In our study, we identified 190 col

In our study, we identified 190 colon cancer deaths in 30,600 women in the alendronate cohort and 1,083 in the 124,000 untreated controls.
In a small epidemiological study with less than 1,000 bisphosphonate users and equal number of controls, oral bisphosphonates, statins, vitamin D and low-dose aspirin reduced the risk of colorectal cancer [15]. Also, a non-significant reduction in risk of colorectal cancers (HR 0.87, 95% CI 0.77–1.00) in bisphosphonate users was recently reported using data from the large UK GPRD database [16], a study which also described an increase in oesophageal cancers. However, another study using the same database did not find any difference in the combined risk ofoesophageal andgastric cancers [17]. In the present study, we have found a pronounced and significant reduction in deaths from colon cancer.Our use of mortality data eliminates ascertainment bias as an explanation for the risk reduction, and has provided data on the relative contributions of changes in colon cancer incidence and changes in post-diagnosis survival.
In our study, alendronate users were approximately twice as likely as non-users to die from pulmonary causes, but they were also three times as likely to have pulmonary disease at the start of treatment. However, repeating the analysis in a new matched analysis where all subjects with known pre-existing pulmonary disease or use of pulmonary medications were excluded did not influence our initial findings. Finally, a propensity score matched analysis gave similar results. Perhaps most importantly, the reduction in cancer deaths could not be due to excess non-cancer deaths (Table 3). The observed all-cause mortality in alendronate users was slightly lower despite greater baseline comorbidity, with 26% of alendronate users dying within 5 years compared with 28% of age-matched non-users (p

Hasil (Bahasa Indonesia) 1:

In our study, we identified 190 colon cancer deaths in 30,600 women in the alendronate cohort and 1,083 in the 124,000 untreated controls.In a small epidemiological study with less than 1,000 bisphosphonate users and equal number of controls, oral bisphosphonates, statins, vitamin D and low-dose aspirin reduced the risk of colorectal cancer [15]. Also, a non-significant reduction in risk of colorectal cancers (HR 0.87, 95% CI 0.77–1.00) in bisphosphonate users was recently reported using data from the large UK GPRD database [16], a study which also described an increase in oesophageal cancers. However, another study using the same database did not find any difference in the combined risk ofoesophageal andgastric cancers [17]. In the present study, we have found a pronounced and significant reduction in deaths from colon cancer.Our use of mortality data eliminates ascertainment bias as an explanation for the risk reduction, and has provided data on the relative contributions of changes in colon cancer incidence and changes in post-diagnosis survival.In our study, alendronate users were approximately twice as likely as non-users to die from pulmonary causes, but they were also three times as likely to have pulmonary disease at the start of treatment. However, repeating the analysis in a new matched analysis where all subjects with known pre-existing pulmonary disease or use of pulmonary medications were excluded did not influence our initial findings. Finally, a propensity score matched analysis gave similar results. Perhaps most importantly, the reduction in cancer deaths could not be due to excess non-cancer deaths (Table 3). The observed all-cause mortality in alendronate users was slightly lower despite greater baseline comorbidity, with 26% of alendronate users dying within 5 years compared with 28% of age-matched non-users (p<0.001). Among alendronate users, the reduction in cardiovascular deaths was significant (p<0.001), which is interesting in that fewer cardiovascular and pulmonary deaths have also been reported to contribute to the reduction in mortality seen with IV zoledronate [13].How can alendronate produce these effects and are there plausible mechanisms to explain them? There are many studies on tumour cells in vitro and in animal studies that suggest that bisphosphonates may have actions on cancer cells that cannot be explained solely in terms of their better known skeletal effects [18]. Any inhibitory effects of oral BPs on the development and progression of colorectal cancer could be due to either local or systemic effects on the colonic mucosa. The local effects are expected to dominate in patients treated with oral bisphosphonates as only1% of the orally administered dose is absorbed by the duodenum and jejunum while the remaining ~ 99% moves slowly through the colorectal segments out of the intestine so that the colonic mucosa may be exposed to alendronate concentrations that are potentially into the millimolar range. Interestingly, in our study, the weekly dosing of alendronate appeared more effective than the daily administration in lowering the risk of colon cancer death. It could well be that the higher concentration of alendronate (7-fold) achieved in the gut on the day of the administration of the weekly regimen is more effective than the lower daily dose.A dominant mechanism involved in the anti-tumour effects of N-BPs in particular are likely to be mediated via their inhibitory effects on the mevalonate pathway [1, 18]. Such effects have been shown in many types of cells including cancer cells, and the results in the inhibition of prenylation of small GTP-binding proteins that are critical for intracellular signalling events. These GTP-binding proteins are involved in colorectal cancer [19, 20]. In vitro, several N-BPs inhibit the growth and induce apoptosis of

Hasil (Bahasa Indonesia) 2:

Dalam penelitian kami, kami mengidentifikasi 190 kematian akibat kanker usus besar pada wanita 30.600 dalam kelompok alendronate dan 1.083 di 124.000 kontrol yang tidak diobati.
Dalam sebuah penelitian epidemiologi kecil dengan kurang dari 1.000 pengguna bifosfonat dan jumlah yang sama kontrol, bifosfonat lisan, statin, vitamin D dan aspirin dosis rendah mengurangi risiko kanker kolorektal [15]. Juga, pengurangan non-signifikan dalam risiko kanker kolorektal (HR 0,87, 95% CI 0,77-1,00) pada pengguna bifosfonat baru-baru ini dilaporkan menggunakan data dari database besar Inggris GPRD [16], sebuah studi yang juga dijelaskan peningkatan esofagus kanker. Namun, penelitian lain menggunakan database yang sama tidak menemukan perbedaan dalam risiko gabungan ofoesophageal kanker andgastric [17]. Dalam penelitian ini, kami telah menemukan penurunan diucapkan dan signifikan dalam kematian dari penggunaan cancer.Our usus dari data kematian menghilangkan bias yang pemastian sebagai penjelasan untuk pengurangan risiko, dan telah memberikan data pada kontribusi relatif dari perubahan kejadian kanker usus besar dan perubahan pasca-diagnosis kelangsungan hidup.
Dalam penelitian kami, pengguna alendronate adalah sekitar dua kali lebih mungkin sebagai non-pengguna untuk meninggal akibat paru, tetapi mereka juga tiga kali lebih mungkin untuk memiliki penyakit paru pada awal pengobatan. Namun, mengulangi analisis dalam analisis cocok baru di mana semua mata pelajaran dengan penyakit paru yang sudah ada sebelumnya diketahui atau penggunaan obat paru dikeluarkan tidak mempengaruhi temuan awal kami. Akhirnya, skor kecenderungan cocok analisis memberikan hasil yang sama. Mungkin yang paling penting, pengurangan kematian akibat kanker tidak bisa karena kematian non-kanker kelebihan (Tabel 3). Mengamati semua penyebab kematian di pengguna alendronate sedikit lebih rendah meskipun komorbiditas dasar yang lebih besar, dengan 26% dari pengguna alendronate mati dalam waktu 5 tahun dibandingkan dengan 28% dari usia yang sama non-pengguna (p <0,001). Di antara pengguna alendronate, pengurangan kematian kardiovaskular yang signifikan (p <0,001), yang menarik bahwa sedikit kematian kardiovaskular dan paru juga telah dilaporkan untuk berkontribusi pada pengurangan kematian terlihat dengan IV zoledronate [13].
Bagaimana bisa alendronate menghasilkan efek ini dan ada mekanisme yang masuk akal untuk menjelaskan mereka? Ada banyak penelitian pada sel tumor in vitro dan pada hewan yang menunjukkan bahwa bifosfonat mungkin memiliki tindakan pada sel-sel kanker yang tidak dapat dijelaskan semata-mata dari segi efek rangka mereka lebih dikenal [18].
Setiap efek penghambatan BPs lisan pada pengembangan dan perkembangan kanker kolorektal bisa disebabkan baik efek lokal atau sistemik pada mukosa kolon. Efek lokal diharapkan mendominasi pada pasien yang diobati dengan bifosfonat oral only1% dari dosis oral diserap oleh duodenum dan jejunum sedangkan sisanya ~ 99% bergerak perlahan melalui segmen kolorektal dari usus sehingga mukosa kolon mungkin terkena konsentrasi alendronate yang berpotensi ke kisaran milimolar. Menariknya, dalam penelitian kami, dosis mingguan alendronate muncul lebih efektif daripada pemerintahan sehari-hari dalam menurunkan risiko kematian kanker usus. Ini bisa jadi bahwa konsentrasi yang lebih tinggi dari alendronate (7 kali lipat) dicapai dalam usus pada hari administrasi rejimen mingguan lebih efektif daripada dosis harian yang lebih rendah.
Mekanisme dominan terlibat dalam efek anti-tumor dari N -BPs khususnya kemungkinan akan dimediasi melalui efek penghambatan mereka pada jalur mevalonat [1, 18]. Efek seperti telah ditunjukkan dalam berbagai jenis sel termasuk sel-sel kanker, dan hasilnya dalam penghambatan prenilasi GTP-binding protein kecil yang sangat penting untuk acara sinyal intraseluler. Protein GTP-binding ini terlibat dalam kanker kolorektal [19, 20]. In vitro, beberapa N-BPs menghambat pertumbuhan dan menginduksi apoptosis