Global guidance for the recognition, diagnosis, and management of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by mesenchymal tumors that secrete fibroblast growth factor 23 (FGF23). Patients present with progressive bone pain, muscle weakness, and fragility fractures. TIO is characterized by hypophosphatemia, excess renal phosphate excretion, and low/inappropriately normal 1,25-dihydroxyvitamin D (1,25(OH)2 D) levels. Rarity and enigmatic clinical presentation of TIO contribute to limited awareness among the medical community. Accordingly, appropriate diagnostic tests may not be requested, leading to delayed diagnosis and poorer patient outcomes. We have developed a global guidance document to improve the knowledge of TIO in the medical community, enabling the recognition of patients with TIO and appropriate referral. We provide recommendations aiding diagnosis, referral, and treatment, helping promote a global standard of patient management. We reviewed the literature and conducted a three-round Delphi survey of TIO experts. Statements were drafted based on published evidence and expert opinions (≥70% consensus required for final recommendations). Serum phosphate should be measured in patients presenting with chronic muscle pain or weakness, fragility fractures, or bone pain. Physical examination should establish features of myopathy and identify masses that could be causative tumors. Priority laboratory evaluations should include urine/serum phosphate and creatinine to assess renal tubular reabsorption of phosphate and TmP/GFR, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25(OH)2 D, and FGF23. Patients with the clinical/biochemical suspicion of TIO should be referred to a specialist for diagnosis confirmation, and functional imaging should be used to localize causative tumor(s). Recommended treatment is tumor resection or, with unresectable/unidentifiable tumors, phosphate salts plus active vitamin D, or burosumab.

Tumor-Induced Osteomalacia: A Systematic Clinical Review of 895 Cases.

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months-90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ - 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences.

Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial.

BACKGROUND: No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe osteoporosis. METHODS: In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to -1·50. Participants were randomly assigned to receive 20 µg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41). FINDINGS: We enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5·4%) of 680 patients in the teriparatide group and 64 (12·0%) of 680 patients in the risedronate group (risk ratio 0·44, 95% CI 0·29-0·68; p<0·0001). Clinical fractures occurred in 30 (4·8%) of 680 patients in the teriparatide group compared with 61 (9·8%) of 680 in the risedronate group (hazard ratio 0·48, 95% CI 0·32-0·74; p=0·0009). Non-vertebral fragility fractures occurred in 25 (4·0%) patients in the teriparatide group and 38 (6·1%) in the risedronate group (hazard ratio 0·66; 95% CI 0·39-1·10; p=0·10). INTERPRETATION: Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate. FUNDING: Lilly.

Osteonecrosis of the jaw related to non-antiresorptive medications: a systematic review.

INTRODUCTION: The reporting of osteonecrosis of the jaw (ONJ) related to anticancer agents without known antiresorptive properties (non-antiresorptives), such as antiangiogenics, tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, immune checkpoint inhibitors, and cytotoxic chemotherapy is increasing. OBJECTIVE: To review characteristics of ONJ in cancer patients receiving non-antiresorptives. METHODS: A systematic review of the literature between 2009 and 2017 was conducted by the Bone Study Group of MASCC/ISOO. RESULTS: Of 6249 articles reviewed and from personal communication, 42 ONJ cases related to non-antiresorptives were identified. No gender predilection was noted. Median age was 60 years and ONJ stage 2 was most common, with predilection for posterior mandible. Exposed bone, pain, and infection were common at diagnosis. In comparison to bone targeting agents (BTAs), radiology, histology, and management were similar, with medication often discontinued. Delayed diagnosis (median 8 weeks) was noted. Important differences included earlier time to ONJ onset (median 20 weeks), absence of trigger event (40%), and greater likelihood of healing and shorter healing time (median 8 weeks) as compared to BTA-related ONJ. Gastrointestinal cancers predominated, followed by renal cell carcinomas compared to breast, followed by prostate cancers in BTA-related ONJ, reflecting different medications. CONCLUSIONS: Data about non-antiresorptive-related ONJ is sparse. This type of ONJ may have better prognosis compared to the BTA-related ONJ, suggested by greater likelihood of healing and shorter healing time. However, the delay in diagnosis highlights the need for more education. This is the first attempt to characterize ONJ associated with different non-antiresorptives, including BRAF and immune checkpoint inhibitors.

Assessment of bone quality with trabecular bone score in type 2 diabetes mellitus: A study from the FRISBEE cohort.

OBJECTIVE: The purpose of our study was to compare bone mineral density (BMD) and trabecular bone score (TBS) values between patients with type 2 diabetes (T2D) and control subjects with similar FRAX scores in order to evaluate TBS as an additional tool for assessing fracture risk in diabetic subjects. METHODS: A cross-sectional analysis was performed using BMD results from 260 subjects participating in the FRISBEE study (Fracture RISk Brussels Epidemiological Enquiry), an ongoing prospective epidemiological study in a population-based cohort (Brussels, Belgium) of 3560 postmenopausal women aged 60-85 years. TBS measurement was possible in 1108 subjects from the FRISBEE cohort. Among these 1108 subjects, 65 had known T2D at inclusion. For each diabetic case we selected 3 controls from our database. (n = 195). Diabetic subjects and controls were matched for age and baseline FRAX score for major osteoporotic fractures. RESULTS: BMD (g/cm2 ) tended to be higher in T2D than in control subjects, significantly so at the total hip 0.90 ± 0.13 versus 0.87 ± 0.12 (P = 0.015). On the contrary, TBS was significantly lower in the T2D group (mean = 1.19 ± 0.17) compared with the control group (mean = 1.27 ± 0.13) (P = 0.005). Mean TBS remained significantly lower in T2D (1.22 ± 0.17) compared with the control group (1.27 ± 0.13) (P = 0.02) after adjustment for body mass index. CONCLUSION: Our data suggest that TBS complements BMD at the total hip, in demonstrating the "diabetes-associated bone disease".

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

BACKGROUND: 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. MAIN TEXT: 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. CONCLUSION: 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.

Physicians' preferences for bone metastases treatments in France, Germany and the United Kingdom.

BACKGROUND: Several bone-targeted agents (BTAs) are available for preventing skeletal-related events (SREs), but they vary in terms of efficacy, safety and mode of administration. This study assessed data on European physicians' treatment preferences for preventing SREs in patients with bone metastases from solid tumours. METHODS: Physicians completed a web-based discrete-choice experiment survey of 10 choices between pairs of profiles of hypothetical BTAs for a putative patient. Each profile included five attributes within a pre-defined range (primarily based on existing BTAs' prescribing information): time (months) until the first SRE; time (months) until worsening of pain; annual risk of osteonecrosis of the jaw (ONJ); annual risk of renal impairment; and mode of administration. Choice questions were developed using an experimental design with known statistical properties. A separate main-effects random parameters logit model was estimated for each country and provided the relative preference for the treatment attributes in the study. RESULTS: A total of 191 physicians in France, 192 physicians in Germany, and 197 physicians in the United Kingdom completed the survey. In France and the United Kingdom, time until the first SRE and risk of renal impairment were the most important attributes; in Germany, time until the first SRE and delay in worsening of pain were the most important. In all countries, a 120-min infusion every 4 weeks was the least preferred mode of administration (p < 0.05) and the annual risk of ONJ was judged to be the least important attribute. CONCLUSIONS: When making treatment decisions regarding the choice of BTA, delaying the onset of SREs/worsening of pain and reducing the risk of renal impairment are the primary objectives for physicians.

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.

An observational time and motion study of denosumab subcutaneous injection and zoledronic acid intravenous infusion in patients with metastatic bone disease: results from three European countries.

PURPOSE: Denosumab (administered via subcutaneous injection) demonstrated superior efficacy versus the intravenously administered zoledronic acid in the prevention of skeletal-related events in an integrated analysis of three head-to-head phase III trials in patients with bone metastases secondary to solid tumors. To date, no studies have evaluated treatment administration duration endpoints of these two agents. METHODS: A multinational, multi-site, observational time and motion study conducted in 10 day oncology units (DOUs) across Belgium, Germany, and Italy. Observations of process time included task time and active healthcare professional (HCP) time for pre-defined tasks. Patient time measurements included entering/exiting the DOU, treatment room, and treatment chair or examination table. RESULTS: A total of 189 patients were enrolled (82 received zoledronic acid and 107 received denosumab) and 238 observations were recorded (104 for zoledronic acid and 134 for denosumab). Mean total task time was reduced by 81% when denosumab was used versus zoledronic acid (8.4 versus 44.2 min; p < 0.0001; pooled analysis across all countries). Pooled estimates for active HCP time were 12.2 min for zoledronic acid and 6.9 min for denosumab (44% reduction; p < 0.0001). CONCLUSIONS: In the countries studied, using denosumab compared with zoledronic acid reduced total task time and active HCP time. Thus, HCPs have more time to dedicate to other patients or care activities. An ability to increase the volume of appointments within DOUs could reduce waiting lists in sites operating at full capacity and increase overall productivity and efficiency in hospital processes.

Effects of Dairy Products Consumption on Health: Benefits and Beliefs--A Commentary from the Belgian Bone Club and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.

Dairy products provide a package of essential nutrients that is difficult to obtain in low-dairy or dairy-free diets, and for many people it is not possible to achieve recommended daily calcium intakes with a dairy-free diet. Despite the established benefits for bone health, some people avoid dairy in their diet due to beliefs that dairy may be detrimental to health, especially in those with weight management issues, lactose intolerance, osteoarthritis, rheumatoid arthritis, or trying to avoid cardiovascular disease. This review provides information for health professionals to enable them to help their patients make informed decisions about consuming dairy products as part of a balanced diet. There may be a weak association between dairy consumption and a possible small weight reduction, with decreases in fat mass and waist circumference and increases in lean body mass. Lactose intolerant individuals may not need to completely eliminate dairy products from their diet, as both yogurt and hard cheese are well tolerated. Among people with arthritis, there is no evidence for a benefit to avoid dairy consumption. Dairy products do not increase the risk of cardiovascular disease, particularly if low fat. Intake of up to three servings of dairy products per day appears to be safe and may confer a favourable benefit with regard to bone health.

Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases.

PURPOSE: Bone metastases secondary to solid tumors increase the risk of skeletal-related events (SREs), including the occurrence of pathological fracture (PF), radiation to bone (RB), surgery to bone (SB), and spinal cord compression (SCC). The aim of this study was to evaluate the impact of SREs on patients' pain, analgesic use, and pain interference with daily functioning. METHODS: Data were combined from patients with solid tumors and bone metastases who received denosumab or zoledronic acid across three identically designed phase 3 trials (N = 5543). Pain severity (worst pain) and pain interference were assessed using the Brief Pain Inventory at baseline and each monthly visit. Analgesic use was quantified using the Analgesic Quantification Algorithm. RESULTS: The proportion of patients with moderate/severe pain and strong opioid use generally increased in the 6 months preceding an SRE and remained elevated, while they remained relatively consistent over time in patients without an SRE. Regression analysis indicated that all SRE types were significantly associated with an increased risk of progression to moderate/severe pain and strong opioid use. PF, RB, and SCC were associated with significantly greater risk of pain interference overall. Results were similar for pain interference with emotional well-being. All SRE types were associated with significantly greater risk of pain interference with physical function. CONCLUSIONS: SREs are associated with increased pain and analgesic use in patients with bone metastases. Treatments that prevent SREs may decrease pain and the need for opioid analgesics and reduce the impact of pain on daily functioning.

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer.

PURPOSE: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. METHODS: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. RESULTS: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9%) and 31 (1.2%) in the denosumab and ZA groups, respectively. In total, 32 (6.9%) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1%, in patients continuing and switching to denosumab, respectively. CONCLUSION: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports.

Patients' preferences for bone metastases treatments in France, Germany and the United Kingdom.

PURPOSE: The aim of this study was to assess patients' preferences for efficacy, safety, and mode of administration in relation to available bone-targeted agents (BTA) for the prevention of skeletal-related events (SREs) associated with bone metastases in Europe. METHODS: Adults in France (n = 159), Germany (n = 166), and the United Kingdom (UK; n = 159) with a self-reported physician diagnosis of bone metastases secondary to a solid tumour completed an online discrete- choice experiment survey of ten questions, choosing between pairs of hypothetical BTA profiles. Profiles were defined by five treatment attributes: delay of first SRE, delay of worsening of pain, annual risk of osteonecrosis of the jaw (ONJ), annual risk of renal impairment, and mode of administration. Profiles were generated using an experimental design with known statistical properties. A main-effects random parameters logit (RPL) model was applied to relate participants' choices to the characteristics of the BTA profiles. RESULTS: The most important treatment attributes for patients across all three countries were time until first SRE, annual risk of renal complications and time until pain worsening. For these attributes, better levels of outcomes were significantly preferred to worse levels (p < 0.05). A 120-minutes infusion every 4 weeks was the least preferred mode of administration. Risk of ONJ was judged by patients in the UK and Germany to be the least important attribute. CONCLUSIONS: Patients consider delaying SREs, avoiding renal impairment and delaying pain worsening as the most important goals to consider when selecting treatment to prevent the bone complications commonly associated with bone metastases.

Patient preferences for treatments to delay bone metastases.

BACKGROUND: Most patients with advanced prostate cancer (PCa) develop bone metastases (BM) and present with bone complications like fracture. Bone-targeted agents that prevent metastasis-induced bone complications can cause adverse events. Understanding how patients view treatment options may optimize care. This study aimed to quantify how PCa patients value a hypothetical treatment that delays BM but can cause osteonecrosis of the jaw (ONJ). The study also assessed the value patients place on avoiding metastasis-induced bone complications versus increased survival. METHODS: PCa patients from the United Kingdom (n = 201) and Sweden (n = 200) on androgen-deprivation therapy or hormone therapy for ≥ 3 years completed a 10-question discrete-choice-experiment survey examining whether patients would accept a BM-delaying treatment. Two time-tradeoff questions assessed patients' willingness to tradeoff between survival and bone complications. Percentages of patients choosing treatment were summarized by levels of treatment efficacy and ONJ risk. Odds ratios from a logit model were used to evaluate how patient and medication characteristics affected treatment choice. Proportions of patients choosing each tradeoff scenario were calculated. RESULTS: A majority of patients accepted treatment at the lowest benefit level (5-month BM delay) and highest risk level (9% ONJ risk). PCa symptoms and prior treatment affected patient preferences. Nearly 80% of patients would tradeoff at least 3 months of survival to avoid bone complications. CONCLUSIONS: PCa patients in the U.K and Sweden may value a medication that delays BM, despite the risk of ONJ. Furthermore, patients were willing to tradeoff up to 5 months of survival for prevention of bone complications.

Equivalence trial of proposed denosumab biosimilar GP2411 and reference denosumab in postmenopausal osteoporosis: the ROSALIA study.

Denosumab is a monoclonal antibody used to reduce risk of fractures in osteoporosis. ROSALIA was a multicenter, double-blind, randomized, integrated phase I/phase III study comparing the efficacy, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of proposed biosimilar denosumab GP2411 with reference denosumab (REF-DMAb) (Prolia®; Amgen). Postmenopausal women with osteoporosis were randomized 1:1 to 2 60-mg doses of GP2411 or REF-DMAb, one at study start and one at week 26. At week 52, the REF-DMAb group was re-randomized 1:1 to a third dose of REF-DMAb or switch to GP2411. The primary efficacy endpoint was percentage change from baseline (%CfB) in LS-BMD at week 52. Secondary efficacy endpoints were %CfB in LS-BMD, FN-BMD, and TH-BMD at weeks 26 and 78 (and week 52 for FN-BMD and TH-BMD). Primary PK and PD endpoints were the area under the serum concentration-time curve extrapolated to infinity and maximum drug serum concentration at week 26, and the area under the effect-time curve of the %CfB in serum CTX at week 26. Secondary PK and PD endpoints included drug serum concentrations and %CfB in serum CTX and P1NP during the study period. Similar efficacy was demonstrated at week 52, with 95% CIs of the difference in %CfB in LS-BMD between treatment groups fully contained within prespecified equivalence margins. Similarity in PK and PD was demonstrated at week 26. Immunogenicity was similar between groups and was not impacted by treatment switch. The rate of new vertebral fractures was comparable. Treatment-emergent adverse events were comparable between groups (63.6% [GP2411/GP2411]; 76.0% [REF-DMAb/REF-DMAb]; 76.6% [REF-DMAb/GP2411]). In conclusion, ROSALIA showed similar efficacy, PK and PD, and comparable safety and immunogenicity of GP2411 to REF-DMAb in postmenopausal osteoporosis.

Denosumab is a biologic treatment that stops bone breakdown. This clinical trial evaluated how similar GP2411 (a denosumab biosimilar in development) is compared with European-approved reference denosumab in women with post-menopausal osteoporosis. Biosimilars are highly similar to the original treatment ('reference denosumab') and may have a lower price. 263 patients were randomly assigned to receive GP2411 and 264 to reference denosumab. Treatment was given at the study beginning, at Week 26 and at Week 52. 124 patients were re-assigned at Week 52 to test the effect of changing from reference denosumab to GP2411. The study showed similarity in how the body interacts with the treatments, what effects the treatment has (both measured over 26 weeks), and bone mineral density (measured over 78 weeks). Antibody responses to GP2411 were detected in similar proportions of patients on each treatment. Reported adverse events were similar between treatments before Week 52, and from Week 52 to 78, and <5% of patients experienced serious adverse events. A change of treatment from reference denosumab to GP2411 did not affect outcomes. These results showed similarity between GP2411 and reference denosumab in this population. In future, GP2411 may enable more patients to benefit from denosumab.

Pain outcomes in patients with advanced breast cancer and bone metastases: results from a randomized, double-blind study of denosumab and zoledronic acid.

BACKGROUND: In this study, the authors evaluated the effect of denosumab versus zoledronic acid (ZA) on pain in patients with advanced breast cancer and bone metastases. METHODS: The prevention of pain, reduction in pain interference with daily life activities, and the proportion of patients requiring strong opioid analgesics were assessed in a randomized, double-blind, double-dummy phase 3 study comparing denosumab with ZA for preventing skeletal-related events in 2046 patients who had breast cancer and bone metastases. Patients completed the Brief Pain Inventory-Short Form at baseline and monthly thereafter. RESULTS: Fewer patients who received denosumab reported a clinically meaningful worsening of pain severity (≥2-point increase) from baseline compared with patients who received ZA, and a trend was observed toward delayed time to pain worsening with denosumab versus ZA (denosumab, 8.5 months; ZA, 7.4 months; P = .08). In patients who had no/mild pain at baseline, a 4-month delay in progression to moderate/severe pain was observed with denosumab compared with ZA (9.7 months vs 5.8 months; P = .002). Denosumab delayed the time to increased pain interference by approximately 1 month compared with ZA (denosumab, 16.0 months; ZA, 14.9 months; P = .09). The time to pain improvement (P = .72) and the time to decreased pain interference (P = .92) were similar between the groups. Fewer denosumab-treated patients reported increased analgesic use from no/low use at baseline to strong opioid use. CONCLUSIONS: Denosumab demonstrated improved pain prevention and comparable pain palliation compared with ZA. In addition, fewer denosumab-treated patients shifted to strong opioid analgesic use.

Health technology assessment in osteoporosis.

We review the various aspects of health technology assessment in osteoporosis, including epidemiology and burden of disease, and assessment of the cost-effectiveness of recent advances in the treatment of osteoporosis and the prevention of fracture, in the context of the allocation of health-care resources by decision makers in osteoporosis. This article was prepared on the basis of a symposium held by the Belgian Bone Club and the discussions surrounding that meeting and is based on a review and critical appraisal of the literature. Epidemiological studies confirm the immense burden of osteoporotic fractures for patients and society, with lifetime risks of any fracture of the hip, spine, and forearm of around 40 % for women and 13 % for men. The economic impact is also large; for example, Europe's six largest countries spent €31 billion on osteoporotic fractures in 2010. Moreover, the burden is expected to increase in the future with demographic changes and increasing life expectancy. Recent advances in the management of osteoporosis include novel treatments, better fracture-risk assessment notably via fracture risk algorithms, and improved adherence to medication. Economic evaluation can inform decision makers in health care on the cost-effectiveness of the various interventions. Cost-effectiveness analyses suggest that the recent advances in the prevention and treatment of osteoporosis may constitute an efficient basis for the allocation of scarce health-care resources. In summary, health technology assessment is increasingly used in the field of osteoporosis and could be very useful to help decision makers efficiently allocate health-care resources.

Reducing the burden of bone metastases: current concepts and treatment options.

BACKGROUND: Bone metastases occur frequently in patients with solid tumours such as those of the prostate, breast and lung, and are associated with an increased risk of skeletal-related events (SREs). This article reviews the personal, social and economic burdens of bone metastases and SREs, and approaches to treatment. METHODS: PubMed searches were conducted using a broad range of search terms. Articles identified were refined by author review of abstracts. Additional material was identified by searching recent relevant congress abstracts. RESULTS: Bone metastases often decrease quality of life, but quantitative data on the extent of this effect are limited. Data from the USA demonstrate a significant financial burden associated with bone metastases; similar trends are now being uncovered in Europe as the number of assessments of health economics and healthcare resource utilisation in the region increases. The bisphosphonate zoledronic acid reduces the incidence of SREs compared with placebo. Recent phase 3 studies have shown that therapy with the RANK ligand inhibitor denosumab is superior to zoledronic acid for preventing or delaying SREs in patients with bone metastases from solid tumours. Denosumab also has a comparable safety profile to bisphosphonates, with reduced risk of renal toxicity and acute phase reactions. Data from Europe suggest that denosumab is cost-effective for the prevention of SREs compared with zoledronic acid. Additionally, several new experimental bone-targeted agents show promise. CONCLUSION: Recent progress may help to reshape evidence-based guidelines to improve patient care and reduce the economic burden of bone metastases.

Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: integrated results from three randomized, double-blind studies of denosumab and zoledronic acid.

PURPOSE: This analysis evaluated patient-reported outcomes and analgesic use in patients with bone metastases from solid tumours across three comparative studies of denosumab and zoledronic acid. METHODS: Pooled data were analysed from three identically designed double-blind phase III studies comparing subcutaneous denosumab 120 mg with intravenous zoledronic acid 4 mg monthly in patients with bone metastases from breast cancer (n = 2,046), castration-resistant prostate cancer (n = 1,901) or other solid tumours (n = 1,597). Pain severity, pain interference, health-related quality of life and analgesic use were quantified. RESULTS: At baseline, approximately half of patients had no/mild pain (53 % [1,386/2,620] denosumab; 50 % [1,297/2,578] zoledronic acid). Denosumab delayed onset of moderate/severe pain by 1.8 months (median, 6.5 vs 4.7 months; hazard ratio, 0.83; 95 % CI, 0.76-0.92; p < 0.001; 17 % risk reduction) and clinically meaningful increases in overall pain interference by 2.6 months (median, 10.3 vs 7.7 months; hazard ratio, 0.83; 95 % CI, 0.75-0.92; p < 0.001; 17 % risk reduction) compared with zoledronic acid. Strong opioid use and worsening of health-related quality of life were less common with denosumab. CONCLUSIONS: Across three large studies of patients with advanced solid tumours and bone metastases, denosumab prevented progression of pain severity and pain interference more effectively than zoledronic acid.

Risk factors predicting the 'time to first fracture' and its association with imminent fractures: a substudy of the FRISBEE cohort.

Only previous glucocorticoid use and rheumatoid arthritis were predictors of an early fracture (< 2 years after inclusion). A shorter 'time to first fracture' was not an independent clinical risk factor for imminent fractures. PURPOSE: Risk factors for fragility fractures independent of BMD were assessed in several prediction models. However, predictors of a shorter 'time to first fracture' and its impact on imminent fractures are unknown. METHODS: We studied the concept of 'time to first fracture' in the FRISBEE ("Fracture RIsk Brussels Epidemiological Enquiry") cohort (3560 postmenopausal women). Validated fractures were divided into 3 groups: first fracture < 2 years, 2-5 years, and > 5 years after inclusion. Factors associated with first fracture risk were evaluated with uni- and multivariate analyses using Cox modeling. We examined 'time to first fracture' as a risk factor for imminent fractures in untreated subjects and in those receiving pharmacological treatment. RESULTS: Classical risk factors (age, prior fracture, fall history and low BMD) were associated with first fracture in all groups. Previous glucocorticoids and rheumatoid arthritis (RA) were predictors for fracture < 2 years. Imminent fractures were similar in subjects with or without osteoporosis treatment, despite a higher estimated 10-year risk of fragility fracture in those treated, suggesting that treatment is efficient. 'Time to first fracture' was not an independent risk factor for imminent fractures. CONCLUSION: Among the risk factors considered, previous glucocorticoid use and RA were predictors for early fracture, consistent with the concept of very high risk. The 'time to first validated fracture' was not an independent risk factor for imminent fractures. Patients with a first osteoporotic fracture should thus be considered at very high risk for re-fracture, independent of the 'time to first fracture'.