This 5-year study reports the risk of developing osteonecrosis of the jaw [ONJ] [2] while using Denosumab [Xgeva], Zoledronic acid [Zometa] or both for bone mets.
The study was not restricted to PCa.
"The 5-year incidence proportions of ONJ were 5.7% ... in the {denosumab inception cohort}, 1.4% ... in the {zoledronic acid inception cohort}, and 6.6% ... in the {denosumab-switch cohort}."
So those who switched to Denosumab fared worse than those who started on it.
Given the difference in risk (& the major unpleasantness of ONJ), Zoledronic acid is the clear choice.
Note that "Incidence proportions and incidence rates were highest in patients with prostate cancer and in Denmark", so the risks are a bit higher than the above numbers suggest.
My understanding is this: you normally have constant turnover in your bones, with osteoblasts building them up and osteoclasts tearing them down. Both drugs cause you to have fewer osteoclasts and thus less tearing down of the bone. Zoledronic acid gets absorbed into your bones and kills osteoclasts as they work to tear it down. Denosumab inhibits RANKL, which keeps osteoclasts from maturing, so same bottom line, fewer of them to tear down your bones. Eventually, in both situations, the osteoblasts get the message that there is enough bone around that they slow down, and you don't get an overgrowth of bone.
I had one infusion of zoledronic acid and had flu-like symptoms for days. Some people on the forum seem to be ok with that. My doc used that as a reason to switch me to denosumab, and I have had hardly any side effects with it.
Similar. I had zoledronic acid (brand name Reclast) first, had severe chills followed by mild fever for a day, but after that no issues. Next time (six months later), got denosumab (brand name Prolia) instead, no issues at all. DEXA scans show my bone density is still slowly decreasing, but I can only hope that it is decreasing more slowly than it would if I weren't still getting a Prolia shot every six months. No ONJ so far, so that's good.
When men with normal bone density go on ADT, bone loss is to be expected when estradiol [E2] falls below 12 pg/mL. I am on DES presently and my last labs showed E2<5 pg/mL. This would normally be catastrophic since bone loss would be rapid at such a low level, but DES is a synthetic estrogen & usage is not associated with osteoporosis.
Men make estradiol through aromatization of testosterone [T] via the aromatase enzyme - so castrate T = E2 deficiency. Men need E2 for bone health. Not very much, so a low-dose E2 patch perhaps every other day might be sufficient.
"Five dosage strengths of Vivelle-Dot (estradiol transdermal system) are available to provide nominal in vivo delivery rates of 0.025, 0.0375, 0.05, 0.075, or 0.1 mg of estradiol per day via the skin." The 0.025 mg is the one to use.
I'm surprised that you conclude "given the difference in risk (& the major unpleasantness of ONJ), Denosumab is the clear choice." The list of statistics you cite (that are also in the article) shows ONJ incidence with Denosumab as 5.7% vs. 1.5% with zoledronic acid.
It might be good for some out there to know Zoledronic acid has been linked to lower kidney function problems and ever renal failure, particularly if lower kidney function is already present. Denosumab didn't affect the kidneys at all in clinical trial, even when recieving dialysis.
Not in the study but also with risk of osteonecrosis is Fosomax. I'm about to start treatment with Orgovyx and have been advised, by PA case manager, to start taking it. My DEXA scan results were .9 lumbar and -1.3 femur, so osteopenia. FRAX score 7.3% major and 2.3% hip. I really don't want to take this drug. Comments?
I'm saying that estradiol [E2] must be in the 12-20 range for bone health. There will be bone loss if E2 is in the single digits.
ADT = castrate T = E2 deficiency. It is a known issue, yet doctors respond to bone loss with a knee-jerk bisphosphonate script. I suggest that docs should first fix E2 deficiency. But better still, monitor E2 from ADT initiation & perhaps avoid bone loss.
This will work for ADT without bone mets, but it should be done when there are bone mets too. Heavy duty drugs can be used later if bone density doesn't recover.
In my view bone density is not the only or even the best criteria in APC. These two drugs protect against skeletal related events ( mainly pathological fractures) that does not track with just osteopenia. It is a major long term risk downstream in the evolution and progression of PC. I would suggest that nearly every man with APC who is on ADT should be on a bone strengthening regimen. And Zometa is clearly superior in those at highest risk for ONJ due to sub optimal dental status. That should be fixed first and have fastidious dental hygiene. The other big reason in favor of these drugs is that the soft evidence suggests that they make changes in the bone micro environment that make the bones less hospitable for establishing new mets. Of course that is an important factor to consider, even before this is fully quantified in clinical trials.
I agree that estradiol is a valuable adjunct also while on ADT. You suggest the lowest dose patch. But I would suggest going higher for many might have additional further benefits such as the elimination of many ADT side effects such as hot flashes, fatigue and brain fog. I use 0.10 mg/24 hrs patch twice weekly when on ADT.
In the Dr. Myers video (2016) that I have just used in a response to bigdoggatto, Myers says that when he started to prescribe low-dose transdermal estradiol, osteoporosis cases "plummeted". This occurs at ~6:00.
I would say that doctors who are giving the drugs to men because of osteopenia or osteoporosis should take care of the E2 issue first and, based on Dr. Myers comment, it looks as though the drugs would be largely unnecessary.
The value of the drugs against bone cancer is another matter & I'm not up on current thinking for PCa.
However, my wife is being treated for recurrence of a solitary plasmacytoma, which is an unusual form of multiple myeloma. Basically, most oncologists treat it as though it were full-blown MM. Her bone density is normal but she was put under pressure to agree to Xgeva. As a compromise, she gets it only every 4 months, but isn't happy about it.
The literature on solitary plasmacytoma & Xgeva is non-existant of course.
Anyway, I do understand that that the drugs are not always prescribed because of bone loss. Thanks for bringing that up.
"A 2012 meta-analysis found that denosumab was better than placebo, zoledronic acid and pamidronate in reducing the risk of fractures in those with cancer." [Wikipedia].
Patrick,I also had one plasmacytoma and was treated as if I had full blown MM. Underwent Stem Cell Transplant in Dec. 2019 and now in complete remission. MO started me on Zometa infusions in March 2020. Had 2 infusions and now she switched me to Xgeva. Never had an E2 test from my MM MO or PCa MO. I will definitely asked both on my next visits. Bad news is PCa is is going nuts. Had to have my bladder removed in 12/2020 and PCa has also spread to my liver. Now on chemo.
You must have had the same oncologist as my wife's first oncologist. Stem Cell Transplant is extremely aggressive for a solitary plasmacytoma. When we went to Wake Forest to meet the team, they basically told my wife that she was crazy to want stem cell treatment. One said: "Don't you realize that there is a 2.5% chance of dying during treatment?" "You only have a solitary plasmacytoma."
When the full team arrived, the leader said it would eventually turn to MM, and that it might be wise to go through the harvesting phase for later, while the body is strong. I looked at my wife. She was down to 105 from 144 lbs because of the chemo, & she didn't look strong enough for anything. So we canceled the treatment.
Her second oncologist was more into treating the patient rather than treating the disease & to hell with the patient. He put her on low-dose Revlamid & she has been fine for over 2 years.
My sister died of MM & I am always a little nervous when my wife has blood tests, but I question the assumption that a solitary plasmacytoma inevitably becomes MM. Where's the data?
For 20 years no one could find any PCa, only a PSA of 95 at DX. PCa only took off when I underwent treatment for MM. I think that destroying my immune system during the SCT was a major factor in PCa advaneing. No evidence just a feeling
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