Systematic Reviews Published in the April 2015 Issue of the Cochrane Library

The Cochrane Library of Systematic Reviews is published quarterly as a DVD and monthly online (http://www.thecochranelibrary.com). The April 2015 issue (first DVD for 2015) contains 6390 complete reviews, 2410 protocols for reviews in production, and 36,600 short summaries of systematic reviews published in the general medical literature. In addition, there are citations of 848,000 randomized controlled trials, and 15,700 cited papers in the Cochrane Methodology Register. The Health Technology Assessment database contains some 15,000 citations. One hundred new reviews have been published in the previous 3 months, of which five have potential relevance for practitioners in pain and palliative medicine. The impact factor of the Cochrane Library stands at 5.939. Readers are encouraged to access the full report for any articles of interest, as only a brief commentary is provided.     

Pharmacotherapeutic options for complex regional pain syndrome

Introduction: Complex regional pain syndromes (CRPS) are rare painful conditions characterized by considerable variability in possible triggering factors, usually traumatic, and in the clinical scenario. The limited knowledge of the pathophysiological mechanisms has led to countless treatment attempts with multiple conservative and surgical options that act by different mechanisms of action.

Areas covered: In this narrative review, the authors discuss key points about CRPS definitions, diagnostic criteria and pitfalls, pathophysiological hypotheses, and treatment strategies with particular reference to pharmacotherapy. The article was based on a literature search using PubMed while the available guidelines for the management of CRPS were also examined.

Expert opinion: According to the quality of evidence, pharmacological interventions for CRPS seem to be more effective all the more so when they act on peripheral mechanisms, particularly on nociceptive pain, and when applied early in the disease, while reliable evidence about central mechanisms of chronic pain in CRPS is lacking. In our opinion, drug therapy should be preferred as early as possible, particularly in warm forms of CRPS to prevent significant functional limitation, psychological distress, and social and economic fallout.     

Biological effects of aromatic bis[aminomethylidenebis(phosphonic)] acids in osteoclast precursors in vitro

Nitrogen‐containing bisphosphonates (N‐BPs) inhibit bone resorption by preventing osteoclast activity. Most clinically used BPs are hydroxybisphosphonates with the exception of incadronate, which belongs to the class of aminomethylidenebisphosphonic acids. The aim of this study was to evaluate the antiproliferative activity of two previously reported aminobisphosphonates (WG8185B2 and WG9001B) in combination with doxorubicin and cisplatin toward J774E cells (a model of osteoclast precursors in vitro). WG8185B2 and WG9001B BPs enhanced the cytotoxic activity of doxorubicin and cisplatin, especially when applied 24 hr prior to cytostatics. The antiproliferative effect of studied BPs was related to the changes in cell cycle progression. WG8185B2 leads to significant accumulation of J774E cells in S phase, whereas WG9001B causes transient arrest in G₂/M phase, followed by an increase in the percentage of cells in S phase. Moreover, WG8185B2 and WG9001B BPs showed enhanced proapoptotic activity in osteoclast precursors, which was manifested by an increase in caspase‐3 activity and percentage of apoptotic cells. In addition, both compounds influenced the motility of J774E cells. The exact molecular mechanism of action of examined BPs remains to be determined; however, results show an interesting biological activity of these compounds, which may be of interest in the context of antiresorptive therapy.     

Medical management of polymyalgia rheumatica

Importance of the field: Polymyalgia rheumatica (PMR) is a relatively frequent condition in individuals older than 50 who originate from Western countries. Corticosteroids constitute the cornerstone therapy in the management of patients with PMR.

Areas covered in this review: This review summarizes the current literature on clinical clues for the diagnosis of PMR, conditions mimicking PMR, relapses in the setting of PMR and the main therapeutic strategies.

What the reader will gain: With this information, the reader receives an overview on the current available data on clinical diagnosis and treatment options in PMR.

Take-home messages: An initial dose of prednisone of 10 – 20 mg/day yields clinical improvement in the majority of patients with PMR. This is generally achieved within 7 days of the onset of this therapy. Conditions different from isolated PMR should be considered in atypical cases or when a good response to 20 mg/day of prednisone is not achieved. Relapses of PMR are not uncommon when the dose of prednisone is equal to or below than 5 mg/day. Methotrexate is the most commonly used corticosteroid sparing agent. Osteoporosis prophylaxis is also recommended.     

Pharmacotherapy of bone metastases in breast cancer patients – an update

Introduction: Bone metastases in breast cancer patients are a common clinical problem and pose a threat to the quality of life of such patients. Multiple randomized trials have demonstrated the benefit of both bisphosphonates and denosumab in reducing the incidence and delaying the onset of skeletal related events (SREs) in breast cancer patients with bone metastases.

Areas covered: We review the current literature on the use of bisphosphonates and denosumab along with strategies to maximize benefit and minimize risk of these agents. We also review potential future targets.

Expert opinion: Despite the potent osteoclast inhibiting effects of the bone-targeted agents in current clinical use, we have likely maximized their ability to inhibit SREs and must in turn focus on minimizing their potential toxicity. The future will likely involve more novel treatment strategies as well as the development of new agents. The current ‘one size fits all’ approach for the management of breast cancer bone metastases will be replaced by ‘tailored’ treatment for each individual patient as we usher in the era of ‘personalized medicine.’ In addition, new bone-targeted agents (e.g., sclerostin inhibitors) and combinations will continue to be explored, as will the evaluation of the bone-targeting properties of more conventional non-osteoclast targeting therapies.     

Treatment of malignant hypercalcaemia

Hypercalcaemia is a common paraneoplastic syndrome caused by the production by tumours of several factors which affect bone resorption and/or tubular calcium reabsorption. Antihypercalcaemic therapy in cancer patients involves rehydration manoeuvres, as well as the use of a variety of available drugs which inhibit bone resorption, namely plicamycin, calcitonin, bisphosphonates and gallium nitrate. While plicamycin is currently out of use because of its considerable toxicity, bisphosphonates have become the standard therapy in hypercalcaemia of malignancy (HM). These compounds are potent inhibitors of bone resorption but they do not affect tubular calcium reabsorption, which limits their efficacy in humoral HM (HHM) cases. In these patients, gallium nitrate should be the therapy of choice. Among the available bisphosphonates, pamidronate administered in a single infusion of 90 mg, normalises serum calcium levels in > 90% of HM patients. A recently introduced bisphosphonate, zoledronate, is likely to replace pamidronate as a first-line therapy in these patients. The effectiveness of calcitonin in HM treatment is limited, although it seems to be useful at the outset in cases with severe symptomatic hypercalcaemia. Future treatment options of HM are likely to include new bone resorption inhibitors, for example, naturally-occurring osteoprotegerin, or alternate approaches aimed at reducing the tumour production of parathyroid hormone-related protein with noncalcaemic analogues of calcitriol or ras-isoprenylation inhibitors. The development of putative therapeutic agents targeted to inhibit distal calcium reabsorption should be valuable in the management of HHM cases.     

Bisphosphonate anticancer activity

Bone metastases have a major impact on morbidity and on mortality in cancer patients. Despite its clinical relevance, metastasis remains the most poorly elucidated aspect of carcinogenesis. Different pathways or molecules such as RANK/RANKL/OPG, cathepsin K, endothelin-1, Wnt/DKK1 and Src have recently emerged as potential targets, and preclinical and clinical trials are now underway. The results from clinical trials indicate the importance of treating and preventing bone metastases in many different cancer populations.