Transcript Osteoporosis 2013 – Where Are We Now? Mary Zoe Baker, M.D. The Three Ages of Woman Gustav Klimt, 1905

Osteoporosis 2013 –
Where Are We Now?
Mary Zoe Baker, M.D.
The Three Ages of Woman
Gustav Klimt, 1905
Disclosures
• Industry Research Support to Institution –
VM BioPharma, Novo Nordisk, Merck
Sharp & Dohme Corp., BoehringerIngelheim, Corcept Therapeutics, Inc.,
Pfizer, Inc.
• Consultancies, Financial Holdings or
Speaker’s Bureau – None
• Discussion of unlabeled use of drugs None
Objectives
• To identify the optimal treatment plans
and duration of treatment for common
osteoporosis (OP) drugs.
• To describe how to apply the FRAX
fracture assessment tool to clinical
practice.
• To recognize the risk factors for atypical
femoral shaft fractures.
Incidence of
Osteoporotic Fractures in Women
Annual incidence
per 1000 women
40
Vertebrae
30
20
Hip
Wrist
10
50
60
70
Age (Years)
80
Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72
Annual incidence x 1000
Osteoporotic Fractures:
Comparison with Other Diseases
2000 Annual incidence
all ages
1 500 000
1500
250 000
hip
1000
250 000
forearm
250 000
other sites
500
0
annual estimate
women 29+
513 000 annual estimate
women 30+
750 000
vertebral
Osteoporotic
Fractures
228 000
Heart
Attack
Stroke
1996 new cases,
184 300 all ages
Breast
Cancer
American Heart Association,1996
American Cancer Society,1996
Riggs BL & Melton LJ 3rd, Bone, 1995;17(5 suppl):505S-511S
All fractures are Associated
With Morbidity
Unable to carry out at
least one independent
activity of daily living
80%
Unable to walk
independently
Permanent
disability
Death within
one year
40%
30%
20%
Cooper C, Am J Med, 1997;103(2A):12S-17S
Vertebral Fractures
• Most common fracture type
• Often silent
• Insidious, progressive nature
• Associated with significant
morbidity
• Predict future spine and hip
fractures
• Associated with 2-fold increase in
risk of death
WHO Criteria for Diagnosis of
Bone Status
Diagnostic criteria*
Classification
T is above or equal to -1
Normal
T is between -1 and -2.5
Osteopenia (low
bone mass)
T is -2.5 or lower
Osteoporosis
T is -2.5 or lower + fx =
Severe or est.
osteoporosis
*Measured in "T scores." T score indicates the number of
standard deviations below or above the average peak
bone mass in young adults.
10-Year Fracture Risk: Age
and BMD
Hip fracture risk (% per 10 Years)
AGE
20
80
15
70
10
60
5
50
0
-3
-2.5 -2 -1.5 -1 -0.5
BMD T-score
0
0.5
1
Kanis JA et al, Osteoporos Int,
2001;12:989-995
WHO Absolute Fracture Risk Model
FRAX
• Estimates absolute fracture risk using
epidemiology of osteoporosis, risk factors and
therapeutic data.
• By basing treatment decisions on fracture
probability, therapy can be targeted to those
who would receive the greatest benefit.
• Calculation tool is online and calculates the 10
year risk for hip fractures and any osteoporosis
related fracture.
• Using a series of clinical questions, BMD data,
weight and height the tool calculates these risks
for individual patients.
• Treatment is recommended for a 10 year hip
fracture risk over 3% and a 10 year
osteoporotic fracture risk over 20%.
Screening for Osteoporosis: U.S.
Preventive Services Task Force
Recommendation Statement
• Recommendations: The USPSTF
recommends screening for osteoporosis in
women aged 65 years or older and in younger
women whose fracture risk is equal to or
greater than that of a 65-year-old white
woman who has no additional risk factors.
(Grade B recommendation).
• The USPSTF recommends using a 10-year
fracture risk threshold of 9.3% to screen
women aged 50 to 64 years.
Ann Intern Med. 2011;154:356-364.
New England Journal of Medicine.
366(3):225-33, 2012 Jan 19.
Management of PMO: Goals of Therapy
• Prevent first fragility fracture or future
fractures if one has already occurred
• Stabilize/increase bone mass
• Relieve symptoms of fractures and/or
skeletal deformities
• Improve mobility and functional status
• Initiate lifestyle changes to enhance
prevention of fractures
– Smoking
– Alcohol
Pharmacologic Treatment
Targets
Osteoclast
Inhibition of resorption
Osteoblast
Stimulation of formation
Pharmacologic Treatment of OP:
Overview
Treatment
Estrogen replacement therapy
Selective estrogen receptor
modulators (SERMs)
Calcitonin
Bisphosphonates
Denosumab
Parathyroid hormone
Action
Inhibit bone resorption
Maintain or increase
bone mass
Reduce fracture risk
Increase bone formation
Maintain or increase
bone mass
Reduce fracture risk
Pharmacologic Treatment of PMO:
Overview
Pharmacologic Treatment of PMO:
Overview
Denosumab
Strong evidence
Strong evidence
Strong evidence
Treatment
Ann Intern Med. 2008;149:404-415
Osteoporosis Treatments
Fracture Reduction
•
•
•
•
•
Alendronate
Risedronate
Ibandronate
Evista
Calcitonin
52%
49%
56%
50%
36%
Monitoring Response to Therapy
• BMD
– May not tell the whole story
– Remember rate of change must be greater than the
precision of the densitometric method
– Unclear if bone density changes reflect the whole
picture
– May want to repeat BMD in another year before
changing therapy
• Bone Markers
– High variability make use in individual patients risky
– May have a role in younger women
It’s Not All Bone Density
• Similar changes in BMD may not
translate into consistent efficacy for
reduction in fracture risk when
comparing agents eg. Fluoride
• Patients with higher bone turnover
may be at higher risk of fracture eg.
glucocorticoids even with a normal
bone mineral density
• Bone density may not capture all
aspects of fracture reduction eg.
Sensory or drug effects
Bisphosphonate Therapy - Risks
• Initial studies taken to the FDA to gain approval
for these drugs identified a lower than expected
risk of GI side effects
• No unexpected side effects were seen in these
studies
• However, about 15 years ago, cases of
osteonecrosis of the jaw which dentists had not
seen for a least a century, began to appear
• Subsequently, the possibility of an increased risk
of atypical femur fractures in patients treated
with these drugs was proposed.
ONJ
• Exposed necrotic bone in the maxillo-facial region
• Not healing after 6-8 weeks in patients with no hx
of craniofacial radiation
• Exposed yellow-white hard bone with smooth or
ragged borders, often in the site of dental
extraction or other invasive dental procedure with
poorly fitting dentures
• Over 90% of reported cases in cancer patients
receiving BP doses 10X higher than used to treat
osteoporosis
• Estimated incidence in OP: 1:10,000-1:100,000
Khosla et al. ASBMR Rask Force, JBMR 2008;23:159.
Woo S-B et al, Ann Intern Med 2006;144:753-761.
Femoral Shaft Fractures
• In 2005, Odvina et al reported a series of nine
patients with spontaneous, atypical fractures, all on
bisphosphonate therapy for a period of time ranging
from 3 to 8 years.
• Four with fractures in the subtrochanteric region and
one each with fractures of the sacrum, rib, ischium,
pubic rami and lumbar spine.
• 6/9 had delayed or absent healing during
management.
• Histology revealed over suppression of bone
turnover, possibly linked to bisphosphonate usage,
but other factors, i.e.. estrogens and glucocorticoid
use left much room for debate.
Odvina et al JCEM2005;90:1294–1301
Figure 1
Figure 1 . Radiographs of Fractures
of the Femoral Shaft Showing the
"Simple with Thick Cortices"
Pattern Panel A shows a fracture of
the femoral shaft in an 83-year-old
woman with a 9-year history of
alendronate use. Panel B shows a
similar fracture in a 77-year-old
woman with a 5-year history of
alendronate use.
Atypical Fractures of the Femoral Diaphysis in
Postmenopausal Women Taking Alendronate.
Lenart, Brett; Lorich, Dean; Lane, Joseph
New England Journal of Medicine. 358(12):1304-1306, March
20, 2008.
Femoral Shaft Fractures
• Usually occur in the proximal third of the
femoral shaft
• May have a prodrome of thigh pain
• Often bilateral or sequential
• X-rays prior to fracture may reveal some
beaking of the cortex and cortical
thickening of the proximal femoral shaft.
• Early identification may require
intervention – but exactly what is unclear
Atypical Femoral Fracture
A
C
B
D
Conventional AP radiograph of the pelvis (A) shows bilateral focal cortical thickening from
periosteal new bone formation (arrows). Corresponding bone scintigraphy (B)
demonstrates focal increased radionuclide uptake in the proximal lateral femoral cortices
(arrows). MRI images of the femurs (C) demonstrate subtle decreased signal on T1weighted and increased signal on T2-weighted images only of the right femur on
this section. Similar findings on AP DXA hip images (D) show focal bilateral cortical
thickening consistent with early, evolving femoral insufficiency fractures.
Shane et al, JBMR 25:2010;25:2267–2294.
Bisphosphonate Use and the Risk of
Subtrochanteric or Femoral Shaft
Fractures in Older Women
L. Park-Wyllie, PharmD, MS, M. Mamdani, PharmD,
MA, MPH, D. Juurlink, MD, PhD, G. Hawker, MD, MSc,
N. Gunraj, MPH, P. Austin, PhD, D. Whelan, MD, MSc, P.
Weiler, MD, MASc, P Eng. Laupacis, MD, MSc
Population-based, nested case-control study in a cohort of women
aged 68 years or older from Ontario, Canada treated with oral
bisphosphonate between April 1, 2002, and March 31, 2008.
Primary analysis - association between hospitalization for a
subtrochanteric or femoral shaft fracture and duration of
bisphosphonate exposure
Secondary analysis - association of bisphosphonate use and classic
intertrochanteric or femoral neck fractures
JAMA. 2011;305(8):783-789
Summary
• 716 (0.35%) suffered a subtrochanteric or
femoral shaft fracture after receiving
bisphosphonate therapy.
• Cases were matched with 3580 controls
• Bisphosphonate treatment to prevent typical
femoral fractures should last at least 5 years.
• Bisphosphonate treatment for more than 5 years
begins to increase the risk for atypical femoral
shaft fractures which are still extremely rare.
JAMA. 2011;305(8):783-789
Atypical Fractures
• Can occur in BP naïve patients
– 6% of cases reviewed by ASBMR Task Force
had no BP exposure
– Most case series include a minority with no
BP exposure
• Occur in other bone diseases
Bisphosphonates: Decreased
Mortality
• IV – Post-hip fracture: 28% Decreased RR
• PO - Post-hip fracture: 63% decreased
relative risk/year of Rx
• Dubbo OP Study: Decreased Mortality in
women, possibly in men
• Institutionalized elders:HR [0.7390.560.940]
Lyles, NEJM 357:1799,2007
Beaupre OI 22:983,2011
Center JCEM 96:1006,2011
Sambrook OI 22:2551,2011
Bisphosphonate Therapy
Benefits
•
•
•
•
•
Decreased
Decreased
Decreased
Decreased
Decreased
risk of breast cancer
risk of colorectal cancer
risk of stroke
risk of gastric cancer
overall mortality
Nelson Watts – Endocrine Society
National Meeting - 2012
Bisphosphonates for Osteoporosis
— Where Do We Go from Here?
• The available data do not identify
patients likely to benefit from treatment
beyond 3-5 years.
• … decisions to continue treatment must
be based on individual assessment of
risks and benefits and on patient
preference.
NEJM 366:2048, 2012
How Long to Treat With
Bisphosphonates?
• Patients who did not need treatment in the first place
– Discontinue Treatment
• Lower risk patients, if DXA is stable/increasing
– Consider a drug holiday after 3-5 years of treatment
• Higher risk patients (fractures, corticosteroid Rx, very low
BMD)
– Consider a drug holiday after 10 years of therapy
– May use teriparatide or raloxifene (but not another
potent antiresorptive agent – ie. denosumab) during
the holiday from bisphosphonates
Watts and Diab JCEM, 2010 95:1555.
Proposed Guidelines for Use of
Bisphosphonates
• Patients with bone density T-scores of -2.5 or lower at
femoral neck after 3 to 5 years of treatment at highest
risk for vertebral fractures and appear to benefit most
from continued therapy (for up to 10 years).
• Patients with an existing vertebral fracture and T-scores
up to −2.0 may also benefit from continued therapy.
• Patients with femoral neck T-scores above −2.0 have low
risk of vertebral fractures and are unlikely to benefit from
continued treatment after 3-5 years.
Black et al. 2012, NEJM 366:2051
*
*Use FRAX to estimate risk
Watts and Diab JCEM, 2010 95:1555.
When Should the Holiday End?*
• Arbitrary* - Longer for drugs with highest
skeletal affinity (zoledronic acid), shorter for
drugs with lowest skeletal affinity
(risedronate)? Many patients will have been on
more than one - complicating matters.
• Some use bone turnover markers (measure
degree of active bone resorption) – but which
ones and what cut off values to use is unclear.
There is no good evidence here.
• BMD – If significant decrease seen with annual
testing
* To quote Dr. Watts himself, this is an
evidence free zone.
Watts and Diab JCEM, 2010 95:1555.
Bisphosphonates for
Osteoporosis - Summary
• Risk/Benefit Ratio – favorable for most high
risk patients
• Length of treatment depends upon fracture
risk
• Risks of ONJ and AFF may increase after 5
years but risk is low
• What to do about ONJ and AFF?
– ONJ: Look in the mouth
– AFF: Instruct patient to report thigh/groin pain and
investigate if clinically indicated.
– Review films of any reported femur fx
10 Year Probabilities
• Major OP fracture in untreated 72 year-old
woman with FN T- score of -3.0 = 25%
• Major OP fracture in treated 72 year-old
woman with FN T- score of -3.0 = 12.5%
• Fatal MVA = 0.11%
• Murder = 0.06 %
• ONJ = 0.01%
• Atypical Femur Fracture = 0.50%
Shane – Endocrine Society
Annual Meeting - 2012
www.hormone.org
A systematic review of persistence and compliance
with bisphosphonates for osteoporosis
Percentages of daily and weekly bisphosphonate users
persistent with therapy after 1 year based on prior
bisphosphonate usage
Osteoporos Int (2007) 18:1023–1031
The Endocrine Society Recommends Patient-Centered
Approach to Long-Term Bisphosphonate Use for the
Treatment of Osteoporosis - A review of the May 2012
FDA Analysis - May 16, 2012
• “The Endocrine Society is concerned that a
superficial reading of the FDA analysis will
result in an inappropriate abandonment of
bisphosphonates for both short- and long-term
use in patients with osteoporosis. Therefore,
the Society urges its members to engage in a
patient-specific dialogue about the
appropriateness of long-term bisphosphonate
use...
Prolia – A Word
• Antiresorptive agent anti RANK ligand ab
• IV twice a year
• Evidence for prevention of vertebral, nonvertebral and hip fractures
• Risk of significant hypocalcemia –
particularly in renal failure
• May be safer in renal failure (key word is
may)
• Not any safer than bisphosphonates with
regards to ONJ and atypical femur
fractures.
Vitamin D
• 400 I.U. in usual multivitamins
• Found in combination with calcium
supplements
• Can be found as a single component
• Not in yogurt, cheese etc. unless
noted on packaging.
• Monitor using 25(OH) vitamin levels
aiming for 25 ng/ml (recently
adjusted normals)
• May need larger doses for
replacement – 50,000 IU weekly,
biweekly or monthly
IOM Report - 2010
Associations of dietary calcium intake and calcium
supplementation with myocardial infarction and stroke
risk and overall cardiovascular mortality in the
Heidelberg cohort of the European Prospective
Investigation into Cancer and Nutrition study
• EPIC-Heidelberg cohort
• 25,540 local residents aged 35-64 years
• Excluded diagnosis of MI, stroke, or transient ischemic attack
at baseline (n = 1322)
• Self-administered food questionnaire
• Interview to assess ever use of vitamins and calcium
supplements
• Incident cardiovascular events during follow-up were reported
by participants or their next of kin in follow-up surveys.
• Reported cardiovascular events were verified by tracking
medical records or official death certificates.
Heart 2012;98:920-925.
Multivariate HRs and 95% CIs for MI and stroke
incidence and CVD mortality by quartile of total dietary
calcium intake
Heart 2012;98:920-925
Calcium Intake and CV disease
• In conclusion, this study suggests
that increasing dietary calcium
intake from diet might not confer
significant cardiovascular benefits,
while calcium supplements, which
might raise MI risk, should be
taken with caution.
Too Much Calcium Could Cause Kidney, Heart
Problems, Researchers Say
by Patti Neighmond
Morning Edition NPR – August 13, 2012
•
•
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•
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So, in a culture that often considers "more" to be "better," one might ask, if
1,200 milligrams of calcium is good, is 2,000 mg of calcium better?
No, says Dr. Ethel Siris, Columbia University Medical Center, NYC, "You need
enough; you don't need extra."
Extra calcium can build up in the bloodstream and, when excreted through
kidneys in urine, it can cause a kidney stone. That's been known for a while. But
recently, a few studies raised concern that excess calcium may also calcify
coronary arteries in susceptible individuals and even precipitate heart attack.
While these studies are far from conclusive, and far more research needs to be
done, Robert Eckel, an endocrinologist and past president of the American Heart
Association, says they do raise the question about whether there's potentially
some danger in over-the-counter calcium supplements that go beyond our usual
dietary intake of calcium.
"At this point in time, there's a bit of a ‘signal’ that should raise caution but
remains highly controversial. I don't think anyone has stepped up to say
calcium supplements should be abandoned," says Eckel.
That's particularly because calcium is so critical for bone health. The best plan of
action, says Siris: Eat more calcium-rich foods.
So, estimate your daily intake of calcium from food, says Siris, and then
calculate whether you need to take an extra supplement. You may just need
300 or 600 milligrams of calcium extra, and you may not even need that every
day.
Calcium Supplementation
and CV Disease
• Appears to be associated with
supplemental not dietary calcium
• May be more of a problem in men
than women
www.nof.org
IOM Report - 2010
Osteoporosis screening and treatment
guidelines: are they being followed?
Participants - women sent for dualenergy x-ray absorptiometry screenings
Schnatz et al. Menopause 18:1075, 2011
Osteoporosis - Primary
Prevention
•
•
•
•
Adequate calcium intake and vitamin D
Weight bearing exercise
BMD in patients at risk
Adequate estrogen in high risk
individuals
• Avoid smoking and excess alcohol
Summary
• Osteoporosis is a significant health risk –
particularly in postmenopausal women
and men over 65
• Bone mineral density testing is the best
available test to help assess fracture risk
• Treatment should be instituted in patients
with increased risk of fracture as
calculated by FRAX
• There are several treatment options
available supported by strong evidence
Summary
• Bisphosphonates remain the most
potent antiresorptive agents available
• Recent analysis of the risks and
benefits of bisphosphonate therapy
have started to clarify how long they
can be used
• Adequate vitamin D and calcium
supplementation should be instituted