Update on the Diagnosis and Treatment of Osteoporosis: 2008 Michael Maricic, MD Catalina Pointe Rheumatology Clinical Associate Professor of Medicine University.

Update on the Diagnosis and Treatment of Osteoporosis: 2008

Michael Maricic, MD

Catalina Pointe Rheumatology

Clinical Associate Professor of Medicine

University of Arizona

Disclosures

Speakers Bureau, Consultant or Clinical Research Grant Support• Merck• Proctor and Gamble • Aventis• Lilly• Novartis• Amgen• Roche • Glaxo-Smith-Kline

Pre-Test Questions

?

Update Objectives

WHO Fracture Assessment Tool 2008 NOF Guidelines for Treatment Calcium and Vitamin D New Treatment Data Osteonecrosis of the jaw

1999 NOF Treatment Guidelines

Treat women with a fragility fracture Treat if T-score >-2.0 Treat if T-score > -1.5 with risk factors

Problem- Which risk factors are more important in deciding to treat osteopenic women

National Osteoporosis Foundation Risk Factors for Low Bone Mass and Fractures (1999)

Personal history of a fracture as an adult

History of a fracture in a first-degree relative

Caucasian race advanced age female sex dementia poor health/frailty

Current cigarette smoking Low body weight (< 127 lbs) estrogen deficiency low calcium intake (lifelong) alcoholism impaired eyesight recurrent falls inadequate physical activity

Non-modifiable Modifiable

Use of WHO Fracture Risk Algorithm

The WHO Fracture Risk Assessment Tool (FRAX®) was developed to calculate the 10-yr probability of a hip fracture and any major osteoporotic fracture • vertebral • hip• forearm • humerus

The algorithm takes into account femoral neck BMD and clinical risk factors for fracture

Non-density Related Risk Factors

Age Previous low trauma fracture Parental history of hip fracture Current cigarette smoking High alcohol intake (> 3 units/day) Rheumatoid arthritis Prior or current glucocorticoid use

Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.

Quantifying Fracture Riskwww.shef.ac.uk/FRAX

http://www.shef.ac.uk/FRAX

WHO Absolute Risk Prediction Model

10-Year probability of experiencing an osteoporosis-related fracture

Model mimics the Framingham Heart Study 10-year coronary heart disease (CHD) risk predictor

Treatment intervention thresholds will vary by country

Recommendations for treatment based on absolute fracture risk—not simply on T-scores

National Osteoporosis Foundation

Clinician’s Guide to Prevention and Treatment of Osteoporosis 2008

Dawson-Hughes B, Lindsay R, Khosla S, Melton J, Tosteson A, Favus M, Baim S

Synopsis of Major Recommendations General Recommendations

A.Counsel on the risk of osteoporosis and related fractures.

B. Check for secondary causes.

C. Advise on adequate amounts of calcium (at least 1200 mg/d, and vitamin D (800 to 1000 IU

per day of vitamin D3).

D. Recommend regular weight-bearing and muscle-strengthening exercise to reduce the risk of falls and fractures.

E. Advise avoidance of tobacco smoking and excessive alcohol intake.

Basic Care (suitable for all)

Assess Risk Factors and BMD (if risk factors)

T-score between -1.0 and -2.5

10-year probability of hip fractures > 3% or

probability of all major fractures >

20% (FN or total T-score only)

Hip or vertebral fractures

orT-score ≤ -2.5

(spine, FN, or total hip)

2008 NOF Guide: Treatment Initiation Postmenopausal Women and Men ≥ 50 years

www.NOF.org

Other fractures > age 50

(excluding fingers, toes

and face)

Secondary causes with high fracture

risk*

*Such as glucocorticoid use or total immobilization

Nutrition:

• Calcium supplementation

• Vitamin D

Other lifestyle modifications• Avoiding alcohol and tobacco abuse

Exercise: Fall prevention

Treatment of OsteoporosisNon-Pharmacological Options

National Osteoporosis Foundation: March 2007 Recommendations

Recommended Intake for Adults 50 Years and Older

Calcium Calcium

(mg/day)(mg/day)

Vitamin DVitamin D33 (IU/day)(IU/day)

Previous Previous (2003)(2003)11 12001200 400400–800–800

March March 2007 2007 revisionrevision22

12001200 800–1000800–1000

1. National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Available at: http://www.nof.org/physguide/index.asp. Accessed April 26, 2007.

2. National Osteoporosis Foundation. National Osteoporosis Foundation’s Updated Recommendations for Calcium and Vitamin D3 Intake. Available at: http://www.nof.org/prevention/calcium_and_VitaminD.htm. Accessed April 26, 2007.

What type of Calcium should we use ?

Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture

Case-control study conducted using the GPRD in the UK Users of PPI therapy, H2 receptor antagonists and nonusers of

acid suppression drugs older than 50 years There were 13,556 hip fracture cases and 135,386 controls The adjusted odds ratio (AOR) for hip fracture associated with

more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59)

The strength of the association increased with increasing dose and duration of PPI therapy

Yang Y, Lewis J, Epstein S. JAMA. 2006;296:2947-2953

Vitamin D Insufficiency (<30 ng/mL): Prevalence by Latitude

42 N

35 N

n=198/362

(54.7%)

n=259/532

(48.7%)

n=342/642

(53.3%)

P = NS for Test of Trend.

Holick MF et al. JCEM 2005

Vitamin D Inadequacy and Effects on Osteoporosis and Muscle Strength

“Insufficiency” (< 30 ng / ml)• Suboptimal calcium aborption• 2nd hyperparathyroidism• Decreased BMD, decreased response to pharmacological therapy, increased fracture risk

Frank Deficiency (< 10 ng / ml)• Osteomalacia• Proximal myopathy, Increased postural instability, sway, falls

Effect of Vitamin D and Calcium Effect of Vitamin D and Calcium Supplementation on Risk of FallingSupplementation on Risk of Falling

122 women living in long-term care units

Age: 63–99 Randomized, double-

blind, controlled trial• Calcium 1200 mg/day• Calcium 1200 mg/day

+ vitamin D 800 IU/day 12-week duration Mean serum 25(OH)D 12

ng/ml at baseline

Adapted from Bischoff HA et al J Bone Miner Res 2003;18:343–351.

Calcium only

(n=44)

Calcium + vitamin D

(n=45)

Fal

l ris

k

0.0

0.2

0.4

0.6

0.8

1.0

1.2

–49%

Reduction in falls

p=0.01

*With appropriate calcium and vitamin D.

PREVENTION

• Estrogen

• Raloxifene

• Alendronate

• Risedronate

• Ibandronate

TREATMENT

•Salmon Calcitonin

• Raloxifene

• Alendronate

• Risedronate

• Ibandronate

• Zoledronic acid

•Teriparatide (rhPTH)

FDA-Approved Therapies for Postmenopausal Osteoporosis

Low BMD on DXA Does Not Equal Postmenopausal Osteoporosis

WHI Estrogen+Progestin TrialStudy Results - Fractures

WHI Estrogen+Progestin TrialStudy Results - Fractures

0

2

4

6

8

10

12

14

16

Clin

ical

Ou

tco

mes

Hip Vertebral

Estrogen+Progestin Placebo

34% Reduced Risk* 34% Reduced Risk**

*Hip Fractures: HR 0.66; Nominal 95% CI (0.45-0.98), Adjusted 95% CI (0.33-1.33) **Vertebral Fractures: HR 0.66; Nominal 95% CI (0.44-0.98), Adjusted 95% CI (0.32-1.34)Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333.

FDA Recommendations on ET/HT

• When prescribing medication to prevent osteoporosis, physicians should consider all non-estrogen preparations first

• When prescribing ET/HT, physicians should prescribe the smallest dose for the shortest amount of time to achieve treatment goals

• Physicians should prescribe ET/HT products only when the benefits are believed to outweigh the risks for a specific patient

US Food and Drug Administration. FDA News, January 8, 2003.

• Although other doses and combinations of estrogens and progestins were not studied, the FDA believes the risks attributable to the combination in the WHI Study are applicable to all HT products.

Effect of Raloxifene on New Clinical Vertebral Fractures at 1 Year

Maricic M, et al. Arch Intern Med. 2002;162:1140-1143. *P=.01 vs placebo

0.0

0.5

1.0

1.5

RR 0.32*(95% CI = 0.13-0.80)

68%

Placebo(N=2576)

Raloxifene 60 mg/d

(N=2557)

% o

f Wo

me

n W

ithIn

cide

nt V

ert

ebra

l Fra

ctu

res

Raloxifene: Effect on Nonvertebraland Hip Fracture (MORE)

Pooled Data (60 mg and 120 mg*)

PlaceboRaloxifene pooled

Months

Perc

ent o

f Pat

ient

s W

ith In

cide

ntN

onve

rteb

ral F

ract

ures

Non-Vertebral Fractures Hip Fractures

Months

PlaceboRaloxifene pooled

060 12 18 24 30 36 60 12 18 24 30 36

5

10

15

1

0

2

3

*Not FDA-approved dose.Ettinger B, et al. JAMA. 1999;282(7):637-645.

Effect of Raloxifene on Breast Cancer Incidence MORE Trial - 4 Years

Years since RandomizationTotal Cases = 77

Arrow denotes annual mammogram

Cauley J, et al. Breast Cancer Res Treatment. 2001;65:125-134

% o

f Ran

dom

ize

d P

atie

nts

Raloxifene

0.0

2.0

0 1 2 3 4 5

PlaceboRR = 0.38 (95% CI = 0.24-0.58)*

1.0

1.5

0.5

*P < .001

Which Bisphosphonate is Best?

We don’t know

Real-World Persistence to Daily and Weekly Bisphosphonate Therapies

Data from Downey TW, et al. South Med J. 2006;99:570-575.

0

10

20

30

40

50

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12

Months of Continuous Persistence

DailyWeekly

% o

f Pat

ient

s

P = NS

Oral Bisphosphonates

Alendronate- Weekly Risedronate- Weekly, monthly Ibandronate- Monthly

I.V. Bisphosphonates: Potential Clinical Usage

Oral bisphosphonate intolerance

Contraindications to oral bisphosphonates

Dysphagia, severe GERD,

Bed-ridden patients

Assure compliance where there is evidence for non-compliance

I.V. Bisphosphonates

Ibandronate- 3 mg Q 3 months Zoledronic acid- 5 mg once yearly

• I.V. Route of administration- bypasses GI tract- assures compliance

Continued Increases in BMD in Women With Postmenopausal Osteoporosis

Following 2 Years of IV Ibandronate: Dosing Intravenous Administration Study (DIVA)

Lane N, Genant HK, Barr CE, Lewiecki EM, Maricic M

Presented at the American College of Rheumatology. 11/06

Objectives

Assess the efficacy of IV ibandronate 3 mg quarterly versus 2.5 mg PO daily in terms of relative (%) change from baseline in Bone Mineral Density at 1 and 2 years

Assess the change from baseline in serum CTX (marker of bone resorption)

Assess safety

DIVA StudyDIVA Study

Lane N, et al. ACR 11/06

DIVA: Year 2 BMDPercent Change from Baseline

3.1*2.2

3.5

4.9*

6.3*

4.8

Total Hip Femoral Neck TrochanterLumbar Spine

Mea

n %

Cha

nge

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

2.82.2

2.5 mg Daily PO (n=330) 3 mg Quarterly IV (n=333)

Quarterly IV dosing regimen had a significantly greater effect on mean BMD at Year 2 than the PO dosing regimen, PP population *P<0.0001


Safety Parameters: DIVA study

Acute Phase Reaction (APR)• Occurred in 10% of patients receiving 3 mg IV

quarterly• Generally transient and mild to moderate in

intensity • Most cases occurred in the first year only

Others• Changes in serum creatinine were not

significant• Osteonecrosis of the jaw was not reported


Zoledronic AcidHORIZON Pivotal Fracture Trial

Randomized, double-blind, placebo-controlled, multinational study of the efficacy and safety of Zoledronic acid for the treatment of postmenopausal osteoporosis• 7736 osteoporotic women aged 65-89 years• Zoledronic acid administered once a year for 3

consecutive years, as a single 5 mg dose, for a total of 3 doses

Two primary efficacy variables• Incidence of hip fractures over a median duration

of 3 years• Incidence of morphometric vertebral fractures at

3 years

Key secondary efficacy variables• Incidence of clinical fractures over 3 years• Incidence of non-vertebral fractures over 3 years• Percentage change in BMD at lumbar spine,

femoral neck, and total hip at 3 years

HORIZON Pivotal Fracture TrialHORIZON Pivotal Fracture Trial

Black DM, et al. N Engl J Med. 2007;356:1809-1822.

HORIZON Pivotal Fracture Trial: Effect on Vertebral Fractures

0–1 years 0–2 years 0–3 years

3.7%

1.5%

7.7%

2.2%

10.9%

3.3%

% P

ati

ents

Wit

h N

ew

V

ert

ebra

l Fr

act

ure

*P < .001RRR = Relative risk reduction

0

5

10

15

ZA 5 mgPlacebo

RRR 60%*

RRR 71%* RRR 70%*

Proportion of Patients WithNew Morphometric Vertebral Fractures


1

2

3

0

Placebo (n = 3861) ZA (n = 3875)

Time to First Hip Fracture (months)

0 3 6 9 12 15 18 21 24 27 30 33 36

Cu

mu

lati

ve I

ncid

en

ce (

%)

HORIZON Pivotal Fracture Trial: Effect on Hip Fractures Over 3 Years

HORIZON Pivotal Fracture Trial: Effect on Hip Fractures Over 3 Years

RRR41%

Stratified log-rank test P-value = .0024

Cumulative Incidence of Hip Fractures Over 3 Years


*Excluding finger, toe and facial fractures†Includes clinical thoracic and clinical lumbar vertebral fractures‡Excluding finger, toe, facial, and clinical thoracic and lumbar vertebral fractures

HORIZON Pivotal Fracture Trial: Effects on All Clinical Fractures Over 3 Years

HORIZON Pivotal Fracture Trial: Effects on All Clinical Fractures Over 3 Years

8.4%

12.8%

2.6%

0.5%

10.7%

8.0%

RRR 33%

RRR 77%

RRR 25%

Even

t R

ate

(%

)

0

2

4

6

8

10

12

14

Any ClinicalFracture*

ClinicalVertebralFracture†

Non-VertebralFracture‡

ZA 5 mg(n = 3875)

Placebo(n = 3861)


Adverse Reactions

Total SAEs were similar between groups (29.2% zoledronic acid vs 30.1% placebo)

The most common adverse events were post dose symptoms• Majority occur within 3 days after dosing • Usually resolves within 3 days

7%7%8%

9%

18%

02468

101214161820

Fever Myalgia Flu-LikeSymptoms

Headache Arthralgia

Inci

dence

rate

(%

)

Zoledronic Acid: Hypocalcemia

• All women received 1,000 to 1,500 mg calcium plus 400 to 1,200 IU vitamin D per day

• Following zoledronic acid administration, ~0.2% of patients had notable declines in serum calcium levels (less than 7.5 mg/dL)

• No symptomatic cases of hypocalcemia


Zoledronic Acid: Atrial Fibrillation

• Overall incidence of atrial fibrillation AEs was 2.5% of zoledronic acid patients vs 1.9% in placebo patients

• Adjudicated Serious Adverse Events of atrial fibrillation (requiring hospitalization) occurred in 1.3% of patients compared to 0.4% in the placebo group

• Over 90% of these events in both groups occurred more than a month after the infusion


Zoledronic Acid: Renal Safety

Not recommended for use in patients with severe renal impairment (creatinine clearance <35 mL/min)

Monitor serum creatinine before each dose. Transient increase in serum creatinine may be greater in patients with impaired renal function; consider interim monitoring of serum creatinine in at-risk patients

1. Black DM, et al. N Engl J Med. 2007;356:1809-1822.2. . Miller P, et al. Poster presented at: 7th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; March 28-31, 2007; Porto, Portugal. Poster P308.

Mean

(±

SE)

Ch

an

ge F

rom

B

aselin

e in

Calc

ula

ted

C

reati

nin

e C

leara

nce (

mL/m

in)

Reclast (n = 3862)

Placebo (n = 3852)

0 12 24 36

–15

–10

–5

0

Months

Changes in Calculated Creatinine Clearance* From

Baseline Over Time3

*Cockcroft-Gault equation

Zoledronic Acid: Osteonecrosis of the Jaw

In the HORIZON Pivotal Fracture Trial, out of 7736 patients, symptoms consistent with ONJ occurred in • 1 patient treated with placebo and • 1 patient treated with zoledronic acid over 3

years Both cases resolved after appropriate treatment


Osteonecrosis of the Jaw (ONJ): Definition

A confirmed case of bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a health care provider• in a patient who was receiving or had been

exposed to a bisphosphonate

J Bone Miner Res. 2007 Oct;22(10):1479-91.

Challenges of Studying ONJ

ONJ rare event• Difficult to get background rates in general

population• Difficulty in identifying cases with ONJ in

databases- no unified definition The incidence of ONJ in the general population

not exposed to bisphosphonates is unknown Although this association is consistent with a

role for bisphosphonates, bisphosphonates have not been proven to be causal.


Case Reports: ONJ in Osteoporosis

Most cases have been described in cancer patients receiving monthly IV bisphosphonates

As of Oct. 2007, 57 cases have been associated with oral bisphosphonate treatment for osteoporosis after duplicated case reports had been excluded.


Recommendations

Patients taking bisphosphonates should be encouraged to maintain good oral hygiene, and to have regular dental visits

They should be urged to report any oral problems to their dentist and physician

It is not necessary to recommend a dental examination before beginning oral bisphosphonate therapy or to otherwise alter routine dental management.


Recommendations

Patients should be informed that the risk of developing bisphosphonate-associated ONJ with routine oral therapy for osteoporosis appears to be low, ranging between 1/100,000 and 1/250,000

This risk should be balanced with the risk of osteoporotic fractures in that patient


Teriparatide PTH (1-34): Indications

Postmenopausal women or men with osteoporosis at high risk of fracture

“High-risk” includes:• Men and women with previous osteoporotic

fracture(s)• Men and women with multiple risk factors

for fracture• Those who have failed or are intolerant to

other osteoporosis therapies

US food and drug administration. FDA talk paper. November 26, 2002

Effect of Teriparatide (rhPTH(1-34)) on the Risk of New Vertebral Fractures

*p <0.001 vs. Placebo

Ris

k R

edu

ctio

n (

RR

)

Placebo(n=448)

rhPTH 20(n=444)

rhPTH 40(n=434)

64 22 19100%

75%

50%

0%

25%

% o

f Wo

men

8

0

246

101214

RR 0.31 (95% CI, 0.19 to 0.50)*

RR 0.35 (95% CI, 0.22 to 0.55)*

65% 69%

Neer RM, et al. N Engl J Med. 2001;344(19):1434-1441.

Effect of rhPTH(1-34) on the Risk of Nonvertebral Fragility Fractures

* p = 0.02 vs. Placebo** p = 0.01 vs. Placebo

0

1

2

3

4

5

6

7

Placebo rhPTH 20 rhPTH 40

% o

f W

om

en

30 14 14

53% 54%

(n=544) (n=552)(n=541)

No. of women who had > 1 fragility fracture

RR 0.46 (95% CI, 0.25 to 0.86)**

RR 0.47 (95% CI, 0.25 to 0.88)*

Teriparatide PTH (1-34): Adverse Effects

Side effects are usually mild and may include nausea, leg cramps or dizziness

Use currently limited to 2 years PTH trials were stopped early due to the finding of

osteosarcoma in animal studies FDA assigned a black box warning because of

osteosarcoma findings in animal studies.

US Food and Drug Administration. FDA. Talk Paper. November 26, 2002.

Teriparatide PTH (1-34): Warnings Hypercalcemia Paget's disease of bone Growing children and young adults Pregnant or nursing women A history of bone cancer A history of cancer that has metastasized to

the bones Radiation to the skeleton from any condition

US food and drug administration. FDA talk papers. November 26, 2002

Other Issues with Teriparatide

Cost How to combine/sequence it

with bisphosphonates

*With appropriate calcium and vitamin D.

PREVENTION

• Estrogen

• Raloxifene

• Alendronate

• Risedronate

• Ibandronate

TREATMENT

•Salmon Calcitonin

• Raloxifene

• Alendronate

• Risedronate

• Ibandronate

• Zoledronic acid

•Teriparatide (rhPTH)

FDA-Approved Therapies for Postmenopausal Osteoporosis

Post-Test Questions

?

Clinical Practice Recommendation Practice Recommendation:

All postmenopausal women should be evaluated for risk factors of osteoporosis which include increasing age, white race, low weight or weight loss, nonuse of estrogen replacement, history of previous fracture, family history of fracture, history of falls, and low scores on one or more measures of physical activity or function.

Evidence-Based Source:

AHRQ

Web Site of Supporting Evidence:

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1.chapter.39885

Strength of Evidence: A systematic review of 530 articles about risk factors, 123 about bone measurement tests, 23 about bone density monitoring, 277 about biochemical markers, and 53 about costs. An additional 242 studies were retrieved after reviewing reference lists of studies and by suggestion of the expert panel or leading researchers in the field

Clinical Practice Recommendation

Practice Recommendation:

Bisphosphonates (alendronate, etidronate, and risedronate) are recommended as treatment options for the secondary prevention of osteoporotic fragility fractures

Evidence-Based Source:

National Guideline Clearinghouse Web Site of Supporting Evidence:

http://www.guideline.gov/summary/summary.aspx?doc_id=3862

Strength of Evidence: The recommendations are based primarily on the available

evidence from randomized controlled trials.

Update on the Diagnosis and Treatment of Osteoporosis: 2008 Michael Maricic, MD Catalina Pointe Rheumatology Clinical Associate Professor of Medicine University.

Documents

fracture slide

risk of osteoporosis

year fracture risk

quantifying fracture

jaw slide

kline slide

treatment of osteoporosis

clinical risk factors