Closing the Gateway of Diseases: Hypocalcemia Control

- So I suppose we are a little bit of after 11 o'clock and we can start today's webinar.

And this is gonna be actually webinar number four of our series on metabolic diseases.

And today, again, we have had Dr. Van Saun from Penn State University, but before I'm going to introduce him, I would like to just say that the webinar will be recorded and posted at the Penn State Extension website.

Our attendees are encouraged to use the Q and A box for questions, and those questions will be answered either during, you know, Dr. Van Saun's talk or right away after.

And I will be sending those links to the recordings to our participants along with a link to a survey.

And I would like if you can take just the five minutes and fill it out.

The survey would have the same structure as those previous surveys, so you know what's coming, what you can do.

So now, Dr. Van Saun is a professor at Extension Veterinarian at the Department of Veterinary and Biomedical Sciences at Penn State University.

He earned his DVM degree at Michigan State and his PhD at Cornell University.

His research and extension interest focused on transition cow metabolism, diseases, and their prevention.

Today, Dr. Van Saun, he is gonna discuss and focus on how to control hypoglycemia in dairy cows.

Bob?

- All right, Michael, thank you.

And welcome everyone.

I think we're just looking at the participant list here.

It looks like we have people from all over the globe.

So good morning, good afternoon, good evening, good early morning for some of you.

Topic today, of course, is trying to deal with this disease that has been around for quite some time and has received a tremendous amount of interest in and research.

And so I wanna try and address sort of the scope and focus, of course, on the more important thing of how do we prevent this disease.

So, Michael introduced me.

I have been in veterinary practice, private veterinary practice in New York, and in the state of Michigan.

And then I was an ambulatory clinician at the Veterinary School at Oregon State University and at Michigan State University and have completed graduate research and graduate studies in reproduction and ruminant nutrition.

And that extended from my experiences in practice, considering that, you know, we get taught how to fix and cure diseases, but we don't, at least when I went through vet school, we didn't learn much about the prevention side of things.

And so that was what motivated me to go on and do this aspect of education, additional education.

I've been at Penn State for 20, almost 25 years now, and do a fair amount of lecturing and consulting internationally and nationally and all around and really enjoy the opportunity to try and share and learn from people.

So again, I wanna emphasize what Michael said.

If you have questions as we go through, feel free to type 'em in the Q and A and Michael will pass them on to me, or raise your hand or do something.

And I'm more than happy to stop and explain something.

All right?

Okay, so my agenda for today.

I wanna do a little bit of sort of what I call redefining hypocalcemia.

What I learned, and I noticed one of the participants is an old colleague from Michigan State.

What we learned, you know, was pretty straightforward, book learning of hypocalcemia, this classic, you know, the cow goes down right after calving and we treat her with calcium and the miracle cure gets her up and so on.

But if it was all that easy, we wouldn't have done all the research that we've done.

And that's why I want to give you some historical perspectives because that puts things in pers, in place, in terms of appreciating and understanding how we might go about approaching prevention of hypocalcemia.

And then we'll kind of summarize some of these things.

So, you know, we, most people have been taught hypocalcemia just means low blood calcium.

And classically what we've seen or address is the clinical milk fever cow.

The cow that goes down right around the time of calving or immediately at calving or beyond.

If you measured blood at that time, she'd have quite a low total pro, or excuse me, total calcium concentration.

And she would respond, most of the time, to appropriate IV treatment.

That's gone on, and, you know, we've made some adjustments here.

We've recognized some of these issues of why hypocalcemia is such an important disease for us, as we're gonna see in terms of how it interacts with so many other diseases.

We know that calcium is important for muscle contractility, and so slowing of the teat sphincter closure results in a greater risk of mastitis.

And, and this has been shown through epidemiologic studies.

We also know that the GI tract smooth muscle is dependent upon calcium for contractility.

And so with reduced GI motility, we can see losses in dry matter intake, which then of course set us up with negative energy balance, negative protein balance and some other issues.

And a left displaced abomasum is another sequelae.

This, we also now, as we start to see and understand the biology a little bit more, calcium is a very important intracellular messenger and has been shown to be important in neutrophil and many other immune cell functions.

And again, this opens up the door to potential mastitis, metritis, retained fetal membranes, all disease complexes that we associate with a dysfunctional immune response.

And as a result, you know, we see lost milk production, impaired reproduction, greater risk for culling.

And so, you know, that's the classic approach.

But more recently, we've started to recognize in many of our diseases, like ketosis, some of our previous webinars were on subclinical ketosis.

We are recognizing this subclinical form of hypocalcemia where the animals have this lower blood calcium concentration, but not to the point of showing that the classic clinical signs of being down and so on.

And you know, these are often those droopy cows or ain't doing right cows or just not coming on well cows.

And so, you know, we have sort of, in essence then, redefined the whole process of hypocalcemia.

It's not this black and white disease process anymore.

There's many shades of gray with this subclinical phenomenon.

And so if we go back and look at the classic issue here, this is some data from Kimura outta Jeff, Jesse Goff's lab, where they looked at blood calcium concentration and then you can see the precipitous drop around the day of calving and immediately afterwards, and so this is the classic clinical milk fever cow.

But then we have these cows that, you know, most cows that drop and come back up.

And this period, depending on when you're measuring, is this area of subclinical hypocalcemia.

And so, you know, the immediate response as we started to address this was, we gotta stop this and stamp this out, but there's some nuances here.

Now why did this become so important?

Well, this was again, some work from the USDA metabolic disease lab.

Reinhardt was the lead author, but this was, it included Jess Goff and Ron Horst in all of this.

And this was data that they extracted from blood samples that were collected for the NAMS, the National Animal Health Monitoring Service, or survey that was done in the US in 2007.

And they measured basically total calcium, all right?

In these blood samples.

And they were all taken within just a few hours of calving.

And you can see they distributed the animals by their number of lactations.

And then what percentage of the cases, based on criteria where they said anything below 1.5 millimolar, which would be that around 6 or so milligrams per deciliter, and then 2 would be 8 milligrams per deciliter.

So anything below this was considered a clinical milk fever case.

And as we've all been taught as the animal ages, the risk or the prevalence of clinical milk fever increases.

And, you know, we've established some of the metabolic issues associated there.

But what was really highlighted in this particular study was this subclinical just being essentially arbitrarily defined as anything below the "lab normal' of 8 or 2, 8 milligram per deciliter, or 2 millimoles and above the clinical stage.

And even in our first lactation cows, they found about 25% of these animals were here and then 40, 50%, so a very significant proportion of the animals.

But we expect this.

If you go back to the previous slide, you know, these animals do drop and really what's more important is what happens, not in that immediate first 24 hours or so, but more down the road.

And as part of that, this study here, you know, you can see the calcium concentration that they plotted by lactation number, the 125, the active form of vitamin D, actually goes up.

So you can see that, you know, the, even these cows here that are having the challenges of later lactation and calcium, they have very high concentrations of the active form of vitamin D, but we also see that they are off feed based on the non-esterified fatty acid levels.

You know, so there's some interactions there.

This is some work by Jess McArt at Cornell University.

And I think this really is what we need to start thinking about as we start to look at the subclinical phenomenon of hypocalcemia.

This, these two graphics, the upper graphic is from primiparous cows, and then the bottom graphic is from cows that have second lactation and greater.

And what these investigators highlighted here is there's essentially kind of four populations of cows relative to their calcium homeostasis over the first five days post calving.

And if we focus more on the older cows, since they're the ones that are at greatest risk of dyscalcemia, we have a population of what they call the normal, where they maintain fairly normal calcium concentrations.

Yeah, they had the dip, but that's just normal physiology, the loss of calcium.

But they recovered quite rapidly.

And so when we look at this, we can see other cows.

Here, we have, let's look at the red line here.

You have a more significant decline, but then a very rapid increase over the first two or three days.

And so this is what they call the transient hypocalcemia.

And then you have this persistent subclinical hypocalcemia, and then you have this delayed kind of hypocalcemia here, the green line and the persistent is this blue line.

And so, obviously cows don't all respond in a similar way, in their calcium homeostasis.

And it turns out in this work, these cows that had the transient hypocalcemia actually had higher milk production and did quite well.

So the normal cows and the transient hypocalcemic cows.

So the moral of this story is depending on when you measure this calcium, if you're trying to evaluate subclinical hypocalcemia, you may not get the right picture of what's going on because of the dynamics that are going on here.

We really want to identify these delayed and these persistent hypocalcemic, subclinical hypocalcemic cows because those are the ones that are ultimately accounting for the problems that have been associated with hypocalcemia or subclinical hypocalcemia.

Now again, tapping into Dr. Goff's work, since he has such a large body of just fantastic information on this, if we look at this interplay amongst all of the postpartum disease conditions.

We're focusing today on hypocalcemia.

And as I mentioned earlier, the new work is suggesting immune suppression, which is a key player.

And this ties into some of our previous webinar information, talking about stressors and active inflammation.

But you can see why cal, hypocalcemia is called the gateway disease because it's associated with so many other of the diseases and preliminary changes that lead to these diseases.

And based on what we're gonna talk about today, some of the primary nutritional factors that lead to hypocalcemia are this high dietary cation, anion difference, this alkalizing effect.

The new work that's come out of Germany and elsewhere on high phosphorus diets, although that's reiterating some of the very early work in the 1950s and in low magnesium diets.

So let's take a look at some of the historical perspectives here in thinking about hypocalcemia as a disease.

It wasn't until the 1930s, 1940s that investigators started to recognize the role of milk secretion relative to this disease process.

And then from there, some of the initial dietary factors that they investigated were obviously calcium and phosphorus, and then the calcium phosphorus ratio in the diet.

This, as we started to understand better the role of vitamin D and the metabolism of vitamin D, which wasn't until the 1960s that that became a player.

And then in the 1970s, some of the seminal work by Charlie Ramberg at the University of Pennsylvania started to show the metabolism and the target tissue response.

And that's where we got into, you know, restricting calcium in the diet.

So what I've done is, and I, and you'll get a handout that has all my slides from today, just kind of summarize some of these things here and just to give you some appreciation of how much research has gone into this disease and making us wonder why we haven't eliminated this disease or greatly controlled the disease.

We have, you know, I don't wanna be too negative, we have made a dent in the clinical disease, although we still see a lot of variation farm to farm.

But now we're starting to deal with this specter of the subclinical disease.

So you can see in the 1930s and '40s, as I mentioned, the etiology, you know, we started out thinking it was a glucose deficiency disease, a calcium deficiency, low parathormone.

There was, you know, the field application, they actually, that some of the original work was using a bicycle pump to pump air into the udder and then keep that air in and the pressure in the udder of course, as we know, would stop the milk secretion process and the cows would, you know, respond to that.

In the 1950s and early '60s, dietary management with the use of vitamin D to reduce milk fever incidence.

We, the application here, dietary formulation to manipulate the calcium phosphorus ratio.

I know when I first came into the vet field, you know, we focused a lot on maintaining this two to one calcium phosphorus ratio, feeding alfalfa and so on.

So we ended up adding a lot of phosphorus to our diets.

We probably were shooting ourselves in the foot, in hindsight.

The dietary calcium content of the diet was a big focus.

And then vitamin D supplementation, although that aspect kind of died out fairly quickly because of the restrictions and challenges that we need.

And we'll talk about that too.

Then in the '70s, as I said, some of the seminal work by Ramberg and Kronfeld at the University of Pennsylvania, they documented, you know, the whole calcium homeostatic mechanisms using isotope tracer studies and you know, they identified the target organ responsiveness.

And then this really brought out the whole idea of, in combination with two studies that were published, that showed if you feed low calcium diets, you can control milk fever.

And so that was the prevailing perspective and approach.

Then in the 1980s, there was again another seminal paper by out of the Ontario and or McGill University that used the concept of DCAD and showed how it could reduce the milk fever response and improve calcium homeostasis.

And so a whole proliferation of work followed that in many, many groups.

You know, Gary Oetzel when he was at Colorado State and then to Wisconsin, Dave Beede down in Florida, Bill Sanchez, then he went, worked with Beede and then went out to Idaho.

I mean, you can go on and on.

Plus of course Ron Horst and Jesse Goff.

But you go back and look at the literature in the '80s and just the massive number of studies that were done looking at this whole DCAD concept.

And at that point we were using inorganic salts and ran into some challenges with those.

In the 19, the other thing that happened in the 1980s was the work that came out of Cornell by Chuck Curtis that showed the interrelationships between milk fever and all these diseases.

That's how we got into this whole gateway of disease.

The 1990s, we started to recognize how dry matter intake had a important, was an important player in the whole transition disease complex.

And we saw development of protein-based anionic salts to help improve or address some of the DCAD and we recognized better the role of potassium and chloride and stuff in DCAD and in milk fever pathogenisis.

And so we saw some changes there in how we were starting to approach and finessing the DCAD approach some.

And then in the early 2000s, this is where the subclinical hypocalcemia started to come in, the role of calcium and immune function, and, you know, modeling of the DCAD response and milk fever prevalence And so this helped us to further define how to approach our control.

And then in the most recent is the change that has started to address the issue of phosphorus.

So just to kind of show this original work, this is from Curtis, two papers that he published in "Journal of Dairy Science" and "JAVMA".

And it was just showing these path analyses, which was the big thing in the '80s from a statistical perspective of the role of parturient paresis in sort of this whole postpartum disease complex.

And, then also age and age of the animal on risk factors and milk production capacity.

This is some of the work that came out of the metabolic disease lab that really started to focus us onto what was the key player and how strong ions had some influence in our the pH regulation process and ultimately on calcium homeostasis.

This was a study where they injected parathormone on a pulse dosing and they had cows on either a high chloride diet or a high potassium diet.

And what they saw was that cows on the chloride diet had a greater calcium concentration in response to the parathormone.

And when they looked at the active form of vitamin D, they saw again, what they expected here is the reason for this increase in calcium was a greater vitamin D, active vitamin D, concentration in those animals.

So there was something between calcium or, excuse me, potassium and chloride that was impacting the active form of vitamin D.

Now, jumping ahead a little bit, this is in the early 2000s, this work where we were starting to finesse the idea of acid-base balance based on strong ions.

And so there was multiple equations.

This is DCAD1, is the traditional DCAD equation that's used across many species and was the traditional one first used.

And then we recognized that there are other ions, anions and cations that could contribute to this, but they weren't as equally absorbed as the electrolytes, sodium, potassium and chloride.

And so that propagated a number of equations that addressed some of these responses.

And so what this work did is took a body of data and calculated all these DCAD equations to look at those that predict or look at and associate with clinical milk fever.

And so what the study found was all DCAD equations significantly and negatively associated with clinical milk fever and with urine pH.

So this became the marker, but equations 3 and 5.

All right, so these are equations.

This equation many of you may remember was the equation that was used like in the Spartan program, the dairy program.

And then this is the one that accounts for a lot of the variation in availability.

These were most highly associated with clinical milk fever.

And again, one of the challenges we found here was dry matter intake reduction was associated with lowering of the DCAD, and you saw about a 1.3 kilogram decline in dry matter per day, or about 11% for lowering the DCAD by 300 milliequivalents.

So there's a limitation to the amount of anionic difference that can be done without compromising.

And we'll talk about that a little bit.

All right, so it's quite a bit of background here.

Let's get into the, you know, the understanding of how we can take this information now and use it to try and control and better improve the cows' homeostatic process relative to the macrominerals, but mostly on calcium.

Bottom line here is it's not only about dietary calcium.

I know there are some groups, again, there's not consistency or consistent opinion.

There's still some groups that really focus on the calcium content of the diet and and so on.

But the bottom line is all macrominerals are involved here.

And if you heard as I progressed, you know, through there, we kind of touched on most of these things.

The only one I didn't really talk about was magnesium.

And that's really a main player.

DCAD involves relationships with sodium, and potassium, chloride and sulfur predominantly, but also to some extent magnesium, phosphorus and calcium.

But magnesium is really a important relative to parathormone release by the parathyroid gland and for its function at the level of the kidney.

And now we know that excess phosphorus is being recognized as a concern.

So essentially, all our macrominerals are involved in trying to control, and this probably accounts for why we never had a, what I'll call a profound recognition of how or a single approach to reducing milk fever consistently.

So why is this all coming about?

And in a presentation that Dr. Goff had given, using some older data, you know, he explained it as simply as it could be.

You know, during late pregnancy, if you, we think about the calcium requirements of the cow.

She's got a maintenance requirement, and this is based just on studies that measured fecal and urinary losses.

And these have been quantified to, you know, somewheres in the range of 7 to 8 grams, maybe 9 grams per day, all right?

For a 650-kilogram cow.

And then for pregnancy requirements, this accounts for the loss of calcium in support of fetal bone.

Now, we really didn't have good numbers on this until the work by Alan Bell at Cornell came out and got published in the mid-1990s.

But now that accounts for about 9 to 10 grams per day.

And so in essence, total what I'll call net calcium, or available calcium, needs of the cow is only about 16 to 18 grams.

Now, that's not the same as dietary calcium, right?

'Cause we have to account for the bioavailability.

All right?

So this is sort of, if we think about protein, we talk about crude protein, digestible protein, metabolizable protein and net protein.

Net protein is what it's actually used or deposited or helps to support the physiologic functions.

When we then go from this late pregnant state to the early, you know, right at calving and within the first, you know, couple milkings after calving, we still have that 7 to 8 grams of maintenance, but then we lose about 18 grams of calcium in the colostrum.

Colostrum contains approximately 2.3 grams of calcium per kilogram.

Mammary uptake occurs then, on the mammary gland after the colostrum's taken out, the mammary gland's gonna suck up calcium from the blood.

That's to support the next milking.

So that's about 10 to 12 grams.

And then you're gonna lose, at the second milking another 15 grams.

Milk contains less calcium, about 1.7 grams, and then the mammary uptake from the blood, another 9 grams.

So you're looking at somewheres in the range of 55, 60, 65 grams of net calcium being utilized.

And so obviously there's this huge change and a need for an immediate influx of calcium from whatever source is there.

And so that brings us to the classic overall picture here.

If we look at this, this is the extracellular pool.

So this is what the body is monitoring.

So the parathyroid glands are sensing, there's sensory cells that are picking up on the ionized calcium concentration.

And so the serum pool contains approximately 3.5 grams and the extracellular pool, 11 grams.

So you can see that's, you know, almost four, four to five times less than what they're gonna be losing in that early postpartum period.

And so where are the key players here when we think about control?

Well, dietary calcium certainly has been the main focus.

And so the amount of calcium in the typical diet can range from about 45 grams.

This would be what the dry cow, and this is, this would be total calcium in the diet, not the net calcium that we talked about, about 45 grams.

And then during lactation, they're gonna need upwards of 150 grams.

And this is going to have some influence on the parathyroid hormone secretion.

And magnesium availability can influence this process.

And then parathormone in trying to upregulate the influx of calcium to the pool.

So if we look at the influx arrows, we can come from bone of two different sources, fluid bone and then osteoclast breakdown of bone, right?

And we have passive transport from the gut and active transport from the gut.

And then the active transport has to be initiated through the activation of vitamin D.

And so high potassium, high sodium, high phosphorus downregulate this activation process and low magnesium also prevents parathyromone from initiating this process.

So these are three key factors that greatly influence the upregulation of active vitamin, active calcium absorption.

We also know that increase in chloride and sulfur, anions in the diet, this can help mobilize the fluid bone and bring more calcium into the system.

Now, there is data that suggests vitamin D receptors, which are important to get this active calcium system going because proteins have to be made to facilitate this process.

We see a lowering of the vitamin D receptors in older cows and specifically in the Jersey breed.

So this starts to account for some of the breed predilections here.

And then we know that through this fluid bone calcium and sulfur, or excuse me, chloride and sulfur, this will increase urine calcium excretion from about 0.2 grams up to as much as maybe 6 grams.

But this increase here in urine can be recaptured by the presence of parathormone to help contribute to the pool.

Then one of the thoughts here was if we increased endogenous fecal losses through binding of calcium in the diet, and this was the original thought with the use of the aluminum silicate compounds or what's called Zeolite, that this would reduce the calcium and sort of jumpstart this system, essentially doing what we were do, we're thinking we were doing by feeding a low calcium diet.

We now know that the Zeolite is not as much of a calcium binder as it is a phosphorus and magnesium binder.

And that has changed our thought process there.

So let's work through these minerals in establishing their role.

These two graphics are the two meta-analyses that were done where they looked at studies reporting the calcium content of dry cow diets and what the milk fever rate was or the milk fever incidence was.

And you can see this was a newer or more the more recent study from Ian Lean and colleagues down in Australia.

And you can see here somewhere between 1 and 1.5% calcium in the diet sort of peaked milk fever.

And we, this sort of confirms that the low calcium diet reduces, but then there was this higher calcium that seemed to have an effect on reducing milk fever too, which was always something that people struggle with.

Gary Oetzel showed that back in 1991, you know, and again, he was right in that same range.

So it's interesting, both studies, you know, showed that the same sort of moderate calcium concentration in the diet as being the most risky relative to milk fever incidence, but either very low calcium or very high calciums were also protective.

Now, one of the challenges with feeding a high calcium diet is calcium can interfere with magnesium.

And this was a study where they fed 13.6 grams of dietary calcium per kilogram or 1.36% of the diet and then they also fed 0.49 or 0.93, so three levels of calcium in the diet.

And this higher calcium concentration impaired magnesium absorption during the dry period and resulted in decreased magnesium concentration after calving.

And this has always been a concern.

I know Dr. Goff, you know, talks about the lower magnesium by taking blood concentrations of magnesium in 10 cows, if even one has lower concentration than desired or what the guide is, that's a concern.

And so, you know, one of the issues here then is we really don't necessarily wanna be feeding high calcium in the diet even if we are feeding a DCAD diet, you know, that was the original approach.

We were all worried about calcium being lost through the kidneys and so on, but, and so there was the recommendation that we needed to be feeding 1.5, 1.8% of the diet, much higher.

And we know that as we get that calcium up too high, it's gonna impede dry matter intake.

Now why magnesium is so important is really born out in the meta-analysis that Ian Lean and colleagues had published in 2006.

They used data from 87 different trials and did a couple of different modeling processes to look at the prediction of milk fever.

And I'm just showing that one of the tables and of interest here, if you see a negative number here, that means it had a positive effect of preventing milk fever and if the number's positive, the coefficient is positive, it promoted milk fever.

And so they accounted for some breed differences here.

And then you can see calcium in the diet seemed to promote milk fever, which is what we kind of thought, but magnesium was the strongest relative to preventing milk fever.

And you can see here phosphorus also promoted milk fever.

And notice that DCAD really wasn't that important.

So that this was a bit of a discussion amongst many people.

You know, why this was, you know, it seemed to go against and what it, the train of thought or the prevailing thought of DCAD and the application of DCAD.

But it did really highlight that the need for magnesium that many of us had thought about.

This is from that same study.

Their second model, again, just depending on how they looked at things here, they just had one breed, Jersey versus the Holstein Friesian being the reference breed.

And again, what we see is magnesium had the greatest protective effect followed by sulfur and calcium squared, you know, kind of interesting.

But notice DCAD wasn't in here and potassium wasn't near as significant.

So this threw a little bit of a wrench in the works of appreciating that, you know, it's just DCAD, and so it did throw some more emphasis on the magnesium side of things.

Then this paper came out in 2000, or excuse me, in 1997, which sort of set the stage for this.

So I kind of jumped ahead and then coming back.

This was really the study that highlighted and emphasized that it's not calcium per se, but it's the potassium concentration in the diet.

Or, similarly the sodium, and I know this is a really complex slide, lemme just show you here's three different levels of potassium in the diet.

1.1, 2.1 and 3.1.

And then two levels of calcium in the diet, 0.5% or 1.5%.

And then you can see, they looked at milk fever, subclinical milk fever, calcium treatments, urine pH, ionized or calcium concentration and then milk fever, actual clinical milk fever.

And so you can see here, what they showed was looking at just the calcium side of things, there really wasn't any difference between milk fever incidence, 11 outta 32 versus 12 outta 31 on the calcium and similar.

But when you looked at the differences relative to potassium concentration, there was a significant effect of potassium as well as sodium.

And so, the bottom line in this study looking at just this part of it here, was it's potassium and not or sodium and not the calcium that's the big player.

Now when you go into this study and look at how they formulated the diets, I just wanted to point out two things.

They had very high phosphorus concentrations and they had differences in magnesium concentrations between the two diets.

Now you would think on the low calcium diet, the higher one or higher magnesium might be somewhat protective compared to the lower magnesium here on the high calcium diet.

But the bottom line is, I'm wondering now, in retrospect, you know, now that we know about the role of phosphorus, if this phosphorus concentration really was a big player.

Now they fed 48 grams of phosphorus, doing the calculations, and 47 grams of phosphorus on these two diets.

And those certainly are higher than what we would typically wanna see in the diet now that we know what's going on with phosphorus.

All right, so certainly the body of research that occurred in the '80s and '90s and in the early-2000s really focused on the application of dietary cation anion indifference or DCAD, on calcium metabolism.

And there's a whole body here that shows the positive effects of feeding a anionic diet on reducing clinical milk fever, reducing subclinical milk fever and increasing the percentage or number of normal cows going on.

And hopefully as a consequence from our understanding of calcium deficiency being the gateway disease, we would have less other postpartum diseases.

Now it's been a challenge to sort of explain this.

And this is a concept that has been promoted, and I think fairly well supported.

And it, I just wanted to again show this.

This is from Dr. Jesse Goff.

He's promoted this idea and it ties in the pH effect as well as the magnesium effect here.

And so we know parathormone as a protein hormone.

Protein hormones can't pass through the cell membrane.

So at the level of the kidney, where vitamin D needs to be activated, parathormone has to interact with its receptor and it's believed that magnesium is necessary to stabilize that interaction.

And once that happens, there is transference of this interaction to stimulate a g-protein process that ultimately activates adenylyl cyclase.

And then that will upregulate the 1-alpha hydroxylase enzyme that will then take 25 hydroxy vitamin D and make it into 125 dihydroxy vitamin D, which is the active form, the biologically active form of vitamin D, which then can act in the gut and on the kidneys and elsewhere.

Now we all know that proteins are very sensitive to pH changes and so this would be the under the conditions of a fairly normal blood pH.

We also know that blood pH doesn't change very much without becoming a risk of death.

But even minor changes, it's thought, so this would be a more alkaline pH of the blood.

And so it's thought that these proteins will change their confirmation under this slight pH change.

And then that prevents the interaction, that the lock and key interaction that we all learned about in basic sciences between the parathormone and its receptor and therefore we don't activate vitamin D.

And then when we have a normal pH but lacking magnesium, it seems magnesium is necessary for this interaction to stimulate the upregulation of adenylyl cyclase and make cyclic AMP and activate this.

So, this is a really nice concise cartoon that helps sort of explain the pH side of things and the magnesium side of things in looking at how the whole calcium homeostatic system is connected.

And we can follow this with the fact that we use urine pH 'cause the kidneys are our first responding tissue or organ to changes in blood pH to try and maintain blood pH normality.

And so when there's any excess of alkalizing or acidifying compounds, they're gonna be excreted out through the kidneys.

So we can see dramatic changes.

A typical herbivore diet with the high potassium in many of the forages are gonna run a urine pH of up in the 8 to 8.5 range, okay?

But as we add acidifying agents, we can start to drop the pH in that urine as the urine starts to kick out these acidifying agents to help maintain acid-base balance.

And so this diagram starts to explain, again that it's, there's a very dynamic range between a DCAD value, in this we're looking at milliequivalents per kilogram of diet.

So once you kind of get below zero and down to maybe minus 100, this is a really dynamic range here in responsiveness in terms of urinary pH.

Once you start to get urinary pH below you know, 5.8 or something like that, now you're starting to get in a more danger zone.

And so these really negative DCADs, remember if we go back to the situation, if we did more than minus 300, we, DCAD, we saw a drop in dry matter intake.

And that's associated with the animal's response to metabolic acidosis.

You know, just stop eating so you're not taking in this acid.

I mean there's really no other way.

They're gonna try and use compensatory respiratory changes to blow off some more acid and renal changes.

But one of the first things they're gonna do is just stop eating.

And so what this is showing us is I'm gonna show you the work here, we gotta get below 7.5 to really start to get a response.

So we need to be below the zero.

But we don't wanna go much below say 100 to 125 or so, although I know there's many studies that have gone further on that.

Now the other issue that's always been a big question mark with DCAD is how much calcium should we put be putting in the diet?

As I said earlier, we traditionally just went ahead and added calcium to the diet out of fear of calcium being lost from the bones and excreted out through the kidneys and those kind of things.

So this was one of the earlier studies Dave Beede had performed at Michigan State University.

He fed five different diets.

You can see the DCADs were, this is per hundred grams, so this would be a plus 180, a minus 40, minus 40, minus 40, minus 40.

And in the calcium range from 0.47% of the diet dry matter.

And then in the acidified diets, between 0.47 on up to 1.95.

So a very high calcium concentration.

These are all third or greater parity cows, quite a number of cows.

And we can see that there was some differences in the hypocalcemia clinical milk fever.

There was improvements here, but basically there they didn't see, they had a lower dry matter intake with these two higher calciums, but with these two, they really didn't see any difference in the parameters and they were better than without.

And so this was probably, at least in my memory, one of the first studies that started to suggest we really don't need to be feeding that really high calcium diet.

And there was another study that used minus 60 milliequivalents per kilogram.

So a little bit more negative and again they really didn't see any difference between 0.99 and 1.5.

So nothing that really supported this need for the very high calcium.

And this is probably one of the more recent studies that kind of addressed this same issue, again.

They looked at two dietary levels of calcium, 0.46 and 0.72, and then they had cows that were fed a low calcium diet and no anions.

And then the two level of pods of calcium, the 0.46, 0.72 with anions.

And so you can see the control diet was at a plus 167.

And then the 0.4 and 0.72 calciums were at 0.13 or minus 13 and minus 17.

So not really low, right?

Just below that zero point.

And in the high potassium diet, you know, they were all in a positive.

And so what, you know, kind of the bottom line, there's all the measures here, but basically dietary calcium at 0.46 was not low enough.

And the bottom line here was they said you gotta get below that pH of 7.5 to really have that response.

So this not only looked at the calcium level, but it also told us we have to get below that 7.5.

So just getting below that zero level of DCAD.

Now, last thing here is the role of dietary phosphorus.

And, you know, I, when I came out into veterinary practice, I used to see a fair number of these what we call creeper cows, alert downers.

Through the years, you know, these cows were put into float tanks, and all kinds of things.

We recognized the low concentration of phosphorus in the blood and as a result, you know, we treated with phosphorus.

Unfortunately some of our treatments were inappropriate phosphorus sources, the phosphinic acid rather than phosphoric acid.

But there's been some really fascinating work coming out of Walt Reuteberger's lab in Hanover, Germany, where they fed really low phosphorus diets to try and mimic this disease.

This down cow, alert down cow disease.

And they couldn't do it.

But what they found was the low phosphorus diets really improved calcium homeostasis.

And so, you know, there's this from their first abstract presented in 2018.

You can see that the phospho, the quote phosphorus deficient cows where they fed less than 0.2% phosphorus in the diet.

Remember that study I showed you was feeding 0.6% and they basically saw that calcium was improved, the parathormone response was good, bone response was highly elevated, all right?

And this is probably due to a downregulation of a new factor that has come into play.

Here is actually from that Dave Beede study.

They showed a very similar, they fed 0.21 phosphorus, 0.31 phosphorus and 0.44 phosphorus.

And what they found is that lower prepartum phosphorus feeding dropped serum phosphorus, but it had a very positive effect on calcium homeostasis.

And if you went up to that 0.44, you saw this negative effect on calcium homeostasis into 0.31.

This is some recent work from out Cornell by Kerwin and colleagues.

And they basically showed essentially the same thing.

They fed the Zeolite A product, the idea was to bind calcium.

And what we can see is the dotted lines are the control cows and you can see the dotted lines are much lower, on the cows for calcium that were not fed the Zeolite.

And we can see that the phosphorus concentration in the Zeolite fed cows were much lower and the magnesium was lower.

And so it seems by binding of this phosphorus, making less phosphorus available, this had a positive effect on the calcium homeostasis.

And it, and what they saw was there was a marked decline in subclinical hypocalcemia in this critical period that we talked about earlier in those cows that were fed the control diet versus those cows that were fed the Zeolite diet.

So, how do we start to put all of this together?

So, prevention of hypocalcemia is really critically dependent upon knowing the macromineral content of the forage and the total diet.

You have to have ongoing monitoring of dietary mineral status because if you change forages, there could be really some big changes in the macromineral content.

The big question also comes is should we just sort of, instead of dealing with all of this, why don't we just use boluses or drenches or IV calcium?

So if we can summarize where we are, this is from Ron Horst and others.

If the DCAD of the diet is less than 250 milliequivalents per kilogram, we can increase parathormone receptor sensitivity through restricting potassium, having adequate magnesium in the diet, and adding anions like chloride to achieve less than 10 zero milligrams per or milliequivalents per kilogram.

Trying to get that urine pH below that minimal 7.5.

If the DCAD is above this, then we're gonna be in somewhat of a problem trying to add enough anions without negatively affecting intake.

Now the research has shown using calcitropic type hormones, parathormone or analogs of vitamin D, these all can work, but none of these have been approved.

So it's really not an avenue for us.

The other option is the old, let's try and induce a negative calcium balance.

So we can use low calcium forages, low calcium grains, and then you know, the question was add calcium binding feed additives, which was the original thought, but now we know that it's not calcium binding, it's actually phosphorus binding.

And then the other thing is the passive calcium absorption, oral calcium sources, gels, boluses and things like that.

So milk fever prevention strategies, avoid feeding high potassium forages for those close-up cows.

Add anions, reduce blood and urine pH, supplement the diet to at least 0.4 magnesium from an available source.

That's another whole issue. All right?

So here's some guidelines, I've modified these from Dave Beede and, you know, consider going with that lower magnesium concentration.

This is if you're gonna try and do it without anions and this is using some anionic salt.

So adding some chloride into here.

Now the typical strategies for DCAD as I've kind of outlined here.

If we can just try and reduce the potassium, feed a lower calcium source, it's gonna help but it's not gonna really improve all, especially subclinical hypocalcemia.

If we actually include the DCAD, we can certainly make it work better.

And if we use a full DCAD program, keep that the magnesium up, phosphorus low, we really don't need to add the high level of calcium that we've traditionally done.

Where I see the problems is people try to mix the two.

They sort of add some anions and they add extra calcium and those to me have been the milk fever wrecks on the farms.

All right, our other approaches, reduce calcium content to less than 20 grams.

Not very feasible with the forages we have and the binder that we have doesn't do what we thought it did, but reducing dietary phosphorus with the Zeolite or through formulation.

Vitamin D administration, this is way too complicated and challenging.

Here, cows, that vitamin D requirement can be easily met with 20,000 IUs of vitamin D per day, upper limit maybe 60,000.

You don't wanna go much higher than that.

However, if you're gonna use vitamin D for milk fever prevention, it, you're gonna have to feed massive quantities like 200 to 300,000 IUs per day orally or administer a million international units per a hundred pounds of body weight IM.

But the thing is, is this has to be within 7 to 10 days prior to calving, otherwise you're actually gonna cause more milk fever.

So the problem with these are we really see a lot more vitamin D intoxication and increase in milk fever.

And that's why, you know, the tradition or the old use of vitamin D has not really worked.

This is a really interesting study just published in "Journal of Dairy Science," where they fed a negative DCAD diet and a positive DCAD diet and then they administered calcium, IV calcium or dextrose.

And basically what they found is when they give IV calcium, you spike that calcium, but you get this massive drop in calcium and actually a period of significant subclinical hypocalcemia.

And they saw that whether they were in a negative DCAD or a positive DCAD situation.

So administering IV calcium, probably if for a cow that's standing, is probably not a good good option here.

The boluses have certainly been shown to help but they don't always get these numbers up as well.

And there was some negative impacts of even the calcium on phosphorus concentrations in the postpartum period.

So, we are much better off manipulating hypocalcemia and calcium homeostasis through the diet rather than using the bandaid approach of let's just give boluses or oral calcium.

Certainly you still need to do that for treating cows and there is even some data that suggests heifers are adversely affected with boluses put in there.

So, final thing here, key mineral players that we've talked about in preventing milk fever.

We certainly want low or moderate levels of calcium depending on our approach.

We want lower dietary phosphorus than what we've traditionally done.

Low potassium, low sodium, although we need to provide sodium.

High magnesium and a DCAD for the diet that's less than zero milliequivalents per kilogram.

Things that will induce milk fever, moderate levels of calcium, that 1% to 1.25%, high dietary phosphorus up into 0.4% and greater, high potassium, high sodium, low magnesium and a high positive DCAD.

So with that Michael, that's the talk for this morning or afternoon, depending on where we are.

And let's deal with any questions you might have.

- Well, thank you very much.

We have one question.

Is Zeolite the same as X-Zelit or Cow Bow?

- Yes, that is. - How many days or weeks does it need to be fed before calving?

What are the pro and cons of using it?

- Yeah, so the studies are just starting to come out.

Most of the studies have fed the Zeolite or the Zelit at 500 grams per day and about half a kilo and there, it's fed for a minimum of three weeks.

- What are the pros and cons of using it?

- Well the cons of course is the extra cost and the space in dry matter that you know, 500 grams, that could be protein or energy or other things.

And the fact that it not only binds phosphorus, but it binds magnesium.

And so as I showed, there could be a lower magnesium, which is something we don't need and may be contributing to some of the subclinical, prolonged subclinical hypocalcemia.

The positives are it helps us to deal with some of the forages that we have to feed to dry cows and overcoming the risks for milk fever.

- All right, thank you.

And it doesn't appear to me that you would have more questions, lots of good informations.

Much appreciated.

And so, that would conclude our webinar.

I thank you to all for the participation and hopefully I will see you all next week at the "Feeding Practices to Prevent Subacute Ruminant Acidosis" webinar, again with Dr. Van Saun.

Thank you very much.

Oh, there is one question, another one just popped in.

Would it be beneficial to feed extra magnesium then?

What are, what is the best source of magnesium?

- Yeah, so that's a great question and nobody's really addressed it.

We certainly want to get that magnesium concentration upwards of a minimum of 0.4% of the diet dry matter, maybe 0.45.

Some people have gone as high as 0.5.

The best source of magnesium, Dr. Jess Goff has a nice little trial.

Magox is a very common source that we use in our diets.

But Magox availability, the magnesium availability from magnesium oxide varies tremendously.

It depends on particle size and some of the processing that's occurred.

And so Dr. Goff has a procedure where if you take 3 grams of your magnesium oxide and then you add 40 milliliters of white vinegar very slowly, you mix that up and let it sit for 15 minutes and then measure the pH.

The pH of white vinegar should be down around two and a half or so, maybe three.

And so magnesium oxide, if it's functional or available, should buffer that and it should bring the pH up to about 8 or 8.2 or so.

But if it doesn't, then that suggests the magnesium isn't very available.

So that's one way.

The other thing is you can look at other magnesium sources like magnesium chloride or magnesium sulfate, but magnesium chloride isn't always available everywhere and it's certainly more expensive than magnesium oxide.

Magnesium sulfate is reasonable, but the concentration of magnesium requires so much more to be added in compared to magnesium oxide.

So, there's give and takes there.

- Great. Thank you.

Any other questions from the audience?

Well, if not, thank you very much and I will see you next week.

Thank you.