Breast Cancer and Our Bones: An Update on Denosumab

TenderIsOurMight

I'd like to offer some further followup on Denosumab, a potential bone-modifying drug whose mechanism differs from the commonly used bisphosphonates.

Looking around where to post this, I elected this thread, as we breast cancer patients are smart to educate ourselves on our bones in general. It's good to learn how bones modulate break down and repair, how lifestyle can boost or limit their integrity, the simplistic yet question provoking requirements of calcium replacement and newer studies supporting Vitamin D in bone maintenance, and knowledge on new and older drugs which may strengthen bones, maintain bones, and hopefully someday soon help with bone metastasis from breast cancer.

I have no connection with the makers of Denosumab, but open-minded as you, it does pique my patient interest. I apologize for referencing the company's recent news release, as this smacks of possible inherent bias. I have read it thoroughly and feel it succinctly comments on recent clinical trial updates presented at the May, 2008 ASCO clinical meeting for oncologists, researchers and patients. I take full responsibility for your critique of doing such and note I don't have money for their stock nor own any, but time is valuable for us all so I choose to go to the source for their comments. I'll try to add oncology Society views later on RANKL inhibitors, and I'm providing clinical trial links on Denosumab from cancer.gov. My best to you all. Tender

May. 31, 2008Amgen Reports Positive Data at ASCO from Three Studies of Denosumab in Cancer PatientsPhase 2 Study of Patients Previously Treated with IV Bisphosphonates Showed Denosumab Reduced Bone Resorption and Skeletal-Related EventsComparison of Phase 2 Studies Showed Consistent Reduction of Bone Resorption with Denosumab in either Bisphosphonate-Naive or -Treated PatientsSub-group Analysis of Phase 3 Study Showed Denosumab Increased Bone Mineral Density Throughout the Skeleton In Women With Non-Metastatic Breast Cancer Receiving Aromatase Inhibitor TreatmentABSTRACT NUMBERS: 9574, 3596, and 546CHICAGO--(BUSINESS WIRE)--May 31, 2008--Amgen (NASDAQ: AMGN) today announced results from three denosumab studies in cancer patients. A Phase 2 study of metastatic patients previously treated with IV bisphosphonates found that denosumab normalized a key marker of bone resorption at a significantly greater rate than that seen with continuation of IV bisphosphonates, and also patients receiving denosumab experienced fewer skeletal-related events (SREs). A separate retrospective analysis comparing the results of this study to another Phase 2 study of patients never treated with an IV bisphosphonate revealed that the effect of denosumab on bone turnover markers was similar regardless of previous exposure to bisphosphonates. In addition, a sub-analysis of a Phase 3 trial in an earlier-stage cancer population of non-metastatic breast cancer patients showed that denosumab increased bone mineral density (BMD) at all sites measured, including cortical bone. These results were presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO).Phase 2 Data of Patients Previously Treated with IV BisphosphonatesThe study evaluated patients whose urinary N-telopeptide (uNTx) levels had not normalized despite treatment with IV bisphosphonates. The primary endpoint of patients with uNTx less than 50 at week 13 was achieved by 71 percent of patients in the denosumab arms compared with 29 percent in the IV bisphosphonate arm (p less than 0.001). In addition, denosumab induced suppression of uNTx levels faster than IV bisphosphonate (9 days versus 65 days, respectively).At week 25, denosumab treatment was associated with fewer on-study SREs (8 percent) than were seen in those receiving IV bisphosphonate therapy (20 percent). Skeletal-related events include fractures, radiation or surgery to bone, and spinal cord compression.The adverse event profile of denosumab was similar to that of advanced cancer patients receiving treatment, and balanced across treatment arms. The most common adverse events included bone pain, nausea, anemia, constipation, and asthenia. No neutralizing anti-denosumab antibodies were observed."Skeletal-related events can be a devastating complication of bone metastases," said Karim Fizazi, M.D., Ph.D., Head of the Department of Medical Oncology, Institut Gustave-Roussy, Villejuif, France. "Elevated markers of bone resorption are routinely accepted indicators of poor outcomes for our advanced cancer patients. So it was encouraging to see that in this study, denosumab was able to further suppress bone turnover in patients previously on bisphosphonates, and that denosumab patients also reported fewer skeletal-related events."Comparison of Phase 2 Data on Bone Turnover Markers of IV Bisphosphonate-Treated Versus Bisphosphonate-Naive PatientsIn a comparison of the effect of denosumab on bone turnover markers in two Phase 2 trials, one trial involving patients previously treated with IV bisphosphonates versus a second trial involving patients not previously treated, denosumab was found to suppress bone resorption to a similar extent, regardless of prior bisphosphonate exposure. This side-by-side comparison of changes in serum-C telopeptide (sCTx), a marker of bone breakdown, from baseline to week 25, showed that at the six months time point, denosumab suppressed bone resorption by 85 percent in bisphosphonate-naive patients compared with 80 percent in patients with prior exposure to IV bisphosphonates. In patients previously treated with IV bisphosphonates, denosumab suppressed bone resorption by 80 percent compared with 45 percent in patients who continued on IV bisphosphonates.In this comparison, the incidence of serious adverse events was similar across treatment groups in both studies. Types of adverse events were consistent with a population of patients with advanced cancer, and patients treated with IV bisphosphonates. The most common adverse events across all treatment arms were arthralgia, bone pain, asthenia, and nausea.Phase 3 Sub-Group Analysis of BMD in Women With Non-Metastatic Breast Cancer Undergoing Aromatase Inhibitor TreatmentSub-group analysis results of a Phase 3 pivotal study also presented at ASCO showed denosumab increased BMD at all skeletal sites measured, including in highly cortical sites, in non-metastatic breast cancer patients receiving adjuvant aromatase inhibitor (AI) therapy. The new analysis showed consistent increased BMD at the lumbar spine, total hip, femoral neck, and distal 1/3 radius at 12 months, regardless of duration or type of AI therapy, prior tamoxifen use, age, body mass index, or baseline T-score. The sub-group analysis findings presented at ASCO remain consistent with the efficacy and safety findings presented at the 2007 San Antonio Breast Cancer Symposium (SABCS).In this study, overall rates of adverse events were similar to those seen with placebo (91 percent denosumab versus 90 percent placebo). The most common adverse events, consistent with adverse events usually associated with AI therapy, were arthralgia, pain in extremity, back pain, and fatigue."Because denosumab specifically targets RANK Ligand, we believe it works in a different way from other bone loss and destruction treatments," said Roger Dansey, M.D., Global Development Leader for Denosumab Oncology at Amgen. "Results from the denosumab oncology program presented thus far are encouraging and we look forward to results from additional clinical trials in the bone loss and SRE settings."About Denosumab and Amgen's Research in Bone Biology

Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, the essential regulator of osteoclasts (the cells that break down bone). With more than 19,000 patients participating in trials across indications worldwide, the denosumab development program is the largest ever initiated by Amgen. This broad and deep development program demonstrates Amgen's commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumor types across the spectrum of cancer induced bone disease. Over 11,000 patients are currently enrolled in denosumab oncology clinical trials testing the drug for bone loss associated with cancer treatment-induced bone loss in breast and prostate cancers, for the prevention of skeletal related events due to the spread of cancer to the bone in multiple myeloma and multiple solid tumors, and for its potential to delay bone metastases in prostate cancer. The denosumab oncology program has a specific commitment in prostate cancer, studying more than 4,300 patients to determine the treatment effect of denosumab to treat and prevent bone loss, treat and prevent SREs and delay bone metastases in men with prostate cancer. Source:http://www.amgen.com/media/media_pr_detail.jsp?year=2008&releaseID=1160926 

http://clinicaltrials.gov/ct2/results?term=denosumab 

otter

Thanks, Tender.  One more thing in the armory to use in the fight, I guess.

I have to admit that I'm a bit leery of drugs and products that target a "normal" physiologic process, like bone remodeling.  I just read an article a week or two ago (darned if I can remember where) that reported increased fractures and poor bone quality in women on bisphosphonates.  The problem, of course, is that osteoclasts are needed to destroy "old" bone so it can be replaced with "new" bone.  When the osteoclasts or their activities are put out of commission, bone remodeling can't take place.

The report I read said that women who were on bisphosphonates were getting microfractures that led to clinical fractures.  I gathered that microfractures occur normally during life, but we aren't aware of them because they are healed so quickly by the normal bone remodeling processes. In the women on bisphosphonates, the microfractures weren't healing because osteoclast activity was being suppressed. 

So, once again, if it's not one thing, it's another...   <sigh>

otter 

TenderIsOurMight

I read this about bisphosphates too, Otter. A gentleman with multiple myeloma talked about long-term bisphosphonate use (I think it was IV Zometa) and onset of bone fractures which his doctors were felt were contributed by the long term Zometa use.

 

Clearly much vigilance is needed on IV bisphosphonates as well as in-depth consideration of the risk: benefit analysis. I think the downside of bisphosphonates: ONJ, avascular necrosis of the femur head, bone brittleness causing potential fracture risk and plain old chronic bone pain made me started looking around for alternatives.

 

It certainly got me quickly compliant with Calcium supplementation (about 1200 mg per day in two divided doses since kidney spills excess calcium at about 500 mg point) and Vitamin D (simple to get a blood 25 OH (hydroxy) D3, and then follow your doctors advice. I take 2000 IU which is higher than most advise based on my review of the Vit D matter. My blood Vit D level is now normal range but I doubt it was when I was diagnosed with breast cancer.

 

Exercise, particularly strength bearing, and limiting caffeine beverages wthin reason since caffeine promotes calcium loss seems to help. Also for our teenagers and twenty somethings, a time when bone calcium layering/integration is creating the essential bone mass, less carbonated beverages. Phosphorus in sodas also acts as a leach to body calcium deposition. I tell every teen I see about this. I tell them about vitamin D too, and am thinking of requesting blood levels at their upcoming sport physicals. 

 

I came back to post the link to breastcancer.org's BONE HEALTH. It has an amazing wealth of information!

Link: http://www.breastcancer.org/tips/bones/index.jsp 

 

Tender