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    • The pathophysiology underlying ONJ is unclear Decreased bone

    2019-05-13

    The pathophysiology underlying ONJ is unclear. Decreased bone remodeling induced by bisphosphonates or inhibition of osteoclast function, which interferes with healing of the microfractures and trauma occurring after dental extraction, have been hypothesized as potential mechanisms for ONJ, but these have not been confirmed [133]. No specific myeloma treatments have been clearly implicated in the pathogenesis of ONJ, although dexamethasone and thalidomide have been suggested as additional risk factors [134]. Interestingly, patients with ONJ are more frequently diabetic or have impaired glucose tolerance when compared to an age-matched population [135]. Culture of some ONJ lesions has revealed actinomycetes, suggesting that infection may also play a role in the development of ONJ [130].
    Conclusions
    Conflict of Interest Statement
    Introduction In recent years, intravenous zoledronic toll like receptors (ZOL) has become an integral component of therapy for patients with metastatic bone disease (MBD) to reduce the risk of skeletal-related events (SREs) [1]. Initially, ZOL demonstrated superiority over pamidronate (the former standard of care) for managing hypercalcaemia of malignancy (HCM) [2]. Subsequently, across a range of cancers including breast cancer (BC) [3], castration-refractory prostate cancer (CRPC) [4], non-small cell lung cancer (NSCLC), and a variety of other solid tumours (OST) metastatic to bone [5], placebo-controlled trials have shown that monthly (every 3 to 4 weeks) ZOL reduces the overall risk of SREs by 27% to 41% and extends the time to first and subsequent SREs. Preclinical and emerging clinical data from multiple settings also suggest that ZOL has anticancer properties that may delay disease recurrence and improve survival [6–13]. Recently, ZOL was shown to improve overall survival (OS) and progression-free survival versus clodronate in a phase III trial in 1960 patients with multiple myeloma [10]. Furthermore, in a large, randomised trial of 1803 premenopausal patients with early endocrine-responsive BC, ZOL also reduced the risk of disease relapse by 32% versus endocrine therapy alone (P=.009) [8]. Together with interim results from the AZURE trial in stage II/III BC [14], these data suggest fluid feeders anticancer benefits from ZOL may occur in specific patient populations, all of which are expected to have elevated osteolysis levels because of oestrogen deprivation (e.g., premenopausal patients with low-risk BC receiving goserelin, postmenopausal patients receiving letrozole, and patients with stage II/III BC with established postmenopausal status) [7,8,14]. Despite preventing >30% of SREs, some of which correlate indirectly or directly with reduced survival [15], ZOL did not significantly increase OS in three placebo-controlled phase III trials [3–5]. This may be partially attributable to the individual trials not being powered to detect OS benefit. Additionally, in many patients death may be related more to overall disease burden or complications from visceral metastases, aspects of the disease that a bone-targeted treatment are unlikely to influence. It is now evident that overall prognosis is especially poor for patients with aggressive bone lesions (as evidenced by substantially elevated levels of the bone turnover marker N-telopeptide of type I collagen [NTX]) [16,17], greater extent of skeletal disease at baseline [18], or overall high burden of disease (e.g., reflected by hypoalbuminaemia, poor performance status [PS], or rapid weight loss) [19–23]. Additionally, rapid normalisation of elevated NTX levels during ZOL therapy has been associated with improved survival versus persistently elevated NTX levels [24,25]. These observations prompted us to perform exploratory analyses of the potential correlations between baseline disease characteristics, with particular focus on the rate of bone resorption and possible survival benefits with ZOL in patients with MBD from solid tumours who were included in three contemporaneous, phase III, placebo-controlled trials of ZOL.