Drug-induced osteoporosis: from Fuller Albright to aromatase inhibitors.

Many commonly prescribed medications, such as selective serotonin reuptake inhibitors, proton pump inhibitors, thiazolidinediones, aromatase inhibitors, and androgen deprivation therapy, have been associated with adverse skeletal effects. The levels of evidence in support of a causal relationship between drug use and the development of bone loss and fractures are variable. For some drugs, a causal relationship is suspected (but not proven) based on observational studies, while in others causality is firmly established with randomized, controlled clinical trials. The mechanism of action for skeletal damage is poorly understood for some drugs and well known for others. Guidelines for managing bone health in patients taking some medications with potential skeletal toxicity have been developed using the best available evidence and expert opinion. This is a review of selected medications that have been associated with bone loss and fractures, with recommendations for clinical care.

Threonine phosphorylation of the MMAC1/PTEN PDZ binding domain both inhibits and stimulates PDZ binding.

Two-hybrid searches with the tumor suppressor MMAC1/PTEN isolated the proteins hDLG and hMAST205. Further two-hybrid analysis and microtiter plate binding assays localized the sites of interaction to PDZ domains from hDLG and hMAST205 and the PDZ binding domain at the COOH terminus of MMAC1/PTEN. A synthetic peptide derived from the MMAC1/PTEN PDZ binding domain (MMAC1/PTEN-PDZBD) was used to coprecipitate proteins from A431 human cell lysate. The recovered proteins were resolved by SDS-PAGE and immobilized on a nitrocellulose membrane. Treatment of this membrane with an anti-hDLG antibody identified a Mr 140,000 band, consistent with the size of hDLG. Treatment of this membrane with the MMAC1/PTEN-PDZBD peptide identified a single prominent band of slightly larger than Mr 200,000 (Mr 200,000 kDa). Threonine phosphorylation of the MMAC1/ PTEN-PDZBD peptide inhibited both microtiter plate binding to the hDLG and hMAST205 PDZ domains and coprecipitation of the Mr 140,000 and > 200,000 proteins, but promoted coprecipitation of proteins of approximately Mr 90,000 and Mr 120,000 from A431 cell lysate. This result suggests phosphorylation of the MMAC1/PTEN PDZ binding domain can both inhibit and promote PDZ interactions.