Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation

Anterior knee pain in younger adults as a precursor to subsequent patellofemoral osteoarthritis: a systematic review

Background Patellofemoral osteoarthritis (PFOA) is a common form of knee OA in middle and older age, but its relation to PF disorders and symptoms earlier in life is unclear. Our aim was to conduct a systematic review to investigate the strength of evidence for an association between anterior knee pain (AKP) in younger adults and subsequent PFOA. Methods The search strategy included electronic databases (Pubmed, EMBASE, AMED, CINAHL, Cochrane, PEDro, SportDiscus: inception to December 2009), reference lists of potentially eligible studies and selected reviews. Full text articles in any language, - identified via English titles and abstracts, were included if they were retrospective or prospective in design and contained quantitative data regarding structural changes indicative of PFOA, incident to original idiopathic AKP. Eligibility criteria were applied to titles, abstracts and full-texts by two independent reviewers. Data extraction included study location, design, date, sampling procedure, sample characteristics, AKP/PFOA definitions, follow-up duration and rate, and main findings. Foreign language articles were translated into English prior to examination. Results Seven articles satisfied eligibility (5 English, 2 German). Only one case-control study directly investigated a link between PFOA and prior AKP, providing level 3b evidence in favour of an association (OR 4.4; 95%CI 1.8, 10.6). Rough estimates of the annual risk of PFOA from the remaining six small, uncontrolled, observational studies (mean follow-up range: 5.7 to 23 years) ranged from 0% to 3.4%. This was not the primary aim of these studies, and limitations in design and methodology mean this data should be interpreted with caution. Conclusions There is a paucity of high-quality evidence reporting a link between AKP and PFOA. Further, well-designed cohort studies may be able to fill this evidence gap