Treatment Of Bone Complications Research Articles

Impact of denosumab (DMB) compared with zoledronic acid (ZA) on renal function in the treatment of myeloma bone disease.

8005 Background: Osteolytic bone disease and renal dysfunction are complications of multiple myeloma. ZA, used for the prevention and treatment of bone complications, can be nephrotoxic. DMB inhibits RANKL and thereby osteoclast function, and is not renally cleared. This international, phase III, randomized, double blind study evaluates the efficacy and safety of DMB compared with ZA in newly diagnosed myeloma patients (pts). Methods: Eligible pts were randomized 1:1 to DMB 120mg SC Q4W or ZA 4mg (renally adjusted) IV Q4W along with anti-myeloma therapy. Pts with baseline CrCl<30mL/min were excluded due to ZA dosing restrictions. The primary endpoint was non-inferiority of DMB to ZA with respect to time to first on-study SRE. Overall survival (OS) was a secondary endpoint; progression-free survival (PFS) was an exploratory endpoint. Renal toxicity and safety were assessed. Results: 1718 pts were randomized, 859 to each arm. Baseline renal insufficiency (CrCl ≤ 60mL/min) was reported in 26.7% of pts. DMB was non-inferior to ZA ( P = 0.01) in delaying time to first on-study SRE. Fewer AEs potentially related to renal toxicity were reported with DMB compared to ZA overall (10.0% vs 17.1%, P < 0.001) in those with baseline CrCl > 60mL/min (8.8% vs 14.2%) and particularly in those with baseline CrCl ≤ 60mL/min (12.9% vs 26.4%). 12.5% of pts on DMB experienced an increase in creatinine, compared to 20.8% of those on ZA. Median cumulative exposure (Q1, Q3) to DMB was 15.75 months (8.18, 25.79) compared to 14.78 months (7.46, 24.87) for ZA. PFS yielded a HR (95%CI) of 0.82 (0.68, 0.99); descriptive P = 0.036. OS HR (95%CI) between DMB and ZA was 0.9 ([0.70, 1.16]; P = 0.41), with fewer deaths in DMB (121 [14.1%]) than in ZA (129 [15.0%]). Conclusions: DMB achieved the primary endpoint of non-inferiority to ZA in delaying time to first on study SRE in pts with newly diagnosed MM. Pts on DMB had a significantly lower rate of renal AEs compared to ZA; more importantly this rate was 2-fold lower in pts with renal insufficiency (CrCl≤60mL/min). The bone specific benefits in combination with the renal function results and possible prolongation of PFS with DMB therapy is promising. Clinical trial information: NCT01345019.

Osteonecrosis of the jaw and bisphophonates in oncology

Bisphosphonates are potent osteoclastic inhibitors that are indicated in the prevention of bone complications. They could also be of interest in the prevention of bone metastases. Several recent international publications have highlighted the onset of osteonecrosis of the jaw (ONJ) in patients treated with bisphosphonates. These osteonecroses manifest in the form of bone exposure, recent tooth mobility, swelling and inflammation and, occasionally, localised pain but they can remain asymptomatic for weeks or even months. The prevalence of these osteonecroses in cancer patients treated with bisphosphonates could range from 1 to 10%. In most cases (60 to 80%), ONJ develops after alveolo-dental surgery (e.g. tooth extraction). Length of exposure to bisphosphonate probably increases the risk. Our recommendations regarding the diagnosis, classification, prevention and treatment of cases of ONJ observed during bisphosphonate administration are based on published studies and our experience. It is obvious that the use of bisphosphonates is undoubtedly beneficial in the treatment of bone complications but the incidence of ONJ during long-term treatments and at high doses warrants preventive measures. These measures are straightforward : bucco-dental repair prior to treatment, good hygiene and regular monitoring during treatment. Current, non-invasive procedures are still permitted. In other cases, the suspension of treatment is indicated until healing is complete. The increase in the incidence of ONJs, serious adverse events, raises the issue regarding duration and administration of bisphosphonate treatment in the management of bone metastases. Studies are currently underway in an attempt to answer this issue.

The role of bone markers in metastatic bone disease

Patients with advanced cancer often develop bone metastases that lead to significant skeletal morbidity and substantially reduced functionality and autonomy [Coleman RE, Rubens RD. Bone metastases. In: Clinical Oncology, 2nd edn. New York: Churchill Livingstone. 2004, p. 1091-128]. As current methods of diagnosing bone metastases are cumbersome and not cost-effective, there is great interest in exploring the potential of biochemical assays that measure bone turnover activity. These markers may have value in measuring metastatic bone disease (MBD) progression and identifying patients at higher risk for metastases. Bone markers are also being evaluated as a possible guide to optimize treatment of bone complications. In the reports included in this supplement, experts at the frontiers of bone marker research offer insights on their progress.

Treatment of bone complications in advanced prostate cancer: Rationale for bisphosphonate use and results of a phase III trial with zoledronic acid

Prostate cancer often metastasizes to bone during disease progression. Patients who develop bone metastases have a high risk of developing skeletal complications, including pathologic fractures, spinal cord compression, and severe bone pain. Bisphosphonate therapy is widely used for the prevention of skeletal complications in patients with bone lesions from multiple myeloma and breast cancer. Until recently, however, no bisphosphonate had ever shown objective clinical benefit in patients with prostate cancer and osteoblastic bone lesions. A recent multicenter, randomized, placebo-controlled trial found zoledronic acid (4 mg) to be a safe and effective therapy in patients with bone metastases from hormone-refractory prostate cancer. Zoledronic acid significantly reduced the proportion of patients who experienced skeletal complications and extended the time to first skeletal complication. Further, zoledronic acid significantly reduced the risk of skeletal complications over this 15-month study and provided consistent reductions in bone pain that were significant at the 3- and 9-month time points compared with placebo. These results suggest that zoledronic acid may become an important advancement in the care of patients with prostate cancer metastatic to bone. The role of zoledronic acid in the treatment of patients with prostate cancer continues to evolve.