Calcinosis Cutis and Trilostane

I will be posting this on four members' threads, all of whom are dealing with calcinosis cutis. Kerry, Millie's Mama; Crystal, Annabelle's Mama; Shelly, Lucy's Mama and Pat, Peety's Mama.

I've seen too many dogs on Trilostane who have either had little to no effect on Calcinosis Cutis or a worsening effect while on the drug. Based on the frequency with which we've seen calcinosis cutis on this forum, there seems to be a correlation with the increased popularity of Trilostane for treatment of cushing's. I've had a gut feeling for a very long time that Trilostane is responsible for worsening calcinosis cutis due to it's effects on the sex hormones. Dr. Oliver, was the leading expert on adrenal steroids and he firmly believed that 11-deoxycortisol levels build-up in dogs being treated with Trilostane as did other intermediate steroid such as androstenedione, 17-hydroxyprogesterone, estradiol and progesterone. I've never been able to find anything in layman's terms that explains the affect, if any, these steroids have on calcium metabolism. While searching for that connection, I stumbled upon something even better. It was an abstract of a study entitled, "Canine hyperadrenocorticism: effects of trilostane on parathyroid hormone, calcium and phosphate concentrations". The last sentence of that abstract was eye opening.

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[B]Despite no significant difference between calcium concentrations in the pretreatment HAC and control groups, calcium concentrations increased significantly with treatment....and....These results show that adrenal secondary hyperparathyroidism resolves with treatment and suggest that increased calcium and phosphate levels have a role in its pathogenesis./B]

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It looks to me that cortisol isn't the only adrenal steroid that can cause elevations in blood calcium levels. Dr. David Bruyette, a renown endocrine expert, readily admits that he has had bad luck in resolving cc with trilostane. That's pretty telling coming from a high profile specialist who is a contributor to Dechra's continuing education program for veterinarians. This is not a new study. As a matter of fact, I believe it may have been published before Vetoryl was approved by the FDA.

You can find the complete abstract here: http://onlinelibrary.wiley.com/doi/1...283.x/abstract

I'm just sharing my thoughts with those of you who may want to start asking more questions of your vets....or you may even consider calling Dechra, the manufacture of Vetoryl (Trilostane). I'd be very interested to hear what they have to say about this study.

Glynda

Glynda, this is a really interesting study, that's for sure. I hope you don't mind, but I've placed a copy of your post here so that we have one consolidated place in which to post general replies so as to avoid having to repeat them on each of the four separate members' threads. I'll come back in a little while to add some thoughts of my own.

Marianne

OK, I'm back with a few thoughts to add. I'm really interested in tracking down this study and reading it myself. Good find, Glynda!

I definitely agree with you that we've recently seen a huge increase in the number of dogs presenting with Calcinosis Cutis. But my own memory is that the majority have come to us prior to any treatment at all. In fact, it is the CC that is contributing to the Cushing's diagnosis in the first place. I believe three of the four dogs in whose threads you earlier posted all exhibited CC before they began treatment. I think Annabelle is the only one who has developed initial skin problems subsequent to treatment. My memory may certainly be wrong, but I think it remains somewhat unusual for us to see a dog who has been stabilized on trilostane to subsequently develop CC for the very first time later on down the road.

So that leads me to believe that there is some other unrelated mechanism that is increasing the incidence of CC, or perhaps vets are just becoming more knowledgeable and/or vigilant as to their awareness that skin issues may warrant a speciality derm referral or a Cushing's work-up.

Now as to whether trilostane helps/hinders the resolution of pre-existing Calcinosis Cutis once treatment is initiated -- I think that's a different question, and this study may be very valuable in that regard.

Marianne

All I can say is "Oh Geez." I'll be watching for this in Keesh.

I'm pretty relieved to read your assessment Marianne. So basically the cal cutis existed on all but one dog (on this forum) prior to the start of Trilostane?
I found myself starting to re-think the med choice if it was the Trilostane causing the ailment itself. So much scary stuff associated with this disease.

You all are amazing experts and researchers! This site has, by far, the most comprehensive Cushing's info bank on the internet. None of the sites for animal health or vet info has anything near what is on this forum!
The vet schools should all have their students on this site so they can learn a few things!

Thank you all for the time spent getting the word out on this board..it's helping so many people (and pups) in so many ways!

Barbara

Amen to that Barbara, and when I spoke to Dechra, I told them how often they are mentioned on here and they should take a look at the forum. She told me they try to stay away from here... their loss.

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Originally Posted by Trixie

I'm pretty relieved to read your assessment Marianne. So basically the cal cutis existed on all but one dog (on this forum) prior to the start of Trilostane?

Barbara

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Hi Barbara, the four dogs I mentioned are four currently active members who are battling CC, and on whose threads Glynda had earlier today posted the info about the study result. And yes, I think that of those four, only one developed CC subsequent to beginning trilostane treatment. Over the years, we have had additional dogs on the forum with CC, but we've suddenly seen a surge in the incidence of the disorder. So that is what is really prompting our special interest now.

I haven't gone back through our archives to review the status of all the other dogs with CC, but my memory is that the majority were already afflicted with CC prior to diagnosis/treatment. So that is why I'm doubtful that trilostane is to blame for the overall increased incidence that we're seeing.

If somebody had the time to do it, it probably would be interesting to go back through our archives and make note of all the dogs diagnosed with CC, whether the diagosis preceded treatment, which drug was used to treat the Cushing's, and whether or not the CC ultimately resolved satisfactorily.

A nice project for a rainy day, right???? ;)

Marianne

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Originally Posted by labblab

If somebody had the time to do it, it probably would be interesting to go back through our archives and make note of all the dogs diagnosed with CC, whether the diagosis preceded treatment, which drug was used to treat the Cushing's, and whether or not the CC ultimately resolved satisfactorily.

A nice project for a rainy day, right???? ;)

Marianne

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I am on vacation next week and I'll look into that. ;)

YAY, Lori!!!!!!!!!!!!! :) :) :) :)

Glynda,

Thanks for your work on our behalf! Before these recent weeks of reading posts, I just assumed everyone's dog had Cutis.

I am racking my brain to remember the exact sequence...which came first, the Cutis or the Vetory. There may have been one crusty bump at the time of Lucy's diagnosis, but I couldn't swear to it. I will say this for sure, since the start of her Vetoryl therapy, the Cutis has really escalated, probably increasing by 5 % each month of her 9 months of treatment. It is the main reason we switched vets and why we increased her dose of Vetoryl from 30mg to 40mg.

I will have more info after we get her next ACTH 7/24. Then she will have been on the 40 mg dose for 3 weeks.
Shelly

Hey Marianne: CoCo has CC on his tail and developed it after the Trilostane, about 6 calcium bumps and the end of his tail is without hair. His hair is so thin all over and has never regrown where shaved which was early in his testing. Really makes you wonder. I am really concerned since I took CoCo to the speciality hospital. I kind of dismissed the vet until I read her report yesterday. She said that possibly CoCo had atypical rather than typical and I tuned her out after that since she said take him off Trilostane for 30 days and check for atypical. Now I am rethinking what she said. Can someone stop my thinking processes, I am obsesssed with Cushings in my dog. I have too much thinking to do with my human medical problems to start over again with my little dog.
Anything for the furbabies. Thanks Marianne. Love, JoAnne

Hi JoAnne,

Thanks for telling us about CoCo's history with the CC. We staffers are going to start putting together a summary of our members' experiences, and now we'll be able to add CoCo's info as well. Have his bumps stayed about the same, or have they been changing over time?

As far as his diagnosis, I agree with the other folks who have written on your thread that CoCo was originally accurately diagnosed with traditional Cushing's due to his highly elevated cortisol. It is probably true that he also has elevations in at least some of his other adrenal hormones, because that seems to go hand-in-hand with elevated cortisol (in the absence of high cortisol, those elevations would be referred to as "Atypical"). Whether or not those other elevations are also figuring into his problems, we do not know. Apparently the IMS with whom you consulted worries that may be the case, but there is a difference of opinion about that even among the experts.

I'm afraid what we "do" know is how much we really "don't" yet know about all these complicated endocrinological interconnections! Since the majority of Cushpups do not develop Calcinosis Cutis regardless of which medication is used to treat their Cushing's, it seems to me that there have to be multiple (as yet, unknown) factors at play in order for the CC to manifest. As I read in one article about the disorder:

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Calcinosis Cutis develops in some animals but not in others, even though they have similar steroid hormone or blood calcium concentrations.

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I am so sorry that poor little CoCo continues to have such problems. You are a wonderful mom, and I know how hard things have to be feeling to you right now. :o

Marianne

And Shelly, thanks for sharing Lucy's history, as well!

Marianne

Marianne: CoCo's calcium bumps have been on his tail about 9 months, have not changed much, end of tail has hair loss, some worse in the past few months. He has been on Vetoryl since 7/12. I did not start him on medication for about 14 months after first noticing the water drinking and hungry, treated him with Melatonin and HMR Lignans. Ultrasound was done in 5/12 and it was decided he had pituitary Cushings, and started on 10 mg Vetoryl in 7/12, then cortisol went up and started on 20 mg in 12/12 and that is where we are now. Post cortisol was 6 in 6/13. His tail does have about 5 or 6 calcium bumps on it that are above the hair, but his tail does look bumpy so I suspect there are some under the tail hair, so could possibly be caused by the Vetoryl or cortisol, who knows. Hates to have his tail examined. His hair really looks bad all over, really thin and no regrowth. This is a good place to find out the symptoms since all have cushings and on same medications. I have thought that the Vetoryl has caused the hair loss and weight loss. Love, JoAnne

While naturally occurring cushing's and prednisone administration are the most common causes, there are other causes as well. Leptospirosis, hyperparathyroidism and administration of calcium for hypoparathyroidism and renal disease. The connection is any condition that raises calcium and I believe phosphate levels. I don't think anybody has figured out why some dogs never develop CC while a small number of dogs do.

Zoe started this disease with hair/coat skin issues. It was her main complaint. She developed mineral bumps on her tail with hair loss prior to treatment. She was put on melatonin and lignans which controlled estradiol,her cortisol continued to rise. Her hair and skin issues continued to worsen and she developed very dry skin and dandruff. We started treating her with Vetoryl but because of her IBD I allowed her cortisol to remain on the high side. Her skin worsened, and she developed white pimple bumps that a derm vet identified as Calcinosis Cutis.

As soon as I dropped her cortisol down under five, the first symptom to improve were those same white hard bumps. They became smaller, pin head size. When her cortisol rose, they became larger.

After her vulva surgery we lost control of her cortisol and Zoe developed many secondary skin issues and her CC worsened but never to the extent of some of the other dogs here. Her skin got worse before it got better.

We have now successfully treated her secondary skin issues, her cortisol was post 4ug/dl and her white hard pimple bumps are very tiny and most of them are gone, she is regrowing hair for the first time in three years and her caramel colored spots are returning.

The two hard bumps on her tail remain. Her tail is the one spot I cannot get rid of her secondary skin issues as I cant suds it up with the Ketochlor as well as other parts of her body.

Zoe has been on name brand Vetoryl, no compounded drug, for two years. Her blood work in 2010 showed phosphorus at 3.4 (normal range 2.5-7.9) and calcium 9.7 (normal range 8.7-12)

After two years on Vetoryl her blood work show 4.3 phosphorus and 10.3 calcium. (same normal range as previous)

The first test in 2010 was a fasted test, the last test was non fasted.

For my dog- I contribute her skin/coat issues as well as her minor Calcinosis Cutis to high cortisol that needed much tighter control than I provided. My dog needs a post under five to show improvement in her Calcinosis Cutis and her secondary skin issues well controlled.

Hi Addy,

Did your derm vet diagnose the CC? Do you remember how it was done? I wanted to mention that I made a mistake when I posted phosphorus. It should have been phosphate. I think phosphates are an element of phosphorus but they are two different elements.

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Dr. McKeever founded the veterinary dermatology program at the University of Minnesota , and served as the primary professor there for 27 years. Many of the veterinary dermatology specialists in Minnesota have studied with him at one time or another.

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Zoe saw this dermatologist one time. He did a history and a physical exam. He did fine needle aspiration- cytology- on the hard white lumps- He diagnosed her with Calcinosis Cutis. He also took some skin samples with tape from her paws and did a scraping of her skin.

I posted in Pia's thread, but I'm going to post here, too, and keep up with anything and everything about CC. My poor Pia seems to have started with it. She's been on Vetoryl for just over a month, and I think I saw the first spot of what I'm guessing is CC before or right after her start, but it was a couple little patches that didn't change and then about a month after starting Vetoryl, I saw another small patch in front of her other ear canal and then found a few small spots on her side, and last night I found a big, about 2" long, ridge on Pia's upper back that was a ridge of "crud" with the hair still in the crud, and underneath it's raw, red and oozing. I gave her a bath less than a week ago, and saw absolutely nothing of this. She's a short-haired dog, a French bulldog, so I can't imagine that I'd have missed it.

I showed the young student and resident vets at Davis the smaller spots of this last Monday (our regular Davis vet was unavailable) and they didn't know what it was. (seriously???) On Wednesday Pia went to our local vet for a B12 shot, and when I pointed out the smaller ones she thought they were "calcium deposits" from Cushings. I don't know what to do next. Biopsy? Topical medication? Someone mentioned salt baths. I don't know what that is or how to do it. I can't put honey on Pia - our old blind dog would drive her crazy trying to lick it off. What has worked seems like such a mishmash of different things. My brain is fried and I can't seem to sort all the different things out. I really need help on this one.

Is it possible that dogs with cc might be on a dose that is too high?

I have noticed that not everyone specifies whether their ACTH tests were done fasting. If I hadn't included the information that I was told to fast my Rosie prior to the test, I would not have found out that it invalidates the test, specifically that it runs the risk of values being returned too high, prompting unnecessary increases in dosage and therefore risking an overdose.

I have also noticed that some dogs here are on quite high doses once a day. Somewhere I read that trilostane levels begin to drop off after about four hours, and that giving lower doses twice a day would keep levels more consistent and therefore control symptoms better.

I'm quite new here and I apologize if I'm bringing up things that have been already discussed elsewhere; I still have a lot of reading to do on this forum!

One thing I'm wondering is if the cc occurs mainly in pituitary or adrenal Cushing's, or equally in both?

Karen, you may be new to cushing's but you've learned much and are asking very good questions.

Every dog responds differently to Vetoryl and no matter what the dose, if it's too high, cortisol will drop too low and the dog will get sick. If you have had an opportunity to read some of the studies on this drug, you will note that there was a huge disparity in the ultimate dose that eventually achieved stabilization.

It is more likely that a dog with pituitary depending cushing's will experience calcinosis for two reasons; 1) most dogs (approximately 85%) of dogs diagnosed with cushing's have a pituitary tumor and 2) adrenal tumors have random secretion patterns and don't always over secrete cortisol.

You are correct that Vetoryl has a short half life so yes, it's enzyme inhibiting abilities starts to wane after several hours, which is why some dogs won't see resolution of symptoms even if the pre and post stimulated cortisol levels are within the therapeutic levels set by Dechra, the manufacturer of Vetoryl. For this reason, many vets feel that dogs with diabetes will benefit from twice daily dosing as cortisol is more evenly controlled throughout the day and night. It stands to reason that if cortisol is the adrenal steroid responsible for calinosis cutis, twice daily dosing would probably be beneficial for these dogs.

Glynda

Oh boy! For a minute my heart sank!
As of right now, Daisy does not have CC and she's been on Trilostane since May off and on.

Now that she's acclimated well and I'm seeing improvement in her Cushings symptoms, it would be a shame for something else to crop up.

I'll be anxiously waiting for input from those of you who are more experienced Cushmoms. Thanks Marianne for your assessment and I sure hope that the two are unrelated.