osteoporosis diagnosis and therapy veronica piziak md, phd scott & white professor of...
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OsteoporosisDiagnosis and Therapy
Veronica Piziak MD, PhDScott & White
Professor of Endocrinology Texas A&M HSC
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Objectives
Discuss: Diagnosis of osteoporosis Dosages of calcium and vitamin D and their role in
bone disease Risks and benefits of bisphosphonates Role of Denosumab
Disclosures: Warner Chilcott- speaker Novartis, P+G research support
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Bone loss accelerates with menopause (~1%-2% per year)
Age-related bone loss (~0.5%-1.0% per year)
6 50 100
AGE in YEARS
HIGHER PEAK BONE MASS
MANOPAUSE
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How much calcium?What kind?
Patients with renal insufficiency may not be able to clear usual doses of calcium and coronary artery calcification may progress
Russo D, Miranda I, Ruocco C, Battaglia Y, Buonanno E, Manzi S,et al. The progression of coronary artery calcification in predialysis patients on
calcium carbonate. Kidney Int 2007;72:1255-61.
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700 mg
1200 mg
1000 mg 1300 mg
X
Institute of Medicine 2010
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Calcium: How much and what kind? Do calcium supplements increase the
risk of heart attack? Meta analysis:Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010),
1-2 gms calcium no D in supplements Hazard ratio 1.31 p 0.0305 Dietary calcium no increased risk MI Boland et al BMJ 2010; 341:c3691
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Calcium intake and vascular calcification
No correlation of coronary artery calcification or abdominal aortic calculations with dietary calcium or calcium intake in healthy men and women.
Wang TK et al JBMR Jul 2010 Calcium supplementation and the risks of
atherosclerotic vascular disease in older women: results of a 5‐year RCT and a 4.5‐year follow‐up
No increased incidence of CV disease -1200 mg/day
Joshua R Lewis JBMR on line 2010 Look at the ASBMR website
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DIETARY CALCIUM 1200 mg very possible Remember fortified foods Total, OJ, pasta, granola bars, yogurt Bread, raisins Cheese 300 mg/ slice (Borden)
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Vitamin D MetabolismVitamin D
Dehydrocholecalciferol (diet, skin)
25-hydroxylase
1a-hydroxylase
25-hydroxyvitamin D 1,25-dihydroxyvitamin D
increased GIcalcium absorption
increasedavailablecalcium
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INCREASES PHOSPHORUS ABSORPTION
DECREASES PTH SYNTHESIS
CA x P
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How much Vitamin D?
600 IU /day everyone thru age 70 800 IU for people > age 70 More then 4000 IU / day is not
recommended
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THE 25(OH)D CONTINUUM
(ng/mL)
(nmol/L)
“deficiency”
“insufficiency”“normal”
(ng/ml)
modified after Heaney
0 10 20 30 40 50 60
0 25 50 75 100 125 150
PTH is elevated
CALCIUM ABSORPTION INCREASES
?
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Who to Screen for Deficiency Patients who do not increase BMD on
bisphosphonates Patients with hip fracture, nonunion
fractures Young patients with fracture at any site Patients with hyperparathyroidism
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Who to Screen for Deficiency
Breast fed infants not given vitamin D supplementation
Institutionalized elderly- decreased sunshine exposure
Obese individuals – decreased production Fibromyalgia patients ? Paget’s disease – Rapid bone turnover Medications that interfere with vitamin D
absorption or metabolism.
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Who to Screen for Deficiency Malabsorption Pancreatic insufficiency Inflammatory bowel disease Gastric bypass Severe Liver dysfunction -
decreased 25 hydroxylation
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Replacing Vitamin D
1000 IU daily from the 25-30 range Raises the level to about 40 ng/ml For significant deficiency 50,000 IU (D2) may give once a week for 8
weeks check 25OH D Holick et al 1998 lancet 351:805
May give 50,000 IU once a month safely for 5 years
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Definition of Osteoporosis A skeletal disorder characterized by… Excessive osteoclast-mediated bone resorption Compromised bone strength Increased risk of fracture at all skeletal sites
Boyle WJ, et al. Nature. 2003;423:337-342.NIH Consensus Development Panel. JAMA. 2001;285:785-795.Images are of a paired iliac crest biopsy and courtesy of Yebin Jiang MD, PhD. Osteoporosis & Arthritis Lab, University of Michigan.
Normal
“Osteoporosis has financial, physical, and psychosocial consequences, all of which significantly affect the individual, the family,
and the community.” –NIH Consensus Statement
Osteoporosis
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WHO. Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis; 1998.
T-Score
OsteopeniaOsteoporosis
Normal
–2.5 –2 –1 0
WHO = World Health Organization.
WHO Diagnostic Categoriesfor Osteopenia
REMEMBER BONE STRENGTH ,DISEASE STATE
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BMD Testing
Recommended by the Surgeon General’s report in 2004: US Preventive health task force 3/2011
Postmenopausal women with FRAX score 9.3% risk osteoporotic fracture
Women>/=65 years of age with fractures - required by NCQA
Younger women with risk factors Men and Women with fragility fractures People on medications or with diseases
that can increase the risk of fractures
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Who to treat?Goal - prevent fracturesPatients at significant risk
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Fracture rate
60
50
40
30
20
10
0Fra
ctu
re p
er
100
0 P
ers
on
-Ye
ars
Adapted from Siris ES, et al. Arch Intern Med. 2004;164:1108-1112.
BMD distribution
BMD T-Scores (Peripheral)
>1.01.0 to 0.5
0.5 to 0.00.0 to –0.5
–0.5 to –1.0–1.0 to –1.5
–1.5 to –2.0–2.0 to –2.5
–2.5 to –3.0–3.0 to –3.5
< –3.5
No. of women with fractures
450
350
300
250
200
100
0
150
50
400
No
. of W
om
en
With
Fra
ctu
res
Population BMD Distribution, Fracture Rates, and Number of Women With Fractures
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http://www.shef.ac.uk/FRAX/index.htm
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http://www.shef.ac.uk/FRAX/index.htm
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Updated NOF Clinician’s GuideIncorporation of WHO Algorithm New NOF Guide (2008)
Initiate Treatment in PM women and men age ≥50 with:•Hip or vertebral fracture•Other prior fracture and low bone mass (T-score -1.0 to -2.5)•T-score <-2.5 (2º causes excl.)•Low bone mass and 2º causes associated with high risk of fracture•Low bone mass AND 10-yr hip fracture probability ≥3% or 10-yr major OP-related fracture probability of ≥20%
PreviousNOF Guide (2003)
Initiate Treatment in those with :
•T-score <-2.0 & no risk factors
•T-score <-1.5 & ≥ risk factors
•Hip or Vertebral Fracture
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OSTEOPOROSIS How to Treat? Approved medications Raloxifene Bisphosphonates PTH 1-34 Denosumab
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ALENDRONATE
Approved for: Prevention and therapy Postmenopausal osteoporosis Steroid induced osteoporosis 70mg/week Generic available! Long life in bone, most commonly
associated with bone suppression
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Risedronate and Ibandronate
Risedronate 150 mg Once a Month Minimum of 30-minute wait before eating Approved for prevention and therapy of Postmenopausal osteoporosis, male
osteoporosis, steroid induced osteoporosis Enteric coated form now availableIbandronate 150 mg Once a MonthMinimum of 60 minute wait before eating
Approved for prevention of vertebral fractures
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IV Bisphosphonates: Considerations Potentially increased compliance Only eliminate GI adverse events Adverse events and considerations
Flu-like syndromes Injection-site reactions Renal toxicities (Check creatinine) Long-term use
Osteonecrosis of the jaw Electrolyte abnormalities (hypocalcemia)
Conte et al. Oncologist. 2004;9(suppl 4):28.
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IV Ibandronate
15 second IV push Store at room temperature 3 mg/every three months Creatinine clearance at least 37 ml/min
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Zoledronic acid/ Reclast
Approved as a once / year IV therapy for postmenopausal and male osteoporosis,
15 minute infusion 5 mg/100 ml Side effects – hypocalcemia, fever, muscle
pain, flu-like symptoms and headache Not for use in pregnancy or with creatinine
clearance < 35ml/min MAKE SURE PATIENTS TAKE CALCIUM! MAKE SURE THEY ARE WELL HYDRATED Consider obtaining 25 OH Vitamin D
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Code properly
Billed under Medicare Part B Must have “senile/postmenopausal
osteoporosis 733.01 T- score -2.5 + 995.29 Unspecified adverse effect of other
drug V12.79 Personal Hx of digestive system
disease V49.84 bed confined status = payment
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RISEDRONATE CONTROL
P < 0.01
VS CONTROL
Hip fracture reduction by 9 months
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ALENDRONATE OVER 10 YEARS BONE AND LIBERMAN ET AL NEJM 2004;350:1189-1199
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BUT does over suppression result in fractures?
In the past 4 years, reports have been published implying that long-term bisphosphonate therapy could be linked to atraumatic femoral diaphyseal fractures
Long-term alendronate therapy 8+ years ? Associated with unilateral low-energy subtrochanteric and diaphyseal femoral fractures in a small number of patients.
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JBMR Publishes ASBMR Task Force Report on Atypical Femoral FracturesWho is at risk?
Date: September 14, 2010
In the most comprehensive scientific report to date on the topic, the task force reviewed 310 cases of "atypical femur fractures," and found that 94 percent (291) of patients had taken the drugs, most for more than five years. The task force members emphasized that atypical femur fractures represent less than one percent of hip and thigh fractures overall and therefore are very uncommon. They MAY be related to long term use.
More than half of patients with atypical femur fractures reported groin or thigh pain for a period of weeks or months before fractures occurred, according to the report. More than a quarter of patients who experienced atypical femur fractures in one leg experienced a fracture in the other leg as well
Warnings PI: Thigh or groin pain look for fracture – Plan film of the area may show sclerosis.
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FLEX – FIT EXTENSION
WHO SHOULD NOT STOP?
PREVIOUS VERTEBRAL OR NONVETEBRAL FRACTURE
VERY LOW BMD <- 2.5 BLACK ET AL JAMA 2006;296:2927-38 EDITORIAL JAMA 2006;296:2968-2969
FDA agrees 2010
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Reanalysis of FLEX/FITwho could stop?
In previous studies, ALN efficacy for NVF prevention in women without prevalent vertebral fracture was limited to those with femoral neck (FN) T-score </= -2.5.
Continuing alendronate for 10 years instead of stopping after 5 years reduces non-vertebral fracture risk in women without prevalent vertebral fracture whose FN T-score, achieved after 5 years of ALN, is </= -2.5, but does not reduce risk of NVF in women whose
T-score is > -2 after 5 years could stop
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Long Term Use– a Plan
Drug holiday after 5-10 years Duration of the treatment and holiday depend
on fracture risk. Continue for 10 years if osteoporosis or if
holiday use another agent (? PTH 1-34) Low fracture risk then stop at 5 years and
monitor the DXA stay off if stable and no fractures.
Watts et al JCE&M 95: 1555-1565 2010
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Human Parathyroid Hormone 1-34 and 1-84
1 10
20
30
Ser Val Ser Glu Ile Gln Leu Met His AsnLeu
GlyLysHisLeuAsnSerMetGluArgValGlu
Trp
LeuArg Lys Lys Leu Gln Asp Val His Asn Phe
50
40
6070
80
-COOH
H2N-
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When to use
Severe osteoporosis T score – 3, previous fractures Fractures on bisphosphonate Unresponsive to bisphosphonates Few side effects Very expensive
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Role of RANK Ligand in Bone Resorption
HormonesGrowth factorsCytokines
RANKL
RANK
OPG
Bone Formation
Adapted from Boyle WJ, et al. Nature. 2003;423:337-342. Bone Resorption
Activated Osteoclast
CFU-M Pre-FusionOsteoclast
MultinucleatedOsteoclast
In the presence of M-CSF
CFU-M=colony forming unit macrophageM-CSF=macrophage colony stimulating factor
Provided as an educational resource. Do not copy or distribute.© 2007 Amgen. All rights reserved.
Osteoblasts
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Cytokines Growth factors
HormonesPrefusion osteoclast
RANKL-Inhibitors: Mechanism of Action
Adapted from Boyle et al. Nature. 2003;423:337.
CFU-M
Multinucleatedosteoclast
RANKL
OPG
BONE
OPG RANKL
Stromal
cells
InhibitorsRANK
Active OsteoclastOsteoblast
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Denosumab SC q6mo: Effect on Lumbar Spine BMD
Placebo (n=46)
Denosumab 60 mg (n=46)Denosumab 100 mg (n=41)
Alendronate 70 mg/wk (n=46)
Denosumab 14 mg (n=53)
Denosumab 210 mg (n=46)
Months
Me
an
ch
an
ge
fro
m b
as
elin
e (
%)
-2
-1
0
1
2
3
4
5
6
0 2 4 6 8 10 12
Adapted from McClung et al. N Engl J Med. 2006;354:821.
60 mg dose sub q every 6 months
Spine 6.5% 2 years, Hip 3.4%, Radius 1.4% (cortical bone)
96% responder rate 4/1/08 Endo Soc
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Steven R. Cummings, M.D., Javier San Martin, M.D., Michael R. McClung, M.D., NEJM 2009;361 Aug 19th
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Approved by the FDA!
Denosumab (Prolia) Indication: postmenopausal osteoporosis With a high risk of fracture Sub q every 6 months (prefilled syringe) Contraindicated in hypocalcemia May use in renal insufficiency ( monitor
calcium, phosphorus, magnesium)
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Side Effects
Side effects: dermatitis, significant infections, pancreatitis
ONJ has been reported Examine the mouth If patient has an infection they need to
call
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TREAT OSTEOPOROSIS
10 million Americans with osteoporosis and it is treatable
Yet Calcium intake is low in the US
After hip fracture <25% given calcium and vitamin d <10% treated with bone active agents
50% no longer take medications at 1 year
Keep trying