Physiology of the aging bone and mechanisms of action of bisphosphonates

Abstract

Fragility fractures, a major public health concern, are expected to further increase due to aging of the world populations because age remains a cardinal, independent determinant of fracture risk. With aging the balance between bone formation and resorption during the remodeling process becomes negative, with increased resorption and reduced formation. Bisphosphonates (BPs) are widely prescribed anti-resorptive agents that inhibit osteoclasts attachment to bone matrix and enhance osteoclast apoptosis. BPs can be divided into nitrogen-containing (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). Both classes induce apoptosis but they evoke it differently. Several studies have examined the molecular mechanisms underlying BPs' effects on osteoclasts and bone remodeling. N-BPs (alendronate, risedronate, zoledronate) inhibit the intracellular mevalonate pathway and protein isoprenylation, via the enzyme farnesyl pyrophosphate synthase. N-BPs act by competition, binding to the natural substrate-binding site of the enzyme. The less potent non-N-BPs (etidronate, clodronate), do not inhibit the mevalonate pathway and protein isoprenylation, but are metabolized intracellularly to metabolites, which are cytotoxic analogs of ATP. N-BPs represent the first choice treatment for diseases associated with excessive bone resorption, such as fragility fractures (due to postmenopausal-, male, glucocorticoid- and transplant-induced osteoporosis), Paget's disease of bone, and bone metastasis. Better understanding of BPs' effects on osteoblasts/osteocytes (e.g., preventing apoptosis) and differential distribution may further help explain anti-fracture benefit and bone quality effects. Lower affinity BPs (e.g., risedronate) may allow better access to osteocyte network. Effects of BPs on bone senescence, cancer cells apoptosis and prevention of cardiovascular calcifications may open new avenues for biogerontological research.

Medication-related osteonecrosis of the jaw. Introduction of a new modified experimental model

“…The main effect of the drug is inhibition of bone resorption [1][2][3][4][5] . Despite the great benefits of BP in patients with benign or malignant conditions, an oral complication was observed arising from the use of this drug, especifically: Medication-related osteonecrosis of the jaw (MRONJ), which aroused attention from the medical and dental professionals.…”

“Bisphosphonates: Possible Modes of Action and Implications for Dental Implant Treatment. A Review of the Literature”

“…This means that bisphosphonates may be released from the bone surfaces in the acidic environment of the osteoclast lacunae, giving rise to localised high concentrations of bisphosphonates that are in solution or as calcium salts [50,[61][62][63]. Bisphosphonates are structural analogues of pyrophosphates with a core P-C-P structure.…”

“…Bisphosphonates are classified as nitrogen-containing bisphosphonates and non-nitrogen containing bisphosphonates. Adapted from Dominguez et al [61]. Zolendronate and risendronate are the most potent bisphosphonates with a hydroxyl group in the R 1 position and tertiary nitrogen within a ring structure in the R 2 position [64].…”

“…They are believed to act on bone through several mechanisms simultaneously [5,50,61,[75][76][77][78][79][80][81][82]. The reduction in osteoclastic activity occurs as a result of internalisation of bisphosphonates by the osteoclasts, causing disruption of osteoclastmediated bone resorption [1,3,7,[26][27][28]55,60,65].…”

Tectorigenin inhibits RANKL‐induced osteoclastogenesis via suppression of NF‐κB signalling and decreases bone loss in ovariectomized C57BL/6

“…There are several targets within osteoclast for intervention to prevent bone loss. Biophosphonates, as one of the most widely used anti‐osteoporosis drugs, inhibit attachment to bone matrix and induce osteoclast apoptosis 7, 8. However, serious gastrointestinal reactions from this kind of drug remain unpleasant for patients 9…”