In addition to local treatments such as surgery or radiation for more immediate and directed therapy for bone metastases, there is a commonly used and FDA-approved approach with Zometa, also known as zoledronate or zoledronic acid. It is one of a class of drugs known as bisphosphonates that can reduce the rate of progression with skeletal complications. They bind tightly to calcium and then distribute especially to sites of active bone remodeling, such as bone metastases. In addition to increasing calcium deposits in bone, bisphosphonates like Zometa and others inhibit cells called osteoclasts, which break down bone (and can have a normal function in remodeling during the healing process for bone).
More than 10 years ago, clinical trials with other bisphosphonates demonstrated reductions in the risk of future skeletal fractures and pain in patients with osteoporosis and cancer-related bone disease. A key trial, known as Zometa 011 (abstract here) evaluated Zometa at either 8 or 4 mg given IV every three weeks for 9 months, compared with a placebo in patients with bone metastases from lung cancer or another solid tumor. A total of 773 patients were enrolled, of whom 436 had lung cancer (378 with NSCLC, 58 with SCLC), representing by far the largest cancer type involved in the study. Participants also received supplemental calcium with vitamin D. In an earlier safety analysis, it was noted that patients on the higher dose of zometa were experiencing problematic declines in their kidney function over time, and the trial was modified to focus exclusively on the lower dose of 4 mg IV every three weeks. The trial was also modified to give the Zometa or placebo over 15 minutes instead of 5, since this had been found in other testing to be associated with lower risk of kidney problems.
The trial demonstrated a significant reduction in the rate of progression with skeletal-related events, defined as a new fracture, increased bone pain, spinal cord compression, or an elevation in blood levels of calcium (hypercalcemia), as shown here:
(click to enlarge)
The toxicity of zometa was quite mild overall, and all groups reported bone pain, nausea, and anemia as the most common side effect, but in fact bone pain was more common in the placebo arm than the other groups. Decreased kidney function was initially seen more commonly with Zometa, but after the administration was changed to a longer infusion, it was no longer associated with a significant increase in compromised kidney function. Based on these results, the US FDA approved Zometa for the treatment of skeletal-related complications in patients with known bone metastases from a solid tumor or myeloma (a cancer with uncontrolled proliferation of plasma cells, the specialized blood cells that make antibodies), specifically at 4 mg IV every 3-4 weeks, over a minimum of 15 minutes.
Over the past several years, as use of Zometa and other bisphosphonates increased, we gained a greater understanding of the extent of potential side effects. The possibility of kidney problems, even with close monitoring as recommended, is sometimes seen with ongoing use (reference/extract here), and there are established guidelines for dose reduction with diminished kidney function. We also knew of the possibility of developing low blood calcium levels with Zometa (not surprising since it’s a treatment for excessively high blood calcium levels). However, in the last few years another potentially serious complication, known as osteonecrosis of the jaw (ONJ), was identified. This essentially means part of the jawbone dies, and it typically leads to pain in the jaw. It is most typically associated with dental infections and/or significant dental work such as extractions. Unfortunately, at this time there is really no effective treatment, so the focus is on trying to warn people of the early symptoms of ONJ to prevent them from receiving further zometa, and to identify the patients at significant risk for developing it. In addition, a baseline dental evaluation and good dental hygeinse are recommended, and it is also advised to avoid dental surgery during treatment with Zometa. ONJ may be seen with any or all of the drugs in the bisphosphonate class but may be more likely to occur with IV bisphosphonate therapy like Zometa.
While the earlier work suggested very minimal risk with Zometa, we now recognize that with a risk of kidney damage and ONJ, as well as other potential side effects that are more likely with continued use, we do need to weigh the anticipated risks and benefits of agents like Zometa. There are also studies being conducted to test whether Zometa needs to be given as frequently as every 3-4 weeks, or whether the benefits of Zometa may be comparable if given as infrequently as 2-6 times per year, which would presumably reduce the long-term risk of complications. However, we await further information before such an approach would be widely recommended.
posted by Dr. West @ 12:22 am link to this post
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February 23rd, 2007 at 11:22 pm
Dr. West,
Is a bisphosphonate a common therapy in lung cancer where there has been metastases to bone? Is it normally started early for prevention or does there have to be a symptom like spinal pain? My wife just celebrated her 1 year survival since dx and is just now receiving Zometa for pain cause by multiple blastic leisons.
The oncology nurse said that if it works her pain will diminish. How long will that take? (crystal ball?) I have notice less complaints about pain and less use of breakthrough pain meds and it’s only been 1 week since the first dosage. Does it work that quick?
Only side effect so far is she had a couple of full body sweats during sleep. No fever, just damp PJs.
What blood tests should we ask for to test for calcium and kidney function?
So she should also supplement with Calcium and Vitamin D? There are also some supplements that boost calcium absorption for postmenopausal women. Do you know of any cautions or limits with these supplements.
She is excellant with her dental hygeine and has no problems with teeth. Hopefully ONJ is low risk for her compared with the benefits I hope she receives.
Thanks for your most complete posts on bone metastases
Chanwit
February 24th, 2007 at 9:32 am
Chanwit,
There is a good bit of variability in how enthusiastically oncologists recommend Zometa, since there is no identified survival benefit and there can be side effects. However, it’s indicated for patients with bone mets in general, not just for painful metastases. I generally talk about with my patients early on, whether their bone metastases are symptomatic or not.
I haven’t seen significant pain improvement in most of my patients, really just a minority, but it can happen within days or a week or so. Fortunately, I also haven’t had my patients develop osteonecrosis of the jaw and only very rarely any kidney problems. My general approach with using Zometa for patients with bone metastases is to slow progression of skeletal complications in the future, rather than to significantly improve the situation now.
-Dr. West
February 24th, 2007 at 4:51 pm
Dr West
Thank you for all the posts on bone mets. My husband and I are trying to absorb all of it and he’s still trying to decide if or when he will continue treatment. We are to meet with a Onc nurse on Monday for education on Topotecan and Zometa. We feel that we are better informed because of your website.
Laurie
February 28th, 2007 at 10:41 pm
Dr. West,
The following abstract from British Journal of Cancer reported a benefit of Zometa. Is this finding relevant to the bone mets in lung cancer? Second question, at what Creatinine level is it better to stop Zometa?
Thanks,
Prem
British Journal of Cancer (2007) 96, 255-261.
doi:10.1038/sj.bjc.6603548 www.bjcancer.com
Combined effects of a third-generation bisphosphonate, zoledronic acid with other
anticancer agents against murine osteosarcoma
Bisphosphonates (BPs) are widely used to treat bone diseases and also appear to
possess direct antitumour activity. We have previously reported that third-generation
BPs such as zoledronic acid (ZOL) and minodronic acid (YM529) synergistically augment the effects of anticancer agents in various cancer cells. Recently, we have also
reported the antitumour effects of YM529 on murine osteosarcoma cells. As YM529 has not been clinically available, we herein focused on the anti-osteosarcoma effects
of ZOL which is clinically available. In addition to ZOL alone, we evaluated the
concurrent or sequential combined effects of ZOL with other anticancer agents against
murine osteosarcoma cell lines. ZOL showed almost same anti-osteosarcoma activity compared with YM529 and more sensitive growth inhibitory effects against osteosarcoma
cells than normal cells. Moreover, ZOL acted synergistically in vitro when administered
concurrently with paclitaxel (PAC) or gemcitabine (GEM), not only in wild-type osteosarcoma
cells but also in P-glycoprotein (P-gp)-overexpressing osteosarcoma cells, which were much less sensitive against each anticancer agent. Furthermore, 24 h of ZOL
pretreatment significantly augmented the sensitivity of doxorubicin (DOX), PAC or
GEM against osteosarcoma cells. These findings suggest that combined administration
of ZOL with other anticancer agents may improve the osteosarcoma treatment
February 28th, 2007 at 11:38 pm
It’s been quite common to give zometa concurrently with chemo, which is pretty much what the vast majority of patients with bone metastases from lung cancer are receiving. Thus far, there has been a modest trend toward improved survival, but not a statistically significant benefit in terms of overall survival. I would consider an abstract looking at osteosarcoma cells in a test tube setting to be pretty different from lung cancer in real people. The effect of a bone medication could be very different in a bone-based tumor than in metastases from a lung tumor. And many, many drugs have been shown to do great things against cancer cells in test tubes or animal models with mice, but then fail in patients with cancer. So I would consider the existing real life experience to be much more instructive than this abstract.
In terms of the amount of kidney damage that would be appropriate to stop zometa, there isn’t a number. To me, it depends on how much the creatinine has changed at least as much as what the number is. And I’d be less inclined to continue zometa in a patient who has one or a few asmptomatic bone metastases than I would in a patient with multiple painful bone metastases. And between full-dose zometa every 3-4 weeks and stopping entirely, it’s also possible to reduce the dose and/or the frequency of zometa treatment. We’re getting some evidence from trials with bisphosphonates that less frequent treatment may provide most or all of the benefits of more frequent treatment.
-Dr. West