The VERT study found that daily treatment with risedronate significantly reduced the risk of new vertebral fractures by 41% and new morphometric vertebral fractures by 49% compared to placebo in postmenopausal women with osteoporosis over 3 years. Risedronate also reduced the risk of hip fractures by 39% and other nonvertebral fractures by 25%, although the results for nonvertebral fractures were not statistically significant. The study demonstrated that risedronate is a safe and effective treatment for reducing fracture risk in postmenopausal osteoporosis.
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
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
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
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
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
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
