Bisphosphonates and Bone

Romanian Journal of Rheumatology

This article aims to establish, on the basis of medical literature and of the authors’ experience, whether bisphosphonates still have a role in treating skeletal diseases, with increased bone resorption. The effects of bisphosphonates on the bone tissue, as well as the diseases in which they are recommended and the benefits obtained are reviewed. Possible side effects are emphasized, both the immediate ones, which are better known and the late ones, occurring after a long-term administration. It is shown that the benefit/risk ratio remains favorable. The conclusions highlight the fact that nowadays bisphosphonates still have an important place in the treatment of skeletal diseases.

Annals of the New York Academy of Sciences, 2006

The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating journey that is still not over. In clinical medicine, several BPs are established as the treatments of choice for various diseases of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. Bisphosphonates are chemically stable analogues of inorganic pyrophosphate, and are resistant to breakdown by enzymatic hydrolysis. Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed to mineral surfaces in bone, where they interfere with the action of the bone-resorbing osteoclasts. Bisphosphonates are internalized by osteoclasts and interfere with specific biochemical processes. Bisphosphonates can be classified into at least two groups with different molecular modes of action. The simpler non-nitrogen-containing bisphosphonates (such as clodronate and etidronate) can be metabolically incorporated into nonhydrolyzable analogues of adenosine triphosphate (ATP) that may inhibit ATP-dependent intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate, and zoledronate) are not metabolized in this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the biosynthesis of isoprenoid compounds that are essential for the posttranslational modification of small GTP-binding proteins (which are also GTPases) such as rab, rho, and rac. The inhibition of protein prenylation and the disruption of the function of these key regulatory proteins explain the loss of osteoclast activity and induction of apoptosis. The key target for bisphosphonates is farnesyl pyrophosphate synthase (FPPS) within osteoclasts, and the recently elucidated crystal structure of this enzyme reveals how BPs bind to and inhibit at the active site via their critical N atoms. In conclusion, bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, and their mode of action is being unraveled. As a result their full therapeutic potential is gradually being realized.

General dentistry, 2018

23 Despite being synthesized in the late 1800s, bisphosphonates have only been used clinically for the last 5 decades. In fact, on the 50th anniversary of the first clinical use of a bisphosphonate (1968, etidronate disodium), it is interesting to remember that the origin of bisphosphonates stems from dental research. In the 1960s, Procter & Gamble was hoping to develop a topical agent for use against dental calculus. By the end of the decade, their researchers were working with analogs of pyrophosphate, the disphosphonates, which had a similar structural backbone to the former but centered around a –P–C–P– bond instead of a –P–O–P– bond (Figure). Conformationally, in 3 dimensions this structure created a “bony hook,” resulting in a high affinity of these compounds for hydroxyapatite in bone. Following successful treatment of a young girl who had myositis ossificans progressiva and subsequent studies, etidronate (Didronel) was granted regulatory approval in 1977 for several indicati...

The aim of this review is to give an update on the protocols to be followed by the dentists for dental procedures for patients on bisphosphonate therapy. Presently there is an increasing prevalence of patients receiving bisphosphonate therapy. This review has included the pathological effects on alveolar bone, epithelium, variations in healing time, angiogenesis,and the risk factors associated with Bisphosphonate related osteonecrosis of the jaw (BRONJ) development. The consensus management protocols as recommended by experts is presented comprehensively. It is envisaged that dental practitioners should have a better understanding of bisphosphonate therapy and the complications associated with various dental procedures so as to enable them to render care with confidence and to improvethe quality of life of their patients on bisphosphonate therapy.

Dentistry today, 2006

The authors look into the research studies into bisphosphonates, the important classification of drugs for the treatment of bone diseases. Are bisphosphonates safe when used during or around implant treatment? The authors have some good news for us.

Bone, 2011

The ability of bisphosphonates ((HO) 2 P(O)CR 1 R 2 P(O)(OH) 2 ) to inhibit bone resorption has been known since the 1960s, but it is only recently that a detailed molecular understanding of the relationship between chemical structures and biological activity has begun to emerge. The early development of chemistry in this area was largely empirical and based on modifying R 2 groups in a variety of ways. Apart from the general ability of bisphosphonates to chelate Ca 2+ and thus target the calcium phosphate mineral component of bone, attempts to refine clear structure-activity relationships had led to ambiguous or seemingly contradictory results. However, there was increasing evidence for cellular effects, and eventually the earliest bisphosphonate drugs, such as clodronate (R 1 =R 2 = Cl) and etidronate (R 1 = OH, R 2 = CH 3 ), were shown to exert intracellular actions via the formation in vivo of drug derivatives of ATP. The observation that pamidronate, a bisphosphonate with R 1 = OH and R 2 = CH 2 CH 2 NH 2 , exhibited higher potency than previously known bisphosphonate drugs represented the first step towards the later recognition of the critical importance of having nitrogen in the R 2 side chain. The synthesis and biological evaluation of a large number of nitrogencontaining bisphosphonates took place particularly in the 1980s, but still with an incomplete understanding of their structure-activity relationships. A major advance was the discovery that the anti-resorptive effects of the nitrogen-containing bisphosphonates (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their potency as inhibitors of the enzyme farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids utilized in sterol synthesis and for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of bisphosphonates have been synthesized and studied. Interest in expanding the structural scope of the bisphosphonate class has also motivated new approaches to the chemical synthesis of these compounds. Recent chemical innovations include the synthesis of fluorescently labeled bisphosphonates, which has enabled studies of the biodistribution of these drugs. As a class, bisphosphonates share common properties. However, as with other classes of drugs, there are chemical, biochemical, and pharmacological differences among the individual compounds. Differences in mineral binding affinities among bisphosphonates influence their differential distribution within bone, their biological potency, and their duration of action. The overall pharmacological effects of bisphosphonates on bone, therefore, appear to depend upon these two key properties of affinity for bone mineral and inhibitory effects on osteoclasts. The relative contributions of these properties differ among individual bisphosphonates and help determine their clinical behavior and effectiveness. This article is part of a Special Issue entitled Bisphosphonates.

Dental Press Implantology, 2015

International Journal of Basic & Clinical Pharmacology

Bisphosphonates are chemical-related to pyrophosphate. The oxygen atom in pyrophosphate is substituted by a carbon atom in these compounds, resulting in a P-C-P bond. They are potent antiresorptive medicines because they have a strong inhibitory effect on osteoclasts. It lowers fracture risk by reducing bone turnover, increasing bone mineral density, and decreasing fracture risk in the lumbar spine and hip. Bisphosphonates are strongly attracted to bone surfaces, where they accumulate, primarily at remodeling sites. They are rarely associated with systemic side effects due to their selectivity in action. Irritation of the upper gastrointestinal tract is the most common side effect. A strong third-generation bisphosphonate, zoledronate, is currently approved to treat postmenopausal-induced osteoporosis. This review mainly focuses on the mechanism of action, therapeutic uses, and its adverse effects.

Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology, 2009

Australian Dental Journal, 2005