ASCO Backs Bone Drugs for Myeloma

Recommended for patients with or without evidence of lytic damage

Patients with symptomatic multiple myeloma should receive bone-modifying therapy irrespective of evidence of lytic destruction or spinal compression fracture, according to an updated guideline from the American Society of Clinical Oncology (ASCO).

Treatment options consist of the intravenous bisphosphonates pamidronate and zoledronic acid (Zometa) or, alternatively, the RANK ligand inhibitor denosumab (Xgeva). Denosumab might be preferred over zoledronic acid for patients with renal impairment, as the RANKL inhibitor has been associated with fewer renal adverse events.

 The primary purpose of the update, and associated expert-panel review, was to determine whether the 2007 recommendations remain valid. ASCO initially published clinical guidance about the use of bone-modifying agents in myeloma in 2002.

“These recommendations are consistent with the previous recommendations, with new information on denosumab,” the guideline authors stated. “Additional modifications were made to some of the recommendations on the basis of recent data to better clarify the indications for treatment, duration of treatment, and associated complications of treatment.”

The panel, chaired by Kenneth Anderson, MD, of Dana-Farber Cancer Institute in Boston, and Robert A. Kyle, MD, of the Mayo Clinic in Rochester, Minnesota, updated the ASCO recommendations after examining 35 relevant studies identified by means of a targeted systematic literature review. The review included randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies.

Key recommendations included:

  • Initiate bone-modifying therapy for patients with imaging-based evidence of lytic disease and for patients with osteopenia in the absence of lytic disease
  • Use bone-targeted agents as adjunctive therapy for controlling pain associated with osteolytic disease and for patients receiving other interventions for existing or impending fractures
  • Initiate intravenous bisphosphonates in patients with normal radiographs or osteopenia by bone mineral density measurements
  • Do not use bone-modifying agents in patients who have monoclonal gammopathy of undetermined significance, except when osteopenia exists
  • Reduce the dose of zoledronic acid in patients who have pre-existing mild or moderate renal impairment
  • Consider denosumab as an alternative to zoledronic acid for patients with compromised renal function
  • Use serum creatinine monitoring before each dose of a bisphosphonate, in accordance with FDA labeling
  • Perform intermittent evaluation of all bisphosphonate-treated patients for presence of albuminuria

The updated guideline also includes a table with the estimated cost of bone-modifying agents. Pamidronate and zoledronic acid had per-dose costs of $30.67 and $53.64, respectively, whereas each dose of denosumab cost $1,995.48. The estimated 1-year costs were $398.71 for pamidronate, $214.56 for zoledronic acid administered every 12 weeks, $697.37 for zoledronic acid every 4 weeks, and $25,9341.24 for denosumab every 4 weeks.

A compendium of ASCO recommendations related to bone-modifying therapy in myeloma is available on the organization’s website. The update was also published in the Journal of Clinical Oncology.

Denosumab reduces cortical porosity in women with postmenopausal osteoporosis

Cortical porosity of the proximal femur shaft was reduced in women treated with denosumab therapy, study data show.

The reduced cortical porosity results in increased mineralized matrix volume as well as improved strength, according to the researchers.

Ego Seeman, MD, of the department of endocrinology at Austin Health, University of Melbourne in Australia, and colleagues evaluated data from the FREEDOM study on women with postmenopausal osteoporosis randomly assigned to subcutaneous denosumab (60 mg) every 6 months (n = 28) or placebo (n = 22) for 36 months.

A non-threshold-based segmentation algorithm was used to quantify porosity, and finite element analysis was used to estimate bone strength.

Higher total cortex porosity was found in participants with higher serum C-terminal telopeptide (sCTX; P = .02). Lower areal BMD (P < .01), lower total cortical volumetric BMD (P < .01), thinner cortices (P = .02), lower cortical mass (P < .01) and lower estimated integral strength (P = .03) were found among participants with higher total cortex porosity.

Porosity of all cortical regions decreased from baseline to 36 months in thedenosumab group: -3.6% for the total cortex, -6.7% for the compact-appearing cortex, -5.9% for the outer transitional zone and -1.1% for the inner transitional zone (P < .01 for all). However, porosity of all cortical regions remained relatively stable in the placebo group.

Significant differences were found between the denosumab and placebo group for porosity in all cortical regions at 36 months (P < .001 for all). Porosity reduction in the denosumab group was linked with an increased estimated integral strength for total cortex (P = .03), compact-appearing cortex (P = .02) and outer transitional zone (P < .01).

“We confirm and extend reports of ex vivo studies in animal models, and reports in human subjects documenting a reduction of cortical porosity associated with denosumab therapy,” the researchers wrote. “Quantification of cortical porosity of the hip provides a means of assessing fracture risk and the effects of treatment on this important determinant of bone strength. The benefits of denosumab treatment in reducing porosity at this location are relevant to our understanding of the structural basis of the reduced nonvertebral and hip fracture risk observed in clinical trials.” –by Amber Cox

Osteonecrosis of the Jaw Is Rare With Denosumab for Bone Loss

Osteonecrosis of the jaw (ONJ) is rare in patients taking the antiresorptive drug denosumab (Prolia), even when invasive dental procedures are performed, according to up to 8 years of data from the FREEDOM and FREEDOM extension studies.

“The clinical significance of these findings is that doctors and patients can be reassured that, even with long-term denosumab therapy, the risk of developing ONJ is very low,” said study investigator Michael McClung, MD, from the Oregon Osteoporosis Center in Portland.

“For patients with osteoporosis who deserve treatment to reduce fracture risk, concern about ONJ should not prevent them from receiving appropriate, effective osteoporosis treatment.”

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) study (N Engl J Med 2009; 361(8): 756-765) randomized women ages 60 to 90 years with osteoporosis to receive either 60 mg denosumab (n=3902) or placebo (n=3906) every 6 months for 3 years, explained McClung, who presented the findings at the annual meeting of the American College of Rheumatology.

At the end of the study, subjects in the placebo arm were given the opportunity to continue or cross over to the active drug for another 7 years in the ongoing FREEDOM extension study (J Endocrinol Metab 2013; 98(11): 4483-4489).

Three years into the extension study, patients were asked every 6 months about invasive oral procedures or events (OPE), which have been suggested as risk factors for ONJ.

Of the 3,536 women who agreed to complete the questionnaire, 58% (n=2036) reported no OPEs, and 42% (n=1500) reported OPEs such as root scaling, tooth extraction, dental implants, spontaneous tooth loss, or other invasive procedures involving the jaw.

There were a total of eight adjudicated ONJ cases, seven of which (0.47%) were reported in women with a history of OPEs and one (0.05%) in a woman with no OPE history. “She had dentures and upon removing them exposed bone was seen,” said McClung. “She was asymptomatic, but a diagnosis of adjudicated ONJ was made.”

Looking at duration of denosumab exposure, the study found that the percentage of patients with OPEs was balanced between those who had been on treatment from the start of the FREEDOM study and those who had crossed over to active treatment for the FREEDOM extension trial (41.8% versus 43.1%).

“This is likely similar to the frequency of OPEs among women of the same age without osteoporosis or without denosumab therapy — since there is no evidence that denosumab therapy increases the frequency of OPEs,” he said

Of the eight ONJ cases, five were in the long-term treatment arm, occurring after 11 doses (n=2), 12 doses (n=2), and 13 doses (n=1) of denosumab, while the three cases in the crossover arm occurred after three, four, and eight doses respectively.

During the extension study, the overall exposure-adjusted incidence of ONJ was 4.2 per 10,000 patient-years.

While OPEs were common on the cohort and appear to be a risk factor for ONJ, “the risk of ONJ in such patients is very low, even among those who underwent OPEs,” with the risk remaining much in patients with cancer-related bone diseases receiving high doses of the drug.

“No one knows for sure why the risk of ONJ is so very much higher with zoledronic and denosumab used to treat patients with cancer,” he commented. “Certainly the doses used in those patients are higher — but the patients are also very different: they have cancer, are receiving chemotherapy, and are immunocompromised. It is certainly not as simple as a dose effect.”

Denosumab increased adherence, BMD in postmenopausal patients.

Patients previously treated with a bisphosphonate who still have a high risk for fracture may benefit from the addition of denosumab, according to data presented at ASBMR 2013.

 “We have in fact shown a more robust increase in [bone mineral density] at the end of the 1 year, based on total hip, femoral neck and lumbar spine. We also showed a larger reduction in bone turnover markers,” Jacques P. Brown, MD, of the CHU de Quebec Research Center and Laval University in Canada, told Endocrine Today.

The multicenter, randomized, open-label, parallel-group studies included postmenopausal women aged at least 55 years who were randomly assigned to denosumab 60 mg (Prolia, Xgeva; Amgen) subcutaneously every 6 months (n=852) or a bisphosphonate (ibandronate [Boniva, Roche] orrisedronate [Actonel, Warner Chilcott]) 150 mg by mouth each month for 12 months (n=851; mean age, 67 years). The mean T-scores of the patients were: –1.7 at the total hip, –2 at the femoral neck, and –2.4 at the lumbar spine.


The researchers conducted a combined post-hoc analysis on patients with a greater risk for fracture administered denosumab or bisphosphonate.

Patients at higher risk for fracture who were administereddenosumab appeared to have a significantly increased BMD compared with those assigned to a bisphosphonate at the total hip (2.2% vs. 0.8%), femoral neck (1.8% vs. 0.3%), and lumbar spine (3.8% vs. 1.4%), according to 12-month data.

“The important finding was that patients who appeared to be noncompliant with bisphosphonates improved their level of adherence when switched to denosumab,” Brown told Endocrine Today.

These findings were consistent with the overall study population (treatment-by-risk subgroup interaction P>.05), according to data. Further, adverse events and serious adverse events were similar between those assigned denosumab compared with those assigned bisphosphonates.

“There is a clear advantage to switching postmenopausal patients to a more convenient approach like a subcutaneous injection every 6 months,” Brown said.

Source: Endocrine Today.


Combined Teriparatide and Denosumab Is More Effective Than Either Drug Alone.

Bone-mineral density was increased significantly by combination therapy in postmenopausal women with high fracture risk.


Bisphosphonate therapy, the first-line treatment for patients with osteoporosis, usually doesn’t restore normal bone-mineral density (BMD) and sometimes is not well-tolerated. Teriparatide (Forteo; a parathyroid hormone analog that stimulates bone formation when injected daily) and denosumab (Prolia; a long-acting injectable agent that inhibits bone resorption) are approved for treating patients with osteoporosis and high fracture risk. Combinations of bisphosphonates with teriparatide have proven to be no more effective than either agent alone, but the combination of teriparatide and denosumab has not been studied.

In a partially industry-funded study, investigators randomized 100 postmenopausal women at high risk for fracture to receive teriparatide (20 µg subcutaneously daily), denosumab (60 mg subcutaneously every 6 months), or both for 1 year. At 12 months, BMD increased significantly more in the combination group than in the monotherapy groups at the lumbar spine (9.1% vs. 6.2% and 5.2%, respectively) and at the hip. Serious adverse events in all three groups were deemed to be unrelated to study treatments.

Comment: Although only indirect comparisons can be made, combination teriparatide and denosumab seems to increase BMD more than other approved therapies do. However, this combination would need to substantially improve clinical outcomes — not just surrogate markers — to justify its very high cost (about US$9000 annually, compared with $100 annually for alendronate). Although BMD is a reliable predictor of fractures, in future studies, researchers will need to assess directly the effects of combination teriparatide and denosumab on fractures and its long-term safety.


Source: Journal Watch General Medicine



Two Drugs Better Than One in Postmenopausal Osteoporosis.

Combination therapy with teriparatide and the monoclonal antibody denosumab increases bone mineral density (BMD) to a greater extent than either drug alone in women with postmenopausal osteoporosis, according to an industry-funded study in the Lancet.

Researchers randomized 100 postmenopausal women with high fracture risk to receive subcutaneous teriparatide (daily), denosumab (every 6 months), or both for 1 year. At the end of treatment, posterior-anterior spine BMD had increased significantly more with combination therapy (9% increase from baseline) than with either agent alone (roughly 6% each). Femoral-neck BMD and total-hip BMD had also increased more with combination therapy.

“The BMD changes in the combined-therapy group were greater than have been reported with any approved therapies,” the researchers write. They conclude that their findings “suggest that this specific combination of drugs could be a useful option in the treatment of patients with osteoporosis at especially high risk of fracture.”

Source: Lancet


Denosumab Delays Development of Bone Metastases in Prostate Cancer

Denosumab recipients achieved a 4.2-month improvement in bone metastasis–free survival compared with placebo recipients.

Prostate cancer is a highly bone-tropic neoplasm, as illustrated by the near universal presence of bone metastases in men dying of the disease. Drug development for prevention of bone metastases has been focused largely on prevention or delay of skeletal-related events (SREs), which include pathologic fracture, spinal-cord compression, bone pain, and the need for radiation therapy or surgery in patients with castration-resistant metastatic disease. One agent that was found to be superior in delaying the time to SREs when compared to the bisphosphonate zoledronic acid is denosumab, a human monoclonal antibody that binds and inactivates RANK ligand (RANKL), which mediates the interaction between osteoblasts and osteoclasts.

To determine whether denosumab can delay the development of bone metastases in men with castration-resistant prostate cancer and no metastases, international investigators conducted an industry-sponsored, phase III trial involving 1432 such patients with evidence of prostate-specific antigen progression (PSA values 8.0 within 3 months before randomization or PSA doubling time 10 months or both) and castrate levels of testosterone (<50 ng/mL). Patients were randomized to receive subcutaneous denosumab (120 mg) or placebo every 4 weeks. The primary endpoint was bone metastasis–free survival or death from any cause; secondary endpoints included time to first bone metastasis and overall and progression-free prostate cancer survival.

The median time on study for denosumab and placebo recipients was 20.2 and 19.0 months, respectively. Denosumab recipients achieved a 4.2-month improvement in bone metastasis–free survival compared with placebo recipients as well as longer time to both first and symptomatic bone metastases. Median overall survival was similar between the denosumab and placebo groups (43.9 and 44.8 months), as were rates of the most common adverse events: back pain, constipation, arthralgias, diarrhea, and urinary tract infections. Osteonecrosis of the jaw occurred in 5% of denosumab recipients versus no placebo recipients.

Comment: The results of this clinical trial provide additional insight into the role of RANKL in prostate cancer bone metastases. As noted by an editorialist, the delay in time to metastases documented in this trial is similar to the delay in time to SREs reported in the aforementioned comparison of denosumab against zoledronic acid in men with metastatic castration-resistant prostate cancer without an effect on survival. This observation provides a rationale to suggest the optimal time for the use of this agent is at the time of bone metastases in the castrate setting.

Source: Journal Watch Oncology and Hematology


The Role of RANK-Ligand Inhibition in Cancer: The Story of Denosumab

The diagnosis of bone metastases is an event with certain consequences for the patient. They often mean pain and can also mean pathological fractures, hypercalcemia, and spinal cord compression, all synonymous with a diminished quality of life and often also hospitalization. Since the advent of the intravenous bisphosphonates, things began to look a bit brighter for patients with bone metastases—bone destruction was kept at bay a little longer. The next generation of bone metastasis treatments is well on its way in clinical development, and among them, the most advanced drug is denosumab. Denosumab is a fully human monoclonal antibody that inhibits osteoclast maturation, activation, and function by binding to receptor activator of nuclear factor kappa B ligand, with the final result being a reduced rate of bone resorption. In this review, we give an overview of relevant preclinical and clinical data regarding the use of denosumab in patients with solid tumors in general and prostate cancer in particular.

source: the oncologist