Whats new in Osteoporosis What s new in Osteoporosis Jesse A - - PowerPoint PPT Presentation

What’s new in Osteoporosis What s new in Osteoporosis

Jesse A Pewarchuk, MD FRCPC

Table of Contents Table of Contents

Section 1: Osteoporosis in 2012 Section 1: Osteoporosis in 2012 Section 2: Diagnosis of Osteoporosis Section 2: Diagnosis of Osteoporosis – FRAX & CAROC FRAX & CAROC Section 3: Treatment of Osteoporosis Section 3: Treatment of Osteoporosis Section 4: Drug Costs Section 4: Drug Costs Section 5: Drug Holidays Section 5: Drug Holidays Section 6: Section 6: Glucocorticoids Glucocorticoids Section 8: Osteonecrosis Section 8: Osteonecrosis Section 7: Men Section 7: Men Section 6: Section 6: Glucocorticoids Glucocorticoids Section 8: Osteonecrosis Section 8: Osteonecrosis Section 9: Atypical Fractures Section 9: Atypical Fractures

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What is osteoporosis in ‘13 What is osteoporosis in 13

• Defined based on fracture risk not bone

Defined based on fracture risk not bone density (major change from 2002)!

• Osteoporosis: High risk of fragility fracture
• Osteoporosis: High risk of fragility fracture

– HIGH RISK: Risk of fracture > 20% over next 10 years years – MODERATE: Fracture Risk 10‐20% over next 10 years years – LOW RISK: Risk of fracture < 10% over next 10 years years

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Who to screen?? Who to screen??

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Who would the experts screen? Who would the experts screen?

Adults aged 50

Fragility Fracture Prolonged Glucocorticoid

Parental Hip Fracture V t b l F t

to 65

Prolonged Glucocorticoid use Use of other high risk medications

Vertebral Fracture or Osteopenia on X‐ray Active smoking > 3 alcoholic beverages per day

Premature gonadal failure (before 45) Hypogonadism Malabsorption syndrome Primary

> 3 alcoholic beverages per day Body weight below 60 kg Weight loss of > 10% from age 25

Primary Hyperparathyroidism

25 Rheumatoid Arthritis

Adults under age 50

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Great, but where’s your calculator? Great, but where s your calculator?

• Two options endorsed by Osteoporosis

Two options endorsed by Osteoporosis Canada

– WHO’s FRAX risk calculation tool – WHO s FRAX risk calculation tool – CAROC’s Risk index

• Both are only valid if aged 50 or over, no valid

tool exists for people under 50.

• Outstanding concordance between the two!

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FRAX! FRAX!

h // h ffi ld k/FRAX/ l j ? 19 http://www.sheffield.ac.uk/FRAX/tool.jsp?country=19

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FRAX FRAX

• Developed by the WHO

Developed by the WHO

• Each country has individualized formulae

taking into account local risk patterns taking into account local risk patterns

• Very simple to use and gives a very accurate,

ll lid d i k well validated risk score

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FRAX Variables FRAX Variables

• Age

g

• Gender
• Rheumatoid arthritis
• Secondary osteoporosis (disorder strongly associated with OP)
• A prior osteoporotic fracture (including vertebral fracture)
• Parental history of hip fracture
• Femoral neck BMD
• Current smoking
• Current smoking
• Low body mass index (kg/m2)
• Alcohol intake (3 or more drinks/d)

Alcohol intake (3 or more drinks/d)

• Oral glucocorticoids ≥5 mg/d of prednisone for ≥3 m (ever)

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FRAX FRAX

• Not included in FRAX currently but also an

Not included in FRAX currently but also an independent predictor of fragility fracture is a history of Diabetes history of Diabetes.

FRAX Advantages FRAX Advantages

• Web‐based format that is easily accessed and

Web based format that is easily accessed and can be bookmarked

• Very user friendly
• Very user friendly
• Includes wide variety of important risk factors
• DOES NOT REQUIRE BONE MINERAL DENSITY
• BMD helps refine the score but is not essential

p

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FRAX Disadvantages FRAX Disadvantages

• Must use the WHO sponsored website

Must use the WHO sponsored website

• No downloadable program for PC, need to

have web access to use have web access to use

• Only iPhone/iPad app is $5.99 at App Store
• May underestimate effect of high dose

prolonged steroids

• No access to base formulae, just the output
• Takes 30 seconds to input the variables

Takes 30 seconds to input the variables

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CAROC CAROC

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CAROC CAROC

• Simple system developed in Edmonton and

Simple system developed in Edmonton and used by radiologists across the nation

• Base Risk is derived from a nomogram of bone
• Base Risk is derived from a nomogram of bone

mineral densities Th i i h d i h i k

• The patient is pushed into the next risk

category by having a fragility fracture OR h 3 h f l i id greater than 3 months of glucocorticoids

• If both risk factors, automatically High Risk

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CAROC: Advantages CAROC: Advantages

• Very simple to use it’s laid out for you on

Very simple to use, it s laid out for you on paper in an unambiguous manner

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CAROC disadvantages CAROC disadvantages

• Does not take into account most of the

Does not take into account most of the contributing risk factors

• For example does not take into account
• For example, does not take into account

important items such as family history that are heavily weighted in FRAX heavily weighted in FRAX

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Prevention: Exercise Prevention: Exercise

• Exercise involving RESISTANCE TRAINING or

Exercise involving RESISTANCE TRAINING or weight bearing aerobic exercise

• Exercises focusing on BALANCE (tai chi etc)
• Exercises focusing on BALANCE (tai chi, etc)

should be considered in those at fall risk I i h i HIP PROTECTORS

• In nursing home patients, HIP PROTECTORS

should be used in those deemed high risk for f lli falling

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PREVENTION: Vitamins/Minerals PREVENTION: Vitamins/Minerals

• These numbers apply to people aged 50+

These numbers apply to people aged 50+

– Calcium (all risk groups): Total Daily Dose (diet plus supplement): 1200 mg plus supplement): 1200 mg – Vitamin D (low risk): 400‐1000 iu daily – Vitamin D (mod risk): 800‐1000 iu daily – Vitamin D (mod risk): 800‐1000 iu daily – Vitamin D (high risk): up to 2000 iu daily plus measurement of body Vitamin D levels after 4 measurement of body Vitamin D levels after 4 months of supplementation

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PREVENTION: LIFESTYLE PREVENTION: LIFESTYLE

• Smoking Cessation

Smoking Cessation

• Elimination of excess alcohol consumption

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Treatment Treatment

• Tailored based on risk category

Tailored based on risk category

• Nonpharmacologic

Di t – Diet – Lifestyle – Vitamins and minerals

• Pharmacologic

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Oral Bisphosphonates Oral Bisphosphonates

• Examples:

Examples:

– Alendronate, Risedronate

• Mechanism:

Mechanism:

– Incorporated into bone, prevents osteoclast action

• Adverse Effects:

Adverse Effects:

– Peptic Ulcer Disease, Esophagitis, Dyspepsia – Rare: Osteonecrosis of jaw atypical femur fracture Rare: Osteonecrosis of jaw, atypical femur fracture

• Important that these be taken on empty

stomach or poor absorption stomach or poor absorption

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Oral Bisphosphonate Benefits Oral Bisphosphonate Benefits

• Risedronate reduces vertebral fractures by 41‐

Risedronate reduces vertebral fractures by 41 49% and non‐vertebral fractures by 36% over three years three years

• Hip fractures reduced by 26%

Si il b f l d

• Similar numbers for aledronate
• NOTE: Etidronate (Didrocal) is the only

bisphosphonate with no proven reduction in hip fracture

Rahmani P et al. Prevention of osteoporosis‐related fractures among postmenopausal women and older men. CMAJ. 2009. 181 (11): 815.

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IV Bisphosphonate IV Bisphosphonate

• Examples:

Examples:

– Zoledronic Acid/Aclasta

• Side effects:

Side effects:

– IV route eliminates very common GI side effects and assures compliance – Flu like symptoms following administration are common (10%) but diminish on subsequent doses – Risk of osteonecrosis reported less than 1/10,000 – Rare atypical femur fractures

Rahmani P et al. Prevention of osteoporosis‐related fractures among postmenopausal women and older men. CMAJ. 2009. 181 (11): 815.

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IV Bisphosphonate IV Bisphosphonate

• Zoledronic Acid is much better:

Zoledronic Acid is much better:

– Vertebral Fracture 68% relative risk reduction – Hip fracture 40% relative risk reduction p – Nonvertebral 20% relative risk reduction

• But Zoledronic acid goes further than simply

But Zoledronic acid goes further than simply fracture prevention. It has been shown to reduce mortality by 28% vs placebo when given to patients with recent hip fracture. NNT = 29

Lyles KW, Colon‐Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799‐809.

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SERM Agents SERM Agents

• Raloxifene
• Side Effects:

– Hot flushes (less than 10%) – Leg cramps (uncommon) – Increased risk of VTE (OR = 2.08)

• Mechanism:
• Mechanism:

– Stimulates estrogen receptors on bone

• Increases bone density and shown to reduce

y vertebral fractures (no effect shown on other sites); RR = 0.60; NNT = 99 to 2381 over 2 years

Cranney A Tugwell P Zytaruk N et al Meta analyses of therapies for postmenopausal Cranney A, Tugwell P, Zytaruk N, et al. Meta‐analyses of therapies for postmenopausal

• steoporosis. IV. Meta‐analysis of raloxifene for the prevention and

treatment of postmenopausal osteoporosis. Endocr Rev 2002;23:524‐8.

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Calcitonin Calcitonin

• Calcitonin Nasal Spray

Ca c to asa Sp ay

• Inhibits osteoclast function
• Side Effects:

Side Effects:

– Rhinitis > 10%

• Modest effect makes this second line agent

g

• Decreased vertebral fracture rate ‐ but barely RR

= 0.79 (CI 0.62 – 1.00)

• Can also be used as an adjuvant analgesic in

acute vertebral fractures

Chesnut CH III et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of

• steoporotic fractures study. PROOF Study Group. Am J Med 2000;109:267‐76.

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Calcitonin Calcitonin

• In 2012 the European Medicines Agency

In 2012, the European Medicines Agency determined that long term Calcitonin use increases Cancer risk by 2 4% increases Cancer risk by 2.4%.

• Osteoporosis Canada now advises not to use

this medication as the minimal benefit does this medication as the minimal benefit does not justify this risk. Thi d NOT l h f

• This does NOT apply to short term use for

vertebral compression fracture pain.

PTH analogues PTH analogues

• Synthetic recombinant peptide

Sy t et c eco b a t pept de

• Teriparatide/Forteo (injected SQ daily)
• Side Effects:

Side Effects:

– Injection site pain; nausea, leg cramps, mild hypercalcemia, long term use concern of cancer

• Reduced vertebral fractures (RR 0.35, 95% CI

0.22–0.55; NNT = 11 for 21 months of treatment)

• Nonvertebral fractures (RR 0.65, 95% CI 0.43–

0.98; number needed to treat = 29)

Cranney A, Papaioannou A, Zytaruk N, et al. Parathyroid hormone for the treatment

• f osteoporosis: a systematic review. CMAJ 2006;175:52‐9.

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RANKL Antibodies RANKL Antibodies

• Denosumab/Prolia

Denosumab/Prolia

• An injected treatment that interferes with

RANK‐Ligand signaling pathways that cause RANK Ligand signaling pathways that cause bone breakdown

• Main side effect is increased eczema, cellulitis

Main side effect is increased eczema, cellulitis

• Reduction in fractures of all types at 3 years:

– Vertebral 68% Vertebral 68% – Nonvertebral 20% – Hip 40% Hip 40%

Cummings SR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009 Aug 20;361(8):756‐65. Epub 2009 Aug 11.

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CO$T$ CO$T$

MEDICATION COST ($CDN) per year $ Alendronate 70 mg PO weekly (generic) $390.00 Risedronate 35 mg PO weekly (generic) $370.50 Zoledronic Acid/Aclasta 5 mg IV over 15 min ONCE $735.00 YEARLY Raloxifene 60 mg PO daily $941.20 Teriparatide 20 mcg SQ daily (not available) $12,000 Calcitonin 200 iu intranasally daily $819.00 Vitamin D 1000 iu PO daily $32.85 Calcium 500 mg PO BID (generic Calcium Carbonate) $20 50 Calcium 500 mg PO BID (generic Calcium Carbonate) $20.50 Denosumab/Prolia $734.00 Didrocal Pack (generic) $134.00 Quotes from LONDON DRUGS Colwood Corners Victoria BC Quotes from LONDON DRUGS, Colwood Corners, Victoria BC. **Priced as of February 13, 2011.

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What is best? Menopausal Women What is best? Menopausal Women

• First‐line treatments recommended for

First line treatments recommended for prevention of hip, vertebral and nonvertebral fractures: fractures:

– alendronate, risedronate – risedronate, – zoledronic acid Denos mab – Denosumab

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Guidelines for Menopausal Women Guidelines for Menopausal Women

• Second‐line for prevention of vertebral fractures

Second line for prevention of vertebral fractures (not other types)

– Raloxifene Raloxifene

• If other indication for hormone replacement, this

can function as first line therapy to prevent hip, can function as first line therapy to prevent hip, vertebral and non vertebral fractures

• If intolerant of ALL FIRST LINE or SECOND LINE

If intolerant of ALL FIRST LINE or SECOND LINE AGENTS, calcitonin and etidronate (didrocal) are recommended

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Drug Holidays Drug Holidays

• “Individuals at high risk for fracture should

Individuals at high risk for fracture should continue osteoporosis therapy without a drug holiday” – 2010 Canadian Osteoporosis Guidelines

• FLEX trial: 50% more fractures in those

stopping Fosamax after 5 years of therapy

• ver subsequent 5 years compared to those

who continue

• HORIZON 6 year data showed similar

divergence

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Who do I offer Holidays to? Who do I offer Holidays to?

• Patients that were started purely based on

Patients that were started purely based on BMD and are actually at low or medium risk when FRAX calculation is applied when FRAX calculation is applied

• Medium risk FRAX/CAROC score

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Who do I offer Holidays to? Who do I offer Holidays to?

• Brief holiday for dental surgery (3 months on

Brief holiday for dental surgery (3 months on each side of procedure)

– Done more to satisfy Dentist demands – Done more to satisfy Dentist demands – An ongoing Cochrane Review is looking into this question specifically with dental surgery question specifically with dental surgery

• 2008 BONJ Guidelines from Journal of

Rheumatology suggest this however concede Rheumatology suggest this, however concede there is no evidence to support the practice

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Who should not be offered a Holiday? Who should not be offered a Holiday?

• Anyone at high risk should be only given “drug

Anyone at high risk should be only given drug holidays” for brief time periods to overcome dentist apprehension dentist apprehension

• Note that BONJ risk is correlated with dosage,

and risk factors such as poor oral hygiene and risk factors such as poor oral hygiene, smoking, periodontal disease. Th ll difi bl i k f !

• These are all modifiable risk factors!

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Osteoporosis in men: therapy Osteoporosis in men: therapy

• Amino‐bisphosphonates are standard approach

– effective in men with low sex steroids – Men with hip fractures, suggest IV zoledronic acid

• Teriparatide good for severe osteoporosis especially if
• Teriparatide good for severe osteoporosis, especially if

corticosteroid induced

– low BMD and multiple fractures, especially spinal

d h f

• Testosterone not a good therapy for osteoporotic men

– No fracture reduction data – No data on combinations with testosterone

• Canadian Guidelines only support Bisphosphonates for

male osteoporosis. Prolia approved for men by FDA, not yet by Health Canada Data supports its use not yet by Health Canada. Data supports its use.

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Glucocorticoid‐Induced Osteoporosis Glucocorticoid Induced Osteoporosis

• Glucocorticoids alter BMD/fracture relationship

/ p

– Bone weaker than BMD suggests – Rapid losses in bone strength

W k l d i f ll i k

• Weakens muscle and increases falls risk
• FRAX likely

underestimates for doses >7 5 mg/d – underestimates for doses >7.5 mg/d – overestimates for doses <2.5 mg/d – High dose intermittent and inhaled steroids may also not be adequately considered

• Adjustment for FRAX coming soon

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Treatment of Glucocorticoid‐Induced Osteoporosis

• ALL PATIENTS should receive prophylactic Vitamin D

and Calcium. (Cochrane Review supports)

• Bisphosphonate efficacy similar for glucocorticoid‐

induced and postmenopausal osteoporosis induced and postmenopausal osteoporosis

• Zoledronic acid vs risedronate

– superiority for zoledronic acid

• Teriparatide vs alendronate

– teriparatide significantly less new vertebral fractures than alendronate

• Teriparatide vs risedronate

– At 18 months teriparatide had greater BMD and bone strength than risedronate strength than risedronate

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Glucocorticoid‐Induced Osteoporosis d recommendations

• Low risk – Vitamin D and Calcium
• Medium risk – any non‐etidronate bisphosphonate
• High risk – any non‐etidronate bisphosphonate or

teriparatide

• Data‐free zone

I di ti P l ? – Indications: Premenopausal women? – Surveillance: frequency of DXA, use BTMs? – Duration of Therapy: What after teriparatide? py p – Use of therapy after glucocorticoid discontinuation – Drug holidays?

Grossman et al. 2010, Arth Care Res; Harrison et al. 2011, JBMR

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What’s my practice? What s my practice?

• There is a lot of steroid use at doses above 7 5

There is a lot of steroid use at doses above 7.5 mg Prednisone for over 3 months in GIM

• Do a FRAX score at the outset of therapy
• Do a FRAX score at the outset of therapy

(usually no BMD available) A l i id i FRAX

• Assume glucocorticoid use in FRAX
• ALL patients get full dose Vitamin D and Cal
• Medium and high risk patients are offered

bisphosphonates p p

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When to stop? When to stop?

• At the conclusion of glucocorticoid therapy

At the conclusion of glucocorticoid therapy, check a BMD

• If high risk continue agent
• If high risk, continue agent
• If not high risk, stop, but re‐check BMD in 3

years.

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Osteonecrosis of the Jaw Osteonecrosis of the Jaw

• A condition of exposed jaw bone for > 8 weeks

A condition of exposed jaw bone for > 8 weeks

• Incidence unknown but estimated to be under

1/10 000 for osteoporosis patients a large 1/10,000 for osteoporosis patients – a large German registry study put the rate at <1/100 000 for osteoporosis dosage <1/100,000 for osteoporosis dosage

• Much more common in patients receiving high

d h f h b dose therapy for cancer – the rate may be as high as 0.1% in this unique population

Silverman SL et al Osteonecrosis of the jaw and the role of bisphosphonates: a critical review Silverman SL et al. Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. American Journal of Medicine. 2009 Feb;122(2 Suppl):S33‐45. Khan AA et al. Canadian Consensus Practice Guidelines for Bisphosphonate Associated Osteonecrosis of the Jaw. J Rheumatol 2008;35:1391–7

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BRONJ BRONJ

• Recent evidence from the dental literature

Recent evidence from the dental literature suggests BRONJ is the result of actinomyces infection infection

• This is not a “spontaneous problem” and has

clear risk factors clear risk factors

• Can and does occur without any osteoporosis

di i medication

J Craniomaxillofac Surg. 2010 Jun;38(4):255‐9. doi: 10.1016/j.jcms.2009.06.005. Epub 2009 Jul 9.

BRONJ BRONJ

• Patients should be told that this condition can

Patients should be told that this condition can

• ccur and is very rare but can be persistent
• Good oral hygiene must be stressed
• Good oral hygiene must be stressed
• A pre‐bisphosphonate dental exam is not

d d f i i (i i recommended for osteoporosis patients (it is for cancer patients, however)

• Patients should stop smoking and drink

minimal alcohol

Silverman SL et al Osteonecrosis of the jaw and the role of bisphosphonates: a critical review Silverman SL et al. Osteonecrosis of the jaw and the role of bisphosphonates: a critical review. American Journal of Medicine. 2009 Feb;122(2 Suppl):S33‐45. Khan AA et al. Canadian Consensus Practice Guidelines for Bisphosphonate Associated Osteonecrosis of the Jaw. J Rheumatol 2008;35:1391–7

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Atypical Fractures Atypical Fractures

• So‐called “Chalk‐stick fractures”

So called Chalk stick fractures

• Often spontaneous fractures in areas that are

not typical for osteoporosis such as the not typical for osteoporosis such as the femoral shaft and subtrochanteric femur

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Atypical Fractures Atypical Fractures

• Very large case‐control study between

Very large case control study between comparing postmenopausal women age 68 or

• lder taking > 5 years of bisphosphonates with
• lder taking > 5 years of bisphosphonates with

matched controls taking < 5 years

• Huge population of 52 595 studied
• Huge population of 52,595 studied

Sellmeyer DE. Atypical fractures as a potential complication of long‐term bisphosphonate therapy JAMA 2010 Oct 6;304(13):1480 4 bisphosphonate therapy. JAMA. 2010 Oct 6;304(13):1480‐4. Park‐Wyllie L, et al. Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women. JAMA. 2011;305(8):783‐789.

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Atypical Femoral Fractures Atypical Femoral Fractures

• 71 extra patients had an atypical femoral

71 extra patients had an atypical femoral fracture at year 6 on bisphosphonates compared to those who stopped

• 46 more patients had a fracture of this sort by

7 years on bisphosphonates

• BUT, incremental reduction in typical
• steoporotic fractures continued beyond 5

years if medication was continued (OR, 0.76; 95% confidence interval, 0.63‐0.93)

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Atypicals Atypicals

• Essentially so long as only high risk patients

Essentially, so long as only high risk patients are treated, the risk/benefit analysis favors treatment treatment

RebalanceMD Osteoporosis Clinic RebalanceMD Osteoporosis Clinic

• Physicians desiring assistance with the

Physicians desiring assistance with the management of Osteoporosis cases can consult the Osteoporosis Clinic consult the Osteoporosis Clinic

• Common referral form available upon request

from RebalanceMD from RebalanceMD

• Currently clinic consists of consultation

i h l i l services, however, plans are in place to provide allied health care services in future

Summary Summary

• Osteoporosis has changed a great deal in the

Osteoporosis has changed a great deal in the last 5 years

• Risk stratification is key to determining who to
• Risk stratification is key to determining who to

treat M i il bl

• Many treatment options are available
• Side effects are rare and so long as high risk

people are selected for treatment, the risk/benefit calculus clearly favors treatment

Thank you Thank you

For more information: For more information: OSTEOPOROSIS CANADA i www.osteoporosis.ca REBALANCEMD www.rebalancemd.com