the three ages of woman gustav klimt, 1905 osteoporosis 2013 – where are we now? mary zoe baker,...
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The Three Ages of Woman Gustav Klimt, 1905
Osteoporosis 2013 – Where Are We Now?
Mary Zoe Baker, M.D.
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Disclosures
• Industry Research Support to Institution – VM BioPharma, Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer-Ingelheim, Corcept Therapeutics, Inc., Pfizer, Inc.
• Consultancies, Financial Holdings or Speaker’s Bureau – None
• Discussion of unlabeled use of drugs - None
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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.
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Vertebrae
Hip
Wrist
50 60 70 80
40
30
20
10
Age (Years)
An
nu
al in
cid
en
ce
per
1000 w
om
en
Incidence of Osteoporotic Fractures in Women
Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72
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Osteoporotic Fractures:Comparison with Other Diseases
1996 new cases,all ages184 300
750 000 vertebral
250 000 other sites
250 000forearm
250 000hip
0
500
1000
1500
2000
Osteoporotic Fractures
HeartAttack
Stroke BreastCancer
An
nu
al in
cid
en
ce x
10
00
1 500 000
Annual incidenceall ages
513 000
annual estimatewomen 29+
228 000
annual estimatewomen 30+
American Heart Association,1996American Cancer Society,1996
Riggs BL & Melton LJ 3rd, Bone, 1995;17(5 suppl):505S-511S
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All fractures are Associated With Morbidity
Cooper C, Am J Med, 1997;103(2A):12S-17S
40%
Unable to walk independently
30%
Permanentdisability
20%
Death within one year
80%
One year after an
hip fracture:
Pat
ien
ts (
%)
Unable to carry out at least one independent activity of daily living
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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
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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.
WHO Criteria for Diagnosis of Bone Status
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Hip
fra
ctu
re r
isk
(% p
er
10 Y
ears
)
-3
60
70
80
AGE
0
5
10
15
20
50
BMD T-score-2.5 -2 -1.5 -1 -0.5 0 0.5 1
10-Year Fracture Risk: Age and BMD
For a given BMD,
risk increases with age
Kanis JA et al, Osteoporos Int, 2001;12:989-995
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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%.
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Screening for Osteoporosis: U.S. Preventive Services Task ForceRecommendation 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.
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New England Journal of Medicine. 366(3):225-33, 2012 Jan 19.
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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
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Osteoclast
Inhibition of resorption
Osteoblast
Stimulation of formation
Pharmacologic TreatmentTargets
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Pharmacologic Treatment of OP: Overview
Treatment Action
Estrogen replacement therapy Selective estrogen receptor
modulators (SERMs)
CalcitoninBisphosphonatesDenosumab
Inhibit bone resorption Maintain or increase
bone massReduce fracture risk
Parathyroid hormoneIncrease bone formationMaintain or increase
bone massReduce fracture risk
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Pharmacologic Treatment of PMO: Overview
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Pharmacologic Treatment of PMO: Overview
Ann Intern Med. 2008;149:404-415
Denosumab Strong evidence Strong evidence Strong evidence Treatment
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Osteoporosis TreatmentsFracture Reduction
• Alendronate 52%• Risedronate 49%• Ibandronate 56%• Evista 50%• Calcitonin 36%
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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
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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
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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.
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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.
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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
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Figure 1
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.
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.
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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
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Atypical Femoral Fracture
Shane et al, JBMR 25:2010;25:2267–2294.
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 T1-weighted and increased signal on T2-weighted images only of the right femur onthis section. Similar findings on AP DXA hip images (D) show focal bilateral cortical thickening consistent with early, evolving femoral insufficiency fractures.
A B
DC
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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
JAMA. 2011;305(8):783-789
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 exposureSecondary analysis - association of bisphosphonate use and classic intertrochanteric or femoral neck fractures
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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
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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
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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 [0.7390.56-
0.940]Lyles, NEJM 357:1799,2007Beaupre OI 22:983,2011Center JCEM 96:1006,2011Sambrook OI 22:2551,2011
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Bisphosphonate Therapy Benefits
• Decreased risk of breast cancer• Decreased risk of colorectal cancer• Decreased risk of stroke• Decreased risk of gastric cancer• Decreased overall mortality
Nelson Watts – Endocrine Society National Meeting - 2012
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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
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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.
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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
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Watts and Diab JCEM, 2010 95:1555.
*
*Use FRAX to estimate risk
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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
Watts and Diab JCEM, 2010 95:1555.
* To quote Dr. Watts himself, this is an evidence free zone.
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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
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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
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www.hormone.org
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Percentages of daily and weekly bisphosphonate userspersistent with therapy after 1 year based on prior bisphosphonate usage
A systematic review of persistence and compliancewith bisphosphonates for osteoporosis
Osteoporos Int (2007) 18:1023–1031
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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...
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Prolia – A Word• Antiresorptive agent anti RANK ligand ab• IV twice a year• Evidence for prevention of vertebral, non-
vertebral 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.
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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
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IOM Report - 2010
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• 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.
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
Heart 2012;98:920-925.
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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
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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.
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Too Much Calcium Could Cause Kidney, Heart Problems, Researchers Sayby Patti Neighmond Morning Edition NPR – August 13, 2012
• 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.
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Calcium Supplementation and CV Disease
• Appears to be associated with supplemental not dietary calcium
• May be more of a problem in men than women
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www.nof.org
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IOM Report - 2010
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Osteoporosis screening and treatment guidelines: are they being followed?
Schnatz et al. Menopause 18:1075, 2011
Participants - women sent for dual-energy x-ray absorptiometry screenings
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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
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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
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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