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I am posting this in several places because I want you all to print it out and take it to your oncs and ask to get on this therapy-

February 12, 2009

Bone Drugs May Help Fight Breast Cancer

A drug of a class commonly used to combat bone loss may reduce by a third the chance that some breast cancers will spread or recur, a large study has found.

While it may sound odd to treat cancer with a drug that acts on bone, evidence is accumulating that such drugs may do more than just prevent the loss of bone. Other studies are testing the drugs in patients with prostate or lung cancer.

The new study, published in Thursday’s New England Journal of Medicine, involved 1,803 premenopausal women with tumors that were fueled by estrogen. As part of their treatment, all received drugs that shut down their ovaries, preventing them from making estrogen, along with drugs that stymie cancer cells from using estrogen to grow.

Half also got the bone drug zoledronic acid, or Zometa, as an intravenous infusion twice a year for three years. Those who took the drug had a 36 percent reduction in cancer recurrences and metastases, compared with women who did not get it. After nearly four years, 54 women who received zoledronic acid and 83 who did not had a recurrence of their cancer or had a new cancer in the opposite breast or a metastasis to their bones.

Some cancer researchers said they wanted to see the results from two other large studies of bone drugs and breast cancer before advocating that all women with breast cancer get such drugs. The studies, which include both premenopausal and postmenopausal women, are nearing completion, and their results should be available within the next few years. But the new study has buoyed researchers’ hopes.

“This is really a landmark study,” said Dr. James N. Ingle, head of the breast cancer research program at the Mayo Clinic Cancer Center. “It’s a reason for real enthusiasm.”

But for now, he said, “I think it is the general consensus that we are not ready to make this a standard treatment.”

Others are more persuaded.

Dr. Marc E. Lippman, a breast cancer expert who is chairman of the department of medicine at the University of Miami, said many women taking hormonal therapy for breast cancer already take drugs to protect their bones. The hormonal therapy deprives the body of the bone-building effects of estrogen. So, he said, why not give these women zoledronic acid, the bone drug used in the study?

“This is something of a mitzvah,” Dr. Lippman said. “The very therapy you might want to do to counteract the toxicity” of the hormonal therapy “has an additional advantage.”

“I think you have to give it,” he said.

The idea of using a drug like zoledronic acid arose from research into why some cancers, like breast cancers, have a predilection to spread to bone.

One reason, Dr. Ingle said, is that cancer cells interact with a type of bone cell, osteoclasts, whose role is to break down bone. Breast cancer cells that migrate to the bones stimulate osteoclasts. Osteoclasts then produce substances that stimulate the cancer cells.

“You get this vicious cycle,” he said.

Drugs used to treat osteoporosis, the bone-thinning disease that often occurs in the elderly, home in on osteoclasts and stop them from releasing substances that cause bone loss. As the osteoclasts stop working, they die.

So the idea arose: Perhaps osteoporosis drugs might prevent cancer cells from growing in bones.

Other studies of the osteoporosis drugs, known as bisphosphonates, indicated that they might also have other anticancer effects. In the laboratory, at least, they stopped cancer cells from growing new blood supplies. And bisphosphonates made cancer cells self-destruct in laboratory studies.

In addition, said Dr. Eric P. Winer, a breast cancer specialist at the Dana-Farber Cancer Institute in Boston, still other studies indicated that bisphosphonates affected how well cancer cells stuck to surrounding tissue and whether they were able to invade other tissue and proliferate.

And, said Dr. Michael Gnant of the Medical University of Vienna, the lead author of the new study, recent research indicates that particularly in the early stages of many cancers, there is a population of tumor cells that migrate to the bones and hide in bone marrow. Bisphosphonates, he said, might squelch those cells, affecting the ability of the disease to recur.

“This is a general mechanism for all cancers,” Dr. Gnant said. “Not just cancers that metastasize to bone.”

The idea for the cancer studies began when researchers, like Dr. Trevor J. Powles, a professor of breast oncology at Parkside Oncology in London, started asking whether bisphosphonates could treat cancer that had already spread to bone. They could, it turned out, and zoledronic acid and other bisphosphonates were subsequently approved for that use and shown to prevent further spread of cancer in bones. In fact, Zometa is approved only for bone complications of cancer, like fractures — it is not licensed as an osteoporosis drug.

Those discoveries led Dr. Powles and his colleagues and, independently, two other groups of researchers, to ask whether the drugs, in the high doses used to treat cancer, might prevent breast cancer from spreading in the first place.

The results, published a few years ago, were mixed. Dr. Powles’s study found that when women took a bisphosphonate their cancer was less likely to spread to their bones and they lived longer. Another study also found that the cancer was less likely to spread. But the third study found no effect.

Dr. Gnant, in the meantime, had begun a much larger study with intravenous zoledronic acid at a much lower dose, given twice a year for three years. The concern with the drug is a rare and very serious side effect, osteonecrosis of the jaw. But in this study at least, it did not occur.

And the surprising result of his study, if it holds up, indicates that zoledronic acid could add a benefit to existing breast cancer therapy that is nearly the same magnitude as the benefit conferred by chemotherapy or hormonal therapy alone.

But Dr. Gnant urges caution.

“While everyone is very excited, we still need to be conservative about what we recommend to patients,” he said. “In clinical science we do clinical trials. I am still hesitating to say, ‘Well, this is good for everyone.’ In the history of science we sometimes extrapolated and turned out to be absolutely wrong.”

“The right way to proceed,” Dr. Gnant said, “is to wait for data to come in from other studies.”




Goddess Forever
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Reply with quote  #2 

I mentioned the possible action of bone-loss drugs to my Oncologist.  He is aware.  This is of interest too.  A friend of my deceased parents, who is 84 years of age, has been seeing the same Oncologist I am seeing for a while.  She has battled lymphoma.  She had a recurrence a few months back.  Her PET scan came back clear last week. As I understand it, the Oncologist is giving her a drug that boosts her immune system and is controlling bad cell growth.  It targets a protein I think. They are continuing her on this drug every 2 months.  She is doing great at age 84.  I read where this drug is also given for Rheumatoid Arthritis.

Kay Mobley

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Goddess Forever
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Reply with quote  #3 
I have been on Fosamax for half a year now and I would like to switch, seeing my onc this month.
My blood work (but haven't done TM's yet) is okay sofar, back to normal after Lexapro (remember my MRI/BMB/high red blood count).
I have muscle pain which I attribute to Lexapro (leptosomething side effects talk about rigid muscles, low oxigen..., but it could be the Fosamax too?)

You think it would be safe to switch?

Anybody fare better on Zometa than Fosamax regarding bone pain or muscle pain?
In a way I am scared because once in you can't take it out, on the other hand I would love to have the extra protection....... 

Thank you for posting this article

~ There are lies, damned lies and statistics ~

Chief of Research
Posts: 1,129
Reply with quote  #4 



Apologies for not having noticed this, and responded, sooner.


A Very Short Course on the Benefits of Zoledronic Acid (Zometa, Reclast

First, a switch to zoledronic acid (Zometa, Reclast) may provide significant anticancer benefit, and although it is strongly suspected that all bisphosphonates may exhibit such anticancer activity, at present we have more data on the benefit from Zometa than from the other bisphosphonates.  These benefits include:


  • indirect (via osteoclasts) and direct antitumor action
  • antiangiogenic activity
  • impressive recurrence risk reduction
  • anti-metastatic activity
  • a statistically significant improvement in DFS (disease-free survival)
  • an improvement in tumor response rates
  • a reduction of disseminated tumor cells in bone marrow
  • potential synergy with chemotherapy  


among several others receiving confirmation (and bear in mind the above is a very abbreviated list). Given this, I should note in this connection that the sentiment expressed in the article is against the cumulative weight of the evidence, which includes that of multiple robust randomized controlled trials such as Z-FAST, ZO-FAST, EZO-FAST, ABCSG-12, and the AZURE trial, as well as Erich-Franz Solomayer's DTC study reported out at ASCO 2008, among many others. 


Indeed, it is the case that every large trial of bisphosphonates in breast cancer therapy has to date demonstrated impressive reductions in recurrence rates, and I should note the same is true in my research across multiple other malignancies besides breast cancer. Even more importantly,  the large robust ZO-FAST trial achieved a reduction in the risk of recurrence of close to 40%, a reduction benefit I have repeatedly observed is in excess of that achieved by chemotherapy.  And I would predict that the in-progress NSABP B-34 trial will only confirm and extend these conclusions.  


Taming ONJ

Second, as to the concern about ONJ (osteonecrosis of the jaw), the incidence is quite low if prudent precautions are exercised, especially meticulous oral hygiene because, as I have documented in my own research, there is an association between ONJ and the presence of the Actinomyces microbe (an opportunistic gram positive bacterium); consult my consumer-oriented review  on ONJ Watch where I have distilled the best-evidence guidance on this and other defensive strategies against ONJ. Such precautions render the already low incidence even lower  and at near-inappreciable levels, and the risk is furthermore massively overwhelmed by the potential benefits in any risk-benefit analysis. 


I should note that in my own research I am exploring data on alternative / non-standard  schedules of bisphosphonates, including intermittent dosing and reduced-dosing among others, and there is  some evidence from other malignancies that a step-down reduced dosing where Zometa is administered monthly during the first year and then every 3 months thereafter provides an eight-fold lower  risk of ONJ compared to the standard schedule (based on the findings of Alessandro Corso and colleagues); it is growing increasingly apparent that the long-term bone-matrix residency of bisphosphonates suggests that reduced or intermittent dosing after the first year may still sustain all benefits, and although we are awaiting confirmation in breast cancer, these alternatives schedules may obviate significantly the long-term risk of ONJ development, although as I noted the precautions I outline in my review themselves are ONJ risk reductive.    


Musculoskeletal Adverse Events

Third, as to the muscle pain you are experiencing, this symptom has a low incidence from escitalopram (Lexapro), where musculoskeletal adverse events are about 3% in incidence (although there can be about 5% occurrence of flu-like symptoms); muscle stiffness has only been reported rarely and in postmarketing surveillance of Lexapro. With alendronate (Fosamax), there can be about 4.1% incidence of musculoskeletal adverse events. However this incidence is much higher with zoledronic acid (Zometa, Reclast), in the range of at least 10% ranging to as high as 55% approximately, although this upper range is relatively infrequent. COX-2 inhibitors like celecoxib (Celebrex) may provide significant relief, and remember that more patients do not experience QoL-affecting musculoskeletal side effects than do. 


But I should note here that true rigid muscles may be part of a cluster of neuroleptic malignant syndrome (NMS)-like reactions so you should definitely report this as soon as possible if the symptoms are severe, of the "lead pipe" muscle rigidity sort.  NMS like symptoms tend to be consequent to drug interactions rather than to a single agent like an antidepressant on its own, so the total menu of agents you're on needs to be critically reviewed and appraised if indeed you are experiencing serious rigidity - the test is always, does it feel like "pipe-like" muscle rigidity or more like muscle aching?  Common muscle aching with or without some modest accompanying bone pain is not a serious issue, in contrast to true rigidity.


The Balance

In closing, it is the general consensus that even with the modest possibility of some musculoskeletal symptomology and the quite small risk of ONJ, that (1) potential bone health benefits as well as (2) anticancer benefits, outweigh the risks of bisphosphonate therapy with zoledronic acid (Zometa, Reclast).   



Constantine Kaniklidis

Breast Cancer Watch


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Goddess Forever
Posts: 2,525
Reply with quote  #5 
thank you very much for the detailed outline.

I do follow your recommendations of osteo necrosis prevention, I appreciate your knowledge and your website very much (had my DD read through it too! She was on Boniva and Fosamax for a while). So very much appreciated!

The lower dose administration that you mentioned, is that something one can only explore in a trial setting or would my oncologist be able to do that?

You mentioned in another thread yet another agent, that might come available at the end of this year, would that be superior to Zometa?

As to my muscle, I am guessing right now but I will speak with a doc this week, who hopefully knows something about that field (Physiatrist?)
I have no idea if the muscle is related, I got physical therapy for hip pain, which I thought was the result of falling on the knee and my posture after, yet it didn't stop me from jogging.
The muscle/sciatica or whatever it is at the back of the leg started hurting after Lexapro and Fosamax in October. Then the red blood being high after that funky MRI and the bone marrow biopsy confirmed, what my sluggishness, yawning and slow breathing was telling me already, low blood oxygen.
I never thought this could be related (and it might not be) until I saw on Medwatch, that all the antidepressants now seem to have the warning.

I can do what I want (run, jump, walk, I am flexible), I cannot for the life of it stretch the muscle without pain, it feel shortened (right under the sit bone), I can feel where the pain originates, push on it with my finger. But I also can run the mountainous trail without problem meaning skeletal problem (I am huffing and puffing and walking inbetween, I am not that sporty ).

As a matter of fact, I am better of standing, walking or running than sitting.
It doesn't make sense to me at all. I might just be old. It might be a combo of low estrogen(which isn't so low at 19.4) and Fosamax and the 2 month stint on Lexapro.

Sign me 'the old one'

Thank you for your expertise!

~ There are lies, damned lies and statistics ~

Chief of Research
Posts: 1,129
Reply with quote  #6 



Always glad to help a not-old friend.


As to the intermittent / reduced dosing schedule of zoledronic acid (Zometa, Reclast) I discussed, this can indeed be done outside of a trial setting - bisphosphonate dosing and scheduling is on flexible administration and so various different regimens can be implemented without constraint.


As to the muscle pain issue, I am not at all clear what FDA warning you are referring to - the latest official FDA-approved product labeling for escitalopram (Lexapro) contains no FDA alert, warning or precaution concerning muscle pain - it does contains an alert about NMS (neuroleptic malignant syndrome) as I described, where the syndrome can involve muscle rigidity (not muscle pain - and they mean true extreme rigidity). Muscle pain like you describe is far more likely to be associated with bisphosphonates like alendronate (Fosamax) than with any antidepressant (and there is an FDA safety news bulletin on this symptomology: Alendronate and Risedronate: Reports of Severe Bone, Joint, and Muscle Pain).  A trial of a brief drug holiday from Fosamax might suggest whether it is bisphosphonate-related or not, and  in any case it might be useful to have the symptom checked by an orthopedist (or sports medicine specialist).


Finally, the agent I discussed was denosumab, and the available evidence is indeed suggestive of several advantages over bisphosphonates, including lack of any ONJ risk, lack of being incorporated into the bone mineral matrix and hence lack of long-term dwelling of the drug, and the degree to which denosumab suppresses bone turnover and reduces skeletal-related events (SREs) is non-inferior to intravenous bisphosphonates (like Zometa), with no  serious toxicity or adverse events.  It's been compared head-to-head with Fosamax, the results showing that significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites as well as significantly greater reduction of bone turnover markers compared with alendronate Fosamax)  therapy.  In addition, among patients with elevated bone markers representing excessive bone resorption (urinary NTx) despite ongoing intravenous bisphosphonate therapy (as with Zometa), denosumab normalized levels more frequently than bisphosphonate continuation. And although at this time, we still have more data on the venerable zoledronic acid (Zometa, Reclast) than on the relative newcomer denosumab, the gap is narrowing with a blitz of in-progress  studies to appear in the near future, and there are half a dozen clinical trials on denosumab in breast cancer, and another half dozen in other malignancies.   


In closing, I'll wax lyrical ever so briefly (then back into my medical research cocoon):


May you climb on every rung,


May your song always be sung

May you stay forever young

[apologies to Dylan]


 Constantine Kaniklidis

Breast Cancer Watch


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Goddess Forever
Posts: 2,525
Reply with quote  #7 

thank you for responding so quickly.
The muscle feels very stiff, yet I can do 'what I want' if that makes sense.
When I stretch, it feels to short and no matter what, I cannot get it 'longer', elastic, flexible. My hip joints etc. are all flexible even with pains here and squeaks there, just the one muscle isn't. Maybe that is not rigid, which would be a good thing because it could go away with a medication break. Nice to know it might not be final, however, don't want to get of a bone strenghtening drug at the moment.
I just have to accept the squeaky non-old me the way I am

Denosumab sounds like the better drug.  Would be nice if the FDA would approve this one soon.

You have quite nice music to chose from in your cocoon. I will try to not disappoint Dylan
Thank you for sharing  

~ There are lies, damned lies and statistics ~

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Goddess Forever
Posts: 2,525
Reply with quote  #8 
Old me here

Doc thinks it's 'over use' of my muscle  or maybe side effect from Fosamax.
He's going to do an ultrasound on it in a couple of weeks (neat, I didn't know they ultrasound muscles....).
My body is telling what my mind doesn't want to hear.....How does that song go?? ...."over the hill" into the woods...tadadada.... 
He offered a shot into the muscle, some anesthetic.....
But I can't give up my trail, he says it's okay

~ There are lies, damned lies and statistics ~
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