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New Guidelines for Osteoporosis Prevention and Management

Professor Peter R Ebeling AO

MBBS MD FRACP

Head, Department of Medicine

School for Clinical Sciences

Monash Health Translation Precinct

Monash University, Clayton, Victoria

The Annual Women’s and Children’s Health Update Brisbane, 22nd July 2017

MonashHealth

Potential Conflicts

• Departmental research funding from Merck, Novartis, Amgen and Eli-Lilly

• Honoraria to Department from Amgen, Viiv Healthcare and Merck

MonashHealth

The Crisis in the Treatment of Osteoporosis

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Declining Osteoporosis Treatment Rates Post-hip Fracture

MonashHealth

Media Tries to Provide a Positive Message Half of Hip Fracture Patients Give Us Advance Notice

1. J Endocrinol Invest 1999;30:583-588 Kanis JA & Johnell O

2. Osteoporosis Review. 2009;17(1):14-16 Mitchell PJ

‘Hip fracture is all too often the final destination of a thirty year journey

fuelled by decreasing bone strength and increasing falls risk’2

Opportunities for GP intervention

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WHO Criteria for Osteoporosis

Diagnosis T-score

Normal > –1

Osteopaenia –1 to –2.5

Osteoporosis ≤ –2.5

Severe osteoporosis ≤ –2.5 and ≥ 1 fracture

Kanis JA, et al. J Bone Miner Res. 1994;9:1137-1141.

National Osteoporosis Foundation, 2003.

• For every 1 SD from normal, the relative risk of

fracture increased by 1.5- to 2.5- fold

* Reference standard for “normal” BMD is a 30-year-old healthy

woman

Absolute Fracture Riskwww.fractureriskcalculator.com

Vitamin D + Ca in Institutionalised Elderly

0

2

4

6

8

10

12

All Nonvertebral Hip

Vit D + CaVit D + Ca

PlaceboPlacebo

%

Chapuy et al, NEJM, 1992

p<0.04

p<0.015

3270 women, mean age 84, living in nursing homes,

randomised to 1.2g Ca + 800 IU Vit D or placebo for 18 mths

Secondary Prevention: RECORD Trial

Recent low trauma fracture

n 5292

Setting Comm

Dose 800 IU

25OHD 38 62

Adherence 54%

Grant AM et al. Lancet 2005

Effects of Vitamin D on FracturesImportance of Vitamin D Dose

Bischoff-Ferrari al. Am J Clin Nutr 2006

Effects on Hip and Non-vertebral Fracture

400 IU/d

dose

400 IU/d

dose

RR 26% RR 23%

700 - 800 IU/d 700 - 800 IU/d

Effect of calcium supplements with or without vitamin D on cardiovascular events: Based on patient-level data

Bolland M J et al. BMJ 2011;342:bmj.d2040©2011 by British Medical Journal Publishing Group

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MI Risk and Baseline Risk

Factors

Bolland M J et al. BMJ 2010

341:C3691

Cardiovascular Events in RCT of 5 Yrs Calcium vs Placebo &

4.5 Yrs Follow up in 1460 Postmenopausal WomenITT Analysis

Lewis J et al. J Bone Miner Res (epub July 2010)

Health Benefits of Higher Dietary Calcium Intakes

Khan B et al., J Bone Miner Res 2015;30:1758-66

Effects of Calcium on Myocardial Infarction

• Numerous large studies of Ca plus vitamin D have shown no

increased risk of cardiovascular events

• However, concern exists that MI risk is increased

• Food remains the best source of calcium

• Supplements should be used only when adequate dietary Ca intake

cannot be achieved

• Beneficial effects of calcium are found with relatively low doses

(500-600 mg)

• In almost every osteoporosis treatment RCT, adequate Ca and

vitamin D were also required

• Elderly individuals and others with impaired renal function who

take calcium supplements may be at higher risk of CVD

Vitamin D Reduces Falls

• Meta-analysis showed that vitamin D supplementation

reduces falls by 22% in ambulatory or institutionalised

elderly individuals

• 15 patients would need to be treated with vitamin D to

prevent one fall

• Should be part of multi-faceted falls prevention program

• Larger doses of 60,000 IU per mth, or 500,000 IU per yr,

are associated with an increased falls risk

Bischoff-Ferrari HA et al., JAMA 2004, 2016

Position Statement – Risks and Benefits of Sun Exposure 2016 - CCV, ACD, OA, ANZBMS, ESA

• UV Index >3: A few minutes of mid-morning or mid-afternoon

sun exposure to arms and hands (or equivalent area) on most

days of the week should be sufficient to maintain adequate

vitamin D levels

• UV Index <3 (May-August in southern states): Sun protection is

not recommended

- During these times, to support vitamin D production it is

recommended that people be outdoors in the middle of the day

with some skin uncovered on most days of the week

- Being physically active while outdoors will further assist

with maintaining vitamin D levels. A brisk walk at lunchtime or

gardening are examples of being physically active outdoors

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Vitamin D Supplements

Recommended daily vitamin D3 dose: at least 800 IU/d

•Vitamin D3 supplement recommended

•Higher dose (>1000 IU) vitamin D supplements now available in OsteVit-D liquid, Bioceuticals D3 drops forte, and from compounding pharmacists

•Biological Therapies - 50,000 IU capsules

Osteoporosis - Prevention, Diagnosis and Treatment - NHMRC/RACGP Guidelines (Draft April 2008)

+ 315 mg Ca)

• Ostevite D or Blackmores Vitamin D 1000 IU (D3), Ostelin 1000 IU (D3)1000 IU + 600 mg Ca)

Tailoring Therapy- Which Option for Who?

First-line drugs for osteoporosis are “anti-resorptive”

•Oestrogen +/- progestogen, if menopausal symptoms are present

•Selective oestrogen receptor modulating drugs (e.g. raloxifene)

•Oral bisphosphonates (alendronate, risedronate)

•Intravenous bisphosphonates (zoledronic acid)

•Subcutaneous denosumab injections (human RANK ligand Ab)

Second-line drugs

•Stimulates bone formation [subcutaneous PTH(1-34) or teriparatide

injections]

•Strontium ranelate (uncertain mode of action; CV safety)

Minimal trauma hip or vertebral fracture

Initiate treatment with anti-osteoporosis medication

• Bisphosphonates (Grade A)• Denosumab (Grade A women, Grade B men)• Oestrogen replacement therapy (Grade A)• Strontium ranelate - second line only (Grade A)

Non-modifiableParental history of fractureModifiable and lifestylePremature menopause*Hypogonadism*Multiple fallsLow physical activity/immobilityLow body weightLow muscle mass and strengthPoor balanceProtein or calcium undernutritionSmokingAlcohol > 2 standard drinks/dayVitamin D insufficiency

Where appropriate: implement falls reduction strategies (Grade A), encourage exercise participation (Grade A), modify diet, smoking and alcohol intake (Grade C), provide

education and psychosocial support (Grade D)

No history of minimal trauma fracture

Assess risk factor profile (Grade B)Major risk factors that qualify for MBS reimbursement of DXA*

Diseases or conditions^^Rheumatoid arthritis*Hyperthyroidism*Hyperparathyroidism*Chronic kidney disease*Chronic liver disease*Coeliac disease or malabsorption* Diabetes mellitusMyeloma/MGUSOrgan transplantBone marrow transplantHIV infectionDepression

Aged 70 or over^(Grade D Consensus)

Treatment not recommended

Initiate treatment with anti-osteoporosis medication• Bisphosphonates (Grade A)• Denosumab (Grade A women, Grade B men)• Oestrogen replacement therapy (Grade A)• Strontium ranelate - second line only (Grade A)

DXA of spine and proximal femur (Grade A)

High 10 year risk of fractureHip fracture > 3%, any fracture > 20%

OR T-score ≤ -2.5

Low risk of

fracture

Estimate absolute fracture risk Garvan Fracture Risk Calculator OR FRAX® (Grade D Consensus)

T-score ≤ -2.5 ?

No

Yes

Osteoporosis risk assessment, diagnosis and management Recommendations restricted to postmenopausal women and men over

50

DXA to establish baseline BMD –recommended but not essential

Medications (large effect)Glucocorticoids*^^^(>3 months 7.5mg/day)Excess thyroid hormone replacementAromatase inhibitorsAnti-androgen therapy*Medications (modest effect)SSRIsAnti-psychoticsThiazolidenedionesAnti-epileptic medicationsPPIs

^^^See other guidelines specific to glucocorticoid treatment for more information and recommendations regarding glucocorticoid use and risk of osteoporosis and fracture

⌃Consensus recommendation. The Medicare Benefits Scheme (MBS) reimburses costs for measurement of BMD testing in any person aged 70 or over

**Excluding fingers and

toes

DXA of spine and proximal femur

(Grade A)

Minimal trauma fracture at any other site**

DXA of spine and proximal femur (Grade A)

T-score ≤ -1.5

T-score > -1.5

Refer for specialist

review

^^Treatment of an underlying condition may improve bone strength

Effect of Denosumab on Fracture Risks at 36 Mths

FREEDOM Trial

RR = risk reduction

Cummings SR, et al. N Engl J Med. 2009;361:756-765.

7.2%

8.0%

1.2%

6.5%

0.7%

2.3%

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

New Vertebral Nonvertebral Hip

Inc

ide

nc

e a

t M

on

th 3

6 (

%)

Placebo

Denosumab

RR = 40%

P = 0.04

RR = 20%

P = 0.01RR = 68%

P < 0.001

NNT

=20

NNT

=66

NNT

=200

Denosumab Re-treatment and Changes in

Lumbar Spine and Total Hip BMDPhase 2 Study in Women With Low BMD

Miller PD, et al. Bone. 2008;43:222-229

Lumbar Spine Total Hip

Pe

rce

nt

Ch

an

ge

(LS

Me

an

±S

E)

Months

-6

-4

-2

0

2

4

6

8

Months

0 6 12 18 24 36 48-4

-2

0

2

4

6

8

10

12

14

0 6 12 18 24 36 48

Re-treatment

60 mg Q6M

Discontinued

Treatment

Re-treatment

60 mg Q6M

Discontinued

Treatment

Placebo

30 mg Q3M

Pe

rce

nt

Ch

an

ge

(LS

Me

an

±S

E)

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This information has been provided to you in response to your unsolicited request.

Denosumab Continues to Increase BMD

Over 8 Years

Adapted from Papapoulos S et al. Eight Years of Denosumab Treatment in Postmenopausal Women With Osteoporosis: Results From the First Five

Years of the FREEDOM Extension; LB-MO26, ASBMR 2013, Baltimore.

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Why Change Therapy?

• Sequential therapy for osteoporosis may be considered

–When there has been significant bone loss or a fracture on

antiresorptive therapy for >12 months

–In the presence of adverse events

–Insufficient adherence, e.g. the elderly

–Dosing inconvenience or intolerance with oral bisphosphonate

therapy

–Patients with CKD where bisphosphonates are contraindicated

–To consolidate increases in BMD following anabolic therapy

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Treatment-

naïve

Head-to-head Studies of Denosumab vs Bisphosphonates in Both Pre-treated or Treatment-naïve Subjects

Data are least-squares means and 95% confidence intervals. *p < 0.0001 denosumab vs BP. 1Recknor C et al. ASBMR Poster FR0388. 2Kendler DL et al. J Bone Miner Res. 2010;25:72-81. 3Brown JP et al. J Bone Miner Res. 2009;24:153-161

Roux C et al, ASBMR; Minneapolis, MN; October 12-15, 2012.

IBN

ALN

ALN

RIS

1.6%*1.4%*

0.9%*

1.0%*

1 2 3

Pre-treated

Pre-treatedPre-treated

To

tal

Hip

Pe

rce

nt

Ch

an

ge

Fro

m B

as

eli

ne

PBS Reimbursement for Teriparatide in Patients

with Severe Osteoporosis

• Severe osteoporosis

• T score < -3.0

• 2 minimal trauma fractures

• One fracture occurred after 12 mths of anti-resorptive drugs

• Or, intolerance to oral and intravenous bisphosphonates and denosumab

• Treatment initiated by specialist, but may be continued by GP - limited to 18 months per lifetime

Radiographic Features

Short-oblique configurationDiffuse cortical thickening

Focal lateral cortical thickening

(“beaking”)

No comminution

Medial spike

Early Detection

- Radionuclide Bone Scintigraphy -

Risk of Atypical Femoral Fracture Associated with Bisphosphonate Use during the 3 Years (2005–2008) Preceding the Fracture.

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

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Clinical Features I

• Prodromal pain in 70% (158 of 227)

• Concomitant GC use in 34% (26 of 76)

– incr fracture risk in one large series (OR 5.2)

• Bilateral fractures present in 28% (60 of 215)

• Bilateral radiological changes present in 28% (63 of 224)

• Delayed healing in 26% (29 of 112)

Physician and Patient Education

• The majority have a prodrome of thigh or groin pain

• Educate physicians and patients about this symptom

– physicians to ask patients on BPs and other potent antiresorptive agents about thigh or groin pain

• Urgent radiographic evaluation of both femora (even if pain is unilateral) is needed

– if plain radiographs are normal, MRI or radionuclide scintigraphy scans should be performed

Jaw Osteonecrosis

MRONJ

• Originally called bisphosphonate-associated

osteonecrosis of the jaw (2008 ADA Council advisory

statement)

• Since then a few cases of ONJ have been described in

patients treated with denosumab for osteoporosis,

and more in patients treated with denosumab for

metastatic breast and prostate cancer and with

chemotherapeutic anti-angiogenic agents for cancer

• Medication-related ONJ (2014 statement)

Frequency of MRONJ – Benign Indications

• Retrospective assessment• ASBMR consensus rep. 1/10,000-1/100,000

• German study 1/13,500

• ADA < 1/100,000

• Canadian study < 1/100,000

• Kaiser-Permanente 1/952-1/1,537

• Prospective assessment• HORIZON (>10,000 pts) 2 BP/1 placebo (incl follow up study)

• 2,000,000 pts used zoledronic acid so far

• Not a single ONJ case reported

• Risk in oncology trials is much higher 1-2%

• In oncology trials, denosumab has the same risk of ONJ as zoledronic acid – also 13 pts in osteoporosis 7-year FREEDOM trial extension with denosumab

Risk Factors for ARONJ

• Age > 65 yrs

• Periodontitis

• Use of bisphosphonates > 2 yrs

• Smoking

• Denture wearing

• Diabetes mellitus

• Invasive bone procedures such as tooth extractions

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Antiresorptive Drug Holidays

• “Insufficient evidence to recommend a holiday

from Antiresorptive drug therapy or waiting periods

before performing dental treatment for prevention

of ARONJ”

• “Significant therapeutic benefits of AR agents in

patients with osteoporosis far outweigh the small

risk of developing ARONJ”

Hellstein JW et al, JADA 2011

How Long to Continue Bisphosphonate Therapy?

Effect of Continuing or Stopping Alendronate after 5 Years of

Treatment on Total Hip BMD

Black et al JAMA 2006;296:2927-2938

0 1 2 3 4 0 1 2 3 4 5

16

14

12

10

8

6

4

2

0

-2

Total Hip

FIT FLEX

BM

D c

ha

ng

e f

rom

FIT

ba

se

lin

e

me

an

%

Year Year

Alendronate 662 660 658 656 460* 657 642 628 599 580 553

Placebo 437 436 436 432 297* 437 428 415 401 380 361

*Measured in clinical fracture arm only. †All subjects had received alendronate during FIT.

FLEX treatment group†

Alendronate (pooled)

Placebo

Effect of Continuing or Stopping Alendronate After 5 Years

of Treatment on Clinical Vertebral Fractures

Black et al JAMA 2006;296:2927-2938

20

15

10

5

0 12 24 36 48 60 72

Time to first fracture, mo

Cu

mu

lati

ve i

ncid

en

ce,

%

Clinical vertebral fractures

RR, 0.45 (0.24-0.86)

No. at riskPlacebo 437 428 429 421 417 414

Alendronate 662 659 657 654 650 646

FLEX treatment group†

Alendronate (pooled)

Placebo

Effect of Continuing or Stopping Zoledronate After 3 Years of Treatment: Spine, Total Hip BMD

Black et al J Bone Miner Res 2012;27:243-254

14

12

10

8

6

4

2

0

0 1 2 3 4 5 6

Percent change in Lumbar Spine BMD

% C

han

ge

Z6+12.1%

Z3P3+10.1%

Time (Years)Time (Years)

8

7

6

5

4

3

2

1

0

Percent Change in Total Hip BMD

Z6+4.3%

Z3P3+2.8%

Δ, p<0.0001

% C

han

ge

0 1 2 3 4 5 6

Effect of Continuing or Stopping Zoledronate After 3

Years of Treatment: Fractures

Increase in

vertebral fractures

if stop ZOL after 3

years

Black et al J Bone Miner Res 2012;27:243-254

15

10

5

0

Pati

en

ts w

ith

new

vert

eb

ral

fractu

res (

%)

Extension study (year 3-6)

Morphometric vertebral fractures

Odds ratio = 0.51

(0.26-0.95)Z3P3

6.2%

Z6

3%

Core PBO10.9%

Core ZOL3.3%

Managing Osteoporosis in Patients on Long-Term Bisphosphonate

Treatment: Report of a Task Force of ASBMR

Adler RA et al., J Bone Miner Res 2016

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Thank You!

Q & A