Osteo = bone

Porosis = full of holes

Osteoporosis = means bones that are full of holes

OsteoporosisOsteoporosis

• The most common metabolic bone disorder The most common metabolic bone disorder • Systemic skeletal disease characterized by:Systemic skeletal disease characterized by:

– Low bone massLow bone mass– Microarchitectural deterioration of bone tissueMicroarchitectural deterioration of bone tissue– Increased bone fragility and susceptibility to fractureIncreased bone fragility and susceptibility to fracture

Not a natural part of aging Increased risk for women, post-menopausal, over age 65 All races, sexes, and ages are susceptible Preventable and treatable!

In the USA, the estimated prevalence of osteopenia is 15 million in women and 3 million in men.

The estimated prevalence of osteoporosis is 8 million in women and 2 million in men.

Although, osteoporosis affects >10 million individuals in the United States, only 10 to 20% are diagnosed and treated

80% are women

Osteoporosis - Prevalence

Osteoporosis in PerspectiveLifetime risk at age 50

Osteoporotic Fractures:Comparison with Other Diseases

1996 new cases,all ages184 300

750 000 vertebral

250 000 other sites

250 000forearm

250 000hip

0

500

1000

1500

2000

Osteoporotic Fractures

HeartAttack

Stroke BreastCancer

Annu

al in

ciden

ce x

100

0

1 500 000

Annual incidenceall ages

513 000

annual estimatewomen 29+

228 000

annual estimatewomen 30+

American Heart Association,1996American Cancer Society,1996

Riggs BL & Melton LJ 3rd, Bone, 1995;17(5 suppl):505S-511S

All fractures are Associated With Morbidity

Cooper C, Am J Med, 1997;103(2A):12S-17S

40%

Unable to walk independently

30%

Permanentdisability

20%

Death within one year

80%

One year after an

hip fracture:

Patie

nts

(%)

Unable to carry out at least one independent activity of daily living

Osteoporosis Is a Serious Public Health Problem

• Affects 10 million Americans (80% women)

• 2 million fractures yearly• Direct cost $17 billion

Distribution of Fractures

Primary Care Providers Are Critical for Osteoporosis Management, Screening,

Diagnosis, and Treatment

Why Recognize & Treat Osteoporosis?Why Recognize & Treat Osteoporosis?

To Prevent FracturesTo Prevent Fractures • 1.5 million fractures/yr1.5 million fractures/yr• $17 billion direct costs$17 billion direct costs• 300,000 hip fractures/yr300,000 hip fractures/yr

– 20% die20% die– 25% confined to long-term care facilities25% confined to long-term care facilities– 50% long-term loss of mobility50% long-term loss of mobility

launched in 2010.

Vision: Towards a society free from osteoporotic fractures.

Mission: Promote health awareness among Saudi society about osteoporosis and it's relative high risk factors ,build up screening programs and comprehensive health care.

The plan contain 7 targets:•primary prevention of Osteoporosis.•secondary prevention of Osteoporosis.•improve the quality of health services at it's three levels provided to Osteoporosis patients.•support monitoring, follow up, evaluation methods related to Osteoporosis control program.• implement and support research methods and respective studies related to Osteoporosis.•society partnership to control osteoporosis

Types of osteoporosisPrimary Osteoporosis•Postmenopausal Osteoporosis

•Senile OsteoporosisSecondary Osteoporosis• Diet

• Drug

• Endocrine disease

• Other Systemic Disorders.

Impact of OsteoporosisImpact of OsteoporosisSigns Kyphosis Loss of height Abdo bulges Clinically

diagnosed fracture

Symptoms Neck becomes

weak Pain in back Breathing

difficulties Indigestion & GOR Stress incontinence Difficulty with

mobility following a fracture

Risk Factors• Chronic liver disease • Excessive secretion of cortisol (Cushing's syndrome)• Radiographic evidence of osteopenia or vertebral

deformity • Previous fracture not caused by a major accident • Cancer • Significant loss of height or an abnormal bend in the

upper spine (thoracic kyphosis)

Risk factors that have the potential to be modified include:

• Cigarette smoking • Excessive alcohol intake • Inactivity • Low body weight • Poor general health • Prolonged immobilization

Risk factors that cannot be modified include:

• Caucasian race • Advanced age • Female sex • Premature menopause (<45

years) • Prolonged time (>1 year) without a menstrual period

Conditions associated with osteoporosis:

• Anorexia nervosa • Malabsorption syndromes • Excessive secretion of

parathyroid hormone • Excessive secretion of thyroid

hormone • Post-transplantation • Chronic renal disease

BMI less than or equal to 20

BMI less than or equal to 20

Vertebrae

Hip

Wrist

50 60 70 80

40

30

20

10

Age (Years)

Annu

al in

cide

nce

per

1000

wom

en

Incidence of Osteoporotic Fractures in Women

Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72

Hip

frac

ture

risk

(% p

er 1

0 Ye

ars)

-3

60

70

80

AGE

0

5

10

15

20

50

BMD T-score-2.5 -2 -1.5 -1 -0.5 0 0.5 1

10-Year Fracture Risk: Age and BMD

For a given BMD

,risk increases with age

Kanis JA et al, Osteoporos Int, 2001;12:989-995

10-Y

ear P

roba

bilit

y of

Sy

mpt

omat

ic F

ract

ure

(%)

Age Is a Major Risk Factorfor Fracture

With kind permission from Springer Science+Business Media: Kanis JA ,et al. Ten year probabilities of osteoporoticfractures according to BMD and diagnostic thresholds. Osteoporos Int.2001;12:989-995. Adapted from Fig. 3. © 2001 International Osteoporosis Foundation and National Osteoporosis Foundation.

8070

60

50

AGE

Age 70T-score -2.524% Fx Risk

-3 -2 -1

Combined Effect of Bone Density Combined Effect of Bone Density and Risk Factorsand Risk Factors

Rate ofHip Fracture/

1000Woman-Years

Bone Density

Cummings SR et al. N Engl J Med. 1995;332:767-773.

Number ofRisk Factors

27.3

14.79.4

0

5

10

15

20

25

30

Lowest Third Middle Third Highest Third

53-4

0-2

Web Version 3.4

http://www.shef.ac.uk/FRAX/. Accessed August 2014.

Example of Applying the FRAX Tool

Which Woman is at Higher Fracture Risk?

54 year old smoker with a T-score of -2.0or

81 year old with no prior fracture with a T-score of -1.4

10 year risk of hip fracture = 2.5%; major osteoporotic fracture = 10%

10 year risk of hip fracture = 3.2%; major osteoporotic fracture = 26%

a 10 year probability of fracture in women with relation to age and T-score

Composition of bone…

Determinants Of Peak Bone Mass

Peak Bone Mass

Physical activity Gonadal status

Nutritional statusGenetic factors

Bon

e M

ass

Age (years)

Attainment of Peak Bone Mass

Consolidation Age-related Bone Loss

Men

Women

Menopause

0 10 20 30 40 50 60

FractureThreshold

Compston JE. Clin Endocrinol 1990; 33:653–682.

Age Related Changes in Bone Age Related Changes in Bone MassMass

Pathogenesis• Diminished bone mass can result from:

– failure to reach an optimal peak bone mass in early adulthood

– increased bone resorption– decreased bone formation after peak bone mass has

been achieved• All three of these factors probably play a role in

most elderly persons. Low bone mass, rapid bone loss, and increased fracture risk correlate with high rates of bone turnover (ie, resorption and formation).

• In osteoporosis, the rate of formation is inadequate to offset the rate of resorption and maintain the structural integrity of the skeleton

Osteoporosis – ScreeningX-ray findings are generally insufficient for the

screening of primary osteoporosis:• A normal x-ray of bone cannot reliably measure bone density but is useful to identify spinal factures, explains back pain, height loss or kyphosis.• X-rays may detect osteopenia only when bone loss is > 30%.• X-ray findings can also suggest other causes of metabolic bone disease, such as the lytic lesions in multiple myeloma and the pseudofractures characteristic of osteomalacia.

Bone densitometry is the only method for diagnosing or confirming osteoporosis in the absence of a fracture

Screening- Ultrasound DensitometryUltrasound densitometry can assess the density and structure of the skeleton and appears to predict fracture risk in the elderly. The apparatus is relatively inexpensive, portable, and uses no radiation but can be used only in peripheral sites (eg, the heel), where bone is relatively superficial. Ultrasound devices do not expose the patient to ionizing radiation.

Dual-Energy X-RayAbsorptiometry

• “Gold Standard” test to determine a diagnosis

• Measures hip & spine • Painless, safe and requires no

injections• Takes 5-10 minutes• Determines risk for fracture

Screening - DEXADual energy x-ray absorptiometry (DEXA) • DEXA measures areal density (ie, g/cm2)

rather than true volumetric density.

• The test is non-invasive and involves no special preparation.

• Radiation exposure is minimal, and the procedure is rapid. This is the most popular and accurate test to date and the test only takes about 20 to 40 minutes, with a 5 mrem dose of radiation (a full dental x-ray is 300 mrem).

#1 :Questions about Osteoporosis

When should Bone Density Measurement be performed?

USPSTF 2010 Recommendations :Screening for Osteoporosis

BMD testing for women 65 & older BMD in 60-64 yo if ↑ fx risk

- Use WHO FRAX® risk tool

If clinical based fracture risk of 9.3% then order bone density measurement

Nelson et al Ann Int Med July 2010

Who Should Have a Bone Density Test?AAFP and NOF

AAFP: Sweet MG, et al. Am Fam Physician. 2009;79(3):193-200.NOF: National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. www.nof.org. Accessed August 2014.

Women age 65 and older Men age 70 and older

Postmenopausal women and men ages 50–69 with clinical risk factors

Adults who have a fracture after age 50

Adults with a condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids) associated with low bone mass or bone loss

T-score

Normal -1 Osteopenia < -1 and > -2.5

Osteoporosis -2.5 Severe Osteoporosis

-2.5 with Fracture

OsteoporosisWorld Health Organization Criteria

Postmenopausal Caucasian with DXA measure

WHO Study Group JBMR 1994

Screening - DEXA

DEXA of the proximal femur in a young woman, age 37, with unsuspected femoral-neck osteopenia (T score, -1.6).

DEXA of the lumbar spine in a young woman, age 37, with unsuspected lumbar spine osteopenia (T = -1.8)

Screening - DEXA

T scores vs. Z scoresT score – number of SDs a patient’s

BMD deviates from a reference population of normal young adults

Z score – number of SDs a patient’s BMD deviates from a reference population of

subjects of the same age and sex Z scores indicate whether the BMD

result is expected for the patient’s age. If it is much less than expected, suspect

a secondary cause of osteoporosis (use –2 as a cutoff)

2014 Universal Recommendations

http://www.nof.org/hcp/practice/tools. Accessed August 2014.

Counsel on the risk of fracturesEat a diet rich in fruits and vegetables (supplemented if necessary) to a total calcium intake of•1000 mg per day for men 50-70 •1200 mg per day for women ≥ 51 •1200 mg per day for men ≥ 71 Vitamin D intake should be 800-1000 IU per day (age ≥50), supplemented if necessary Regular weight-bearing and muscle-strengthening exerciseFall prevention evaluation and trainingCessation of tobacco use and avoidance of excessive alcohol intake

The good news: Osteoporosis is preventable for most people!

75

Calcium requirements vary by age

Source: The 2004 Surgeon General’s Report on Bone Health and Osteoporosis: What It Means to You at http://www.surgeongeneral.gov/library/bonehealth

If this is your ageThen you need

this much calcium each day (mg)

0 to 6 months 2107 to 12 months 2701 to 3 years 5004 to 8 years 8009 to 18 years 1,30019 to 50 years 1,000Over 50 years 1,200

Growthspurt

FOOD SERVING SIZE CALCIUM(mg)MILK - WHOLE 1 GLASS (190ML) 225

MILK - SEMI-SKIMMED 1 GLASS (190ML) 231

MILK - SKIMMED 1 GLASS (190ML) 236YOGHURT 1 POT (150g) 225

CHEDDAR CHEESE S MALL PIECE (30g) 216COTTEGE CHEESE 2 TABLESPOONS 58

ICE-CREAM 2 SCOOPS 156SARD DIINES (with bones) 2 CAN NED 230

ORANGE 1 MEDIUM 75WHITE BREAD 2 SLICES 72BAKED BEANS 3 TABLESPOONS 64

77

Calcium An easy way to meet calcium needs

is consuming 3 cups (8 oz.) each day of fat-free or low-fat* milk or equivalent milk products in combination with a healthy diet. Children ages 2–8 years need 2 cups.

MyPyramid equivalents: • 8 oz. milk• 1 cup yogurt• 1-1/2 oz. natural ..or 2 oz. processed ..cheese

* Fat-free and low-fat are for health but not for calcium

differences

% DV calcium: Milk group• Yogurt

1 cup (8 oz.) = 30% DV• Milk

1 cup = 30% DV • Cheese

1 ½ oz. natural/2 oz. processed = 30% DV • Milk pudding

1/2 cup = 15% DV • Frozen yogurt, vanilla, soft serve

½ cup = 10% DV• Ice cream, vanilla

½ cup = 8% DV • Soy or rice milk, calcium-fortified

1 cup = varies—check label

Choose fat-free or low fat

most often

% DV calcium: Grain products group

• Cereal, calcium- fortifiedServing size and amount of calcium varies—check label

% DV calcium: Vegetable group

• Broccoli, raw1 cup = 9% DV

• Collards كرنب1/2 cup = 20% DV

• Turnip greens, لفت1/2 cup = 10% DV

% DV calcium: Fruit group

• Orange juice and other calcium-fortified beverages6 oz. = 20 to 30% DV, varies—check label

Look for 100% juice

% DV calcium: Meat & Beans Group

• Baked beans1 cup = 14% DV

• Salmon, canned, with edible bones3 oz. = 18% DV

• Sardines, canned, in oil, with edible bones3 oz. = 32% DV

• Soybeans, cooked1 cup = 26%

• Tofu, firm, with calcium ½ cup = 20% DV; check label

Calcium supplement Calcium supplement considerationsconsiderations

Calcium carbonate vs. citrate

Calcium carbonate• Needs acid to

dissolve and for absorption

• Less stomach acid as we age

• Often taken at meals when more stomach acid

Calcium citrate• Doesn’t require

stomach acid for absorption

• May be taken anytime—check with your healthcare provider

• May cost more

Limit calcium to 500 mg at a time

Our bodies can best handle about 500 mg calcium at one time from food and/or supplements.

Spread your calcium sources throughout the day.

Increase amount slowly• Start supplements with 500 mg

calcium daily for about a week, gradually adding more.

• Gas and constipation can be side effects:– Increase fluids and high fiber

foods if diet is low in whole grains and fruits and vegetables.

– Try a different type of supplement if side effects continue.

87

Vitamin D from sunlight exposure• Vitamin D is manufactured in your skin

following direct exposure to sun.

• Amount varies with time of day, season, latitude and skin pigmentation.

• 10–15 minutes exposure of hands, arms and face 2–3 times/week may be sufficient (depending on skin sensitivity).

• Clothing, sunscreen, window glass and pollution reduce amount produced.

Source: National Osteoporosis Foundation Web site; retrieved July 2005 at http://www.nof.org

You need more vitamin D as you age

Age

Daily vitamin D needs in International Units (IU)

Food Sources of Vitamin DFood Sources of Vitamin D Cod liver oil – 1 TBS Salmon 3.5 oz. Mackerel 3.5 oz. Tuna, canned, in oil, 3 oz. Sardines 3.5 oz. Milk (fortified) 8 oz. Ready to eat cereal (fortified) ¾ -

1 cup Egg 1 whole Liver, 3.5 oz. Cheese, swiss 1 oz.

1,360 IU 360 345 200 250 98 40

20 15 12

90

Sources of Vitamin D? Main dietary sources of vitamin D are:

• Fortified milk (400 IU per quart)

• Some fortified cereals

• Cold saltwater fish (Example: salmon, halibut, herring, tuna, oysters and shrimp)

• Some calcium and vitamin/mineral supplements

Vitamin D PreparationsVitamin D Preparations

FALL PREVENTION

OsteoporosisFalls Break Bones

• You can prevent most falls– Improve your balance, coordination, and strength

through weight-bearing physical activity such as dancing or Tai Chi

– Review medicines with a health care professional (some medicines may cause drowsiness or dizziness)

– Have your vision checked– Make your home safer

Protect Your BonesWays to Make Your Home Safer

1

2

3

4

5

6

7

8

9

10

11

Have handrails and plenty of light in all stairways.

Wear shoes that give good support and have non-slip soles.

Don’t use stepstools. Keep items you need within easy reach.

Maintain a clear path to the bathroom.

Make sure your walkways are wide enough.

Remove all small rugs. They can make you trip.

Move phone and electrical cords away from walkways and open areas.

Make sure that all areas are well lit. Use bright light bulbs.

Be aware that some medications, including over-the-counter medicines, can make you dizzy or sleepy.

Get your vision checked.

Remove things that you may trip over from stairs and places where you walk.

Protect Your Bones Ways to Make Your Home Safer

12

5 Remove all small rugs. They can make you trip.

Use non-slip mats in the bathtub or shower. Have grab bars put in next to your toilet and in the bathtub or shower.

Whom to Treat: NOF Guidelines 2014Whom to Treat: NOF Guidelines 2014Women ≥ 65 and men ≥ 70(younger with risk factors)

T-score between -1.0 and -2.5

T-score ≤ -2.5 in the lumbar spine, total hip, or femoral neck

or Hip or spine fracture (clinical or radiographic)

DXA test

≥ 3% for hip fracture or

≥ 20% for major osteoporotic fractures

FRAX10-y fracture risk

Candidate for TREATMENT

YES

YES

nof.org/hcp/resources/913. Accessed August 2014.

Osteoporosis Therapy AlgorithmPostmenopausal Women

At Risk/Osteopenia Osteoporosis Severe OsteoporosisSTAGELowerHigher

-2.5BMD (T-score)

Raloxifene

PTH

CalcitoninHRTHRTHRTHRT

During Hot Flushes

Post Vasomotor SymptomsPre fracture Post Fracture

Risk of Fracture

AGE

Bisphosphonates Or Strontium Ranelate

50 55 60 65 70 75 80 85 90

Osteoporosis Prevention and Treatment

Age

Hormonal Replacement

Bisphosphonates Strontium

SERM

20 40 60 80

Vitamin D

PTH

Life Style

Treatmentchoice

One-Minute Treatment DecisionOne-Minute Treatment Decision

Therapy DecisionTreat all patients with an existing fracture

High Risk-Treat

Moderate Risk - Treat if other risk factors

Low Risk-Check again in 1-2 years

T-Score *

Below -2.0

-1.5 to -2.0

Above -1.5

National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998.

Osteoclast

Inhibition of resorption

Osteoblast

Stimulation of formation

Pharmacologic TreatmentTargets

Prevention Treatment

FDA-Approved Therapeutic Options

Estrogen

AlendronateRisedronateIbandronate

Zoledronic acidRaloxifene

Calcitonin

PTH (teriparatide)Denosumab

FDA-approved Medications

OsteoporosisPost-

menopausalGlucocorticoid-

induced Male

Drug Prevent Treat Prevent Treat

Estrogen

Calcitonin* (Miacalcin®, Fortical®)

Raloxifene (Evista®)

Ibandronate (Boniva®)

Alendronate (Fosamax®)

Risedronate (Actonel®)

Risedronate (Atelvia®)

Zoledronate (Reclast®)

Denosumab (Prolia™)

Teriparatide (Forteo®) Diab DL, Watts NB. Endocrinol Metab Clin North Am. 2013;42(2):305-317.

DrugVertebra

l Fracture

Nonvertebral Fracture

Hip Fracture

Calcitonin Raloxifene Ibandronate Alendronate Risedronate Zoledronic acid Denosumab Teriparatide

Evidence for Fracture Reduction

Diab DL, Watts NB. Endocrinol Metab Clin North Am. 2013;42(2):305-317.

Estrogen Treatment (ET)

• Several approved oral and transdermal preparations• Treats symptoms of estrogen deficiency• Skeletal effects:

– Decrease in biochemical markers of 50% to 60%– 2-year BMD increase of 4% to 6% at hip and spine– Decreased incidence of vertebral and hip fractures (34%) after 5

years in the Women’s Health Initiative (WHI)– Effects in women with osteoporosis have not been evaluated in

randomized controlled trials

• Concern about adverse effects• Long-term use not recommended

Rossouw JE, et al. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

The Concept of a SERMSelective Estrogen Receptor Modulator (EAAs: Estrogen Agonist/Antagonists)

Binds to the estrogen receptors

Produces an estrogen agonist effect in some tissues

Produces an estrogen antagonist effect in others

Raloxifene• Raloxifene (60 mg daily)• Skeletal effects:

–Decrease in biochemical markers of 30%–3-year BMD increases of 2% to 3% at hip and spine–Decreased incidence of vertebral fractures (30% to 50%) in women with pre-existing vertebral fractures or low bone density. No effect on nonvertebral or hip fractures has been observed

• Extra-skeletal effects: reduction in invasive breast cancer

Ettinger B, et al. JAMA. 1999;282:637-645.

Raloxifene Adverse effects

Hot flashes

2- to 3-fold increased risk of venous thromboembolic events

No increased risk of stroke, but Black Box Warning for increased risk of death following stroke

Leg cramps

Sontag A, Wan X, Krege JH. Curr Med Res Opin. 2010;26:71-76.

Calcitonin

Calcitonin (200 units daily by nasal spray) Skeletal effects:

Decrease in biochemical markers of 20% Small effect (1% to 2%) on bone density in spine Reduced incidence of vertebral fractures (36%) in women with pre-

existing vertebral fractures No effect on nonvertebral or hip fractures has been observed

Adverse effects Nasal stuffiness Possible increased cancer risk

Chesnut CH 3d, et al. Am J Med. 2000;109:267-276. http://effectivehealthcare.ahrq.gov/slides/?pageaction=displaySlides&tk=49&dpg=9&scroll=314. Accessed: September 13, 2013. European Medicines Agency. Press release. July 20, 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/07/WC500130122.pdf. Accessed: September 13, 2013.

BisphosphonatesAlendronate, Risedronate, Ibandronate, and Zoledronic Acid

• Alendronate: 10 mg daily (tablet) or 70 mg weekly (tablet or liquid) for treatment, 5 mg daily or 35 mg weekly for prevention

• Risedronate: 5 mg daily or 35 mg weekly (tablet); 150 mg monthly (tablet)

• Ibandronate: 150 mg monthly by tablet; 3 mg intravenously over 15 to 30 seconds every 3 months

• Zoledronic acid: 5 mg by intravenous infusion over a minimum of 15 minutes once every year for treatment—and every other year for prevention

*2012 Jun 25;172(12):930-6

National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2013. Available at: http://www.nof.org/hcp/clinicians-guide. Accessed September 13, 2013.

Clinical Benefit of Bisphosphonates• Relative risk reduction for fractures • Postmenopausal women with osteoporosis• 3 years bisphosphonate treatment

Vertebrae Hip

Khosla S, et al. J Clin Endocrinol Metab. 2012;97(7):2272-2282.

Bisphosphonates: Indications Treatment and prevention of postmenopausal

osteoporosis Alendronate, risedronate, ibandronate, zoledronic acid

Prevention and/or treatment of glucocorticoid-induced osteoporosis Risedronate, zoledronic acid, alendronate

Treatment of men with low bone density Alendronate, risedronate, zoledronic acid

Contraindications/Warnings/Precautions– Hypocalcemia

– Creatinine clearance <30 cc/min (<35 cc/min for zoledronic acid)

– For oral dosing: Esophageal stricture or impaired esophageal motility (alendronate); inability to stand or sit for at least 30 minutes (alendronate/risedronate) or 60 minutes (ibandronate)

Notes: UGI symptoms per se are not a contraindication to oral dosing.Use in pregnancy: Class C

Oral dosing requirements– Tablets (with exception of delayed release risedronate) taken on an empty stomach

after overnight fast with 6 to 8 oz of plain water while in an upright position

– Patients should not eat or lie down for at least 30 minutes (alendronate and risedronate) or 60 minutes (ibandronate)

– Calcium and vitamin D supplements, if needed, should be taken at a different time of day than the oral bisphosphonate

Bisphosphonates

National Osteoporosis Foundation. Med Lett. 2011;53(1360):24.

• “Class warning” regarding UGI symptoms (no increase in UGI complaints in randomized controlled trials)

• Influenza-like symptoms may occur after first monthly oral dose of IV bisphosphonate

• “Class warning” regarding infrequent bone, joint, and/or muscle pain

• “Class warning” regarding jaw osteonecrosis

• “Class warning” about atypical fractures following long-term therapy

Bisphosphonates: Side Effects

“Osteonecrosis” of the Jaw (ONJ)

An area of exposed alveolar or palatal bone that typically shows poor healing over several months 95% of cases have been reported with high-dose,

chronic IV bisphosphonate treatment of myeloma and cancer metastatic to bone1

Can occur with denosumab2

Pain in 2/3 cases: infection may or may not be present Known risk factors: invasive dental procedures, oral

trauma, periodontitis, poor oral hygiene, radiotherapy to the jaw, chemotherapy, corticosteroids, infection

Pathogenesis is not known3

1. Woo SB, et al. Ann Intern Med. 2006;144:753-761. 2. Sutton EE, Riche DM. Ann Pharmacother. 2012;46:1000-1009.3. Khosla S, et al. J Bone Miner Res. 2007;22:1479-1491.

Atypical Fractures of Femur in PatientsTaking Anti-Resorptive Agents Long Term

Park-Wyllie LY, et al. JAMA. 2011;305:783-789. Shane E, et al. J Bone Miner Res. 2013 May 28. [Epub ahead of print]. Watts NB, Diab DL. J Clin Endocrinol Metab. 2010;95:1555-1565. Meier RP. Arch Intern Med. 2012;172:930-936.

• May begin with stress reaction or stress fracture of lateral femoral cortex (A)

• Transverse fractures of femoral diaphysis or in subtrochanteric region (B)

• Often bilateral

• Prodromal pain in thigh or groin in 70%

• Occurs in untreated patients, but increased incidence with long-term antiresorptive therapy, particularly bisphosphonates and denosumab

Bisphosphonate Therapy: “Long-Term” Treatment Stopping treatment in high-risk patients

After 5 years of alendronate-decline in BMD, rise in biochemical markers, no increased fracture risk except clinical vertebral fractures1

After 3 years of risedronate, spine BMD rose, vertebral facture risk was still reduced compared with control patients2

After 3 years of zoledronic acid, slight increase in morphometric fractures vs clinical vertebral fractures3

Long-term treatment has not clearly been associated with safety issues or loss of efficacy

Cessation of treatment after 2 to 5 years is associated with some persisting effect on biochemical markers, as well as BMD; this has been best characterized for alendronate and zoledronic acid

1. Black DM, et al. JAMA. 2006;296:2927-2938. 2. Watts NB, et al. Osteoporosis Int. 2008;19:365-372. 3. Black DM, et al. J Bone Miner Res. 2012;27:243-254.

Recently Approved

• Boniva – 150 mg monthly– 2.5 mg daily approved May, 2003– Vertebral fracture efficacy shown with daily– Based on 1 year BMD data, 150 mg monthly is

superior to the 2.5 mg daily – 60 minute post dose fast, not 30 minute

• Fosamax PLUS D – 70 mg/2800 IU weekly

How Long to Treat with bisphosphonates?

5–10 years appears to be safe for most patients Assess for risk:

Watts NB and Diab D. J Clin Endocrinol Metab. 2010;95(4):1555-1565.

Drug Holiday After 3-5 years

Drug Holiday After 10 years

Higher RiskLower Risk

Baseline 3 Years

VERT-NA: Placebo Patient

Increased perforation

Trabecular thinning

Borah, et al, JBMR 16 (Suppl 1), 2001

Similar thickness of trabeculae and number of perforations

Baseline 3 Years

Borah, et al, JBMR 16 (Suppl 1), 2001

VERT-NA: Risedronate Patient

Bisphosphonates for Osteoporosis

• Benefit: reduction of fracture risk (alendronate, risedronate, ibandronate)

• Problem: poor adherence to therapy• Cause: multifactorial, including issues of

convenience (complexity of dosing) and tolerability (GI irritation in clinical experience)

• Possible solutions: larger doses given less frequently, parenteral administration

Bisphosphonates: Molecular Mechanisms of Action

• Interfere with the action of osteoclasts– Recruitment, differentiation, and action– Two mechanisms:

• Incorporated into cytotoxic ATP analogs (etidronate)– Affect cellular activity

• Interfere with the mevalonate pathway (nitrogen-containing BPs)– Cause apoptosis

Russell R, et al. Osteoporos Int. 1999;(suppl 2):S68-S80.

Bisphosphonates: Contraindications and Warnings

• Contraindications– Hypocalcemia– Known hypersensitivity to any component of this product– Inability to stand or sit upright for at least 30 minutes

• Warnings– Bisphosphonates may cause upper gastrointestinal disorders such as

dysphagia, esophagitis, and esophageal or gastric ulcer

.

Denosumab Monoclonal antibody to RANKL 60 mg subcutaneous injection every 6 months 9% increase in spinal BMD after 3 years in the pivotal

FREEDOM trial; 4% to 5% increase in hip BMD Reduction in fracture risk after 3 years:

68% decrease in new vertebral fractures 40% decrease in hip fractures 20% decrease in nonvertebral fractures

8-year data: continued increase BMD, reduced bone turnover, good safety

Cummings SR, et al. N Engl J Med. 2009;368:756-765Prolia (prescribing information). Thousand Oaks, CA: Amgen; June 2012. McClung MR, et al. Osteoporos Int. 2013;24(1):227-235.

Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function, and Survival

RANKL

RANK

OPG

Denosumab

Bone Formation Bone Resorption Inhibited

Osteoclast Formation, Function, and Survival Inhibited

CFU-GM PrefusionOsteoclast

Osteoblasts

HormonesGrowth Factors

Cytokines

Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.

Proven osteoporotic fracture reductionthroughout the skeleton

In the pivotal FREEDOM study (published in the New England Journal of Medicine), Denosumab reduced the risk of fracture at key osteoporotic

fracture sites versus placebo

PROLIA®: PROTECTION AGAINST FRACTURE

The absolute risk reductions demonstrated for Prolia® versus placebo were 4.8%, 1.5% and 0.5% for vertebral, non-vertebral and hip fractures respectively. 1

6

P

Denosumab Adverse EventsAdverse events that occurred more commonly in denosumab group (as listed in the PI):

Serious infections leading to hospitalization Dermatitis, eczema, rashes Back pain, pain in the extremity, musculoskeletal pain,

hypercholesterolemia, cystitis Pancreatitis Osteonecrosis of the jaw Significant suppression of bone remodeling

Prolia (prescribing information). Thousand Oaks, CA: Amgen; June 2012.

Teriparatide: rhPTH [1-34]• The only treatment agent that is anabolic—stimulates bone

formation rather than inhibiting bone resorption• 20 μg daily (subcutaneously) for no more than 2 years• Indication: treatment of men and postmenopausal women

with osteoporosis who are at high risk for fracture • Effects:

– Increased bone density in spine by 9% and hip by 3% vs placebo over 18 months

– Reduced incidence of vertebral fractures (65%) and nonvertebral fragility fractures (53%) in women with pre-existing vertebral fractures

– Studies too small to evaluate effect on hip fractures• Adverse reactions: arthralgia, pain, nausea; warning about

osteosarcoma risk in ratsNeer RM, et al. N Engl J Med. 2001;344:1434-1441. Forteo (prescribing information). Indianapolis, IN: Eli Lilly and Company; March 21, 2012.

Latest in Osteoporosis Treatment1.Carotenoids, Lycopene Reduce Fracture Risk

(Antioxidants)

“…reactive oxygen intermediates may be involved in the bone-resorptive process and that fruit and vegetable-specific antioxidants, such as carotenoids, are capable of decreasing this oxidative stress. Therefore carotenoids may help in preventing osteoporosis.

In particular, an inverse relation of carotenoids and lycopene with biochemical markers of bone turnover has recently been demonstrated.”

J Bone Miner Res. 2009 Jun;24(6):1086-94.

2.Omega-3 Fatty Acids Reduce hs-CRP1

“This study provides evidence that in healthy individuals, plasma n-3 fatty acid concentration is inversely related to hs-CRP…”

“High sensitivity C-reactive protein (hs-CRP) is a marker of low grade sustained inflammation.”

“Increased hs-CRP by just 1SD increases fracture risk by an amazing 23 percent2.”

Consider supplementing the diet with omega-3 fatty acids (fish oil). They’re a great way to help reduce inflammation,  hs-CRP, cardiovascular disease, and fractures related to osteoporosis.

1. Micallef M A et al., European Journal of Clinical Nutrition, 2009; April 8 [Epub ahead of print].2. Pasco et al. JAMA. 2006;296(11):1353-1355

3.Vitamin K Improves Bone Strength and Reduces FracturesReview of RCTs showed that vitamin K(1) and

vitamin K(2) supplementation reduced serum undercarboxylated osteocalcin levels regardless of dose but that it had inconsistent effects on serum total osteocalcin levels and no effect on bone resorption.”

Iwamoto J et al., Nutrition Research, 2009; 29(4): 221-228.