Update on Diagnosis and Treatment of Osteoporosis

Update on Diagnosis and
Treatment of Osteoporosis
Sophia Ish-Shalom
Bone and Mineral
Metabolism Unit
Rambam Health
Care Campus
Outline
• Assessment of fracture risk
• Differential diagnosis: Osteoporosis vs. Osteomalacia
• Vitamin D Dosage and administration
• Glucocorticoid induced osteoporosis
• Treatment of osteoporosis
– Antiresorbing
– Novel therapies( strontium ranelate, denosumab)
– Anabolic treatment
– Treatment of GIOP
– Rare complications of treatment Atypical fractures
and ONJ)
‫תיאור מקרה‬
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‫אישה בת ‪ 77‬ילידת פולין‪ ,‬נ‪ ,3+‬פרופ' בפנסיה‬
‫באוניברסיטה‪ ,‬עדיין עובדת‪ .‬כעת עורכת ספר בתחום‬
‫בלשנות‪ .‬מבלה שעות רבות ליד מחשב‪.‬‬
‫סבלה לפני ‪ 4‬חודשים מתמט ב‪ ,L4 -‬לאחר שהחליקה‬
‫בחדר אמבטיה‪.‬‬
‫צפיפות עצם בע"ש – ( ‪ T SCORE ( -1.2‬וצוואר הירך‪-‬‬
‫)‪T SCORE ( -2‬‬
‫בדיקת צפיפות עצם בוצעה מספר פעמים‪ ,‬מגיל ‪ ,60‬אך‬
‫נאמר לה שמצבה אינו מצריך טיפול תרופתי מלבד‬
‫‪ 1 CALCIUM + D‬ביום‪ ,‬בגלל צריכת סידן בלתי מספקת‬
‫בתזונה‪.‬‬
‫צפיפות עצם בע"ש עלתה תוך טיפול זה‪.‬‬
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‫יתר לחץ דם וסוכרת מאוזנת ב‪. GLUCOPHAGE -‬‬
‫היפרליפידמיה מטופלת ב‪ 20 Simvastatin -‬מג'‪/‬יום‪.‬‬
‫יתר לחץ דם מטפל ב‪ENALADEX -‬‬
‫מזה שנה סובלת מכאב לאורך הירכיים בהליכה‪,‬‬
‫תחושה של חוסר יציבות בהליכה‪ ,‬נפלה ‪ 3‬פעמים‬
‫בשנה האחרונה‪.‬‬
‫לפני שנתיים‪ ,‬סבלה מכאב גב לאחר ש"נחתה"‬
‫בחוזקה למושב באוטובוס בעת נסיעה‪ ,‬הייתה‬
‫מרותקת לבית במשך ‪ 3‬שבועות‪ .‬הכאב הוקל‬
‫בהדרגה אך עדיין קיים ומתגבר לאחר עמידה‬
‫ממושכת‪.‬‬
‫אמה נפטרה בגיל ‪ 78‬לאחר שבר צוואר הירך‪.‬‬
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‫לאחר בצוע צילום ע"ש בו נצפו ‪ 2‬תמטים בחוליות‪ ,‬אחד‬
‫חדש‪ L4 -‬ואחר ישן ‪ D12-‬נבדקה רמת ‪11 - 25OHD‬‬
‫נג‪/‬מל ( ‪ 27.5‬נמול‪/‬ל)‬
‫לאחר ‪ 3‬חודשי טיפול בוויטמין ‪ 4000 D‬יחב"ל ביום הרמה‬
‫תקינה‪ ,‬במקביל חשה הקלה בכאב בירכיים בהליכה‬
‫החולה אינה מעוניינת בהוספת תרופות היות ולדבריה וגם‬
‫כך נוטלת מספיק‬
‫שוכנע לקחת ‪ 150 ACTONEL‬מג'‪/‬חודש‬
‫לאחר ‪ 3‬חודשים מסרה על כאבי שרירים‪ ,‬כאב‬
‫באפיגסטריום וצרבת‬
‫הוחל טיפול ב‪ OMEPRADEX -‬עם הקלה בתסמינים‬
‫גסטרואינטסטינליים אך כאבי שרירים ללא שינוי‬
‫מה ההצעה להמשך טיפול?‬
Osteoporosis - Definition
Osteoporosis is a systemic skeletal disease characterized by
a low bone mass and/or microarchitectural deterioration of
bone tissue leading to increased bone fragility and increased
fracture risk.
Prevention and Management of Osteoporosis: report of a WHO scientific group.
http://whqlibdoc.who.int/trs/ WHO_TRS_921.pdf December 2, 2008.
Implications of Osteoporotic Fractures
• In 2000 - nine million osteoporotic fractures
worldwide; 1 in 5 of these were hip fractures
• Osteoporotic fractures:
•  mortality
•  quality of life
•  direct and indirect costs
• Approach to reduce the burden of fractures:
• Primary prevention = to identify men and women
at high risk and intervene before the fracture
occurs). BMD T score -2.5?
• Most fragility fractures occur among patients who
have a BMD T-score in the osteopenic range.
Dawson-Hughes B et al. Osteoporos Int. 2010 21(1):41-52
Fractures are Associated with a
Significant Increase in Mortality
Dubbo Study: women 2245; Men 1769; age ≥60
Higher fracture incidence in women
Nb fractures over 5 years
300
283
Higher mortality in fractured patients
Fractures
Men
Deaths
Women
250
200
Hip
Women 32/1000 ps. years
Men 17/1000 ps. years
183
154
150
Spine
133
100
107
118
77
50
69
63
65
50
37
Other major
fractures
0
Hip
Vert. Major*
Women
Hip
Vert. Major*
0
Men
*Includes pelvic, distal femur, proximal tibia, multiple rib, and
proximal humerus.
Bliuc D., et al. JAMA 2009; 301(5): 513-521
†Ratio
1
2
3
Standardised Mortality Ratio†
4
of observed to expected deaths, by gender and
fracture type.
Estimated Age-Standardized Distribution of
Incident Low-Trauma Fractures by Risk Category
(BMD and prior fracture) for men and women 50–
7448 partic
90 yr of age.
Age 50-90.
Osteoporosis - 21% of # in men and 39% in women; L. Langsetmo et
Osteopenia - 54% of # in men and 51% in women
al, JBMR 2009
Incidence of First and Repeat Low-Trauma
Fracture in Men and Women by Age Group
•  in osteoporotic fractures - 60–70% per decade and similar for first and
repeat fractures
• the incidence of repeat fractures was at least double the incidence of first
fractures.
L. Langsetmo et al, JBMR 2009
Grading Scheme for a Semiquantitative Assessment of
Vertebral Deformities after Genant
0 no deformity
1  20-25% vertebral height
 10-20% projected area
2  25- 40% vertebral height
 20%- 40% projected area
3  40% vertebral height
 40% projected area
Genant HK et al.. J Bone Miner Res 1993;8:1137 –1148
Incidence of First and Repeat Low-Trauma Fracture in
Men and Women by Vertebral Deformity Status.
• The incidence of first and repeat fracture was = among men with grade 1 VD
• In all other subgroups, the incidence of repeat fracture was x3 – x4 than the
incidence of first fracture
L. Langsetmo et al, JBMR 2009
Diagnosis of Osteoporosis
DXA:
Dual-energy
X-ray
Absorptiometry
Quantifiable
Risk Factor not a
Disease
Definition of Osteoporosis in Women
According to WHO (diagnostic criteria)
Definition
BMD T score
Strategy
Normal
≥ -1 SD
Prevention
Osteopenia
-1 SD < -2.5
Osteoporosis
≤ -2.5
Prevention/
Treatment
(FRAX)
Treatment
Severe
Osteoporosis
Osteoporosis with Treatment
fractures
Fracture Risk Calculator FRAX
Secondary Osteoporosis in Frax
• Enter yes if the patient has a disorder strongly
associated with osteoporosis:
• type I (insulin dependent) diabetes
• osteogenesis imperfecta in adults.
• untreated long-standing hyperthyroidism
• hypogonadism or premature menopause (<45)
• chronic malnutrition
• chronic malabsorption
• chronic liver disease
‫‪ FRAX‬אבחון ‪ ,‬מעקב ומעבר מטיפול לטיפול‬
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‫‪ FRAX‬משמש להערכת סיכון אבסולטי לשברים לעשור הקרוב‪,‬‬
‫בחולה לפני טיפול‬
‫אינו מתאים להערכת סיכון בחולים שנוטלים טיפול‬
‫בפועל‪ ,‬אין לנו כלים להערכת תגובה או הצלחה טיפולית‪:‬‬
‫בדיקת צפיפות עצם אינה רגישה מספיק ברמה של נבדק בודד‬
‫בגלל שגיאת המדידה של המכשור‪ ,‬שלרוב עולה על ההבדל המושג‬
‫על ידי הטיפול‬
‫שברים לא בהכרח מעידים על כשלון טיפולי היות ואף טיפול אינו‬
‫מונע שברים ב‪ ,100% -‬אך יחד עם זאת היות ושבר מצביע על‬
‫תוצא טיפולית בלתי מספקת הוא מהווה התוויה למעבר לטיפול‬
‫אנבולי בחולים שקבלו טיפול נוגד פרוק במשך שנה אחת לפחות‪.‬‬
‫הטיפול האנבולי היחיד אשר רשום בישראל הנו ‪FORTEO‬‬
Excessive Remodelling Contributes
to Osteoporosis
Increased bone
remodelling
Structural
deterioration
Images courtesy of David W. Dempster, PhD.
Increased
skeletal fragility
Increased
fracture risk
Lips P et al, Primer on the Metabolic Bone Diseases and Mineral Metabolism 7th edition, 2008,329-334
Vitamin D Metabolism
290 – 315 nm
Food: Salmon, Mackerel
Cod liver oil, Yeasts,
Plants, Fortified Foods
SKIN
Prostate, Placenta
Breast; Colon
Osteoblasts
Keratynocytes
Immune cells
1,25(OH)2D3
Regulation
of cell
growth
(cancer
prevention)
Regulation
ofRegulation
immune
of immune
function
function
PH Anderson et al. Clin Biochem Rev. 2003 February; 24(1): 13–26
7 dehydrocholesterol
Major circulating
metabolite
used to determine
vitamin D status
Bone Effects of Vitamin D Deficiency
• Ca X P insufficient insufficient mineralization
• Osteoblasts continue bone deposition
• Endoosteal surface
• Periosteal surface
Rubbery matrix with
insufficient support
• Matrix hydrates and expands under periosteal
covering  outward pressure on periosteal
covering innervated with sensory nerves
Lips P et al, Primer on the Metabolic Bone Diseases and Mineral Metabolism 7th edition, 2008,329-334
‫ספיגת הסידן במעי‬
1,25(OH)2D
‫חלל המעי‬
TRPV 6
TRPV 5
‫ < של סידן שנצרך בתזונה‬10% – 15%
Ca++
‫ מהזרחן שנצרך בתזונה‬60% ‫עד‬
‫ נספגים‬D ‫ויטמין‬
‫במצב של ספיקה תקינה של‬
Transcellular
transport
saturation at 400
25(OH)D80%
D3
31,25(OH)
‫מהסידן‬
‫ עד‬230%
mg/day
‫ מהזרחן‬80% ‫ עד‬70%
Paracellular transport
1,25(OH)2D
•
•
ATP
VDR ADP
PMCA
‫ נספגים‬D
‫ויטמין‬
‫בחסר‬
++
Ca
++
Ca
calbindin
30 mg per 100 mg of
ingested calcium
Lips P et al, Primer on the Metabolic Bone Diseases and Mineral Metabolism 7th edition, 2008,329-334
Lips P et al, Primer on the Metabolic Bone Diseases and Mineral Metabolism 7th edition, 2008,329-334
A High Prevalence of Vitamin D Inadequacy*
Was Seen Across All Geographic Regions
In a cross-sectional, international study in postmenopausal women with
osteoporosis
90
81.8%
N=2589
80
Prevalence (%)
Risk factors for vitamin D inadequacy :
70
71.4%
63.9%
60.3%
57.7%
2
53.4% kg/m (odds ratio, 2.4 [ 1.83, 3.14])
• body60mass index >30
50
• living40in a nonequatorial climate (1.91 [1.58, 2.32])
30
• possessing
fair to poor health (1.86 [1.49, 2.33])
20
10
• no recent
travel to sunny areas (1.86 [1.54, 2.25])
0
All
Latin
America
Europe
Middle
East
Asia
Australia
• vitamin D supplementation <400 IU/day (1.78 [1.41, 2.24])
Regions
• no vitamin D supplementation
(2.36 [1.97, 2.82]).
*Vitamin D inadequacy was defined as serum 25(OH)D <30 ng/mL.
Study Design: Cross-sectional, international study of 2589 community-dwelling women with osteoporosis from 18 countries to evaluate
serum 25(OH)D distribution
Adapted from Lips P et al. J Intern Med. 2006 Sep;260(3):245-54.
Adherence to vitamin D Treatment
3 Month after Hospital Discharge
29 (24%)
93 (76%)
non-adherent
adherent
E. Segal et al. JAGS, 2004; 52: 474-475(2)
‫מטאנליזה – מניעת‬
‫שברים ונפילות‬
‫• אנשים בני ‪+65‬‬
‫• ‪ 12‬מחקים מבוקרים כפולי‬
‫סמיות –שברים בגפיים‬
‫• ‪ 8‬מחקרים – שבר צוואר‬
‫הירך‬
‫• ‪ 40,886‬משתתפים‬
‫• במינונים מעל ‪ 700‬יחב"ל‬
‫• ‪ ‬בהיארעות שברים ב‪-‬‬
‫‪ 29%‬בקרב המתגוררים‬
‫בקהילה‬
‫• ‪ ‬בהיארעות שברים ב‪-‬‬
‫‪ 15%‬בקרב דיירי מוסדות‬
‫• נפילות‪ 8 :‬מחקרים ‪2426‬‬
‫משתתפים ‪ ‬ב‪19% -‬‬
‫‪H. A. Bischoff-Ferrari et al 2009 , Arch Intern Med 169(6):551-61‬‬
Definition of Vitamin D Status for
Multiple Health Outcomes
Vitamin D Status 25(OH)D ng/ml x 2.5= nmol/l
10
 25
Insufficiency
10 – 15
25 – 37.5
RDA 50-70years 600 IU/day
Normal
RDA >70 years 800 IU/day >15
Upper limit
4000 IU/day >37.5
Deficiency
20
50
20 - 30
50 - 75
> 30
>75
Holick
2007
Parfitt,
1970
Recommended target valueMfor
25OHD≥
20ng/ml M.
(75
nmol/l)
Glucocorticoid Induced Osteoporosis
• Osteoporosis has been reported to occur in up to
50% of patients who require long-term therapy.
• Fractures can occur soon after treatment initiation,
with a predilection for sites that are rich in trabecular
bone: spine, ribs, proximal humerus, distal radius
and hip
• Patients receiving glucocorticoids fracture bones at
thresholds of BMD that are > those seen in
postmenopausal osteoporosis, the fracture risk in
patients receiving glucocorticoids  X2 when T
scores fall below –1.5.
Arthritis Care & Research; 62;11, 2010, 1515–1526 © 2010, American College of Rheumatology
Variability of Skeletal Response to
Glucocrticoid Treatment
• A 40 years old woman with sarcoidosis of the heart, treated
with glucocorticoids for 20 years, lowest prednisone dose 15
mg/day – normal BMD, never fractured, treated with calcium
and vitamin D supplements
• A 52 years old woman, X-ray technician, 1 year after
menopause, treated with glucocorticoids for dermatomyositis
for 3 months, prednisone 6020 mg/day and calcium and
vitamin D supplements, symptomatic fractures of D12, L1, L3.
6 months later , symptomatic fractures of L2, L4 and further
compression of D12, L1, Teriparatide ( Forteo) treatment for
18 months no additional fractures till present
Clinical Factors that may Shift an Individual to
a Greater Risk Category for Glucocortcoid-Induced
Osteoporosis
•
•
•
•
•
•
•
•
•
•
Age 
Menstrual status: postmenopausal risk > premenopausal
Low BMI (body mass index)
Parental history of hip fracture
Current smoking
3 alcoholic drinks per day
Higher daily glucocorticoid dose
Higher cumulative glucocorticoid dose
Intravenous pulse glucocorticoid usage
Declining central bone mineral density measurement that
exceeds the least significant change
Arthritis Care & Research; 62;11, 2010, 1515–1526 © 2010, American College of Rheumatology
09ca121
Treatment
8 out of 10 women do not receive treatment
during the first year after fracture
Brown SA, Rosen CJ. Med Clin North Am 2003;87;1039-1063
‫נשים ‪ -‬פרויקט למניעת שבר נוסף ברמב"ם‬
‫‪450‬‬
‫‪385‬‬
‫‪400‬‬
‫‪350‬‬
‫‪300‬‬
‫‪250‬‬
‫‪200‬‬
‫‪25%‬‬
‫(‪95‬‬
‫מטופלות)‬
‫‪150‬‬
‫‪21%‬‬
‫(‪81‬מטופלות)‬
‫‪100‬‬
‫‪50‬‬
‫‪0‬‬
‫מטופלות אחרי שבר מטופלות לפני שבר מספר נשים בפרויקט‬
‫גברים ‪ -‬פרויקט למניעת שבר נוסף ברמב"ם‬
‫‪180‬‬
‫‪160‬‬
‫‪162‬‬
‫‪140‬‬
‫‪120‬‬
‫‪100‬‬
‫‪80‬‬
‫‪60‬‬
‫‪17( 10.5%‬‬
‫מטופלים )‬
‫‪1.2%‬‬
‫(‪ 2‬מטופלים )‬
‫‪40‬‬
‫‪20‬‬
‫‪0‬‬
‫מטופלים אחרי שבר מטופלים לפני שבר מספר גברים בפרויקט‬
Antiresorbing Agents
Fracture Risk Reduction
Fracture Site
HT
Evista
Calcitonin
LS
+
+
+
Proximal
Femur
+
Non
Vertebral
Bisphosphonates Pharmacokinetics
Food interferes
with absorption
Fast uptake into bone; 20-80%
PLASMA
Intestinal
Absorption is
low; 0.5-1%
OH R1 OH
O = P—C —P = O
OH R2 OH
Slow release from
bone
No biliary
secretion
Urine is main route of
elimination.
No metabolites
Bisphosphonates Use in Osteoporosis
Fracture Site
Bisphosph.
Fracture Risk and Mortality Reduction
70 – 25% risk reduction
Zoledronate
Aclasta
Alendronate
Fosalan
Fosavance (D)
Risedronate
Actonel
Zoledronate (Aclasta) 28%  in all cause
Vertebral
++ patients++
mortality++
in hip fracture
Proximal
Femur
++
++
+
Non
Vertebral
++
++
++
Common )≥5% in ZOL) Post-Dose Symptoms
Occurring within 3 Days after Infusion
Pyrexia
16
Placebo values cross-hatched
15%
Incidence (%)
14
12
Myalgia
10
Flu-like illness
8%
8
7%
6%
6
4
2%
2
0
2%
1%
1
2
3
2%
1%
1
2
3
1
Headache
2
3
5%
2%
1%
1
Arthralgia
2
2%
1%
3
1%
1
2
3
Annual Infusion
Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, et al. N Eng J Med 2007; 356:1809
Why Consider Adherence?
Patients (%) with > 80% adherence in first year of therapy
100
80
Adherence to current
osteoporosis therapies
is low
72.3%
65.4%
60
54.6%
51.2%
40
20
0
Hypertension
Type 2
Diabetes
Hyper
cholesterolemia
Osteoporosis
Lekkerkerker et al, Osteoporos Int 2007;8(10):1311–7
Briesacher at al. Pharmacotherapy 2008;28(4):437–443
Poor Adherence is Associated with
Increased Fracture Risk
low
Fracture Risk by Adherence Level
high
p < 0.0001
Increased Risk of Fracture
p = 0.0002
1.4
1.2
p = 0.12
1.09
1.18
1.21
50 to <80%
<50%
1
1.0
0.8
0.6
0.4
0.2
0.0
>90%
80 to 90%
high
Huybrechts KF, et al. Bone. 2006;38:922-928.
Adherence Level
low
Data from 38,000 women in a managed care database
Strontium Renalate Consists of Two Atoms of Stable
Strontium and an Organic Moiety (Ranelic Acid)
•
•
•
•
•
•
•
•
Alkaline earth divalent cation
Trace element in the human body
0.00044% of the body mass
Atomic weight of 87.6 > x2 calcium (40.07)
Normal diet 2-4 mg of Sr/day vegetables /cereals
Sr competes with Ca for intestinal absorption ratio 0.6-0.7
In bone Sr in mainly absorbed onto the crystal surface
Therapeutic dose 2 gr/day = 8 mmol Sr ; 8mml Ca = 320 mg
40
Effect of Strontium Ranelate on BMD and
Bone Turnover
• BMD -  from baseline by 12.7% at the lumbar
spine, 7.2% at the femoral neck, and 8.6% at the
total hip.
• BMD adjusted for strontium content  by 6.8%
the lumbar spine after 3 yr compared with a  of
1.3% in the placebo
• Bone-specific alkaline phosphatase  8%
• Serum type 1 collagen C-telopeptide cross-links
(CTX)  by 12%
Strontium and vertebral fractures
►SOTI (Spinal
osteoporosis
therapeutic
intervention) –
41%  in
Vertebral
fractures
42
Mounier et al. NEJM 2004;350:459-68
TROPOS – Treatment of Peripheral
Osteoporosis (5091 pt)
43
►Nonvertebral fractures 
16% (p=0.04)
►Hip fractures  – 15%
reduction – NS
►Major non vertebral OP
fractures 19% p=0.031
►Hip fractures in high risk
group – age above 74,
femoral T < -2.4
NHANES, -  36%,
p=0.046
Safety of Strontium Ranelate
• During clinical trials, the most common side effects were
nausea and diarrhea (-7% versus 5% in the placebo group
over 5 yr), headache, and skin irritation
• By pooling SOTI and TROPOS trial data, a significant  in
the risk of venous-thrombosis embolism event was found
(relative risk: 1.42; p = 0.036). However, no coagulation
abnormality has been detected in relation with strontium
ranelate treatment.
• Recently, a few cases of DRESS syndrome Drug Reaction
with Eosinophilia and Systemic Symptoms – severe form of
adverse drug reaction is a severe, acute drug reaction: fever,
skin eruptions and systemic symptoms, including enlarged
lymph nodes, abnormal liver function, renal impairment, and
pulmonary and cardiac infiltrates, as well as haematological
abnormalities, primarily hypereosinophilia and lymphocytosis)
Le Merlouette et al, Ann Dermatol Venerol,2011 138(2):124-8
RANK Ligand Is an Essential Mediator of
Osteoclast Formation, Function, and Survival
RANKL
Prefusion
Osteoclast
CFU-GM
RANK
Multinucleated
Osteoclast
Hormones
Growth factors
Cytokines
Osteoblasts
Activated
Osteoclast
Bone Formation
Bone Resorption
Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.
© 2009 Amgen. All rights reserved.
Do not copy or distribute.
OPG Is a Decoy Receptor That Prevents RANK
Ligand Binding to RANK and Inhibits Osteoclast
Formation, Function, and Survival
CFU-GM
Pre-Fusion
Osteoclast
RANKL
Formation
inhibited
RANK
OPG
Hormones
Growth factors
Cytokines
Osteoblasts
Function and Survival
inhibited
Bone Formation
Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
Bone Resorption IS INHIBITED
Denosumab and Mechanism of Action
CFU-GM
Pre-Fusion
Osteoclast
RANKL
RANK
OPG
Denosumab
Hormones
Growth factors
Cytokines
Osteoclast Formation, Function,
and Survival Inhibited
Osteoblasts
Bone Formation
CFU-GM=colony forming unit granulocyte macrophage
© 2007 Amgen. All rights reserved.
Bone Resorption
Inhibited
Provided as an educational resource. Do not copy or distribute.
Pharmacologic Properties of
Denosumab
Model of Denosumab
• Fully human monoclonal antibody
(100% human protein)
• IgG2 immunoglobulin isotype
• High affinity for human RANK Ligand
• High specificity for RANK Ligand
– No detectable binding to TNFα,
TNFβ, TRAIL, or CD40L
• No neutralizing antibodies detected in
clinical trials to date
Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.
Data on file, Amgen.
Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149.
McClung MR, et al. New Engl J Med. 2006;354:821-31.
Denosumab and Bisphosphonates
Work Differently
RANK L
BP
RANK
BP BP
OPG
Denosumab
BP
Denosumab
blocks
RANK
Ligand
X
Denosumab blocks osteoclast
formation, function and survival
BP = bisphosphonates
Courtesy of Graham Russell
BP
BP
BP
BP
Bone
BPs bind to
bone mineral at
sites of bone
resorption BPBP BP
BP
BP
Bone
BP
BP
BP
BP
BP
BP
BP
BP
BP
Bone
BPs cause loss of resorptive function
but ‘disabled’ osteoclasts may persist
FREEDOM Study Design
International, multi-center, randomized, double-blind, placebocontrolled study
S
C
R
E
E
N
I
N
G
n = 3902
R
A
Denosumab SC 60 mg Q6M
N = 7808 N
D
O
All subjects received daily
M
calcium (≥ 1 g) and vitamin D
I
(≥ 400 IU) supplementation
Z
A
T n = 3906
I
Placebo
O
N
Study
End
Primary endpoint
New vertebral
fracture over
36 months
Secondary endpoints
Time to first
nonvertebral fracture
Time to first hip
fracture
36 months.
Key Inclusion Criteria:
• Postmenopausal women aged 60 to 90 years
• T-score < -2.5 at the lumbar spine or total hip
and not < -4.0 at either site
Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65
Key Exclusion criteria:
• Any severe or > 2 moderate vertebral fractures
• Conditions that alter bone metabolism
The Effect of Denosumab on Fracture Risks at
36 Months
Phase 3: The FREEDOM Trial
9%
Incidence at Month 36 (%)
8%
7%
68%
P < 0.001
Placebo
Denosumab
20%
P = 0.01
8.0%
7.2%
6.5%
6%
5%
4%
3%
2%
40%
P = 0.04
2.3%
1%
1.2%
0.7%
0%
New Vertebral
Nonvertebral
Hip
Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65
The Effect of Denosumab on New Vertebral
Fractures Year by Year
Phase 3: The FREEDOM Trial
3.5%
Crude Incidence (%)
3.0%
2.5%
2.0%
Placebo
Denosumab
61%
P < 0.001
78%
P < 0.001
3.1%
65%
P < 0.001
3.1%
2.2%
1.5%
1.0%
1.1%
0.9%
0.7%
0.5%
0.0%
Year 1
Year 2
Year 3
Intent-to-treat, last observation carried forward analysis
The percentage of new vertebral fractures was calculated using the number of patients with a baseline and at least one post-baseline spine x-ray evaluation.
Adapted from: Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65.
Cumulative Incidence (%)
The Effect of Denosumab on Time to First Hip
Fracture Through 36 Months
Phase 3: The FREEDOM Trial
Placebo
Denosumab 60 mg Q6M
1.2
1.2%
0.8
0.7%*
0.4
0.0
0
6
12
Number of patients at risk
18
Month
24
30
36
Placebo, n
3,906
3,799
3,672
3,538
3,430
3,311
3,221
Denosumab, n
3,902
3,796
3,676
3,566
3,477
3,397
3,311
Hip fractures were reduced by 40% (95% CI: 0.37, 0.97)
Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65
*P = 0.04
Adverse Events Over 36 Months (continued)
Phase 3: The FREEDOM Trial
Placebo
(n = 3,876)
Denosumab
60 mg Q6M
(n = 3,886)
2,108 (54.4)
2,055 (52.9)
Malignancy
166 (4.3)
187 (4.8)
Injection site reaction
26 (0.7)
33 (0.8)
Clinical hypocalcemia
3 (0.1)
0 (0)
Delayed fracture healing
4 (0.1)
2 (0.05)
Femoral shaft fracture
3 (0.1)
0 (0)
Humerus nonunion fracture
1 (0.03)
0 (0)
0 (0)
0 (0)
Eczema
65 (1.7)
118 (3.0)
Fall*
219 (5.7)
175 (4.5)
Flatulence
53 (1.4)
84 (2.2)
Adverse events, n (%)
Adverse events
Infection
Osteonecrosis of the jaw
Adverse events occurring with  2% incidence and P  0.05
*Excludes falls occurring on the same day as a fracture
Adapted from: Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65.
Human Parathyroid Hormone
1-34 and 1-84
hPTH (1-34)
1
H2 N -Ser
10
Val Ser
Glu
Ile
Gln Leu
Met
His
Asn
Leu
20
Glu
Val
Arg
Gly
Glu
Met Ser
Asn Leu His
Lys
Trp
Leu
Arg Lys
Lys Leu Gln Asp
Val
His
Asn Phe
30
40
50
60
70
hPTH/PTHrP
Receptor
80
-
COOH
hPTH 1-34
Adapted from Proc Natl Acad Sci USA (1974);71:384
Adapted from Jin et al. J Biol Chem (2000);35:27238
(crystal structure)
2004
Therapeutic Effect of PTH in
Osteoporosis
Teriparatide Improves
Skeletal Architecture
Baseline
Patient treated
with teriparatide 20µg
Data from Jiang et al. JBMR 2003 (in press)
Follow up
Female, age 65
Duration of therapy: 637 days (approx 21 mos)
BMD Change:
Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%)
Total Hip:
+5.2% (group mean = 2.6 ± 4.9%)
Jiang UCSF
EFOS: Study design
1645 pt
On Teriparatide Treatment
Observations up to 18 Months
T1
T2
T3
Post-Teriparatide
Follow-up 18 Months
T4
T5
T6
T7
Start
3 months
Baseline
assessment
3 months
6 months
6 months
6 months
Stop
teriparatide
treatment
12 months
Final visit
Teriparatide - EFOS
European Forsteo Observational Study
A 36-month, European, prospective
observational study to evaluate fracture
outcomes, back pain, health-related quality of
life, and compliance in postmenopausal women
with osteoporosis treated with Forsteo.
Back Pain Visual Analogue Scale, mm
EFOS Back Pain VAS (mean ± SD)
57.7 ± 26.6
42.8 ± 25.1
38.2 ± 25.4
34.6 ± 25.7
90
31.6 ± 25.6
*****
80
70
60
50
40
30
20
10
0
Baseline
(n=1627)
3 months
(n=1428)
6 months
(n=1382)
12 months 18 months
(n=1274)
(n=1162)
***** P<0.001 vs. baseline
Langdahl B et al. Calcif Tissue Int. 2009 Dec;85(6):484-93
EFOS On-Study Fracture Rate
Observation
Fractures per
Patients with P-value
Total number
10,000
≥1 on-study vs. 0-6
of fractures
patient-years
fracture
months
0-6 months
(n=1560)
1113
83
72 (4.6%)
-
6-12 months
(n=1302)
768
50
45 (3.5%)
0.036
12-18 months
(n=1200)
583
35
33 (2.8%)
0.004
Total
(n=1577)
821
168
138 (8.8%)*
-
n=number of patients who attended observation
Because some patients experienced a fracture in >1 interval, total column does
not sum the number of patients with fracture each interval
Langdahl B et al. Calcif Tissue Int. 2009 Dec;85(6):484-93
Number of Subjects With New Vertebral and
Nonvertebral Fractures
>1 Radiographic
vertebral*
>1 Clinical
vertebral†
>1 Nonvertebral
>1 Nonvertebral
fragility
Alendronate
(n=169)
n
Teriparatide
(n=173)
n
pvalue
13 (7.7%)
169
3 (1.7%)
173
0.007
4 (2.4%)
169
0
173
0.037
15 (7.0%)
214
16 (7.5%)
214
0.843
5 (2.3%)
214
9 (4.2%)
214
0.256
* Subjects with baseline and post baseline spinal radiographs.
† A clinical vertebral fracture was a new radiographically confirmed fracture that was associated with
symptoms such as back pain
Saag KG et al. Arthritis & Rheumatism 2009; 60: 3346-3355
Locations of Common Hip and Femur
Fractures.
7 – 10% of hip fractures
75 % associated with major trauma
>50% spiral
Mortality rate 25% in 24
months
75% unable to return to the
previous level of function
Atypical Subtrochanteric and Diaphyseal Femoral
Fractures: Report of a Task Force of the American
Society for Bone and Mineral Research
Major and Minor Features of Complete and Incomplete Atypical
Femoral Fractures:
Major:
• location in the subtrochanteric region and femoral shaft
• transverse or short
oblique orientation
• minimal or no
associated trauma
• a medial spike when
the fracture is
complete
• absence of
comminution
A. Shane et al, JBMR Nov 2010
ONJ: Clinical Description
Clinical Features of Suspected ONJ
• Exposed bone in maxillofacial
area that occurs in association
with dental surgery or occurs
spontaneously, with no evidence
of healing*
Working Diagnosis of ONJ
• No evidence of healing after
6 weeks of appropriate evaluation
and dental care
• No evidence of metastatic disease in
the jaw or osteoradionecrosis
*Refer for appropriate dental evaluation and care as soon as possible
‫מה הטיפול המומלץ לחולה זו? חולה בת ‪ 77‬עם תמטים בחוליות‪:‬‬
‫חסרונות‬
‫יתרונות‬
‫טיפול‬
‫‪Evista‬‬
‫‪‬סיכון מאורעות טרומבואמבוליים‪,‬‬
‫אינה ‪ ‬סיכון שברים בגפיים ובצוואר הירך‬
‫נטילה יומית נוחה‪ ,‬אין תופעות ‪GI‬‬
‫בד"כ‪.‬‬
‫תופעות ‪ ,GI‬אומנם פחתו תוך טיפול ב‪-‬‬
‫‪ , OMEPRADEX‬שקשור ב‪ ‬סיכון שברים‪ ,‬יעילות‬
‫ב‪-‬שברי צוואר הירך ב‪post-hoc analysis -‬‬
‫מנה חודשית פומית אחת‪ ,‬נוחות מתן‬
‫‪Actonel‬‬
‫ביספוספונט פומי ‪ ,‬תופעות ‪,GI‬כמו ‪,ACTONEL‬‬
‫מתן שבועי‪ ,‬מקשה על החולה‬
‫יעילות מוכחת במחקרים‬
‫פרוספקטיביים ב‪  -‬שברים בכל אתרי‬
‫השלד‬
‫‪Fosalan‬‬
‫מתן במרפאה המאושרת לטיפול תוך ורידי‪ .‬ב‪-‬‬
‫‪15%‬תסמונת דמוית שפעת לאחר נטילה‬
‫ללא מעבר במערכת העיכול‪ ,‬מתן אחת‬
‫לשנה‪ ,‬יעילות‬
‫‪Aclasta‬‬
‫מתן יומי פומי ‪ 2‬ש' קיבה ריקה‪ ,‬מנגנון פעולה לא‬
‫ברור‪ ,‬סיכון מאורעות טרומבואמבוליים‪,DRESS ,‬‬
‫יעילות מוכחת ב‪ -‬שברים בחוליות‬
‫וגפיים‬
‫‪Protelos‬‬
‫יעילות ב‪-‬שברי צוואר הירך ב‪post-hoc analysis -‬‬
‫יש להקפיד על מתן זריקות במועד‪ ,‬אחת ל‪6-‬‬
‫חודשים‪ ,‬תופעות לוואי –זיהומים עוריים‪.‬‬
‫ללא מעבר במערכת העיכול‪ .‬הזרקה‬
‫תת עורית פעמיים בשנה‪ ,‬יעילות‬
‫מוכחת‪ ,‬ב‪  -‬שברים בכל אתרי השלד‬
‫‪Prolia‬‬
‫תכשיר בקירור‪ ,‬הזרקה יומית עצמית‪ ,‬אינו כלול‬
‫בסל הבריאות כקו ראשון‪ ,‬פרט לניצולי שואה‬
‫תכשיר אנבולי‪ .‬משקם מבנה‬
‫מיקרוסטרוקטורלי‪ ,‬של העצם‬
‫‪Forteo‬‬
‫תו‪D‬‬
‫ה על ההקשבה‬