OSTEOPOROSISnew.ppt

OSTEOPOROSIS

Kristen M. Nebel, DOMarch 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 US22 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 65-69 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 TESTINGRECOMMENDATIONS USPSTF/ NOF

ALL women 65+MEN >/= 70Younger postmenopausal women and men

50-70 with clinical RF’sAdults with fracture after age 50Adults with a condition or a medication a/w

low bone massPerimenopausal 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 MEDICARECOVERAGE (ICD-9 CODES) Medicare covers BMD testing for the

following individuals 65 and olderEstrogen 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 forALL men >70Men 50-70 with risk factors

BMD should be compared to male references so that osteoporosis diagnoses are not missedBMD 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

LabsCMP, phosphate, CBC, ESR, TSH/FT4Testosterone/ EstrogenSPEP24 hour urine for calcium and creatinine25-OH Vit. D Intact PTHBiochemical markers of bone turnover

ImagingX-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 monthsCorticosteroid tx for > 1 month: start calciumNew Dx: Evaluate meds for secondary

causesNew 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 prescribingComplianceTolerancePriceRisk 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 intakeVitamin 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 College of Rheumatology

position paperCase 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

Glucocorticoid-induced, 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 TylenolRisk 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 OPT-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 guidelinesStudy to compare stopping Alendronate

after 5 years vs. continuing x 10yrs.Discontinuing Alendronate after 5 years

showed moderate decline in BMDNo significant change in nonvertebral

fracturesSlight 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;296:2927-2938)

FUTURE THERAPIES

Denosumab Monoclonal Ab against RANKL: inhibits

osteoclasts FREEDOM trial (NEJM 2009:361:756-65)

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

Vs. Alendronate 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

Cochrane Review: Daily treatment x 3 years vs placebo- Decrease in vert fx (37%), nonvert fx (14%). NNT=9

Tibolone 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 cementRestores vertebral body height in 70%Reduces fracturePartially 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