Transcript Care Working Group - Osteoporosis Canada

2010 Guidelines
2010 Clinical Practice
Guidelines for the
Diagnosis and Management
of Osteoporosis in Canada
Papaioannou A, et al. CMAJ 2010 Oct 12. [Epub ahead of print].
2010 Guidelines
Strategies for
Fracture Prevention
Section Five
2010 Guidelines
Modalities 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
2010 Guidelines
Recommended Vitamin D Supplementation
Group
Recommended
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.
2010 Guidelines
Vitamin D: Optimal Levels
• To most consistently
improve clinical
outcomes such as
fracture risk, an optimal
serum level of 25hydroxy vitamin D is
probably > 75 nmol/L
– For most Canadians,
supplementation is
needed to achieve this
level
Hanley DA, et al. CMAJ 2010; 182:E610-E618.
2010 Guidelines
When to Measure Serum 25-OH-D
• In situations where deficiency is suspected or where
levels 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 routine
screening of otherwise healthy individuals are not
necessary
Click here for more information on vitamin D.
Hanley DA, et al. CMAJ 2010; 182:E610-E618.
2010 Guidelines
Recommended Calcium Intake
• From diet and supplements
combined: 1200 mg daily
– Several different types of calcium
supplements are available
• Evidence shows a benefit of
calcium 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.
2010 Guidelines
Summary Statements for
Calcium & Vitamin D
Statement
Vitamin D3 with calcium supplementation increases bone density
in postmenopausal women and men over age 50 and reduces
the risk of fractures
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
Strength
Level 1
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.
2010 Guidelines
Summary Statement for Other
Nonpharmacologic 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 longterm care residents; however adherence with their use may
pose a challenge for the older adult
Level 2
2010 Guidelines
Medications Indicated for
Osteoporosis in Canada
• Bisphosphonates—
oral and IV
• Calcitonin
• Denosumab (RANK
ligand inhibitor)
• Hormone therapy
• Raloxifene (SERM)
• Teriparatide (PTH
analogue)
2010 Guidelines
First Line Therapies with Evidence for Fracture
Prevention in Postmenopausal Women*
Bone
formation
therapy
Antiresorptive therapy
Type of
Fracture
Bisphosphonates
Raloxifene
Hormone
therapy
(Estrogen)**
Teriparatide
Alendronate
Risedronate
Zoledronic
acid
Denosumab
Vertebral







Hip




-

-
Nonvertebral+




-


* 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.
2010 Guidelines
Reduction in Mortality with
Anti-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.
2010 Guidelines
Summary Statements for
Pharmacotherapy
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
2010 Guidelines
Summary Statements for
Pharmacotherapy (Cont'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
2010 Guidelines
Summary Statements for
Pharmacotherapy (Cont'd)
Statement
Strength
Teriparatide reduces vertebral and non-vertebral fractures
Level 1
Denosumab reduces vertebral, non-vertebral, and hip
fractures
Level 1
2010 Guidelines
Recommendations for
High-risk Individuals
Recommendation
Grade
For 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.
2010 Guidelines
Recommendations for
High-risk Individuals (Cont'd)
Recommendation
Grade
For 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
2010 Guidelines
Recommendation for
Duration 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.
2010 Guidelines
Summary 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
2010 Guidelines
Summary Statements
on 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
2010 Guidelines
Summary Statements
on Treatment Initiation (Cont'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
2010 Guidelines
Recommendations on Treatment Initiation
Recommendation
Grade
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
2010 Guidelines
Recommendations
on Treatment Initiation (Cont'd)
Recommendation
Grade
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
2010 Guidelines
Testosterone in Men: Summary
Statement and Recommendation
Statement
Testosterone maintains BMD in hypogonadal men but has
not been shown to reduce the risk of fractures
Recommendation
Testosterone is not recommended for the treatment of
osteoporosis in men
Strength
Level 2
Grade
B
2010 Guidelines
Recommendation for Adverse Events
Recommendation
Potential benefits and risks of the prescribed agent should be
discussed with each patient prior to initiating therapy to support
informed decision-making
Click here for more information on adverse events.
Grade
D
2010 Guidelines
Considerations 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)?
2010 Guidelines
When 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
2010 Guidelines
When to Refer to Specialist Care:
Special 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
2010 Guidelines
Integrated Approach to Management of
Patients Who Are at Risk for Fracture
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
Age < 50 yr
• 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
Age 50-64 yr
• 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
Initial BMD Testing
Age > 65 yr
• All men and women
2010 Guidelines
Integrated Approach, Continued
Initial BMD Testing
Assessment of fracture risk
Low risk
(10-year fracture risk < 10%)
Moderate risk
(10-year fracture risk 10%-20%)
Unlikely to benefit from
pharmacotherapy
Reassess in 5 yr
Lateral thoracolumbar
radiography (T4-L4) or vertebral
fracture assessment may aid in
decision-making by identifying
vertebral fractures
Factors warranting
consideration of pharmacologic
therapy…
High risk
(10-year fracture risk > 20% or
prior fragility fracture of hip or
spine or > 1 fragility fracture)
Always
consider
patient
preference
Good evidence of
benefit from
pharmacotherapy
2010 Guidelines
Integrated Approach, Continued
Initial BMD Testing
Assessment of fracture risk
Low risk
(10-year fracture risk < 10%)
Moderate risk
(10-year fracture risk 10%-20%)
Unlikely to benefit from
pharmacotherapy
Reassess in 5 yr
Lateral thoracolumbar
radiography (T4-L4) or vertebral
fracture assessment may aid in
decision-making by identifying
vertebral fractures
Factors warranting
consideration of pharmacologic
therapy…
High risk
(10-year fracture risk > 20% or
prior fragility fracture of hip or
spine or > 1 fragility fracture)
Always
consider
patient
preference
Good evidence of
benefit from
pharmacotherapy
2010 Guidelines
Integrated Approach, Continued
Initial BMD Testing
Assessment of fracture risk
Low risk
(10-year fracture risk < 10%)
Moderate risk
(10-year fracture risk 10%-20%)
Unlikely to benefit from
pharmacotherapy
Reassess in 5 yr
Lateral thoracolumbar
radiography (T4-L4) or vertebral
fracture assessment may aid in
decision-making by identifying
vertebral fractures
Factors warranting
consideration of pharmacologic
therapy…
High risk
(10-year fracture risk > 20% or
prior fragility fracture of hip or
spine or > 1 fragility fracture)
Always
consider
patient
preference
Good evidence of
benefit from
pharmacotherapy
2010 Guidelines
Integrated Approach,
Continued
Moderate risk
(10-year fracture risk 10%-20%)
Lateral thoracolumbar radiography (T4-L4) or vertebral
fracture assessment may aid in decision-making by identifying
vertebral fractures
•
•
Repeat BMD in
1-3 yr and
reassess risk
•
•
•
•
•
•
•
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
pharmacotherapy
2010 Guidelines
Integrated Approach,
Continued
Moderate risk
(10-year fracture risk 10%-20%)
Lateral thoracolumbar radiography (T4-L4) or vertebral fracture assessment may aid in decision-making by identifying vertebral fractures
Repeat BMD in
1-3 yr and
reassess risk
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
pharmacotherapy
2010 Guidelines
Back-up Material
Additional slides that can be accessed from
hyperlinks on core slides
Section Five – Fracture Risk Assessment
2010 Guidelines
Classification of Vitamin D Status by
Serum Level of 25-OH-D
Serum
25-OH-D,
nmol/L*†
Category
Level of
evidence
< 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.”
Hanley DA, et al. CMAJ 2010; 182:E610-E618.
2010 Guidelines
Vitamin D Supplementation (D3) and
Reduced Non-vertebral Fracture Risk
Bischoff-Ferrari HA, et al. JAMA 2005; 293(18):2257-2264.
2010 Guidelines
Fracture Risk Reduction with Vitamin D
and Calcium
Boonen S, et al. J Clin Endocrinol Metab 2005; 293(18):2257-2264.
2010 Guidelines
Vitamin D: Reduction of Falls in the
Elderly
Return to main presentation
Bischoff-Ferrari HA, et al. BMJ 2009; 339:b3692.
2010 Guidelines
Calcium Supplements
Supplement type
Notes
Calcium 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.
2010 Guidelines
Association of Calcium Intake with
Hip Fracture Risk
Return to main presentation
Tang BM, et al. Lancet 2007; 370(9588):657-666.
2010 Guidelines
Potential Risks of Calcium Supplementation
• High-dose calcium supplementation has been
associated with
– Renal calculi in older women
– Cardiovascular events in older women
– Prostate cancer in older men
Return to main presentation
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.
2010 Guidelines
Benefits of Exercise:
Fractures and Bone Health
• Programs > 1 year
including aerobic
exercises and strength
training have
demonstrated positive
effects on BMD and
thoracic kyphosis but
have limited evidence
for fracture reduction1
• Moderate to vigorous exercise has demonstrated an
ability to reduce hip fracture risk2
Return to main presentation
1. De Kam D, et al. Osteoporos Int 2009; 20(12):2111-25.
2. Moayyeri A. Ann Epidemiol 2008; 18:827-835.
2010 Guidelines
Nonpharmacologic Interventions
Associated 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).
2010 Guidelines
Benefit of Hip Protectors in
Long-term Care
• A modest reduction in hip fractures in elderly
long-term care residents1,2
• Cost effective for fracture reduction in longterm care3
• Compliance poses a challenge1
• Not effective for older adults residing in the
community1,4
Return to main presentation
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.
2010 Guidelines
Oral Bisphosphonates: Summary
Drug (Brand name) Dosing Schedules
Alendronate (Fosamax®,
Fosavance®)
10 mg daily
70 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 on
patient instructions, precautions and adverse events
Return to main presentation
2010 Guidelines
IV Bisphosphonate: Summary
Drug (Brand name) Dosing Schedule
Zoledronic Acid (Aclasta®)
5 mg intravenously once yearly
See notes page for information on
patient instructions, precautions and adverse events
Return to main presentation
2010 Guidelines
Other Medications: Summary
Drug (Brand name) Dosing Schedule
Calcitonin (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
See notes page for information on
patient instructions, precautions and adverse events
Return to main presentation
2010 Guidelines
Zoledronic Acid Hip Fracture Trial:
Reduction in Mortality
Return to main presentation
Lyles KW, et al. N Engl J Med 2007; 357(18):1799-809.
2010 Guidelines
Meta-analysis of Anti-osteoporosis
Medication: Reduction in Mortality
RR
(95% CI)
Analysis Studies included
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.
2010 Guidelines
Clinical Vertebral Fractures in Patients Continuing
or Stopping Alendronate Therapy: FLEX Study
Return to main presentation
Black DM, et al. JAMA 2006; 296(24):2927-2938.
2010 Guidelines
New Vertebral Fractures in Those Stopping or
Continuing Risedronate Therapy
Stopped
risedronate
Return to main presentation
Continued
risedronate
Watts NB, et al. Osteoporos Int 2008; 19(3):365-372.
2010 Guidelines
Evidence with Pharmacotherapies for
Patients 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
Return to main presentation
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.
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.
2010 Guidelines
Evidence for Zoledronic Acid in Women
with 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 loss
with early breast cancer more effectively than delaying
therapy until BMD loss or fracture occurs2
• When added to adjuvant endocrine therapy improves
disease-free survival in premenopausal patients with
estrogen-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.
2010 Guidelines
Evidence for Risedronate in Women
with Breast Cancer Receiving AIs
• Reduces AI-associated bone loss
• Associated with a significant
increase in lumbar spine and total
hip BMD
Return to main presentation
Van Poznak C, et al. J Clin Oncol 2010; 28(6):967-975.
2010 Guidelines
Evidence for Treatment in Men Receiving Androgendeprivation Therapy for Prostate Cancer
• Insufficient fracture data in studies with
bisphosphonates and selective estrogen receptor
modulators (SERMs)
• Denosumab showed a decreased cumulative
incidence 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.
2010 Guidelines
Factors that Warrant Consideration for
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
2010 Guidelines
Disorders Associated with Osteoporosis and
Increased 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 )
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2010 Guidelines
Adverse Events of Osteoporosis
Therapies
• 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
2010 Guidelines
Bisphosphonates and
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.
2010 Guidelines
Bisphosphonates 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
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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.
2010 Guidelines
Interpretation of Serial BMD
Measurements
• 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.
2010 Guidelines
Recommendations for Frequency of
BMD 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 testing
interval (5 – 10 years) may be sufficient
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2010 Guidelines
Importance of Adherence
in 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.
2010 Guidelines
Poor Adherence Leaves Patients at
Higher Risk of Fracture
Probability of fracture
0.12
0.11
0.10
0.09
50% adherence leaves
patients at approximately
the same fracture risk
as no therapy
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
MPR
Siris E, et al. Mayo Clin Proc 2006; 81:1013-22.
2010 Guidelines
Types and Rates of Non-adherence
in 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.
2010 Guidelines
Approaches for Optimizing Adherence
•
•
•
•
•
Reminders
Patient information
Counselling
Simplification of the dosing regimen
Self-monitoring
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2010 Guidelines
Desirability 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
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2010 Guidelines
Criteria Used to Assign Levels of
Evidence: Studies of Diagnosis
Level
1
Criteria
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
2010 Guidelines
Criteria Used to Assign Levels of Evidence:
Studies of Treatment and Intervention
Level Criteria
1+
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
5
Non-RCT or cohort study
Before/after study, cohort study with non-contemporaneous
controls, case-control study
Case series without controls
6
Case report or case series of < 10 patients
4
RCT = randomized, controlled study
2010 Guidelines
Criteria Used to Assign Levels of
Evidence: Studies of Prognosis
Level
Criteria
i
ii
1
Inception cohort of patients with the condition of interest, but
free of the outcome of interest
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
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2010 Guidelines
Criteria Used to Assign
Grades 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 assign
a grade in recommendation; consensus was required in addition.
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