benign adenomas.
- Malignant Disease: Increased bone resorption predominantly due to tumor release of PTH-RP. [Commonest cancers = metastatic breast and multiple myeloma]
What are the three commonest causes of hypercalcemia?
- Hyperparathyroidism.
- Malignant Disease.
- Sarcoidosis
Which cause of hypercalcemia is most common in outpatients? Which is most common within inpatient populations?
Hyperparathyroidism
Malignant Disease
Hyperparathyroidism and Malignancy are the cause of 90% of hypercalcemic cases. What is the best way to differentiate between the two.
In hyperparathyroidism serum PTH will be elevated. In malignancy serum PTH will be very low. This is because tumour cells produce PTH-RP which, though it causes to same effects as PTH, does not show up in our testing for endogenous PTH. The PTH-RP suppresses endogenous PTH production.
How is acute hypercalcemia treated?
- Hydration with normal saline to rehydrate and facilitate calcium excretion via the kidneys and urine.
- Bisphosphonates to inhibit bone resorption.
- If very severe furosemide and dialysis.
What is furosemide?
A diuretic that causes renal calcium excretion.
How is chronic hypercalcemia treated?
- Oral bisphosphonates to protect from progressive calcium loss from bones.
- Calcimimetics which activate the calcium receptor, reducing PTH levels.
What causes the symptoms of hypocalcemia?
Hypersensitivity of neuromuscular function. Nerve impulses at lower degrees of depolarization.
What are the initial symptoms of hypocalcemia?
Numbness and tingling (usually around the mouth, and in the fingers and feet). With increasing severity muscle spasms (tetany) may start.
What is Chvostek’s sign?
A twitching of the facial muscles caused by a tap over the facial nerve where it crosses the zygomatic arch. It is used to diagnose hypocalcemia.
What is Trousseau’s sign?
A carpal muscle spasm caused by obstruction to blood flow in the arm by a blood pressure cuff (kept above systolic pressure for at least two minutes). It is used to diagnose hypocalcemia.
Name three ways that nerve excitability may be increased.
Hypocalcemia, Hyperkalemia, and Alkalosis.
What are the four main causes of hypocalcemia?
- Hypoparathyroidism (after thyroidectomy - due to transient ischemia from surgery).
- Inadequate Vitamin D (gut malabsorption).
- Chronic Renal Failure (hyperphosphatemia leads to impaired formation of calcitriol).
- Hypomagnesemia (dietary deficiency or alcoholism).
What is required for PTH to be released?
Magnesium
What is the incidence of transient and permanent hypocalcemia due to thyroidectomy?
10% transient and < 1% permanent.
How is acute hypocalcemia treated?
IV Calcium
How is chronic hypocalcemia treated?
Calcium and Calcitriol supplements.
Phosphorus absorption is directly proportional to?
Dietary intake.
What stimulates the active transport of 20% - 40% of phosphorus?
Vitamin D3
What percentage of phosphorus is stored in bone?
85%
What is one of the only ways to become phosphorus-deficient through diet?
Chronic and extreme alcoholism.
When is hyperphosphatemia of clinical importance?
In situations of chronic renal failure high levels of phosphorus inhibit Vitamin D production. The high levels of calcium and phosphorus in the blood can precipitate as crystals in the soft tissues.
When does hypophosphatemia commonly occur?
Chronic alcoholism, starvation, diabetic ketoacidosis, and gut malabsorption.
Symptoms are rare and only present in extreme deficiencies.
What is magnesium used for?
It is an important cofactor in various intracellular enzymes and may be required for PTH release and action.
Hypercalcemia causes many symptoms, some of these can be linked to the fact that in a hypercalcemic state neurons?
Become more hyperpolarized making it more difficult for them to fire.
What is multiple myeloma?
Cancer of the plasma B cells.
How does sarcoidosis lead to hypercalcemia?
Increased 1-alpha hydroxylation of vitamin B2 by granulomas results in excess calcitriol. This in turn increases absorption of calcium from the gut.
Too little ______ or too much ______ results in hypocalcemia.
Magnesium; Impaired PTH secretion.
Phosphate; Inhibits 1-alpha hydroxylation of vitamin B2.
What is the prevalence of primary hyperparathyroidism?
In the population it is ~1%; hyperparathyroidism is 2-3 x more likely in females.
What are some of the symptoms of hyperparathyroidism?
Chronic fatigue, polyuria, polydipsia, kidney stones (10 - 30%), abdominal pain, and constipation.
What does the physical exam show for patients with hyperparathyroidism?
Physical exam is generally normal with hypertension in 50% of patients. Some patients have muscle weakness or peripheral neuropathy due to elevated PTH.
What is the commonest presentation of hyperparathyroidism?
90% of patients are asymptomatic and are diagnosed during routine blood screening.
What are the actions of excess PTH?
- Decreased serum PO4.
- Hyperphosphaturia
- Increased serum calcium.
- Hypercalciuria
How are the benign adenomas of the parathyroid gland best localized?
Surgical exploration has >95% success.
Ultrasound and CT have <75% success.
What are some eye related symptoms of hypocalcemia?
Cataract formation and basal ganglia calcification.
What is pseudohypoparathyroidism?
A disease in which there is cellular resistance to PTH due to a variety of defects in the signal transduction pathway of PTH.
What is a common symptom of metabolic bone disease? What are two examples of metabolic bone diseases?
Osteopenia
Osteoporosis & Osteomalacia
What is DEXA (Dual Energy X-ray Absorptiometry)?
A special type of X-ray called bone densitometry which measures bone calcium content. It does not differentiate between osteoporosis and osteomalacia but gives you an idea of BMD.
What is the only way to differentiate unequivocally between osteoporosis and osteomalacia?
Bone biopsy. Usually it is not necessary to biopsy as 100% certainty is not needed.
What are the two causes of osteomalacia?
- Lack of vitamin D or metabolites (rickets).
- Phosphate deficiency (rare).
In hypophosphatemic rickets serum calcium is ______ but serum PO4 is ______.
Normal, Low
What is a Colles’ fracture?
A fracture of the distal radius with dorsal displacement of the wrist and hand.
What percentage of fractures occur after 70 years of age?
90%
Who should be assessed for osteoporosis?
All post menopausal women and men older than 65.
What is kyphosis?
Condition of over curvature of the thoracic vertebrae. {Think hunchback}.The thoracic portion of the spine loses its lordotic profile.
Most androgen action on bones is after conversion to what?
Estrogen
What percentage of patients with osteoporosis also have some degree of osteomalacia due to a vitamin D deficiency?
30%
If malabsorption is suspected what test is ordered? What condition are you looking for?
Anti-tranglutaminase; Celiac disease
What supplements should be given to people with osteoporosis?
Vitamin D {400 - 1000 units/day < 50; 800 - 2000 units/day > 50}.
Calcium {1200 mg}.
What is adynamic bone?
Bone in which the bone renewal cycle stops. PTH must be higher than physiological norm to stimulate the formation-resorption cycle.
What are some of the abnormalities that can occur with renal osteodystrophy?
Osteitis fibrosa {marrow fibrosis}, osteomalacia, and adynamic bone.
What is osteitis fibrosa?
Caused by secondary hyperparathyroidism. Decreasing renal mass causes decreased phosphate excretion. The increased serum phosphate inhibits formations of calcitriol, this prevents normal calcium absorption from the gut. Low serum calcium causes PTH secretion which stimulates marrow fibroblasts to proliferate (fibrosa). The new bone is often weak “woven” bone.
What is the etiology of Paget’s disease?
Possibly due to a “slow-virus” (paramyxovirus like measles) infection with a strong genetic component.
Which bones are commonly affected by Paget’s disease?
Vertebrae, bones of the shoulder, and hip joints.
What is FRAX?
An online calculator for determining fracture risk using fracture risk databases for different countries around the world.
What is the “thrifty gene”?
The idea that a genetic predisposition exists for gaining weight, having a more efficient metabolism, and a lower basal metabolic rate because it was once advantageous.
What is required for an individual to be a candidate for bariatric surgery?
A BMI > 40 OR a BMI > 35 and co-morbidities or significant risk factors.
What is better for weight loss? A single 1800 calorie meal each day or 5 small meals totalling 2000 calories each day?
5 single meals totalling 2000 calories. Spread out meals prevent the body from going into starvation mode.
In children, what percentile is marked as overweight and obese, respectively?
85th percentile and 97th percentile in children >5.
97th percentile and 99.9th percentile 2 - 5.
What two factors contribute most to obesity?
Genetic predisposition and environment.
What will be high with osteomalacia?
Alkaline Phosphatase
What is osteoarthritis?
Wear and tear arthritis which involves any joint of the body.
Calcitonin is a useful marker for what type of cancer?
Medullary Thyroid Cancer
What are three actions of FGF23?
- Stimulates renal NaPT2a cotransporter degradation to inhibit phosphate reabsorption.
- Inhibits PTH release from the parathyroid glands.
- Inhibits 1,alpha-hydroxylase in the kidney.
What stops the actions of FGF23?
PHEX endopeptidase.
What cells produce leptin and what do high levels of leptin tell our body?
Leptin is produced by adipocytes; it probably signals ‘thinness” and decreases food seeking while increasing thermogenesis.
Obesity includes a problem with the signalling of?
Leptin
Orexins?
Stimulate hunger. Ex. Neuropeptide Y.
What is neuropeptide Y and what inhibits it?
Neuropeptide Y is the most potent stimulator of feeding (orexin). It is inhibited by protein YY from the gut.
What is POMC?
Pro-opiomelanocortin is a pro-hormone for ACTH.
It indirectly inhibits feeding.
What does serotonin do to appetite?
Stimulation of the serotonin 2C receptor suppresses appetite.
Stimulate of the 2A serotonin receptor increases appetite (A for appetite).
What does Cholecystokinin (CCK) stimulation do to appetite?
CCK-1 receptor stimulation decreases appetite.
Where is Ghrelin produced and what is its effect on appetite?
It is produced by an empty stomach and stimulates neuropeptide Y (NPY) and AGRP, increasing hunger.
What effect do the endocannabinoids on appetite?
Increase appetite (causes the ‘munchies”).
What is the only drug approved for weight loss in North America?
Orlistat
