Osteoporosis Flashcards
What is osteoporosis?
a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk
What are the negative impacts of osteoporosis?
QoL impact of a fracture is high
significant contributor to mortality risk
What is fragility fracture/osteoporosis-related fracture?
occurs as a result of falling from a standing height or when force is applied to the bone judged to be insignificant to fracture a normal bone
Which sort of fractures are categorized as major osteoporotic fractures?
hip, vertebra, humerus and distal forearm
-hands, feet, and craniofacial bones are not
What is the most common bone disorder seen in clinical practice?
osteoporosis
What are the two types of bone?
cortical:
-80% of the weight of the adult skeleton
-dense, forms outer shell
cancellous (trabecular):
-20% of the weight of the adult skeleton
-porous, forms interior structures
What are the three types of bone cells?
osteoblasts
-builds bone through synthesis of collagen
-groups of osteoblast units create hydroxyapatite
osteoclasts
-reabsorbs bone
-necessary for homeostasis of acid-base, calcium & phosphate
osteocytes
-regulate rate of bone mineralization
Briefly describe the pathophysiology of osteoporosis.
once remodeling balance is -ve, BMD declines
advancing age causes many bone changes:
-oxidative stress
-osteoblast senescence
-autophagy declines
sex steroids play a role
osteocyte death accelerates with age
osteocyte death leads to:
-increased surface remodeling
-replacement with weaker mineralized connective tissue
-disruption in repair signaling
-decrease in bone vascularity
low Ca–>PTH release–>mobilization of Ca & PO4 from bone
=vit D activation: increased Ca, PO4, Mg absorption, decreased PTH, increased bone resorption
high Ca–>calcitonin release
=decreased absorption of Ca and PO4, Ca excretion, prevents bone resorption
What are the roles of calcium and vitamin D?
calcium: required for mineralization of bone
vitamin D: helps regulate calcium
When does bone mass peak?
3rd decade of life
What are the risk factors for osteoporosis?
race
age
sex
weight
small stature
calcium intake during growth
menopause
family history
secondary causes (drugs, conditions, lifestyle, history)
What are some medical conditions associated with osteoporosis?
oophorectomy
hypogonadism or premature menopause
hyperparathyroidism
hyperthyroidism
Cushings
multiple myeloma
malabsorption syndromes
chronic inflammatory diseases
other (COPD, T1DM, renal)
What are some drugs associated with osteoporosis?
androgen deprivation therapy
anticoagulants
SSRIs, SNRIs, lithium
antineoplastics
antiretrovirals
calcineurin inhibitors
antiepileptics
SGLT2i, TZDs
loop diuretics
glucocorticoids (>3mo/yr, 7.5mg/d)
Depo Provera
excess thyroid supp
excess vit A and retinoids
PPIs
What are some lifestyle factors associated with osteoporosis?
nutrition
caffeine
alcohol
smoking
exercise
sunshine
What are some risk factors for falls and fractures?
age-related
environmental hazards
drug falls (anti-HTN, psychotropics)
What is the presentation of osteoporosis?
no symptomatic manifestations until fracture occurs
unexplained pain & height loss may indicate vertebral fracture
vertebral fracture=most common
-many are silent
-then distal forearm and hip
What is diagnostic of osteoporosis?
vertebral compression fracture, hip fracture or > 1 fragility fracture over 50 years of age
-single fragility fracture warrants screening and monitoring
Differentiate osteoporosis and osteopenia.
osteoporosis: BMD T-score < -2.5 SD normal peak
osteopenia:BMD T-score -1 to -2.5 SD normal peak
Who should be screened for osteoporosis?
men and women over 50yrs
-screened + low risk: reassess in 5yrs
-moderate risk + no tx: reassess in 1-3yrs
What are the steps in assessing for osteoporosis and fracture risk?
- detailed history
- physical examination
- biochemical tests
- BMD in selected individuals
- use of risk assessment tools (CAROC, FRAX)
- vertebral imaging in selected individuals
What are some considerations when collecting a history for osteoporosis assessment?
identify risk factors for low BMD, falls, and fractures
ask about:
-acute/chronic back pain
-contributing disease
-meds
What are some things we are looking for during a physical examination for osteoporosis?
weight loss
-low body weight (<60kg)
->10% weight loss since age 25
height loss
-historical height loss (>6cm)
-measure height loss (>2cm)
Get-Up-and-Go-Test
What are the recommended biochemical tests for osteoporosis assessment?
calcium
phosphate
eGFR
TSH
25-OH-D
ALP
What is the most widely used and accurate tool for BMD testing?
dual-energy X-ray absorptiometry (DXA)
Describe DXA.
“total hip”, “femoral neck” and “lumbar spine”
should not be the sole indication for treatment
measured as SDs the persons BMD is above/below control
When does diagnosis with DXA become unreliable?
if < 50 yrs
-T score=adults > 50
-Z score=adults < 50
What are the limitations of DXA?
BMD does not measure bone loss since peak bone density achieved
measures bone quantity not quality
What are the indications for BMD testing?
postmenopausal women
age 50-64 with previous osteoporotic-related fracture or > 2 risk factors
age > 65 with 1 risk factor
age > 70
What are the two risk assessment tools available for osteoporosis?
CAROC
FRAX
True or false: treatment decisions can be made from the risk assessment tools
true
Describe the CAROC tool.
validated for postmenopausal women and men > 50yrs
easier to understand than T-score
basal risk category obtained from age, sex, and T-score at femoral neck
What are the three zones with the CAROC tool?
low=<10%
moderate=10-20%
high=>20%
fragility fracture (not vertebra or hip) after age 40 or recent prolonged steroid use shifts risk category higher
fragility fracture or vertebra or hip or > 1 fragility fracture=high risk
Describe the FRAX tool.
incorporates more risk factors than CAROC
computes 10yr probability of hip fracture AND major fracture
can be used without BMD
What is the preferred risk assessment tool according to the new osteoporosis guidelines?
FRAX
What are the caveats with the risk assessment tools?
for treatment naive patients only
cannot be used to monitor response to therapy
should not be applied to individuals younger than 50
does not reflect risk reduction with therapy
may underestimate risk with certain risk factors
When should we repeat BMD?
10yr fracture risk > 15% or on pharmacotherapy:
-3yrs
10yr fracture risk 10-15%:
-5yrs
10yr fracture risk <10%:
-5-10yrs
3yrs after stopping a bisphosphonate
What are the treatment goals for osteoporosis?
prevent fractures
prevent disability and loss of independence
preserve or improve BMD
reduce modifiable risk factors
What are the lifestyle modifications to prevent fractures?
exercise
fall prevention
other
-smoking cessation and reduce alcohol
reduce caffeine
calcium
vitamin D
What are the benefits of exercise on bone?
stimulates osteoblast activity
improves QOL, strength, pain, balance, physical function
clinical benefits:
-decreased fall risk
-decreased fracture risk
-better maintenance of BMD
Which forms of exercise should be prioritized in osteoporosis?
balance, functional, and resistance training > twice weekly
-increase difficulty, pace, frequency, volume over time
What is balance exercise?
exercises that challenge aspects of balance
-shifting weight
-reduce base of support
-balance while moving
What is functional exercise?
exercises that improve ability to perform everyday tasks
What is resistance training?
exercises where major muscle groups work against resistance
What are some strategies to prevent falls?
patient education
home safety assessments
hip protectors
bars, canes, walkers
remove tripping hazards
improve balance and strength
avoid drugs associated with increased fall risk
What are some “other” lifestyle modifications to make for osteoporosis?
smoking cessation
-1 pack yr history=~10% BMD reduction
-negates protective effects of HRT for women
-BMD may return to non-smoker lvl within 10yrs
reduce alcohol intake
avoid excess caffeine
->4 cups/day may lower BMD 4%
-no fracture risk increase found
What are the RDAs for calcium?
men:
-51-70yrs: 1000mg/d
->70yrs: 1200mg/d
women:
->50yrs: 1200mg/d
What are the recommendations for calcium supplementation for a patient who has adequate dietary intake?
supplement not recommended to prevent fractures
-balanced diet: supp will have no to little effect on fractures
What are the available salts of calcium?
calcium carbonate: 40% elemental
calcium citrate: 20% elemental
calcium lactate: 13% elemental
calcium gluconate: 9% elemental
How is calcium best taken?
calc carb best taken with food (acidity to dissolve)
calcium citrate if on PPI or want to take it without food
consuming <550mg elemental calcium at one time maximizes absorption
What are the drug interactions of calcium?
PPIs (decrease absorption)
decreased absorption of ciprofloxacin, iron, protease inhibitors, tetracycline, thyroid meds
What are the adverse effects of calcium when exceeding 2000mg/d?
nephrolithiasis
CV disease
dyspepsia
constipation
dietary sources preferred over supps as excess supp can have adverse effects
What is the quick estimation method for calcium intake?
automatically give 300mg for Ca in all dietary sources
give extra 300mg for foods high in Ca
What is the RDA for vitamin D?
men and women:
-<70yrs: 600IU vitamin D/d
->70yrs: 800IU vitamin D/d
HC recommends a supp. of 400IU/d to meet RDA
What are the dietary sources of vitamin D?
few food sources:
-fatty fish (salmon, trout)
-fortified foods (milk)
-eggs
sun exposure
Describe vitamin D monitoring.
routine monitoring not recommended
-most Canadians are deficient
monitor if pt requires higher doses
if monitoring, do not rpt any sooner than 3 months after supp
What is the optimal vitamin D level for bone health?
unknown, however the following definitions are accepted:
-<30nmol/L: high risk of deficiency
-30-50nmol/L: risk of inadequacy for bone health
->50nmol/L: adequate for bone health and overall health
->125nmol/L: linked to AE
What are the choices of pharmacologic therapy for osteoporosis?
anti-resorptive:
-bisphosphonates
-denosumab
-raloxifene
-hormone therapy
anabolic:
-teriparatide
-romosozumab
When do we initiate pharmacotherapy for osteoporosis?
low risk: do not recommend
-10yr fracture risk <15% OR T-score > -2.5 (>70yrs)
intermediate risk: suggest pharmacotherapy
-10yr fracture risk 15-19.9% OR T-score < -2.5 (>70yrs)
high risk: recommend pharmacotherapy
-10yr fracture risk >20% OR T-score < -2.5 (>70yrs)
very high risk: recommend pharmacotherapy
-recent severe vertebral fracture OR > 1 vertebral fracture and T-score < -2.5
-“recent”=past 2 yr
-“severe vertebral”=vertebral body height loss > 40%
refers to postmenopausal women and males > 50yrs
What is the recommend treatment for intermediate and high risk patients?
1st line: bisphosphonates
2nd line: denosumab
What is the recommend treatment for very high risk patients?
teraparatide or romosozumab followed by a bisphosphonate
What is the mainstay of therapy and 1st line for most patients with osteoporosis?
bisphosphonates
-halts BMD decline and slightly reverses loss
-fracture risk decreases independent of BMD changes
What are the indications for bisphosphonates?
postmenopausal osteoporosis tx and prevention
osteoporosis tx in men
tx and prevention of glucocorticoid-induced osteoporosis
Pagets disease
What are examples of bisphopshonates?
alendronate
risedronate
zoledronic acid
What is the MOA of bisphosphonates?
analogues of pyrophosphate which allows for incorporation into bone
bind to hydroxyapatite undergoing surface remodeling
inhibit osteoclast activity
induce osteoclast apoptosis
may prevent osteoblast apoptosis
What are some differences in the dosing frequencies amongst the bisphosphonates?
alendronate: daily or weekly
risedronate: daily or weekly or monthly (Actonel DR)
risedronate: IV once yearly
Describe proper administration of bisphosphonates.
extremely poor F: space from all meds
IR tablets:
-empty stomach with 1 cup of water
-30 mins before food, drink, and other meds
-stay upright for 30 mins
DR tablets:
-take with 1 cup of liquid immediately after breakfast
-stay upright for 30 mins
zoledronic acid: once yearly IV infusion over 15 mins
What is the onset of bisphosphonates?
weeks to observe bone changes
years to observe clinical benefits
What are the clinical benefits of bisphosphonates?
therapy x 3yrs resulted in 20-30 vertebral, 10 nonvertebral, and 3 fewer hip fractures per 1000 people than no tx
very few harms with short-term use (<3y)
What are the common adverse effects of bisphosphonates?
GI complaints
headache
dizziness
musculoskeletal pain
zoledronic acid: infusion rx (fever, myalgia, HA, flu-like)
-free from GI issue
all: transient decrease in blood Ca levels
What are the serious adverse effects of bisphosphonates?
osteonecrosis of the jaw
atypical sub-trochanteric fractures
severe MSK pain
acute renal injury
atrial fibrillation
esophagitis, reflux and ulcers
esophageal cancer
Describe ONJ as a serious AE of bisphosphonates.
pain, swelling, exposed bone, local infection and jaw fracture
most cases:
-cancer pts, immunocompromised, invasive dental procedure, smoker, diabetes, steroid use, high dose, IV ZA
dentists should be aware of bisphosphonate therapy
risk doubles with use > 5 yrs
Describe atypical sub-trochanteric fractures as a serious AE of bisphosphonates.
changes in bone remodeling may inhibit healing of microtrauma
onset: typically 7yrs into tx
risk increases with duration, declines to baseline with d/c
may present as thigh pain or dull ache
Describe severe MSK pain as a serious AE of bisphosphonates.
severe, debilitating pain (case reports)
onset is highly variable
may not completely resolve upon d/c
report unusual, non-resolving pain ASAP
Describe acute renal injury as a serious AE of bisphosphonates.
may cause small decline in CrCl
most prevalent with ZA
-ensure adequate hydration
Describe afib as a serious AE of bisphosphonates.
most data shows no association
caution in severe AF or heart disease
Describe esophagitis, reflux and ulcers as a serious AE of bisphosphonates.
local irritation of the esophagus
proper admin largely avoids this
avoid in pts with esophageal disorders
Describe esophageal cancer as a serious AE of bisphosphonates.
inconsistent data
What are the precautions of bisphosphonates?
pregnancy
-crosses placenta and accumulates in fetal bone
-scarce human data, animal models show harm
-long t1/2=limit to special circumstances
What are the contraindications of bisphosphonates?
esophageal abnormalities
inability to stand or sit-up for 30 min
hypocalcemia
CrCl < 35ml/min?
What is the duration of treatment for bisphosphonates?
needs to be highly individualized
-long bone t1/2=less benefit and more harm with long term use
-“drug holiday”=temporary dc after certain time period
new guidelines say 3-6 yrs
-6 if hx of hip, vertebral, or multiple non-vertebral fractures OR new or ongoing risk factors
if inadequate response or ongoing concern for fracture:
-extend or switch therapy, reassess for secondary causes and seek referral to specialist
What is the MOA of denosumab?
binds to RANKL
-RANKL naturally secreted by osteoblasts, which binds to RANK receptor
-RANKL binding to RANK activates osteoclasts
denosumab will bind to RANKL instead, preventing osteoclast activation
What are the roles for 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 decrease within 3d
maximal reduction within 1 month
What is the duration of therapy for denosumab?
indefinite therapy recommended
-benefits of denosumab lost upon d/c
-fracture risk sharply increases
How frequently is denosumab dosed?
once every 6 months
What CrCl can denosumab be used down to?
down to CrCl 30ml/min
-cautiously between 15-30ml/min
-not recommended if < 15ml/min or dialysis
What are the common adverse effects of denosumab?
very well tolerated
-eczema/rash
-MSK pain
What are the serious adverse effects of denosumab?
hypocalcemia
osteonecrosis of the jaw
atypical fractures
effect on the immune system?
rebound fracture risk upon d/c
Describe hypocalcemia as a serious AE of denosumab.
causes a significant, transient decline in Ca lvls
no concern in healthy patients with adequate Ca intake
if at risk pt, ensure adequate Ca lvls prior to initiation
True or false: denosumab poses a greater risk of ONJ than bisphosphonates
false
similar risk
What are the effects of denosumab on the immune system?
concern with increased infection risk
most data suggests none
not considered immunosuppressive
Describe rebound fracture risk upon d/c as a serious adverse effect of denosumab.
any BMD gains made lost within 12-24 months
retreatment returns BMD levels to previous highs
vertebral fracture risk sharply increases 12mo after d/c
sequential bisphosphonate therapy 6mo after last denosumab dose
Describe proper monitoring for denosumab.
Ca lvls if renal impairment
otherwise, as with bisphosphonates
What are the contraindications of denosumab?
hypocalcemia
pregnancy or lactation
Describe the efficacy of denosumab.
observational data suggests similar fracture risk reduction vs bisphosphonates
AE risk slightly higher
What is the MOA of raloxifene?
a selective estrogen receptor modulator (SERM)
binds to estrogen receptor 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 tissue
What are the roles for raloxifene?
3rd line prevention option for postmenopausal women
pts who cant tolerate bisphosphonates or denosumab
postmenopausal at risk of invasive breast cancer
What is the onset and duration of therapy for raloxifene?
years to observe maximum BMD changes
typically lifelong therapy
no residual benefit to bone after d/c
-BMD decreases similar to placebo after d/c
What are the common adverse effects of raloxifene?
flushing
flu-like sx
leg cramps
increased TGs
peripheral edema
What are the serious adverse effects of raloxifene?
VTE
-risk highest in first 4 months
-should d/c if anticipate prolonged immobilization
stroke
-rate similar to placebo
What are the precautions for raloxifene?
high risk of VTE or stroke
moderate to severe renal impairment
hypertriglyceridemia
What are the contraindications for raloxifene?
history of VTE
pregnancy
What are the drug interactions for raloxifene?
no CYP enzyme interactions
decreased absorption with bile acid sequesterants
decreased absorption of levothyroxine
Describe proper monitoring for raloxifene.
lipid profile if at risk of hypertriglyceridemia
otherwise, as with bisphosphonates
Describe the efficacy of raloxifene.
less BMD increase than bisphosphonates and denosumab
does not reduce hip fractures
ineffective in premenopausal women
What are the non-bone benefits of raloxifene?
decreased LDL but does not decrease risk of heart dx
reduces risk of invasive breast cancer
does not cause endometrial hyperplasia
reduces risk of mortality IF used in right population
-high risk of vertebral fracture AND breast cancer
What is the role of hormone therapy?
women with persistent menopausal sx who cant tolerate bisphosphonate or denosumab
postmenopausal women < 60yrs or within 10yr who prioritize alleviation of menopausal symptoms
What is the duration of hormone therapy for osteoporosis?
maximum protection if used longer and initiated shortly after menopause
-reassess q1-12 months
likely accelerated bone loss after stopping estrogen
True or false: high dose estrogens are used for hormone therapy for osteoporosis
false
low doses may effectively prevent bone loss
What are the safety concerns of hormone therapy?
risk of endometrial/breast cancer
thromboembolism risk
CHD risk increases
stroke risk
urinary incontinence
What are drugs that are more potent than bisphosphonates and denosumab?
teriparatide
romosozumab
What is the role of teriparatide?
men and postmenopausal women with highest fracture risk
-very low BMD
-prior fragility fractures and continue to have fractures despite treatment
-BMD continues to decline on other treatments
What is the MOA of teriparatide?
recombinant human PTH
acts as an anabolic agent
stimulates osteoblast function, increases Ca uptake
What is the duration of therapy for teriparatide?
maximum approved lifetime duration was 2 yrs due to cancer concern
-recently changed by FDA
What is the dosing frequency of teriparatide?
SC injection OD x 24 months
What are the common adverse effects of teriparatide?
nausea
dizziness
leg cramps
orthostasis/syncope
What are the serious adverse effects of teriparatide?
hypercalcemia
-increases 10-fold after injection, returns to baseline in 4h
-alt day dosing is an option
hypercalciuria
-theoretical risk of precipitating kidney stones
osteosarcoma
-rare
What are the precautions of teriparatide?
pre-existing orthostasis
history of renal stones
moderate renal impairment
What are the contraindications of teriparatide?
pre-existing hypercalcemia
pregnancy or lactation
history of bone cancer
severe renal dysfunction
hyperparathyroidism
Describe proper monitoring for teriparatide.
Ca, PO4, SCr, and ALP prior to iniation
Ca every 3-6mo thereafter
What is the efficacy data for teriparatide?
significant reductions in vertebral and non-vertebral fractures
-hip fractures unknown
reduces back pain associated with osteoporosis
may accelerate fracture healing time
What should be done after discontinuing teriparatide?
initiate bisphosphonate or denosumab to preserve BMD gains
What is the role of romosozumab?
see teriparatide (same)
What is the MOA of romosozumab?
MAB against sclerostin (glycoprotein that inhibits bone formation)
anabolic and anticatabolic
What is the duration of therapy for romosozumab?
12 months
BMD gains lost after d/c (start antiresorptive)
How frequently is romosozumab dosed?
SC injections monthly
What are the common adverse effects of romosozumab?
injection site pain
MSK pain
headache
What are the serious adverse effects of romosozumab?
ONJ
atypical fractures
MI, stroke
What is a precaution for romosozumab?
history of MI/stroke in past year
What are the contraindications for romosozumab?
pre-existing hypocalcemia
pregnancy or lactation
What is a monitoring parameter for romosozumab?
baseline calcium
What is the efficacy data for romosozumab?
see teriparatide (same)
-one difference: reduction in hip fractures
What should be done after d/c romosozumab?
transition to bisphosphonate or denosumab to preserve BMD gains
What is the benefit of combo therapy?
BMD benefits but no fracture benefits
-not really done
What is treatment failure?
BMD decreasing or fracture or substantial bone density decline despite adherence and adequate tx course (>1yr)
-fracture and decline doesnt necessarily=failure
-assess adherence, absorption, Ca/Vit D intake
What should be done for true treatment failure?
raloxifene or hormone therapy–>bisphosphonate or denosumab
po bisphosphonate–>ZA or denosumab
ZA or denosumab–>teriparatide
Describe treatment after a fracture.
fracture healing requires normal bone remodeling
bisphosphonate best-started 2-12wks post fracture
already on bisphosphonate:
-do not d/c
-small healing delay
if atypical femur fracture while on bisphosphonate:
-d/c due to significantly delayed healing
