Transcript OSTEOPOROSIS

OSTEOPOROSIS
Kristen M. Nebel, DO
March 10, 2010
OBJECTIVES
Define
 Review Bone pathology
 Review risk factors, updated screening
recommendations, evaluation
 Male Osteoporosis
 Skilled care and osteoporosis
 Prevention and Treatment
 Vertebral Fracture management

OSTEOPOROSIS
Definition: A disease characterized by low bone
mass and microarchitechtural deterioration of
bone tissue leading to enhanced bone fragility
and a consequent increase in fracture incidence.
 WHO: BMD T-score of -2.5 or less

STATISTICS
 Effects

approx. 8 million women in US
22 million women with osteopenia
 By
2020 14 million men and women
 Risk of fragility fractures


250,000 hip and 500,000 vertebral/ year in
women
MORE trial: Risk of osteoporotic fracture >
risk of CV event (MI or CVA) or breast CA
 Risk
of 2nd vertebral fracture within one
year is 20%
STATISTICS

Impact of osteoporosis-related fractures:
2005 estimated Healthcare cost:$17 billion
 432,000 hospital admissions
 183,000 skilled care admissions (NOF.org)

BONE PATHOPHYSIOLOGY

Bone Strength

Related to bone mass (measured by BMD) and other
factors, such as remodeling frequency (bone
turnover), bone size and area, bone
microarchitechture and degree of bone mineralization
BONE PATHOPHYSIOLOGY

Normal: Cyclic bone remodeling

Osteoclasts: The mineral content of matrix is first dissolved
and the remaining protein components of the matrix
(primarily collagen) are then degraded by proteolytic
enzymes secreted into the resorption space.
BONE PATHOPHYSIOLOGY

Normal bone remodeling:

Osteoblasts: Synthesize new bone by first laying
down a new protein matrix, principally composed of
Type I collagen into the resorbed space.
Individual collagen molecules become interconnected by
formation of pyridinoline cross-links to provide extra
strength.
 Bone mineralization occurs with deposition of
hydroxyapatite.

BONE PATHOPHYSIOLOGY

Bone Turnover Markers

Formation: bone-specific alkaline phosphatase and
osteocalcin

Resorption: carboxy terminal peptides of mature
collaged (N-telopeptide and C-telopeptide) and
deoxpyridinoline
SOMETHING SOMEWHERE WENT
TERRIBLY WRONG
BONE PATHOPHYSIOLOGY

Abnormal: Imbalance of remodeling

High bone turnover rate leads to weakening due to
weaker trabecular/ cancellous bone
BONE MASS CHANGES
Peaks by mid-30’s
 Bone loss begins several years prior to
menopause
 Risk of fracture increases with BMD loss



Compared to younger women: odds of having OP in 6569 y/o is 5.9x higher and in 75-79 y/o is 14.3x higher
Genetic factors contribute 80% to a women’s risk
of osteoporosis


BMD is likely to be lower in women with + FHX of
osteoporosis than those without.
Risk of hip fx:
50% greater if 1st degree relative had + fx
 127% greater if parent had hip fx

OSTEOPOROSIS:
CONSEQUENCES
Reduced QOL
 Increased mortality (20%)
 Failure to return to baseline (50%)
 Depression

RISK FACTORS FOR
OSTEOPOROTIC FALLS: NOF
Body weight <70kg
or BMI<21
 Corticosteroids
 Personal history of
fractures as adult
 First-degree
relative with
fragility fracture
 Current smoking

Early menopause
 Nutrition
 Decreased activity
 ETOH
 Impaired vision
 Dementia
 Poor health
 Recent falls

FRACTURE RISK ASSESSMENT
(FRAX)

Introduced in 2008:



WHO’s new guide to identify an individual’s 10-yr risk
of osteoporotic fracture
Goal: Ensure that those at high risk are treated
Accounts for nine clinical risk factors +/- hip
BMD

Allows for calculation even if no BMD available
Designed to decide who and when to newly treat
(not for those currently on treatment)
 Therapy indicated if 10-yr. risk of hip fracture
>/= 3% or other major fracture risk >/= 20%


Cut-off for therapy based on new cost-effective
treatment thresholds (Tosteson et al. Osteop. Int. 2007)
FRAX


FRAX
Does not apply to premenopausal women and
men < 50 y/o
BMD TESTING
RECOMMENDATIONS
 USPSTF/
NOF
ALL women 65+
 MEN >/= 70
 Younger postmenopausal women and men 5070 with clinical RF’s
 Adults with fracture after age 50
 Adults with a condition or a medication a/w
low bone mass
 Perimenopausal women with high-risk risk
factors (ie-meds, low BMI, h/o low-trauma
fracture)

SCREENING METHODS

Dual-energy x-ray absorptiometry = preferred
Femoral neck BMD is best predictor of hip fx
 Forearm BMD predicts non-hip fractures


Ultrasound densitometry (sahara screen)
SCREENING AND MEDICARE
COVERAGE (ICD-9 CODES)
 Medicare
covers BMD testing for the
following individuals 65 and older




Estrogen deficient women at clinical risk for
osteoporosis (627.2)
Individuals with vertebral anomalies (733.90)
Individuals receiving, or planning to receive,
long-term glucocorticoid therapy of at least
5mg for 3 months (V58.69)
Individuals with primary HPTH (252.00)
 Medicare
permits repeat BMD testing
every 2 years
OSTEOPOROSIS EVALUATION

“Silent fractures”
Check for loss of height (>5cm)
 Up to 70% of vertebral fractures may be
asymptomatic
 In an evaluation of 2 primary care offices only 38% of
patients with a history of vertebral fracture were
evaluated for and treated for osteoporosis.

(Neuner et al. JAGS 2003)
MALE OSTEOPOROSIS
Morbidity and mortality much higher in men
than women with osteoporotic fracture
 Secondary causes more common accounting for
50%


ETOH (15-20%), glucocorticoid (20%), and
hypogonadism (15-20%)


Androgens may inhibit bone resorption
3-6% of men in US (NHANES III study)

28-47% with osteopenia
1/3 of men 60+ are likely to have an osteoporotic
fracture
 Average onset is 10 yrs later than in women
 Men often asymptomatic at onset

MALE OSTEOPOROSIS
 Previously,
no formal recommendations
 Now, WHO recommends BMD for


ALL men >70
Men 50-70 with risk factors
 BMD
should be compared to male
references so that osteoporosis diagnoses
are not missed

BMD of hip is most reliable indicator due to
prevalence of spinal degenerative changes
OSTEOPOROSIS EVALUATION

When to suspect secondary causes:





Premenopausal women
Patient without risk factors
Men <70
Multiple health problems
Worsening osteoporosis despite therapy
SECONDARY CAUSES
 Medications
 Renal
insufficiency  secondary HPTH
 Cushing’s
 Hyperthyroid
 Multiple myeloma
 Osteomalacia
 Paget’s Dz
 GI malabsorption / celiac
 Mets to bone
OSTEOPOROSIS EVALUATION
 Labs







CMP, phosphate, CBC, ESR, TSH/FT4
Testosterone/ Estrogen
SPEP
24 hour urine for calcium and creatinine
25-OH Vit. D
Intact PTH
Biochemical markers of bone turnover
 Imaging

X-rays not good for early detection: 20-40% of
BMD must be lost to detect
OSTEOPOROSIS AND SKILLED
CARE: TO TREAT OR NOT TO
TREAT?
 AMDA
2004 Quality Indicators:
Prevention: Within 1 month of admission all
females to be offered Calcium, vitamin D, and
weight-bearing exercises.
 Mobilization: Attempted in bedfast individuals
unless contraindicated
 New Dx: Calcium and Vitamin D started
within 1 month
 New Dx: Therapy started within 3 months
 Corticosteroid tx for > 1 month: start calcium
 New Dx: Evaluate meds for secondary causes
 New Osteoporotic fx in ambulatory resident:
Physical therapy should be started within 1
month

OSTEOPOROSIS AND SKILLED
CARE: TO TREAT OR NOT TO
TREAT?
 Osteoporosis
present in up to 80% of
residents
 Most significant independent RFs for fracture

Low BMD and dependence for transfers (>3x
fracture risk of those w/o low BMD)
(Duque et al. JAMDA ’06)
 Dx
in LTC
BMD not always appropriate
 Quebec Symposium for LTCI: Diagnosis based on
patient risk factors, physical exam (kyphosis,
fractures), x-ray and loss of height
 Calcaneal BMD
 Vitamin D level

OSTEOPOROSIS AND SKILLED
CARE: TO TREAT OR NOT TO
TREAT?
 Studies
estimate that therapy for
osteoporosis, including calcium and
vitamin D, is prescribed in only 9-20% of
residents with documented disease.
(Wright. JAMDA
2007)
 Factors




contributing to lack of prescribing
Compliance
Tolerance
Price
Risk vs. Benefit

Life expectancy, ambulation, time to efficacy
GENERAL TREATMENT AND
PREVENTION RECOMMENDATIONS
 Nutrition

Calcium
Dose increases with age due to decreased absorption
 Decrease bone loss by 1%/ yr.
 Greatest benefit in elderly, late-menopausal, and
those with low baseline calcium intake


Vitamin D

Recommended intake 800-1000 IU
Meta-analysis (JAMA) showed reduced risk of hip and
non-vertebral fractures with 700-800 IU/day
 Natural sources: fatty fish, fish liver oils, and fortified
foods
(milk = 400 IU /qt.)

GENERAL TREATMENT AND
PREVENTION RECOMMENDATIONS

Calcium and Vitamin D

Augmentation of other agents

Studies of etidronate in individuals with Vitamin D > 40
showed greater increase in BMD measured at L-S and
femoral neck compared with levels < 40
(Boonen et al. JAGS 2004)


Given to all on osteoporosis therapy
Patients receiving corticosteroids


RA patients on prednisone lost 1-2% BMD/ yr. Those
randomized to calcium (1000mg/d) and Vit. D (500IU/d)
gained BMD at about 0.5%/yr.
Those with or at risk of deficiencies

Secondary HPTH due to hypovitamin D showed improved
BMD on Alendronate and Vit. D compared with those only
on Alendronate
(Baron et al. JAGS 2005)
GENERAL TREATMENT AND
PREVENTION RECOMMENDATIONS

Caffeine




Recommend < 4 cups/ d
May reduce calcium absorption
Some association with increased bone loss and fracture
rates
Vitamin K

May help with bone metabolism and reducing urinary
calcium excretion


No recommendations for supplementation
No association between Coumadin and fractures
GENERAL TREATMENT AND
PREVENTION RECOMMENDATIONS

Vitamin A



RDA of 700 micrograms
High levels have been associated with increased risk of hip
fracture in 2 out of 3 studies
Magnesium
Some epidemiologic studies showed correlation with increased
BMD in elderly and females
 Easily obtained in daily food intake
 Deficiencies may exist in elderly and those with GI
malabsorption


ETOH
Can suppress osteoblasts
Moderate intake (1-2 oz/week) in women 65+ is associated
with higher BMD and decreased risk of hip fracture
 Heavy intake (>7oz/week) increases risks of falls and hip
fractures


NON-PHARMACOLOGIC
INTERVENTIONS

Rehabilitation

Exercise
Strengthening muscles: backs and legs
 Prospective 10-year study showed decreased risk of
vertebral fractures (Sinaki)





Orthotics
Gait training
Pain Management
Avoiding substances of abuse
PHARMACOLOGIC OPTIONS

Who to treat (NOF Clinician’s Guideline 2008)

Treatment: Postmenopausal women and men 50+ with
BMD T-score of -2.5 or less
 Any hip or vertebral fracture
 BMD T-score of -1.0 to -2.5 AND prior fracture (new)
 BMD T-score of -1.0 to -2.5 AND secondary causes a/w high
risk of fracture
 BMD T-score of -1.0 to -2.5 AND 10-yr prob. of hip fx >/=
3%, major fx >/= 20%


Prevention
Women with BMD hip T-score of -2.0 or less and no risk
factors
 Women with BMD hip T-score of -1.5 with one or more risk
factors and does not meet FRAX criteria

PHARMACOLOGIC OPTIONS

Antiresorptives
Estrogens/HRT
 Selective-estrogen receptor modulators (SERMS)
 Calcitonin
 Bisphosphonates


Anabolic

PTH
ESTROGENS/HRT
Recommended for prevention only
 WHI: 5 years - 16K women ages 50-79 (mean 63)
w/ uterus and no screening for osteoporosis
 Increase in BMD
 Decrease in hip, vertebral, and other osteoporotic
fracture rates
 Increased risk of CV events, VTE, and Breast
CA; decrease in colon CA

SERMS: RALOXIFENE (EVISTA)
Prevention and Treatment of postmenopausal
OP Vertebral fracture risk
 Daily oral dosing
 Modest increase in BMD of spine and hip;
decreases bone turnover
 Multiple Outcomes of Raloxifene Evaluation
(MORE): 3 year study of 7,700 women with OP


Postmenopausal OP +/- previous vertebral fracture


Insignificant results: 30% and 50% reduction in risk of
vertebral fracture
Side effects: hot flashes, leg cramps, increased
VTE
CALCITONIN (MIACALCIN)
Treatment of postmenopausal OP (at least 5
yrs.) only
 Patients unable to tolerate other agents
 Daily dosing as nasal spray, SC injection, and
oral
 Minimally inhibits bone resorption; possible
analgesic effect for acute vertebral fx
 PROOF trial: At 5 yrs 33% reduced risk of new
vertebral fx (200 mcg). After 5 yrs, increased dose
(400 mcg) required to perpetuate BMD increase
 Side effects: nasal irritation, nausea, local
inflammation and flushing

BISPHOSPHONATES: ALENDRONATE
(FOSAMAX)






Prevention and Treatment of Male and Postmenopausal
OP, Treatment of Glucocorticoid-induced OP
Daily or weekly dosing; oral form (tab or liquid)
Inhibits osteoclasts, Increases BMD
+ h/o spine fx: Reduces risks of all osteoporotic fractures by
50% over 3 yrs. (NOF)
- h/o spine fx: Reduces incidence of spine fx by 46% over 3
yrs.
Side effects: Gastric irritation and ulcers, CrCl <35,
hypocalcamia, ONJ
OSTEONECROSIS OF THE JAW
 American
paper
College of Rheumatology position
Case review found 60% of cases to be following oral
surgery or dental extraction. 94% of the cases
occurred with IV bisphosphonates (Pamidronate or
Zoledronic acid) and 85% had MM or metastatic
breast CA to bone.
 Non-cancer patients and oral meds not considered
risk factors
 Recommendations to avoid ONJ: treating infections
and obtaining routine dental care prior to therapy
 Appearance of intraoral lesion with exposed bone +/painful ulcers, ragged

RISEDRONATE (ACTONEL)
Prevention and Treatment of Glucocorticoidinduced, male, and Postmenopausal OP
 Daily, weekly, or monthly (75mg on 2 consecutive
days) dosing, oral form only
 + h/o spine fracture reduces risk of spine fracture
by 41-49% and hip fractures by 36% over 3 yrs.
(NOF)
 Polled data of VERT and HIP trials for women
80+ with OP showed NNT = 12 to prevent 1 new
vertebral fracture after 1 year of therapy. After 3
years of therapy NNT = 16

IBANDRONATE (BONIVA)
Prevention and Treatment of Postmenopausal
OP
 Dosing: IV q 3 months or orally daily or monthly
 Decreases risk of vertebral (not hip) fracture by
50% over 3 yrs.
 RCT by Delmas et al: Comparison of oral and IV
dosing


1400 women with OP of lumbar of lumber spine


At 1 year lumbar/ femur BMD greater in IV group greater
than PO
Side effects: flu-like illness with 1st infusion, GI
upset, arthralgias
ZOLEDRONATE (RECLAST)
 Treatment
of Postmenopausal OP
 Dosing: 5mg IV yearly
 Reduces incidence of spine fracture by
70%, hip fractures 41%, and non-vertebral
fx 25% over 3 yrs.
 Side-effects: Acute phase reactants
(arthralgia, HA, myalgia, fever)- may
pretreat with Tylenol

Risk of side effects tapers with
subsequent dosing
BISPHOSPHONATES AND ATRIAL
FIBRILLATION

Conflicting reports from population-based case
controlled studies
Reanalysis of several trials did not show increased
risk of atrial fibrillation.
 Current recommendations are not to withdraw
therapy

PTH (1-34):
TERIPERATIDE (FORTEO)
 Treatment
of high risk postmenopausal
and male OP

T-score of -3.5, fractures + T-score -2.5, and
those who fail 2 yrs of bisphosphonate therapy
 Daily
SC injections (only approved for 2
years duration)
 Anabolic: Stimulates osteoblast activity->
increased trabecular bone density
PTH (1-34):
TERIPERATIDE (FORTEO)
Side effects: dizziness, leg cramps, osteosarcoma
seen in rat trials
 Contraindications: Paget’s disease of bone, prior
radiation therapy of the skeleton, bone
metastases, hypercalcemia, or a h/o skeletal
malignancy

PTH (1-34):
TERIPERATIDE (FORTEO)

“Fracture Prevention Trial”: 20mcg/d reduced
vertebral and non-vertebral fractures by 65% and
53%, respectively

Review of FPT to assess safety and efficacy in women 75+
compared with younger women found that lumbar and femoral
neck BMD both increased significantly and new vertebral
fractures risk NNT =11
(Boonen et al. JAGS 2006)

Limitation of study: Subjects were ambulatory w/o significant
comorbidities.
CONCURRENT THERAPY
 Synergism:
Teriperatide and
Alendronate?

Small RCT 83 men: Spine and femoral neck
BMD increased greatest in PTH only group

Alendronate impaired PTH anabolic activity
(Finkelstein et al. NEJM 2003)

Recommended that bisphosphonate therapy
follows PTH (Teriperatide).
 Simultaneous
use of bisphosphonate and
other not generally recommended
EVALUATING TREATMENT EFFICACY
Repeat BMD testing every 1-2 years while
patient on therapy
 Step-up therapy
 Ensure compliance
 Evaluate for secondary causes if no improvement

STOPPING THERAPY

No real guidelines
 Study
to compare stopping Alendronate
after 5 years vs. continuing x 10yrs.
Discontinuing Alendronate after 5 years
showed moderate decline in BMD
 No significant change in nonvertebral
fractures
 Slight increase in clinical vertebral fracture
risk
 Stopping for up to 5 years does not significantly
increase fracture risk
 Patients with very high fracture risk may benefit
from continued therapy

(JAMA. 2006;296:2927-
FUTURE THERAPIES

Denosumab

Monoclonal Ab against RANKL: inhibits osteoclasts

FREEDOM trial (NEJM 2009:361:756-65)





Vs. Alendronate



3 year study, >7500 postmenopausal women (60-90) with low BMD
received med vs placebo
Improved BMD of LS (10%) and total hip (4%)
Reduced biochemical markers
Reduced incidence of new vertebral, hip, and nonvertebral fractures
Slight increase BMD with Denosumab (NEJM 2006;354:821)
Similar side effects
BMD gain is reversal with stopping medication
FUTURE THERAPIES

Strontium ranelate


Decreases osteoclast/ increases osteoblasts
? Antiremodeling effect


Tibolone


Cochrane Review: Daily treatment x 3 years vs placebo- Decrease
in vert fx (37%), nonvert fx (14%). NNT=9
Synthetic steroid with estrogenic, androgenic, and
progestagenic properties increase BMD
Growth Hormones
MANAGEMENT OF
VERTEBRAL FRACTURES
Limited clinical occurrences
 Conservative

Oral pain management
 Physical therapy


Surgical
Kyphoplasty
 Vertebroplasty

KYPHOPLASTY
 Balloon
creates a cavity in vertebral body
in which to inject cement



Restores vertebral body height in 70%
Reduces fracture
Partially corrects kyphosis
 Complications:
nerve damage and
bleeding
 Pain relief in 80-90%
 Studies vs. conservative treatment show
benefit in short-term f/u but not long-term
(Lancet. 2009 Mar 21;373(9668):1016-24)
VERTEBROPLASTY
Fluoroscopic procedure where cement is injected
into vertebral body
 Prevents further collapse, does not restore height
 Pain relief within 48 hours generally, effective in
75-90%
 Complications: fracture of pedicle, psoas muscle
hemorrhage, cement leakage, ARDS

VERTEBROPLASTY

Indications:





Painful osteoporotic fractures
Painful vertebrae secondary to invasion of tumor
Painful fracture a/w osteonecrosis
Any fracture where inflammation/ edema present on imaging
(at least 2 weeks old).
Contraindications:





Asymptomatic vertebral compression fracture
Ongoing local/ systemic infection
Retropulsed bone fragment causing myelopathy
Uncorrectable coagulopathy
Physical obstruction of spinal canal (JVIR 2003)
VERTEBROPLASTY

2 recent studies showed no significant
improvement in pain or function following
vertebroplasty vs. sham procedures
(NEJM 2009:361:569-79, NEJM 2009: 361:557-568)
THE END