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Fancy

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Angel
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Reply with quote  #1 
My onc prescribed Fosamax to go with my Femara in May, '06.  In April, 07 or so, one of the cancer groups recommended that all women taking AI's also be given Fosamax or similar supplement to help prevent bone mets.  I remember it so clearly because I chuckled, knowing I had been taking both drugs for a year.

Can you give me information about this recommendation?  Thanks!




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edge

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Reply with quote  #2 

Sorry to disappoint you Fancy (see below), but as always you raise great issues.

Lessons in Bisphosphonates, and Bone Metastasis
The report being alluded to may have been that all women at elevated risk of bone fracture - meaning either those frankly osteoporotic at baseline, or threatening the very border of osteopenia and osteoporosis, or with an pre-existing history of fracture - should receive bisphosphonate therapy, but that was in regard to protection from AI-induced bone density loss, not in regard to risk of bone metastasis. There was also by the way a report that alendronate (Fosamax) may be as active as intravenous zoledronic acid (Zometa) for reducing bone turnover markers in women with breast cancer AND bone metastases, but that of course is advice only in pre-existing bone mets, not for risk reduction.

Unraveling the Issues
But in fact I can't help feeling that your oncologist appears to be conflating two distinct issues:

  1. potential deployment of bisphosphonates (alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), zoledronic acid (Zometa, pamidronate (Aredia), and clodronate (Bonefos) for anti-osteoporotic benefit against AI-induced bone density loss,
    versus the radically different issue of:
  2. potential deployment of bisphosphonate therapy for anti-bone-metastatic activity.

The reason I sense these are being garbled is his recommendation that all women (with breast cancer) on AIs be given such therapy, rather than that all women with breast cancer regardless of whatever therapy they're on (endocrine, biological, and/or chemotherapy) AND regardless of their biological receptor status (ER, PR and HER2) be put on a bisphosphonate. If one is convinced that prophylactic use of bisphosphonates can mitigate any significant degree of risk of the development of bone metastases, then since all women on all oncotherapies, and regardless of receptor status, are at risk of bone metastases, not just the ones on AI therapy, one could consistently only recommend universal deployment of bisphosphonates prophylactically against bone metastatic risk for all women with breast cancer, period - either they exert this activity or they don't, and neither the risk nor the potential benefit is in any way restricted to women receiving AIs.

So let me try to unravel the issues; in fact virtually everyone has some confusion about the role of bisphosphonates anywhere in oncology for any purpose, and the issues are subtle, and critical to understand as to when a bisphosphonate is compelling motivated.

First the facts:

Bisphosphonates, AI Therapy and Osteoporosis / Fracture Risk
The only evidence-based and/or authoritative guidelines on either (1) osteoporosis or (2) bone metastasis or (3) cancer-related bone pain or (4) aromatase inhibitor associated musculoleskeletal adverse events, even as of today - and even several pending publication I am reviewing - advise a bisphosphonate but not any one specific bisphosphonate, with these key qualifications:
  1. In the bone metastasis context, guidelines correctly note that there is a larger and more robust evidence base for zoledronic acid (Zometa) over all the other aminobisphosphonates (those that are nitrogen-containing, which essentially is all of them, including Fosamax) except for clodronate (Bonefos)).
  2. In the same context, zoledronic acid (Zometa) has the highest associated incidence of ONJ (osteonecrosis of the jaw) and on the opposite extreme, clodronate (Bonefos) is essentially devoid of such association, and in addition all IV-administered bisphosphonates (Zometa, Aredia) have some elevated association with adverse renal toxicity.
  3. In all other (non-metastatic) contexts, guidelines advise the use of a bisphosphonate only if frank osteoporosis is confirmed (in keeping also with osteoporosis guidelines).
  4. No group has yet recommended prophylactic use of bisphosphonates for anti-osteoporotic therapy in the absence of measurable osteoporosis, although many practitioners prescribe bisphosphonates - off-protocol and against the evidence, with a wink and a nod as it were - for osteopenia, a precursor condition thought by some, not irrationally, to be a biomarker of elevated risk for osteoporosis.

It is critical to note in all this what is absent: that no authoritative guideline or recommendation advises the deployment of bisphosphonate therapy as a beneficial intervention in aromatase inhibitor induced musculoskeletal adverse events for these excellent reasons:

  1. In all systematic reviews and meta-analyses (including my own), the scientific literature is wholly devoid of any evidence, at any level, for any positive activity of bisphosphonate therapy in this context.
  2. Potential benefit is against reason, in addition to being against the evidence (as above): AI-induced adverse musculoskeletal events are secondary to the AI-induced radical estrogen deprivation state (and are also seen in postmenopausal states, and in ovarian ablative states such as from oophorectomy (OO)), and there is no evidence that bisphosphonates influence or operates over any estrogen pathways, and hence they are precisely and equally beneficial in hormone-negative and hormone-positive patients without exception for osteoporosis, not are otherwise useless for any AI-induced musculoskeletal adverse events.
  3. Not only is any BP therapy of no use in (non-bone-metastatic) AI therapy contexts, but both alendronate (Fosamax) and risedronate (Actonel) are actually well-evidence to be associated with the induction of musculoskeletal adverse events, not reducing them: the FDA CDER database is rich with data on Fosamax and Actonel associated severe bone, joint, and muscle pain, and as also decisively documented by Diane Wysowski with the FDA's Office of Drug Safety and Jennie Chang of FDA-DDRE.
Bisphosphonates: Potential for Reducing Risk of Osteoporosis / Fracture / Bone Loss on AI Therapy?
So two questions remain, the first being, what about prophylactic use of bisphosphonates to mitigate the risk of AI-induced bone density loss?

Here too, although often misunderstood, there is no motivated use of bisphosphonates unless and only if the patient at baseline of AI therapy initiation is frankly osteoporotic. Many clinicians of course reason, incorrectly however, that surely bisphosphonates would also be of value for patients who are not osteoporotic but are only osteopenic. But they are not: several studies have shown that no women who was osteopenic at the beginning of AI therapy was induced over to being osteoporotic either during or after AI therapy, despite the known bone density loss: if you are osteopenic and not osteoporotic before AI therapy, you will remain so during the therapy and upon therapy termination, and be returned to the same level of bone density which at no time would become true osteoposrosis. AI-induced bone density loss is therefore clinically relevant only in women with pre-existing osteoporosis, and taking a bisphosphonate defensively will not benefit as bone density is the same before and after AI therapy for all women who are only osteopenic at baseline, and the bisphosphonate therapy would therefore only subject these women to the adverse risks of extended bisphosphonate therapy, which includes ONJ, unnecessarily and without any clinical benefit, and since AI therapy is typically for at least three to five years or longer, and ONJ risk rises dramatically with duration, especially 3+ years and above, patients would be sustaining elevated adverse risks with no compensating benefit.

So clinical practice rule, and all authoritative evidence-based guidelines: if and only if you are measurably osteoporotic at baseline of AI therapy, add a bisphosphonate, otherwise (even in osteopenia), don't. There is no robust and convincing evidence against this guidance.

Bisphosphonates: Potential for Reducing Risk of Bone Metastasis?
That leaves the second question: is the use of prophylactic bisphosphonates in the absence of bone (or indeed, any) metastases, of any benefit in mitigating the risk of the development of bone metastases?

And if this potential is compelling evidenced, is it shared equally by all bisphosphonates?

First, all bisphosphonates have direct effects on cell proliferation and apoptosis in different breast cancer cell lines, but not all bisphosphonates act equally on breast cancer cells: zoledronic acid (Zometa) seems on the weight of the evidence to date to be the most potent of aminobisphosphonates; clodronate (Bonefos) is not an aminobisphosphonate, and there is some evidence to suggest that it may be the most powerful of all bisphosphonates in direct anti-tumor / anti-bone-metastatic activity, but it is not as yet available in the US although widely and beneficially used every else (and lacks significant ONJ potential, with greater convenience than Zometa because it is orally administered).

In addition, just breaking data from human clinical trials shows that Zometa
metronomic therapy (I am a strong advocate of metronomic therapy everywhere), meaning repeated low-dose schedule (1 mg of Zometa every week for four times (days 1, 7, 14, and 21) followed by 4 mg of Zometa with a standard 28-day schedule repeated three times (days 28, 56, and 84)) significantly decreases VEGF-circulating levels, demonstrating bevacizumab (Avastin)-like antiangiogenic activity, and at least part of the antitumor activity of bisphosphonate therapy is attributed to an antiangiogenic effect. In addition, Zometa (and IV-pamidronate (Aredia)) exerts an inhibitory effect on endothelial cell adhesion and migration processes, both fundamental to metastatic progression, by a modulation of adhesion molecules (called integrins) that are involved in angiogenesis. Even a single dose of IV-administered bisphosphonate therapy induces a significant decrease of circulating levels of VEGF in bone metastatic cancer patients, an effect not yet documented in alendronate (Fosamax).
 
The highly promising benefit here is due to metronomic therapy, already shown of significant benefit with frequent (daily or weekly) administration of low-dose chemotherapy agents, resulting in minimal near-zero toxicity but profound antiangiogenic effects, aiding in antitumor efficacy and prevention of drug resistance, and hence exert potent antitumor activity in vivo against the progression of visceral metastases. The demonstration by Daniele Santini's team of the significant, early and long-lasting decrease of VEGF serum levels during low and repeated doses of a bisphosphonate represents the first clinical evidence in humans of the antiangiogenic potential of metronomic use of Zometa. And there is some suggestion that metronomic bisphosphonate administration may lead to significant intracellular accumulation over time in tumor cells. These findings are further supported by the previous findings last year of significant antitumor effect of Zometa, and of the unique non-aminobisphosphonate, clodronate (Bonefos), in a mouse model of bone metastasis conducted by Florence Daubiné and colleagues, but again only under the metronomic therapy scheme of administration, so preclinical and clinical findings converge. (Oral clodronate (Bonefos), note (at 1600 mg daily for 2 years) when added to standard treatment for primary operable breast cancer, has already been shown to significantly reduce the risk of bone metastases by 31% over a 5-year period, uniquely therefore significantly improving the 5 year bone relapse free survival (bone-RFS)).

Finally, although it does not appear to have suggested itself to the investigators, I would speculate that such low-dose intermittent administration could dramatically reduce the risk and associated incidence of ONJ, which pending trials will explore.

Conclusions
But note:
  1. That there is no comparable clinical-level evidence for any such activity from alendronate (Fosamax), so the aggregate evidence to date shows that not all bisphosphonates are created equal.
  2. That the antitumor benefit was demonstrated, and exerted, only in the active bone metastasis context, not prophylactically, and so there is absolutely no evidentiary support for the prophylactic deployment of bisphosphonates, against the risk, rather than the reality, of bone metastasis (it may be tempting to infer that since some intervention is of benefit in the active disease setting, then it must also be of value in chemoprevention of that same disease, but this is illicit, and there are innumerable examples to the contrary).

Based on this, I can find nor infer any compelling basis for your onc's recommendation, and no authoritative evidence-based guidance in its support. Yes, it's possible for bisphosphonates to have some preventive pre-bone mets disease benefit, but we have no data whatever, neither clinical or pre-clinical, to support this hypothesis, and based on complex considerations of bisphosphonate operation, the pathways underlying bone metastases, and the molecular genomic profile of a BMS (Bone Metastases Signature), it is unclear how a beneficial effect could be realized.

Still, I hope this serves as a mini-summary of the true role of bisphosphonates in oncology, based on the evidence to date.


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com
Karen1956

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Reply with quote  #3 
several studies have shown that no women who was osteopenic at the beginning of AI therapy was induced over to being osteoporotic either during or after AI therapy, despite the known bone density loss: if you are osteopenic and not osteoporotic before AI therapy, you will remain so during the therapy and upon therapy termination, and be returned to the same level of bone density which at no time would become true osteoposrosis. AI-induced bone density loss is therefore clinically relevant only in women with pre-existing osteoporosis, and taking a bisphosphonate defensively will not benefit as bone density is the same before and after AI therapy for all women who are only osteopenic at baseline, and the bisphosphonate therapy would therefore only subject these women to the adverse risks of extended bisphosphonate therapy.....

Constantine - I find the above quite interesting. I had a DEXA scan after finishing chemo when I started on Arimidex - I was borderline osteopenic. PCP put me on 1500mg Calcium/D daily.  15 months later, this past November, I had another DEXA scan and was borderline osteoporitic.  PCP increased calcium/D to 2000mg daily and Actonel 35 mg/weekly.  This seems to go against what you wrote about AI bone density decline only if a woman had osteoposis before starting AI's. BTW, during this time, I had rads and an ooph.  Guessing the ooph contibuted to the decline in bone density along with the AI's.  Thanks, karen
edge

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Reply with quote  #4 
Karen:

On the contrary, you are neither a counterexample to the conclusions I cited nor to the associated supporting trials.

First, individuals outside of a controlled trial setting cannot be confirmable counterexamples to statistical conclusions drawn within a controlled trial setting, for precisely the reason of lack of control by eligibility testing and enforcement, and protocol and methodology compliance, and all associated monitoring. Outside of the trial setting, we cannot know that you were not already at high (not just elevated) risk of osteoporosis and/or fracture: we don't know your pre-therapy 25-OHD levels as to potential pre-existing hypo status of Vitamin D3, nor relevant calcium levels, nor indeed any of dozens of risk factors (slender body habitus, family history of fracture, or first-degree relative with hip fracture before age 80 yr, any history of smoking, past history of fracture, etc.), including previous treatment history (for example, all chemotherapies have a known adverse impact on bone density).

Second, the conclusions of all trials are statistical truths (however they are stated by convention, this being always understood), declared at a certain level of confidence, which must be computed and stated, and isolated outlier results - if instanced - only modify the degree of confidence of the conclusions drawn, not the conclusion itself (unless they are not isolated and are systematically against the hypothesis being tested). We have no robust and compelling, verifiable and independently validated, evidence of such a contrary challenging set of data over thousands of patients in multiple studies over the better part of a decade, and so the conclusions I cited, as statistical truths at stipulated levels of confidence, stand unmodified.

Third, even if you could have made it into any of the supporting trials, you could not possible have remained a valid subject: as you note, at some time you underwent surgical ovarian ablation via oophorectomy: but ovarian ablation of any form is well-evidenced to be associated not only with clinically significant bone density loss and elevated fracture risk, but the degree of adverse impact on bone density and risk of fracture is known to be at least as great as any induced by AI therapy (and the weight of the evidence indeed suggests it to be considerably greater) - to say nothing of radiotherapy, another highly adverse factor on these same outcomes. And the adverse impact of surgical ovarian ablation on bone density and fracture risk, unlike the transient impact of AI therapy, is in the long-term, and permanent. The trials had to control for AI therapy and could not countenance additional systematically confounding factors like oophorectomy, radiotherapy (nor pre-existing or concurrent chemotherapy for that matter). Under ethical guidelines you may indeed may been permitted access to the active therapy as a trial participant, but definitely not as a trial subject, and as a trial participant, your variables and outcomes even if measured must necessarily be discounted in all final computations. The magnitude of heightened adverse risk secondary to just two overlapping and confounding factors, namely AI therapy itself coupled with oophorectomy, ignoring many others, must necessarily be abnormally high (and in any case of course that was not the intervention being tested).


Constantine Kaniklidis
Breast Cancer Watch
edge@evidencewatch.com

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Reply with quote  #5 
This is such an informative statement, Constantine, Thank you.

I was not aware of all the above and have just wondered if a bone density test every 18 to 24 months would be adequate in this setting (ooph and AI vs. regular menopause and AI).

I lost 9.1 % in my lower spine in 18 months of Femara (had ooph after chemo and rads at age 41).

Of course I am very consistent with my calcium and Vitamin D, which I was not made aware of at the beginning (actually my onc said I lost a "little bit" only - I did not have a copy of my report at the time, 9.1 is almost 10% and a LOT in my opinion).

I am at the border of osteopenia/osteoporosis going south....

Trail hiking and jogging 5 days a week is obviously is great for the hip joint (only 4.4% loss) but not enough for the spine. I might just pay for a dexa scan myself at the year point to see how it's going....

Anyways,
just want to thank you for your insight and I appreciate very much your time and knowledge.

God Bless

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Reply with quote  #6 
Dear Constantine,
Can you please recommend the proper type of Calcium and how much we need to take?


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ShirleyHughes

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Reply with quote  #7 
I had my onc visit this last Wednesday.  I had a dexa right after beginning AIs and a year later.  I was still in the normal range.  My onc said I did not need a dexa every year.  She said if one starts out in the normal range then one unusually does not have a problem. 
 
I payed for my own dexa last year.  If I had my primary doctor order one this year it would be covered by my insurance.  Should I get one?  Or just not worry about it.
 
My onc is now seeing how many people are vitamin D deficient.  I've been reading about vitamin D for years.  What has taken the medical community so long to jump on the band wagon.  She says that vitamin D levels are too low when in the 30's range.  DUH!  She gives prescriptions to those who are in the 30s.  I forgot to ask her what levels she would like to see.  Guess I'll call and ask her.
 
Thanks for all your info, Edge.
Shirley
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