Purpose This randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases. Patients and Methods Patients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). Results Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P .39). Conclusion Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases. J Clin Oncol 28:5132-5139. © 2010 by American Society of Clinical Oncology

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2010.29.7101

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study

Purpose This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. Patients and Methods Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. The primary end point was progression-free survival (PFS), as determined by an independent review facility. Results From November 2000 to March 2002, 462 patients were enrolled. Treatment arms were balanced. No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab. Combination therapy sign...

Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer

Purpose: To update the 2000 ASCO guidelines on the role of bisphosphonates in women with breast cancer and address the subject of bone health in these women. Results: For patients with plain radiographic evidence of bone destruction, intravenous pamidronate 90 mg delivered over 2 hours or zoledronic acid 4 mg over 15 minutes every 3 to 4 weeks is recommended. There is insufficient evidence supporting the efficacy of one bisphosphonate over the other. Starting bisphosphonates in women who demonstrate bone destruction through imaging but who have normal plain radiographs is considered reasonable treatment. Starting bisphosphonates in women with only an abnormal bone scan but without evidence of bone destruction is not recommended. The presence or absence of bone pain should not be a factor in initiating bisphosphonates. In patients with a serum creatinine less than 3.0 mg/dL (265 μmol/L), no change in dosage, infusion time, or interval is required. Infusion times less than 2 hours with pamidronate or less t...

American Society of Clinical Oncology 2003 Update on the Role of Bisphosphonates and Bone Health Issues in Women With Breast Cancer

Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with iron-binding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules. In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 microg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngal-dependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.

/pdf/endocytic-delivery-of-lipocalin-siderophore-iron-complex-4efecuaq4r.pdf

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

A 47-year-old woman with a history of breast cancer presents with confusion and dehydration. The serum calcium level is 18.0 mg per deciliter. She has postural hypotension and low central venous pressure. The serum phosphorus level is 5.0 mg per deciliter, the blood urea nitrogen level 80 mg per deciliter, the serum creatinine level 2.0 mg per deciliter, and the albumin level 3.3 g per deciliter. Bone scintigraphy reveals no evidence of skeletal involvement by the tumor. How should she be treated?

https://www.nejm.org/doi/pdf/10.1056/NEJMcp042806

Clinical practice. Hypercalcemia associated with cancer.

Collapsing focal segmental glomerulosclerosis (FSGS) is a distinct clinicopathologic entity seen most commonly in young African American patients who present with renal insufficiency and nephrotic syndrome. The only epidemiologic factor previously linked to collapsing FSGS is HIV infection. Here clinicopathologic findings are reported for a distinctive population of seven patients, who were older, Caucasian, and HIV negative and developed collapsing FSGS during active treatment of malignancy (multiple myeloma in six patients and metastatic breast carcinoma in one). Although oncologic treatment regimens included vincristine for four patients, doxorubicin for five patients, cisplatin for two patients, and total-body irradiation for one patient, the only agent common to all patients was pamidronate (Aredia). All patients had normal renal function before the administration of pamidronate. Patients began therapy with pamidronate at or below the recommended dose of 90 mg, intravenously, monthly, which was increased to 180 mg monthly in two patients and 360 mg monthly in three patients. Patients received pamidronate for 15 to 48 mo before presentation with renal insufficiency (mean serum creatinine, 3.6 mg/dl) and full nephrotic syndrome (mean 24-h urinary protein excretion, 12.4 g/d). Pamidronate, which is a member of the class of bisphosphonates, is widely used in the treatment of hypercalcemia of malignancy and osteolytic metastases. At the recommended dose of 90 mg, intravenously, monthly, renal toxicity is infrequent; however, higher doses have produced nephrotoxicity in animal models. The temporal association between pamidronate therapy and the development of renal insufficiency, the use of escalating doses that exceed recommended levels, and the distinctive pattern of glomerular and tubular injury strongly suggest a mechanism of drug-associated podocyte and tubular toxicity. These data provide the first association of collapsing FSGS with toxicity to a therapeutic agent.

Collapsing Focal Segmental Glomerulosclerosis Following Treatment with High-Dose Pamidronate

Toxic acute tubular necrosis following treatment with zoledronate (Zometa)

Nephrotic syndrome after treatment with pamidronate

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/jftr.12489

Final editorial: Principles that cut across professions and disciplines

A 68-year-old white woman with no significant past medical history presented with skeletal pain and anemia in December 1998. Subsequent evaluation disclosed multiple compression fractures of the thoracic and lumbar spine and lytic skull lesions. A bone marrow biopsy revealed 50% plasmacytosis, diagnostic of multiple myeloma.At that time, the patient had no significant proteinuria ( 150 mg/d), and serum creatinine was 0.9 mg/dL. She immediately began treatment with pulse dexamethasone administered in 40-mg doses for 4 consecutive days three times per month for 3 months. At the end of 3 months, repeat bone marrow biopsy revealed the absence of plasmacytosis. Since that time, the patient has been treated with pulse dexamethasone for 4 consecutive days once per month, and her myeloma remains in clinical remission. Her only additional oncologic treatment was thalidomide, administered briefly in July 2001 and discontinued because of a severe, incapacitating pruritic rash. The patient has not received a stem cell transplant, radiation therapy, cisplatin, or melphalan. The patient’s clinical course has been dominated by massive and diffuse compression fractures of the thoracic and lumbar spine. The resultant thoracic deformity has led to significant restrictive pulmonary disease requiring bronchodilator therapy and nocturnal oxygen supplementation. The mainstay of treatment for the bone disease has been pamidronate (Aredia). In January 1999, the patient began treatment with pamidronate at a dose of 90 mg intravenously once per month, which subsequently was increased to 180 mg intravenously once per month in May 1999, then to 180 mg intravenously twice per month in March 2000. At that time, she had a creatinine of 0.9 mg/dL and a 24-hour urine protein of 105 mg/d. In June 2000, her 24-hour urine protein increased to 2.1 g/d. In August, the patient had a 24-hour urine protein of 6.3 g/d; albumin, 3.1 g/dL; creatinine, 1.2 mg/dL; and severe peripheral edema. Urine protein electrophoresis revealed mainly albumin. A renal biopsy was performed.

https://www.ajkd.org/article/S0272-6386(02)18792-0/pdf

Paul L. Fine

Papers

Collapsing Focal Segmental Glomerulosclerosis Following Treatment with High-Dose Pamidronate

Toxic acute tubular necrosis following treatment with zoledronate (Zometa)

Nephrotic syndrome after treatment with pamidronate

Final editorial: Principles that cut across professions and disciplines

RENAL BIOPSY TEACHING CASE Nephrotic Syndrome After Treatment With Pamidronate