Bisphosphonates
Drugs

Author: lea solavagione
Date: 24/05/2007

Description

DESCRIPTION

These compounds are pyrophosphate analogues with a P-C-P structure and two side chains: R1 controls the ability of binding to crystals in the bone, R2 confers the antiresorptive potency to the bisphosphonates

INDICATIONS

  • prevention of spontaneous fractures
  • neoplastic hypercalcemia
  • osteoporosis
  • bone metastases of various cancers
  • Paget's disease
  • multiple myeloma

IMPORTANT CHARACTERISTICS

  • high affinity for hydroxyapatite due to their structure
  • short plasma half-life (between 20 minutes and 2-3 houres) and very long bone half-life (from months to years)
  • prevailing accumulation in bone areas where bone resorption and formation is taking place

CLASSIFICATION

  1. non nitrogen-containing bisphosphonates:etidronate, clodronate, tiludronate
  2. nitrogen-containing bisphosphonates:pamidronate, alendronate, ibandronate, zoledronate and risedronate that act as isoprenoid diphosphate lipid analogues

ACTION

  1. inhibition of ectopical calcification (above all non nitrogen-containig bisphosphonates)
  2. inhibition of bone resorption (above all nitrogen-containing bisphosphonates)
  3. inhibition of matrix metalloproteinases
  4. inhibition of tumoral cells adhesion

MECHANISM

  • decrease of bone turnover rate through inibition of deposition,aggregation and dissolution of the crystals

-preventing their formation from mononuclear haematopoietic precursors
-acting on their recruitment
-inhibiting their activity
-inducing their apoptosis via interruption of the mevalonate pathway
-inducing osteoblasts to secrete an osteoclast inhibitor

inhibition of angiogenetic process
modification of circulating angiogenetic factors

SIDE EFFECTS

Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. 2011

Nitrogen-containing bisphosphonates , with greater power and slower metabolization,can lead to:

FDA MedWatch - Bisphosphonates- Possible Cause of Severe and Sometimes Incapacitating Bone, Joint, and/or Muscle Pain 2007

Link

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Bisfosfonati ostacolano guarigione osso alveolare
I bisfosfonati possono ostacolare la guarigione e rallentare il turnover dell'osso alveolare anche anni dopo la sospensione della loro assunzione. Sono state finora riportate centinaia di casi di osteonecrosi della mandibola correlati a questi farmaci, ed è stato postulato che essi aumentino l'attività osteoblastica e riducano quella osteoclastica. Nei pazienti che ne fanno uso, la presenza di cavità residue dopo un intervento di chirurgia dentale costituisce un'ulteriore prova della scarsa guarigione dell'osso o di un turnover osseo estremamente rallentato. E' molto importante che odontoiatri ed oncologi siano a conoscenza del fatto che questa significativa complicazione possa intervenire spontaneamente o dopo qualsiasi intervento dentoalveolare nella popolazione a rischio. (General Dentistry 2009: 130-5)

Comments
2012-11-29T14:59:41 - luca savoldi

Therapeutical importance in Paget's disease of bone

During bone resorption bisphosphonates are ingested by osteoclasts. Once inside the cell most bisphosphonates inhibit the enzyme farnesyl pyrophosphate synthase. Disruption of this pathway adversely affects the osteoclast cytoskeleton and can result in osteoclast apoptosis. For most bisphosphonates, their clinical potency is determined by a combination of their affinity for hydroxyapatite (which determines skeletal uptake) and the potency of their inhibition of the target enzyme.

Luca Savoldi,
Emanuele Coda

2011-07-17T18:05:46 - Gianpiero Pescarmona

Lancet Oncol. 2011 Jul;12(7):631-641. Epub 2011 Jun 5.
Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. 2011
Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M, Pristauz G, Bauernhofer T, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Hochreiner G, Forsthuber EP, Fesl C, Greil R; on behalf of the Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria.
Source
Medical University of Vienna, Vienna, Austria.
Abstract
BACKGROUND:
Analysis of the Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) at 48 months' follow-up showed that addition of zoledronic acid to adjuvant endocrine therapy significantly improved disease-free survival. We have now assessed long-term clinical efficacy including disease-free survival and disease outcomes in patients receiving anastrozole or tamoxifen with or without zoledronic acid.

METHODS:
ABSCG-12 is a randomised, controlled, open-label, two-by-two factorial, multicentre trial in 1803 premenopausal women with endocrine-receptor-positive early-stage (stage I-II) breast cancer receiving goserelin (3·6 mg every 28 days), comparing the efficacy and safety of anastrozole (1 mg per day) or tamoxifen (20 mg per day) with or without zoledronic acid (4 mg every 6 months) for 3 years. Randomisation (1:1:1:1 ratio) was computerised and based on the Pocock and Simon minimisation method to balance the four treatment arms across eight prognostic variables (age, neoadjuvant chemotherapy, pathological tumour stage; lymph-node involvement, type of surgery or locoregional therapy, complete axillary dissection, intraoperative radiation therapy, and geographical region). Treatment allocation was not masked. The primary endpoint was disease-free survival (defined as disease recurrence or death) and analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00295646; follow-up is ongoing.

FINDINGS:
At a median follow-up of 62 months (range 0-114·4 months), more than 2 years after treatment completion, 186 disease-free survival events had been reported (53 events in 450 patients on tamoxifen alone, 57 in 453 patients on anastrozole alone, 36 in 450 patients on tamoxifen plus zoledronic acid, and 40 in 450 patients on anastrozole plus zoledronic acid). Zoledronic acid reduced risk of disease-free survival events overall (HR 0·68, 95% CI 0·51-0·91; p=0·009), although the difference was not significant in the tamoxifen (HR 0·67, 95% CI 0·44-1·03; p=0·067) and anastrozole arms (HR 0·68, 95% CI 0·45-1·02; p=0·061) assessed separately. Zoledronic acid did not significantly affect risk of death (30 deaths with zoledronic acid vs 43 deaths without; HR 0·67, 95% CI 0·41-1·07; p=0·09). There was no difference in disease-free survival between patients on tamoxifen alone versus anastrozole alone (HR 1·08, 95% CI 0·81-1·44; p=0·591), but overall survival was worse with anastrozole than with tamoxifen (46 vs 27 deaths; HR 1·75, 95% CI 1·08-2·83; p=0·02). Treatments were generally well tolerated, with no reports of renal failure or osteonecrosis of the jaw. Bone pain was reported in 601 patients (33%; 349 patients on zoledronic acid vs 252 not on the drug), fatigue in 361 (20%; 192 vs 169), headache in 280 (16%; 147 vs 133), and arthralgia in 266 (15%; 145 vs 121).

INTERPRETATION:
Addition of zoledronic acid improved disease-free survival in the patients taking anastrozole or tamoxifen. There was no difference in disease-free survival between patients receiving anastrozole and tamoxifen overall, but those on anastrozole alone had inferior overall survival. These data show persistent benefits with zoledronic acid and support its addition to adjuvant endocrine therapy in premenopausal patients with early-stage breast cancer.

FUNDING:
AstraZeneca; Novartis.

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