In enamel and dentin to prevent dental caries and

In organisms, bone undergoes continual resorption and formation and is kept in balance by osteoblasts creating bone and osteoclasts destroying bone. Osteocytes is the major cells in adult skeleton, which takes up over 95% in quantity (Teti A, Zallone A., 2009). It plays an important role in transducing the signals for bone resorption and formation. Osteoblasts and osteoclasts cooperating with bone osteocytes implement bone remodeling to enable the repair of damage, maintenance of calcium level and bone density (Brown JP, Josse RG., 2002). “Osteoporosis is a disease where increase bone weakness increases the risk of a broken bone (National Institiution of Health, August 2014).” It occurs when the balance between osteoblasts and osteoclasts is broken, in which the extent of bone resorption exceeds that of bone formation. The cell biology of the bone among osteoblasts, osteoclasts, osteocytes and the proteins will be explained later in section 2 with more details.

Bisphosphonates is today the main class of drugs used to prevent the loss of bone mass and to treat osteoporosis (a disease where increased bone weakness increases the risk of a broken bone) and other similar bone diseases charaterised by bone loss and fractures. It inhibits the digestion of bone by inducing osteoclasts apoptosis, or cell death, thereby slowing down bone loss.

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Bisphosphonates was first synthesized in the late 1800s but had not been used clinically until 1960s (M.D. Francis; D.J. Valent, 2007). In 1960, bisphosphonates were first used commercially by Blazer and Worms for detergent solutions as complexing agents for calcium and magnesium. In the 1960s, Procter & Gamble Co. (P&G) launched an investigation on the mechanism of action of fluoride on enamel and dentin to prevent dental caries and discovered that some compounds can change the action of fluoride and form a thin and cohesive layer with large calcium fluoride (CaF2) crystals to completely protect the enamel surface (M.D. Francis; D.J. Valent, 2007). From P&G’s studies, it was then found out that compounds such as polyphosphates can largely promote the CaF2 crystal growth. Based on this research, P then investigated on removing calculus with the 1-hydroxy, 1-ethylidene bisphosphonate salt (EHDP) received from Henkel Corporation Germany and discovered that no damage was made to the highly polished dental enamel through tests. From a previous review by Francis, these tests began the comprehensive researches on the physical chemical and biological properties of bisphosphonates (M.D. Francis; D.J. Valent, 2007).

Hydroxyapatite (HAP) is a naturally mineral form of calcium apatite with the formula Ca5(PO4)3(OH). It can be found in teeth and bones within the human body. HAP is commonly used as a filler to replace amputated bone or as a coating to promote bone ingrowth into prosthetic implants (Sadat-Shojai, 2010). In biological systems, bisphosphonates chemisorb to the calcium of HAP in bones and form an ultra-thin cohesive layer on the surfaces, which blocks the dissolution of HAP crystal and lead to the presumption that bisphosphonates might restrain bone resorption to reduce bone loss.

The medical use of the first bisphosphonates, etidronate disodium was in 1968 to treat a young patient with myositis ossificans progressive (M.D. Francis; D.J. Valent, 2007). The early work and numerous studies in the 1970s-1980s led to the regulatory agency approvals for etidronate for the treatment of Paget’s disease of bone (disorganised bone remodeling caused by the excessive breakdown and formation of bone). In the mid-1980s, P&G undertook a clinical program to evaluate the efficacy and safety of a cyclical regimen of etidronate in the prevention and treatment of postmenopausal osteoporosis (M.D. Francis; D.J. Valent, 2007). This research demonstrated that etidronates significantly increased the bone mineral density and lessened the rate of vertebral fractures in patients with high fracture potential. The effort inspired the development of risedronate sodium, a highly potent bisphosphonate with stable long-term efficacy and safety. Subsequent investigative studies were then carried out on other differently structured bisphosphonate compounds including alendronate, clodronate, ibandronate, pamidronate and zoledronate.

All bisphosphonates treat osteoporosis by inducing osteoclasts apoptosis. There may be some osteoclasts survive from the process and remain in the bone, but will be less active in resorptive activities (Baron R, Ferrari S, Russell RG., 2011) (Russell RGG, Watts NB, Ebetino FH, Rogers MJ., 2008). Alendronate, risedronate and zoledronate are the only three bisphosphonates currently identified by Osteoporosis Canada Clinical Practice Guideline as first-line treatment options (Papaioannou A, Morin S, Cheung AM et al., 2010).

From Russell’s review article in 2008, however, some recent reports indicate that the strength of the bones for patients who have received bisphosphonates treatment for years is weaker than previous (Russell RGG, Watts NB, Ebetino FH, Rogers MJ., 2008). This has induced the search for alternative drugs that will conduct minimal long-term negative effect on the bones. As a result, the idea of using denosumab for the treatment of osteoporosis in women was raised. “Denosumab is a human monoclonal antibody for the treatment of osteoporosis (Pageau, 2009).” Receptor activator of nuclear factor kappa-B ligand (RANKL) is a protein in humans which controls the regeneration and remodeling of the bone. Denosumab binds with the RANKL and works as the RANKL inhibitor to inhibit osteoclasts formation and function and thereby to induce osteoclasts apoptosis. Through intense researches and clinical investigations, denosumab was approved for marketing by the European Commission in 2010.

This literature review will provide a summary of the chemical mechanism of bisphosphonates and their interaction with the mechanism of bones and an overview of the effects that various drugs have on the mechanical properties of the bones. A comparison among the clinical outcomes and characteristics of various bisphosphonates (i.e. alendronate, risedronate and zoledronate) and their alternative (i.e. denosumab) will also be included in this review.

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