Transcript Osteoporosis Diagnosis and Therapy

Osteoporosis
Diagnosis and Therapy
Veronica Piziak MD, PhD
Scott & White
Professor of Endocrinology
Texas A&M HSC
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
HIGHER PEAK
BONE MASS
MANOPAUSE
Bone loss accelerates with
menopause (~1%-2% per year)
Age-related bone loss
(~0.5%-1.0% per year)
6
50
AGE in YEARS
100
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
700 mg
X
1200 mg
1000 mg
1300 mg
Institute of Medicine 2010
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
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
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Joshua R Lewis JBMR on line 2010
Look at the ASBMR website
DIETARY CALCIUM

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1200 mg very possible
Remember fortified foods
Total, OJ, pasta, granola bars, yogurt
Bread, raisins
Cheese 300 mg/ slice (Borden)
Vitamin D Metabolism
Vitamin D
Dehydrocholecalciferol
(diet, skin)
increased GI
calcium absorption
increased
available
calcium
25-hydroxylase
25-hydroxyvitamin D
1,25-dihydroxyvitamin D
1a-hydroxylase
CA x P
INCREASES
PHOSPHORUS
ABSORPTION
DECREASES PTH
SYNTHESIS
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
THE 25(OH)D CONTINUUM
“deficiency”
“insufficiency”
?
0
10
20
30
“normal”
40
50 (ng/ml)60
(ng/mL)
0
25
50
75
PTH is elevated
CALCIUM ABSORPTION INCREASES
100
125
150
(nmol/L)
modified after Heaney
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
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.
Who to Screen for
Deficiency

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Malabsorption
Pancreatic insufficiency
Inflammatory bowel disease
Gastric bypass
Severe Liver dysfunction decreased 25 hydroxylation
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
Definition of Osteoporosis
A skeletal disorder characterized by…
 Excessive osteoclast-mediated bone resorption
 Compromised bone strength
 Increased risk of fracture at all skeletal sites
Normal
Osteoporosis
“Osteoporosis has financial, physical, and psychosocial consequences,
all of which significantly affect the individual, the family,
and the community.” –NIH Consensus Statement
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.
WHO Diagnostic Categories
for Osteopenia
WHO. Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis; 1998.
Normal
Osteoporosis
Osteopenia
–2.5 –2
–1
0
T-Score
WHO = World Health Organization.
REMEMBER BONE STRENGTH ,DISEASE STATE
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
Who to treat?
Goal - prevent fractures
Patients at significant risk
Fracture per 1000 Person-Years

50
BMD distribution
Fracture rate
No. of women
with fractures
40
350
300
250
30
200
20
150
100
10
0
400
50
>1.0
0.5 to 0.0
–0.5 to –1.0 –1.5 to –2.0 –2.5 to –3.0
< –3.5
1.0 to 0.5
0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5
BMD T-Scores (Peripheral)
Adapted from Siris ES, et al. Arch Intern Med. 2004;164:1108-1112.
0
No. of Women With Fractures
Population BMD Distribution,
Fracture Rates, and Number
of 60Women With Fractures 450
http://www.shef.ac.uk/FRAX/index.htm
http://www.shef.ac.uk/FRAX/index.htm
Updated NOF Clinician’s
Guide
Incorporation of WHO Algorithm
Previous
NOF Guide (2003)
Initiate Treatment in those
with :
•T-score <-2.0 & no risk
factors
•T-score <-1.5 & ≥ risk
factors
•Hip or Vertebral Fracture
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 OPrelated fracture probability of ≥20%
OSTEOPOROSIS
How to Treat?
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Approved medications
Raloxifene
Bisphosphonates
PTH 1-34
Denosumab
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
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 available
Ibandronate 150 mg Once a Month
Minimum of 60 minute wait before eating
Approved for prevention of vertebral fractures
IV Bisphosphonates:
Considerations
 Potentially increased compliance
 Only eliminate GI adverse events
 Adverse events and considerations
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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.
IV Ibandronate
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15 second IV push
Store at room temperature
3 mg/every three months
Creatinine clearance at least 37 ml/min
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
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
RISEDRONATE CONTROL
Hip fracture
reduction by 9
months
P < 0.01
VS
CONTROL
ALENDRONATE OVER 10
YEARS
BONE AND LIBERMAN ET AL NEJM 2004;350:1189-1199
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.
JBMR Publishes ASBMR Task Force
Report on Atypical Femoral Fractures
Who 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
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Warnings PI: Thigh or groin pain look for fracture –
Plan film of the area may show sclerosis.
FLEX – FIT EXTENSION
 WHO SHOULD NOT STOP?

PREVIOUS VERTEBRAL OR
NONVETEBRAL FRACTURE
 VERY LOW BMD <- 2.5
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BLACK ET AL JAMA 2006;296:2927-38
EDITORIAL JAMA 2006;296:2968-2969
 FDA agrees 2010
Reanalysis of FLEX/FIT
who 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
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
Human Parathyroid Hormone
1-34 and 1-84
1
H2N-
Ser
10
Val
Ser
Glu
Ile
Gln
Leu
Met
His
Asn
Leu
20
Gly
Glu
Val
Arg
Glu
Met
Ser
Asn
Leu
His
Lys
Arg
Lys
Lys
Leu
Gln
Asp
Val
His
Asn
Phe
Trp
Leu
30
40
50
60
70
80
-
COOH
When to use
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Severe osteoporosis
T score – 3, previous fractures
Fractures on bisphosphonate
Unresponsive to bisphosphonates
Few side effects
Very expensive
Role of RANK Ligand in Bone
Resorption
Pre-Fusion
Osteoclast
CFU-M
RANKL
RANK
Multinucleated
Osteoclast
OPG
Hormones
Growth factors
Cytokines
Activated
Osteoclast
Osteoblasts
Bone Formation
In the presence of M-CSF
CFU-M=colony forming unit macrophage
M-CSF=macrophage colony stimulating factor
Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
© 2007 Amgen. All rights reserved.
Bone Resorption
Provided as an educational resource. Do not copy or distribute.
RANKL-Inhibitors: Mechanism
of Action
OPG
RANKL
RANK
Inhibitors
CFU-M
Cytokines
Prefusion
osteoclast
Growth factors
Hormones
OPG
Multinucleated
osteoclast
Active Osteoclast
Stromal
cells
Adapted from Boyle et al. Nature. 2003;423:337.
BONE
Denosumab SC q6mo:
Effect on Lumbar Spine BMD
6
Mean change
from baseline (%)
5
4
Placebo (n=46)
Denosumab 14 mg (n=53)
Denosumab 60 mg (n=46)
Denosumab 100 mg
(n=41)
Denosumab 210 mg (n=46)
Alendronate
70 mg/wk (n=46)
3
2
1
0
-1
-2
0
2
4
6
Months
8
10
12
60 mg dose sub q every 6 months
Spine 6.5% 2 years, Hip 3.4%,
Radius 1.4% (cortical bone)
Adapted from McClung et al. N Engl J Med. 2006;354:821.
96% responder rate
4/1/08 Endo Soc
Steven R. Cummings, M.D., Javier San Martin, M.D.,
Michael R. McClung, M.D., NEJM 2009;361 Aug 19th
Approved by the FDA!
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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)
Side Effects
 Side effects: dermatitis, significant
infections, pancreatitis
 ONJ has been reported
 Examine the mouth
 If patient has an infection they need to
call
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