**3. Pharmacokinetics of the bisphosphonates**

Bisphosphonates are chemically stable analogs of non-organic pyrophosphates (PPi) related to skeleton mineralization. Their development is related to inventing inhibitors of calcification in order to resist hydrolysis with alkaline phosphatase. PPi and BPs could not only slow down bone growth but also destroy hydroxyapatite crystals. BPs are remarkably efficient inhibitors to bone resorption during experiments in vitro and in vivo. During the process of their clinical application in the 1990s, it became clear that in order to clarify the chemical and physical reactions, and explain the variety of their biological effects, it is necessary to study the cell to cell interactions. Bisphosphonates suppress bone resorption by selective absorption to mineralized bone surface where they counteract to osteoclasts.

**Figure 3.** Basic molecular structure

Bisphosphonates couldcan be classified to at leastinto two groups with different molecular action mechanisms. The first one: is nitrogen free bisphosphonates (like etidronate and clodoronate) that interfere ATP-dependent intercellular ways. The second group is bisphosph‐ onates with nitrogen, they that are more powerful (including pamidronate, alendronate, rizedronate, ibandronate, and zoledronate) they). They are metabolized differently, by inhibiting key enzymes of mevalonat/cholesterol biosynthetic way.

Precisely because of the obviously differentobvious biochemical and pharmacological differencedifferences and uneven intercellular interaction is important the division of, BPs in tohave been divided into separate groups and their specific usage according to a specific disease.

They are incorporated in skeletal bone without being degraded. Bisphosphonates are attached to Ca2+ in areas with increased bone resorption and stay integrated in the bone for 10 to 40 years – alendronate. For example, alendronate's half-life for example is 12 to 28 years. Once taken, BPs unlock cascade biochemical processes leading to loss of osteoclast ability to resorb bone or even to their apoptosis.

Biological Concepts on Bisphosphonate Treated Patients in the Context of Increasing Patient Life Quality... http://dx.doi.org/10.5772/61731 131

**Figure 4.** The way to bone fracture by solid bone tumors (after R.E. Marx).

reactions, and explain the variety of their biological effects, it is necessary to study the cell to cell interactions. Bisphosphonates suppress bone resorption by selective absorption to

Bisphosphonates couldcan be classified to at leastinto two groups with different molecular action mechanisms. The first one: is nitrogen free bisphosphonates (like etidronate and clodoronate) that interfere ATP-dependent intercellular ways. The second group is bisphosph‐ onates with nitrogen, they that are more powerful (including pamidronate, alendronate, rizedronate, ibandronate, and zoledronate) they). They are metabolized differently, by

Precisely because of the obviously differentobvious biochemical and pharmacological differencedifferences and uneven intercellular interaction is important the division of, BPs in tohave been divided into separate groups and their specific usage according to a specific

They are incorporated in skeletal bone without being degraded. Bisphosphonates are attached to Ca2+ in areas with increased bone resorption and stay integrated in the bone for 10 to 40 years – alendronate. For example, alendronate's half-life for example is 12 to 28 years. Once taken, BPs unlock cascade biochemical processes leading to loss of osteoclast ability to resorb

inhibiting key enzymes of mevalonat/cholesterol biosynthetic way.

mineralized bone surface where they counteract to osteoclasts.

**Figure 3.** Basic molecular structure

130 Immunopathology and Immunomodulation

bone or even to their apoptosis.

disease.

**Figure 5.** Prevention of bone resorption by bisphosphonate osteoclast inhibition (after R.E. Marx).

#### **4. Bisphosphonate-induced osteonecrosis of the jaws**

It is undoubtedly thatUndoubtedly, the intake increases the quality of life of the treated patients in general, but negative effecteffects should also be taken in tointo consideration. Stomach disorders, erosions of the esophagus, uveitis, flueflu-like conditions, muscle and joint pain, and severe necrosis in the maxillofacial area, known as BONJ – (bisphosphonate osteonecrosis of the jaw) could appear.

Recently inIn recent literature is found date for, a new type of complication associated with bisphosphonate intake –has been found, which is called avascular necrosis of the jaws. It is defined as necrosis associated with or without dental procedures, which could persist for more than 6-8 weeks with irresponsive to conservative treatment, found in patients without history of previous radiotherapy in the area affected but treated with nitrogen group bisphosphonates with nitrogen group, i.v. through IV for at least a year or per os for longer period, and associated with general condition withof bone resorption. Similar cases arewere published for the first time in 2003 by Marx with patients treated with pamidronate and zoledronate. Later, Carter and Gross, Ruggierro, Migliorati, and Wang reportalso reported similar cases. In 2005, Novartis (Aredia and Zometa48 producer) officially declaredeclared 475 cases of Bisphosph‐ onate bisphosphonate-related osteonecrosis of the jaws. In nowadaysNowadays, the number of affected patients worldwide is unknown. Scientific literatures says the BONJ is from 1,.3% to 10%. More There are more than 5,.1 million patients are treated with bisphosphonates. More and more than 2 million acceptaccepted BPs as antimalignatanti-malignant therapy. The number of patients treated for osteoporosis with BPs is increasing rapidly. More than 10 million patients, mainly women in the USA has, have osteoporosis,. It and it is supposed that the number will increase to 12 million and 34. Thirty-four million patients older than 50 have decreased bone density and considered high risk for osteoporosis development. Oral BPs arewere prescribed to more than 70% of the patients diagnosed with osteoporosis in US during the USA in 2003- to 2006.((American association of Oral and Maxillofacial Surgeons)). More than 190 million prescriptions arewere issued in North America. In 2003 Alendronate, alendronate is 19th most prescribed medicine (17 million prescriptions) Risedronate), risedro‐ nate is 72nd (6 million prescriptions) zolendronate), while zoledronate is used from more than 300,000 sick people.
