Bone Metabolism and Osteoporosis Flashcards
Two most important minerals for cellular function.
calcium
phosphate
Approximately what percentage of calcium and phosphorous are in bone?
98% of calcium
85% of phosphorous
What can abnormalities in bone metabolism lead to?
wide variety of cellular dysfunction
defects in structural support
loss of hematopoietic activity
How much total calcium is present in bone?
How much of this is protein bound?
How much is ionized?
2.5mM; 40% protein bound; 50% ionized
What happens when there is a fall in plasma calcium concentration?
a fall in plasma calcium leads to secretion of PTH from the parathyroid which stimulates conversion of calcifediol to calcitriol which causes increased calcium absorption from intestine, decreased excretion from the kidneys, and increased mobilization from bone to ultimately increase plasma calcium levels
What two things does calcitonin do to decrease blood calcium levels?
prevents the kidneys from “decreasing excretion” and decreases mobilization of calcium from bone
3 hormones serve as the principle regulators of calcium and phosphate. What are they?
parathyroid hormone
fibroblast growth factor 23 (FBF23)
vitamin D
What does PTH cause stem cells to differentiate into? What about monocytes?
stem cells become preosteoblasts which become osteoblasts; monocytes become preosteoclasts which become osteoclasts
What does calcitriol (active VitD) do to Ca+ in the gut?
increases Ca+ absorption
What does calcitriol do to PTH release from parathyroid gland?
decreases it
What effect does FGF23 have on vitamin D?
decreases the formation of the active form
When rank ligand is released from osteoblasts, it can be taken away by (blank) to form an inactive RANKL/OPG complex
OPG
If rank ligand is allowed to bind to its receptors on osteoblast precursors, what does it form?
osteoclasts
an 84 amino acid peptide produced by the parathyroid gland
parathyroid hormone
Regulation of PTH is achieved in three ways. What are they?
- Ca+ sensitive protease cleaves PTH into fragments, so it limits PTH production
- Ca+ sensing receptor in parathyroid gland is stimulated by Ca+ to reduce PTH production and secretion
- The parathyroid gland contains the Vit D receptor and CYP27B1 to produce the active metabolite of Vit D to suppress PTH production
What does PTH do? It’s synthetic forms are Parathar or Teriparatide
Mobilizes calcium in bone
Decreases renal excretion of calcium
Stimulates Vit D synthesis
*Promotes phosphate excretion
Administration of PTH has limited use clinically. What is preferred?
Admin of Vit D3 and calcium (more direct effect)
Vitamin D biosynthesis: What takes 7-Dehydrocholesterol to Pre D3? What takes Pre D3 to D3? Where is D3 hydroxylated to 25(OH)D3? Where is 25(OH)D3 taken to its active form? What is the secondary product formed when the active form of Vit D is plentiful?
UV light; heat; liver; kidney; 24,25(OH)2D3 (secalciferol)
Why is secalciferol formed in addition to calcitriol?
When calcitriol is already plentiful, this is formed. When Ca++ and P are high
Calcitriol is derived from two sources
from the diet
generated in the skin as pro-vitD3 and then hydroxylation steps take place in liver and kidney
What part does PTH play in formation of active form of Vit D?
Increases it
T/F: Vit D and its metabolites circulate in the blood bound to Vit D binding protein and is rapidly cleared by the liver from the blood.
True
Vit D stimulates absorption of (blank) in the intestine and mobilization of (blank) from bone.
calcium and phosphate; calcium
Can be administered to treat osteomalacia and hypocalcemia associated with hypoparathyroidism.
Calcitriol
A single-chain protein with 251 amino acids that inhibits 1,25(OH)2D production and phosphate reabsorption in the kidney
fibroblast growth factor 23
What does fibroblast growth factor 23 do?
inhibits active Vit D production and phosphate reabsorption in the kidney
How is FGF23 produced?
produced by osteoblasts and osteocytes
How is FGF23 inactivated? What can mutations in this site lead to?
by cleavage at an RXXR site; Mutations in this site lead to excess FGF23, the underlying cause of autosomal dominant hypophosphatemic rickets
What stimulates FGF23 production directly? What inhibits FGF23 production indirectly?
1,25(OH)2D; DMP1
What can mutations in DMP1 lead to?
increased FGF23 and osteomalacia
Effects of PTH on the following: Intestine Kidney Bone Net effect?
increased Ca and phosphate absorption (indirect)
decreased Ca excretion and increased P excretion
Ca and phosphate resorption from bone (high doses). Bone formation (low doses).
Net effect: serum Ca increase, serum phosphate decrease
Effects of Vit D on the following: Intestine Kidney Bone Net effect?
increased Ca and P absorption decreased Ca and P excretion
increased Ca and P resorption (may cause bone formation)
Net effect: serum Ca increase, serum phosphate increase
Effects of FGF23 on the following: Intestine Kidney Bone Net effect?
Intestine: decreased Ca and P absorption because decreased calcitriol production
Kidney: increased phosphate secretion
Bone: decreased mineralization due to low phosphate and low calcitriol levels
Net effect: decreased serum phosphate
A number of hormones modulate PTH, FGF23, and VitD. The physiological impact of secondary regulators on bone mineral homeostasis are (blank), but can be exploited therapeutically
minor
Protein hormone (32 aa) produced by the thyroid gland. Overall effect is to lower plasma calcium. Used in the treatment of hypercalcemia associated with some neoplasms.
calcitonin
How is calcitonin regulated? Calcitonin inhibits (blank) and decreases reabsorption of both (blank) and (blank) in the proximal kidney tubules.
regulated by plasma calcium; osteoclasts; calcium and phosphate
Alter bone mineral homeostasis by antagonizing vitamin D-stimulated intestinal calcium transport, stimulating renal calcium excretion and blocking bone formation
glucocorticoids
Glucocorticoids can be used pharmacologically to reverse (blank) associated with lymphomas and granulomatous diseases in which Vit D production is elevated
hypercalcemia
Prolonged use of glucocorticoids can lead to (blank) in adults and (blank) in children
osteoporosis; stunted skeletal development
What can glucocorticoids do to the following: bone quality bone formation bone resorption bone mass calcium balance muscle weakness and myopathy risk of fracture
decrease; decrease; increase; decrease; negative calcium balance; increase; increase
What percentage of women’s bone mass is estrogen dependent?
10-20%
Estrogens can prevent accelerated bone (blank) and transiently increase bone (blank) in postmenopausal women
Estrogens act to reduce the bone-resorbing actions of (blank)
loss; formation; PTH
Estrogen increases blood levels of (blank), but has no direct effect its production. Increased (blank) as a result of estrogen treatment decreases serum calcium and phosphate
1,25[OH]2D (Calcitrol)
Estrogen receptors are found in (blank) and estrogen has direct effects on bone (blank)
bone; remodeling
What is the principle therapeutic action of estrogen?
to treat or prevent osteoporosis in post-menopausal women
*Long term use of estrogens may have adverse consequences
Bone disease by characterized by a reduced quantity of bone
osteoporosis
Bone disease characterized by a lack of mineralization
osteomalacia
Bone disease characterized by the production of abnormal bone
Pagets disease
Affects approximately 3% of the population over age 60
Disease of the bone that presents with bone pain, skeletal deformity, neurological complications or fractures
Incidence is highly variable: common in Central Europe, UK, Australia, New Zealand and USA. Rare in Africa, Middle East and Scandinavia
Pathology is excessive bone resorption and formation in 3 phases: osteolytic, osteoblastic and quiescent. All three phases may be present in the same patient at the same time
Pagets disease
Caused by decreased mineralization of new bone matrix. In children, what does this lack of calcification result in?
osteomalacia; growth failure and deformity or Rickets
How might an adult present with osteomalacia?
bone pain
proximal myopathy
fractures with minor trauma
What is osteomalacia commonly caused by? What else can it be caused by?
What are some biomarkers?
Vit D deficiency;
insufficient exposure to sun, malnutrition
renal tubular acidosis; malnutrition during pregnancy; Malabsorption syndrome; Hypophosphatemia; Chronic renal failure; Tumor induced ostemalacia; Long term anti-convulsive therapy; Coelaic disease; Cadmium poisoning
biomarkers: low calcium, secondary elevation in PTH, low plasma Vit D
Common disorder in post-menopausal women that may result in hip, forearm and spinal fractures
Caused by a thinning of the bone with aging
Increased morbidity and mortality
osteoporosis
What is osteoporosis accelerated by?
premature or surgical loss of ovaries
drugs (corticosteroids)
lifestyle (alcohol, smoking)
What are these: Increase in age Female Caucasian or Asian Family history Small stature Low weight Early menopause Sedentary lifestyle Low Ca+ intake Alcoholic Cigarette smoking
Risk factors for osteoporosis
Bone formation increases from birth to (blank) years of age in men and women and then slowly declines
30
T/F: With treatment after menopause, you can maintain bone mass. Without treatment, more bone can be lost.
True
What happens to mortality risk following fractures?
It is elevated
What test is used to determine bone density in women age 65 or older and patients aged 60 who are at an increased risk of osteoporosis?
Dual-energy X-ray (DEXA)
In a DXA test, what T score indicates normal bone density? What T score indicates osteopenia (bone density below normal)? What T score indicates osteoporosis?
above -1
-1 to -2.5
less than -2.5
Estrogen replacement therapy at the time of menopause inhibits the effect of (blank) on bone resorption and increases bone (blank)
osteoclasts; density
What is the most widely prescribed medication for treatment of postmenopausal osteoporosis?
oral estrogens
What is one downside to HRT?
may lead to increased cardiovascular events (esp for women with a history of disease)
What HRT can be considered for patients that have not had a hyst?
progesterone
In 2002 the Women’s Health Initiative showed that HRT causes an increase in strokes, heart attacks, breast cancer, blood clots, dementia, etc. So, current guidelines suggest that HRT be used to treat (blank) of menopause and for the (blank) period of time possible.
symptoms; shortest
T/F: After a hysterectomy, estrogen-only hormone therapy does not increase a woman’s risk of breast cancer.
True!
What are SERMs? What can they protect against?
SERMS are selective estrogen receptor modulators. They can act competitively on alpha estrogen receptors (ex: in the breast) to to prevent binding of estrogen. They can also act as agonists on beta estrogen receptors (ex: uterine tissue). They can protect against osteoporosis.
What are two examples of SERMs that protect against osteoporosis?
tamoxifen
raloxifene
This drug blocks the estrogen receptor in breast cancer cells whose growth is estrogen-dependent. It is now thought to be beneficial for the prevention of breast cancer in women at risk. It is often used in conjunction with surgical and or chemotherapeutic options.
Tamoxifen
Tamoxifen can cause an increased risk in (blank) and has these side effects. It has some antiestrogenic side-effects but is not thought to alter lipid profiles or accelerate (blank)
endometrial cancer; hot flashes, nausea, vomiting; osteoporosis
First approved as a treatment for osteoporosis. It has estrogenic activity but not on all sensitive tissues. It increases bone density and appears to decrease number of fractures. It can also decrease total cholesterol
patients taking the drug for the Tx of osteoporosis were followed for cancer and found to have a 50+% decrease in overall cancer incidence
Adverse effects include increased risk of thromboembolic events similar to estrogen. Some women report hot flashes and leg cramps
Raloxifene
These are enzyme-resistant analogs of pyrophosphate (P-O-P structure replaced by P-C-P). They cause reduced turnover of bone by preventing the number and activity of osteoclasts. They take about 48 hrs to block bone resorption. They block the transformation of calcium phosphate into hydroxyapatite thus inhibitint the formation of these crystals in the bone.
bisphosphonates
In general, what do bisphosphonates do?
decrease osteoclast activity
bisphosphonates that increase bone density by 4-9% over the first 3 years of treatment and reduce vertebral fractures by 50%
etidronate
alendronate
risedronate
This drug should not be given continuously because it may cause osteomalacia. Should be dosed over two weeks with periods off the drug
etidronate
This drug 10mg/day can reduce the incidence of single vertebral fractures by 50% or 90% for multiple vertebral fractures
alendronate
This drug 5mg/day can reduce the incidence of single vertebral fractures by 50% or 90% for multiple vertebral fractures
risedronate
What should you avoid while taking bisphophates because they inhibit drug absorption? What are some adverse effects? What is the recommendation when taking them?
avoid milk products, food, or Ca+
may cause GI, gastric ulcers, erosive oseophagitis
take with water, avoid lying supine for 30 mins
This drug inhibits the maturation of pre-osteoclasts into osteoclasts and therefore prevents bone resorption. It mimics the actions of osteoprogenin (OPG), an endogenous RANKL inhibitor that is decreased in patients with osteoporosis.
Denosumab
Human monoclonal antibody against RANKL and is used for the treatment of osteoporosis, treatment of bone loss and bone metastasis, rhuematoid arthritis, multiple myeloma and giant cell tumor of the bone
Denosumab
a synthetic C-19 steroid with weak hormonal properties. Short term studies have shown increases in bone mass in the spine and prevention of bone loss from the forearm in postmenopausal women
tiboline
osteoporosis therapies
Ca supplements
Vit D analogs facilitate Ca2+ absorption from the gastrointestinal tract and may have an effect on bone formation and resorption
tibolone
teriparatide
T/F: Calcium supplements have a small beneficial effect in preventing bone loss
True
(PTH analog) used in cyclic doses has been shown to be effective in the treatment of osteoporosis
teriparatide
Hypercalcemia is a life threatening condition. Fluid resuscitation is essential. What can be used to augment renal Ca++ excretion? What can rapidly reduce Ca++ but response is transient? What can help manage hypercalcemia?
loop diuretics; calcitonin; intravenous bisphosphates
A calcium senor mimetic
Inhibits PTH secretion by the parathyroid gland
FDA approved for secondary hyperparathyroidism due to chronic kidney disease or hypercalcemia associated with parathyroid carcinoma
Cinacalcet
T/F: Bone formation and resorption can be semi-quantified on bone biopsy or radiographic imaging
True
T/F: Osteoporotic women have a higher incidence of fractures than incidence of heart attack, stroke, and breast cancer in women population combined.
True
Precursors of osteoclasts express (blank), a member of the TNFR family. What is this activated by which is present on the surface of oesteoblasts and converts pre-osteoclasts to osteoclasts to resorb bone?
RANK; RANKL
So RANK, when bound to RANKL on the surface of osteoblasts, forms osteoclasts
Adverse affects of Denosumab? Contraindications?
Adverse effects include increased urinary and respiratory tract infections, rashes, joint pain, eczema
Contraindications: Hypocalcemia
Which drug causes the greatest % change in the lumbar spine in treatment of osteoporosis?
teriparatide
