6533b855fe1ef96bd12b0ab1
RESEARCH PRODUCT
Physiology of the aging bone and mechanisms of action of bisphosphonates.
Ligia J. DominguezMario BarbagalloMario BelvedereGiovanna Di Bellasubject
Malemedicine.medical_specialtyAgingSettore MED/09 - Medicina Internamedicine.medical_treatmentOsteoporosisurologic and male genital diseasesBone resorptionBone and BonesBone remodelingOsteoclastInternal medicinemedicineHumansCellular SenescenceBONE BONE TURNOVER FRAGILITY FRACTURES AGING BISPHOSPHONATESOsteoblastsBone Density Conservation AgentsDiphosphonatesbusiness.industryBone metastasisOsteoblastBisphosphonatemedicine.diseaseEndocrinologymedicine.anatomical_structureOsteocyteFemaleBone RemodelingGeriatrics and GerontologybusinessGerontologyhormones hormone substitutes and hormone antagonistsdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-06-22 | Biogerontology |