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OSTEOPOROSIS UPDATE2015

Heather Hofflich, DO, FACE

Associate Clinical Professor of Medicine

University of California, San Diego

Introduction

Osteoporosis

FRAX

Diagnosis/Secondary Causes

Therapies

Controversies

NOF Guidelines

Osteoporosis: The Definition

• Impaired bone strength

– Low BMD

– poor bone quality

• Increased fracture risk

due to bone loss

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Osteoporosis

1.Micro-architecture 1. Size and

2. Turnover/stress geometry

3. Damage 2. Mineralization

4. Matrix quality

Bone Strength Bone Qualities Bone Density= +

Hip Fracture

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Vertebral Fracture

Diagnosis of Osteoporosis

DEXA Machine

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DEXA

• DEXA measure only two areas:

BONE MINERAL CONTENT (G)

AREA (CM2)

WHO Bone Density Criteria

Diagnostic Criteria* Classification

•T score = BMD compared to a “young normal” adult of the same sex• Z score= BMD compared to a “young normal” adult of the same AGEand sex

T is above or equal to -1.0 Normal bone density

T is between -1.0 and -2.5 Osteopenia

T is -2.5 or lower Osteoporosis

T is -2.5 or lower Severe established

+fragility fracture osteoporosis

NOF Indications for BMD testing

• Women age 65 years and older

• Men age 70 years and older

• Age 50-69 with risk factor

• Fracture after age 50

• Women in menopausal transition if a specificrisk factor (low body weight, prior low-traumafracture or high risk medication)

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How Often Should I Have a DXA?

• Important to have DXA on same machine(brand) preferable at same location as priorstudy

• Every 2 years per Medicare

• Recent studies state if osteopenia--?repeat in5 years or longer

Secondary Causes ofOsteoporosis

Secondary Causes of Osteoporosis

Adapted from AACE Guidelines onosteoporosis, 2001

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Medications that cause osteoporosis

• Glucocorticoids (≥ 5 mg/d

of prednisone for ≥ 3 months)

• Immunosuppresants(cyclosporines, tacrolimus)

• Heparin/Coumadin

• Anticonvulsants(gabapentin)

• Opioids

• PPI’s

• Lithium

• Aromatase Inhibitors

• Androgen DeprivationTherapy

• Depo Provera

• Excess thyroidmedication

• SSRI’s

• TZD’s

PPI’s and hip fracture

• Study in 2006 showed possible association btwn hipfractures and chronic PPI use

– Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapyand risk of hip fracture. JAMA : the journal of the American Medical Association.2006;296(24):2947-53. Epub 2006/12/28.

• PPI use and increased risk for hip fracture in tobaccousers– Khalili H, Huang ES, Jacobson BC, Camargo CA, Jr., Feskanich D, Chan AT. Use of

proton pump inhibitors and risk of hip fracture in relation to dietary and lifestylefactors: a prospective cohort study. BMJ. 2012;344:e372. Epub 2012/02/02.

•

Lab Tests for Secondary Causes ofBone Loss

• CBC

• CMP

• 24 hour urinecalcium/creatinine

• TSH

• 25-OH vitamin D

• Testosterone (Males

• SPEP/UPEP

• TTGIGA (celiac)

• Phosphorus

• Magnesium

• PTH

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Who do we treat?

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FRAX

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FRAX Summary

• If t score is between -1.0 and -2.5 treatment isrecommended if:

The 10 year probability of a hip fracture is≥ 3%

The 10-year probability of a majorosteoporosis-related fracture ≥ 20

Prevention ofOsteoporosis

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Non pharmacological approachesto the prevention of

osteoporosis

• Adequate intake of dietary calcium

• Regular physical activity

• Minimize alcohol intake—1-2 small glasses/daily

• Encourage smoking cessation

• Minimize risk of fall

Your mother always toldyou to drink your milk…

She was right!

Current Calcium Recommendations

• 1200 mg daily for women older than 50

• 1000 mg daily for men older than 50

• 1200 mg daily for men older than 70

• Try and obtain from food sources, thensupplement

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Calcium and MI association?

• 2010 metanalysis showed possible assoc.btwn MI and >1500 mg of calcium daily– Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, et

al. Effect of calcium supplements on risk of myocardial infarction andcardiovascular events: meta-analysis. BMJ 2010;341:c3691

• However, recent study showed no assoc.btwn. calcium and inc. risk of MI– Prentice RL, Pettinger MB, Jackson RD, Wactawski-Wende J, Lacroix AZ,

Anderson GL, et al. Health risks and benefits from calcium and vitamin Dsupplementation: Women's Health Initiative clinical trial and cohort study.Osteoporosis international : a journal established as result of cooperationbetween the European Foundation for Osteoporosis and the NationalOsteoporosis Foundation of the USA. 2012. Epub 2012/12/05.

Calcium Calculator

Product Servings/Day Calcium (mg) Total

Milk (8 oz.) X 300 =

Yogurt (6 oz.) X 300 =

Cheese (1 oz. or 1cubic inch)

X 200 =

FortifiedFoods/Juices

X 80-1,000 =

Estimated total from other foods = 250

Total daily calcium intake, in mg =

Which Type of Calcium?

• Calcium Carbonate---needs to be taken withfood for best absorption

• Calcium Citrate—does not need to be takenwith food

• Calcium Phosphate

• Calcium Gluconate

• Calcium Lactate

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Calcium Supplements

Vitamin D

• Vitamin D is added to milk and OJ andis in liver and fatty fish.

• You can get vitamin D from the sun.But, you need sunscreen to protectyour skin which also blocks vitamin D.

• To get enough vitamin D, many peopleneed to take a supplement.

Vitamin D

• 800-1000 IU daily

• Max. dose recommended : 4000 IU daily

• Recent studies show no association withcardiovascular disease or reduction in breastcancer

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EXERCISE

Weight-bearing Exercises

• Which exercise is for you?

– Low impact: walking, elliptical, low impactaerobics, stair-stepper, tai chi

– High impact: jogging or running, aerobicdancing, hiking, jumping rope, stair climbing

Weight-bearing Exercises

• Which exercise is for you?– Try to do the exercises with greatest impact

that do not cause problems

• Try to do 30 minutes of weight-bearingexercise, at a moderate pace, most daysof the week

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Muscle-strengthening Exercises

• Muscle-strengthening exercises makeyou move your body, a weight or someother resistance against gravity

• Some options include:– Lifting weights (machines or free weights)

– Calisthenics (partial or full push ups, wallslide/wall sits, prone trunk lifts)

– Using exercise bands or tubes

Fall Prevention

• Have your eyes checked

• Have your medications checked

• Stay active and do weight bearing exercise

• If needed use walker, cane or other source tohelp prevent falls

• Ask you doctor about physical therapy

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What about Caffeine?

• Coffee--calcium intake with coffee

• Tea—?evidence

• Soda—Cola—Tufts study showed phosphoricacid did cause significant bone loss

Alcohol and Tobacco

• Minimize ETOH use to <2 glasses daily

• Smoking cessation is key to healthy bones

Therapies forOsteoporosis

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FDA approved therapies forOsteoporosis

• Bisphosphonates–Alendronate–Risedronate– Ibandronate–Zolendronic Acid

• Raloxifene• Denosumab• Teripartide- formation

• Life stylemodifications– Calcium and vitamin D– Weight bearing exercises– Fall prevention

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Osteoclast

Inhibition of resorption

Osteoblast

Stimulation of formation

Treatment objectives

Benefits of Osteoporosis Therapy

• Reduction in fracture risk

• Reduction in pain and disability

• Preservation of independence

• Reduction in height loss

• Positive effect on mortality (?)

• Positive effect on BMD

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Bisphosphonates

• Work by inhibiting osteoclast function

• Oral and IV forms

• Side effects:

– Renal impairment

– Rash

– Esophagitis

– Osteonecrosis of the Jaw

Atypical Femur Fracture

• Located at diaphyseal area

• Lateral cortical thickening

• Transverse Fracture with short obliqueextension medially (beaking)

• Often Bilateral

• More common in Asians, priorbisphosphonate use

• Occur with longer term use >5-10 years

X-rays showing an impending femoral shaft fracture (A) and a representative atypicaldiaphyseal femoral fracture (B) with thickened cortices and a beak or spike. [Courtesy of J.

Lane and A. Unnanuntana, Hospital for Special Surgery, New York, NY.].

Watts N B , Diab D L JCEM 2010;95:1555-1565

©2010 by Endocrine Society

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Duration of BisphosphonateTreatment

Watts et al., JCEM 2010

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Teriparatide [rDNA origin] injection

FORTEO®

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Parathyroid hormone (PTH) –Mechanism of action

PTH binds to cell surface G protein-coupled receptor

Decreased apoptosisof osteoblasts

Stimulates differentiationof bone lining cells and

preosteoblasts to osteoblast

Net increase in number and action of bone forming osteoblasts

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Teriparatide Indications

• Previous Fragility Fracture inpostmenopausal women and men

• T score: -3.0 without fracture

• Cannot tolerate another therapy

• Bone loss or fracture on another therapy

Teriparatide

• The teriparatide Pen is a prefilled deliverydevice that can be used up to 4 weeks (28daily doses)

• Dose: 20 mcg once daily

• Administered as a subcutaneous injection intothe thigh or abdominal wall

• Duration of therapy: 18-24 months

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Side Effects of Teriparatide

• Mild transient increase in serum calcium

• Mean increase in urine calcium of 30 mg in 24 hrs

• Leg cramps

• Dizziness

• Black Box warning-- incidence ofosteosarcoma with high dose longer-termexposure

• Transient tachycardia/HTN after 1st dose

In male and female rats, teriparatide caused an increase in the incidence of

osteosarcoma (a malignant bone tumor), that was dependent on dose and

treatment duration. The effect was observed at systemic exposures to teriparatide

ranging from 3 to 60 times the exposure in humans given a 20 mcg dose. Because of

the uncertain relevance of the rat osteosarcoma finding to humans, teriparatide

should be prescribed only to patients for whom the potential benefits are

considered to outweigh the potential risk. Teriparatide should not be prescribed for

patients who are at increased baseline risk for osteosarcoma (including those with

Paget’s disease of bone or unexplained elevations of alkaline phosphatase, open

epiphyses, or prior external beam or implant radiation therapy involving the

skeleton) (see WARNINGS and PRECAUTIONS, Carcinogenesis)

FORTEO® (teriparatide [rDNA origin] injection)Important Safety Information

Warning

Contraindications to Forteo

• Paget’s disease/ alkaline phosphatase

• History of radiation to bone

• Open Epiphyses

• Primary or Metastatic skeletal malignancy

• Hypercalcemia or increased PTH

• Pregnancy/lactation

• Renal insufficiency

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Raloxifene (Evista)

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RALOXIFENE

• FDA approved for treatment of osteoporosis inpostmenopausal women

• Reduced risk of new vertebral fractures byabout 55% and 30% in women with priorvertebral fractures

• Did not reduce fracture risk in hip andnonvertebral in clinical trials

• Increased risk of DVT, hot flashes, and CVA inhigh risk populations

Denosumab

• Human monoclonal antibody

• Binds to Rank-L and prevent it from binding toRANK

• Action: inhibits osteoclasts

• Works like OPG

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Regulation of osteoclastogenesis by factorsfrom osteoblast/stromal cells

Hofbauer LC & Heufelder AE, JMol Med, 2001;79:243-253

Osteoclast precursor

Differentiation

Inhibition

OPG"decoy receptor"

Osteoblast / stromal cell

M - CSF RANK

RANKL

RANKL

Mature osteoclast

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Freedom Trial

• Randomized, placebo-controlled trial

• 60 mg of Denosumab SQ every 6 months for 3years

• Reduced vertebral fracture risk by 68%

• Reduced hip fractures by 40%

• Reduced nonvertebral fractures by 20%

Side Effects of Denosumab

• Increased skin infections: cellulitis, erysipelas

• Over-suppression of the bone

• Atrial fibrillation, ONJ, and mortality weresimilar in placebo group and treated group.

New Therapies

• Odanacatib—cathepsin-K inhibitor. Currentlyin phase III clinical trials

• Romosozumab—anti-sclerostin abs. Currentlyin phase III clinical trials

• PTHrp—Phase III clinical trials

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Romosozumab

• 12 month phase II trial data showed whengiven every month significant improvementsin BMD—more than other medications

• Bone formation!

NEJM, 2014

Romosozumab

NEJM, 2014

Romosozumab

NEJM, 2014

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Sarcopenia and Osteoporosis

• Sarcopenia = age-related loss of muscle mass, strength, and

functionality

• Sarcopenia and osteoporosis go hand-and -hand as muscles

generate the mechanical stress required to keep our bones

healthy

• Increasingly now recognized as a serious health problem thatafflicts millions of aging adults

WILL YOUR BONES LAST AS LONG AS YOU DO?

Any questions orcomments?

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hhofflich@ucsd.edu

Osteonecrosis of the Jaw

• Def: Exposed bone in the maxillofacial regionthat does not heal within 8 weeks in a patientexposed to an anti-resorptive agent (BP orDmab)

• Decreased osteoclast activity plays a role

• Typically devlops after a tooth extraction orother ivasive oral surgical procedure

Osteonecrosis of the Jaw (ONJ)

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Prevention of ONJ

• Antimicrobial mouth rinses

• Antibiotics before and after invasiveprocedure

• Maintenance of good oral hygeine

• ?stop anti-resportive prior to procedure (3mos) –no evidence