Osteoporosis Flashcards
Which form of calcium is preferred?
Dietary
If you exceed more then 2000mg/day what may occur?
– Nephrolithiasis
– Cardiovascular disease
– Dyspepsia
– Constipation
What is the RDA of Vitamin D for people under 70
600 IU
What is the RDA for vitamin D for people over 70
800 IU
TO meet RDA health canada recommends a supplement of?
400 IU
Which form of Vitamin D is preferred?
D3
What are the sources of D3
- Fatty fish (salmon, rainbow trout)
- Fortified foods (cow’s milk, plant-based beverages)
- eggs
Sun exposure
How long after supplementation initiation of D3 should monitoring take place?
Usually dont monitor, but 3 months generally
What does Serum 25-Hydroxyvitamin level indicate?
Indicates Vitamin D levels
What is the “name” of Vitamin D3
Cholecalciferol
What is the name of Vitamin D2?
Ergocalciferol
What level of serum 25-hydroxyvitamin indicated high risk of deficiency?
<30 nmol/L - high risk of vitamin D deficiency
Is routine monitor essential for vitamin D monitoring?
No instead we focus on 400 across the board
What is the average half life of vitamin D?
15-20 days, hence the serum levels take a while to adjust (3mo)
What is the range for potential risk of inadequacy for bone health for 25-hydroxyvitamin?
30 to <50nmol/L
What is generally considered adequate for bone and overall health
in healthy individuals 25-hydroxyvitamin?
≥50 nmol/L
What is the level of 25-hydroxyvitamin level that may be linked to potential adverse effects
> 125 nmol/L
What are the antiresorptive classes of drugs with respect to osteoporosis drugs
A. Bisphosphonates
B. Denosumab
C. Raloxifene
D. Hormone Therapy
What are the anabolic medication(s) for Osteoporosis?
Teriparatide
Romosozumab
When should pharmacotherapy be recommended?
Intermediate Risk and High risk
What is the definition of intermediate risk? (10 year fracture risk or T score?)
- 10-year fracture risk 15 – 19.9% OR
- T-score < -2.5 (and age <70)
What is considered high risk (10 year fracture risk or T score)
- 10-year fracture risk >20% OR
- T-score < -2.5 (and age >70)
What is considered low risk (10 year fracture or T score)
- 10-year fracture risk <15% OR T-score > -2.5
What are the recommended first line treatments for Intermediate and high risk individuals of osteoporosis?
– Bisphosphonates first line, denosumab second line
What is the classification of very high risk?
Recent severe vertebral fracture or >1 vertebral fracture
and T-score < -2.5
What are the recommended pharmacotherapies for individuals at very high risk?
– Teraparatide or Romosumab should be followed by a
bisphosphonate
What is the 5-10year follow up monitoring parameters?
- 5 – 10 yr if the risk of major osteoporotic fracture is < 10%
What is the 5 year follow up monitoring parameters?
- 5 yr if the risk of major osteoporotic fracture is 10%–15%
What is the 3 year follow up monitoring parameters?
- 3 yr if the risk of major osteoporotic fracture is > 15%.
For those on pharmacotherapy what is the retesting window?
3 years
When would an individual require a shorter testing window?
for those with
secondary osteoporosis or new clinical risk factors, such as a
fracture
What is the mainstay therapy for osteoporosis?
Bisphosphonates
What are the indications of Bisphosphonates?
– Postmenopausal osteoporosis treatment and prevention
– Osteoporosis treatment in men
– Treatment and prevention of glucocorticoid-induced
osteoporosis
– Paget’s disease
What drugs are included under the drug class Bisphosphonates?
Alendronate
Risedronate
Zoledronic Acid
What is the MOA of Bisphosphonates?
Are analogues of pyrophosphate which allows for
incorporation into bone
– Binds strongly to hydroxyapatite undergoing remodeling
***– Inhibits osteoclast activity at site
– 2nd generation bisphosphonates additionally inhibit farnesyl
pyrophosphate synthase → osteoclast apoptosis
May prevent osteoblast apoptosis
What is the general dosing of alendronate?
What is the dosing of risedronate?
What is the dosing of zoledronic acid?
What is the caveate with bisphophonates?
– Extremely poor bioavailability – space from all medications
How should bisphosphonates be taken? (Immediate release?)
– Immediate-release tablets: empty stomach with 1 cup of
water, >30 minutes before food, drink and other medications.
Remain upright for 30 minutes.
How should the delayed release bisphosphonates be taken?
– Delayed-release tablets: take with 1 cup of liquid immediately
after breakfast. Remain upright for 30 minutes.
Why should we remain upright for 30 minutes post dosing?
May lead to side effects otherwise in the esophagus
With respect to Zoledronic acid how long should the infusion be?
– Zoledronic acid: once yearly IV infusion over 15 minutes
What is the general onset of Bisphosphonates?
– Weeks to observe bone changes
– Years to observe clinical benefit
What are the clinical benefits of Bisphosphonates?
After 3 years results in major reduction in breaks and fractures, compared to placebo
Are there many harms with the short term usage of bisphosphonates?
Not really, More so with long exposure
What are the common SE of bisphosphonates? (8)
– GI complaints
- Abdominal pain(7%),
Dyspepsia(2%),
Nausea(4%),
Diarrhea/Constipation (3%)
– Headache (2%)
– Dizziness (4%)
– Musculoskeletal pain (5%)
Hence remaining upright will help with GI side effects
What are the zoledronic acid side effects?
- Infusion reaction – fever, myalgia, headache, flu-like
symptoms, arthralgia - Free from GI issue
How might be avoid the side effects of oral bisphosphonates?
We can in some circumstances provide the doses in monthly intervals to only provide side effects once a month
What are the serious side effects of Bisphosphonates?
Osteonecrosis of the jaw
Atypical sub-trochanteric fractures
Severe musculoskeletal pain
Acute renal injury
Atrial fibrillation
Esophagitis, reflux and ulcers
Esophageal cancer
What is Osteonecrosis of the jaw?
– Complication associated with pain, swelling, exposed bone,
local infection and jaw fracture
How is osteonecrosis of the jaw caused?
- Cancer patients; Immunocompromised; High dose; IV zoledronic acid;
Invasive dental procedures; Steroid use; Smokers;Diabetes
What are the oral bisphosphonate risk? (Person year)
25 per 100 000 person years
Doubles with use >5 years
Which other healthcare provider should be aware of bisphosphonate therapy?
- If invasive dental procedure planned, some would prefer delaying the
initiation or holding bisphosphonate, but there is a lack of data in this
area
What is Atypical sub-trochanteric fractures?
Changes in bone remodeling may inhibit ability of bone to
heal micro-trauma
What is the onset of atypical sub-trochanteric fractures?
Generally occurs 7 years into the treatment
Where does a sub trochanteric fracture occur?
Occurs not at the joint but away from it
What leads to an increase to atypical sub-trochanteric fractures?
– Risk increases with duration of exposure
– Risk returns to baseline once discontinued
If atypical sub-trochanteric fractures how would it present?
– May present as unusual thigh pain or dull ache
– Recommend further evaluation with a bone scan
– If atypical fracture identified: discontinue
bisphosphonate, use alternate therapy
Which drug is more associated with acute renal injury?
zoledronic acid
What is important to do prior to recieving a zoledronic acid infusion?
Must ensure adequate hydration prior to infusion
What populations should Bisphosphonates be cautioned in?
Pregnancy, Crosses the placenta and accumulates in fetal bones
No harms noted though (Only anmimal data)
Generally someone taking Bisphosphonates would not be pregnant
What medication conditions are Bisphosphonates be contraindicated? (5)
– Esophageal abnormalities
– Inability to stand/sit up for 30 minutes
– Hypocalcemia
– CrCl <35ml/min?
What is the duration of therapy for Bisphosphonates?
– Needs to be highly individualized
* Long bone half-life, less benefit with increased risks with long term use
- “Drug holiday”= Temporary discontinuation after a certain time period
3-6 years
Why would we have a duration of therapy >6 years?
6 if hx of hip, vertebral or multiple nonvertebral fractures OR new or
ongoing risk factors for accelerated loss or fracture
What would be a means of extending therapy of bisphosphonates?
If in adequate response or ongoing concern for fracture during
therapy, extend or switch therapy, reassess for secondary causes
and seek referral to specialist
What is defined as an inadequate response of Bisphosphonates?
In adequate response should be considered when > 1 fracture or
substantial bone density decline (e.g., > 5%) despite adherence to tx
(typically >1 year)
What are someo f the key counselling points of Bisphosphonates?
Explain the benefits?
Importance of proper administration
Discuss importance of other factors for bone heatlh
Exercise, adequate calcium and vitamin D intake, lifestyle factors
What are some common side effects to counsel on with bisphosphonates?
mild heartburn/reflux, mild MSK pain
Take a moment to review the next slide about Bisphosphonates
What is Prolia?
Denosumab
What is the MOA of Denosumab?
Binds to RankL which will prevent the activation of osteoclasts
What are the main roles of Denosumab?
– Cannot adhere to dosing requirements of oral
bisphosphonates
– Intolerance to oral bisphosphonates
– Severe renal impairment
What is the onset of Denosumab?
– Markers of bone resorption markedly decreased within 3 d
– Maximal reduction within 1 month
What is the duration of therapy with Denosumab?
– Indefinite treatment recommended:
* Benefits of denosumab rapidly lost upon discontinuation
* Fracture risk sharply increases
What is the dosing administration of denosumab?
For all osteoporosis indications: 60mg administered once
every 6 months
What is the renal impairment Restrictions of Denosumab?
- Used down to CrCl 30ml/min
- May be cautiously used between 15-30ml/min
- Generally not recommended if <15ml/min or dialysis
What are the common side effects of Denosumab?
– Very well tolerated
– Only a few side effects greater than placebo rates:
* Rash / eczema
* MSK pain
What are the serious side effects of Denosumab?
Hypocalcemia
Osteonecrosis of Jaw
Atypical fractures
Immune system?
Rebound fracture risk upon discontinuation
What populations are we worried about with individuals who use Prolia with respect to calcium
– If at risk patient (eg. renal impairment), ensure adequate
calcium levels prior to initiation
What is the concern with effect on the immune system with respect to prolia?
Concern with increased infection risk, but this drug is not considered an immunosuppressive
May increase severe infection such as Cellulitis requiring
hospitalization, Diverticulitis, Pneumonia, Appendicitis
Denosumab Rebound fracture risk upon discontinuation description
Just generally increased and any BMD gains are lost within 12-24 months
What is important for monitoring when on prolia?
– Calcium levels if renal impairment
– Otherwise, as with bisphosphonates
When is prolia contraindicated?
– Hypocalcemia
– Pregnancy or lactation
What is the overall efficacy of denosumab/prolia?
– Observational data suggests similar fracture risk reduction vs.
bisphosphonates
– But a/e risk slightly higher
What are important counseling points for this drug?
Adherence
Indefinite therapy generally
Calcium and Vit D intake
Watch for Severe dental pain, atypical fractures, infections
What is the MOA of Raloxifene
Selective estrogen receptor modulator
Binds to estrogen receptor and acts as an agonist, Therefore decreasing bone resportion, increasing BMD,
Acts as an estrogen antagonist in breast and uterine tissues
What role is raloxifene?
– 3rd line prevention option for postmenopausal women
– Patient who cannot tolerate bisphosphonates or denosumab
– Postmenopausal women with increased risk of invasive breast
cancer
What is the onset of Raloxifene?
– Years to observe maximum BMD changes
– Typically lifelong therapy
– No residual benefit to bone after discontinuation
– BMD decreases similar to placebo upon discontinuation
What is the dosing and administration of Raloxifene?
- 60 mg once daily
- Caution if CrCl <50ml/min
What are the common side effects of Raloxifene?
– Flushing
– Flu-like symptoms
– Leg cramps
– Peripheral edema
– Increase in triglycerides
What are the serious side effects that may occur when on raloxifene”
Venous thromboembolism
Stroke
When is VTE risk highest when on raloxifene?
first 4 months of therapy
What are the precautions of raloxifene?
– High risk of venous thromboembolism or stroke
– Hypertriglyceridemia
– Moderate-severe renal impairment
What are the contraindications of Raloxifene?
– Pregnancy
– History of venous thromboembolisms
What are the Drug interactions of Raloxifene?
– No CYP enzyme interactions
– Bile acid sequesterants decreases absorption of raloxifene
– Raloxifene decrease absorption of levothyroxine
What should be monitored with raloxifene therapy?
– Lipid profile if at risk of hypertriglyceridemia
– Otherwise, as with bisphosphonates
What is the efficacy data in women? (3)
– Less BMD increases than bisphosphonates and denosumab
– Does not reduce hip fractures
– Ineffective in premenopausal women
What are the Non-bone benefits?
Decreases LDL, but does not decrease risk of CVD,
Reduces Breast cancer risk,
Possible higher risk of DVT/stroke
Does not cause endometrial hyperplasia
Lowers mortality if used in proper populaton
Reduces high risk of vertebral fractures and breast cancer (Not huip fractures)
What are the counselling points of raloxifene?
– Raloxifene is typically longterm therapy
– Emphasize Calcium and Vitamin D intake
– Lifestyle modifications
– Common side effects: flushing, edema, cramps
– Watching for serious side effects:
* Signs and symptoms of a DVT
– Assess and be aware of risk factors for DVT
What is the role of hormone therapy for osteoporosis?
- Aimed at preventing menopausal associated bone loss
- Additional benefit of treating menopausal symptoms
What is the role of hormone therapy
– Women with persistent menopausal symptoms and cannot
tolerate bisphosphonates or denosumab
– For postmenopausal females aged < 60 yr or within 10 yr of who
prioritize alleviation of substantial menopausal symptoms, HRT can be
an alternative option to bisphosphonate therapy.
What is the general duration of treatment of hromone therapy?–
– Maximum protection if used longer term and initiated
shortly after menopause
- But HRT is not used indefinitely and should be reassessed q1-12
months
– Likely accelerated bone loss after stopping estrogen
What is the dosage and administration of hormone therapy?
– Lower doses of estrogen may effectively prevent bone loss
* Conjugated estrogen 0.3mg oral daily
* Micronized estradiol 0.5mg oral daily
* Estradiol patch (25ug to 50ug weekly)
What are the safety concerns of hormone therapy?
– Increased endometrial / breast cancer risk
– Thromboembolism risk
– CHD risk increase
– Stroke risk
– Urinary incontinence
(Low frequencies)
What is Teripartide?
- More potent than bisphosphonates and denosumab
- Expensive, non-formulary drug
What is the role of teriparatide?
– For use in men or postmenopausal women with the highest
fracture risk:
- Prior fragility fractures who continue to have fractures
despite treatment - Very low BMD
- BMD continues to decline on other treatments
What is the MOA if Teriparatide?
– Is recombinant human parathyroid hormone
– Acts as an anabolic agent, similar to physiologic parathyroid
hormone
– Stimulates osteoblast function, increases calcium uptake
What is the onset and duration of Teriparatide?
– Maximum approved duration of lifetime was 2 years – cancer
concern; but recently changed by FDA
What is the dosage and administration of Teriparatide?
– Subcutaneous 20mcg once daily into thigh or abdomen x 24
months
– Available as a multidose, prefilled syringe
What are the common side effects of teriparatide?
– Nausea
– Dizziness
– Leg cramps
– Orthostatic hypotension / syncope
What are the serious side effects of Teriparatide?
Hypercalcemia,
Hypercalciuria
Osteosarcoma
What is hypercalciuria?
Renal stones
Who should we seek guidance from with respect to teriparatide?
Specialists
Why is the duration of terparatide lower?
Osteosarcoma potential
What should be monitored while on Teriparatide?
– Must check Ca, SCr, PO4 and ALP prior to initiation
– Calcium every 3-6 months thereafter
What is the efficacy data of teriparatide?
– Significant reductions in vertebral and non-vertebral fractures,
Unknown benefit in hip fractures
– Additionally reduces back pain associated with osteoporosis
– May accelerate fracture healing time
How do we discontinue teriparatide?
Transitioning to a bisphosphonate or denosumab will preserve
BMD gains
What is the MOA of Romosozumab?
– humanized monoclonal antibody directed against sclerostin (an
osteocyte-derived glycoprotein that inhibits bone formation
– Acts as an anabolic agent and anticatabolic
What is the onset and duration of therapy of romosozumab?
– Treatment duration is 12 months
– Gains in bone density are lost after stopping unless an
antiremodelling agent is started
What is the role of Romosozumab?
For use in men or postmenopausal women with the highest
fracture risk: Fractures despite treatment. Very low BMD continues to decline on other treatment
What is the dosage and administration of Romosozumab>
– Monthly SC injections (210 mg q month)
What are the common side effects of Romosozumab?
– Musculoskeletal /joint discomfort
– headache
– Injection site pain/erythema
What are the serious side effects of Romosozumab>
– Osteonecrosis of the Jaw
– Atypical fractures
– MI, stroke
What are the precautions one should take before starting Romosozumab
– History of MI/stroke within the last year
What is Romosozumab contraindicated?
– Pre-existing hypocalcemia
– Pregnancy or lactation
What are the two different type of bone?
Cortical and Cancellous
What is Cortical Bone?
80% of weight if the adult skeleton that forms the dense outershellWh
What is Cancellous?
20% of weight of the adult skeleton and it is porous forms interior structures
What are osteocalsts?
- Builds bone through synthesis of collagen matrix
- Groups of osteoblast units (osteoids) create hydroxyapatite
What are osteoclasts?
- Reabsorbs bone
- Necessary for homeostasis of acid-base, calcium & phosphate
What are osteocutes?
Regulate rate of bone mineralization
What is oxidative stress?
The process of breakdown and resorption
What is Osteoblast senescence?
Where we have the slowing down of development of Osteoblast
What is autophagy
provide quality control of bone cells hence as we age it declines and bone building becomes less robust
What occurs in decreases of sex steroid?
This is important for osteoclast activity as we see increases with lowered sex hormones
What is the role of Calcium and vitamin D in bone formation?
Calcium required for mineralization
Vitamin D helps regulate calcium
What occurs when we have low serum calcium levels/
What occurs when have have high serum calcium levels?
What occurs as we age?
Osteocute death accelerates,
What does osteocyte death lead to>
– Increased surface remodeling
– replacement with weaker mineralized connective tissue
– disruption in repair signaling
– decrease in bone vascularity
When does bone mass peak?
3rd decade of life and decreases by 0.5% per year
Women will lose what % of trabecular and % of cortical bone?
Women will lose 50% of trabecular and 35% of cortical bone. Men
will lose 2/3 of these amounts
What are the most common fractures?
Vertebral fractures most common (50%), followed by hip and
distal forearm
How does Race increase risk of osteoporosis?
White and asian are at higher risk
How does Calcium intake during growth increase risk of osteoporosis?
Low calcium means we have low bone growth
How does menopause increase risk of osteoporosis?
Decrease in estrogen especially women who go through early menopause
How does Family history increase risk of osteoporosis?
Parenteral hip fractures
How does small stature increase risk of osteoporosis?
Low body weight and fine bone structure
How does weight increase risk of osteoporosis?
Low body weight is a risk factor, and weightlessness
How does Oophorectomy and hypogonadism increase risk of osteoporosis?
Delayed puberty leads to delayed bone formation
How does cushings syndrome increase risk of osteoporosis?
Increases in steroid
How does multiple myeloma increase risk of osteoporosis?
Just because it is a cancer
How does malabsorption syndromes increase risk of osteoporosis?
Unable to absorb calcium
How does heparin increase risk of osteoporosis?
Long term use 10-15% per year if used long term.
what duration of therapy does glucocorticoid
therapy do we need to consider increase risk of osteoporosis?
– (>3 months cummul/yr; avg dose 7.5mg/d)
What do the antiepileptics do with risk of osteoporosis?
They increase the the breakdown of vitamin D
Which drugs in excess may lead to osteoporosis?
Thyroid supplement and vitamin A/retinoids excess
What are some criteria for diagnosis of osteoporosis?
Vertebral compression fracture, hip fracture, or >1 fragility
fracture over 50 years of age is diagnostic
What score helps us differentiate between osteoporosis and osteopenia?
BMD <-2.5, (Osteoporosis)
BMD -1 to -2.5 (Osteopenia)
Who should be screened for osteoporosis?
Men and women >50 should begin routine assessment of risk
factors for osteoporosis and fracture
After screening what are the years of re-screening recommended?
– If screened and low risk, reassess in 5 years
– If moderate risk (and not treating), reassess in 1-3 years
What may be indicative osteoporosis when performing a physical?
What are the labs usually ordered for osteoporosis diagnosis?
- Calcium, corrected for albumin
- Phosphate
- Creatinine (eGFR)
- Alkaline phosphatase
- Thyroid stimulating hormone (TSH)
- 25-hydroxy vitamin D (25-OH-D)
– Should be measured after 3-4 months of adequate
supplementation and should not be repeated if an optimal
level ≥75 nmol/L is achieved. - Serum protein electrophoresis for patients with vertebral
fractures
If under 50 what score do we use?
Z-score which is catered for individuals within their age demographic
What are the indications for BMD testing in adults?
– Age 50 – 64 with a previous osteoporotic-related fracture or > 2
clinical risk factors for fracture
– Age > 65 with 1 clinical risk factor
* See risk factors on next slide
– Age > 70
What is secondary osteoporsis?
Generally secondary to a medication start
What is the Caroc?
The one with the graph
What is Frax
Incorporates more variables
When should BMD be repeated?
How much caffeine may cause increases in lower BMD rate?
> 4 cups per day
What should be the average calcium intake for men?
– Men
* 51-70 years: 1000 mg calcium /day
* > 70 years: 1200 mg calcium /day
What should be the average calcium intake for women?
- > 50: 1200 mg calcium /day
