Bone Metabolism Flashcards
How are calcium stored in bones?
hydroxyapatite crystals (99%…1% as free)
What are the acute and chronic responses to hypocalcemia?
- acute – release from rapid exchange pool (minutes)
- regulated by osteocyte (osteocytic osteolysis) - chronic – resorption of bone (requires days)
- regulated by osteoclast
What are the acute and chronic effects of PTH?
Bone – acute release rapid pool Ca++,
then chronic resorption
Kidney – increased Ca++ resorption
- decreased PO4 (phosphate) resorption (increased ionized Ca2+)
- increased 1,α hydroxylase (required for synthesis of active form of VitD3 [1,25-dihydroxycholecalciferol]
Gut –> effect only via VitD3 facilitates absorption of Ca2+ and PO4-
Where is calcitonin made and what is its releveance in humans?
Made in C-cells [parafollicular cells] in thyroid and is stimulated by hypercalemia –> reduces Ca/PO4 resorption in bone and kidneys
Human relevance:
Useful as marker for medullary thyroid cancer
Excess can cause diarrhea eg medullary cancer
Where is calcium sensing receptors located?
parathyroid
What the effect of 1, 25 - VitD3 on the gut?
increased Ca and PO4 absorption (for phosphate it increases from 65% absorption to 85/90%)
What does high calcium do to PTH release?
turns off PTH release
What type of phosphates exist in the body?
85% as hydroxyapatite crystals; 12% bound to protein;
What two processes promote VitD3 production and 1-alpha hydroxylase
hypocalcemia, and hypophosphatemia
From where is FGF-23 released and in response to what?
released by osteocytes and osteoblasts in response to high phosphates and high VitD3
What does FGF-23 do?
- suppress PTH release
- degrade renal NaPT2 cotransporter (reduces phosphate reabsorption)
- inhibit alpha-hydroxylase
What is Hypophosphatemic Diseases?
- rare disease where FGF-23 is not broken down (as a result to mutation to PHEX) or increased FGF-23 due tumor
- leads to fractures
What are the two fracture risk calculators?
CAROC or FRAX
What is bone remodelling?
formation and resorption
Which group of bone cells help in formation, and resorption respectively?
osteoblast - formation - 3 months
osteoclasts - resorption - 3 weeks
What is the physiological trigger for bone formation?
microfracture
What are osteocytes and their function?
Osteoblasts that stay in the bone and become osteocytes:
- functions to sense microfractures
- inhibits formation of osteoblasts
Which cells express PTH and VitD receptors, and alkaline phosphatases?
osteoblasts (ie. release FGF-23 if VitD3 or phosphate high)
Whats the role of osteoblasts?
synthesize and secrete organic matrix
- also regulates osteoclast formation and activation (via RANKL and osteoprotregin)
What cells are multinucleated and aid in Ca resorption?
osteoclast (from hematopoietic cells)
- secretes enzymes that dissolve bone (cathepsin K)
- RANKL from osteoblasts stimulte their development
What are some anti-resorptives?
Those that stimulate osteoprotegrin (inhibits osteoclasts):
- Estrogen, Testosterone, calcitonin, bisphosphonates, IFN gamma
What are pro-resorptives
Those that potentiates RANKL (stimulates osteoclasts):
-PTH, 1, 25 VitD3, corticosteroids, IL-6
What are some signs and symptoms of hypercalcemia?
CNS effects – confusion, lethargy
- hypotonia, hyporeflexia
Gut effects – constipation, nausea, vomiting, anorexia, abdominal pain
Renal effects – polyuria (osmotic diuresis)
- chronic – renal stones, nephrocalcinosis
Heart – arrhythmias, asystole
(short Q-T time on EKG)
What are the 3 most common causes of hypercalcemia?
1) Primary hyperparathyroidism
- Excess PTH from autonomous benign adenomas (80% only one gland, 20% all four [familial])
2) Malignant disease
- tumors make PTH-related protein (PTH-RP) and other osteoclast-activating substances (RANKL)
- PTH-RP binds to PTH receptors and mimics PTH action exactly
3) Granulomas (sarcoidosis, TB)
- have 1-alpha hydroxylase and convert 25 (OH)-vit. D3 to 1,25 (OH)2 D3
What are some rare causes of hypercalcemia?
1) Vitamin D overdose – increased gut absorption
2) Thyrotoxicosis – increased bone turnover
3) Thiazide diuretics – increased calcium reabsorption
4) Familial hypocalciuric hypercalcemia (FHH) [RARE]
- inherited deficiency of calcium level sensor protein, resulting in hypercalcemia (new set point)
- receptor mutations cause decreased sensitivity to calcium levels
5) Milk alkali syndrome
Diuresis and water and Na+ loss, which leads to increased bicarbonate reabsorption and alkalosis.
Alkalosis enhances calcium reabsorption
How to calculate corrected serum?
For every 10 g albumin decrease below 40 g/L, add 0.2 mmol/L serum calcium
eg albumin = 30 g/L, serum calcium = 2.0 mmol/L
Thus corrected calcium = 2.2 mmol/L
What do a low serum PTH, and high serum PTH usually mean in the context of hypercalcemia?
- low serum PTH malignancy
- high serum PTH hyperparathyroidism
What is usually the treatment for primary hyperparathyroidism?
- single parathyroid adenoma removed
- near total thyroidectomy because of nodules
- bisphosphonates (only protects bones but not calcium levels)
- calcimimetics (binds to Ca sensing receptors leading to decreased PTH release)
True or False: cardiac arrythmia may cause death in primary hyperparathyroid patients
True
What are some lab test findings with primary hyperparathyroidism?
- high PTH, high calcium
- hypercalcemia, hypophophatemia, hyper- calciuria/phophaturia
What are some common causes of hypocalcemia?
1) Inadequate PTH
- hypoparathyroidism (post-surgical [usually transient] or idiopathic)
- low magnesium (needed for PTH release) [due to malnutrition/alcoholism]
2) Inadequate VitD3
- gut malabsorption, poor intake, chronic renal failure, high phosphate (via FGF-23)
What is the temporary and long-term treatment (for non-transient) surgical hypoparathyroidism?
- transient: IV Ca
- permanent: Ca + VitD3
What are some hallmarks for secondary hyperparathyroidism?
- high PTH, high Ca, low VitD3
- asymptomatic
What are some symptoms of hypocalcemia?
- numbness, hand cramps, tingling of mounth and fingers, muscle spasms, tetany
- Chvostek’s and Trousseau’s (for moderate to severe hypocalcemia)
What are some common causes of hypomagnesemia and what is treatment?
- decreased absorption – poor diet intake eg alcoholism
- gut malabsorption
- increased gut losses – diarrhea, vomiting, nasogastric suction
- treatment: IV magnesium
What are some hallmarks of secondary hypoparathyroisism?
- low PTH, low/normal calcium, low VitD3, low magnesium
- VitD3 is low because low PTH results lower gut absorption of it (and additional malabsorption)
What would be the emergency therapy of hypercalcemia?
- Hydrate with saline – patient is dehydrated from osmotic diuresis induced by hypercaluria; Na+ in saline exchanges with Ca++ in kidney to promote calciuria
- Furosemide – causes Ca++ excretion in kidney tubules
- Bisphosphonates I.V. – pamidronate – inhibits bone resorption caused by PTH-RP; current most potent drug is zoledronate
- Calcitonin I.V. – faster action but smaller effect on bone resorption than bisphosphonates
- Hemodialysis – fastest therapy; should be used in critical emergencies
What is osteomalacia?
increase in proportion of unmineralized bone (osteoid)
What is osteoporosis?
decrease in total bone [mineralized and unmineralized] (osteoid- normal proportion)
What is osteomalacia caused by?
Inadequate substrate (calcium, phosphate) and/or vitamin D (to stimulate calcium/phosphate absorption) to allow normal mineralization of osteoid
True or False: osteoporosis is multifactorial?
True:
- low peak bone mass – mostly genetically determined
- decreased gut calcium absorption with aging
- decreased 1,25 (OH)2 D3 formation
- decreased renal calcium reabsorption with aging
- hormonal – decreased E2, T, IGF-1 (these are anti-resorptives)
Provide reasons why females are at a higher risk of fracture:
Lower peak bone mass
Loss of sex steroids (E2); men gradually have T decline
Women lose bone by loss of connecting arms in trabecular bone, men have thinning of arms
- structurally weaker
Women have higher endosteal resorption without much periosteal deposition of bone
- men have more periosteal deposition- T effect
How would assess risk in a individual suspected of osteopenia?
Targeted history and physical
- clinical risk factors
- measurement of height (loss implies vertebral fractures)
- get up and go test (mobility and balance)
BMD – calculate risk category using CAROC or FRAX
Vertebral spine xrays
What is the bone mineral density (BMD) values for osteopenia?
BMD between -1 and -2.5 SD below young adult mean
What is the bone mineral density (BMD) values for osteoporosis?
BMD < -2.5 SD below young adult mean
What is severe osteoporosis?
BMD < -2.5 SD below young adult mean
additional “fragility” fractures
What tool is used to asses bone mineral density?
Dual x-ray absorptiometry (DEXA)
What are the clinical risk factors for fractures?
Fragility fracture after the age of 40
Parental history of hip fracture
Premature menopause
Glucocorticoid use (> 7.5 mg/d) 3 months or more in the prior year (resorptive)
Lifestyle factors: smoking, excessive alcohol (> 3 units/d), and physical inactivity
Weight loss since age 25 >10%
Poor nutrition, calcium intake, vitamin D status
Recurrent falls, gait and balance
Low bone density
What is a fragility fracture?
A fracture occurring spontaneously or following minor trauma such as a fall from standing height or less.
***Excluding craniofacial, hand, ankle and foot fractures
Who should go for BMD testing?
All women and men age > 65
Postmenopausal women, and men aged 50 – 64 with clinical risk factors for fracture.
What disorders can contribute to increased risk of fracture?
Primary hyperparathyroidism
Type I diabetes
Osteogenesis imperfecta
Untreated long-standing hyperthyroidism, hypogonadism, orpremature menopause (< 45 years)
Cushing’s disease
Chronic malnutrition or malabsorption
Chronic liver disease
Chronic obstructive pulmonary disease (COPD)
Chronic inflammatory conditions (e.g., rheumatoid arthritis [RA], inflammatory bowel disease)
True or False: FRAX and CAROC take into account pelvic fractures and undiagnosed vertebral fractures.
False and so underestimates the total osteoporotic burden
What factors increase CAROC basal risk by one category (ie low to moderate)?
Fragility fracture after age 40
Recent prolonged systemic glucocorticoid use
What are some risk factors taken into account for FRAX?
Parental hip fracture Prior fracture Glucocorticoid use Current smoking High alcohol intake Rheumatoid arthritis
What are the treatment option for low, moderate, and high risk groups for fracture?
Low and moderate risk:
- lifestyle modification
- take adequate calcium and vitamin D
High risk:
- pharmacotherapyWhat biochemical lab tests should be sought for an individual suspected of osteoporosis?
Calcium, corrected for albumin Complete blood count Creatinine Alkaline phosphatase Thyroid stimulating hormone (TSH) Serum protein electrophoresis for patients with vertebral fractures 25-hydroxy vitamin D (25-OH-D)
What are Looser’s Lines?
Pseudofractures seen in osteomalacia as seen in plain x-rays
What instrument would give a definite diagmosis for osteomalacia?
bone biopsy
What are the symptoms and signs for osteomalacia?
– adult – diffuse aching pain – rare
- child – failure to grow, short stature,
bony deformities
- signs – hypotonia, decreased reflexes, muscle weakness (similar to hypercalcemia)
List the causes of osteomalacia:
A) Lack of vitamin D (rickets)
- inadequate diet – malnourished, elderly
- inadequate sunlight
- *gut malabsorption eg small bowel disease – Crohn’s, celiac disease
- lack of renal 1,25 (OH)2D3 synthesis
- renal failure
- anticonvulsants
B) Phosphate deficiency states
- dietary (rare); hereditary states (rare)
What are some therapies for osteoporosis?
Nutritional – increase vitamin D to 800-1000 units / day
Pharmacotherapy choices:
- anabolic (growth stimulating): teriparatide (PTH)
- antiresorptive: bisphosphonates, calcitonin,
estrogen, raloxifene, denosumab
True or False: Raloxifene can be used for non-vetebral fractures
False: only for vertebral
What drugs can be used for vertebral, non-vertebral, and hip fractures?
Bisphosphonates, denosumab, estrogen (for menopausal)
Which type of fractures can be treated with Teriparatide?
verterbral, and non-vertebral
What are the mechanism of action of raloxifene?
– estrogen receptor modulators
- estrogenic actions: on bone, blood clotting factors
- antiestrogenic actions – on breast and uterus
What is the mechanism of action for bisphosphonate?
- inhibit resorption
- promote osteoclast apoptosis - stored in bone (may cause atypical femoral fractures, jaw osteonecrosis) –> inhibits bone formation by slowing down bone turnover
What is the mode of action for Denosumab?
Denosumab – monoclonal antibody to RANKL
- inhibit osteoclasts from forming
- may have same long-term use side effects as bisphosphonates
True or False: Cathepsin K inhibitors withdrawn from market?
True: increased stroke
What is the therapy for Paget’s Disease?
- Usually none required (treatment)
- Bisphosphonates
- 50-96% remission of disease (alk. Phosphatase decrease) after 2-6 mo therapy; 50% pain, functional improvement
- *zoledronate (most effective), alendronate, risedronate
What is renal osteodystrophy?
decreased renal function and renal mass
What diseases can result from osteodystrophy?
(1) osteitis fibrosa: secondary hyperparathyroidism and marrow fibrosis (60%)
(13% mixed osteitis + osteomalacia)
(2) osteomalacia: - inadequate calcitriol
(3) adynamic bone (40%) – no formation: static
