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Nelson B. Watts, MD

OSTEOPOROSIS AND BONE HEALTH SERVICESCINCINNATI, OHIO

OSTEOPOROSISWHAT’S NEW AND ON THE HORIZON IN SCREENING, DRUG

HOLIDAYS, SUPPLEMENTS, CONSERVATIVE THERAPYDISCLOSURES

• Stock options/holdings, royalties, company owner, patent owner, official role: OsteoDynamics co-founder, shareholder, director

• I have received honoraria for lectures from the following companies in the past year: Amgen, Merck

• I have received consulting fees from the following companies in the past year: AbbVie, Amgen, Merck, Radius

• Through my employer, I have research support from the following companies: Merck, NPS

WHO SHOULD HAVE ABONE DENSITY TEST?

• Women age 65 and older and men age 70 and older

• Younger postmenopausal women and men age 50-69 about whom you have concern based on their clinical risk factor profile

• 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

National Osteoporosis FoundationClinician’s Guide to Prevention and Treatment of Osteoporosis

www.nof.org

Use FRAX® to estimate 10-year fx risk Treat if risk is

≥3% for hip fracture or ≥20% for major osteoporotic fractures

T-scores between -1.0 and -2.5and increased fracture risk

WHOM TO TREATNOF GUIDELINES 2008/2013

After exclusion of secondary cause, treat postmenopausal women and men age 50 and older who have…

Osteoporosis

Clinical diagnosis: hip or spine fracture

DXA diagnosis: T-score -2.5 or below in the spine or hip

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TRABECULAR BONE SCORE (TBS)

Silva et al. JBMR 2014; Epub.

TBS is a texture analysis parameter which correlates with micro-architecture parameters

Roux JP et al. ASBMR 2012 Hans et al. JCD 2012

Resch et al. ASBMR2012 Bilezikian JCEM 2013

TRABECULAR BONE SCORE (TBS)

TBS, BMD AND FRACTURE RISK

• 11 cross-sectional studies; 7 prospective

• Consistent association between TBS and fracture risk

• Meta-analysis prospective cohorts (14 studies)

• GR major osteoporotic fracture = 1.44 (1.28-1.62)

• Similar predictive power in men and women

• Independent of LS and FN BMD

Adapted from Hans et al., JBMR 2011

TRABECULAR BONE SCORE (TBS)

BMD alone:

BMD + TBS

Based on Spine

TBS

≥ 1.300

1.200 < > 1.300

≤ 1.200

Based on minimum hip or spine BMD T‐score

Normal Osteopenia Osteoporosis

BMD AloneColor Code

Sub‐category of risk 

of Major osteoporotic 

fracture per 1'000 

women per year

≤ 4

] 4 - 5 ]

] 5 - 7 ]

] 7- 10 ]

] 10 - 14 ]

] 14 - 20 ]

> 20

Adapted from Hans et al. J Bone Miner Res. 2011;26:2762-9

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FUNDAMENTAL MEASURES FOR BONE HEALTH

CALCIUM

VITAMIN D

EXERCISE

Slide courtesy of Nelson Watts

EFFECT OF CALCIUM INTAKE ON BONE MASS AND FRACTURE RISK

0.650

0.700

0.750

0.800

0.850

0.900

30 40 50 60 70

Met

acar

pal

In

dex

Matkovic V, Am J Clin Nutr 1979;32:540

0

10

20

30

40

50

60

30 40 50 60 70

Hip

Fra

ctu

re R

ate

per

100

0/Y

r

High calcium district Low calcium district

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Nieves J et al, Am J Clin Nutr 1998;67:18-24

ESTROGEN WITH CALCIUM INCREASES BMDMORE THAN ESTROGEN WITHOUT CALCIUM

0.0

1.0

2.0

3.0

4.0

5.0

LumbarSpine

(P=0.01)

FemoralNeck (P=0.04)

Forearm(P=0.04)

ERT with calcium(n=20)

ERT alone (n=11)

PercentChangein BMD

CALCIUM SUPPLEMENTATIONREDUCES RISK OF SPINE FRACTURES

0

10

20

30

40

50

60

Previous fracture No prev. fracture

Placebo

Calcium carbonate, 1.2 g/day

Pe

rce

nt

of s

ubj

ect

s w

ith n

ew

spin

e f

ract

ure

s o

ver

4.3

ye

ars

Elderly women (avg. age 73.5 years)

Recker R et al, JBMR 1996;11:1961

*P=0.023

ARE CALCIUM SUPPLEMENTS BAD FOR THE HEART?

Bolland & Reid BMJ 2011Bolland & Reid BMJ 2010

Metanalysis of CVD events reported in calcium

supplement trials (Ca intake ≥1500 mg/d)

RR for MI = 1.27 (p=0.038)RR for MI, stroke or sudden

death= NS

Time to MI in Ca supplement trial

Lewis, Prince et al JBMR, 2011

5 year RCT of 1000 mg/d calcium supplement in 1460 older women with 4 years additional follow-up

MI or ASCVD death RR =0.9 NS

If preexisting CVD, data suggest a slight

decrease in risk

ARE CALCIUM SUPPLEMENTS NOT BAD FOR THE HEART?

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VITAMIN D REDUCES RISK OF FALLING

Bischoff-Ferrari HA et al, JAMA 2004;291:1999-2006

Meta-Analysis

31% decreasein fall risk

META-ANALYSIS OF EFFECT OF VITAMIN D ON FRACTURES

Bischoff-Ferrari HA et al, JAMA 2005;293:2257-2264

RR 0.74 (CI 0.61-0.88) RR 0.77 (CI 0.68-0.87)

26%↓ 23%↓

NS NS

Copyright restrictions may apply.

Autier P et al. Arch Intern Med 2007;167:1730-1737

VITAMIN D AND MORTALITY:META-ANALYSIS OF 9 TRIALS

8% increase in survival

HIGH DOSE VITAMIN DINCREASES FALLS AND FRACTURES

• 2,256 community-dwelling women, age ≥70, at high risk of fracture

• Oral cholecalciferol 500,000 IU or placebo once yearly (autumn or winter)

• Falls and fractures ascertained by monthly calendar and confirmed by telephone interview

• Falls and fractures were increased for 3 mos after dosing

• Peak 25-OH D level was ~50 ng/mL

Sanders KE et al, JAMA 2010;303:1815-1822

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VITAMIN D AND RARE CANCERS

Renal Cell Non-Hodgkin lymphoma

Pancreatic

OvarianEndometrial

Upper GI

Helzlsouer KJ et al. Am J Epidemiol 2010;172:4-9

Slid

e co

urte

sy o

f N

elso

n W

atts

Too much information?

Slide courtesy of Nelson Watts

WHAT IS WRONG WITH Ca/D STUDIES?

• Supplements won’t help

– If you are not deficient

– If you are deficient but the dose is inadequate

• In most published studies

– Baseline status was not known (serum 25-OH D, calcium intake/absorption) or was adequate

– Some used a dose of supplement that would not be adequate (400 IU/d of vitamin D would raise blood 25-OH D level by only ~3 ng/mL)

Slide courtesy of Nelson Watts

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HOW 25-OH D IS MEASUREDMAKES A DIFFERENCE

Binkley N et al, Clin Chem Acta 2010;411:1976-1982 Powe CE et al. N Engl J Med 2013; 369:1991-2000

Powe CE et al. N Engl J Med2013; 369:1991-2000

VITAMIN D AND MORTALITY

Melamed ML et al, Arch Intern Med 2008;168:1629-1637

DIETARY CALCIUM AND FRACTURES

Warensjö E et al, BMJ 2011;342:d1473

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Bauer D, N Engl J Med 2013;369:537-543

CALCIUM AND VITAMIN D SUMMARY

• Adequate calcium and vitamin D are necessary for optimal bone health

• For high risk patients, calcium and vitamin D are “necessary, but not sufficient”

• Calcium intake of 1000-1200 mg/d is adequate; caution against the use of over-aggressive supplementation

• Vitamin D 2000 IU/d is a reasonable supplement for those concerned about bone health or fall risk

• For higher-risk patients, measure 25-OH D and titrate dose to maintain a blood level 30-50 ng/mL

Slide courtesy of Nelson Watts

FDA-APPROVED MEDICATIONSINDICATIONS

Postmenopausal Osteoporosis

Glucocorticoid-induced Osteoporosis

Men

Drug Prevention Treatment Prevention Treatment

Estrogen

Calcitonin

(Miacalcin®, Fortical®)

Raloxifene (Evista®)

Ibandronate (Boniva®)

Alendronate (Fosamax®)

Risedronate (Actonel®)

Risedronate (Atelvia®)

Zoledronate (Reclast®)

Denosumab (Prolia™)

Teriparatide (Forteo®)

DrugVertebral Fracture

Nonvertebral Fracture

Hip

Fracture

Calcitonin

(Miacalcin®, Fortical®)

No effect demonstrated

No effect demonstrated

Raloxifene (Evista®) No effect

demonstratedNo effect

demonstrated

Ibandronate (Boniva®) No effect

demonstratedNo effect

demonstrated

Alendronate (Fosamax®)

Risedronate (Actonel®, Atelvia®)

Zoledronic acid (Reclast®)

Denosumab (Prolia™)

Teriparatide (Forteo®) No effect

demonstrated

FDA-APPROVED MEDICATIONSEVIDENCE FOR FRACTURE REDUCTION

Evidence for effect but not an FDA-approved indication

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BISPHOSPHONATES AVAILABLE IN THE US

Daily Weekly Monthly IV

Alendronate*

(Fosamax®)5 & 10 mg 35 & 70 mg

Risedronate

(Actonel®, Atelvia®)

5 mg 35 mg† 150 mg

Ibandronate

(Boniva®)2.5 mg 150 mg 3 mg q 3 mo

Zoledronate

(Reclast®5 mg/yr

*Alendronate available as alendronate alone (brand or generic) or 70 mg with vitamin D 2800 or 5600 IU (brand only)

†Atelvia should be taken once weekly, immediately after breakfast

• A question unique to bisphosphonates; no other agent used to treat osteoporosis (or other chronic disease) has a cumulative effect or potential for residual benefit

• Bisphosphonates have a long residence time in bone

– Does long-term treatment create safety concerns that limit the duration of treatment?

– Given the long retention in bone, with release and possibly recycling of drug, does cumulative exposure lead to a reservoir in bone, so that after therapy is stopped, sufficient drug will be released to exert a continuing benefit?

HOW LONG SHOULD TREATMENT LAST?

Rodan G et al. Curr Med Res Opin 2004;20:1291-1300

ESTIMATED ALENDRONATE RETENTION

If treatment were to stop after 10 years of administration of [alendronate] 10 mg per day (or 70 mg per week), the

estimated skeletal release of ALN into the circulation from remodeling would be approximately the same as that produced

by an oral daily dose of 2.5 mg.

BISPHOSPHONATESSIDE EFFECTS / SAFETY CONCERNS

• Short-term side effects

– Hypocalcemia

– Esophageal irritation (oral)

– Acute phase response (IV and high-dose oral)

– Acute renal damage (IV)

– Musculoskeletal pain*

• Long-term safety concerns

– Osteonecrosis of the jaw*

– Atypical femur fractures*

*Reports from post-marketing surveillance

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“SIDE BENEFITS” OF BISPHOSPHONATE THERAPY

• Decreased risk of breast cancer1-5

• Decreased risk of colorectal cancer6

• Decreased risk of stroke7

• Decreased risk of MI8

• Reduced risk of gastric cancer9

• Decreased overall mortality10, 11

7. Kang JH et al. Osteoporos Int 2012; [Epub ahead of print]8. Wolfe F et al, J Bone Miner Res 2013; 28:984-9919. Abrahamsen B et al. J Bone Miner Res 2012;27:679

10. Center JR et al. J Clin Endocrinol Metab 2011; 96:1006.11. Sambrook PN et al. Osteoporos Int 2011; 22:2551.

1. Chlebowski RT et al. J Clin Oncol 2010; 28:3582.2. Dreyfuss JH. CA Cancer 2010; 60:343.3. Newcomb PA et al. Br J Cancer 2010; 102:799.4. Rennert G et al. J Clin Oncol 2010; 28:3577.5. Vestergaard P et al. Calcif Tissue Int 2011; 88:255.6. Rennert G, et al. J Clin Oncol 2011; 29:1146.

OSTEONECROSIS OF THE JAW

• Exposed necrotic bone in the maxillo-facial region, not healing after 6-8 weeks of appropriate management, often at the site of a dental extraction or other invasive dental procedure or in patients with poorly fitting dentures

• Over 90% of reported cases have been in cancer patients receiving BP doses 10x higher than used to treat osteoporosis

• Estimated incidence in osteoporosis: 1:10,000-1:100,000

• Current guidelines from the American Dental Assn. (2011) emphasize the health consequences of osteoporosis, the benefits of bisphosphonate treatment and the low risk of ONJ in osteoporosis patients receiving bisphosphonate therapy

Woo S-B et al. Ann Intern Med 2006;144:753-761Khosla S et al. J Bone Miner Res 2008;23:159-165

Hellstein JW et al. JADA 2011:142:1243-1251

FEMUR FRACTURES

ATYPICAL FEMUR FRACTURES• Prodromal thigh or groin pain• Little or no trauma*• ~30% bilateral• Subtrochanteric*• Transverse/oblique, medial

spike*• Little or no comminution*• Begin as a localized periosteal

reaction of the lateral cortex*• Thick cortices• Delayed healing

TYPICAL FEMUR FRACTURES

• No warning symptoms

• Caused by a fall

• Unilateral

• Proximal

• Acute angle (femoral neck, intertrochanteric)

• May be comminuted

ASBMR Task ForceShane E et al, JBMR 2010;25:2267-2294

*Major featuresRequired for diagnosis

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2014 UPDATE: ASBMR TASK FORCE ONATYPICAL FEMUR FRACTURES

Location: below lesser trochanter, above supracondylar flareMajor Features (four of five)• Trauma: little or none• Direction: lateral transverse, may be oblique on the medial side• Comminution: little or none• Complete fractures: may have a medial spike; incomplete fractures

involve only the lateral cortex• Localized periosteal reaction/thickening of the lateral cortexMinor features (none required)• Generalized increase in cortical thickness of the shaft• Prodromal symptoms such as dull aching pain in groin or thigh• Bilateral incomplete or complete fractures and symptoms• Delayed fracture healing

Shane E et al, JBMR 2014;29:1-23

SUBTROCHANTERIC FEMUR FRACTURE

• This patient had not been on a bisphosphonate or any other treatment for osteoporosis

SUBTROCHANTERIC FRACTURES OF THE FEMUR

Watts NB and Diab D, J Clin Endocrinol Metab 2010;95:1555-1565

ATYPICAL FEMORAL FRACTURES1.5 million women 55 and older with fx from any cause

12,777 (0.9%) had femur fractures

Schilcher J et al, N Engl J Med 2011;364:1728-1737

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ATYPICAL FEMORAL FRACTURES

10.6% of all femur fractures were in the shaft

Schilcher J et al, N Engl J Med 2011;364:1728-1737

ATYPICAL FEMORAL FRACTURES

59 were atypical fractures 0.46% of all femur fractures4.4% of all shaft fractures

10.6% of all femur fractures were in the shaft

Schilcher J et al, N Engl J Med 2011;364:1728-1737

ATYPICAL FEMORAL FRACTURES

Atypical fractures accounted for0.46% of all femur fractures and4.4% of all shaft fractures.

10.6% of all femur fractures were in the shaft

Schilcher J et al, N Engl J Med 2011;364:1728-1737

Absolute risk increase:5 cases per 10,000 pt years

ATYPICAL FEMORAL FRACTURES

Atypical fractures accounted for0.46% of all femur fractures and4.4% of all shaft fractures.

10.6% of all femur fractures were in the shaft

Schilcher J et al, N Engl J Med 2011;364:1728-1737

Absolute risk increase:5 cases per 10,000 pt years

Only 11% were using bisphosphonates!Assume 35% risk reduction –4,000 fractures could have been prevented

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LONG-TERM EXPERIENCE WITH ALENDRONATEFIT LONG-TERM EXTENSION (FLEX) STUDY

• Patients who received ~5 years of alendronate in the Fracture Intervention Trial agreed to a second 5-yr study

• Re-randomized to stay on alendronate (n=672) or changed to placebo (n=437)

• For those who had 10 years of alendronate compared with stopping after 5 years

– Overall, clinical vertebral fractures were reduced 55%

– In women with T-scores -2.5 or below at the start of FLEX, nonvertebral fractures were reduced by 50%

Black DM et al, JAMA 2006;296:2927-2938Schwartz AV et al. J Bone Miner Res 2010;25:976-982

CLINICAL VERTEBRAL FRACTURES IN THE FLEX STUDY

0 1 2 4 5

Cum

ulat

ive

inci

denc

e of

fra

ctur

es (

%)

Years Since FIT

ALN/PLB 437 436 425 412 398 387ALN/ALN 662 660 646 631 615 597

30

1

2

3

4

5

6

ALN 5 years Placebo 5 years

Alendronate 10 years

5.4%

RR 55%P=0.013

2.5%

Black DM et al, JAMA 2006;296:2927-2938

CLINICAL VERTEBRAL FRACTURES IN THE FLEX STUDY

0 1 2 4 5

Cum

ulat

ive

inci

denc

e of

fra

ctur

es (

%)

Years Since FIT

ALN/PLB 437 436 425 412 398 387ALN/ALN 662 660 646 631 615 597

30

1

2

3

4

5

6

ALN 5 years Placebo 5 years

Alendronate 10 years

5.4%

RR 55%P=0.013

2.5%

Black DM et al, JAMA 2006;296:2927-2938 N Engl J Med 2012

Thus, the available data on long-term efficacy do not clearly identify subgroups of patients who are more likely to benefit from drug therapy beyond 3 to 5 years

…decisions to continue treatment must be based on individual assessment of risks and benefits and on patient preference. In this regard, patients at low risk for fracture (e.g., younger patients without a fracture history and with a bone mineral density approaching normal) may prove to be good candidates for discontinuation of bisphosphonate therapy after 3 to 5 years, whereas patients at increased risk for fracture (e.g., older patients with a history of fracture and a bone mineral density remaining in the osteoporotic range) may benefit further from continued bisphosphonate therapy.

FDA POSITION

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N Engl J Med 2012

Thus, the available data on long-term efficacy do not clearly identify subgroups of patients who are more likely to benefit from drug therapy beyond 3 to 5 years

…decisions to continue treatment must be based on individual assessment of risks and benefits and on patient preference. In this regard, patients at low risk for fracture (e.g., younger patients without a fracture history and with a bone mineral density approaching normal) may prove to be good candidates for discontinuation of bisphosphonate therapy after 3 to 5 years, whereas patients at increased risk for fracture (e.g., older patients with a history of fracture and a bone mineral density remaining in the osteoporotic range) may benefit further from continued bisphosphonate therapy.

FDA POSITION

patients at low risk for fracture (e.g., younger patients without a fracture history and with a bone mineral density approaching normal) may prove to be good candidates for discontinuation of bisphosphonate therapy after 3 to 5 years

N Engl J Med 2012

Thus, the available data on long-term efficacy do not clearly identify subgroups of patients who are more likely to benefit from drug therapy beyond 3 to 5 years

…decisions to continue treatment must be based on individual assessment of risks and benefits and on patient preference. In this regard, patients at low risk for fracture (e.g., younger patients without a fracture history and with a bone mineral density approaching normal) may prove to be good candidates for discontinuation of bisphosphonate therapy after 3 to 5 years, whereas patients at increased risk for fracture (e.g., older patients with a history of fracture and a bone mineral density remaining in the osteoporotic range) may benefit further from continued bisphosphonate therapy.

FDA POSITION

patients at increased risk for fracture (e.g., older patients with a history of fracture and a bone mineral density remaining in the osteoporotic range) may benefit further from continued bisphosphonate therapy

N Engl J Med 2012

• In FLEX, number needed to treat (NNT) for 5 years to prevent one clinical vertebral fracture– Women with vertebral fx and T-score -2.0 or below 17

– Women without vertebral fx and T-score -2.5 or below 24

ALGORITHM FOR MANAGEMENT OF POSTMENOPAUSAL WOMEN ON LONG TERM BISPHOSPHONATE THERAPY

ASBMR Long Term BP Task Force, Interim Report September 2014

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WHEN SHOULD THE HOLIDAY END?

• Arbitrary?

– Longer for drugs with highest skeletal affinity (zoledronic acid), shorter for drugs with lowest skeletal affinity (risedronate)

– Longer for lower risk patients, shorter for those at high risk

• Bone turnover markers? Which marker? How high?

• BMD? Decrease more than the least significant change (LSC)

Watts NB and Diab D, J Clin Endocrinol Metab 2010;95:1555-1565

SECONDARY FRACTURE PREVENTION:THE FRACTURE LIAISON SERVICE MODEL

Hip fracture patients

Objective 1: Improve outcomes and improve efficiency of care after hip fractures – by following the 6 “Blue Book” standards

Non-hip fragility fracture patients

Objective 2: Respond to the first fracture, prevent the second – through Fracture Liaison Services in acute and primary care

Individuals at high risk of 1st fragility fracture or other injurious falls

Objective 3: Early intervention to restore independence – through falls care pathway linking acute and urgent care services to secondary falls prevention

Older peopleObjective 4: Prevent frailty, preserve bone health, reduce accidents – through preserving physical activity, healthy lifestyles and reducing environmental hazards

http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/DH_103146

Hip FX to ED Hospital Admit

Ortho Consult and

surgery

FX Liaison Consultscheduled at 2 wk ortho visit for suture removal

Seen 4-6 weeks later by dedicated NP

After eval done and Rx started, f/u care decided in conjunction with PCP

MERCY FLS PILOT PROGRAM

Post Op Order Set In EPIC

(Includes FX Liaison Referral)

• Trabecular bone score (TBS) provides an added dimension to fracture risk assessment

• Calcium and vitamin D are essential for bone health; not everyone needs supplements

• Safe and effective therapies are available

• Osteoporosis remains under-diagnosed and under-treated: most patients are not taking advantage of what we currently have to offer

• Systematically capturing patients after fracture (fracture liaison service – FLS) should improve secondary prevention

• Stay tuned for new developments

OSTEOPOROSISWHAT’S NEW AND ON THE HORIZON IN SCREENING, DRUG

HOLIDAYS, SUPPLEMENTS, CONSERVATIVE THERAPY

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WILL YOUR BONES LAST AS LONG AS YOU DO?

Questionsor

comments?