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-30s 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 womens 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:

WHOs new guide to identify an individuals 10-yr risk of osteoporotic fracture Goal: Ensure that those at high risk are treated
Allows for calculation even if no BMD available

Accounts for nine clinical risk factors +/- hip BMD

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 RFs 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

insufficiency secondary HPTH Cushings Hyperthyroid Multiple myeloma Osteomalacia Pagets Dz GI malabsorption / celiac Mets to bone
Renal

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
X-rays not good for early detection: 20-40% of BMD must be lost to detect

Imaging

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 nonvertebral 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. 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)

Those with or at risk of deficiencies

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 Clinicians 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

PTH

Anabolic

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

paper
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: Pagets 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;296:2927-2938)

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 Slight increase BMD with Denosumab (NEJM 2006;354:821)

Vs. Alendronate

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 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 7590% 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).
Asymptomatic vertebral compression fracture Ongoing local/ systemic infection Retropulsed bone fragment causing myelopathy Uncorrectable coagulopathy Physical obstruction of spinal canal (JVIR 2003)

Contraindications:

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