Vertebral Fractures After Discontinuation of Denosumab: A Post Hoc Analysis of the Randomized Placebo‐Controlled FREEDOM Trial and Its Extension

Denosumab reduces bone resorption and vertebral and nonvertebral fracture risk. Denosumab discontinuation increases bone turnover markers 3 months after a scheduled dose is omitted, reaching above‐baseline levels by 6 months, and decreases bone mineral density (BMD) to baseline levels by 12 months. We analyzed the risk of new or worsening vertebral fractures, especially multiple vertebral fractures, in participants who discontinued denosumab during the FREEDOM study or its Extension. Participants received ≥2 doses of denosumab or placebo Q6M, discontinued treatment, and stayed in the study ≥7 months after the last dose. Of 1001 participants who discontinued denosumab during FREEDOM or Extension, the vertebral fracture rate increased from 1.2 per 100 participant‐years during the on‐treatment period to 7.1, similar to participants who received and then discontinued placebo (n = 470; 8.5 per 100 participant‐years). Among participants with ≥1 off‐treatment vertebral fracture, the proportion with multiple (>1) was larger among those who discontinued denosumab (60.7%) than placebo (38.7%; p = 0.049), corresponding to a 3.4% and 2.2% risk of multiple vertebral fractures, respectively. The odds (95% confidence interval) of developing multiple vertebral fractures after stopping denosumab were 3.9 (2.1–7. 2) times higher in those with prior vertebral fractures, sustained before or during treatment, than those without, and 1.6 (1.3–1.9) times higher with each additional year of off‐treatment follow‐up; among participants with available off‐treatment total hip (TH) BMD measurements, the odds were 1.2 (1.1–1.3) times higher per 1% annualized TH BMD loss. The rates (per 100 participant‐years) of nonvertebral fractures during the off‐treatment period were similar (2.8, denosumab; 3.8, placebo). The vertebral fracture rate increased upon denosumab discontinuation to the level observed in untreated participants. A majority of participants who sustained a vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with greatest risk in participants with a prior vertebral fracture. Therefore, patients who discontinue denosumab should rapidly transition to an alternative antiresorptive treatment. Clinicaltrails.gov : NCT00089791 (FREEDOM) and NCT00523341 (Extension). © 2017 American Society for Bone and Mineral Research.     

Clinical Features of 24 Patients With Rebound‐Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases

We aimed to study the clinical and imaging characteristics of patients sustaining vertebral fractures after denosumab discontinuation. For this purpose, we conducted a computerized advanced literature search that identified 13 published cases, and we additionally included another 11 new cases from our centers. Twenty‐four postmenopausal women with vertebral fracture(s) after denosumab discontinuation, experiencing 112 fractures in total, were analyzed. The mean number of fractures per patient was 4.7. The most commonly affected vertebrae were T12 and L1. All fractures occurred 8 to 16 months after the last denosumab injection. Eighty‐three percent of the patients were treatment naïve, whereas 33% had prevalent vertebral fractures. Five (23%) patients were on concurrent aromatase inhibitor treatment. When patients were divided according to treatment duration with an arbitrary cut‐off of 2 years, those with ≤2 years of denosumab treatment had fewer fractures compared with those with >2 years (mean ± SEM fractures 3.2 ± 0.7 versus 5.2 ± 1.4, p = 0.055). Vertebroplasty was used in 5 patients, resulting in additional clinical vertebral fractures in all cases. We conclude that vertebral fracture(s) after denosumab discontinuation are in the majority of patients multiples, and they occur a few months after the effect of the last dose is depleted. Therefore, patients should not delay or omit denosumab doses. Fractures are typically osteoporotic, located at the lower thoracic and the upper lumbar spine. Vertebroplasty is an unsuccessful treatment strategy for such patients. © 2017 American Society for Bone and Mineral Research.     

A Single Infusion of Zoledronate in Postmenopausal Women Following Denosumab Discontinuation Results in Partial Conservation of Bone Mass Gains

Discontinuation of denosumab is associated with a rapid return of bone mineral density (BMD) to baseline and an increased risk of multiple vertebral fractures. No subsequent treatment regimen has yet been established for preventing either loss of BMD or multiple vertebral fractures after denosumab discontinuation. The aim of this 8-year observational study was to investigate the effect of a single zoledronate infusion, administered 6 months after the last denosumab injection, on fracture occurrence and loss of BMD. We report on 120 women with postmenopausal osteoporosis who were treated with 60 mg denosumab every 6 months for 2 to 5 years (mean duration 3 years) and then 5 mg zoledronate 6 months after the last denosumab injection. All patients were evaluated clinically, by dual-energy X-ray absorptiometry (DXA) and vertebral fracture assessment (VFA), before the first and after the last denosumab injection and at 2.5 years (median) after denosumab discontinuation. During this off-treatment period, 3 vertebral fractures (1.1 per 100 patient-years) and 4 nonvertebral fractures (1.5 per 100 patient-years) occurred. No patients developed multiple vertebral fractures. Sixty-six percent (confidence interval [CI] 57% to 75%) of BMD gained with denosumab was retained at the lumbar spine and 49% (CI 31% to 67%) at the total hip. There was no significant difference in the decrease of BMD between patients with BMD gains of >9% versus <9% while treated with denosumab. Previous antiresorptive treatment or prevalent fractures had no impact on the decrease of BMD, and all bone loss occurred within the first 18 months after zoledronate infusion. In conclusion, a single infusion of 5 mg zoledronate after a 2- to 5-year denosumab treatment cycle retained more than half of the gained BMD and was not associated with multiple vertebral fractures, as reported in patients who discontinued denosumab without subsequent bisphosphonate treatment. © 2020 American Society for Bone and Mineral Research.     

Efficacy of Antiosteoporotic Medications in Patients With Rebound-Associated Fractures After Denosumab Discontinuation

Denosumab discontinuation results in rapid bone loss and increased risk of multiple rebound-associated vertebral fractures (RAVFs). The optimal treatment for patients who have sustained such fractures is currently unknown. We aimed to investigate the bone mineral density (BMD) changes achieved with various regimens in postmenopausal women who had sustained RAVFs after denosumab discontinuation in everyday clinical practice. In this multicenter, retrospective observational study, 39 Greek postmenopausal women from six regional bone centers throughout Greece with RAVFs after denosumab discontinuation were included. We collected BMD and fracture data before and 1 year after treatment with denosumab (n = 20), teriparatide (n = 8), zoledronate (n = 8) or teriparatide/denosumab combination (n = 3). Both lumbar spine (LS)-- and femoral neck (FN)-BMD were preserved with all regimens used. With the exception of zoledronate, a trend towards increase was observed with all regimens in LS-BMD. Three patients sustained additional fractures despite treatment reinstitution (2 with zoledronate and 1 with teriparatide). Among patients with RAVFs following denosumab discontinuation both antiresorptive (zoledronate and denosumab) and anabolic (teriparatide) treatment as well as the combination of denosumab with teriparatide seem to be effective in terms of BMD response.     

Elevated incidence of fractures in women with invasive breast cancer

Summary

This study evaluates the incidence of bone fractures in women with BC.We found that women with invasive breast cancer are at an increased risk for bone fractures, with fractures most commonly occurring at lower extremity and vertebral sites. The risk is further increased in women undergoing cancer therapy.

Introduction

Bone loss and fractures in breast cancer have generally been attributed to aromatase inhibitor use. This study assessed the incidence of fractures after invasive breast cancer diagnosis and evaluated bone density and FRAX risk calculation at time of fracture occurrence.

Methods

Retrospective cohort study of women with invasive breast cancer [June 2003–December 2011] who participated in an academic hospital based genetic biobank. Demographic and clinical characteristics were abstracted from the electronic medical record (EMR).

Results

A total of 422 women with invasive breast cancer were assessed; 79 (28 %) sustained fractures during the observation period; fractures occurred at multiple skeletal sites in 27 cases (116 fractures). The incidence of fractures was 40 per 1000 person-years. Women who sustained fractures were mostly white and had a family history of osteoporosis (36.9 %, p?=?0.03) or history of a prior fracture (6/79, p?=?0.004). Fractures occurred 4.0 years (range 0–12 years) after cancer diagnosis. Fracture cases had femoral neck bone mineral density (BMD) of 0.72?+?0.12 g/cm², T-score of ?1.2, that is, within the low bone mass range. Fractures most commonly occurred in lower extremities, vertebral, and wrist sites. Hip fractures accounted for 11 % of fractures, occurring at a median age of 61 years.

Conclusions

Fractures occur shortly after commencing cancer therapy. Rapid bone loss associated with cancer therapy may precipitate fractures. Fractures occur at relatively higher BMD in BC. Occurrence of fractures in invasive breast cancer raises the possibility of cancer-induced impairment in bone quality.

     

Bone Mass Gains After One Denosumab Injection Followed by Zoledronate

Denosumab discontinuation can lead to bone loss despite subsequent bisphosphonate therapy. This bone loss is more severe in patients treated with denosumab for longer than 3 years. We aimed to evaluate the bone mass changes after only a single denosumab injection followed by zoledronate administration. We screened all of our patients who received a single denosumab injection and who were included in the osteoporosis register from the Swiss Society of Rheumatology between August 1, 2010, and January 31, 2022. This case series assessed the outcome of patients who were consecutively treated with one denosumab injection followed by a single infusion of zoledronate 6 months later. Bone mineral density (BMD) and bone turnover markers (BTM) changes were analysed before therapy and 18 months later. Percentage BMD changes and T-scores were compared with those of registered patients who received 2.5 years of denosumab treatment and one subsequent infusion of zoledronate. Thirty-two patients (31 female, 1 male) received a single denosumab injection and one zoledronate infusion 6 months later. BTM decreased significantly in this period (p = 0.035). Percentage BMD changes from baseline to 1 year after zoledronate treatment were 7.6% [IQR 3.2, 9.4] at the lumbar spine, 3.5% [1.8, 5.9] at the total hip and 4.6% [1.3, 6.0] at the femoral neck. In contrast, percentage changes from baseline in 110 patients with 2.5 years of denosumab treatment and one zoledronate infusion were 5.6% [3.0, 9.1], 2.3% [0.2, 4.9] and 2.3% [?0.9, 4.7], respectively. Differences between the 2 groups were significant at the lumbar spine (p = 0.014), total hip (p = 0.010) and femoral neck (p = 0.010).A single denosumab injection followed by zoledronate led to a remarkable gain of BMD at the lumbar spine and hip within a short time. This observation could help to identify a new short treatment sequence for patients with osteoporosis.     

FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab

Romosozumab is a bone‐forming agent with a dual effect of increasing bone formation and decreasing bone resorption. In FRActure study in postmenopausal woMen with ostEoporosis (FRAME), postmenopausal women with osteoporosis received romosozumab 210 mg s.c. or placebo once monthly for 12 months, followed by denosumab 60 mg s.c. once every 6 months in both groups for 12 months. One year of romosozumab increased spine and hip BMD by 13% and 7%, respectively, and reduced vertebral and clinical fractures with persistent fracture risk reduction upon transition to denosumab over 24 months. Here, we further characterize the BMD gains with romosozumab by quantifying the percentages of patients who responded at varying magnitudes; report the mean T‐score changes from baseline over the 2‐year study and contrast these results with the long‐term BMD gains seen with denosumab during Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) and its Extension studies; and assess fracture incidence rates in year 2, when all patients received denosumab. Among 7180 patients (n = 3591 placebo, n = 3589 romosozumab), most romosozumab‐treated patients experienced ≥3% gains in BMD from baseline at month 12 (spine, 96%; hip, 78%) compared with placebo (spine, 22%; hip, 16%). For romosozumab patients, mean absolute T‐score increases at the spine and hip were 0.88 and 0.32, respectively, at 12 months (placebo: 0.03 and 0.01) and 1.11 and 0.45 at 24 months (placebo‐to‐denosumab: 0.38 and 0.17), with the 2‐year gains approximating the effect of 7 years of continuous denosumab administration. Patients receiving romosozumab versus placebo in year 1 had significantly fewer vertebral fractures in year 2 (81% relative reduction; p < 0.001), with fewer fractures consistently observed across other fracture categories. The data support the clinical benefit of rebuilding the skeletal foundation with romosozumab before transitioning to antiresorptive therapy. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.     

Progression of Rebound-Associated Vertebral Fractures Following Denosumab Discontinuation Despite Reinstitution of Treatment: Suppressing Increased Bone Turnover May Not Be Enough

Rebound-associated vertebral fractures (RAVFs) could occur in a minority of the patients who discontinue denosumab. In such patients, denosumab is often reinstituted to rapidly suppress bone turnover and avert the risk of additional fractures. Herein we report the cases of 2 patients who sustained RAVFs, and in whom resuming denosumab treatment did not avert the occurrence of new RAVFs a few months later, despite the suppression of bone turnover markers. It seems that denosumab reinstitution cannot completely eliminate the risk of new RAVFs and that the rebound of bone turnover may not be the sole mechanism to explain this phenomenon.     

Cancer-associated bone disease

Bone is commonly affected in cancer. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition, causing bone fragility. Bone-modifying agents, such as bisphosphonates and denosumab, are efficacious in preventing and delaying cancer-related bone disease. With evidence-based care pathways, guidelines assist physicians in clinical decision-making. Of the 57 million deaths in 2008 worldwide, almost two thirds were due to non-communicable diseases, led by cardiovascular diseases and cancers. Bone is a commonly affected organ in cancer, and although the incidence of metastatic bone disease is not well defined, it is estimated that around half of patients who die from cancer in the USA each year have bone involvement. Furthermore, cancer-induced bone disease can result from the primary disease itself, either due to circulating bone resorbing substances or metastatic bone disease, such as commonly occurs with breast, lung and prostate cancer, or from therapies administered to treat the primary condition thus causing bone loss and fractures. Treatment-induced osteoporosis may occur in the setting of glucocorticoid therapy or oestrogen deprivation therapy, chemotherapy-induced ovarian failure and androgen deprivation therapy. Tumour skeletal-related events include pathologic fractures, spinal cord compression, surgery and radiotherapy to bone and may or may not include hypercalcaemia of malignancy while skeletal complication refers to pain and other symptoms. Some evidence demonstrates the efficacy of various interventions including bone-modifying agents, such as bisphosphonates and denosumab, in preventing or delaying cancer-related bone disease. The latter includes treatment of patients with metastatic skeletal lesions in general, adjuvant treatment of breast and prostate cancer in particular, and the prevention of cancer-associated bone disease. This has led to the development of guidelines by several societies and working groups to assist physicians in clinical decision making, providing them with evidence-based care pathways to prevent skeletal-related events and bone loss. The goal of this paper is to put forth an IOF position paper addressing bone diseases and cancer and summarizing the position papers of other organizations.     

Vertebral compression fractures in patients under treatment with denosumab: a contraindication for percutaneous vertebroplasty?

Background contextDenosumab (XGeva) is a receptor activator of nuclear factor-κB ligand (RANKL)–antibody that was approved by the Food and Drug Administration (FDA) in 2010 for the prevention of skeletal fractures in patients with bone metastases from solid tumors. Although there is a widespread use of such drug in patients under risk of pathological fractures, the compatibility of denosumab therapy with percutaneous vertebroplasty (an interventional procedure commonly used for pain control in such population) has not yet been established.PurposeTo present the serial imaging findings and technical report of an attempted percutaneous vertebroplasty in a patient with refractory pain and a lytic pathological vertebral fracture related to small cell lung cancer spinal metastasis and who was actively under medical treatment with denosumab.Study designRetrospective review and case report.MethodsThe authors present the imaging findings and technical report of an attempted percutaneous vertebroplasty in the only patient found to be actively under treatment with denosumab after a retrospective review of the databank of patients with pathological fractures referred to the Department of Radiology of the Ohio State University for percutaneous vertebroplasty (a total sample of 20 patients) since the FDA approval of denosumab (November 2010) until June 2013 (a 30-month period).ResultsAlthough the computed tomography scan of the thoracic spine, performed 6 weeks after the initiation of the treatment with denosumab, presented a remarkable remodeling of the previously lytic vertebral lesion (which became markedly sclerotic in appearance), the clinical response in terms of pain improvement was not satisfactory. At the time of the percutaneous vertebroplasty (which was indicated for pain control), after advancing the 11-gauge needle through the pedicle with extreme difficulty, the needle repeatedly deviated laterally and, despite several attempts, it was not possible to penetrate the vertebral body and perform the cement injection.ConclusionsThis is the first report of the technical peculiarities of percutaneous vertebroplasty in patients under medical treatment with denosumab. According to our experience, because of its RANKL-mediated effects on osteoclasts activity, denosumab has been shown to induce a fast and marked sclerotic response on vertebral bodies that may not be accompanied by a satisfactory improvement in pain control (especially in patients with mechanical type of pain) and which may actually prevent the successful performance of percutaneous vertebroplasty. Therefore, it is of paramount importance that future studies evaluating patients with vertebral fractures under treatment with denosumab include long-term pain outcome measures. Additionally, further investigation is warranted to determine the optimal order of treatment and the best timeframe for combining percutaneous vertebroplasty and denosumab therapy in patients presenting with acute vertebral compression fractures and refractory axial pain.     

RANK Ligand-targeted Therapy: A Novel Approach to Prevent Bone Loss and Fractures in Men with Prostate Cancer

ContextThe importance of bone loss associated with both prostate cancer (PCa) and its treatment is being increasingly recognised, and new options to manage this complication are in development.ObjectiveTo assess the impact of androgen-deprivation therapy (ADT) on bone and to outline recently reported and ongoing phase 3 studies of agents designed to prevent bone loss and fractures in men with PCa.Evidence acquisitionThis article is based on a presentation at an Amgen-sponsored satellite symposium held at the European Association of Urology Congress in Stockholm, Sweden, in March 2009.Evidence synthesisADT for PCa is associated with bone loss and an increased fracture risk. Several bisphosphonates have been shown to improve bone mineral density (BMD) during ADT, but their effects on treatment-related fractures are unknown. Denosumab, a fully human monoclonal antibody to RANK Ligand, is being investigated for the management of bone loss associated with PCa. The results of a phase 3 randomised, placebo-controlled trial of denosumab to prevent bone loss and fractures during ADT in men with PCa have recently been reported. Compared with placebo, denosumab (60 mg subcutaneously every 6 mo) significantly reduced the incidence of new vertebral fractures by 62% after 3 yr. Denosumab also increased BMD significantly at various skeletal sites, including the spine, hip, and wrist.ConclusionsADT decreases BMD and increases fracture risk in men with PCa. A recent phase 3 study has demonstrated that denosumab increases BMD and significantly reduces the risk of new vertebral fractures in men with PCa. Two ongoing phase 3 studies are evaluating denosumab for the prevention and treatment of bone metastases in men with castration-resistant prostate cancer.     

Guidance for the prevention of bone loss and fractures in postmenopausal women treated with aromatase inhibitors for breast cancer: an ESCEO position paper

Summary

Aromatase inhibitors (AIs) are widely used in women with breast cancer, but they are known to increase bone loss and risk of fractures. Based on available evidence and recommendations, an ESCEO working group proposes specific guidance for the prevention of AIs-induced bone loss and fragility fractures.

Introduction

Aromatase inhibitors (AIs) are now the standard treatment for hormone receptor-positive breast cancer. However, deleterious effects of AIs on bone health have been reported. An ESCEO working group proposes guidance for the prevention of bone loss and fragility fractures in post-menopausal women with breast cancer receiving AIs.

Methods

A panel of experts addressed the issue of skeletal effects of AIs and effectiveness of antifracture therapies for the prevention of AI-induced bone loss and fractures. Recommendations by national and international organizations, and experts’ opinions on this topic were evaluated.

Results

All aromatase inhibitors are associated with negative effects on the skeleton, resulting in bone loss and increased risk of fragility fractures. Current guidelines suggest approaches that differ both in terms of drugs proposed for fracture prevention and duration of treatment.

Conclusion

The ESCEO working group recommends that all AI-treated women should be evaluated for fracture risk. Besides general recommendations, zoledronic acid 4?mg i.v. every 6?months, denosumab s.c., or possibly oral bisphosphonates should be administered for the entire period of AI treatment to all osteoporotic women (T-score hip/spine <?2.5 or ≥1 prevalent fragility fracture), to women aged ≥75 irrespective of BMD, and to patients with T-score <?1.5?+?≥1 clinical risk factor or T-score <?1.0?+?≥2 clinical risk factors. Alternatively, therapy could be considered in patients with a FRAX-determined 10-year hip fracture probability ≥3%.     

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.     

Discontinuation of denosumab and associated fracture incidence: Analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Trial

Osteoporosis is a chronic disease and requires long‐term treatment with pharmacologic therapy to ensure sustained antifracture benefit. Denosumab reduced the risk for new vertebral, nonvertebral, and hip fractures over 36 months in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. Whereas discontinuation of denosumab has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD), the effect on fracture risk during treatment cessation is not as well characterized. To understand the fracture incidence between treatment groups after cessation of investigational product, we evaluated subjects in FREEDOM who discontinued treatment after receiving two to five doses of denosumab or placebo, and continued study participation for ≥7 months. The off‐treatment observation period for each individual subject began 7 months after the last dose and lasted until the end of the study. This subgroup of 797 subjects (470 placebo, 327 denosumab), who were evaluable during the off‐treatment period, showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T‐scores. During treatment, more placebo‐treated subjects as compared with denosumab‐treated subjects sustained a fracture and had significant decreases in BMD. During the off‐treatment period (median 0.8 years per subject), 42% versus 28% of placebo‐ and denosumab‐treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject‐years of 13.5 for placebo and 9.7 for denosumab (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.49–1.38), adjusted for age and total hip BMD T‐score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off‐treatment period. In summary, there does not appear to be an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off‐treatment period for up to 24 months. © 2013 American Society for Bone and Mineral Research.     

RANK Ligand Inhibition: A Novel Strategy for the Treatment of Bone Metastases

ContextProstate cancer (PCa) is associated with bone metastases, which lead to disruption in the normally well-controlled process of bone remodelling. This disruption may lead to bone pain and fractures. Improvements in the assessment and management of bone metastases are therefore required.ObjectiveTo assess the value of bone turnover markers, particularly N-telopeptide in urine (uNTx), in predicting skeletal events and the potential of the novel agent denosumab to reduce the secondary disruption to bone in men with PCa.Evidence acquisitionThis article is based on a presentation at an Amgen satellite symposium held at the European Association of Urology Congress in Stockholm, Sweden, in March 2009.Evidence synthesisHigh levels of uNTx in patients with bone metastases secondary to a range of cancers, including PCa, are associated with an increased risk of skeletal-related events (SRE) and death. Denosumab is a fully human monoclonal antibody that binds to and inhibits RANK Ligand, currently under development as a potential new treatment for bone metastases associated with a broad range of tumours. Denosumab has been shown to reduce the level of uNTx in patients with bone metastases resulting from breast cancer. Treatment with denosumab also has beneficial effects on other bone markers and the incidence of SRE in these patients. Similarly, denosumab reduces uNTx levels and the risk of SRE in patients with other primary tumours, including PCa. Evidence from an active-comparator study involving patients previously unresponsive to bisphosphonates suggests a benefit of denosumab over continued bisphosphonate treatment.ConclusionsMeasurement of uNTx levels may be a useful marker for identifying patients most at risk of skeletal complications. Denosumab suppresses uNTx levels, and trials evaluating the efficacy of denosumab in preventing and treating complications caused by bone metastases are continuing.     

SHBG levels are associated with bone loss and vertebral fractures in patients with prostate cancer

Summary

Fractures are increased among prostate cancer patients. No data have been reported in patients with prostate cancer about the relation between serum sex hormone-binding globulin (SHBG) and bone metabolism. We found that SHBG levels were inversely related to bone mass and vertebral fractures in this population.

Introduction

Fractures are increased among prostate cancer patients, especially those on androgen deprivation therapy (ADT), but few data are available on the role of SHBG in their bone status. Our objective was to analyze the relation between serum SHBG and bone metabolism in prostate cancer patients.

Methods

This is a cross-sectional study including 91 subjects with prostate cancer (54 % with ADT). We measured serum levels of SHBG and sex steroids, bone mineral density (BMD) by dual-energy X-ray absorptiometry, and prevalent radiographic vertebral fractures.

Results

SHBG levels were inversely related to BMD (femoral neck: r?=??0.299, p?=?0.00; total hip: r?=??0.259, p?=?0.019). Subjects with osteoporosis had higher SHBG concentrations than patients without osteoporosis (60.97?±?39.56 vs 44.45?±?23.32 nmol/l, p?=?0.022). Patients with SHBG levels in the first quartile (>57.6 nmol/l) had an odds ratio (OR) for osteoporosis of 2.59 (95 % CI, 1.30–5.12; p?=?0.009) compared with patients with lower SHBG levels. In patients with SHBG >57.6 nmol/l, the OR for vertebral fractures was 2.34 (95 % CI, 1.15–4.78; p?=?0.034). The calculated OR was higher after adjustment for age (OR, 5.16; 95 % CI, 1.09–24.49; p?=?0.039), estrogens (OR, 6.45; 95 % CI, 1.44–28.95; p?=?0.023), and androgens (OR, 5.51; 95 % CI, 1.36–22.37; p?=?0.017).

Conclusions

In prostate cancer patients, SHBG levels were inversely related to bone mass and vertebral fractures. Determination of the serum SHBG level may constitute a useful and straightforward marker for predicting the severity of osteoporosis in these patients.     

The role of percutaneous vertebral augmentation in patients with metastatic breast cancer: Literature review including report of two cases

Patients with metastatic breast cancer are at high risk for developing vertebral compression fractures due to underlying bone metastases and bone density loss. Vertebral augmentation techniques including percutaneous vertebroplasty and percutaneous balloon kyphoplasty are techniques used to stabilize compression fractures and improve pain. However, rare complications from these interventions have been observed, including spinal cord compression, nerve root compression, venous cement embolism, and pulmonary cement embolism. These complications pose unique potential challenges for patients with cancer who may already have decreased lung function and potential for venous thromboembolism. In this review, we first describe the role of percutaneous vertebral augmentations in patients with metastatic cancer, with a particular focus on patients with breast cancer. Then, we describe complications of vertebral augmentation in two patients with metastatic breast cancer including long-term symptomatic and radiographic follow-up.     

Denosumab and alendronate treatment in patients with back pain due to fresh osteoporotic vertebral fractures

Introduction

Denosumab specifically inhibits the receptor activator for nuclear factor-kappa B ligand (RANKL), and prevents osteoporotic fractures. Several reports have analyzed the effects of denosumab and alendronate alone on bone mineral density (BMD) or reduction of fracture risk. The objective of this study was to analyze the effects of antiresorptive osteoporosis pharmacotherapy on pain relief in patients with fresh vertebral fracture.

Denosumab: A cost-effective alternative for older men with osteoporosis from a Swedish payer perspective

ObjectiveTo assess the cost-effectiveness of denosumab versus other treatments in men with osteoporosis who are ≥ 75 years old from a payer perspective in Sweden.MethodsA lifetime cohort Markov model was developed with seven health states: well, hip fracture, vertebral fracture, other osteoporotic fracture, post-hip fracture, post-vertebral fracture, and dead. During each cycle, patients could have a fracture, remain healthy, remain in a post-fracture state or die. Background fracture risks, mortality rates, persistence rates, utilities, medical and drug costs were derived using published sources. Estimates of fracture efficacy were drawn from available studies in post-menopausal osteoporotic (PMO) women as BMD improvements have been shown to be similar across male osteoporosis (MOP) and PMO populations, and a recent clinical trial suggested that the fracture risk reduction from bisphosphonate therapy in men is similar to that seen in women in comparable studies. Lifetime expected costs and quality-adjusted life-years (QALYs) were estimated for denosumab, generic alendronate, generic risedronate, ibandronate, zoledronate, strontium ranelate and teriparatide. On average, patients in the model were 78 years old, with bone mineral density T-score at the femoral neck of − 2.12. Prevalent vertebral fractures were present in 23% of patients. In the base-case, the model assumed that patients would experience treatment-related effects up to 2 years after discontinuation. Costs and QALYs were discounted at 3% annually. Extensive sensitivity analyses were conducted.ResultsTotal lifetime costs for denosumab, alendronate, strontium ranelate, zoledronate, risedronate, ibandronate and teriparatide were €31,004, €33,731, €34,788, €34,796, €34,826, €35,983 and €37,461, respectively. Total QALYs were 5.23, 5.15, 5.15, 5.17, 5.13, 5.12 and 5.22, respectively. Compared to other treatments, denosumab had the lowest costs and highest QALYs. In the one-way sensitivity analyses, when compared to alendronate (next least expensive strategy), the ICER for denosumab was most sensitive to the relative risk of hip fracture on denosumab. The probability of denosumab being cost-effective compared to the other treatments at a threshold of €66,000/QALY was 96.1%.ConclusionDenosumab dominated all comparators, including generic bisphosphonates, in the treatment of osteoporosis in men who were ≥ 75 years old in Sweden.