Management of bone health in solid tumours: From bisphosphonates to a monoclonal antibody

Patients with solid tumours are at risk of impaired bone health from metastases and cancer therapy-induced bone loss (CTIBL). We review medical management of bone health in patients with solid tumours over the past 30 years, from first-generation bisphosphonates to the receptor activator of nuclear factor kappa B ligand (RANKL)-targeted monoclonal antibody, denosumab. In the 1980s, first-generation bisphosphonates were shown to reduce the incidence of skeletal-related events (SREs) in patients with breast cancer. Subsequently, more potent second-and third-generation bisphosphonates were developed, particularly zoledronic add (ZA). Head-to-head studies showed that ZA was significantly more effective than pamidronate for reducing SREs in patients with breast and castrate-resistant prostate cancer (CRPC), becoming the standard of care for more than a decade. The RANKL inhibitor denosumab was licensed in 2010, and head-to-head studies and integrated analyses confirmed its superiority to ZA for preventing SREs, particularly in breast cancer and CRPC. Bisphosphonates and denosumab have also been investigated for prevention of CTIBL in patients receiving hormonal therapy for breast and prostate cancer, and denosumab is licensed in this indication. Despite advances in management of bone health, several issues remain, notably the optimal time to initiate therapy, duration of therapy, and dosing frequency, and how to avoid toxicity, particularly with long-term treatment. In summary, introduction of ZA and denosumab has protected patients with bone metastasis from serious bone complications and improved their quality of life. Ongoing research will hopefully guide the optimal use of these agents to help maintain bone health in patients with solid tumours

Effects of Diode Laser, Gaseous Ozone, and Medical Dressings on Enterococcus faecalis Biofilms in the Root Canal Ex Vivo

The objective was to compare the antibacterial effects of adjunctive disinfection using diode laser and gaseous ozone compared to the medical dressings calcium hydroxide (Ca(OH)2) and chlorhexidine gel (CHX-Gel) on Enterococcus faecalis biofilms in human root canals ex vivo. Root canals of 180 human extracted teeth were infected by E. faecalis and divided into 3 main groups (G): G1, control; G2, instrumentation and irrigation using 0.9% NaCl; G3, instrumentation and irrigation using 1% NaOCl. In each main group, the following treatments were applied: gaseous ozone, diode laser, and medical dressings of Ca(OH)2 or CHX-Gel for 7 days (). Reduction of colony forming units (CFUs) inside the root canal of planktons and frequencies of adherent bacteria after treatment were calculated. Bacterial reduction was significantly affected by the irrigation protocol () and the disinfection method (), and a significant interaction between both factors could be observed (; ANOVA). In G3 (instrumentation using 1% NaOCl), no significant effect of disinfection methods could be demonstrated on planktonic bacteria (; ANOVA) and frequencies of adherent bacteria (; chi-square test). Instrumentation and irrigation using NaOCl combined with ozone or laser application resulted in comparable bacterial reduction on E. faecalis to the application of medical dressings

Hypercalcaemia and hypocalcaemia: finding the balance

Calcium metabolism in cancer and hypercalcaemia of malignancy: The balance between bone formation and resorption may be disrupted in patients with cancer, leading either to increased bone resorption, calcium release, and possibly hypercalcaemia, or to increased bone formation, sequestration of calcium, and possibly hypocalcaemia. In adults, hypercalcaemia of malignancy is most common in patients with tumours that produce factors that induce osteoclast activation and enhance bone resorption. Impaired renal function and increased renal tubular calcium resorption may further affect calcium levels. Treatment of hypercalcaemia of malignancy: Inhibitors of bone resorption, first the bisphosphonates and, later, denosumab, have been shown to be effective in hypercalcaemia treatment. Bisphosphonates (which are administered intravenously) are approved for hypercalcaemia of malignancy and are the current mainstay of treatment, whereas denosumab (which is administered subcutaneously) may offer an option for patients who do not respond to bisphosphonates or suffer from renal insufficiency. Hypocalcaemia: treatment and prevention: Hypocalcaemia is most common in patients with prostate cancer and osteoblastic bone metastases, but can occur in patients with a variety of tumour types who are receiving inhibitors of bone resorption. While patients often respond to calcium and vitamin D supplementation, prevention should be the aim; at-risk patients should be identified before starting treatment with inhibitors of bone resorption, be closely monitored during at least the first few months of treatment, and receive concomitant calcium and vitamin D supplementation unless hypercalcaemia is present. Conclusion: Both hypercalcaemia and hypocalcaemia can be serious if left untreated. It is therefore important that patients with cancer are closely monitored and receive adequate prevention and treatment measures to maintain normal blood calcium levels.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Hypocalcaemia in patients with prostate cancer treated with a bisphosphonate or denosumab: prevention supports treatment completion.

Most patients with advanced prostate cancer develop bone metastases, which often result in painful and debilitating skeletal-related events. Inhibitors of bone resorption, such as bisphosphonates and denosumab, can each reduce the incidence of skeletal-related events and delay the progression of bone pain. However, these agents are associated with an increased risk of hypocalcaemia, which, although often mild and transient, can be serious and life-threatening. Here we provide practical advice on managing the risk of hypocalcaemia in patients with advanced prostate cancer who are receiving treatment with bone resorption inhibitors. Relevant references for this review were identified through searches of PubMed with the search terms 'prostate cancer', 'bone-targeted agents', 'anti-resorptive agents', 'bisphosphonates', 'zoledronic acid', 'denosumab', 'hypocalcaemia', and 'hypocalcemia'. Additional references were suggested by the authors. Among patients with advanced cancer receiving a bisphosphonate or denosumab, hypocalcaemia occurs most frequently in those with prostate cancer, although it can occur in patients with any tumour type. Consistent with its greater ability to inhibit bone resorption, denosumab has shown superiority in the prevention of skeletal-related events in patients with bone metastases from solid tumours. Consequently, denosumab is more likely to induce hypocalcaemia than the bisphosphonates. Likewise, various bisphosphonates have differing potencies for the inhibition of bone resorption, and thus the risk of hypocalcaemia varies between different bisphosphonates. Other risk factors for the development of hypocalcaemia include the presence of osteoblastic metastases, vitamin D deficiency, and renal insufficiency. Hypocalcaemia can lead to treatment interruption, but it is both preventable and manageable. Serum calcium concentrations should be measured, and any pre-existing hypocalcaemia should be corrected, before starting treatment with inhibitors of bone resorption. Once treatment has started, concomitant administration of calcium and vitamin D supplements is essential. Calcium concentrations should be monitored during treatment with bisphosphonates or denosumab, particularly in patients at high risk of hypocalcaemia. If hypocalcaemia is diagnosed, patients should receive treatment with calcium and vitamin D. With preventative strategies and treatment, patients with prostate cancer who are at risk of, or who develop, hypocalcaemia should be able to continue to benefit from treatment with bisphosphonates or denosumab

Improving quality of life in patients with advanced cancer: Targeting metastatic bone pain

Metastatic bone disease in patients with advanced cancer is frequently associated with skeletal complications. These can be debilitating, causing pain, impaired functioning and decreased quality of life, as well as reduced survival. This review considers how the management of metastatic bone pain might be optimised, to limit the considerable burden it can impose on affected patients. Cancer-related pain is notoriously under-reported and under-treated, despite the availability of many therapeutic options. Non-opioid and opioid analgesics can be used; the latter are typically administered with radiotherapy, which forms the current standard of care for patients with metastatic bone pain. Surgery is appropriate for certain complicated cases of metastatic bone disease, and other options such as radiopharmaceuticals may provide additional relief. Treatments collectively referred to as bone-targeted agents (BTAs; bisphosphonates and denosumab) can offer further pain reduction. Initiation of therapy with BTAs is recommended for all patients with metastatic bone disease because these agents delay not only the onset of skeletal-related events but also the onset of bone pain. With evidence also emerging for pain control properties of new anticancer agents, the potential to individualise care for these patients is increased further. Optimisation of care depends on physicians' thorough appreciation of the complementary benefits that might be achieved with the various agents, as well as their limitations. Appropriate anti-tumour treatment combined with early initiation of BTAs and adequate analgesia plays a key role in the holistic approach to cancer pain management and may minimise the debilitating effects of metastatic bone pain

The role of bisphosphonates or denosumab in light of the availability of new therapies for prostate cancer.

Most men with advanced prostate cancer will develop bone metastases, which have a substantial impact on quality of life. Bone metastases can lead to skeletal-related events (SREs), which place a burden on patients and healthcare systems. For men with castration-resistant prostate cancer (CRPC) and bone metastases, the treatment landscape has evolved rapidly over the past few years. The relatively recent approvals of the hormonal agents abiraterone acetate and enzalutamide, second-line chemotherapy cabazitaxel, and the radiopharmaceutical radium-223 dichloride (radium-223), have provided clinicians with a greater choice of treatments. These compounds have benefits in terms of overall survival based on the results of pivotal phase 3 studies. The bisphosphonate zoledronic acid and the RANK ligand inhibitor denosumab are indicated for the prevention of SREs in men with metastatic CRPC but studies of these compounds have not demonstrated a survival benefit. The important question of the role of bisphosphonates or denosumab in combination with these new agents has thus materialised. Current and emerging evidence from clinical studies of abiraterone acetate, enzalutamide and radium-223, suggest that addition of bisphosphonates or denosumab to these new therapies may provide further clinical benefits for patients with prostate cancer and bone metastases. This evidence may help to shape clinical practice but are based largely on post hoc analyses of clinical trial data. It is therefore apparent that further data are required from both clinical studies and real-world settings to enable physicians to understand the efficacy and safety of combination therapy with the new agents plus bisphosphonates or denosumab