Zometa

[pjoshea13]

A. New Italian study below [A1].

Zoledronic acid (Zometa) (ZA) is an intravenous biphosphonate drug approved for osteoporosis. It is also used in PCa for bone pain.

B. Does ZA have antitumor properties?

It has been reported that ZA has antitumor properties. The new study (more later) concludes that "these findings reinforce the efficacy of ZA as a potential therapeutic approach to reduce cancer aggressiveness". If so, this would translate to increased survival (again, more later).

Note that my review ignores non-human studies (although the new study is a cell/mouse study).

B1. A 2012 Japanese study:

"Although the nadir PSA level and the rate of PSA normalization showed no significant differences between the ZOL and non-ZOL groups, the time to nadir PSA in the ZOL group was significantly shorter than that in the non-ZOL group"

"Simultaneous administration of ZOL and {maximal androgen blockade} as initial treatment delayed {time to progression} in bone-metastatic prostate cancer patients. Initial treatment with ZOL has the possibility of anti-tumor activity to delay disease progression."

B2. A 2011 Japanese study:

"Prostate-specific antigen values in both groups significantly declined at 3, 6 and 12 months compared with pretreatment levels. However, the decline of the prostate-specific antigen was lower in the combined androgen blockade group. Alkaline phosphatase significantly declined at 6 and 12 months in the combination of combined androgen blockade and zoledronic acid group, with no significant changes seen in the combined androgen blockade group. The addition of zoledronic acid to combined androgen blockade showed prostate-specific antigen and bone turnover markers response compared with combined androgen blockade therapy only, suggesting a potential antitumor effect of zoledronic acid in the management of metastatic prostate cancer patients."

C. Does ZA relieve bone pain?

The mineral content of bone is in a state of dynamic equilibrium. Key players are osteoclasts that break bone down & osteoblasts that build bone back up.

Most cancers that go to bone are osteolytic (osteoclastic) - osteoclast activity exceeds osteoblastic activity. PCa is different in that it is largely osteoblastic, often resulting in pain. It's a bit counterintuitive to use ZA for bone pain, since it inhibits osteoclastic activity, but it seems that osteoclasts are behind excess osteoblastic activity. (Note that an osteoblastic lesion consists mostly of normal bone cells.)

C1. A 2011 Italian study:

"Zoledronic acid is ... confirmed to be an effective medicine in preventing the skeleton complications and in controlling the painful symptoms in patients suffering from prostatic carcinoma with bone metastases."

C2. 2010 Canadian study:

"ZOL reduced bone pain and {skeletal-related events} compared with placebo in patients with bone metastases from castration-resistant prostate cancer, irrespective of the baseline pain status, and appeared more efficacious when initiated before the onset of pain."

C3. A 2008 Spanish study:

"Zoledronic acid is effective for reducing pain, improving mobility, and increasing the quality of life in patients with prostate cancer with bone metastasis. Its easy administration and good tolerability make zoledronic acid one of the principal therapeutic tools in the management of patients with pain associated with bone metastasis from prostate cancer."

D. What does ZA do?

One of the most tightly regulated activities in the body is blood calcium homeostasis. A dip in calcium levels triggers a sequence of events. Parathyroid hormone [PTH] is secreted. PTH triggers a rapid response whereby calcium is obtained from bone (resorption). PTH also triggers the production of hormonal vitamin D - i.e. calcidiol is converted to calcitriol by the kidneys. Calcitriol causes an increase in calcium uptake from the gut, & subsequently, the process for replacing calcium taken from bone.

ZA tackles osteoporosis in a crude way - it inhibits osteoclast activity by causing the death of mature osteoclast cells. This flirts with hypocalcemia, & ZA users are often advised to use calcium supplements.

Many men with PCa are aware that calcium use is associated with aggressive disease. The main reason is probably because the kidneys never get the signal to convert calcidiol to calcitriol, & PCa tends to suppress the conversion that naturally occurs in prostate cells. One can have high levels of vitamin D (calcidiol - 25D), but that is inactive - only calcitriol (1,25D) is active against PCa.

E. Osteoporosis in men.

Osteoporosis is often viewed as a female disease, although it is a significant male issue. However, it happens much later in men & at a slower rate. The big exception is when men are treated with ADT. As with women, hormonal changes are implicated.

With testosterone [T] close to zero, estradiol [E2] - which is largely aromatized from T - may drop below ~12 pg/mL, increasing the risk of fractures. A low-dose E2 patch will eliminate that particular risk factor.

The process of returning calcium to bone requires vitamin K. Without K, some calcium will be deposited on arterial walls rather than in bone. Vitamin K2 supplements are prudent when bone density is at risk.

[E1] A 2012 study identified risk factors for fractures in men:

"'Abnormal' was defined as lowest quartile for VitD (<20 ng/mL), bioavailable testosterone (BioT, <163 ng/dL), and bioavailable estradiol (BioE, <11 pg/mL); and highest quartile for SHBG (>59 nM)."

[E2] An ill-considered 2009 study, where Arimidex was given to older men with low testosterone. Arimidex is an aromatase inhibitor. As such, it inhibit the conversion of T to E2, but at the risk of inducing E2 deficiency in men with low T (& therefore low E2) - as though E2, which is essential for female bone health, is somehow irrelevant for men:

"Mean serum testosterone increased from 319 ... ng/dl at baseline to 524 ... ng/dl at month 3"

"Estradiol levels decreased from 15 ... pg/ml at baseline to 12 ... pg/ml at month 3"

"In older men, aromatase inhibition increases testosterone levels, decreases estradiol levels, and appears to decrease {bone mineral density}."

E3. Another 2009 study:

"Men with the lowest bioE2 (<11.4 pg/ml) or highest SHBG (>59.1 nm) had greater risk of all nonvertebral fractures"

E4. 2013 study of low-dose K2 supplement in women:

"MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae."

E5. An in-progress Dutch study:

"Menaquinone-7 {K2} Supplementation to Reduce Vascular Calcification in Patients with Coronary Artery Disease: Rationale and Study Protocol (VitaK-CAC Trial)"

It's a full-text paper & gives the rationale for the study. I expect to see a reversal of cacification in a 2017 paper.

F. Osteonecrosis of the jaw.

There are quite a number of PCa studies on osteonecrosis of the jaw [ONJ]. Currently 46 PubMed hits for <prostate onj>. Very difficult to treat, or to find someone local who knows how to treat it.

A big problem is that there is a lengthy washout period for bisphosphonates. My wife's oncologist said that she should put off any major dental work (root canal or extraction) for 3 months following her last infusion, & not resume Zometa until 3 months after the dental procedure. I doubt very much that this eliminates the risk entirely, but a 6 month break indicates the scope of the issue.

F1. 2012 Japanese study:

"111 patients with PC ... received ZA between September 2006 and March 2011"

"Nine patients (8.1%) developed ONJ during a median follow-up of 14.5 months."

"Using univariate analysis we found that {docetaxel} chemotherapy (... [HR] 6.611), tooth extraction during ZA therapy (... HR 11.254), and high prostate-specific antigen level (... HR 8.008) at the start of ZA were predictive factors."

"Using multivariate analysis we found that {docetaxel} chemotherapy (... HR 56.35), steroid use (... HR = 17.795), and tooth extraction (... HR 7.471) were independent predictors."

"Among those receiving {docetaxel} chemotherapy, multivariate analysis identified tooth extraction ... and nadir WBC counts <1000/µL during {docetaxel} chemotherapy ... as independent risk factors."

"Tooth extraction and nadir WBC counts <1000/µL were found to be risk factors for ONJ in metastatic prostate cancer treated with ZA and TAX combination therapy, showing that leukopenia is an important factor in the development of ONJ."

(HR = risk factor)

G. Does ZA prevent metastasis to bone?

G1. That was the question the Dutch ZEUS trial was designed to answer:

"Zoledronic acid administered every 3 mo was demonstrated to be ineffective for the prevention of bone metastases in high-risk nonmetastatic PCa patients at 4 yr."

H. Does earlier treatment with ZA reduce skeletal events?

H1. "The study was discontinued prematurely ... after the corporate supporter withdrew study drug supply." LOL

"In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs."

I. Does ZA improve overall survival [OS]?

I1. 2016 study (Lebanon/Syria!):

"Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for" CRPC.

"The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials."

I2. 2016 British study:

"Clinical Outcomes and Survival Following Treatment of Metastatic Castrate-Refractory Prostate Cancer With Docetaxel Alone or With Strontium-89, Zoledronic Acid, or Both: The TRAPEZE Randomized Clinical Trial."

"ZA did not improve {clinical progression-free survival} or OS but did significantly improve median SRE-free interval and reduced total SREs by around one-third, suggesting a role as postchemotherapy maintenance therapy"

SRE = skeletal-related events

I3. 2016 paper from the STAMPEDE trial - "men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy":

"Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population."

....

The new study (translation unavailable - LOL):

"We herein unravel a novel anti-tumour activity of ZA in prostate cancer (PCa), by targeting the pro-tumorigenic properties of both stromal and immune cells. Particularly, we demonstrate that ZA impairs PCa-induced M2-macrophages polarization, reducing their pro-invasive effect on tumour cells and their pro-angiogenic features. Crucially, ZA administration reverts cancer associated fibroblasts (CAFs) activation by targeting the mevalonate pathway and RhoA geranyl-geranylation, thereby impairing smooth muscle actin-α fibers organization, a prerequisite of fibroblast activation. Moreover, ZA prevents the M2 macrophages-mediated activation of normal fibroblast, highlighting the broad efficacy of this drug on tumour microenvironment."

Stromal cells, while present in the intact prostate, become irrelevant after surgery or radiation.

The paper seems to indicate that ZA could be useful at a very early stage, but, as [I1], [I2] & [I3] indicate, ZA has not been associated with better overall survival, so any anti-tumor activity is beside the point IMO.

-Patrick

[A1] ncbi.nlm.nih.gov/pubmed/272...

[B1] ncbi.nlm.nih.gov/pubmed/224...

[B2] ncbi.nlm.nih.gov/pubmed/221...

[C1] ncbi.nlm.nih.gov/pubmed/221...

[C2] ncbi.nlm.nih.gov/pubmed/210...

[C3] ncbi.nlm.nih.gov/pubmed/199...

[E1] ncbi.nlm.nih.gov/pubmed/227...

[E2] ncbi.nlm.nih.gov/pubmed/198...

[E3] ncbi.nlm.nih.gov/pubmed/195...

[E4] ncbi.nlm.nih.gov/pubmed/235...

[E5] ncbi.nlm.nih.gov/pmc/articl...

[F1] ncbi.nlm.nih.gov/pubmed/225...

[G1] ncbi.nlm.nih.gov/pubmed/246...

[H1] ncbi.nlm.nih.gov/pubmed/245...

[I1] ncbi.nlm.nih.gov/pubmed/271...

[I2] ncbi.nlm.nih.gov/pubmed/267...

[I3] ncbi.nlm.nih.gov/pubmed/267...

[Dan59]

Patrick, thank you for another good study!

I find it interesting. In my early days with this disease, as a stage 4 patient, I was given zometa every 3 months , it was thought to make the bones an unsuitable environment for cancer to grow, and decrease risk of spinal compression and breaks.All I knowis it may have been what worked for me, I was on 3 month zometa for the first 6 years, And bone progression has not increased much even to 10 years out. But that may have been the prayers too.

Dan

[harryflittle in reply to Dan59]

One thing that patients on Zometa should be aware of is avoid any tooth extraction while on this med. Even after you have stopped Zometa, check with your Oncologist before ant tooth extractions!

[harryflittle in reply to harryflittle]

any tooth extractions

[Dan59 in reply to harryflittle]

Thanks for adding that Harry, That was the first thing they told me 10 years ago, and to do calcium supplements as zometa can deplete CA.

However after almost 8 years on zometa I took 18 months off and had 3 tooth extractions and it was no problem. I find the stable disease in bones after a widespread dx of metastatic disease interesting and I am greatful not to be in pain.

[pjoshea13 in reply to Dan59]

Hi Dan,

Just a clarification:

Zometa doesn't actively deplete calcium. By killing osteoclast cells, it prevents an appropriate response when the diet is deficient in calcium.

The problem with calcium supplementation & PCa is well-known (although I can do a thread on that if there are men in the group taking calcium).

Hunter-gatherers had no problem building bones without access to dairy & 1,000 mg calcium supplements. Leafy greens in the diet seem to do the job at moderate doses.

What calcium dose was recommended to you? Any particular form?

-Patrick

[Dan59 in reply to pjoshea13]

Thanks Patrick , I was originally prescribed twice a day 500 mg, as I for the past many years I only do once a day 500mg oscal. plus d. My serum CA level is normally about 8.9 which is the lower level of normal to 9.1. What is the nature of the problem with Calcium supplementation, Is it that possibly adt uses the calcium channel to work and that Ca supplements block it? In the winter I sometimes do 5,000iu vitd, my d3 levels hover around 60.

Dan

[pjoshea13 in reply to Dan59]

Dan,

Your reservoir of inactive vitamin D (25-D) is fine. The problem is that PCa cells have lost the ability to convert 25-D to the active form (1,25-D). Therefore, we are dependent on the kidneys doing the job.

But the kidneys only make the conversion when calcium levels dip. With Zometa suppressing the availability of calcium from bone, the supplements are an attempt to prevent dips. But they also, in effect, shut down kidney conversion.

Interestingly, there is a clinical trial that combines Zometa (Zoledronate) with 1,25-D (calcitriol):

clinicaltrials.gov/ct2/show...

To me, the idea of adding calcitriol to someone who is on Zometa makes sense. No more dependence on the kidneys. But the rationale here is a bit odd:

(i) "Calcitriol may help prostate cancer cells develop into normal cells." It is a stretch to expect reversal.

(ii) "Zoledronate may delay or prevent the formation of bone metastases." I couldn't find a study to support that, but who knows?

So the aim is to stall metastasis with Zometa until the PCa cells have been made normal. Not the sort of study I'd expect from Sloan Kettering. LOL

In general, I think that men taking vitamin D3 assume that all they have to do is hit a target (>50, up to 75 or higher, depending on who you listen to), but the real target is the active, hormonal form. There is a test for 1,25-D, but it is of limited value, in that the level would vary throughout the day. Of course, with enough tests, one can get an idea of one's 1,25-D status.

Men on Zometa or Xgeva are in an impossible position, since hypocalcemia has to be avoided, but I would investigate the minimum calcium dose that can safely be used.

-Patrick

[luee]

hi Patrick,

your post on Zometa was certainly very timely for me. i am planning to go on a bisphosphonate after my upcoming tooth extraction.

there is one thing i didn't see you mention about the nitrogen-containing versus the nonnitrogen containing bisphosphonates as they relate to jaw necrosis.

i have a hard time understanding the conclusion of a study that seems to indicate that the nonnitrogen bisphophonates produce a much lower incidence of jaw necrosis.

would you please read that study and see if you can understand their conclusion. their wording seems to be a little vague. PMID: 25475039

thanks

michael

[pjoshea13 in reply to luee]

Hi Michael,

The Brazilian study you cite [1] is a little difficult to follow.

It states that 324 patients received bisphosphonates: 94 received Zometa across four different schedules, while 156 received clodronate, & 14 others switch from one to the other. That seems to leave 60 unaccounted for - but then there is reference to a control group later on.

Two cases developed ONJ (0.6%). OK, 2 is 0.6173% of 324, but if 60 did not receive treatment, the occurrence is a bit higher: 0.7576%.

However, those two cases were part of the 14 who switched.

& then the authors conclude that "ONJ seems to be exclusively related to nitrogen content bisphosphonates.", when in fact the two cases used both drugs.

Clodronic acid (clodronate disodium) is a first generation (non-nitrogenous) bisphosphonate, & "is not approved for use in the United States, because it has too many adverse effects." (Wikipedia [2])

Perhaps in the full text we would learn why the 14 switched, & how long they were on each drug. Turned out to be a poor strategy for 14% of them.

From a 2002 British paper [3]:

"The more potent nitrogen-containing bisphosphonates, i.e., pamidronate and zoledronic acid, have demonstrated antitumor activity at approximately 10- to 100-fold lower concentrations than clodronate in vitro."

From a 2010 British paper [4]:

"There is ... considerable evidence to suggest that nitrogen-containing bisphosphonates might exert additive or synergistic interactions with standard cytotoxic agents. However, mature clinical data with bisphosphonates are limited and, thus far, provide conflicting evidence regarding the antitumor role of bisphosphonates, but have mostly been conducted with first-generation bisphosphonates such as clodronate that are not as effective as next-generation bisphosphonates."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/?te...

[2] en.wikipedia.org/wiki/Clodr...

[3] The more potent nitrogen-containing bisphosphonates, i.e., pamidronate and zoledronic acid, have demonstrated antitumor activity at approximately 10- to 100-fold lower concentrations than clodronate in vitro.

[4] ncbi.nlm.nih.gov/pubmed/211...

[luee in reply to pjoshea13]

hi Patrick,

thank you very much for the additional analysis on the bisphophonates.

like much of the cancer research there is a lot of ambiguity in the results. i was all set to use a clodronate but it looks as if i'm shifting back to Zometa.

michael