{"id":3428,"date":"2008-11-29T08:07:00","date_gmt":"2008-11-29T07:07:00","guid":{"rendered":"https:\/\/www.zerodonto.com\/en\/2008\/11\/bisphosphonates-in-dentistry\/"},"modified":"2017-11-28T12:19:13","modified_gmt":"2017-11-28T11:19:13","slug":"bisphosphonates-in-dentistry","status":"publish","type":"post","link":"https:\/\/www.zerodonto.com\/en\/2008\/11\/bisphosphonates-in-dentistry\/","title":{"rendered":"Bisphosphonates in Dentistry"},"content":{"rendered":"

 <\/p>\n

Bisphosphonate therapy and the manifestation of a rare and severe complication, namely the osteonecrosis of the maxillary bone, are currently very important topics to which increasing attention is being given by specialists. The dental surgeon’s awareness and concern toward this pathology, together with a degree of alarmism, is justified by the increasing number of cases that since 2003 till today have enabled observing and studying the clinical and anatomo-pathologic case history, the localization of the pathology, the associated risks and the possible development and consequences of the osteonecrosis lesions. Epidemiological data are more unclear as they do not actually consent defining the exact prevalence and incidence of the phenomenon, the pathogenic hypothesis and the causal relationship related to the use of the bisphosphonates.<\/p>\n

Other uncertainties predominate the scenario of the therapeutic possibilities that seem inadequate to tackle the needs of patients affected by osteonecrosis of the maxillary bone. Till now, there is no therapy leading to resolution of the lesions, neither has the suspension of the therapy, in some cases, led to improve the effects.<\/p>\n

In the light of these considerations, the goal that dental surgery must achieve is to arm itself with whatever means possible in order to at least reduce the negative side-effects of this symptoms, often painful, and the risks of bacterial or other microorganism contaminations which worsen the case history and compromise the general health of the patient. The aim of this article is to illustrate, as a schematic overview, the current knowledge on bisphosphonates.<\/p>\n

Definition:<\/b> Bisphosphonates are non-hormonal substances, active in mineral bone homeostasis. Structural analogues of inorganic pyrophosphates but resistant to enzymatic hydrolysis, bisphosphonates are molecules able, through a rigid bond with hydroxyapatite crystals, to modulate skeletal turnover and, in particular, selectively inhibit osteoclast mediated bone reabsorption.<\/p>\n

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Commercial products<\/span><\/b> <\/span><\/p>\n<\/td>\n

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Preparations<\/span><\/b> <\/span><\/p>\n<\/td>\n

\n

Agent<\/span><\/b> <\/span><\/p>\n<\/td>\n<\/tr>\n

\n

Adronate (Neopharmed)<\/span><\/p>\n<\/td>\n

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Tablets<\/span><\/p>\n<\/td>\n

\n

Alendronic acid <\/span><\/b><\/p>\n<\/td>\n<\/tr>\n

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Alendronato Pliva (Pliva Pharma)<\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Alendronate Ratiopharm (Ratiopharm GmbH-D)<\/span><\/p>\n<\/td>\n

\n

Tablets <\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
\n

Alendronate Teva (Teva Pharma Italy) <\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Alendros (Abiogen Pharma)<\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Dronal (Sigma-Tau) <\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Dronal 70 (Sigma-Tau) <\/span><\/p>\n<\/td>\n

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Tablets<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Fosamax (Merck Sharp Dohme)<\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Genalen (Gentili)<\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Etidron (Abiogen Pharma)<\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

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Etidronic <\/span><\/b><\/p>\n

Acid<\/span><\/b><\/p>\n<\/td>\n<\/tr>\n

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Bondronat (Roche Registration \u2013 GB)<\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

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Ibandronic <\/span><\/b><\/p>\n

Acid <\/span><\/b><\/p>\n<\/td>\n<\/tr>\n

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Bonviva (Roche Registration \u2013 GB)<\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Aredia (Novartis Farma)<\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

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Pamidronic Acid <\/span><\/b><\/p>\n<\/td>\n<\/tr>\n

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Amidrox (Crinos)<\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Pamidronate Disodium IBP<\/span><\/p>\n

Pharma (IBP Pharma) <\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Texpami (Pharmatex Italia)<\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Pamidronate Disodium Mayne (Mayne Pharma Italy) <\/span><\/p>\n<\/td>\n

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Intravenous drug (for hospital use only)<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Actonel (Procter & Gamble)<\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

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Risedronic <\/span><\/b><\/p>\n

Acid<\/span><\/b><\/p>\n<\/td>\n<\/tr>\n

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Optinate (Lepetit)<\/span> <\/span><\/p>\n<\/td>\n

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Tablets <\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Clodronic Acid EG (Eg)<\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

\n

Clodronic <\/span><\/b><\/p>\n

Acid<\/span><\/b><\/p>\n<\/td>\n<\/tr>\n

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Clodronic Acid Sandoz (Sandoz)<\/span><\/p>\n<\/td>\n

\n

Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
\n

Clodronic Acid <\/span><\/p>\n

Union Health (Union Health)<\/span><\/p>\n<\/td>\n

\n

Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Clasteon (Abiogen Pharma)<\/span><\/p>\n<\/td>\n

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Tablets\/phials<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Climaclod (Mastelli)<\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Clodeosten (B&G) <\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Clodron (Fidia pharmaceuticals)<\/span><\/p>\n<\/td>\n

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Tablets\/phials<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Clodronate ABC (ABC pharmaceuticals) <\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Clodronate Teva (Teva Pharma Italia) <\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Clody (Promedica)<\/span><\/p>\n<\/td>\n

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Tablets\/phials<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Difosfonal (SPA) <\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Disodium Clodronate Alter(Alter) <\/span><\/p>\n<\/td>\n

\n

Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Moticlod (Lisapharma)<\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Niklod (Savio I.B.N.) <\/span><\/p>\n<\/td>\n

\n

Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Osteonorm (Piam) <\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Osteostab (Rottapharm) <\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Soclonat (TB Technology) <\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n
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Aclasta (Novartis Europh-GB) <\/span><\/p>\n<\/td>\n

\n

Intravenous drug<\/span><\/p>\n<\/td>\n

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Zolendric <\/span><\/b><\/p>\n

Acid<\/span><\/b><\/p>\n<\/td>\n<\/tr>\n

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Zometa (Novartis Europh-GB)<\/span><\/p>\n<\/td>\n

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Intravenous drug<\/span><\/p>\n<\/td>\n

<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n
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Bone binding affinity and biological potency<\/b><\/p>\n

The antireabsorptive potency of bisphosphonates depends on the bone binding affinity and their ability to inhibit osteoclast action. The binding affinity of various bisphosphonates to the bone depends on the molecular group in the R1 side chain and is increased by the presence of a group – OH or – NH2 in that position. The different affinities of the bisphosphonates influence the drug quantity accumulated, the persistence of the bone matrix and the duration of action.<\/p>\n

 <\/p>\n

In increasing order of affinity: <\/b><\/p>\n

Clodronate, etidronate, pamidronate, risedronate, ibandronate, alendronate, zolendronate [3]<\/p>\n

The potency of inhibition of the osteoclast action depends on the molecular group in R2. Bisphosphonates with a -NH2 group in that position (amino-bisphosphonate) are more potent than those lacking this group (non amino-bisphosphonate) as they are able to arrest the osteoclast action through the inhibition of mevalonic acid pathway (see next paragraph). The potency is also related to the three-dimensional conformation of the R2 chain and therefore, to the length of the chain and to the introduction of methyl, pentilic, imidazole and benzene groups.<\/p>\n

 <\/p>\n

In increasing order of potency: <\/b><\/p>\n

Etidronate, clodronate, pamidronate, alendronate, ibandronate, risedronate, zolendronate [4]<\/p>\n

Biological potency and binding affinity are characteristics closely related to each other in establishing the real anti-reabsorptive potency in vivo. Bisphosphonates with high binding affinity to the mineralized surface are held within the bone to a greater degree and have greater pharmacological effects. Furthermore, the bone matrix functions like a sponge, able to absorb, release locally and reabsorb the bisphosphonates to a greater degree the higher the affinity is. Therefore, this would explain the persistence of the pharmacological effects observed after the administration of bisphosphonates [2]. From the analysis of two schemes, it appears that zolendronate is the drug with the highest affinity and potency, while alendronate has greater potency in inhibition of the bone turnover in comparison to risedronate.<\/p>\n

Mechanism of action<\/b><\/p>\n

Thanks to their high affinity with the hydroxyl-apatite, bisphosphonates firmly bound to the bone crystals, are released in the extracellular space during the phase of bone reabsorption and are then absorbed by endocytosis into the osteoclasts. Inside these cells, the non-amino bisphosphonates (not having aminic terminal groups in the side chain bound to the C atom in position 1- etidronate and clodronate<\/i>) are metabolized in non-hydrolysable analogues of the ATP with consequent cytotoxic effect and death of the cells. On the other hand, the amino-bisphosphonates (alendronate, risedronate, ibandronate, pamidronate and zolendronate) more potent since having – NH2 groups in the side chain R2, selectively inhibit the farnesyl pyrophosphate synthase enzyme implicated in the biosynthesis of the sterols (cycle of the mevalonic acid), and prevent the prenilation of some GTP-ase dependent proteins involved in the cell cycle maintenance with consequent cytoskeleton alteration and cell death by apoptosis [1].<\/p>\n

Chemical structure<\/b><\/p>\n

\"\"<\/a><\/p>\n

 <\/p>\n

Indications <\/b><\/b><\/p>\n

Prevention of the brittle fractures during chronic diseases:<\/p>\n

The use of these drugs, aimed at a reduction in bone turnover, does not however have a curative purpose and is prolonged over time. The reduction of the bone turnover allows the formation of more mineralized and dense bone and reflects in an increase of the mineral bone density. However, an excessive slowdown of the bone remodelling is in turn dangerous for two reasons: 1. the bone, not being able anymore to repair damage by use, may be subject to brittle fracture owing to accumulation of microcracks; 2. an over mineralized bone also results more fragile because it is not elastic [5]).<\/p>\n