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Osteoporosis
“Diagnosis dan Treatment”
Apakah Osteoporosis?
• Penyakit tulang yang ditandai dengan menurunnya massa tulang
(kepadatan tulang) secara keseluruhan 1
• 1 dari 4 perempuan di Indonesia dengan rentang usia 50-80 tahun
memiliki resiko terkena osteoporosis 1
• Gejala umum osteoporosis mulai dari patah tulang, tulang punggung yang
semakin membungkuk, menurunnya tinggi badan, dan nyeri punggung1
• Diagnosis osteoporosis berdasarkan pengukuran BMD dan terjadinya
fraktur (WHO Criteria) 2
1. Infodatin, 2015
2. Szule P, et al. IOF-VFI part I,
Tulang Normal vs. Osteoporosis
https://www.bookingdokter.com/article/mengenal-osteoporosis-dan-osteomalasia
Fraktur
Macam-macam fraktur berdasarkan tempat terjadinya
https://pt.slideshare.net/hanialzo3bi/osteoporosis-48772976
Massa tulang
Adapted from NIH ORBD, Bone 2003 (pp1-2)
SIKLUS REMODELING TULANG
Bone Remodeling 3
Biphosponate mechanism4
3. Pelletier, Mediographica 105
4. Muskoloskeletal Key, Management of Osteoporosis
Diagnosis Osteoporosis
• Pemeriksaan Fisis & Riwayat pasien
• Pemeriksaan Radiologi:
• X-ray, MRI, CT-scan
• Penanda Biokemis (Bone marker)
• Bone Mineral Desity (BMD)
https://www.alodokter.com/osteoporosis/diagnosis
Pemeriksaan Fisis & Riwayat Pasien
• Faktor resiko, termasuk informasi tentang fraktur terakhir
• Riwayat keluarga, termasuk osteoporosis
• Riwayat pengobatan, termasuk pengobatan yang menyebabkan
pengurangan massa tulang (mis, glucocorticoid)
• Konsumsi Kalsium dan Vitamin D
• Pola hidup (mis, olahraga, diet tinggi lemak, merokok, dan
penyalahgunaan obat-obatan dan minuman keras)
• Penyakit yang menyebabkan osteoporosis sekunder (Cushing’s
syndrome, thyroid disease, hyperthyroidism, hypogonadism)
https://www.alomedika.com/penyakit/reumatologi/osteoporosis/diagnosis
Faktor Resiko Osteoporosis
• Jenis kelamin: perempuan
• Usia lanjut
• Etnis Kaukasia atau Asia
• Riwayat patah tulang setelah usia 50 tahun
• Riwayat keluarga terkena osteoporosis
• Gaya hidup pasif
• Struktur kerangka kecil
• Patah tulang yang keropos
• Massa tulang Rendah
• Beberapa kondisi medis yang kronis
• Defisiensi Estrogen karena
menopause
• Kadar testosteron yang
rendah pada pria
• Asupan rendah kalsium atau
vitamin D
• Penggunaan obat-obatan
tertentu (misalnya,
kortikosteroid)
• Merokok
• Konsumsi alkohol berlebihan
https://hellosehat.com/muskuloskeletal/osteoporosis/penyebab-osteoporosis/
Bone Mineral Densitometry/BMD
• Untuk menentukan kepadatan tulang
• Saat ini digunakan dual-energi sinar-X
absorptiometry (DEXA)
• Penggunaannya pada pinggul, tulang belakang, pergelangan tangan, tumit,
jari
• Standar emas untuk diagnosis dan memantau efek pengobatan osteoporosis
• Lama pemeriksaan 10-30 menit
https://www.radiologyinfo.org/en/info
Hasil pemeriksaan dengan DEXA
2. Szule P, et al. IOF-VFI part I,
12
Terapi Osteoporosis
Obat-obat Osteoporosis
• Bisphosphonates
• Oral :
 Alendronate (Harian, mingguan)
 Risedronate (Harian, Mingguan, Bulanan)
 Ibandronate(Bulanan)
• Injeksi IV
 Ibandronate (3 bulan sekali)
 Zoledronate (1 tahun sekali)
• Estrogen Therapy/Hormone Therapy
• Parathyroid Hormone (PTH 1-34)
• Selective Estrogen Receptor Modulator (SERM)
Source:
5. Physician’s Guide to Prevention and Treatment of Osteoporosis. 2nd ed. Washington, DC: National
Osteoporosis Foundation; 2003.
AACE Guidelines – Algoritma Terapi
6. AACE Guidelines
15
Management
Osteoprorosis
(Terapi 1 tahun Sekali
Treatment)
etidronate
pamidronate zoledronic acid
HO
HO OH
OH
OH
O
O
P
P
CH3
OH
OH
OH
OH
O
O
P
P
Cl
Cl
HO
OH
OH
OH
O
O
P
P
S
Cl
clodronate
tiludronate
alendronate
ibandronate
risedronate
BPs yang mengandung Nitrogen
Bisfosfonat Non-Nitrogen
Bisfosfonat (BP)
H2N
HO
HO
OH
OH
OH
O
O
P
P
HO
N
O
O
=
=
P
P
OH
OH
OH
OH
HO
O
O
P
P
OH
OH
OH
OH
H2N
OH
OH
OH
O
O
N P
P
OH
HO
CH3
CH3 N
N
O
O
P
P
HO OH
OH
OH
OH
Konstanta Afinitas (KL) untuk adsorpsi bisphosponate untuk pertumbuhan Hidroxyapatite (pH 7.4)
adalah: zoledronate > alendronate > ibandronate > risedronate > etidronate > clodronate
Adapted from Nancollas GH, et al. Bone 2006;38:617-27
Mekanisme Kerja Biphosponat
Clezardin, P Bone, 2011, 48 : 71-78
Zol 5mg - Efficacy
Farmakologi Zoledronate
Farmakologi Zoledronate
Farmakokinetik Zoledronate
• Setelah infus Zoledronate, konsentrasi
plasma mencapai puncaknya di akhir
periode Infus, diikuti dengan adanya
penurunan kadar di plasma tersisa
sebanyak :
< 10% setelah 4 jam
< 1% setelah 24 jam
• Dalam 24 jam, Zoledronate 61% terikat
di tulang
• Dan dieliminasi melalui ginjal sebanyak
39+ 16%
Chen T, et al. J Clin Pharmacol, 2002;42; 1228-1236
Yearly infusions with Aclasta® significantly reduced fracture
risk at different sites1 (hip, vertebral, non-vertebral†)
Only Zoledronate has demonstrated efficacy for three different types of
fracture protection2-5 (hip, vertebral, non-vertebral†)
†Non-vertebral fracture: includes wrist, rib, arm, shoulder, or hip fracture; excludes finger, toe, or craniofacial fracture
Cumulative incidence of new clinical fractures over 3 years1
1) Black et al. N Engl J Med. 2007;356:1809-1822; 2) Fosamax® weekly tablets SmPC; 3) Actonel® weekly tablets SmPC; 4) Bonviva® tablets SmPC; 5) Aclasta® SmPC
Values above bars are 3 year cumulative event based on Kaplan-Meier estimates.
*p = .002; †p < .001; ‡p < .001; relative risk reduction vs placebo
§Hip fracture was not excluded from analysis of non-vertebral fracture
Cumulative
incidence
(%)
of
new
clinical
fractures
over
3
years
Hip Fracture Clinical vertebral fracture Non-vertebral fracture§
Adapted from reference 14
Zoledronic Acid 5 mg Reduced Subsequent Fracture Risk
Over Time
0
2
4
6
8
10
12
14
16
18
20
Clinical
Fractures
Non-Vertebral
Fractures
Clinical
Vertebral
Fractures
Hip
Fractures
10.7%
(107/1062)
8.6%
(92/1065)
13.9%
(139/1062)
7.6%
(79/1065)
3.8%
(39/1062)
1.7%
(21/1065)
3.5%
(33/1062)
2.0%
(23/1065)
35%*
(16%, 50%)
27%†
(2%, 45%)
46%‡
(8%, 68%)
30%
(-2%, 59%)
*P = .0012; †P = .0338; ‡P = .0210, relative risk reduction vs placebo; NS = not significant.
Values above bars are cumulative event rates based on Kaplan-Meier estimates at Month 24.
Event
Rate
(%)
ZOL 5 mg
Placebo
Lyles KW, et al. N Engl J Med. 2007;357:1799-809
23
Zoledronic Acid 5 mg Produced Significant Increases in Total Hip BMD and
Femoral Neck Over 3 Years vs. Placebo
Excludes Center 829. Bracketed values are least-squares mean difference, ZOL vs placebo.
*P < .0001; P = .0003; P-value computed from 2-way ANOVA with treatment and region in the model.
24 Lyles KW, et al. N Engl J Med. 2007;357:1799–09.
Total Hip BMD Femoral Neck BMD
Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality in Post-
Hip Fracture Patients Over Time
Month
0
2
4
6
8
10
12
14
16
18 Hazard Ratio, 0.72 (95% CI, 0.56–0.93)
P = .0117
Cumulative
Incidence
(%)
0 4 8 12 16 20 24 28 32 36
No. at Risk
ZOL 5 mg 1054 1029 987 943 806 674 507 348 237 144
Placebo 1057 1028 993 945 804 681 511 364 236 149
ZOL 5 mg (n = 1065)
Placebo (n = 1062)
28%
Absolute Risk Reduction, 3.7%
25 Lyles KW, et al. N Engl J Med. 2007;357:1799–09.
Zol 5mg - Safety Profile
Zoledronate is safe and well tolerated
Most common adverse events (“flu-like symptoms”) were transient post-dose symptoms1,2
Additional Key Safety Findings
Renal function Over 3 years, no significant difference in mean creatinine clearance between treatment groups1
Over-suppression Bone turnover normalized to premenopausal levels with no evidence of oversuppression2
Osteonecrosis of the jaw 1 Zoledronate-treated patient, 1 placebo-treated patient1,2
Atrial fibrillation AE reported in 2.4% of Aclasta®-treated patients (94/3862) vs. 1.9% (73/3852) in the placebo group and SAE in 1.3%
(50/3862) vs. 0.5% (20/3852) of patients, respectively1
This imbalance has not been observed in other clinical trials with zoledronic acid1
Most common adverse events within 3 days after annual infusion3
Incidence
(%)
Year of infusion
Placebo values cross-hatched
1) Black et al. N Engl J Med. 2007;356:1809-1822; 2) Aclasta® SmPC 3) Heggland J et. al. Data on file. Novartis Pharma AG
Zoledronic Acid 5 mg VS Another Bisphosponate
Zoledronic Acid 5mg Significantly & Sustain Reduced 3-Year
Risk of Morphometric Vertebral Fractures since The 1st Year
1. Black et al. N Engl J Med. 2007;356:1809-1822. 2. Harris ST, et al. JAMA. 1999;282:1344. 3. Actonel Prescribing
Information. 4. Black D, et al. Lancet. 1996;348;1535. 5. Miller PD, et al. J Bone Miner Res. 2005;20:1315. 6. Reginster JY, et
al. Ann Rheum Dis. 2006;65:684. 7. Boniva Prescribing Information. 8. Neer RM, et al. N Engl J Med. 2001;344:1434.
Years
0-1 0-3
0-2
Years
0-1 0-3
0-2
Years
0-1 0-3
0-2
Years
0-1 0-3
0-2
ZOL 5 mg1 Alendronate
(FIT)4
Risedronate
(VERT-NA)2,3
Ibandronate5
Relative
Risk
Reduction
(%)
71%
0
10
20
30
40
50
60
70
60%
70%
65%
55%
41%
62%
48%
58%
61%
52%
65%
Data not from comparative trials
Fracture Risk Reduction by Biphosponates *
* Data not from comparative trials
Osteoporosis Indications for Bisphosphonate Based on FDA Approved
Zoledronic acid is the only bisphosphonate, investigated in an RCT and
approved by the CHMP and FDA for the treatment of osteoporosis in women
and men with a recent surgical repair of low-trauma hip fracture2
1Clinician’s Guide To Prevention And Treatment Of Osteoporosis. National Osteoporosis Foundation 2013: 1-
53; 2Lyles KW, et al. N Engl J Med. 2007;357:1799–1809
Biphosponate Comparison
33
Management
Osteoprorosis
(Oral Terapi)
34
Clinical Study
From slide #11 to #24 - i will be developing slide from
those references :
• Harris, et al. JAMA. 1999;282:1344-52.
• Reginster, et al. Osteoporos Int (2000) 11:83–91
Risedronate
Effects of Risedronate Treatment on Vertebral
and Nonvertebral FractUREs in Women With
PostmenopaUSAl Osteoporosis
Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral
fractures in women with postmenopausal osteoporosis: a randomized controlled
trial." Jama 282.14 (1999): 1344-1352.
36
Effects of Risedronate Treatment on Vertebral and Nonvertebral
Fractures in Women With Postmenopausal Osteoporosis
(VERT – 1999 – Europe & Aus)
Metode : Acak, double-blind, placebo-controlled trial, parallel-group study, dilakukan di 110 pusat penelitian di Amerika Utara
Tujuan: Menguji kemanjuran dan keamanan terapi harian risedronate dalam mengurangi risiko patah tulang belakang dan
patah tulang lainnya pada wanita pascamenopause yang mengalami osteoporosis
Kriteria Inklusi:
• Wanita pascamenopause
• rawat jalan
• < 85 tahun
• setidaknya 1 patah tulang belakang
Outcome utama:
Kejadian patah tulang belakang baru seperti yang terdeteksi oleh penilaian kuantitatif dan semikuantitatif radiografi;
Kejadian patah tulang nonvertebral yang dikonfirmasi secara radiografis dan perubahan dari baseline dalam kepadatan
mineral tulang (BMD)
Kriteria Eksklusi:
• Kondisi yang mengganggu evaluasi spinal
bone loss
• calcitonin, calcitriol atau cholecalciferol
supplements (1 bulan sebelum penelitian)
• Anabolic steroids, estrogen /
estrogenrelated, / progestins selama 3
bulan
• bisphosphonates, fluoride, implan estrogen
selama 6 bulan
0 1 2 3 yr.
N=2458
Placebo + Ca suppl ~1000mg/d
Risedronate, 2.5 mg/d +
Ca suppl ~1000mg/d
Risedronate, 5 mg/d+ Ca suppl ~1000mg/d
N=815
N=811
N=813
Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal
osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352.
37
Effects of Risedronate Treatment on Vertebral and Nonvertebral
Fractures in Women With Postmenopausal Osteoporosis
(VERT – 1999 – Europe & Aus)
Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal
osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352.
Incidence of New Vertebral
Fractures by Groups Over Time
Incidence of Nonvertebral
Fractures by Study Group Over Time
38
Effects of Risedronate Treatment on Vertebral and Nonvertebral
Fractures in Women With Postmenopausal Osteoporosis
(VERT – 1999 – Europe & Aus)
Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal
osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352.
Mean Percent Change From Baseline in Bone Mineral Density
5.4%
1.6%
3.3%
39
Effects of Risedronate Treatment on Vertebral and Nonvertebral
Fractures in Women With Postmenopausal Osteoporosis
(VERT – 1999 – Europe & Aus)
Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal
osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352.
Median Percentage Change From Baseline in Bone-Specific Alkaline Phosphatase
and Deoxypyridinoline-Creatinine Ratio
40
Kesimpulan
Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal
osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352.
• Terapi risedronate oral dapat ditoleransi dengan baik dan menghasilkan penurunan
yang cepat dan penting secara klinis dalam risiko patah tulang pada wanita dengan
osteoporosis pascamenopause.
• Penurunan yang signifikan dalam kejadian patah tulang belakang baru diamati pada
tahun pertama pengobatan, sedangkan penurunan yang sama pada patah tulang
belakang terlihat setelah 3 tahun.
Risedronate adalah efektif dan dapat ditoleransi dengan
baik untuk pengobatan osteoporosis pascamenopause.
Randomized Trial of the Effects of Risedronate
on Vertebral Fractures in Women with
Established Postmenopausal Osteoporosis
Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women
with established postmenopausal osteoporosis." Osteoporosis international 11.1 (2000): 83-91.
42
Randomized Trial of the Effects of Risedronate on Vertebral Fractures
in Women with Established Postmenopausal Osteoporosis
(VERT NA – 2000 – Europe & Aus)
Metode : Acak, double-masked, placebo-controlled trial, dilakukan di 80 pusat penelitian di Eropa dan Autralia
Tujuan: Untuk menilai kemanjuran dan keamanan risedronate dalam pencegahan patah tulang belakang pada wanita
pascamenopause yang mengalami osteoporosis
Kriteria Inklusi:
• Wanita pascamenopause (min. 5 thn)
• rawat jalan
• < 85 tahun
• setidaknya terkonfirmasi Ro fraktur T4-L4
Outcome utama: Kejadian patah
tulang belakang selama dalam waktu
3 tahun
Kriteria Eksklusi:
• Kondisi yang mengganggu evaluasi spinal
osteoporosis.
• calcitonin, calcitriol atau Vit D supplements
(1 bulan sebelum penelitian)
• Anabolic steroids, estrogen /
estrogenrelated, / progestins selama 3
bulan
• bisphosphonates, fluoride, implan estrogen
selama 6 bulan
0 1 2 3 yr.
N=1226
Placebo + Ca suppl ~1000mg/d or Vit D 500IU/d
Risedronate, 2.5 mg/d +
Ca suppl ~1000mg/d or
Vit D 500IU/d
Risedronate, 5 mg/d+ Ca suppl ~1000mg/d or Vit D 200IU/d
N=407
N=408
N=407
Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal
osteoporosis." Osteoporosis international 11.1 (2000): 83-91.
43
Randomized Trial of the Effects of Risedronate on Vertebral Fractures
in Women with Established Postmenopausal Osteoporosis
(VERT NA – 2000 – Europe & Aus)
Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal
osteoporosis." Osteoporosis international 11.1 (2000): 83-91.
Incidence of a new vertebral fractures Nonvertebral osteoporosis-related fractures
44
Randomized Trial of the Effects of Risedronate on Vertebral Fractures
in Women with Established Postmenopausal Osteoporosis
(VERT NA – 2000 – Europe & Aus)
Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal
osteoporosis." Osteoporosis international 11.1 (2000): 83-91.
Percentage change from baseline in bone mineral density of:
a. lumbar spine b. femoral neck c. midshaft radius
45
Kesimpulan
Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal
osteoporosis." Osteoporosis international 11.1 (2000): 83-91.
Risedronate 5 mg efektif dan dapat ditoleransi dengan
baik terapi untuk osteoporosis pascamenopause yang
berat, mengurangi kejadian patah tulang belakang dan
meningkatkan kepadatan tulang pada wanita dengan
osteoporosis pascamenopause
Risedronate Reverses Bone Loss in
Postmenopausal Women with Low Bone
Mass: Results From a Multinational,
Double-Blind, Placebo-Controlled Tria
(BMD MN – 2015)
Hasil
BMD
• ACTONEL mencegah terjadinya Bone Loss pada wanita (usia 42-63 th) selama 3 tahun.
• Peningkatan BMD ditunjukkan pada pemberian ACTONEL selama 3 bulan
• ACTONEL secara signifikan meningkatkan BMD pada Lumbar Spine, Femoral Neck dan Trochantar
dibanding Placebo pada akhir Studi
48
KESIMPULAN
1. Zoledronic Acid 5mg (Aclasta) terbukti efektif mencegah terjadinya Fraktur Osteoporosis di ketiga titik
penting yaitu vertebrae 70%, hip 41% dan non-vertebrae 25%
2. Zoledronic Acid 5mg memiliki potensi penghambatan sintesa enzim FPPs, sehingga memiliki potensi anti
resorpsi paling maksimal dan dapat digunakan satu tahun sekali.
3. Dalam 24 jam, 61% Zoledronate Acid 5mg terikat di tulang, dan +39% dieliminasi melalui ginjal
4. Zoledronic Acid 5mg terbukti aman dan ditoleransi dengan baik oleh tubuh, AE yang umumnya muncul
bersifat sementara dan dapat diatasi dengan obat-obatan seperti paracetamol ataupun ibuprofen
5. ACLASTA tersedia di JKN
6. Relative Fracture Risk Reduction Aclasta® (Zoledronic Acid) untuk ketiga titik penting (Vertebrae, Hip, &
Non Vertebrae) memiliki nilai yang relative lebih baik dibanding bisphosponate lain (data not from
comparative trial)
7. Risedronate 5 mg (Actonel®) efektif dan dapat ditoleransi dengan baik terapi untuk osteoporosis
pascamenopause yang berat, mengurangi kejadian patah tulang belakang dan meningkatkan kepadatan
tulang pada wanita dengan osteoporosis pascamenopause
8. ACTONEL mencegah terjadinya Bone Loss pada wanita (usia 42-63 th) selama 3 tahun
Terimakasih

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Osteoporosis, How to diagnose and treat _ Oral and Infusion Treatment.pptx

  • 2. Apakah Osteoporosis? • Penyakit tulang yang ditandai dengan menurunnya massa tulang (kepadatan tulang) secara keseluruhan 1 • 1 dari 4 perempuan di Indonesia dengan rentang usia 50-80 tahun memiliki resiko terkena osteoporosis 1 • Gejala umum osteoporosis mulai dari patah tulang, tulang punggung yang semakin membungkuk, menurunnya tinggi badan, dan nyeri punggung1 • Diagnosis osteoporosis berdasarkan pengukuran BMD dan terjadinya fraktur (WHO Criteria) 2 1. Infodatin, 2015 2. Szule P, et al. IOF-VFI part I,
  • 3. Tulang Normal vs. Osteoporosis https://www.bookingdokter.com/article/mengenal-osteoporosis-dan-osteomalasia
  • 4. Fraktur Macam-macam fraktur berdasarkan tempat terjadinya https://pt.slideshare.net/hanialzo3bi/osteoporosis-48772976
  • 5. Massa tulang Adapted from NIH ORBD, Bone 2003 (pp1-2)
  • 6. SIKLUS REMODELING TULANG Bone Remodeling 3 Biphosponate mechanism4 3. Pelletier, Mediographica 105 4. Muskoloskeletal Key, Management of Osteoporosis
  • 7. Diagnosis Osteoporosis • Pemeriksaan Fisis & Riwayat pasien • Pemeriksaan Radiologi: • X-ray, MRI, CT-scan • Penanda Biokemis (Bone marker) • Bone Mineral Desity (BMD) https://www.alodokter.com/osteoporosis/diagnosis
  • 8. Pemeriksaan Fisis & Riwayat Pasien • Faktor resiko, termasuk informasi tentang fraktur terakhir • Riwayat keluarga, termasuk osteoporosis • Riwayat pengobatan, termasuk pengobatan yang menyebabkan pengurangan massa tulang (mis, glucocorticoid) • Konsumsi Kalsium dan Vitamin D • Pola hidup (mis, olahraga, diet tinggi lemak, merokok, dan penyalahgunaan obat-obatan dan minuman keras) • Penyakit yang menyebabkan osteoporosis sekunder (Cushing’s syndrome, thyroid disease, hyperthyroidism, hypogonadism) https://www.alomedika.com/penyakit/reumatologi/osteoporosis/diagnosis
  • 9. Faktor Resiko Osteoporosis • Jenis kelamin: perempuan • Usia lanjut • Etnis Kaukasia atau Asia • Riwayat patah tulang setelah usia 50 tahun • Riwayat keluarga terkena osteoporosis • Gaya hidup pasif • Struktur kerangka kecil • Patah tulang yang keropos • Massa tulang Rendah • Beberapa kondisi medis yang kronis • Defisiensi Estrogen karena menopause • Kadar testosteron yang rendah pada pria • Asupan rendah kalsium atau vitamin D • Penggunaan obat-obatan tertentu (misalnya, kortikosteroid) • Merokok • Konsumsi alkohol berlebihan https://hellosehat.com/muskuloskeletal/osteoporosis/penyebab-osteoporosis/
  • 10. Bone Mineral Densitometry/BMD • Untuk menentukan kepadatan tulang • Saat ini digunakan dual-energi sinar-X absorptiometry (DEXA) • Penggunaannya pada pinggul, tulang belakang, pergelangan tangan, tumit, jari • Standar emas untuk diagnosis dan memantau efek pengobatan osteoporosis • Lama pemeriksaan 10-30 menit https://www.radiologyinfo.org/en/info
  • 11. Hasil pemeriksaan dengan DEXA 2. Szule P, et al. IOF-VFI part I,
  • 13. Obat-obat Osteoporosis • Bisphosphonates • Oral :  Alendronate (Harian, mingguan)  Risedronate (Harian, Mingguan, Bulanan)  Ibandronate(Bulanan) • Injeksi IV  Ibandronate (3 bulan sekali)  Zoledronate (1 tahun sekali) • Estrogen Therapy/Hormone Therapy • Parathyroid Hormone (PTH 1-34) • Selective Estrogen Receptor Modulator (SERM) Source: 5. Physician’s Guide to Prevention and Treatment of Osteoporosis. 2nd ed. Washington, DC: National Osteoporosis Foundation; 2003.
  • 14. AACE Guidelines – Algoritma Terapi 6. AACE Guidelines
  • 16. etidronate pamidronate zoledronic acid HO HO OH OH OH O O P P CH3 OH OH OH OH O O P P Cl Cl HO OH OH OH O O P P S Cl clodronate tiludronate alendronate ibandronate risedronate BPs yang mengandung Nitrogen Bisfosfonat Non-Nitrogen Bisfosfonat (BP) H2N HO HO OH OH OH O O P P HO N O O = = P P OH OH OH OH HO O O P P OH OH OH OH H2N OH OH OH O O N P P OH HO CH3 CH3 N N O O P P HO OH OH OH OH Konstanta Afinitas (KL) untuk adsorpsi bisphosponate untuk pertumbuhan Hidroxyapatite (pH 7.4) adalah: zoledronate > alendronate > ibandronate > risedronate > etidronate > clodronate Adapted from Nancollas GH, et al. Bone 2006;38:617-27
  • 17. Mekanisme Kerja Biphosponat Clezardin, P Bone, 2011, 48 : 71-78
  • 18. Zol 5mg - Efficacy
  • 21. Farmakokinetik Zoledronate • Setelah infus Zoledronate, konsentrasi plasma mencapai puncaknya di akhir periode Infus, diikuti dengan adanya penurunan kadar di plasma tersisa sebanyak : < 10% setelah 4 jam < 1% setelah 24 jam • Dalam 24 jam, Zoledronate 61% terikat di tulang • Dan dieliminasi melalui ginjal sebanyak 39+ 16% Chen T, et al. J Clin Pharmacol, 2002;42; 1228-1236
  • 22. Yearly infusions with Aclasta® significantly reduced fracture risk at different sites1 (hip, vertebral, non-vertebral†) Only Zoledronate has demonstrated efficacy for three different types of fracture protection2-5 (hip, vertebral, non-vertebral†) †Non-vertebral fracture: includes wrist, rib, arm, shoulder, or hip fracture; excludes finger, toe, or craniofacial fracture Cumulative incidence of new clinical fractures over 3 years1 1) Black et al. N Engl J Med. 2007;356:1809-1822; 2) Fosamax® weekly tablets SmPC; 3) Actonel® weekly tablets SmPC; 4) Bonviva® tablets SmPC; 5) Aclasta® SmPC Values above bars are 3 year cumulative event based on Kaplan-Meier estimates. *p = .002; †p < .001; ‡p < .001; relative risk reduction vs placebo §Hip fracture was not excluded from analysis of non-vertebral fracture Cumulative incidence (%) of new clinical fractures over 3 years Hip Fracture Clinical vertebral fracture Non-vertebral fracture§ Adapted from reference 14
  • 23. Zoledronic Acid 5 mg Reduced Subsequent Fracture Risk Over Time 0 2 4 6 8 10 12 14 16 18 20 Clinical Fractures Non-Vertebral Fractures Clinical Vertebral Fractures Hip Fractures 10.7% (107/1062) 8.6% (92/1065) 13.9% (139/1062) 7.6% (79/1065) 3.8% (39/1062) 1.7% (21/1065) 3.5% (33/1062) 2.0% (23/1065) 35%* (16%, 50%) 27%† (2%, 45%) 46%‡ (8%, 68%) 30% (-2%, 59%) *P = .0012; †P = .0338; ‡P = .0210, relative risk reduction vs placebo; NS = not significant. Values above bars are cumulative event rates based on Kaplan-Meier estimates at Month 24. Event Rate (%) ZOL 5 mg Placebo Lyles KW, et al. N Engl J Med. 2007;357:1799-809 23
  • 24. Zoledronic Acid 5 mg Produced Significant Increases in Total Hip BMD and Femoral Neck Over 3 Years vs. Placebo Excludes Center 829. Bracketed values are least-squares mean difference, ZOL vs placebo. *P < .0001; P = .0003; P-value computed from 2-way ANOVA with treatment and region in the model. 24 Lyles KW, et al. N Engl J Med. 2007;357:1799–09. Total Hip BMD Femoral Neck BMD
  • 25. Zoledronic Acid 5 mg Reduced Risk of All-Cause Mortality in Post- Hip Fracture Patients Over Time Month 0 2 4 6 8 10 12 14 16 18 Hazard Ratio, 0.72 (95% CI, 0.56–0.93) P = .0117 Cumulative Incidence (%) 0 4 8 12 16 20 24 28 32 36 No. at Risk ZOL 5 mg 1054 1029 987 943 806 674 507 348 237 144 Placebo 1057 1028 993 945 804 681 511 364 236 149 ZOL 5 mg (n = 1065) Placebo (n = 1062) 28% Absolute Risk Reduction, 3.7% 25 Lyles KW, et al. N Engl J Med. 2007;357:1799–09.
  • 26. Zol 5mg - Safety Profile
  • 27. Zoledronate is safe and well tolerated Most common adverse events (“flu-like symptoms”) were transient post-dose symptoms1,2 Additional Key Safety Findings Renal function Over 3 years, no significant difference in mean creatinine clearance between treatment groups1 Over-suppression Bone turnover normalized to premenopausal levels with no evidence of oversuppression2 Osteonecrosis of the jaw 1 Zoledronate-treated patient, 1 placebo-treated patient1,2 Atrial fibrillation AE reported in 2.4% of Aclasta®-treated patients (94/3862) vs. 1.9% (73/3852) in the placebo group and SAE in 1.3% (50/3862) vs. 0.5% (20/3852) of patients, respectively1 This imbalance has not been observed in other clinical trials with zoledronic acid1 Most common adverse events within 3 days after annual infusion3 Incidence (%) Year of infusion Placebo values cross-hatched 1) Black et al. N Engl J Med. 2007;356:1809-1822; 2) Aclasta® SmPC 3) Heggland J et. al. Data on file. Novartis Pharma AG
  • 28. Zoledronic Acid 5 mg VS Another Bisphosponate
  • 29. Zoledronic Acid 5mg Significantly & Sustain Reduced 3-Year Risk of Morphometric Vertebral Fractures since The 1st Year 1. Black et al. N Engl J Med. 2007;356:1809-1822. 2. Harris ST, et al. JAMA. 1999;282:1344. 3. Actonel Prescribing Information. 4. Black D, et al. Lancet. 1996;348;1535. 5. Miller PD, et al. J Bone Miner Res. 2005;20:1315. 6. Reginster JY, et al. Ann Rheum Dis. 2006;65:684. 7. Boniva Prescribing Information. 8. Neer RM, et al. N Engl J Med. 2001;344:1434. Years 0-1 0-3 0-2 Years 0-1 0-3 0-2 Years 0-1 0-3 0-2 Years 0-1 0-3 0-2 ZOL 5 mg1 Alendronate (FIT)4 Risedronate (VERT-NA)2,3 Ibandronate5 Relative Risk Reduction (%) 71% 0 10 20 30 40 50 60 70 60% 70% 65% 55% 41% 62% 48% 58% 61% 52% 65% Data not from comparative trials
  • 30. Fracture Risk Reduction by Biphosponates * * Data not from comparative trials
  • 31. Osteoporosis Indications for Bisphosphonate Based on FDA Approved Zoledronic acid is the only bisphosphonate, investigated in an RCT and approved by the CHMP and FDA for the treatment of osteoporosis in women and men with a recent surgical repair of low-trauma hip fracture2 1Clinician’s Guide To Prevention And Treatment Of Osteoporosis. National Osteoporosis Foundation 2013: 1- 53; 2Lyles KW, et al. N Engl J Med. 2007;357:1799–1809
  • 34. 34 Clinical Study From slide #11 to #24 - i will be developing slide from those references : • Harris, et al. JAMA. 1999;282:1344-52. • Reginster, et al. Osteoporos Int (2000) 11:83–91 Risedronate
  • 35. Effects of Risedronate Treatment on Vertebral and Nonvertebral FractUREs in Women With PostmenopaUSAl Osteoporosis Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352.
  • 36. 36 Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis (VERT – 1999 – Europe & Aus) Metode : Acak, double-blind, placebo-controlled trial, parallel-group study, dilakukan di 110 pusat penelitian di Amerika Utara Tujuan: Menguji kemanjuran dan keamanan terapi harian risedronate dalam mengurangi risiko patah tulang belakang dan patah tulang lainnya pada wanita pascamenopause yang mengalami osteoporosis Kriteria Inklusi: • Wanita pascamenopause • rawat jalan • < 85 tahun • setidaknya 1 patah tulang belakang Outcome utama: Kejadian patah tulang belakang baru seperti yang terdeteksi oleh penilaian kuantitatif dan semikuantitatif radiografi; Kejadian patah tulang nonvertebral yang dikonfirmasi secara radiografis dan perubahan dari baseline dalam kepadatan mineral tulang (BMD) Kriteria Eksklusi: • Kondisi yang mengganggu evaluasi spinal bone loss • calcitonin, calcitriol atau cholecalciferol supplements (1 bulan sebelum penelitian) • Anabolic steroids, estrogen / estrogenrelated, / progestins selama 3 bulan • bisphosphonates, fluoride, implan estrogen selama 6 bulan 0 1 2 3 yr. N=2458 Placebo + Ca suppl ~1000mg/d Risedronate, 2.5 mg/d + Ca suppl ~1000mg/d Risedronate, 5 mg/d+ Ca suppl ~1000mg/d N=815 N=811 N=813 Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352.
  • 37. 37 Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis (VERT – 1999 – Europe & Aus) Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352. Incidence of New Vertebral Fractures by Groups Over Time Incidence of Nonvertebral Fractures by Study Group Over Time
  • 38. 38 Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis (VERT – 1999 – Europe & Aus) Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352. Mean Percent Change From Baseline in Bone Mineral Density 5.4% 1.6% 3.3%
  • 39. 39 Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis (VERT – 1999 – Europe & Aus) Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352. Median Percentage Change From Baseline in Bone-Specific Alkaline Phosphatase and Deoxypyridinoline-Creatinine Ratio
  • 40. 40 Kesimpulan Harris, Steven T., et al. "Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial." Jama 282.14 (1999): 1344-1352. • Terapi risedronate oral dapat ditoleransi dengan baik dan menghasilkan penurunan yang cepat dan penting secara klinis dalam risiko patah tulang pada wanita dengan osteoporosis pascamenopause. • Penurunan yang signifikan dalam kejadian patah tulang belakang baru diamati pada tahun pertama pengobatan, sedangkan penurunan yang sama pada patah tulang belakang terlihat setelah 3 tahun. Risedronate adalah efektif dan dapat ditoleransi dengan baik untuk pengobatan osteoporosis pascamenopause.
  • 41. Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis." Osteoporosis international 11.1 (2000): 83-91.
  • 42. 42 Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis (VERT NA – 2000 – Europe & Aus) Metode : Acak, double-masked, placebo-controlled trial, dilakukan di 80 pusat penelitian di Eropa dan Autralia Tujuan: Untuk menilai kemanjuran dan keamanan risedronate dalam pencegahan patah tulang belakang pada wanita pascamenopause yang mengalami osteoporosis Kriteria Inklusi: • Wanita pascamenopause (min. 5 thn) • rawat jalan • < 85 tahun • setidaknya terkonfirmasi Ro fraktur T4-L4 Outcome utama: Kejadian patah tulang belakang selama dalam waktu 3 tahun Kriteria Eksklusi: • Kondisi yang mengganggu evaluasi spinal osteoporosis. • calcitonin, calcitriol atau Vit D supplements (1 bulan sebelum penelitian) • Anabolic steroids, estrogen / estrogenrelated, / progestins selama 3 bulan • bisphosphonates, fluoride, implan estrogen selama 6 bulan 0 1 2 3 yr. N=1226 Placebo + Ca suppl ~1000mg/d or Vit D 500IU/d Risedronate, 2.5 mg/d + Ca suppl ~1000mg/d or Vit D 500IU/d Risedronate, 5 mg/d+ Ca suppl ~1000mg/d or Vit D 200IU/d N=407 N=408 N=407 Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis." Osteoporosis international 11.1 (2000): 83-91.
  • 43. 43 Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis (VERT NA – 2000 – Europe & Aus) Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis." Osteoporosis international 11.1 (2000): 83-91. Incidence of a new vertebral fractures Nonvertebral osteoporosis-related fractures
  • 44. 44 Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis (VERT NA – 2000 – Europe & Aus) Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis." Osteoporosis international 11.1 (2000): 83-91. Percentage change from baseline in bone mineral density of: a. lumbar spine b. femoral neck c. midshaft radius
  • 45. 45 Kesimpulan Reginster, J-Y., et al. "Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis." Osteoporosis international 11.1 (2000): 83-91. Risedronate 5 mg efektif dan dapat ditoleransi dengan baik terapi untuk osteoporosis pascamenopause yang berat, mengurangi kejadian patah tulang belakang dan meningkatkan kepadatan tulang pada wanita dengan osteoporosis pascamenopause
  • 46. Risedronate Reverses Bone Loss in Postmenopausal Women with Low Bone Mass: Results From a Multinational, Double-Blind, Placebo-Controlled Tria (BMD MN – 2015)
  • 47. Hasil BMD • ACTONEL mencegah terjadinya Bone Loss pada wanita (usia 42-63 th) selama 3 tahun. • Peningkatan BMD ditunjukkan pada pemberian ACTONEL selama 3 bulan • ACTONEL secara signifikan meningkatkan BMD pada Lumbar Spine, Femoral Neck dan Trochantar dibanding Placebo pada akhir Studi
  • 48. 48 KESIMPULAN 1. Zoledronic Acid 5mg (Aclasta) terbukti efektif mencegah terjadinya Fraktur Osteoporosis di ketiga titik penting yaitu vertebrae 70%, hip 41% dan non-vertebrae 25% 2. Zoledronic Acid 5mg memiliki potensi penghambatan sintesa enzim FPPs, sehingga memiliki potensi anti resorpsi paling maksimal dan dapat digunakan satu tahun sekali. 3. Dalam 24 jam, 61% Zoledronate Acid 5mg terikat di tulang, dan +39% dieliminasi melalui ginjal 4. Zoledronic Acid 5mg terbukti aman dan ditoleransi dengan baik oleh tubuh, AE yang umumnya muncul bersifat sementara dan dapat diatasi dengan obat-obatan seperti paracetamol ataupun ibuprofen 5. ACLASTA tersedia di JKN 6. Relative Fracture Risk Reduction Aclasta® (Zoledronic Acid) untuk ketiga titik penting (Vertebrae, Hip, & Non Vertebrae) memiliki nilai yang relative lebih baik dibanding bisphosponate lain (data not from comparative trial) 7. Risedronate 5 mg (Actonel®) efektif dan dapat ditoleransi dengan baik terapi untuk osteoporosis pascamenopause yang berat, mengurangi kejadian patah tulang belakang dan meningkatkan kepadatan tulang pada wanita dengan osteoporosis pascamenopause 8. ACTONEL mencegah terjadinya Bone Loss pada wanita (usia 42-63 th) selama 3 tahun