update on the diagnosis and treatment of osteoporosis: 2008 michael maricic, md catalina pointe...
Post on 26-Mar-2015
214 Views
Preview:
TRANSCRIPT
Update on the Diagnosis and Treatment of Osteoporosis: 2008
Michael Maricic, MD
Catalina Pointe Rheumatology
Clinical Associate Professor of Medicine
University of Arizona
Disclosures
Speakers Bureau, Consultant or Clinical Research Grant Support• Merck• Proctor and Gamble • Aventis• Lilly• Novartis• Amgen• Roche • Glaxo-Smith-Kline
Pre-Test Questions
?
Update Objectives
WHO Fracture Assessment Tool 2008 NOF Guidelines for Treatment Calcium and Vitamin D New Treatment Data Osteonecrosis of the jaw
1999 NOF Treatment Guidelines
Treat women with a fragility fracture Treat if T-score >-2.0 Treat if T-score > -1.5 with risk factors
Problem- Which risk factors are more important in deciding to treat osteopenic women
National Osteoporosis Foundation Risk Factors for Low Bone Mass and Fractures (1999)
Personal history of a fracture as an adult
History of a fracture in a first-degree relative
Caucasian race advanced age female sex dementia poor health/frailty
Current cigarette smoking Low body weight (< 127 lbs) estrogen deficiency low calcium intake (lifelong) alcoholism impaired eyesight recurrent falls inadequate physical activity
Non-modifiable Modifiable
Use of WHO Fracture Risk Algorithm
The WHO Fracture Risk Assessment Tool (FRAX®) was developed to calculate the 10-yr probability of a hip fracture and any major osteoporotic fracture • vertebral • hip• forearm • humerus
The algorithm takes into account femoral neck BMD and clinical risk factors for fracture
Non-density Related Risk Factors
Age Previous low trauma fracture Parental history of hip fracture Current cigarette smoking High alcohol intake (> 3 units/day) Rheumatoid arthritis Prior or current glucocorticoid use
Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.
WHO Absolute Risk Prediction Model
10-Year probability of experiencing an osteoporosis-related fracture
Model mimics the Framingham Heart Study 10-year coronary heart disease (CHD) risk predictor
Treatment intervention thresholds will vary by country
Recommendations for treatment based on absolute fracture risk—not simply on T-scores
National Osteoporosis Foundation
Clinician’s Guide to Prevention and Treatment of Osteoporosis 2008
Dawson-Hughes B, Lindsay R, Khosla S, Melton J, Tosteson A, Favus M, Baim S
Synopsis of Major Recommendations General Recommendations
A.Counsel on the risk of osteoporosis and related fractures.
B. Check for secondary causes.
C. Advise on adequate amounts of calcium (at least 1200 mg/d, and vitamin D (800 to 1000 IU
per day of vitamin D3).
D. Recommend regular weight-bearing and muscle-strengthening exercise to reduce the risk of falls and fractures.
E. Advise avoidance of tobacco smoking and excessive alcohol intake.
Basic Care (suitable for all)
Assess Risk Factors and BMD (if risk factors)
T-score between -1.0 and -2.5
10-year probability of hip fractures > 3% or
probability of all major fractures >
20% (FN or total T-score only)
Hip or vertebral fractures
orT-score ≤ -2.5
(spine, FN, or total hip)
2008 NOF Guide: Treatment Initiation Postmenopausal Women and Men ≥ 50 years
www.NOF.org
Other fractures > age 50
(excluding fingers, toes
and face)
Secondary causes with high fracture
risk*
*Such as glucocorticoid use or total immobilization
Nutrition:
• Calcium supplementation
• Vitamin D
Other lifestyle modifications• Avoiding alcohol and tobacco abuse
Exercise: Fall prevention
Treatment of OsteoporosisNon-Pharmacological Options
National Osteoporosis Foundation: March 2007 Recommendations
Recommended Intake for Adults 50 Years and Older
Calcium Calcium
(mg/day)(mg/day)
Vitamin DVitamin D33 (IU/day)(IU/day)
Previous Previous (2003)(2003)11 12001200 400400–800–800
March March 2007 2007 revisionrevision22
12001200 800–1000800–1000
1. National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis. Available at: http://www.nof.org/physguide/index.asp. Accessed April 26, 2007.
2. National Osteoporosis Foundation. National Osteoporosis Foundation’s Updated Recommendations for Calcium and Vitamin D3 Intake. Available at: http://www.nof.org/prevention/calcium_and_VitaminD.htm. Accessed April 26, 2007.
What type of Calcium should we use ?
Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture
Case-control study conducted using the GPRD in the UK Users of PPI therapy, H2 receptor antagonists and nonusers of
acid suppression drugs older than 50 years There were 13,556 hip fracture cases and 135,386 controls The adjusted odds ratio (AOR) for hip fracture associated with
more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], 1.30-1.59)
The strength of the association increased with increasing dose and duration of PPI therapy
Yang Y, Lewis J, Epstein S. JAMA. 2006;296:2947-2953
Vitamin D Insufficiency (<30 ng/mL): Prevalence by Latitude
42 N
35 N
n=198/362
(54.7%)
n=259/532
(48.7%)
n=342/642
(53.3%)
P = NS for Test of Trend.
Holick MF et al. JCEM 2005
Vitamin D Inadequacy and Effects on Osteoporosis and Muscle Strength
“Insufficiency” (< 30 ng / ml)• Suboptimal calcium aborption• 2nd hyperparathyroidism• Decreased BMD, decreased response to pharmacological therapy, increased fracture risk
Frank Deficiency (< 10 ng / ml)• Osteomalacia• Proximal myopathy, Increased postural instability, sway, falls
Effect of Vitamin D and Calcium Effect of Vitamin D and Calcium Supplementation on Risk of FallingSupplementation on Risk of Falling
122 women living in long-term care units
Age: 63–99 Randomized, double-
blind, controlled trial• Calcium 1200 mg/day• Calcium 1200 mg/day
+ vitamin D 800 IU/day 12-week duration Mean serum 25(OH)D 12
ng/ml at baseline
Adapted from Bischoff HA et al J Bone Miner Res 2003;18:343–351.
Calcium only
(n=44)
Calcium + vitamin D
(n=45)
Fal
l ris
k
0.0
0.2
0.4
0.6
0.8
1.0
1.2
–49%
Reduction in falls
p=0.01
*With appropriate calcium and vitamin D.
PREVENTION
• Estrogen
• Raloxifene
• Alendronate
• Risedronate
• Ibandronate
TREATMENT
•Salmon Calcitonin
• Raloxifene
• Alendronate
• Risedronate
• Ibandronate
• Zoledronic acid
•Teriparatide (rhPTH)
FDA-Approved Therapies for Postmenopausal Osteoporosis
Low BMD on DXA Does Not Equal Postmenopausal Osteoporosis
WHI Estrogen+Progestin TrialStudy Results - Fractures
WHI Estrogen+Progestin TrialStudy Results - Fractures
0
2
4
6
8
10
12
14
16
Clin
ical
Ou
tco
mes
Hip Vertebral
Estrogen+Progestin Placebo
34% Reduced Risk* 34% Reduced Risk**
*Hip Fractures: HR 0.66; Nominal 95% CI (0.45-0.98), Adjusted 95% CI (0.33-1.33) **Vertebral Fractures: HR 0.66; Nominal 95% CI (0.44-0.98), Adjusted 95% CI (0.32-1.34)Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333.
FDA Recommendations on ET/HT
• When prescribing medication to prevent osteoporosis, physicians should consider all non-estrogen preparations first
• When prescribing ET/HT, physicians should prescribe the smallest dose for the shortest amount of time to achieve treatment goals
• Physicians should prescribe ET/HT products only when the benefits are believed to outweigh the risks for a specific patient
US Food and Drug Administration. FDA News, January 8, 2003.
• Although other doses and combinations of estrogens and progestins were not studied, the FDA believes the risks attributable to the combination in the WHI Study are applicable to all HT products.
Effect of Raloxifene on New Clinical Vertebral Fractures at 1 Year
Maricic M, et al. Arch Intern Med. 2002;162:1140-1143. *P=.01 vs placebo
0.0
0.5
1.0
1.5
RR 0.32*(95% CI = 0.13-0.80)
68%
Placebo(N=2576)
Raloxifene 60 mg/d
(N=2557)
% o
f Wo
me
n W
ithIn
cide
nt V
ert
ebra
l Fra
ctu
res
Raloxifene: Effect on Nonvertebraland Hip Fracture (MORE)
Pooled Data (60 mg and 120 mg*)
PlaceboRaloxifene pooled
Months
Perc
ent o
f Pat
ient
s W
ith In
cide
ntN
onve
rteb
ral F
ract
ures
Non-Vertebral Fractures Hip Fractures
Months
PlaceboRaloxifene pooled
060 12 18 24 30 36 60 12 18 24 30 36
5
10
15
1
0
2
3
*Not FDA-approved dose.Ettinger B, et al. JAMA. 1999;282(7):637-645.
Effect of Raloxifene on Breast Cancer Incidence MORE Trial - 4 Years
Years since RandomizationTotal Cases = 77
Arrow denotes annual mammogram
Cauley J, et al. Breast Cancer Res Treatment. 2001;65:125-134
% o
f Ran
dom
ize
d P
atie
nts
Raloxifene
0.0
2.0
0 1 2 3 4 5
PlaceboRR = 0.38 (95% CI = 0.24-0.58)*
1.0
1.5
0.5
*P < .001
Which Bisphosphonate is Best?
We don’t know
Real-World Persistence to Daily and Weekly Bisphosphonate Therapies
Data from Downey TW, et al. South Med J. 2006;99:570-575.
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7 8 9 10 11 12
Months of Continuous Persistence
DailyWeekly
% o
f Pat
ient
s
P = NS
Oral Bisphosphonates
Alendronate- Weekly Risedronate- Weekly, monthly Ibandronate- Monthly
I.V. Bisphosphonates: Potential Clinical Usage
Oral bisphosphonate intolerance
Contraindications to oral bisphosphonates
Dysphagia, severe GERD,
Bed-ridden patients
Assure compliance where there is evidence for non-compliance
I.V. Bisphosphonates
Ibandronate- 3 mg Q 3 months Zoledronic acid- 5 mg once yearly
• I.V. Route of administration- bypasses GI tract- assures compliance
Continued Increases in BMD in Women With Postmenopausal Osteoporosis
Following 2 Years of IV Ibandronate: Dosing Intravenous Administration Study (DIVA)
Lane N, Genant HK, Barr CE, Lewiecki EM, Maricic M
Presented at the American College of Rheumatology. 11/06
Objectives
Assess the efficacy of IV ibandronate 3 mg quarterly versus 2.5 mg PO daily in terms of relative (%) change from baseline in Bone Mineral Density at 1 and 2 years
Assess the change from baseline in serum CTX (marker of bone resorption)
Assess safety
DIVA StudyDIVA Study
Lane N, et al. ACR 11/06
DIVA: Year 2 BMDPercent Change from Baseline
3.1*2.2
3.5
4.9*
6.3*
4.8
Total Hip Femoral Neck TrochanterLumbar Spine
Mea
n %
Cha
nge
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
2.82.2
2.5 mg Daily PO (n=330) 3 mg Quarterly IV (n=333)
Quarterly IV dosing regimen had a significantly greater effect on mean BMD at Year 2 than the PO dosing regimen, PP population *P<0.0001
Lane N, et al. ACR 11/06
Safety Parameters: DIVA study
Acute Phase Reaction (APR)• Occurred in 10% of patients receiving 3 mg IV
quarterly• Generally transient and mild to moderate in
intensity • Most cases occurred in the first year only
Others• Changes in serum creatinine were not
significant• Osteonecrosis of the jaw was not reported
Lane N, et al. ACR 11/06
Zoledronic AcidHORIZON Pivotal Fracture Trial
Randomized, double-blind, placebo-controlled, multinational study of the efficacy and safety of Zoledronic acid for the treatment of postmenopausal osteoporosis• 7736 osteoporotic women aged 65-89 years• Zoledronic acid administered once a year for 3
consecutive years, as a single 5 mg dose, for a total of 3 doses
Two primary efficacy variables• Incidence of hip fractures over a median duration
of 3 years• Incidence of morphometric vertebral fractures at
3 years
Key secondary efficacy variables• Incidence of clinical fractures over 3 years• Incidence of non-vertebral fractures over 3 years• Percentage change in BMD at lumbar spine,
femoral neck, and total hip at 3 years
HORIZON Pivotal Fracture TrialHORIZON Pivotal Fracture Trial
Black DM, et al. N Engl J Med. 2007;356:1809-1822.
HORIZON Pivotal Fracture Trial: Effect on Vertebral Fractures
0–1 years 0–2 years 0–3 years
3.7%
1.5%
7.7%
2.2%
10.9%
3.3%
% P
ati
ents
Wit
h N
ew
V
ert
ebra
l Fr
act
ure
*P < .001RRR = Relative risk reduction
0
5
10
15
ZA 5 mgPlacebo
RRR 60%*
RRR 71%* RRR 70%*
Proportion of Patients WithNew Morphometric Vertebral Fractures
Black DM, et al. N Engl J Med. 2007;356:1809-1822.
1
2
3
0
Placebo (n = 3861) ZA (n = 3875)
Time to First Hip Fracture (months)
0 3 6 9 12 15 18 21 24 27 30 33 36
Cu
mu
lati
ve I
ncid
en
ce (
%)
HORIZON Pivotal Fracture Trial: Effect on Hip Fractures Over 3 Years
HORIZON Pivotal Fracture Trial: Effect on Hip Fractures Over 3 Years
RRR41%
Stratified log-rank test P-value = .0024
Cumulative Incidence of Hip Fractures Over 3 Years
Black DM, et al. N Engl J Med. 2007;356:1809-1822.
*Excluding finger, toe and facial fractures†Includes clinical thoracic and clinical lumbar vertebral fractures‡Excluding finger, toe, facial, and clinical thoracic and lumbar vertebral fractures
HORIZON Pivotal Fracture Trial: Effects on All Clinical Fractures Over 3 Years
HORIZON Pivotal Fracture Trial: Effects on All Clinical Fractures Over 3 Years
8.4%
12.8%
2.6%
0.5%
10.7%
8.0%
RRR 33%
RRR 77%
RRR 25%
Even
t R
ate
(%
)
0
2
4
6
8
10
12
14
Any ClinicalFracture*
ClinicalVertebralFracture†
Non-VertebralFracture‡
ZA 5 mg(n = 3875)
Placebo(n = 3861)
Black DM, et al. N Engl J Med. 2007;356:1809-1822.
Adverse Reactions
Total SAEs were similar between groups (29.2% zoledronic acid vs 30.1% placebo)
The most common adverse events were post dose symptoms• Majority occur within 3 days after dosing • Usually resolves within 3 days
7%7%8%
9%
18%
02468
101214161820
Fever Myalgia Flu-LikeSymptoms
Headache Arthralgia
Inci
dence
rate
(%
)
Zoledronic Acid: Hypocalcemia
• All women received 1,000 to 1,500 mg calcium plus 400 to 1,200 IU vitamin D per day
• Following zoledronic acid administration, ~0.2% of patients had notable declines in serum calcium levels (less than 7.5 mg/dL)
• No symptomatic cases of hypocalcemia
Black DM, et al. N Engl J Med. 2007;356:1809-1822.
Zoledronic Acid: Atrial Fibrillation
• Overall incidence of atrial fibrillation AEs was 2.5% of zoledronic acid patients vs 1.9% in placebo patients
• Adjudicated Serious Adverse Events of atrial fibrillation (requiring hospitalization) occurred in 1.3% of patients compared to 0.4% in the placebo group
• Over 90% of these events in both groups occurred more than a month after the infusion
Black DM, et al. N Engl J Med. 2007;356:1809-1822.
Zoledronic Acid: Renal Safety
Not recommended for use in patients with severe renal impairment (creatinine clearance <35 mL/min)
Monitor serum creatinine before each dose. Transient increase in serum creatinine may be greater in patients with impaired renal function; consider interim monitoring of serum creatinine in at-risk patients
1. Black DM, et al. N Engl J Med. 2007;356:1809-1822.2. . Miller P, et al. Poster presented at: 7th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; March 28-31, 2007; Porto, Portugal. Poster P308.
Mean
(±
SE)
Ch
an
ge F
rom
B
aselin
e in
Calc
ula
ted
C
reati
nin
e C
leara
nce (
mL/m
in)
Reclast (n = 3862)
Placebo (n = 3852)
0 12 24 36
–15
–10
–5
0
Months
Changes in Calculated Creatinine Clearance* From
Baseline Over Time3
*Cockcroft-Gault equation
Zoledronic Acid: Osteonecrosis of the Jaw
In the HORIZON Pivotal Fracture Trial, out of 7736 patients, symptoms consistent with ONJ occurred in • 1 patient treated with placebo and • 1 patient treated with zoledronic acid over 3
years Both cases resolved after appropriate treatment
Black DM, et al. N Engl J Med. 2007;356:1809-1822.
Osteonecrosis of the Jaw (ONJ): Definition
A confirmed case of bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a health care provider• in a patient who was receiving or had been
exposed to a bisphosphonate
J Bone Miner Res. 2007 Oct;22(10):1479-91.
Challenges of Studying ONJ
ONJ rare event• Difficult to get background rates in general
population• Difficulty in identifying cases with ONJ in
databases- no unified definition The incidence of ONJ in the general population
not exposed to bisphosphonates is unknown Although this association is consistent with a
role for bisphosphonates, bisphosphonates have not been proven to be causal.
J Bone Miner Res. 2007 Oct;22(10):1479-91.
Case Reports: ONJ in Osteoporosis
Most cases have been described in cancer patients receiving monthly IV bisphosphonates
As of Oct. 2007, 57 cases have been associated with oral bisphosphonate treatment for osteoporosis after duplicated case reports had been excluded.
J Bone Miner Res. 2007 Oct;22(10):1479-91.
Recommendations
Patients taking bisphosphonates should be encouraged to maintain good oral hygiene, and to have regular dental visits
They should be urged to report any oral problems to their dentist and physician
It is not necessary to recommend a dental examination before beginning oral bisphosphonate therapy or to otherwise alter routine dental management.
J Bone Miner Res. 2007 Oct;22(10):1479-91.
Recommendations
Patients should be informed that the risk of developing bisphosphonate-associated ONJ with routine oral therapy for osteoporosis appears to be low, ranging between 1/100,000 and 1/250,000
This risk should be balanced with the risk of osteoporotic fractures in that patient
J Bone Miner Res. 2007 Oct;22(10):1479-91.
Teriparatide PTH (1-34): Indications
Postmenopausal women or men with osteoporosis at high risk of fracture
“High-risk” includes:• Men and women with previous osteoporotic
fracture(s)• Men and women with multiple risk factors
for fracture• Those who have failed or are intolerant to
other osteoporosis therapies
US food and drug administration. FDA talk paper. November 26, 2002
Effect of Teriparatide (rhPTH(1-34)) on the Risk of New Vertebral Fractures
*p <0.001 vs. Placebo
Ris
k R
edu
ctio
n (
RR
)
Placebo(n=448)
rhPTH 20(n=444)
rhPTH 40(n=434)
64 22 19100%
75%
50%
0%
25%
% o
f Wo
men
8
0
246
101214
RR 0.31 (95% CI, 0.19 to 0.50)*
RR 0.35 (95% CI, 0.22 to 0.55)*
65% 69%
Neer RM, et al. N Engl J Med. 2001;344(19):1434-1441.
Effect of rhPTH(1-34) on the Risk of Nonvertebral Fragility Fractures
* p = 0.02 vs. Placebo** p = 0.01 vs. Placebo
0
1
2
3
4
5
6
7
Placebo rhPTH 20 rhPTH 40
% o
f W
om
en
30 14 14
53% 54%
(n=544) (n=552)(n=541)
No. of women who had > 1 fragility fracture
RR 0.46 (95% CI, 0.25 to 0.86)**
RR 0.47 (95% CI, 0.25 to 0.88)*
Teriparatide PTH (1-34): Adverse Effects
Side effects are usually mild and may include nausea, leg cramps or dizziness
Use currently limited to 2 years PTH trials were stopped early due to the finding of
osteosarcoma in animal studies FDA assigned a black box warning because of
osteosarcoma findings in animal studies.
US Food and Drug Administration. FDA. Talk Paper. November 26, 2002.
Teriparatide PTH (1-34): Warnings Hypercalcemia Paget's disease of bone Growing children and young adults Pregnant or nursing women A history of bone cancer A history of cancer that has metastasized to
the bones Radiation to the skeleton from any condition
US food and drug administration. FDA talk papers. November 26, 2002
Other Issues with Teriparatide
Cost How to combine/sequence it
with bisphosphonates
*With appropriate calcium and vitamin D.
PREVENTION
• Estrogen
• Raloxifene
• Alendronate
• Risedronate
• Ibandronate
TREATMENT
•Salmon Calcitonin
• Raloxifene
• Alendronate
• Risedronate
• Ibandronate
• Zoledronic acid
•Teriparatide (rhPTH)
FDA-Approved Therapies for Postmenopausal Osteoporosis
Post-Test Questions
?
Clinical Practice Recommendation Practice Recommendation:
All postmenopausal women should be evaluated for risk factors of osteoporosis which include increasing age, white race, low weight or weight loss, nonuse of estrogen replacement, history of previous fracture, family history of fracture, history of falls, and low scores on one or more measures of physical activity or function.
Evidence-Based Source:
AHRQ
Web Site of Supporting Evidence:
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1.chapter.39885
Strength of Evidence: A systematic review of 530 articles about risk factors, 123 about bone measurement tests, 23 about bone density monitoring, 277 about biochemical markers, and 53 about costs. An additional 242 studies were retrieved after reviewing reference lists of studies and by suggestion of the expert panel or leading researchers in the field
Clinical Practice Recommendation
Practice Recommendation:
Bisphosphonates (alendronate, etidronate, and risedronate) are recommended as treatment options for the secondary prevention of osteoporotic fragility fractures
Evidence-Based Source:
National Guideline Clearinghouse Web Site of Supporting Evidence:
http://www.guideline.gov/summary/summary.aspx?doc_id=3862
Strength of Evidence: The recommendations are based primarily on the available
evidence from randomized controlled trials.
top related