Osteoporosis (2) Flashcards
What is osteoporosis?
Bone disorder
low bone density, impaired bone architecture, and compromised bone strength
Predisposes to increased fracture risk
Risk factors (6)
- Age
- Genetics
- Diet/lifestyle … smoking, 3 or more alcoholic drinks/day, low calcium intake, limited exercise
- Hormonal status … postmenopausal, premature menopause
- Diseases (RA, Vit D deficiency)
- Medications (glucocorticoids)
Medical conditions associated with osteoporosis
Endocrine/hormonal
-ovarian failure
-testosterone deficiency
-hyperthyroidism
-Cushing’s syndrome
-growth hormone deficiency in children
-primary hyperparathyroidism
-diabetes
Gastrointestinal
-nutritional disorders (anorexia)
-malabsorptive states
-chronic liver disease
Disorders of calcium/phosphate balance
-hypercalciuria
-vitamin D deficiency
-hypophosphatemia
Inflammatory disorders
-RA
Chronic illness
-CKD
-Malignancies
-HIV/AIDs
-organ transplant
Disuse/immobility
-muscular dystrophy
-MS
-stroke/cerebrovascular accident
Genetic
-osteogenesis imperfecta
-cystic fibrosis
-hemochromatosis
What are some medications that increase risk of osteoporosis (5)
Antiseizure therapy (phenytoin, carbamazepine, phenobarbital, and valproic acid)
Antiretroviral therapy (NRTIs, NNRTIs, protease inhibitors)
Furosemide
Glucocorticoids (long term oral therapy)
PPIs (long term therapy)
When does bone loss occur?
When bone resorption exceeds bone formation or due to high bone turnover
-accelerated bone turnover increases the amount of bone that is not adequately mineralized (so its not good quality bone)
What are the 2 types of bone
Cortical - long bones (make up 80%) , hard bones
Trabecular - vertebrae and end of long bones, spongey bones
-these are metabolically more active and have a higher bone turnover rate because of large surface area and honeycomb like shape
-they are more susceptible to estrogen deficient bone loss
Functions of bone
Mechanical support
Transmission of forces generated by muscles
Protection of viscera
Mineral homeostasis
Place for blood cell production
Constituents of bone
Extracellular matrix
-made of organic component - osteoid (35%) - which is made of protein, collagen mostly
-and a mineral component (65%)
Embedded in the matrix are a variety of specialized bone cells…
osteoblasts - synthesize bone
osteocytes - lay down bone
osteoclasts - resorb bone
The balance between these maintains homeostasis
The unique feature of bone, its hardness, is imparted by what component?
The inorganic components - hydroxyapatite
Osteoblasts
Located on the surface of matrix
Synthesize, transport, and assemble bone matrix and regulate its mineralization
Osteocytes
These are derived from osteoblasts, but these are located within the bone (whereas osteoblasts are on the surface)
They help control calcium and phosphate levels, detect mechanical forces, and translate them into biological activity - mechanotransduction
(also help lay down bone?)
Osteoclasts
These are located on the surface of bone
They are specialized macrophages derived from monocytes - they are responsible for bone resorption
Vitamin D
This is a fat soluble vitamin
A lot of vitamin D is synthesized endogenously in the skin (powered by light)
The active form of vitamin D…
-stimulates intestinal absorption of calcium
-stimulates calcium resorption in renal distal tubules
-collaborates with PTH to regulate blood calcium
-promotes mineralization of bone
Parathyroid hormone (PTH) formation
Peptide (protein) hormone
Made from a precursor produced in the parathyroid gland that is cleaved by a protease to form PTH
This is calcium sensitive protease - presence of calcium therefore limits the production of PTH
Also, there is a calcium sensing receptor (CaSR) which when simulated by calcium limits the production and secretion of PTH
PTH activity (2 functions)
PTH regulates calcium and phosphate flux across membranes in bone and kidney leading to… increased serum calcium and decreased serum phosphate
(makes sense, calcium and phosphate will form a precipitate, so to increase calcium concentration, need to decrease phosphate)
In the bone… PTH increases the activity and number of osteoclasts (which are responsible for bone resorption)
How do PTH and active vitamin D both effect bone in 2 ways
Both PTH and 1,25(OH)2D regulate bone formation and resorption (each is capable of stimulating both processes)
They contribute to the preosteoblast proliferation and differentiate into osteoblasts (resulting in bone formation)
But, they also stimulate the expression of RANKL by the osteoblast
-RANKL (on osteoblast) binds to RANK on osteoclast precursors, causing them to produce functional osteoclast (resulting in bone resorption)
Bone remodeling/demodeling regulation
Bone remodeling/demodeling in balance by action of osteoblasts/osteoclasts
Osteoblasts release MCSF (macrophage colony stimulating factor) which binds binds receptor on osteoclasts - this is one signal
Osteoblasts ligand - RANKL, binds RANK receptor on osteoclasts, boosting differentiation of osteoclasts into active form
MCSF and RANKL induce bone resorption
Osteoblasts also synthesize an antagonist to RANKL - osteoprotegerin (OPG) - this binds to the RANK receptor preventing the binding of RANK (so OPG neutralizes RANKL), inhibiting osteoclast differentiation, and thus inhibiting bone resorption
Different systemic factors affect this balance
-hormones, vitamin D, inflammatory cytokines, growth factors
-PTH and glucocorticoids (promote osteoclast differentiation and bone turnover)
The mechanisms are complex
Sex hormones (estrogen and testosterone) generally have what effect on the bone?
Block osteoclast differentiation or activity by favoring OPG expression (inhibit bone resorption)
(this is why when women go through menopause, there is less estrogen, so increased RANKL expression and increased osteoclast activity, since there is less OPG to neutralize the RANKL)
What is the most common cause of osteoporosis?
Postmenopausal (estrogen deficiency)
Postmenopausal osteoporosis pathophysiology
-estrogen deficiency > significant bone density loss
-increased proliferation and activation of new osteoclasts and prolonged survival of mature osteoclasts occurs
-Interleukins, prostaglandin E2, TNF-α, and interferon γ also increase resulting in more RANKL and less OPG
-There is increase in calcium excretion and decrease in calcium gut absorption
What are some causes of estrogen deficiency
Menopause
Anorexia nervosa
Lactation
Medications (prolonged medroxyprogesterone implants, aromatase inhibitors, gonadotropin releasing hormone agonists)
Menopause related osteoporosis timeline
Bone loss (mass and strength) begins during perimenopause and continues up to 8 years after menopause
note - early menopause increases loss
Male osteoporosis
Males have a lower risk of developing osteoporosis and osteoporotic fractures
They have larger bone size, greater peak bone mass, and an increase in bone width with aging
Also fewer falls and shorter life expectancy may contribute to this
There are secondary causes (medical conditions) that can increase the risk of males developing osteoporosis
Other risk factors include smoking, alcohol abuse, low body weight, weight loss, age, long term glucocorticoid use, androgen deprivation therapy, low testosterone concentrations
Clinical presentation and consequences of osteoporosis
Silent disease
Vertebral fractures can occur
-may be asymptomatic or cause mild back pain, multiple vertebral fractures can cause decrease in height and curve the spine
Most common sites for fractures are hip, spine, and wrist
Results in pain and physical deformity and decreased quality of life
Compression of thoracic region can cause respiratory and GI complications
Hip fracture has the highest mortality rate
Which type of fracture has the highest mortality rate?
Hip fractures
(about 20% die within a year)
FRAX tool
This is a assessment tool that tells us the probability of a patient having a major osteoporotic fracture and hip fracture in the next 10 years
We use this when we consider treatment decisions
Bone mineral density assessment
Peripheral bone mineral density (BMD) devices:
-DXA or QUS (quantitative ultrasonography)
The gold standard is DXA (central dual-energy x ray absorptiometry)
-measures BMD at hip or spine
-assesses fracture risk and establishes the diagnosis (T score) and severity of osteoporosis
(should be done for all women aged 65 years or older, men aged 70 years or older, postmenopausal women younger than 65 years old and men 50 to 69 years old with risk factors for fracture, and patients with an identified secondary cause for bone loss - most insurance will pay every 2 years)
Central DXA scores
T score and Z score
T score
-assesses severity in reference to the general population
-below -2.5 is considered osteoporosis, from -1 to -2.5 is considered osteopenia
Z score
-more useful for men and children
-compares patient’s BMD to the mean BMD of sex and age matched population
How is osteoporosis diagnosed?
Diagnosis is established by measurement of BMD (from central DXA) OR if there is assurance of adult hip or vertebral fracture in the absence of major trauma
Normal T score is -1 and above
Osteopenia (low bone mass) is -1 to -2.5
Osteoporosis is diagnosed when T score is less than -2.5
It is considered severe/established osteoporosis if T score is less than -2.5 and there has been one or more fractures
What is the main goal of therapy for osteoporosis
Prevention
Once it has developed…
-stabilize, improve bone mass and strength
-prevent fractures/falls
-reduce pain, improve QOL
Nonpharm therapy
Proper nutrition (adequate amounts of calcium, vitamin D and protein), moderation of alcohol intake, caffeine, and salt
Maintain a healthy weight
Exercise: moderate-intensity weight bearing activities (walking, jogging, stairs) and resistance activity (free weights, elastic bands)
Smoking cessation
Fall prevention
Recommended calcium intake
Men + women 19-50 … 1000 mg/day
Men 51-70 … 1000 mg/day
Women 51-70 … 1200 mg/day
Men + women 71 and over … 1200 mg/day
But anything below 2000-25000 mg/day is safe and not considered a risk (anything above that we think about CV risk)
Which form of calcium supplement is preferred?
Calcium carbonate
-has highest percent of elemental calcium and is the least expensive
(also used as an antacid- Tums)
Should be taken with meals to enhance absorption- needs acidic environment
Calcium citrate considerations
Acid independent absorption (unlike calcium carbonate) - so good for those taking H2RA or PPI
Can also be taken without regards to food (unlike calcium carbonate)
And has less GI upset than calcium carbonate
What is a big ADR from calcium supplements, what should patients be counseled to do when taking calcium because of this?
Constipation
Counsel patients to increase water, fiber, and exercise
Use of __________ may decrease calcium absorption
PPIs (specifically calcium carbonate, calcium citrate can be used)
Calcium drug interaction considerations
Calcium may decrease absorption of other drugs including…
-iron
-tetracyclines
-quinolones
-bisphosphonates
-thyroid supplements
so administration should be separated by 2-4 hours
Vitamin D therapy considerations
If someone is vitamin d deficient, we need to replace the deficiency with a higher treatment dose first, then continue on a maintenance dose
vitamin D is usually well tolerated, monitor for hypercalcemia
the half life of vitamin D is 1 month, so about 3 months of therapy should be completed before repeating level
The goal is to maintain an active vitamin d of at least 20 ng/mL
Vitamin D drug interaction considerations
Some medications may induce vitamin D metabolism
-rifampin
-phenytoin
-carbamazepine
And some may decrease vitamin D absorption
-cholestyramine
-orlistat
-mineral oil
so in both of these cases you may need higher doses of vitamin D
Which patients should receive prescription drug therapy?
Any man or postmenopausal woman over 50 years old presenting with at least one of the following…
-a hip or vertebral fracture
-T score of -2.5 or less at neck, total hip, or spine
-low bone mass (t score -1 to -2.5) with a FRAX 10 year probability of a hip fracture of 3% or higher, or a FRAX 10 year probability of any fracture of 20% of higher
Prescription therapy should be used in addition to what?
Calcium and vitamin D
(every patient should get these!)
Estrogen and testosterone considerations for osteoporosis
These are NOT prescribed for just osteoporosis treatment
But, if they are needed for other conditions, may have benefit of osteoporosis as well
Which drugs are first line pharmacological options for osteoporosis and why? (4)
Bisphosphonates
1. alendronate
2. risedronate
3. zoledronic acid (IV)
(not ibandronate is a bisphosphonate but is second line)
- denosumab
These drugs are first line because they have efficacy data for the reduction of both hip and vertebral fracture risk
Bisphosphonate MOA
They are analogs of pyrophosphate (a natural metabolite in the body), but they have longer half lives because the P-O-P bond has been replaced with a non-hydrolysable P-C-P bond
They have many effects on bone mineral homeostasis
Major function: retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system
Also…
-inhibit active vitamin D production
-inhibit intestinal calcium transport
-cause metabolic changes in bones - inhibition of glycolysis
-inhibition of cell growth
-changes in acid and alkaline phosphate activity
Bisphosphonates have low ___________
Absorption
(bioavailability is less than 1% and is decreased with food/beverage consumption… important counseling point)
Bisphosphonate ADRs
Oral: esophageal and gastric irritation (because they are acids)
Muscoloskeletal pain
Acute phase reactions… fever, flu like symptoms, myalgia, arthralgia (more with IV form than oral)
Rare but serious: severe GI events (esophageal erosion, ulcer, GI bleeding), osteonecrosis of the jaw (ONJ), subtrochanteric femoral (atypical) fractures
Binding strength of different bisphosphonates
The different bisphosphonates have different binding strengths to bone …
greatest is zolendronic acid > alendronate > ibandronate > risedronate
Bisphosphonate duration of therapy
The ideal duration of therapy is not known
But should last less than 5 years
Bisphosphonate contraindications (3)
CrCl < 30-35 ml/min (drug is absorbed into bone within first 24 hours, the rest is renally excreted)
Serious GI conditions (abnormalities of esophagus)
Pregnancy
Bisphosphonate monitoring parameters
Bone density
Fractures
GI symptoms
Muscle aches
Serum calcium and SCr for zoledronic acid prior to each infusion
ORAL bisphosphonate patient education points
Oral tablet should be taken with 6 ounces of plain water at least 30 minutes before consuming food, supplements, or medications (60 minutes with ibandronate) (no juice, coffee, mineral water, etc.)
Remain upright for at least 30 minutes (60 minutes for ibandronate)
For swallowing difficulties - there is an effervescent form of alendronate, must be dissolved in 4 ounces of water, follows same food/medication restrictions
There is a delayed release form of risedronate - give immediately following breakfast with 4 ounces of plain water
Oral bisphosphonate missed dose counseling points
Most dosing is once weekly (sometimes once monthly)
-if missed once weekly dose - take the next day, if more than 1 day has passed, just skip that dose
-monthly doses can be taken up to 7 days before the next administration
IV bisphosphonate counseling points
Serum calcium concentration must be checked and corrected if needed prior to each infusion
Needs to be administered by health care provider
Can take acetaminophen prior to infusion to decrease fever, flu like symptoms, myalgias, and arthralgias (acute phase reactions)
Denosumab MOA
Humanized monoclonal antibody that binds to and prevents the action of RANKL (inhibiting osteoclast formation and activity)
3 concerns with denosumab
- some immune cells express RANKL, so there can be an increased risk of infection with denosumab use
- bone turnover suppression is similar to that of potent bisphosphonates, so risk of osteonecrosis
- denosumab can lead to transient hypocalcemia
Denosumab place in therapy
Treatment of osteoporosis in patients at high risk for fractures - including…
- glucocorticoid induced osteoporosis
- men receiving androgen deprivation therapy (for prostate cancer)
- women receiving aromatase inhibitor (for breast cancer) with high risk of fracture
Denosumab administration
60 mg SQ every 6 months
-must be administered by health care professional (can be done by pharmacist in some states)
Denosumab renal function consideration
NO renal dose adjustment is currently required
But, hypocalcemia is more common in patients with renal impairment - so monitor patient’s serum calcium within 14 days of administration if CrCl < 30
Denosumab duration of therapy
After 5-10 years patients should be reevaluated for medication continuation, discontinuation, or switching to a different medication
Denosumab ADRs
Common: back pain, arthralgia, eczema, cellulitis, infection
Rare: osteonecrosis of the jaw, atypical femoral shaft fracture
Denosumab monitoring parameters
Bone density
fractures
Serum calcium (hypocalcemia should be corrected prior to dose)
What are the alternative pharm therapy agent options? Why are they considered alternatives?
Parathyroid hormone analogues
1. Abaloparatide
2. Teriparatide
- Ibandronate (second line bisphosphonate)
- Raloxifene (second generation mixed estrogen agonist/antagonist)
- Romosozumab (humanized monoclonal antibody that binds to sclerostin)
These are considered alternative because they have evidence for decreasing vertebral fracture risk but NOT hip fracture risk
What is a last line option for osteoporosis?
Intranasal calcitonin
Teriparatide MOA
Recombinant form of PTH (analog of PTH)
First approved “anabolic” - bone building drug
-increases osteoblast formation and inhibits osteoblast apoptosis
(counterintuitive of what PTH does, but this is what PTH administration has shown)
Teriparatide duration of therapy
Only approved for use for 2 years
-intermittent administration has shown to increase the number of osteoblasts, but continuous administration has shown to increase the number of osteoclasts (which is why duration is limited)
Abaloparatide MOA
Synthetic analog of parathyroid hormone related protein (PTHrP)
-acts similar to PTHrP, binds to and activates PTH1 receptor on osteoblasts and bone stromal cells increasing bone growing and bone density conserving activities
Abaloparatide and teriparatide place in therapy
Both:
postmenopausal women with osteoporosis at high risk for fracture defined as multiple risk factors for fracture, a history of osteoporotic fracture, or failed or intolerant to other therapies
Teriparatide also has an indication for men…
men with idiopathic or hypogonadal osteoporosis who are at high risk for fracture, men intolerant to other osteoporosis medications, and patients with glucocorticoid-induced osteoporosis
Abaloparatide and teriparatide administration
SQ daily injections for 2 years max
(80 mcg for abaloparatide, 20 mcg for teriparatide)
Abaloparatide and teriparatide ADRs and BBW
Orthostatic hypotension
Transient hypercalcemia
Urolithiasis (calcium)
Increased uric acid (keep this in mind if patient has history of gout)
Injection site reactions
BBW: osteosarcoma (data from animal studies)
Abaloparatide and teriparatide monitoring parameters
Orthostatic hypotension
Serum calcium
Urinary calcium (for patients with suspected urolithiasis or preexisting hypercalcemia)
BMD at baseline and 1-2 years following initiation of therapy
Raloxifene MOA
SERM - selective estrogen receptor modulator
It is a mixed agonist/antagonist at the estrogen receptor depending on the tissue (partial agonist of ERalpha and pure antagonist or ERbeta)
-estrogen activity in liver and bone
-anti-estrogen activity in breasts and uterus
Raloxifene place in therapy
for patients who are unable to take bisphosphonates and denosumab, or in patients with a high risk of vertebral fracture and a high risk of invasive breast cancer
Raloxifene administration
PO once daily (60 mg)
Raloxifene ADRs
Hot flashes
Leg pain, cramps, spasms
Peripheral edema
VTE (do not use in high risk patients)
Raloxifene monitoring parameters (2)
Lipid profile
BMD at baseline and every 1-3 years
Raloxifene drug interaction consideration
Highly protein bound, so has interaction with other protein bound drugs… can displace and cause higher concentrations of those drugs in the serum (e.g. warfarin)
Romosozumab MOA
Humanized monoclonal antibody that binds to sclerostin
-sclerostin is a glycoprotein produced by osteocytes that inhibits the Wnt (growth factor) signaling pathway leading to inhibition of osteoblast differentiation/function
By binding to sclerostin, romosozumab prevents the sclerostin from inhibiting the Wnt pathway, so the Wnt pathway will be stimulated - resulting in increased osteoblast formation and therefore increased bone formation
(also decreases bone resorption but to a lesser extent)
Romosozumab place in therapy
postmenopausal women at very high risk for fracture defined as multiple risk factors for fracture, a history of osteoporotic fracture, or failed or intolerant to other therapies
Romosozumab administration/duration
SQ administration, monthly for up to 1 year
-must be administered by health care professional
Romosozumab ADEs/BBW
Headache, arthralgia, hypercalcemia, injection site reaction, hypersensitivity
Theoretical risk of increased malignancy
BBW - Serious cardiovascular events (myocardial infarction, stroke, and cardiovascular death)
-do not use within 1 year of MI or stroke
Romosozumab monitoring parameters
Hypersensitivity
Signs/symptoms of cardiovascular events
Serum calcium
BMD
Calcitonin MOA
Calcitonin is a hormone, its function is to counteract PTH - lowers serum calcium and phosphate levels and inhibits osteoclastic bone resorption
Bone formation is not impaired at first with calcitonin administration, but overtime, both formation and resorption of bone are reduced
Calcitonin place in therapy
Last line therapy
for women who are at least 5 years past menopause; rarely used and should only be considered if no other therapies are appropriate due to cancer risk
Note- short-term treatment may provide analgesic effect in patients with acute painful vertebral fractures (it is the only agent that has analgesic effect, so can be used short term for painful fractures)
Calcitonin administration
IM, SQ, or intranasal spray … daily
Calcitonin ADRs
Rhinitis (with intranasal spray)
Depression
Rash
Nausea
Injection site reactions
Back pain
Malignant neoplasm (this is why it is last line)
