Behandlung von oss?ren Metastasen und therapieinduzierter Osteoporose beim Prostatakarzinom

Patients with prostate cancer and bone metastases on average experience one skeletal-related event per year. To avoid complications caused by bone metastases and androgen deprivation therapy-induced osteoporosis, which lead to significant increases in costs and mortality, bone metabolism can be influenced in several ways. Bisphosphonates, which directly inhibit signalling pathways in osteoclasts, can reduce the rate of skeletal-related events in metastatic prostate cancer. The RANKL antibody denosumab inhibits the crosstalk between osteoblasts, osteoclasts and tumour cells and has been shown to reduce the rate of vertebral fractures in patients with treatment-induced osteoporosis. Furthermore, it has been recently shown to prevent skeletal-related events in prostate cancer patients with metastatic bone disease. In patients with castration resistant prostate cancer, denosumab prolongs bone-metastasis-free-survival. Whereas ample data are available about side effects of bisphosphonates, limited evidence exists about the long-term safety profile of denosumab. Therefore, a thorough patient selection is advocated for therapeutic application of denosumab in patients with prostate cancer.     

Breast Cancer: Rank Ligand Inhibition

Breast cancer and bone health are closely linked. Early menopause induced by gonadotropin-releasing hormone analogues or chemotherapy as well as aromatase inhibitors reduce oestrogen levels, thereby causing cancer treatment-induced bone loss (CTIBL). Furthermore, bone metastases are commonly found in advanced disease. Current treatment options for bone lesions comprise systemic anti-tumour therapy, irradiation, surgery and bisphosphonates. The main mechanism of osteolysis, osteoclast activation, is induced by the RANK ligand and suppressed by osteoprotegerin (OPG). A human antibody targeting the RANK ligand, denosumab, had superior activity compared to OPG and was therefore further developed in the clinical setting. This article reviews clinical data on denosumab. Data were obtained by searching the Medline database and abstracts from the ASCO annual meeting, ASCO breast meeting, ECCO, ESMO, and the San Antonio Breast Cancer Symposium. Clinical trials have demonstrated that denosumab reduces markers of bone turnover, and suggest equal efficacy to bisphosphonates in reducing the rate of skeletal-related events. While overall fewer side effects were observed, a numerically increased rate of osteonecrosis of the jaw was reported. Denosumab was well tolerated, and clinical activity was similar to bisphosphonates in metastatic disease. Trials of denosumab in the prevention of CTIBL are ongoing.     

Bone targeted therapy for preventing skeletal-related events in metastatic breast cancer

Cancer cells can alter physiological mechanisms within bone resulting in high bone turnover, and consequently in skeletal-related events (SREs), causing severe morbidity in affected patients. The goals of bone targeted therapy, as bisphosphonates and denosumab, are the reduction of incidence and the delay in occurrence of the SREs, to improve quality of life and pain control.The toxicity profile is similar between bisphosphonates and denosumab, even if pyrexia, bone pain, arthralgia, renal failure and hypercalcemia are more common with bisphosphonates, while hypocalcemia and toothache are more frequently reported with denosumab. Osteonecrosis of the jaw (ONJ) occurred infrequently without statistically significant difference.The present review aims to provide an assessment on bone targeted therapies for preventing the occurrence of SREs in bone metastatic breast cancer patients, critically analyzing the evidence available so far on their effectiveness, in light of the different mechanisms of action. Thus, we try to provide tools for the most fitting treatment of bone metastatic breast cancer patients.We also provide an overview on the usefulness of bone turnover markers in clinical practice and new molecules currently under study for the treatment of bone metastatic disease.     

Osteoporoseprophylaxe unter Androgendeprivationstherapie

Bone loss is a frequent side effect of androgen deprivation therapy, which leads to a significant number of pathologic fractures. Prevention of osteoporosis aims at reducing skeletal-related events. The RANK ligand antibody denosumab and bisphosphonates are used for this indication. Denosumab has been shown to increase bone density and to reduce the incidence of fractures at any location by 72%. Bone density can also be increased by bisphosphonates; however, there is no conclusive evidence so far that the fracture rate can be reduced significantly. Therefore guidelines do not recommend use of these substances for this indication.     

Update on the pharmacological prevention of skeletal-related events in cancer patients

Metastases to the bone are a frequent complication of advanced cancer. Bone metastases have been linked to skeletal-related events, which is the composite endpoint used in clinical trials evaluating therapy to minimize these complications. This article discusses bisphosphonates, which are the historical standard for the prevention of skeletal-related events in patients with metastases from solid tumors and multiple myeloma, and denosumab, which is the first Food and Drug Administration-approved receptor activator of nuclear factor kappa-β ligand (RANKL) inhibitor.     

On the horizon: can bisphosphonates prevent bone metastases?

Skeletal complications of bone metastases increase the risk of death and undermine patients' functional independence and quality of life. Although bisphosphonates are integral in the treatment regimen of patients with metastatic bone disease and have demonstrated efficacy in delaying the onset and reducing the incidence of skeletal-related events, there is great interest in developing treatments to prevent metastasis to bone. Emerging evidence indicates that the potential benefits of bisphosphonate therapy extend beyond the treatment of metastatic bone lesions. Data from preclinical studies suggest that bisphosphonates may have antitumour activity and may prevent bone metastasis. The mechanisms of these antitumour effects are currently under investigation and may include induction of apoptosis, inhibition of tumour cell invasion and angiogenesis, and tumour growth reduction. Therefore, patients with early-stage disease may benefit from early bisphosphonate therapy, before bone metastasis develops, and investigations are ongoing to determine the clinical utility of bisphosphonates in this setting.     

Individualized Bone-Protective Management in Long-Term Cancer Survivors With Bone Metastases

Antiresorptive therapy is an important component of a multimodal approach to treating patients with advanced malignancies and metastatic bone disease. Over the past decade, overall survival of affected patients has improved in most cancer entities, and long-term disease control is a realistic goal in many cases. There are emerging clinical studies showing the benefits of an initial antiresorptive therapy using bisphosphonates or denosumab. However, some adverse events of these therapies, such as osteonecrosis of the jaw, correlate with the cumulative doses given, and there is an increasing clinical need for new antiresorptive concepts to treat long-term survivors. This review summarizes the clinical evidence of antiresorptive therapies across different cancers with bone involvement and presents concepts of dose-reduction protocols for long-term survivors with established metastatic bone disease. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Die oss?re Metastasierung des Prostatakarzinoms

Bone metastasis and skeletal complications have a devastating impact on the quality of life and are a major cause of morbidity in prostate cancer patients. In addition to established bone-targeted therapies, new drugs such as endothelin A receptor antagonists, MET and VEGFR-2 antagonists or radiopharmaceuticals are in the focus of development. The standard care in prostate cancer patients with bone metastases to prevent skeletal-related events (SRE) are bisphosphonates. Denosumab, a human monoclonal antibody against RANKL, appeared to be superior to zoledronic acid for prevention of SRE and has been shown to prolong bone metastases-free survival. In contrast to zoledronic acid, denosumab clearance is not dependent on kidney function and can be administered subcutaneously. Similar rates of toxicity were observed for both substances; however, long-term data for denosumab are limited.     

Avances en la prevención y el tratamiento de las metástasis óseas en cáncer de próstata. Papel de la inhibición de RANK/RANKL

BackgroundBone metastases are a common complication of prostate cancer, so treatment and prevention are essential to slow the progression of the disease and the occurrence of skeletal related events (SREs), which have devastating consequences for the quality of life of patients.Evidence acquisitionWe reviewed the literature based on analysis of clinical trials developed in the prevention and treatment of bone metastases and in the new strategies in place with association of new therapeutic targets.Summary of evidenceBone metastases are characterized by increased bone turnover and altered balance between osteogenesis and osteolysis, with activation of the RANK and its ligand (RANKL). In patients with metastatic prostate cancer, bisphosphonates have been the bone-targeted agents most commonly used to date. Zoledronic acid has demonstrated efficacy in the reduction and delay of SREs in patients with bone metastases. Denosumab, a RANKL inhibitor, has been demonstrated to be superior to zoledronic acid in the prevention of SREs in castration-resistant prostate cancer (CRPC). Both agents are being considered, along with other new bone-targeted agents, for the prevention of bone metastases in patients with nonmetastatic CRPC, where denosumab has already demonstrated superiority over placebo.ConclusionsDenosumab and zoledronic acid prevent SREs in patients with prostate cancer and bone metastases. Denosumab also has a potential role in delaying bone metastases in nonmetastatic patients. Advances in the treatment of CRPC include an increasing focus on prevention of the progression of bone disease.     

Bisphosphonates and breast cancer incidence and recurrence

Bisphosphonates are commonly used in patients with breast cancer to reduce skeletal-related events in metastatic disease and to mitigate bone loss associated with adjuvant therapy. Preclinical studies have shown that bisphosphonates may directly inhibit breast cancer cell proliferation and metastasis. Clinical trials evaluating the oral bisphosphonate clodronate as a component of adjuvant therapy identified a potential reduction in cancer recurrence. Subsequently, trials of zoledronic acid have demonstrated prolonged disease-free survival in postmenopausal or otherwise estrogen-depleted women with early breast cancer. In the ABCSG-12 trial, the addition of twice-yearly zoledronic acid (4 mg IV) to adjuvant endocrine therapy improved disease-free survival in premenopausal women undergoing ovarian suppression. Similar results were observed in postmenopausal women receiving aromatase inhibitors in the ZO-FAST trial, and in women who were at least 5 years past menopause in the AZURE trial. Four recent observational studies (2 cohort studies and 2 case-control analyses) generally support an association between oral bisphosphonate use and lower breast cancer incidence. Ongoing breast cancer adjuvant clinical trials are further evaluating bisphosphonates and, by their influence on contralateral cancers, may provide more evidence regarding the potential of bisphosphonates for breast cancer prevention.     

Are bisphosphonates an indispensable tool in the era of targeted therapy for renal cell carcinoma and bone metastases?

One third of patients with metastatic renal cell carcinoma (RCC) suffer from bone metastases. Skeletal involvement in RCC is associated with the occurrence of skeletal-related events, and may negatively impact on the outcome of patients treated with systemic therapies. In patients with RCC and bone metastases, therapies that inhibit osteoclasts, as bisphosphonates and denosumab, are used as adjunct to systemic targeted therapies to prevent skeletal-related events. Data suggest that they may also improve the outcome of systemic targeted therapies. Herein we review the preclinical and clinical data on their use, as well as remaining open questions.     

Androgen Deprivation and Bone

Bone health in men with prostate cancer on androgen deprivation therapy (ADT) has gained increased attention in recent years. Therapies that are becoming available to prevent bone loss and associated complications are changing practice for this patient population. In addition to basic vitamin D and calcium supplementation, bisphosphonates may be an option to treat these patients, and denosumab, a receptor activator of nuclear factor-κB ligand inhibitor, has been proven to be effective in preventing bone loss through a randomized clinical trial. This review examines the importance of bone health in patients on ADT, with an overview of available treatment modalities and guidelines for managing these patients.     

Bisphosphonates in oncology

Bone metastases result in considerable morbidity, often affecting quality of life and independence over years, and may place complex demands on health care resources. The bisphosphonates have been shown to reduce skeletal morbidity in multiple myeloma and solid tumours affecting bone by 30-50%. Quite appropriately, these agents are increasingly used alongside anticancer treatments to prevent skeletal complications and relieve bone pain. The use of bisphosphonates in early cancer has become increasingly important to prevent adverse effects of cancer treatments on bone health. These include chemotherapy induced ovarian failure and the use of aromatase inhibitors in breast cancer and androgen deprivation therapy in prostate cancer. Bisphosphonate strategies, similar to those used to treat post-menopausal osteoporosis, are the intervention of choice for patients with low bone mineral density or rapid bone loss, along with adequate calcium and vitamin D intake and a healthy lifestyle. There is a strong preclinical rationale for bisphosphonates to prevent metastasis, primarily through inhibition of the vicious cycle of metastasis within the microenvironment. Recent data suggest that adjuvant bisphosphonates, at least in some patient subgroups, may modify the course of the disease and disrupt the metastatic process, reducing the risks of disease recurrence. In comparison to most other cancer treatments, adverse events related to bisphosphonate therapy are generally mild and infrequent; thus, the benefits of treatment within licensed indications will almost always outweigh the risks.     

Which Bone-Modifying Agent is Associated with Better Outcomes in Patients with Skeletal Metastases from Lung Cancer? A Systematic Review and Network Meta-analysis

BackgroundLung cancer is one of the most commonly diagnosed cancers and is the leading cause of cancer-related deaths. Metastatic bone disease occurs in 20% to 40% of patients with lung cancer, and these patients often present with pain or skeletal-related events (SREs) that are associated with decreased survival. Bone-modifying agents such as denosumab or bisphosphonates are routinely used; however, to our knowledge, there has been no quantitative synthesis of randomized controlled trial data to determine the most effective pharmacologic treatment of metastatic bone disease because of lung cancer.Questions/purposesWe aimed to perform a network meta-analysis of randomized trials to identify the bone-modifying agent that is associated with the (1) highest overall survival, (2) longest time to SRE, (3) lowest SRE incidence, and (4) greatest likelihood of pain resolution.MethodsWe conducted our study according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol and pre-registered the analysis on PROSPERO (ID: CRD42019124364). We performed a librarian-assisted search of MEDLINE, PubMed, EMBASE, Cochrane Library, and Chinese databases including China National Knowledge Infrastructure and Wanfang Data. We included randomized controlled trials reporting outcomes specifically for patients with lung cancer treated with a bisphosphonate or denosumab. SREs included pathologic fractures, spinal cord compression, hypercalcemia of malignancy, or pain resulting in surgical intervention or radiation therapy. We excluded trials exclusively reporting surrogate outcomes such as changes in bone turnover markers. Screening, data extraction, risk of bias evaluation, and Grading of Recommendations Assessment, Development, and Evaluation evaluations were performed in duplicate. We included 131 randomized controlled trials that evaluated 11,105 patients with skeletal metastases from lung cancer. The network meta-analysis was performed using a frequentist model and the R statistical software. Results are reported as relative risks or mean differences, and the I² value is reported for heterogeneity. The P-score, a measure of ranking certainty that accounts for standard error, is reported for each outcome. Heterogeneity in the network was considered moderate for overall survival and time to SRE, mild for the incidence of SRE, and low for pain resolution.ResultsFor overall survival, denosumab was ranked above zoledronic acid and estimated to confer a mean of 3.3 months (95% CI 0.3-6.3) of increased overall survival compared with untreated patients (P-score = 89%). For the time to SRE, denosumab was ranked first with a mean of 9.1 additional SRE-free months (95% CI 6.7-11.5) compared with untreated patients (P-score = 99%), while zoledronic acid conferred an additional 4.8 SRE-free months (95% CI 3.6-6.1). Reduction in the incidence of SREs was not different between patients treated with denosumab (relative risk 0.54; 95% CI 0.33-0.87) and those treated with zoledronic acid (relative risk 0.56; 95% CI 0.46-0.67). Patients treated with the combination of ibandronate and systemic therapy were more likely to experience successful pain resolution than untreated patients (relative risk 2.4; 95% CI 1.8-3.2).ConclusionIn this comprehensive synthesis of all available randomized controlled trial evidence guiding the pharmacologic treatment of bone metastases from lung cancer, denosumab was ranked above zoledronic acid for overall survival and time to SRE and was not different for reducing the incidence of SRE. Both were superior to no treatment for each of these outcomes. Given this, we encourage physicians to consider the use of denosumab or zoledronic acid in treating this patient population. The combination of ibandronate and systemic therapy was the most effective at reducing pain because of metastases. No cost-effectiveness analysis has yet been performed for denosumab and zoledronic acid on patients with metastatic lung cancer, and this represents an avenue for future research.Level of EvidenceLevel I, therapeutic study.     

Epidemiology and pathogenesis of osteonecrosis of the jaw

Osteonecrosis of the jaw (ONJ) is defined as exposed bone in the oral cavity that persists despite appropriate therapy. Over the past decade, ONJ has been reported in about 5% of patients with cancer receiving high-dose intravenous bisphosphonates, and more recently in similar patients treated with denosumab, another potent inhibitor of osteoclastic bone resorption. The condition has also been described in patients treated with bisphosphonates for benign diseases, such as osteoporosis, but whether bisphosphonates or denosumab increase the incidence above that seen in untreated patients of comparable age and frailty is yet to be established. The pathogenesis of ONJ is uncertain: the toxic effects of bisphosphonates in a wide variety of cells could increase susceptibility to infections in the oral cavity or impair mucosal healing, and denosumab might interfere with monocyte and macrophage function. Local osteolysis is an important defense against infection on bone surfaces that is blocked by both bisphosphonates and denosumab. Preventive dentistry prior to high-dose antiresorptive therapy is a critical measure in cancer patients, but is not usually justified in patients with osteoporosis. The management of established ONJ lesions is problematic: the greatest success seems to come from vigorous antimicrobial therapy with judicious use of surgical debridement.     

Skeletal complications of ADT: disease burden and treatment options

Therapy based on androgenic deprivation is one of the standard treatments that many prostate cancer patients receive. Moreover, its use is increasing owing to a clear expansion of the indications for this therapy in patients with localized prostate cancer. Despite classically being considered to be well tolerated, androgenic deprivation has adverse effects. Of these, the loss of mineral bone mass is particularly notable and can lead to osteoporosis, as well as an increased risk of bone fracture. Some fractures, such as hip fractures, may have serious consequences. Useful procedures such as bone densitometry can aid in the diagnosis of these conditions. Once diagnosed, decreases in mineral bone mass can be managed by dietary recommendations, general changes in lifestyle or medication. We review the most important randomized controlled trials evaluating different drugs (bisphosphonates, denosumab and toremifene) in the prevention of bone loss and in the reduction in fracture risk in prostate cancer patients treated with androgen-deprivation therapy. Following the applicable recommendations, urologists must carefully monitor the bone health of prostate cancer patients subjected to androgenic deprivation to obtain an early diagnosis and apply the appropriate general and/or therapeutic measures if necessary.     

Bone health in men receiving androgen deprivation therapy for prostate cancer

PURPOSE: Patients with recurrent or metastatic prostate cancer generally receive androgen deprivation therapy, which can result in significant loss of bone mineral density. We explored androgen deprivation therapy related bone loss in prostate cancer, current treatments and emerging therapies. MATERIALS AND METHODS: Literature published on the pathogenesis and management of androgen deprivation therapy related bone loss was compiled and interpreted. Recent drug therapy findings were reviewed, including treatment guidelines. RESULTS: Men with prostate cancer often present with bone loss and the initiation of androgen deprivation therapy can trigger further rapid decreases. This results in an increased fracture risk, and greater morbidity and mortality. Early detection of osteoporosis through androgen deprivation therapy screening and prompt initiation of therapy are critical to prevent continued decreases. Lifestyle changes such as diet, supplementation and exercise can slow the rate of bone loss. Pharmacological therapy with oral and intravenous bisphosphonates has been demonstrated to prevent or decrease the bone loss associated with androgen deprivation therapy. However, important differences exist among various bisphosphonates with respect to efficacy, compliance and toxicity. Only zoledronic acid has been shown to increase bone mineral density above baseline and provide long-term benefit by decreasing the incidence of fracture and other skeletal related events in men with bone metastases. CONCLUSIONS: Androgen deprivation therapy associated bone loss adversely affects bone health, patient quality of life and survival in men with prostate cancer. Increased awareness of this issue, identification of risk factors, lifestyle modification and initiation of bisphosphonate therapy can improve outcomes. Education of patients and physicians regarding the importance of screening, prevention and treatment is essential.     

Treatment of Bone Metastases in Patients with Advanced Breast Cancer

Bone metastases are usually associated with a variety of skeletal related events (SREs), a term covering both complications (pathological fractures, spinal cord compression) and the need for therapeutic intervention (radiotherapy, surgery to bone) for painful bone lesions and/or lesions carrying a high risk of fracture by which the patient's quality of life, functioning, and independence may be compromised. In view of the availability of improved therapeutic approaches for oncological diseases and the resulting improvements of median overall survival, the aim of preventing and delaying the occurrence of SREs becomes more important. To avoid, wherever possible, therapies requiring hospitalization, is another relevant goal. In recent years, bisphosphonates, along with available tumor-specific medication (chemotherapy, hormone therapy), constituted the standard of care for preventing skeletal complications in treating patients with bone metastases. Recently, a therapeutical alternative with potentially superior efficacy has been found in denosumab, a fully human monoclonal antibody that binds to the receptor activator of nuclear factor-κB ligand (RANKL), thus preventing osteoclast-mediated bone resorption and specifically interfering with bone metabolism.     

Bisphosphonates in Breast Cancer Patients with Bone Metastases

Morbidity and mortality in breast cancer patients are mainly caused by organ failure as a result of distant metastasis. The main target of metastatic disease is the skeleton (next to lungs and liver). Osseous metastases are diagnosed in 75-80% of all women who die due to breast cancer; and the skeleton is the primary metastatic target organ in more than half of these cases. In Germany, the incidence of breast cancer patients with newly diagnosed bone metastases is approximately 11-12,000 cases. Prevalence might amount to 40,000 cases of women with breast cancer and osseous metastases at a median survival time of 3-4 years. The treatment goal at this stage of the disease comprises improvement of quality of life, and reduction of bone pain and typical complications like fractures and hypercalcemia. By consistent use of bisphosphonates these goals can be accomplished. Bisphosphonates improve bone pain significantly and reduce the number of skeletal-related events in women with bone metastases. Bisphosphonates can be administered intravenously or orally, and are well tolerated. Nevertheless, there are side effects and complications including acute phase reaction, nephrotoxicity, osteonecrosis of the jaw, and gastrointestinal disturbances.     

Bone health in the prostate cancer patient receiving androgen deprivation therapy: a review of present and future management options

Osteoporosis and bone fractures are frequently overlooked complications of androgen deprivation therapy in men with nonmetastatic prostate cancer. All such patients should have their bone mineral density (BMD) monitored and be offered preventive measures, such as calcium and vitamin D supplementation; patients with low BMD should be offered treatment. Several agents, including bisphosphonates, are available (although this use is currently off-label), and upcoming treatments, such as denosumab and toremifene, have shown promise in reducing fracture risk in these patients.