As part of the ongoing debate between me and my oncologist about the frequency of Xgeva injections, I've done a bit of online research and found some very interesting things. I'm very curious if anybody else has researched this and what was found, so please share in a reply if you have.
Xgeva, aka denosumab, is a RANKL antibody. RANKL is involved in the production of osteoclasts. Take away the RANKL, you get fewer osteoclasts, less bone turnover, and less "skeletal events" in metastatic cancer. But RANKL also has other effects including in the immune system. To make a long story short, it may have direct anti-cancer effects and also be synergistic with some immunotherapies.
Fun detail: It seems that some cancer cells will produce RANKL, thus accelerating bone damage and impeding the natural immune response.
As far as frequency of dosing, the REDUSE study is underway comparing 4-week vs 12-week dosing. So far it has only produced an interim result that said the 12-week group had fewer cases of hypocalcemia. A smaller study found no statistically significant difference in skeletal events between 4-week and 12-week groups, but a closer look shows there were more events in the 12 week group and only a 3% chance that was random. Depending on the summary article you read they may say go to 12 weeks now or wait until the larger REDUSE study is complete.
And finally, a Chinese study looked at the pharmacodynamics and pharmacokinetics of denosumab in healthy subjects (in Engish, how long it remains in your body and how long it has an effect for). I found figure 3 almost shocking. It shows C-Terminal Telopeptide (a blood marker of bone turnover) dropping 90% and staying down for over 120 days after a single dose, and the same effect was seen for both 60 mg (Prolia) and 120 mg (Xgeva) doses. Of course, these are healthy volunteers without cancer cells producing RANKL, but it does make me wonder how they came up with the original Xgeva dosing. It seems a bit like using a nuclear weapon to kill a fly.
I don't have any answers but you certainly answered my question "will my teeth fall out?" My doctor's explanation of why I was changed to every 3 months is now proven to be stupid. Thank you very much for the post and the links. My teeth may fall out, but probably not from the Xgeva. Thanks again.
"Your teeth might fall out". That was her explanation. (No mention of the jaws they are attached to.) At least she was 0.8% correct. Or something like that. She is Chinese and is very inscrutable. And no, I am not being racist. She is very, very cute. It may be a case of what the patient doesn't know won't hurt him. That's why I come here. I learn something new almost every day. And you have pretty much answered my question of why I was switched to every 3 months. And I'm sure there are some other reasons. Anything that has to do with prostate cancer is like a fungus.
Ah, got it. Yep, there's a lot to learn, and it might not make any difference. I mostly research a lot of this stuff out of curiosity and to get some small sense of control, or at least a sense of involvement.
I receive an Xgeva injection every 6 months. I don't know the dose. I have bone mets and osteopenia. Supposed to help prevent skeletal events. Thanks for the reading material.
My understanding is the reason pharmacists give differing names for these identical drugs is the following: Xgeva is considered four times more powerful than Prolia. This is because Xgeva is twice as powerful in its dosing of milligrams and... it's also scheduled to be injected twice as often as Prolia.
Just as in Patrick-Turner's description below, I also notice an opening crater in the gums and began experiencing mandible pain and feeling like my tongue was fatigued and painful. I went to my dentist, who sent me to an endodontist for a cone beam scan of my jaw. He referred me to oral surgeon No. 1. who ground down, what we thought at the time was, a bone spur. I went in to my dentist's office to get a regularly scheduled teeth cleaning and was told I needed to see an oral surgeon. I informed them that I had an appointment set up in three weeks. To which they informed me I couldn't wait that long. "If you don't see them very soon you're going to lose your jaw" Wow! You don't expect to hear that phrase ever in your life! I went to oral surgeon No. 2, on their referral.
I was fit into the schedule of oral surgeon No.2 the next day. After taking another cone beam CT and an examination, surgery soon was scheduled and I found myself in the chair under local anesthetic as the doctor removed a 2"x 3/4'' section of jaw with just a few wiggles of a set of dental pliers. This took away the pain as there was no loose section of jaw poking through my gums and carving into the side of my tongue.
All of this detail is given in a spirit of giving other patients anecdotal information in asking their Medical oncologists questions about risks of treatment with Xgeva: a heads-up for patients coming along the cancer path a few steps behind me. I was informed when I gave consent to treatment with Xgeva that the odds of me getting this treatment-caused disease was 1.8% so I thought those were very good odds. My doctors all thought the benefits far outweighed the risks. That's why I was distressed reading in your post that researchers were discovering there's now a 30% chance of obtaining MRONJ, or Medicine-related OsteoNecrosis of the Jaw.
Luckily, I seemed to have stopped advancing in this disease as we monitor it quarterly now. I still have no gums on the left side of my mandible as that tissue won't seem to grow back. The loss of solid jawbone on the left side of my jaw has left the roots of my #18 and #19 molars dangling in plain sight on the lengual side of the mandible, their roots still firmly clinging to the buccal side of my jaw. However, I've been surprised at how little it's effected my quality of life so far.
My onco tried to get me taking Xgeva every 2 months in 2017, but after 6 months and 3 doses I began to get beginning of lower jaw necrosis where the lower jaw bone begins to die. Its a side effect that is rare for men not on ADT but when a man had ADT for a long time chance is said to be 30%.
I got an ache in lower jaw and a tiny hole in skin in mouth to allow drainage of junk from jawbone. I saw a dentist then oral surgeon who confirmed my problem and quit Xgeva at once. The reason for prescribing it for me was to slow down Pca bone mets and prevent bone density going too low while there is no testosterone in body.
But I read a German report long ago which dismissed claims bone density drugs stopped Pca growth, and saying its often over prescribed, one dose each 6 months is plenty.
As soon as I quit taking injects of Xgeva, my jaw pain went and all is well, my body has repaired the damage.
Aclasta is another drug for bone density with lasting effect, and too much is no good. I had one dose in 2013, no ill effects except a bit if feverish condition on night after infusion.
Best thing for bone density is walking a mile at least daily.
Thanks for sharing your experience. I'm not a fan of aclasta (zelodronic acid) because it sticks around for so long that it will take a really long time for side effects to resolve.
I walk or run af much as possible but still ended up with cancer in most if not all my bones between my shoulders and my hips. The studies I've seen do show benefits for Xgeva, both in rate of skeletal events and survival, but those studies apply to metastatic castrate resistant cancer. There's literally no data for hormone sensitive cancers.
I read the scholarly articles where they exist for most drugs, and found one that suggested long term ADT users had much bigger chance of lower jaw necrosis,LJN, with Xgeva than those not on ADT. Those not on ADT and who were usually older than me and who could do little exercise and who had thinning fragile bones did get a benefit with higher bone strength, with less chance of fractures, and chance of LJN was 1%.
After 3 injections of Xgeva over 6 months, I got start of LJN, so I quit. I've been on ADT for 10 years, and the dose level was maybe way too high, one injection per 6 months is probably better. It is often prescribed to slow progress of Pca in bones, but a report I read by German researches 18 years ago suggested all bone strengthening drugs have no effect of Pca spread to bones.
When I stopped accepting any more Xgeva, my early LJN symptoms went away completely, and whatever was damaged healed up OK.
There is no point in worrying about 30% failure rate of any drug, because many drugs have that failure rate, but may have 70% success rate.
There are few drugs offering a 100% success rate. And all drugs and therapies for Pca have some uncertainty and failure rate and if we feared all of them we would die earlier. The 30% side effect rate means an average 30% will have side effects, even if the drug or therapy works as intended, so for some, they will have 100% chance of side of bad side effects and some have no side effects. Its very easy to be in the group who get side effects, and side effects are inevitable with some well known Pca treatments such as chemo. Nobody can escape some long lasting neuropathy with Docetaxel, yet ppl don't refuse it because that's all the docs can offer or they can't afford anything else, like Lu177, which worked well enough for me to accept have a bit more of it, because like all cancer therapies it does not give a higher than 70% success rate where success is defined as big reduction in mets seen in scans and reduction of Psa. But Lu177 fails with 30% of men with Pca.
I'll soon be having Veyonda, aka Idronoxil which boosts the effectiveness of Lu177.
The list of possible side effects is a very awful list. with bad effects on liver and kidneys etc,etc, and if these prove to be so bad to tolerate, I will stop taking it.
Its a new drug that is a suppository that I must shove up my arse twice a day, and it could cause arse troubles because I have some rectal damage due to previous RT. But if don't take it, it means I might not get an increase in Lu177 effectiveness, and then die earlier.
I can cease taking Veyonda is side effects are intolerable. I am healthier than 90% of most ppl my age, so should withstand Veyonda better than others.
There are continuing trials of Lu177 going on when combined with other drugs. Veyonda has so far assisted so many men to have a better response with Lu177 so even without official trials to prove it, docs think a high enough % get the benefit without disastrous side effects to use it. Lu177 is not yet been given full approval for use, but for many men there is no alternative, and for some, Lu177 is a god send drug to be used right after initial diagnosis. My signing a consent form means I accept the risks of failure, that that means I won't try to sue the doctors or company if it fails. Vioox was a notorious arthritis drug that was approved, but it killed so many with heart problems that ppl gathered to sue the makers for a billion dollars or more and Vioox was then banned.
The doctors know that Veyonda tends to work, and with so many drugs they know of side effects, and when you read the list of side effects its a terrifying list. With Zytiga, 3 of 10 listed side effects are related to heart function, and sure enough, I had one of them which made my HR irregular, but after I quit Zytiga when it faied to keep Psa low, the heart rate bothers stopped, and I'm cycling 200km+ a week at good speed. I was doing that even while taking Zytiga; the heart rate bother was not life threatening.
I have accepted having a number of treatments with less than 30% of working, all with side effects, and what else could I do? Its part of living with Pca to keep it under control until it finally wins. You can't fight a battle cancer without getting wounded, and usually cancer is the winner if you don't get remission.
Just don't take too much Xgeva, you only need enough, and if it gives you 75% of the benefit of having a maximum amount that will cause LJN, then 75% of the maximum possible benefit is worth having, if it means you don't get any LJN.
Thanks for the great read and food for thought. Support for "antiresorptive therapy" - i.e., denosumab or bisphosphonate zoledronic acid - is based on simple prevention of "skeletal related events (SRE)" - i.e., fractures - with the thought that these present the greatest risk to overall quality of life in an APCa patient. The demonstrated statistical reduction in SREs with the use of antiresorptives is on the order of 10 - 20%...but the implication that chemical RANKL manipulation may actually help our cancer rather than work against it needs to be an explicit part of the entire risk profile, which (currently) it is most certainly not.
In the following summary article from last year's Advanced Prostate Cancer Consensus Conference (APCCC) 2019, which is fairly pro-antiresorptive, there is a nod to the fact that there is "...a lack of conclusive evidence that anti-resorptive therapy significantly improves key outcomes, such as quality of life and overall survival, in the contemporary era of prostate cancer management." At least it is being discussed in the larger APCa care-provider community.
PS - On a personal front, I am on denosumab - injection every 3 months. I admit that, for me, Xgeva is largely just an excuse I use to engage in what my oncologist would call "risky" behavior. It seems to overcomes fear - my family's, and my oncologist's, even my own. To find out that it may be just another instance of making a deal with the devil is unfortunate, but not unexpected! - Joe M.
Interesting. My MO hasn't given me any restrictions, and he knows I'm regularly using a chainsaw and hiking or running in the woods. Last year I slipped on a rock and fell on my elbow. Got a bruise, nothing more. On the other hand, before diagnosis/ xgeva, I cracked a rib resting my weight on the edge of the bathtub trying to deal with a hair clog. So, chainsaws okay, bathtubs dangerous?
HA, exactly! Working as a safety engineer, I know risk is always everywhere and is always relative. My MO has a "boy in the bubble" outlook....likely just for liability. Don't tell is my motto. I took several tumbles over the winter on my mountain bike without major harm, and then I slipped on my driveway and internally dislocated my shoulder...but, as I told my wife, no fractures in my wrist, radius/ulna, humerus, acromion, clavicle....etc..seriously, it was a total win for me even as I sat there in the dark for several minutes figuring on how to get up from the ice. Alas, she remains unconvinced.
Its a bit difficult to know if your dosage per year of denosumab will cause jaw bone necrosis, but when I searched the matter, I saw pictures of old guys with open holes 10mm dia in skin layer inside mouth and outside, and bare bone was clearly visible. To me, that is due to too much of something that may be having on bone density, but I also think that it may be way too high a dose. There's probably only so much denosumab that is needed to keep bone density high enough, and having too much does little more and just causes seriously bad side effects. My oncologist was aware of the problem, and called it "deno-jaw" So not too much, and a bone density scan might tell you what has been achieved in 3 months with 2 doses.
I am doing risky behaviour by cycling 200km a week; the bumps in cycle paths and roads on a rad bike with narrow rims and no suspension shakes the body all over, especially my spine, but bone mets of 1cm dia in middle of a vertebra don't make it fragile. Its a problem when bone mets grow big enough to occupy a large % of vertebra volume, and then a man is in serious trouble, which could put a man into a wheelchair real fast. Its the end of QOL.
So far so good, I feel very well on days I cycle 70km and days after. There there is the work around the house to to; I am always busy and with a list to get done.
Ah...a road cyclist - you are superheroes in my eyes: You go far, fast, and engage the road on slender machines side by side with angry and/or distracted auto drivers trying to run you into the side ditch! I don't know how you mentally do it, much less physically.
I keep to the dusty trails if I have a say - give me a mud puddle in the trail over a side-splash by an auto any day! Oh, and fat tires. Nice, fat tires.
I've never really thought hard about a bone density scan, but after this post, I am going to pursue it. Keep rollin', PT!
Some motorists hate all cyclists who they think should be banned from all roads. They often don't see cyclists and kill them and drive away thinking they'll get away with it, and some do. So that places big onus on road cyclists to have very bright flashing lights to make motorists see them. But that won't stop all crashes involving cars, trucks, buses and bikes.
I've cycled an estimated 250,000 km, further than going to the Moon.
I'm still here, but in this town of mine there's about 500km of secondary "shared paths" for cyclists and pedestrians so I spend 1/2 my km on these paths where its fairly safe, and I doubt anyone has been killed yet on these sealed paths. So once I get away from area near city center, the roads are not busy, and many main big roads have a "breakdown lane" which have become cycle lanes, and these are safe, but only if I take good care to look behind me where entry exit lanes from side roads join main roads.
I have never graduated to riding "dirt bikes" because its usually mostly up or down steep hills, and risk of falling off is high, but I understand those who love getting into wild areas on bush tracks to avoid all tarred roads and cars. There are many km of such bush tracks here. Such cycling in bush shakes and bashes bodies more than smooth tarred roads. 40 years ago I loved dirt roads on motorcycles, but they did little for my cardio vascular health.
Its 10am here now and 7C, so I'll ride 40km after lunch when T goes to 10C.
Its a short ride, because tomorrow I ride same distance to get a PsMa scan,
Then on Thursday I'll do another 40k, so 120k in 3 days and on Sunday I'll do 80km and that makes up the 200km. Eezee Peezee as they say.
Bone density scan is an easy scan to get; some I got just looked at an arm to give an idea of BD. I have not had one for some years now, and its below "normal" but we have more BD than we need. I used to have more than normal before I got Pca, and so the drop below normal was not life threatening, and seems to still not be a threat, but I'll stay away from motorcycles, and riding dirt bicycles down hills on inevitably very bumpy dirt tracks.
No motorcyles for me, alas, but I can't stay away from a good dirt track through a field or wood. Like you, there are some things I use as a personal metric.
You are too humble...."eezee peezee" AND riding to and from your own scan! You are an inspiration...I need to get some more km/miles in...!
Of course I ride to my own scan. Driving my 1986 Ford Laser car is out of the question. I'm independent, no kids or wife or relatives for support, and I don't expect help from friends. I've had hospital stays where nobody visited me and I just listened to the radio or read. I just ain't a needy person.
At 23, when I became a sub-foreman on a large building site, a young laborer said to me " Youse is the man they can't root, shoot, or electrocute" and I just replied to say "well, I am flattered" and we just got on with things. I was fair, firm, didn't lose my temper and found solutions to problems, and the men worked with me well.
My wife is independent like you. Give her a book and a quiet place to read and she needs nothing else. I'm a bit of an introvert myself but next to her I'm the life of the party.
Summary of the details that follow: I’m a fellow PCa patient with no medical training. I’ve been using denosumab over the past four years, but my dosing is based on a bone resorption marker, not the calendar. Using my dosing approach, I am finding that spacing Prolia shots at 9-14 months is working satisfactorily. The details below might be useful to Tom, but most are going to find this TMI.
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As you know, denosumab (Prolia=60 mg/Xgeva=120 mg) has two primary applications—(1) osteoporosis and (2) mitigation/prevention of skeletal events associated with bone mets. The lower-dose Prolia is approved for osteoporosis (incl men at high risk for fracture who are receiving ADT), and the usual tx interval is every six months. The higher-dose Xgeva is approved for skeletal-related events (incl prevention) and the recommended tx interval is monthly. All of that is based on the clinical trials that were used to obtain FDA approval for these applications. Here’s the problem as I see it: In practice, quite a few patients receiving Xgeva monthly started having problems w/ ONJ, so the prescribing docs started backing off on the tx interval. But to my knowledge there’s not much clinical trial info to help individualize and optimize denosumab dosing for either application. Hopefully the REDUCE study, when complete, will add significantly to our understanding of benefits and risks of long-term denosumab at various doses/intervals.
I’ve been taking denosumab since 2016, primarily to help manage my low bone density following ADT in 2009-10. Before starting denosumab I also used Zometa (once, in 2011). Before recommending Zometa, MO Stephen Strum asked me to check my serum CTx (C-telopeptide) and urine DpD which are both bone resorption markers. In Jan 2011 (before Zometa) my CTx was 431 (87-345); bone density T-score was -3.73. After Zometa (5 mg) my CTx fell to 54 (87-345), a drop of 87%, while the urine DpD dropped insignificantly. I later (2012-13) tried the bone resorption marker serum NTx that some MOs and endocrinologists favor. In my case, CTx appears to be a much more sensitive marker for bone resorption activity in response to both Zometa and denosumab treatment.
After my Feb 2011 first and only dose of Zometa my CTx gradually rose over several years. In Jul 2014 CTx was 186 (115-748), then it began a sharp rise in large part due to Forteo injections I also began in Jul 2014. Forteo stimulates both bone resorption and bone formation activity; it’s probably not a good idea for most PCa patients but I didn’t appreciate the risk at the time. Fortunately, my PSA was pretty low in this period (0.3) and so far I haven’t encountered any bone mets. I discontinued the Forteo in Mar 2016 because I checked CTx and was shocked to find it at 3395 (115-748). I then began monthly Xgeva to knock down CTx. It took six months of this to drop CTx to 73 (115-748) in Oct 2016. CTx then gradually rose (with no Xgeva); when CTx reached 350 (115-748) in Mar 2017 I had single Xgeva shot that dropped CTx to 46 (115-748), a drop of 87%.
At this point I had been using LabCorp for my CTx labs since 2014. Something disappointing happened with the LabCorp assay in May 2017: In the prior month (4/10/17) LabCorp showed my CTx was 172 (115-748). Okay, no problem. But my 5/1/17 result was <33 (38-724) (in other words, undetectable). On the 5/1/17 LabCorp report there was a notation of a reference range change, and they obviously also had a change in their assay method. On 5/8/17 I had LabCorp repeat my CTx and received the same result as 5/1: <33 (38-724). Also on 5/8/17 I had Quest check my CTx: 74 (87-345). That convinced me that, while a bit inconvenient, for CTx I needed to rely on Quest from this point forward, not LabCorp.
I’m obviously using CTx to guide my denosumab dosing, not the calendar. My MO is fine with this, although I think I’m his only patient using that approach. (About a year ago, I did encounter an endocrinologist specializing in bone health who uses CTx to determine Zometa and denosumab dose timing.) I was troubled by the magnitude of CTx drop from a single injection when using both Zometa (in 2011) and Xgeva (in 2017). I decided to use a CTx result above 200 (on Quest’s assay) as the trigger for my next denosumab dose, but to begin using Prolia (which is half the strength of Xgeva) as my routine dose. In Mar 2018 my CTx was 205 (87-345) and it had been 12 months since my previous denosumab shot. Two weeks later I had my Prolia shot; after another two weeks CTx was 105 (87-345), a 49% drop. That appeared to validate the switch to Prolia for my situation. Keep in mind I’m focused primarily on managing bone density loss. I’m not recommending my approach to others.
Continuing my saga, 9 months after my 4/4/18 Prolia shot my CTx had risen to 241 (87-345). Since it had crossed my CTx trigger point, I got another Prolia shot (Jan 2019). Two weeks later I checked my CTx and it was 63 (87-345), a 74% drop.
Twelve months later, (Jan 2020) my CTx was only 178 (87-345), although it also tested 178 in Nov 2019 and 193 in Dec 2019. I’m providing this detail because I think it reveals the level of Quest’s CTx test variation, not biological variation (no way to be sure, of course). In any case, four weeks later (Feb 2020) my CTx was 284 (87-345). Since CTx had reached my trigger, I got another Prolia shot. Notice that this was 14 months since my prior Prolia shot. Three weeks later I checked CTx because I was curious about the size of the drop. Mar 2020 CTx was 58, an 80% drop.
Final comment: While I haven’t gone through it personally, my understanding is that discontinuing denosumab after long-term use involves some added risks that are not such an issue when discontinuing Zometa. On discontinuation you can lose the gains achieved unless you switch to another antiresorptive drug to maintain the benefits achieved w/ denosumab. More info on this here: ncbi.nlm.nih.gov/pmc/articl...
Thanks for the extremely detailed reply! You have basically reproduced figure 3 in the last link I posted, which showed a 90% drop in ctx for both xgeva and prolia and lasting for many months.
Tom, I share your concern about what appears to be suggested in figure 3 of the Chinese study you cited. Might the recommended denosumab injection doses (60 & 120 mg) be an order of magnitude too high? I took a look at Amgen’s original phase II study of denosumab for low BMD (2002-07). They tested lots of doses and timing intervals. Here are some of the reported median changes at 12 months:
Amgen’s original phase II study of denosumab for patients with bone mets looked at breast cancer patients (2004-2006). They tested doses of 30, 60, 120 and 180 mg. Timing intervals tested were q month and q 3 mos (but not for every dose tested). Primary study endpoint was % change at week 13 in adjusted urinary UTx (another bone resorption marker); secondary study efficacy metrics included % changes in CTx and bone-specific alkaline phosphatase (BSAP, a bone formation marker). Here are some of the reported mean changes at 13 weeks (there was no placebo):
Looking at the above data doesn’t help me understand why Amgen ended up choosing the 60 mg denosumab dose q 6 months for osteoporosis and the 120 mg denosumab dose q month for cancer patients with bone mets. I’m sure they had good reasons. But their numerous trials failed to detect some fairly rare denosumab adverse effects: ONJ, atypical femoral fracture, and severe hypocalcemia (fatal cases have been reported). Just looking at the data shown above I would have either picked 30 mg q month as the preferred bone mets dose for phase III testing or (preferably) taken multiple dosing options into phase III. Note that reduced new bone formation (BSAP) may be an unfavorable indicator when it comes to ONJ and atypical bone fractures.
There are two clinical trials now underway to explore denosumab “de-escalation” to see if that will produce improved benefit/toxicity ratio, with a focus on reducing ONJ and hypocalcemia. Interestingly, neither of them is directly sponsored by Amgen, the biotech giant that owns the denosumab patent (although for one of these trials Amgen is listed as a study collaborator). Here are the denosumab de-escalation trials:
REDUSE (phase III for breast or PCa, began 2014, nonprofit sponsor=Swiss Group for Clinical Cancer Research) clinicaltrials.gov/ct2/show...
REDUCE (phase II for Bone Giant Cell Tumor, began Sep 2019, nonprofit sponsor= European Organization for Research and Treatment of Cancer) clinicaltrials.gov/ct2/show...
The above two studies acknowledge that the optimal dose and schedule for denosumab are unknown. But they both take very conservative steps toward learning the optimal dose/schedule: begin with all patients receiving 120 mg monthly, then reduce the frequency to 120 mg q 3 months. At this rate it’s unlikely that we will discover the optimal dose and schedule for denosumab in any of our lifetimes.
Thanks for the reply, there's a lot of data in there I hadn't heard before. I did watch a video about the REDUSE trial, and the drug companies had no interest in sponsoring the trials, but the insurance companies did. Apparently the trial itself is revenue neutral for them, and a big win if the result is that lower doses can be used.
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