Connecting the Dots for a Sustainable Future

The global dairy industry is robust and dynamic, but it is not without its challenges such as tight margins, labor shortages, water supply and environmental concerns. Moreover, the continuous improvement in dairy cattle productivity to meet increasing demands is thought to be contributing to a reduction in the number of dairy cows. Simultaneously, the trend towards herd consolidation and the emergence of fewer, larger farms with economies of scale represents a clear strategy for enhancing efficiency. In the face of both trends, dairy producers are intensifying efforts to optimize the overall nutrition and health of the dairy cow.

“Seeking to understand those nutritional nuances that first do no harm, but also maximize the milk yield.“

Recent advances in dairy cow nutritional science are geared towards maintaining the overall health and well-being of the dairy cow while seeking to understand those nutritional nuances that first do no harm but also maximize the milk yield. On the other hand, the attention paid to the circularity of nutrients, nutrient management, and the management of animal waste is rising to new levels. Furthermore, a recent trend in the excellent research conducted around the world is starting to connect the dots of the relatively short- to medium-term nutritional effects on the biochemistry of the dairy cow to the longer-term health aspects such as inflammation, immune response, microbiota optimization, skeletal health, reproduction, and incidence of serious diseases. In the 21^st century, the nutritional challenges are complex and at times confounding; however, they are being met head-on with a more holistic approach than ever.

Joseph McGrath et al. were among the first to review the historical role of nutritional interventions to increase productive longevity, welfare, and environmental sustainability in ruminant production.¹ They suggested that a multidisciplinary approach was needed to develop nutritional strategies that address key components of animal health such as oxidative balance, skeletal development and health, nutrient utilization, and sustainability.  In our discussion below, we will focus mainly on antioxidant supplementation and skeletal health.

Antioxidant supplementation is one strategy that offers the promise of increased health as long as the dots from biochemistry to long-term effects are connected.  Some time ago, it was suggested that antioxidant supplementation may help counter the negative effects of oxidative stress associated with growth in young ruminants, thereby reducing morbidity and mortality and improving performance.^2,3  Moreover, dietary antioxidants can influence growth rates, and antioxidant supplementation in the mother may help improve the antioxidant intake of dairy calves, reducing the incidence of morbidity and mortality and improving performance.⁴ Antioxidant supplementation, especially with vitamins A, D, E, and ?-carotene and antioxidant minerals such as Se, Cu and probably Zn and Mn, before calving, can increase these key antioxidants in colostrum and milk thereby benefiting the calf.^5,6  Antioxidant supplementation can also improve reproductive physiology, as oxidative stress has been implicated in several reproductive events, including oocyte maturation, steroidogenesis, and folliculogenesis.⁷ Dietary ?-carotene supplementation can improve fertility.  Increased ?-carotene concentrations in the oocyte’s micro-environment positively affect follicular development and oocyte quality.⁸ It was shown that selenium and vitamin E represent ideal antioxidant supplements to improve ruminant health, production, and reproduction.⁹ Low-cost vitamin E replacements as well as more efficient sources of selenium like synthetic L-selenomethionine are areas where antioxidant supplementation strategies can improve.  Connecting the dots, it turns out that antioxidant supplementation has been linked to some aspects of overall skeletal health and these nutritional strategies are discussed below.  A more detailed review of oxidative balance is coming in Part 2 of the Connecting the Dots series.

The skeletal health of the dairy cow is top priority, as the bones represent the largest source of calcium and phosphorus required during lactation.

“A biological paradox.”

Recently, Hernandez and McArt offered their perspective on a biological paradox whose solution is becoming more apparent in recent years.¹⁰ The paradox is that the dairy cow maximizes milk production during transition while in a state of hypocalcemia (i.e. low serum Ca levels).  Transient postpartum hypocalcemia is a lactation-induced phenomenon in high-producing dairy cows.¹¹  This type of hypocalcemia is not detrimental and is actually associated with optimal milk production and health.¹²  Early data showed that cows that experience transient hypocalcemia exhibit higher milk production and a lower incidence of early lactation diseases compared to cows with persistent or delayed hypocalcemia.^12,13  Persistent and/or delayed hypocalcemia (i.e. not transient or normal hypocalcemia) are known together as dyscalcemia and defined by serum calcium levels below 8.8 mg/dl at 4 days in milk (DIM).  Hernandez and McArt, like McGrath referenced above, are also connecting the dots for a holistic approach to animal health and welfare.  They suggested that the role of inflammation and immune activation in regulating calcium homeostasis is still unclear, but it may play a role in the development of dyscalcemia.^14,15

Dyscalcemia, particularly in the transition period, is a risk factor for various postpartum diseases in dairy cows.  These diseases include dystocia, uterine prolapse, retained placenta (RP), metritis, and mastitis. Dyscalcemia may impair immune function, leading to increased susceptibility to infectious diseases.^16,17 Reduced calcium availability contributes to impaired neutrophil function, which is critical for controlling inflammation and responses to infectious disease.^18,19

“Dyscalcemia is an important risk factor for long-term health.”

Recent studies using lipopolysaccharide (LPS) challenges provided new insights into the role of calcium in the inflammatory process, suggesting that maintaining blood calcium concentration during an inflammatory challenge may not have the expected benefits and may even potentiate inflammation.²⁰ Given the above, the criticality of calcium is readily apparent. It follows and it is reasonable that nutritional strategies for reducing dyscalcemia may also contribute to the longer-term health of the dairy cow.

There are several factors that can be considered to reduce rates of dyscalcemia in the herd. These include but are not limited to ionic/pH balance, quasi-deprivation of certain elements, and supplementation of actors in the endocrine homeostasis mechanisms.

A bespoke nutritional strategy that manipulates the ionic content and ionic strength of the dairy cows serum through dietary supplementation is known as DCAD or Dietary Cation Anion Difference.  This strategy originated with Peter Stewart, who proposed the Strong Ion Theory of Acid-Base Balance and the strong ion difference equation (SID) in 1978.²¹ In the 21^st century, variations of the SID equation is typically used, which says that the electroneutrality of the fluid must be maintained between the strong cations (i.e. sodium, potassium, and the hydronium ion) and the strong anions (i.e. chloride, volatile fatty acids, hydroxide, and sometimes sulfur (sulfur ion as sulfate SO₄^2-)²² In general, and excess amount of dietary ammonium chloride and sulfur compounds generate a mild state of metabolic acidosis.  Excess chloride ions are eliminated through normal renal processing.  However, in order to maintain electroneutrality in the urine the hydronium cation and calcium cations are excreted as well.

With a drop in serum calcium, the cow’s endocrine system compensates and stimulates the resorption of calcium from the bones along with increased renal absorption of calcium.²³   Dairy producers have been using DCAD diets in dry cow feeding programs for over 20 years to prevent milk fever and subclinical hypocalcemia during the transition period after the link between low potassium ash diets and reduced hypocalcemia and subclinical hypocalcemia  was first observed in Scandinavia.²⁴

There is no question that the DCAD nutritional strategy for dyscalcemia and skeletal health in general was successful.  Leno et al. showed that managing the prepartum DCAD to maintain an average urine pH between 5.5 and 6.0 will result in additional benefits in calcium status, postpartum dry matter intake, and milk yield relative to either no supplementation or a lower level of anion supplementation.⁴⁵  Moreover, Ryan et al. and also connected the dots to better outcomes for cows fed a fully acidified prepartum diet with high dietary calcium and showed improved uterine health and fertility compared to those fed a low-calcium diet. Lower vaginal discharge scores, greater uterine gland epithelial height, increased activity of superoxide dismutase (SOD) were the key observations.⁴⁶ Santos et al. performed a meta-analysis of DCAD strategies and found reduced incidence of milk fever in parous cows and decreased retained placenta and metritis in all cows.⁴⁷  The analysis concluded that parous cows should be fed diets with negative DCAD, but not smaller than ?150 mEq/kg of dry matter (DM).  Little to no effect from manipulating dietary contents of calcium (Ca), phosphorus (P), or magnesium (Mg), except that increasing dietary Ca tended to increase the risk of milk fever in parous cows, especially with positive DCAD diets.

The DCAD nutritional strategy, while successful, and with the underpinnings of holistic benefits notwithstanding, remains a perturbation of the cow’s biochemical system.  Acidifying a cow is not without its challenges.  The cost of deploying such a strategy is constant vigilance, with the main downside to feeding negative DCAD diets being the labor deployed in monitoring the pH of the urine such that an acidogenic condition is maintained in the boundaries of good health.

Since the 1950’s, calcium deprivation in the diet was studied as a way to stimulate the production of parathyroid hormone responsible for mobilizing stored calcium from the skeletal system. ^25-27   Unfortunately, what many in US consider low Ca diet has virtually no effect on reducing milk fever.   The low Ca approach usually works if diets are <~0.2% Ca which is essentially clinically deficient.  This type of low Ca diets is almost impossible to formulate and that is what led to a novel approach.  The administering of zeolite 4A during the prepartum period was found to yield better short-term outcomes and long- term health of the producing cow.²⁹

The addition of certain types of sodium aluminosilicates (i.e. zeolite) to the feed of dairy cows during the prepartum and transition phases of dairy cows was shown to reduce incidences of dyscalcemia despite 20^th century research that essentially concluded the opposite.

“Better short-term outcomes and long term health.”

In 1988, Johnson et al. added synthetic sodium aluminosilicate to the diet of Holstein cows, with and without sodium bicarbonate.²⁸ They concluded that the strategy had detrimental effects on feed intake, milk production, and nutrient digestibility.

Conversely, in 2002, Thilsing-Hansen et al. demonstrated  the effect of prepartum zeolite supplementation on periparturient calcium homeostasis in dairy cows, finding that zeolite supplementation increased plasma calcium levels around calving, possibly due to direct calcium binding and/or aluminum-derived phosphorus binding capacity of zeolite.²⁹ They found that zeolite supplementation significantly increased the plasma calcium level on the day of calving, whereas plasma magnesium and inorganic phosphate were suppressed. Serum 1,25(OH)₂D was significantly increased one week before the expected date of calving among the experimental cows, suggesting that the calcium homeostasis mechanism was initiated prior to the normal lactation induced timeline.  It was concluded that the improvement in available calcium was possibly due to direct calcium binding and/or aluminum-derived phosphorus binding capacity of the zeolite.

Since these early studies, many more zeolite supplementation trials were conducted, advancing our current understanding of how this nutritional strategy works. Pallesen et al. found that combined phosphorus and magnesium supplementation along with zeolite, reduced the “zeolite-induced” hypophosphatemia but also reduced the stabilizing effect of zeolite on parturient serum Ca.  Once again, it was shown that zeolite supplementation prevented milk fever and subclinical hypocalcemia at calving, but this effect was diminished when combined with phosphorus supplementation. Low phosphorus intake and zeolite supplementation were important factors in maintaining a stable calcium level around calving.  Milk fever and hypocalcemia were not prevented by zeolite supplementation in cows offered the same ration supplemented with high phosphorus.³⁰

Grabherr et al. examined the effects of different doses of zeolite A on feed intake, energy metabolism, and mineral metabolism in dairy cows around calving, with the aim of determining an optimal dosage for preventing hypocalcemia.³¹  They found that a daily amount of 23 g zeolite A/kg dry matter of total mixed ration (TMR) and a zeolite:Ca ratio of 5.6:1g feeding for 2 weeks before calving reduced the incidence of subclinical hypocalcemia in older cows by 71% relative to the control group fed no zeolite.

“Actual field results with real herds.”

Actual field results using Nutrilock® CalBal® in the feed of dairy cows, over many herds with slight variations in the ration, are on the order of a 50-60% reduction in dyscalcemia. This represents a possible difference between controlled studies and field studies, as one might expect.

Kerwin et al. did a study involving 55 multiparous Holstein cows that were enrolled in a completely randomized design study, with randomization restricted to balance for parity group and previous 305-d mature equivalent milk production.³²  The key findings of the study include: (1) cows fed zeolite 4A had higher serum Ca concentrations, especially during the prepartum period; (2) zeolite 4A-fed cows had lower serum P concentrations during the prepartum period, but higher concentrations during the postpartum period; (3) zeolite 4A-fed cows had lower serum Mg concentrations during the prepartum period; (4) zeolite 4A-fed cows had a lower prevalence of subclinical hypocalcemia (SCH) during the prepartum and postpartum periods; and (5) zeolite 4A-fed cows had similar milk production and composition compared to control-fed cows.

In another study, Khachlouf  et al. investigated the effects of including zeolite in the rations of lactating dairy cows on milk composition and mineral levels, and found that it increased milk yield and improved calcium levels without adverse effects.³³  The addition of zeolite to the diet of dairy cows during the periparturient period resulted in a significant increase in fat-corrected milk, fat yield, protein yield, lactose yield, and plasma calcium, with no negative effects on milk composition or blood parameters.  They also found that zeolite supplementation improved milk production, energy status, and calcium homeostasis in dairy cows while having no significant effect on milk composition, including protein, fat, and lactose content.   The benefits of zeolite 4A in the feed for dairy cows are readily apparent given the above research.  What is not as clear is the mode of action of zeolite 4A and how it participates in calcium homeostasis over the full parturient period.  The importance of understanding the mode of action can’t be overstated, as it gives the nutritionist and dairy producer alike the confidence that the animal’s mechanisms are not stressed any further before and after calving.  At the same time, this knowledge supports the supposition that any positive response was not just a random event.

Field results using Nutrilock® CalBal® in the feed of dairy cows, over many herds with slight variations in the ration, are on the order of 50-60% reduction in dyscalcemia.³⁴   While the mode of action of zeolite 4A as a nutritional strategy is one that must continue to be researched, we know it works. Feeding zeolite 4A prior to calving reduces the incidences of dyscalcemia by up to 71% in university-led live animal trials.³¹ The observation of calcium deprivation diets prior to calving taught us that reducing the serum Ca most likely turned the calcium homeostasis mechanism on before the onset of skeletal needs of the prepartum calve.^25-27  Let’s not forget that Horst et al. taught that maintaining normal blood calcium concentrations is crucial for mammals, especially dairy cows.³⁵

The parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25(OH)₂D3) play key roles in regulating calcium homeostasis.  In mammals, plasma calcium concentration is maintained between 9-10 mg/dl through the coordinated effects of PTH and 1,25(OH)₂D3.  When plasma calcium levels drop, PTH secretion increases, leading to renal reabsorption of calcium and induction of the renal enzyme 1?-hydroxylase, which produces 1,25(OH)₂D3. The hormone 1,25(OH)₂D3 stimulates active calcium absorption from the intestine. Passive calcium absorption also occurs, especially when calcium intake is adequate or high. During lactation, huge amounts of calcium are secreted into milk and colostrum, requiring massive adaptive changes in calcium homeostasis.  Plasma 1,25(OH)₂D3 levels rise, despite low to normal PTH levels, and maternal bone provides little calcium for fetal use in early pregnancy.  Also, during lactation, calcium (Ca) demands increase significantly, and the body must adapt to meet these demands.  To meet this demand, plasma PTH and 1,25(OH)₂D3 increase, enhancing intestinal Ca absorption.  However, even with increased absorption, up to 19% of the Ca required for milk production comes from the maternal skeleton, resulting in a 15-30% reduction in maternal bone Ca over the first several weeks of lactation.  The cow lactates for 10 months, and Ca demands decrease significantly upon cessation of lactation, despite increasing Ca requirements of the fetal skeleton.  Hernández-Castellano et al. suggested that there may be other hormones that facilitate calcium regulation, thereby leaving the door open for alternate strategies using serotonin supplementation.^36,37 It was initially thought that since dietary calcium was difficult to control in with  feeds commonly available formulating diets substantially deficient in Ca is almost impossible. Therefore, reducing the availability of dietary calcium using zeolite 4A would have a similar effect to the calcium deprivation strategy.  Zeolite 4A was and is a well-known calcium exchanger. Then, the calcium regulation in this case would be driven by PTH and 1,25(OH)₂D3 as described above.

Another school of thought with respect to the mode of action is related to serum phosphorus levels. It was discovered, using measurements of bone resorption markers OC and CTZ, that during dietary P deprivation studies, the hormone levels associated with the normal calcium homeostasis mechanism didn’t fluctuate until closer to calving. This suggests that calcium was being mobilized from the bone sources using an alternate mechanism. Meanwhile, zeolite 4A-based research showed that dietary phosphorus was bound and most likely initiated this mechanism which supports a reduced serum P level observation. We know from dietary P deprivation studies that this mechanism works just as well as the normal Ca homeostasis mechanism with respect to higher serum Ca levels. We also know from dietary P deprivation studies the level of P binding to initiate a very safe/mild state of transient hypophosphatemia, and this paved the way for responsible nutritional strategy relative to the health of the cow.

“A responsible nutritional strategy.”

Thilsing-Hansen’s et al. experiments and discussion suggested that zeolite 4A could also bind dietary phosphorus (see above) as well as calcium, thereby causing a zeolite induced state of hypophosphatemia.^29,30  In 2014, Puggaard et al. studied the long-term effect on milk production and phosphorus utilization in lactating dairy cows, suggesting that phase feeding may be a more suitable strategy to optimize P supply and reduce fecal P excretion.³⁸ They measured serum P, serum Ca, PTH, osteocalcin (OC), carboxy-terminal telopeptide type 1 collagen (CTX), and vitamin D3 levels. It was found that reducing dietary P concentration from 3.4 to 2.3 g P/kg DM reduced dry matter intake (DMI), milk yield, milk protein yield, and plasma P concentration, but did not affect serum concentration of OC in early lactation. Lower dry matter intake and milk production and higher bone resorption for the low P diets compared to those on the medium P and high P diets were observed. Also, the low P diet led to a decrease in plasma P concentration, which was corrected after the treatment was shifted back to normal P diets because of a large number of observed health issues.  There was no effect of treatment on urinary P excretion or pH, while no differences in vitamin D3 status or parathyroid hormone concentrations among the treatment groups were observed, possibly hinting at an alternate mechanism for Ca, P homeostasis.  The researchers did note a safe level to which one could reduce P such that health and production were not compromised.

A year later, Grünberg et al. investigated the effects of transient dietary phosphorus deprivation on muscle function and phosphorus metabolism in lactating dairy cows.³⁹ The study found that P deprivation led to a decline in plasma P concentrations, which was accompanied by an increase in renal excretion of Ca, among other biomarkers.  Then during the repletion phase, despite dietary P deprivation, plasma P concentrations increased, and renal Ca excretion decreased as it would if it was calcium that was deprived. Moreover, Cohrs et al. studied the effect of dietary phosphorus (P) deprivation in late gestation and early lactation on calcium homeostasis in periparturient dairy cows.⁴⁰ They hypothesized that dietary P deprivation in the weeks before calving would result in enhanced bone mobilization before calving and alleviate the decline of plasma Ca commonly observed in periparturient dairy cows. Dietary phosphorus (P) deprivation in late gestation had a positive effect on plasma calcium (Ca) levels in periparturient cows. A lower incidence of clinical hypocalcemia was observed along with plasma Ca levels 10-15% above those of control cows in the first 3 days of lactation. It appeared that P deprivation was associated with lower secretion of PTH in P-deprived cows during the periparturient period, which suggested that a regulatory circuit independent of PTH but equally effective in mobilizing bone tissue was triggered by dietary P deprivation.

Higher plasma CTX, a bone biomarker discussed above, was observed where a marked difference in PTH (i.e. lower) was not associated with any remarkable changes in the level of 1,25-(OH)₂D, which suggested some other regulatory circuit for P and Ca.

“Biomarkers observed for calcium mobilization.”

It was proposed that the fibroblast growth factor 23 (FGF23), a bone-derived phosphatonin which is known to reduce P reabsorption in the kidneys during states of hyperphosphatemia as well as suppress the production of 1,25-(OH)₂D3 synthesis might play a role in calcium and phosphorus homeostasis.  No evidence of FGF23’s role exists currently.

More recently, Wächter determined whether this effect on the Ca balance can be reproduced when limiting the P-restricted feeding to the last four weeks of gestation.⁴¹ They measured PTH, 1,25-(OH)₂D, ionized Ca, total Ca, and serum P as well as CTX.  First and foremost, they confirmed that feeding a P-deficient dry cow diet during the last four weeks of gestation does not aggravate or prolong the transient hypophosphatemic period in dairy cows.  Furthermore, restricting the dietary P supply during the dry period enhances the capacity to absorb dietary P from the digestive tract after switching to a diet with adequate P content.  Interestingly, Wächter et al. observed less bone Ca and P mobilization vs Cohrs et al. with a milder state of hypophosphatemia.  However, Wächter et al.  suggested that bone mobilization in states of P deficiency is at least as efficacious in supplying the extracellular space with Ca as bone mobilization triggered by Ca deficiency, while being less dependent on or even entirely independent of PTH.  Furthermore, they found that restricting dietary P supply during the 28 day prefresh period did not affect milk production, dry matter intake, or body weight in dairy cows. However, it did lead to hypophosphatemia, which was not associated with any clinical signs or symptoms.  The study also found that liver tissue parameters, such as triglycerides, cholesterol, and dry matter, increased over time, while plasma concentrations of total protein, creatinine, sodium, and potassium decreased over time.  Low P cows produced 10% more milk than adequate P cows in the second lactation, and adequate P cows produced 15% more milk than low P cows in the fourth lactation.  Wächter et al. started to connect the dots to the difficulties of P deprivations as a nutritional strategy, much like dry period Ca deprivation strategies from earlier in the 20^th century, and suggested that a P binding strategy might be necessary to consider given the various diets used in the different regions.

Recently, Frizzarini et al. compared DCAD and zeolite 4A nutritional strategies in multiparous Holstein cows.^42,43 Their work appeared to confirm that zeolite 4A and DCAD diets improve postpartum calcium metabolism.  However, these supplementation strategies seemed to work through different modes of action. Feeding synthetic zeolite 4A appeared to work via restricting dietary P, whereas the DCAD strategy tapped the classic Ca regulatory mechanism. Both strategies facilitated better outcomes with respect to dyscalcemia and calcium levels before and after calving.

At Chemlock Nutrition, we posit that both mechanisms are at work in series and in dynamic fashion to facilitate the early mobilization of calcium from bone storage followed by the classic calcium homeostasis regulatory circuit with PTH and 1,25(OH)₂D3 dominating calcium mobilization during the close-up period.  Yes, P deprivation and/or P sequestering is a short-term perturbation in the biochemistry of the cow like DCAD strategy mentioned above.  However, one of the beautiful aspects of this strategy is that states of very mild phosphatemia that prime the calcium mobilization coming into the close-up period are eliminated easily as the normal calcium and phosphorus regulating circuit takes over just before calving. More importantly, this strategy requires no pH monitoring for consistent results.

With the fullness of time, perhaps Hernandez and McArt’s perspective and early observations of reduced incidences of disease with reduced incidence of dyscalcemia will continue, thereby showing that a holistic approach can lead to both short- and long-term solutions. Given the discussions above, it is clear that antioxidants and skeletal health nutritional strategies are making a difference in the overall health of the dairy cow.

“Making a difference in the overall health of the dairy cow.”

What is infinitely fascinating is that the world is still learning how things work behind the scenes of a tall glass of cold milk.  Moreover, in the continuous learning and constantly connecting of the dots in the 21^st century and beyond, we can find ways to contribute to a stronger dairy industry.

One of those ways is to bring innovative products to the market that support nutritional strategies that maximize production while keeping the long-term health and welfare of the milk producer at the top of mind.  Chemlock Nutrition offers Nutricow® CalBal®, which is a synthetic zeolite 4A-based nutritional supplement with a unique chemistry, form factor (it’s a small noodle!), and proprietary formula that was shown to reduce the incidence of dyscalcemia by 60% or more in the field at real dairies.

The mission of Chemlock Nutrition is to use its deep knowledge and understanding of chemistry to bring multi-generational products to the dairy industry that are inherently useful and are born out of connecting the dots in the 21^st century.

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