Osteo TX Flashcards
Strategies to prevent fracture
Exercise stimulates
Stimulates osteoblast activity
Exercise clinical benefit
Lowers fall risk
Decreases risk of fractures
Possibly better maintenance of BMD
Exercise type s
Encourage a variety of types and intensities but prioritize balance, functional and resistance training > twice weekly
- Increase over time
Functional exercises
Exercises that improve ability to perform everyday tasks, or do activities for fun or fitness (e.g., chair stands for sit-to-stand ability, stair-climbing to train for hiking).
Exercise that the patients wants to do
For patients who wish to participate in other activities (e.g, walking, impact exercise, yoga, plates) for enjoyment or other benefits
They should be encouraged if they can be done safely or modified for safety
They should be in addition to, but not instead of balance, functional and resistance training
Exercise guidelines
getting ≥ 150 min of moderate to vigorous physical activity per week, but prioritize balance, functional and resistance training.
Impact exercise?
only progress to moderate (e.g., running, racquet sports, skipping) or high (e.g., drop or high vertical jumps) impact exercise if appropriate for fracture risk or physical fitness level;
safety or efficacy is uncertain in individuals at high fracture risk
Reduce alcohol intake to….
Les sthan 2 drinks per day
caffeine
Avoidexcess - >4 cups per day may lower BMD by 4%
No fracture risk increase found
Calcium RDA’s
Men
51-70 years: 1000 mg calcium /day
> 70 years: 1200 mg calcium /day
Women:
> 50: 1200 mg calcium /day
Is calcium always need to be supplemented?
For people who meet the recommended dietary allowance for calcium with a variety of calcium-rich foods, we suggest no supplementation to prevent fractures
Calcium supllemnt chpoices
Calcium absorption
Prefer Calcium Citrate if patient on PPI or wants to take without food
Consuming ≤ 550mg elemental calcium at one time maximizes abs
Drug Interactions Calcium
PPI’s can decrease Ca absorption
Decreased absorption of ciprofloxacin, iron, protease inhibitors, tetracycline, thyroid medications
What is recommended: DIetary, SUpplement? Why?
Dietary sources are preferred over supplementation as excess supplementation can have adverse effects
Calcium supllement safety
Calcium may have safety issues if exceeding 2000mg/day
Nephrolithiasis
Cardiovascular disease
Dyspepsia
Constipation
Vitamin D RDAs
Men and women
< 70 years: 600 IU vitamin D/ day
> 70 years: 800 IU vitamin D/day
Health Canada recommendation for vit d supplementation
To meet the RDA, Health Canada recommends a supplement of 400 IU/day
For people at risk of vitamin D deficiency additional supplementation should be provided
Typse of vitamin? Which preferred?
Vitamin D3 = cholecalciferol; Vitamin D2= ergocalciferol
Vitamin D3 preferred
Usually 400iu or 1000iu tablets, also drops and liquids
Monitoring of vitamin D
Routine monitoring of Vitamin D is not necessary
Most Canadians are deficient
Possibly monitor if patient may require higher doses, eg. malabsorption disorders, sig. renal impairment, hypo/hyperparathyroidism, CF
If monitoring, do not repeat any sooner than 3 months after supplementation
Serum Vitamin D levels
The optimal serum 25-hydroxyvitamin level for bone health is uncertain, however the following definitions are widely accepted:
<30 nmol/L - high risk of vitamin D deficiency
30 to <50 nmol/L - potential risk of inadequacy for bone health
≥50 nmol/L - generally considered adequate for bone and overall health in healthy individuals
>125 nmol/L - linked to potential adverse effects
When to recommend pharmacotx?
First Line Mod-High
Bisphosphonates first line, denosumab second line
Very High Risk
VERY HIGH RISK (Recommend pharmacotherapy)
Recent severe vertebral fracture or >1 vertebral fracture and T-score < -2.5
Recent fracture” is defined as a fracture occurring within the past 2 yr, and “severe vertebral fracture” as vertebral body height loss of > 40%.
Very High Risk TX
Teraparatide or Romosumab should be followed by a bisphosphonate
Fracture risk guidelines re-test
5 – 10 yr if the risk of major osteoporotic fracture is < 10%
5 yr if the risk of major osteoporotic fracture is 10%–15%
3 yr if the risk of major osteoporotic fracture is > 15%.
For those on pharmacotherapy
3 years
A shorter retesting interval may be appropriate for those with secondary osteoporosis or new clinical risk factors, such as a fracture
First-line all pt’s. WHy?
Bispphosphonates
Halts BMD decline and slightly reverses loss
Fracture risk decreases independent of BMD changes
Indications bisphosphonates
Postmenopausal osteoporosis treatment and prevention
Osteoporosis treatment in men
Treatment and prevention of glucocorticoid-induced osteoporosis
Paget’s disease
Examples bisphosp
Alendronate
Risedronate
Zoledronic Acid
MOA of bisphosph
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 also prevent osteoblast apoptosis
Dose Bisphosphonates
Bioavail Bisphosph
Extremely poor bioavailability – space from all medications
Admin Bisphosp
Immediate-release tablets: empty stomach with 1 cup of water, >30 minutes before food, drink and other medications. Remain upright for 30 minutes.
Delayed-release tablets: take with 1 cup of liquid immediately after breakfast. Remain upright for 30 minutes.
Zoledronic acid: once yearly IV infusion over 15 minutes
Bisphosphonates Onset
Weeks to observe bone changes
Years to observe clinical benefit
Common S/e Bisphosphonates
GI complaints - Abdominal pain(7%), Dyspepsia(2%), Nausea(4%), Diarrhea/Constipation (3%)
Headache (2%)
Dizziness (4%)
Musculoskeletal pain (5%)
Zolderonic CAid S/E
Infusion reaction – fever, myalgia, headache, flu-like symptoms, arthralgia
Free from GI issue
What do all bisphosphonates do?
All cause transient decrease in blood calcium levels
Serious s/e of Bisphosphonates
Osteonecrosis of the Jaw (ONJ)
Atypical sub-trochanteric fractures
Severe Muscoskeletal Pain
AKI
Atrial FIbrilation
Esophagitis, reflux, ulcers
Esophogeal cancer
Bisphosphonate Necorosis of JAw
Complication associated with pain, swelling, exposed bone, local infection and jaw fracture
Dentist should be aware of bisphosphonate therapy
Atypical sub-trchanteric fractures bisphosp
Changes in bone remodeling may inhibit ability of bone to heal micro-trauma
Onset is typically 7 years into treatment
Risk increases with duration of exposure
Risk returns to baseline once discontinued
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
Muscoskletal pain Bisphos
Case reports of severe, debilitating pain
Onset highly variable
May not completely resolve upon discontinuation
Report unusual, non-improving pain immediately
AKI Bisphosp
May cause small decline in CrCl, precipitating acute kidney injury in some
Most prevalent with zoledronic acid
Must ensure adequate hydration prior to infusion
Afib Bisphosp
Most data shows no association with AF
Caution in those with severe AF or heart disease
Esophagitis Bisoph
Local irritation of esophagus
Proper administration largely avoids this
Avoid in patients with esophageal disorders
Pregancy Bisoph
Crosses the placenta and accumulates in fetal bones
Animal models show harm (difficulties with delivery, bone abnormalities, hypocalcemia)
Scarce human data available, but no harms noted
Long half-life means use should be limited to special circumstances
C.I. Bisphosp
Esophageal abnormalities
Inability to stand/sit up for 30 minutes
Hypocalcemia
CrCl <35ml/min
Bisphosp Duration of TX
Needs to be highly individualized
Long bone half-life, less benefit with increased risks with long term use
New guidelines suggest 3-6 years
6 if hx of hip, vertebral or multiple nonvertebral fractures OR new or ongoing risk factors for accelerated loss or fracture
“Drug holiday”= Temporary discontinuation after a certain time period
Inadequate response bisphosp
If in adequate response or ongoing concern for fracture during therapy, extend or switch therapy, reassess for secondary causes and seek referral to specialist
Inadequate response should be considered when > 1 fracture or substantial bone density decline (e.g., > 5%) despite adherence to tx (typically >1 year)
However, fractures or bone density decline do not always indicate in adequate response to tx (secondary causes, falls, imprecise measurements)
Denosumab
Newer biologic agent
MOA Denosumab
Binds to the “Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL)”
RANKL naturally secreted by osteoblasts, which binds to the RANK receptor
RANKL binding to RANK receptors activates osteoclasts
Denosumab will bind to RANKL instead, preventing osteoclast activation
Denosumab main roles
Cannot adhere to dosing requirements of oral bisphosphonates
Intolerance to oral bisphosphonates
Severe renal impairment
Denosumab Onset
Markers of bone resorption markedly decreased within 3 d
Maximal reduction within 1 month
Denosumab Duration
Indefinite treatment recommended
Benefits of denosumab rapidly lost upon discontinuation
Fracture risk sharply increases
Denosumab Dosing
For all osteoporosis indications: 60mg administered once every 6 months
Denosumab Renal
Used down to CrCl 30ml/min
May be cautiously used between 15-30ml/min
Generally not recommended if <15ml/min or dialysis
Common S/e Denosumab
Very well tolerated
Only a few side effects greater than placebo rates:
Rash / eczema
MSK pain
Serious s/e denosumab
Hypocalcemia
Osteonecrosis of Jaw
Atypical fractures
Concern with increased infection
Rebound Fracture upon d/c
Rebound fracture Denosumab. How to adress?
Any BMD gains made lost within 12-24 months
Retreatment returns BMD levels to previous highs
Vertebral fracture risk sharply increases 12 months after discontinuatio
**Sequential bisphosphonate therapy 6 months after last denosumab dose
Monitoring Denosumab
Calcium levels if renal impairment
C.I. Denosumab
Hypocalcemia
Pregnancy or lactation
Raloxifene MOA
A selective estrogen receptor modulator (SERM)
Binds to estrogen receptors in bone and acts as an agonist
Decreases bone resorption, increases BMD
Attenuates estrogen-related losses in menopause
Acts as an estrogen antagonist in breast and uterine tissues
Roloxifene Role
3rd line prevention option for postmenopausal women
Patient who cannot tolerate bisphosphonates or denosumab
Postmenopausal women with increased risk of invasive breast cancer
Onset of Raloxifen
Years to observe maximum BMD changes
Typically lifelong therapy
No residual benefit to bone after discontinuation
BMD decreases similar to placebo upon discontinuation
Dosing Raloxifen and renal
60 mg once daily
Caution if CrCl <50ml/min
Common side-effects Raloxifene
Flushing
Flu-like symptoms
Leg cramps
Peripheral edema
Increase in triglycerides
Raloxifene serious s/e
VTE
Stroke
Precautiosn ramoxifen
High risk of venous thromboembolism or stroke
Hypertriglyceridemia
Moderate-severe renal impairment
C.I. Raloxifene
Pregnancy
History of venous thromboembolisms
Rolixifene Risks
Less BMD increases than bisphosphonates and denosumab
Does not reduce hip fractures
Ineffective in premenopausal women
Hormone Therapy aimedat and extra benefit?
Aimed at preventing menopausal associated bone loss
Additional benefit of treating menopausal symptoms
Hormonal Therapy for who?
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
Dose Hormonal TX
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)
Safety Concerns hormonal tx
Increased endometrial / breast cancer risk
Thromboembolism risk
CHD risk increase
Stroke risk
Urinary incontinence
Teriparatide Role
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
Teripraatide MOA
Is recombinant human parathyroid hormone
Acts as an anabolic agent, similar to physiologic parathyroid hormone
Stimulates osteoblast function, increases calcium uptake
Duration Taeriparatide
Maximum approved duration of lifetime was 2 years – cancer concern; but recently changed by FDA
Dose Teriparatide
Subcutaneous 20mcg once daily into thigh or abdomen x 24 months
Side effects teriparatide
Nausea
Dizziness
Leg cramps
Orthostatic hypotension / syncope
Serious side effects teriparatide
Hypercalcemia, Hypercalciuria, Osteosarcoma
Precautiosn teriparatide
History of renal stones
Moderate renal impairment
Pre-existing orthostatic hypotension
C.I. Teriparatide
Pre-existing hypercalcemia
Severe renal dysfunction
Hyperparathyroidism
History of bone cancers
Pregnancy or lactation
Teriparatide Monitoring
Must check Ca, SCr, PO4 and ALP prior to initiation
Calcium every 3-6 months thereafter
D/C Teriparatide
Transitioning to a bisphosphonate or denosumab will preserve BMD gains
Romosozumab Role
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 continues to decline on other treatments
MOA Romosuzumab
humanized monoclonal antibody directed against sclerostin (an osteocyte-derived glycoprotein that inhibits bone formation
Acts as an anabolic agent and anticatabolic
RomosozumabDuration
Treatment duration is 12 months
Gains in bone density are lost after stopping unless an antiremodelling agent is started
Dose ROsu
Monthly SC injections (210 mg q month)
S/E Rosu
Musculoskeletal /joint discomfort
headache
Injection site pain/erythema
Serious s/e rosu
Osteonecrosis of the Jaw
Atypical fractures
MI, stroke
Precautions rosu
tory of MI/stroke within the last year
C.I. Rosu
Pre-existing hypocalcemia
Pregnancy or lactation
Rosu Monitoring
Baseline calcium
D/C Rosu
ransitioning to a bisphosphonate or denosumab will preserve BMD gains
Combo Tx
In general, combination therapy has BMD benefits, but no additional fracture benefit
Tx Failure
Defined as a BMD decreasing or a > fracture or substantial bone density decline (e.g., 5%) during therapy despite adherence and and adequate tx course (typically >1 year)
