2010 Guidelines Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print]. 2010 Clinical...

2010 Guidelines2010 Guidelines

Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].

2010 Clinical Practice 2010 Clinical Practice Guidelines for the Guidelines for the Diagnosis and Management Diagnosis and Management of Osteoporosis in Canadaof Osteoporosis in Canada


Strategies forStrategies forFracture PreventionFracture Prevention

2010 Guidelines

Section FiveSection Five


Modalities Used to Prevent FractureModalities Used to Prevent Fracture

• Lifestyle modifications– Vitamin D– Calcium– Exercise– Falls prevention

• Pharmacologic therapy– Bisphosphonates– Other anti-resorptives

• Calcitonin• Denosumab • Hormone therapy• Raloxifene

– Parathyroid hormone– Combination therapy


Recommended Vitamin D SupplementationRecommended Vitamin D Supplementation

GroupRecommended

Vitamin D Intake (D3)

Adults <50 without osteoporosis or conditions affecting vitamin D absorption

400 – 1000 IU daily(10 mcg to 25 mcg daily)

Adults > 50 or high risk for adverse outcomes from vitamin D insufficiency (e.g., recurrent fractures or osteoporosis and comorbid conditions that affect vitamin D absorption)

800 – 2000 IU daily(20 mcg to 50 mcg daily)

Hanley DA, et al. CMAJ 2010; 182:E610-E618.


Vitamin D: Optimal LevelsVitamin D: Optimal Levels

• To most consistently improve clinical outcomes such as fracture risk, an optimal serum level of 25-hydroxy vitamin D is probably > 75 nmol/L– For most Canadians,

supplementation is needed to achieve this level



When to Measure Serum 25-OH-DWhen to Measure Serum 25-OH-D

• In situations where deficiency is suspected or wherelevels would affect response to therapy– Individuals with impaired intestinal absorption– Patients with osteoporosis requiring pharmacotherapy

• Should be checked no sooner than three months after commencing an adequate supplementation dose

• Monitoring of routine supplement use and routinescreening of otherwise healthy individuals are notnecessary

Hanley DA, et al. CMAJ 2010; 182:E610-E618.Click here for more information on vitamin D.


Recommended Calcium IntakeRecommended Calcium Intake

• From diet and supplementscombined: 1200 mg daily– Several different types of calcium supplements ar

e available

• Evidence shows a benefit ofcalcium on reduction of fracture risk1

• Concerns about serious adverse effects with high-dose supplementation2-4

1. Tang BM, et al. Lancet 2007; 370(9588):657-666.2. Bolland MJ, et al. J Clin Endocrinol Metab 2010; 95(3):1174-1181.

3. Bolland MJ, et al. BMJ 2008; 336(7638):262-266.4 Reid IR, et al. Osteoporos Int 2008; 19(8):1119-1123.


Summary Statements forSummary Statements forCalcium & Vitamin DCalcium & Vitamin D

Statement StrengthVitamin D3 with calcium supplementation increases bone density in postmenopausal women and men over age 50 and reduces the risk of fractures

Level 1

Vitamin D3 at daily doses of 800 IU (20 mcg) with calcium (1000 mg) reduces the risk of hip and non-vertebral fractures in elderly populations in institutions

Level 1

The evidence in community-dwelling individuals is less strong Level 2

There is evidence that daily 800 IU (20 mcg) vitamin D3 reduces fall risk, particularly in trials that adequately ascertained falls Level 2

A daily intake of 1000 IU vitamin D3 (25 mcg)—a commonly available safe dose—will raise serum 25-OH-D level on average by 15 – 25 nmol/L

Level 2

Click here for a summary of the grading system for levels of evidence.


Summary Statement for Other Summary Statement for Other Nonpharmacologic TherapiesNonpharmacologic Therapies

Statement Strength

Weight bearing, balance and strengthening exercises can improve outcomes in individuals with osteoporosis

Level 2

Exercise-focused interventions improve balance and reduce falls in community-dwelling older people

Level 2

Hip protectors may reduce the risk of hip fractures in long-term care residents; however adherence with their use may pose a challenge for the older adult

Level 2


Medications Indicated for Medications Indicated for Osteoporosis in CanadaOsteoporosis in Canada

• Bisphosphonates—oral and IV

• Calcitonin

• Denosumab (RANK ligand inhibitor)

• Hormone therapy

• Raloxifene (SERM)

• Teriparatide (PTH analogue)


First Line Therapies with Evidence for FractureFirst Line Therapies with Evidence for FracturePrevention in Postmenopausal Women* Prevention in Postmenopausal Women*

Type of Fracture

Antiresorptive therapyBone

formation therapy

Bisphosphonates

Denosumab RaloxifeneHormone therapy

(Estrogen)**Teriparatide

Alendronate RisedronateZoledronic

acid

Vertebral

Hip - -

Non-vertebral+ -

* For postmenopausal women, indicates first line therapies and Grade A recommendation. For men requiring treatment,alendronate, risedronate, and zoledronic acid can be used as first line therapies for prevention of fractures [Grade D]. + In clinical trials, non-vertebral fractures are a composite endpoint including hip, femur, pelvis, tibia, humerus, radius, and clavicle. ** Hormone therapy (estrogen) can be used as first line therapy in women with menopausal symptoms.


Reduction in Mortality with Reduction in Mortality with Anti-osteoporotic MedicationAnti-osteoporotic Medication

• Zoledronic acid has demonstrated a 28% relative reduction in mortality after hip fracture1

– Absolute risk reduction: 3.7%

• Meta-analysis has shown a 10% relative reduction in mortality with anti-osteoporosis therapies in older individuals at high risk of fracture2

– Absolute risk reduction: 0.4%1. Lyles KW, et al. N Engl J Med 2007; 357(18):1799-809.

2. Bolland MJ, et al. J Clin Endocrinol Metab 2010; 95(3):1174-1181.


Summary Statements for Summary Statements for PharmacotherapyPharmacotherapy

Statement Strength

Alendronate prevents vertebral, non-vertebral, hip, and wrist fractures in post-menopausal women

Level 1

Cyclical etidronate prevents vertebral fractures, but has not demonstrated risk reductions for other non-vertebral fracture types

Level 1

Risedronate prevents vertebral, non-vertebral, and hip fractures in post-menopausal women

Level 1


Summary Statements for Summary Statements for Pharmacotherapy (Pharmacotherapy (Cont'dCont'd))

Statement Strength

Zoledronic acid prevents vertebral, non-vertebral, hip fractures in men and women

Level 1

Hormone therapy prevents vertebral, non-vertebral, and hip fractures, but is recommended for women with moderate to severe vasomotor symptoms

Level 1

Raloxifene and calcitonin reduce vertebral fractures, but have not demonstrated risk reductions for non-vertebral fractures

Level 1


Summary Statements for Summary Statements for Pharmacotherapy (Pharmacotherapy (Cont'dCont'd))

Statement Strength

Teriparatide reduces vertebral and non-vertebral fractures Level 1

Denosumab reduces vertebral, non-vertebral, and hip fractures

Level 1


Recommendations for Recommendations for High-risk IndividualsHigh-risk Individuals

Recommendation GradeFor menopausal women requiring osteoporosis treatment, alendronate, denosumab, risedronate, and zoledronic acid can be used as first-line therapies for prevention of hip, non-vertebral, and vertebral fractures

A

For menopausal women requiring osteoporosis treatment, teriparatide can be used as a first-line therapy for prevention of non-vertebral and vertebral fractures

A

For menopausal women requiring osteoporosis treatment, raloxifene can be used as a first-line therapy for prevention of vertebral fractures

A

Click here for a summary of the system for grades of recommendations.


Recommendations for Recommendations for High-risk Individuals (High-risk Individuals (Cont'dCont'd))

Recommendation GradeFor menopausal women requiring osteoporosis treatment and who require treatment for vasomotor symptoms, hormone therapy can be used as a first-line therapy for prevention of hip, non-vertebral, and vertebral fractures

A

Clinicians should avoid prescribing more than one anti-resorptive agent concurrently for fracture reduction

A

For menopausal women intolerant of first-line therapies, calcitonin or etidronate can be considered for prevention of vertebral fractures

B

For men requiring osteoporosis treatment, alendronate, risedronate, and zoledronic acid can be used as first-line therapies for prevention of fractures

D


Recommendation forRecommendation forDuration of TherapyDuration of Therapy

Recommendation Grade

Individuals at high risk for fracture should continue osteoporosis therapy without a drug holiday

D

• Evidence supporting recommendations for duration of treatment is limited

• Data for the above recommendation come from the FLEX study (long-term alendronate treatment)1 and the risedronate discontinuation study2

1. Black DM, et al. JAMA 2006; 296(24):2927-2938.2. Watts NB, et al. Osteoporos Int 2008; 19(3):365-372.


Summary Statements ≥≥for Special GroupsSummary Statements ≥≥for Special Groups

Statement Strength

Osteoporosis therapies including alendronate, risedronate, and teriparatide reduce the risk of vertebral fractures and maintain BMD in those prescribed glucocorticoids for 3 months or longer

Level 1

Etidronate, zoledronic acid, and calcitonin maintain BMD in those prescribed glucocorticoids for 3 months or longer

Level 2

Bisphosphonates and denosumab maintain BMD in women prescribed aromatase inhibitors and men prescribed androgen- deprivation therapy

Level 1


Summary StatementsSummary Statementson Treatment Initiationon Treatment Initiation

Statement Strength

Multiple fractures confer greater risk than a single fracture Level 1

Prior fractures of the hip and vertebra carry greater risk than other fracture sites

Level 1

Pharmacologic intervention, when based on prior fragility fractures affecting the vertebra or hip, has shown fracture benefit in clinical trials

Level 1


Summary StatementsSummary Statementson Treatment Initiation (on Treatment Initiation (Cont'dCont'd))

Statement Strength

In patients who initiated glucocorticoids, fractures can occur quickly (within three to six months) with prednisone doses as low as 2.5 – 7.5 mg daily with a rapid decline in fracture risk toward baseline after cessation

Level 1

Rapid BMD loss in untreated individuals may be an independent risk for fracture

Level 2


Recommendations on Treatment InitiationRecommendations on Treatment Initiation


In individuals over age 50, fragility fracture of the hip or vertebra, or more than one fragility fracture event, constitutes a high risk for future fracture and such individuals should be offered pharmacologic therapy

A

For those at moderate risk (10% – 20% probability for major osteoporotic fracture over 10 years), lateral radiographs or Vertebral Fracture Assessment (VFA) of the thoracolumbar spine is recommended for further risk stratification and in clinical decision-making regarding pharmacologic interventions

A


RecommendationsRecommendationson Treatment Initiation (on Treatment Initiation (Cont'dCont'd))


Pharmacologic therapy should be offered to patients at high absolute risk (> 20% probability for major osteoporotic fracture over 10 years)

D

For those at moderate fracture risk, patient preference and additional clinical risk factors that are not already incorporated in the risk assessment system should be used to guide pharmacologic management decisions

D


Testosterone in Men: Summary Testosterone in Men: Summary Statement and Recommendation Statement and Recommendation

Statement Strength

Testosterone maintains BMD in hypogonadal men but has not been shown to reduce the risk of fractures

Level 2


Testosterone is not recommended for the treatment of osteoporosis in men

B


Recommendation for Adverse EventsRecommendation for Adverse Events


Potential benefits and risks of the prescribed agent should be discussed with each patient prior to initiating therapy to support informed decision-making

D

Click here for more information on adverse events.


Considerations for MonitoringConsiderations for Monitoring

• Rationale for monitoring: To identify individuals with continued BMD loss, despite appropriate osteoporosis treatment

• Aspects of monitoring– Serial BMD measurements– Assessment of adherence– Bone turnover markers (BTMs)?


When to Refer to Specialist Care: GeneralWhen to Refer to Specialist Care: General

• Fracture on first-line therapy with optimal adherence

• Significant loss on follow-up BMD on first-line therapy with optimal adherence

• Intolerance of first- and second-line agents


When to Refer to Specialist Care:When to Refer to Specialist Care:Special PopulationsSpecial Populations

• Referrals to physicians with an interest or expertise in osteoporosis– Secondary causes of osteoporosis outside the comfort

zone of the individual primary care physician

– Patients with extremely low BMD

• Referrals to other specialists– Complex individuals with multiple comorbidities, such as

those with frequent falling, Alzheimer’s disease, stroke, and Parkinson’s disease


Integrated Approach to Management ofIntegrated Approach to Management ofPatients Who Are at Risk for FracturePatients Who Are at Risk for Fracture

Age < 50 yr Age 50-64 yr Age > 65 yr

Encourage basic bone health for all individuals over age 50, including regular active weight-bearing exercise, calcium (diet and supplementation) 1200 mg daily, vitamin D 800-2000 IU (20-50µg) daily and fall-prevention strategies

•Fragility fracture after age 40•Prolonged use of glucocorticoids or other high-risk medications•Parental hip fracture•Vertebral fracture or osteopenia identified on radiography•High alcohol intake or current smoking•Low body weight (< 60 kg) or major weight loss (> 10% of body weight at age 25)•Other disorders strongly associated with

osteoporosis

•Fragility fractures•Use of high-risk

medications•Hypogonadism•Malabsorption syndromes•Chronic inflammatory

conditions•Primary

hyperparathyroidism•Other disorders strongly

associated with rapid bone loss or fractures

•All men and women

Initial BMD Testing


Assessment of fracture risk

Moderate risk(10-year fracture risk 10%-20%)

Low risk(10-year fracture risk < 10%)

Lateral thoracolumbar radiography (T4-L4) or vertebral fracture assessment may aid in decision-making by identifying

vertebral fractures

High risk(10-year fracture risk > 20% or prior fragility fracture of hip or spine or > 1 fragility fracture)

Good evidence of benefit from

pharmacotherapy

Always consider patient

preference

Unlikely to benefit from pharmacotherapy

Reassess in 5 yr

Factors warranting consideration of pharmacologic therapy…

Integrated Approach, ContinuedIntegrated Approach, Continued

Initial BMD Testing


Integrated Approach, ContinuedIntegrated Approach, Continued

Assessment of fracture risk


Low risk(10-year fracture risk < 10%)

Lateral thoracolumbar radiography (T4-L4) or vertebral fracture assessment may aid in decision-making by identifying

vertebral fractures

High risk(10-year fracture risk > 20% or prior fragility fracture of hip or spine or > 1 fragility fracture)

Good evidence of benefit from

pharmacotherapy

Always consider patient

preference

Unlikely to benefit from pharmacotherapy

Reassess in 5 yr

Factors warranting consideration of pharmacologic therapy…

Initial BMD Testing



Lateral thoracolumbar radiography (T4-L4) or vertebral fracture assessment may aid in decision-making by

identifying vertebral fractures

Factors warranting consideration of pharmacologic therapy:•Additional vertebral fracture(s) (by vertebral fracture assessment

or lateral spine radiograph)•Previous wrist fracture in individuals aged > 65 or those with

T-score < -2.5•Lumbar spine T-score much lower than femoral neck T-score•Rapid bone loss•Men undergoing androgen-deprivation therapy for prostate cancer•Women undergoing aromatase inhibitor therapy for breast cancer•Long-term or repeated use of systemic glucocorticoids (oral or

parenteral) not meeting conventional criteria for recent prolonged use•Recurrent falls (> 2 in the past 12 mo)•Other disorders strongly associated with osteoporosis, rapid bone

loss or fractures

Good evidence of benefit

from pharmaco-

therapy

Repeat BMD in 1-3 yr and

reassess risk

Integrated Approach, Integrated Approach, ContinuedContinued



Lateral thoracolumbar radiography (T4-L4) or vertebral fracture assessment may aid in decision-making by identifying vertebral fractures

Factors warranting consideration of pharmacotherapy:•Additional vertebral fracture(s) (by vertebral fracture

assessment or lateral spine radiograph)•Previous wrist fracture in individuals aged > 65 or those

with T-score < -2.5•Lumbar spine T-score much lower than femoral neck T-

score•Rapid bone loss•Men on ADT for prostate cancer•Women on AI for breast cancer•Long-term or repeated use of systemic glucocorticoids

(oral or parenteral) not meeting conventional criteria for recent prolonged use

•Recurrent falls (> 2 in the past 12 mo)•Other disorders strongly associated with osteoporosis,

rapid bone loss or fractures

Good evidence of benefit

from pharmaco-

therapy

Repeat BMD in 1-3 yr and

reassess risk

Integrated Approach, Integrated Approach, ContinuedContinued


Section Five – Section Five – Fracture Risk Assessment

Back-up MaterialBack-up Material

Additional slides that can be accessed fromhyperlinks on core slides


Classification of Vitamin D Status byClassification of Vitamin D Status bySerum Level of 25-OH-DSerum Level of 25-OH-D

Serum 25-OH-D,nmol/L*†

CategoryLevel ofevidence

< 25 Vitamin D deficiency 3

25 – 75 Vitamin D insufficiency‡ 2

> 75 Desirable vitamin D status 3

> 250 Potential adverse effects 2


* Assumes that serum 25-OH-D is measured by a clinical laboratory participating in an external quality assurance program.†2.5 nmol/L = 1 ng/mL.‡ ”Insufficiency” is a milder form of deficiency and should preferably be termed “suboptimal vitamin D status.”


Vitamin D Supplementation (D3) andVitamin D Supplementation (D3) andReduced Non-vertebral Fracture RiskReduced Non-vertebral Fracture Risk

Bischoff-Ferrari HA, et al. JAMA 2005; 293(18):2257-2264.


Fracture Risk Reduction with Vitamin DFracture Risk Reduction with Vitamin Dand Calciumand Calcium

Boonen S, et al. J Clin Endocrinol Metab 2005; 293(18):2257-2264.


Vitamin D: Reduction of Falls in theVitamin D: Reduction of Falls in theElderlyElderly

Bischoff-Ferrari HA, et al. BMJ 2009; 339:b3692.Return to main presentation


Calcium SupplementsCalcium Supplements

Supplement type NotesCalcium carbonate • Can be refined from limestone, natural elements of the

earth, or may come from shell sources, usually oyster• Shell sources are often described on the label as a

"natural" source • Calcium carbonate from oyster shells is not "refined" and

can contain variable amounts of lead

Chelated calcium • Refers to a special way in which calcium is chemically combined with another substance

• Calcium citrate, calcium lactate, calcium gluconate are examples of chelated preparation

Powdered bone (bonemeal)

• Not recommended, as it may contain contaminants

Dolomite • A mineral found in rock

Return to main presentation www.osteoporosis.ca; Accesssed September 2010.


Association of Calcium Intake with Association of Calcium Intake with Hip Fracture RiskHip Fracture Risk

Tang BM, et al. Lancet 2007; 370(9588):657-666.Return to main presentation


Potential Risks of Calcium SupplementationPotential Risks of Calcium Supplementation

• High-dose calcium supplementation has beenassociated with– Renal calculi in older women– Cardiovascular events in older women– Prostate cancer in older men

1. Bolland MJ, et al. J Clin Endocrinol Metab 2010; 95(3):1174-1181.2. Bolland MJ, et al. BMJ 2008; 336(7638):262-266.

3. Reid IR, et al. Osteoporos Int 2008; 19(8):1119-1123.Return to main presentation


Benefits of Exercise:Benefits of Exercise:Fractures and Bone HealthFractures and Bone Health

• Programs > 1 yearincluding aerobic exercises and strengthtraining havedemonstrated positiveeffects on BMD andthoracic kyphosis buthave limited evidencefor fracture reduction1

• Moderate to vigorous exercise has demonstrated an ability to reduce hip fracture risk2

1. De Kam D, et al. Osteoporos Int 2009; 20(12):2111-25.2. Moayyeri A. Ann Epidemiol 2008; 18:827-835.Return to main presentation


Nonpharmacologic InterventionsNonpharmacologic InterventionsAssociated with Reduction in FallsAssociated with Reduction in Falls

• Exercise-focused interventions for community-dwelling older people1

• Tai chi, gait, and balance training1-3

• Home safety assessment (only effective in those at high risk for falls)1

• Cataract removal3

Return to main presentation

1. Gillespie LD, et al. Cochrane Database Syst Rev 2009; CD007146.2. Cameron ID, et al. Cochrane Database Syst Rev 2010; 1(CD005465).3. McClure RJ, et al. Cochrane Database Syst Rev 2008; 1(CD004441).


Benefit of Hip Protectors in Benefit of Hip Protectors in Long-term CareLong-term Care

• A modest reduction in hip fractures in elderly long-term care residents1,2

• Cost effective for fracture reduction in long-term care3

• Compliance poses a challenge1

• Not effective for older adults residing in the community1,4

1. Sawka AM, et al. J Clin Epidemiol 2007; 60(4):336-344.2. Oliver D, et al. BMJ 2006; 334:82-87.

3. Canadian Agency for Drugs and Technologies in Health. Health Technology Inquiry Service (HTIS). Rapid Review.

4. Parker MJ, et al. BMJ 2006; 332(7541):571-574.Return to main presentation


Oral Bisphosphonates: SummaryOral Bisphosphonates: Summary

Drug (Brand name) Dosing Schedules

Alendronate (Fosamax®, Fosavance®)

10 mg daily70 mg weekly

Risedronate (Actonel®) 5 mg daily 35 mg weekly 150 mg monthly

Etidronate (Didrocal®)Cyclical therapy of daily 200 mg for 14 days followed by calcium supplements for 10 weeks

See notes page for information onpatient instructions, precautions and adverse events



IV Bisphosphonate: SummaryIV Bisphosphonate: Summary

Drug (Brand name) Dosing Schedule

Zoledronic Acid (Aclasta®) 5 mg intravenously once yearly




Other Medications: SummaryOther Medications: Summary

Drug (Brand name) Dosing ScheduleCalcitonin (Miacalcin®) 200 IU intranasally daily

Calcium (many formulations) Many dosing schedules

Denosumab (Prolia®) 60 mg subcutaneous injection every six months

Hormone therapy (many formulations)

Many dosing schedules

Raloxifene (Evista®) 60 mg daily

Teriparatide (Forteo®) 20 μg subcutaneously daily




Zoledronic Acid Hip Fracture Trial:Zoledronic Acid Hip Fracture Trial:Reduction in MortalityReduction in Mortality

Lyles KW, et al. N Engl J Med 2007; 357(18):1799-809. Return to main presentation


Meta-analysis of Anti-osteoporosisMeta-analysis of Anti-osteoporosisMedication: Reduction in MortalityMedication: Reduction in Mortality

Analysis Studies includedRR

(95% CI)p

value

Primary

Eight studies of four agents (risedronate, strontium ranelate, zoledronic acid, and denosumab)

0.89(0.80 – 0.99)

0.036

Secondary

Ten studies of five agents (as above, plus two studies of alendronate in which the dose changed during the studies)

0.90(0.81 – 1.0)

0.044

Return to main presentation Bolland MJ, et al. J Clin Endocrinol Metab 2010; 95(3):1174-1181.


Clinical Vertebral Fractures in Patients ContinuingClinical Vertebral Fractures in Patients Continuingor Stopping Alendronate Therapy: FLEX Studyor Stopping Alendronate Therapy: FLEX Study

Black DM, et al. JAMA 2006; 296(24):2927-2938.Return to main presentation


New Vertebral Fractures in Those Stopping orNew Vertebral Fractures in Those Stopping orContinuing Risedronate TherapyContinuing Risedronate Therapy

Watts NB, et al. Osteoporos Int 2008; 19(3):365-372.Return to main presentation

Continuedrisedronate

Stoppedrisedronate


Evidence with Pharmacotherapies for Evidence with Pharmacotherapies for Patients using Long-term GlucocorticoidsPatients using Long-term Glucocorticoids

• Both alendronate1,2 and risedronate3,4 reduce risk of vertebral fracture

• Etidronate is protective against bone loss at the spine but does not prevent fractures5,6

• Zoledronic acid improves lumbar spine BMD more effectively than risedronate7

– Study not powered to detect differences in fracture reduction• Teriparatide reduces radiographic vertebral fractures compared

to alendronate8

• Calcitonin prevents bone loss at the spine but not at the hip compared to placebo; no effect on fracture risk1,9

5. MacLean C, et al. Ann Intern Med 2008; 148(3):197-213.6. Qaseem A, et al. Ann Intern Med 2008; 149(6):404-415.

7. Reid DM, et al. Lancet 2009; 373(9671):1253-1263.8. Saag KG, et al. N Engl J Med 2007; 357:2028-2039.

9. Cranney A, et al. Cochrane Database Syst Rev 2000; (2):CD001983.

1. Adachi JD, et al. Arthritis Rheum 2001; 44(1):202-211.2. Saag KG, et al. N Engl J Med 1998; 339(5):292-299.3. Wallach S, et al. Calcif Tissue Int 2000; 67(4):277-285.4. Reid DM, et al. J Bone Miner Res 2000; 15(6):1006-1013.



Evidence for Zoledronic Acid in WomenEvidence for Zoledronic Acid in Womenwith Breast Cancer Receiving AIswith Breast Cancer Receiving AIs• Reduces aromatase inhibitors (AI)-associated BMD

loss• Prevents bone loss in postmenopausal women with

osteoporosis or low bone mass starting letrozole1

• When used upfront, prevents AI-associated BMD losswith early breast cancer more effectively than delayingtherapy until BMD loss or fracture occurs2

• When added to adjuvant endocrine therapy improvesdisease-free survival in premenopausal patients withestrogen-responsive early breast cancer3

1. Hines SL, et al. Breast 2010; 19(2):92-96.2. Brufsky AM, et al. Clinical Breast Cancer 2009; 9(2):77-85.

3. Gnant M, et al. N Engl J Med 2009; 360(7):679-691.


Evidence for Risedronate in WomenEvidence for Risedronate in Womenwith Breast Cancer Receiving AIswith Breast Cancer Receiving AIs

• Reduces AI-associated bone loss• Associated with a significant

increase in lumbar spine and total hip BMD

Van Poznak C, et al. J Clin Oncol 2010; 28(6):967-975.Return to main presentation


Evidence for Treatment in Men Receiving Androgen-Evidence for Treatment in Men Receiving Androgen-deprivation Therapy for Prostate Cancerdeprivation Therapy for Prostate Cancer

• Insufficient fracture data in studies withbisphosphonates and selective estrogen receptormodulators (SERMs)

• Denosumab showed a decreased cumulativeincidence of new vertebral fractures at 36 months(absolute risk reduction, 2.4%)1

Return to main presentation 1. Smith MR, et al. N Engl J Med 2009; 361(8):745-755.


Factors that Warrant Consideration forFactors that Warrant Consideration forPharmacological Therapy in Moderate Risk Patients Pharmacological Therapy in Moderate Risk Patients

• Additional vertebral fracture(s) (> 25% height loss with end-plate disruption) identified on VFA or lateral spine X-ray

• Previous wrist fracture in individuals > 65 or those with T-score < -2.5

• Lumbar spine T-score much lower than femoral neck T-score • Rapid bone loss • Men on androgen deprivation therapy for prostate cancer • Women on aromatase inhibitor therapy for breast cancer • Long-term or repeated systemic glucocorticoid use (oral or parenteral)

that does not meet the conventional criteria for recent prolonged systemic glucocorticoid use (i.e., > 3 months cumulative during the preceding year at a prednisone equivalent dose > 7.5 mg daily)

• Recurrent falls defined as falling 2 or more times in the past 12 months • Other disorders strongly associated with osteoporosis, rapid bone loss or

fractures


Disorders Associated with Osteoporosis andDisorders Associated with Osteoporosis andIncreased Fracture RiskIncreased Fracture Risk

• Primary hyperparathyroidism• Type I diabetes• Osteogenesis imperfecta• Untreated long-standing hyperthyroidism, hypogonadism, or

premature menopause (< 45 years)• Cushing’s disease• Chronic malnutrition or malabsorption• Chronic liver disease• Chronic obstructive pulmonary disease• Chronic inflammatory conditions (e.g., rheumatoid arthritis,

inflammatory bowel disease )



Adverse Events of Osteoporosis Adverse Events of Osteoporosis TherapiesTherapies

• Consult individual product monographs for adverse event information for approved therapies (click on drug names below to link to online resources)– Bisphosphonates: alendronate, risedronate,

zoledronic acid– Calcitonin– Denosumab– Raloxifene– Teriparatide


Bisphosphonates and Bisphosphonates and Osteonecrosis of the Jaw Osteonecrosis of the Jaw

• Definition: The presence of exposed bone in the maxillofacial region that did not heal within eight weeks after identification by a health care provider1

• Incidence– Oral bisphosphonates: Between 1 in 10,000 and < 1 in

100,000 patient-treatment years– IV bisphosphonates: two cases reported in RCTs in

postmenopausal osteoporosis (one in placebo group)2

• Information on incidence of Osteonecrosis of the Jaw (ONJ) is rapidly evolving: the true incidence may be higher1

1. Khosla S, et al. J Bone Miner Res 2009; 22(10):1479-1491.2. Grbic JT, et al. J Am Dent Assoc 2008; 139:32-40.


Bisphosphonates and Atypical FractureBisphosphonates and Atypical Fracture

• Case series reported increased incidence of subtrochanteric fractures with long-term use of bisphosphonates1

– 15 women treated with alendronate– Causation not proven

• Recent case-control study reported no increase in the incidence in subtrochanteric fractures among patients taking bisphosphonates versus controls2

• Increased incidence of subtrochanteric fractures has not been reported with the use of other bisphosphonates

1. Lenart BA, et al. N Engl J Med 2008; 358:1304-1306.2. Abrahamsen B, et al. J Bone Miner Res 2009; 24:1095-1102.Return to main presentation


Interpretation of Serial BMD Interpretation of Serial BMD MeasurementsMeasurements

• Measurement error must be considered when interpreting serial BMD assessments– Each centre should determine its precision error in order to

estimate the least significant change (LSC)1

• Continued BMD loss exceeding the LSC may reflect:– Poor adherence to therapy– Failure to respond to therapy– Previously unrecognized secondary causes of osteoporosis

• Most anti-osteoporosis therapies do not cause large BMD increases2

– Stable BMD is consistent with successful treatment

1. Baim S, et al. J Clin Densitom 2005; 8(4):371-378.2. Chen P, et al. J Bone Miner Res 2009; 24(3):495-502.


Recommendations for Frequency of Recommendations for Frequency of BMD TestingBMD Testing

• Usually repeated every 1 – 3 years, with a decrease in testing once therapy is shown to be effective

• In those at low risk without additional risk factors for rapid BMD loss, a longer testinginterval (5 – 10 years) may be sufficient



Importance of AdherenceImportance of Adherencein Treatment Successin Treatment Success

• The expectation is that treated patients will experience anti-fracture benefits similar to those reported in clinical trials

• Suboptimal adherence reduces or eliminates anti-fracture benefits1-3

1. Silverman S. et al. Rheum Dis Clin North Am 2006; 32(4):721-731.2. McCombs JS, et al. Maturitas 2004; 48(3):271-287.

3. Gold DT, et al. Curr Osteoporos Rep 2006; 4(1):21-27.


Poor Adherence Leaves Patients at Poor Adherence Leaves Patients at Higher Risk of FractureHigher Risk of Fracture

Siris E, et al. Mayo Clin Proc 2006; 81:1013-22.

50% adherence leaves patients at approximately

the same fracture risk as no therapy

0.12

0.11

0.10

0.09

0.08

0.07

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Pro

babi

lity

of f

ract

ure

MPR


Types and Rates of Non-adherenceTypes and Rates of Non-adherencein Osteoporosis Therapyin Osteoporosis Therapy

• Types of non-adherence:1-3

– Frequently missed doses– Failing to take the medication correctly to optimize

absorption and action– Discontinuation of therapy

• Reported one-year adherence rates: 25% –50%1,3

– Marginally better with less frequent dosing regimens

1. Silverman S. et al. Rheum Dis Clin North Am 2006; 32(4):721-731.2. McCombs JS, et al. Maturitas 2004; 48(3):271-287.

3. Gold DT, et al. Curr Osteoporos Rep 2006; 4(1):21-27.


Approaches for Optimizing AdherenceApproaches for Optimizing Adherence

• Reminders• Patient information• Counselling• Simplification of the dosing regimen• Self-monitoring



Desirability of Serial BTMsDesirability of Serial BTMs

• Have the potential to provide earlier evidence of treatment effects (within first three to six months)

• Further clinical trial validation is required• Measurement variability between individuals

may limit clinical utility



Criteria Used to Assign Levels of Criteria Used to Assign Levels of Evidence: Studies of DiagnosisEvidence: Studies of Diagnosis

Level Criteria

1

i Independent interpretation of test results

ii Independent interpretation of the diagnostic standard

iii Selection of people suspected, but not known to have the disorder

iv Reproducible description of the test and diagnostic standard

v At least 50 people with and 50 people without the disorder

2 Meets four of the Level 1 criteria

3 Meets two of the Level 1 criteria

4 Meets one or two of the Level 1 criteria


Criteria Used to Assign Levels of Evidence: Criteria Used to Assign Levels of Evidence: Studies of Treatment and InterventionStudies of Treatment and Intervention

Level Criteria1+ Systematic overview of meta-analysis of RCTs

1 One RCT with adequate power

2+ Systematic overview or meta-analysis of Level 2 RCTs

2 RCT that does not meet Level 1 criteria

3 Non-RCT or cohort study

4Before/after study, cohort study with non-contemporaneous controls, case-control study

5 Case series without controls

6 Case report or case series of < 10 patients

RCT = randomized, controlled study


Criteria Used to Assign Levels of Criteria Used to Assign Levels of Evidence: Studies of PrognosisEvidence: Studies of Prognosis

Level Criteria

1

i Inception cohort of patients with the condition of interest, but free of the outcome of interest

ii Reproducible inclusion and exclusion criteria

iii Follow-up of at least 80% of participants

iv Statistical adjustment for confounders

v Reproducible description of the outcome measures

2 Meets criterion i and three of the other four Level 1 criteria

3 Meets criterion i and two of the other four Level 1 criteria

4 Meets criterion i and one of the other four Level 1 criteria



Criteria Used to AssignCriteria Used to AssignGrades of RecommendationGrades of Recommendation

Level Criteria

A Need supportive level 1 or 1+ evidence plus consensus*

B Need supportive level 2 or 2+ evidence plus consensus*

C Need supportive level 3 evidence plus consensus

D Any lower level of evidence supported by consensus

* As appropriate level of evidence was necessary, but not sufficient to assigna grade in recommendation; consensus was required in addition.


2010 Guidelines Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print]. 2010 Clinical...

Documents

Transcript of 2010 Guidelines Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print]. 2010 Clinical...