Diagnosis and prevention of MBD/ Osteopenia/ Rickets of prematurity

Hello, I'm Dr. Tala, a board certified neonatologist. And today we are going to cover part two of metabolic bone disease and prematurity. So if you haven't seen part one on the risk factors and the pathophysiology, then go and watch it now. I will wait for you. Joking, I'm about to record this and then I'm probably going to take my dog for a walk. She's sitting over there. So anyway, in this video, we will cover the diagnosis and management of metabolic bone disease. And just before we start, I just want to thank the channel members who asked me to do this video and really forced me to get into the nitty gritty of the subject. Thank you again. Right. Diagnosis. So like we've been alluding to in the previous videos, even though we can all recognize metabolic bone disease with abnormal labs or abnormal x-rays, there isn't really a set criteria or a system to actually diagnose metabolic bone disease, let alone to diagnose different grades of metabolic bone disease. So there really isn't any consistency in the diagnosis, in the prevention or in the management. As we keep saying, we know that the disease results from having a low body calcium and phosphorus. But since most of the calcium and phosphorus in the body is in the bone, often the calcium and the phosphorus will be normal. Even if we do have bad metabolic bone disease of prematurity, it's a lot more likely that the phosphorus is going to be low. But still, that isn't always the case. So what else can we use? Well, one of the tests that we can use in blood as a marker of metabolic bone disease is alkaline phosphatase or ALP. ALP reflects the activity of osteoblasts, which if you remember from the previous lecture, we said are the cells responsible for laying down more bone. So if the bone mineralization is impaired, then the osteoblasts will increase their activity, desperately trying to lay down more bone matrix. So in this case, we would have an increase in the alkaline phosphatase or an increase in ALP. But just quick aside here, remember that there are isotopes of alkaline phosphatase that exist in other organs. So not only is the outpost in bones, but it's also in the gut and in the liver. So we can see an elevated alkaline phosphatase. If you are in liver failure, you've got cholestatic liver failure. We also see an increase in alkaline phosphatase. If a baby develops a spontaneous intestinal perforation, probably from the outpost in the gut, or you can have increased alkaline phosphatase if the baby is going through a growth spurt. So even in the setting of an increased alkaline phosphatase, make sure that you're putting that number into its clinical context. So the most sensitive and specific markers of metabolic bone disease of prematurity is probably the combination of an elevated alkaline phosphatase with a low phosphorus. So, for example, if the phosphorus is less than 5.6 mix per deciliter, which is less than one point eight millimoles per liter in combination with an elevated alkaline phosphatase. So an outpost, especially if it's higher than 800 international units per liter, then that is pretty sensitive and specific to metabolic bone disease. In fact, lots of sources quote these numbers in babies with a phosphorus less than 5.6 and an outpost more than 900. Then that is 100 percent sensitivity and 70 percent specificity for metabolic bone disease of prematurity. So phosphorus of less than 5.6 outposts of more than 900 international units per liter. As you would expect, the higher the outpost is, especially if you're just looking at that number alone, then the more sensitive that is for metabolic bone disease. So some institutions will just get kind of like routine x-rays of the risk or whatever. If the outpost level is above a thousand international units per liter. Another small aside here, realize that outposts may be deceivingly low. So it just isn't as elevated. It should be if the baby is deficient in zinc, which is a whole other video or if the baby is on steroids. So think of those two things when you are evaluating an outpost, especially in the setting of a low phosphorus. Like we keep saying, calcium is not a good marker at all of metabolic bone disease of prematurity. In fact, even with a baby with fractures, calcium might be really low, like less than 8.5 mg per deciliter, or it might actually be really high, like above 10.5 mg per deciliter. It could be high because the PTH is so up regulated and PTH will increase calcium resorption from the bones to increase the calcium in the serum. So really, we can't really trust calcium in the setting of metabolic bone disease. Many units will screen calcium, phosphorus and phosphatase weekly to make sure that we are catching early derangements. In one of the hospitals I work at, we add the phosphorus and the outpost to every single metabolic panel that we get, like the normal electrolytes, which I absolutely love because we can track the outpost kind of similarly in the same way that we're tracking other electrolytes. A recommendation from up to date says that we should be checking these lab values at least every two weeks. Obviously, if the baby is at high risk, so for example, the baby is very TPN dependent or has short gut syndrome, then we should be checking these levels more often than that. Some papers also recommend routinely checking PTH or the parathyroid hormone levels, which honestly are often elevated. PTH is often high as it's trying to keep the calcium in the blood stable. And it's often like *******, you know, the calcium out of the bone and increasing the calcium absorption from the kidneys. So some institutions will check PTH. This is often not done routinely. Another value that comes up in research is the TRP or the tubular reabsorption of phosphorus. So basically what this is measuring is you have to get the phosphorus in the urine and compare it to the phosphorus in the blood and see what percentage of the phosphorus is being reabsorbed. And this can be helpful in kind of predicting the levels of phosphorus and calcium and the hormones in the blood. But clinically, we very rarely check these two values, the PTH and the TRP. Generally, we don't measure vitamin D levels either, although as we talked about in the last video, a good vitamin D level is absolutely crucial to making sure that the calcium and the phosphorus is adequately absorbed from the gut. Interestingly, 25 hydroxy vitamin D. So the vitamin D after it's been metabolized by the liver, but hasn't quite been metabolized to the kidney. So the calcidiol or the 25 hydroxy vitamin D is at the same levels in neonates that have rickets and don't have rickets. So obviously not a good marker at all for metabolic bone disease or prematurity. So the current thinking is, is that we should definitely be supplementing with vitamin D without actually checking levels. Obviously, if the baby's at huge risks for having a vitamin D deficiency, for example, like short gut syndrome or just has very poor absorption, then yes, we probably want to be checking vitamin D levels to make sure that we are giving the baby what they need. Another part of what may be considered screening for metabolic bone disease is actually getting x-rays. As you all know, in the unit, we're often getting x-rays for other reasons, normally chest x-rays. So on those x-rays that we're getting, we might see some demineralization of the bone. So instead of the bone looking like really white, it starts to look a little bit grayish. Other things that we might see, or honestly, the radiologist might see, I can recognize when the bone looks much thinner. And obviously I can see the fractures, but other kind of little changes in the bones I'm not so good at. So other things that we might see is an enlargement of the epiphysis, as well as an irregular border between the growth cartilage and the bony metaphysis, as well as fractures. And let me tell you that if you're not looking for fractures in the x-rays, you will miss them. So sometimes we'll see a fracture on an x-ray and we'll go back and realize that that fracture was there maybe two or three days ago. So also get used to looking at all the bones whenever you're getting an x-ray for whatever other reason. Realize, though, that these are all pretty late findings of metabolic bone disease. Once you start seeing even osteopenia on the x-ray, then a lot of the damage has already been done. And once you are seeing it, make sure that you are following these babies aggressively and treating them as best as you can and handling them very delicately. Obviously, with weaker bones, they're at much higher risk of developing more fractures generally. And this is definitely what's followed in research. The x-rays that will give the most information about the growth plates and the enlargement of the epiphysis are wrist x-rays, as well as knee x-rays. Obviously, the most common x-rays that we do in the unit are x-rays of the chest. And so the most common fractures that we see are actually posterior rib fractures. So, again, when you're looking at those x-rays, really look at those ribs very carefully in the research world and in the adult world where they're used regularly. DEXA scans are used as the gold standard for actually measuring the bone mineral density. So like all the women with osteoporosis are getting DEXA scans. We really don't use those in the unit unless it's kind of like more of a research situation. Kind of the same thing with ultrasound. There are specialized ultrasounds that are pretty good at measuring the bone mass of babies. And generally, the tibia is used to kind of compare that. Again, this would be lovely if we were able to use this more and more, because obviously it's no radiation. And so this would be a very good way of actually comparing bone mass in a very non-invasive way for these babies. So hopefully this will build in the future. Right. Let's cover treatment. So the primary treatment strategy is the same as the prevention strategy, which is to make sure that premature babies, especially babies less than 1500 grams, are getting the calcium, the phosphorus and the vitamin D that they need for their entire NICU stay. Also, if we can, we want to avoid loop diuretics and we want to avoid steroids. Different countries have different recommendations for exactly how much calcium and phosphorus we should be giving to preterm babies, which, again, is just a marker of like how great all the evidence is out there, that there isn't just one solid plan for everybody. But I do want you to realize that if a premature baby is given unfortified breast milk, even if they are receiving 180 ml per kilo per day of unfortified breast milk, they will only get a third of the calcium and the phosphorus that their bodies need. This is also true of a preemie baby being given a term formula. There just isn't enough calcium and phosphorus in it. So it is important that the premature babies are actually given fortified feeds to actually try to give them the calcium and phosphorus that they need. Usually what we're doing is adding a human milk fortifier to mother's breast milk or to donor breast milk. And the human milk fortifier may be cow's milk based or it may be human milk based. Or we could just be giving the baby some premature formula or some some sort of fortified formula. Obviously, we don't like that as much because we know that babies that are mostly fed with breast milk have a lower incidence of that. Ideally, what we're trying to do is just mimic the in utero accretion of the calcium and phosphorus. So we want to give the babies the amount of calcium and phosphorus that they would be receiving from their mommy if mommy was still pregnant with a baby in utero. Preterm infants would normally receive about 120 to 200 milligrams per kilograms per day of calcium. So postnatally, our goal is between 150 and 220 milligrams per kilogram per day. This is the AAP recommendation. Realize that babies absorb about 60 percent of the calcium and 80 percent of the phosphorus that they are given. And we are aiming for 75 to 140 milligrams per kilogram per day of phosphorus supplementation. Again, this is mostly done with the human milk fortification. Also realize, though, that banked breast milk. So like the donor breast milk has much lower phosphorus values than if it was mother's breast milk. So also take that into account when you have a little baby in the unit. I just want to add here again that other societies actually recommend slightly lower amounts of calcium and phosphorus supplementation for babies. And the AAP is actually kind of on the higher side compared to other international organizations. Again, just highlighting that we don't know exactly what the ideal amount is. So all babies less than 1500 grams should definitely be receiving fortified feed with extra calcium and phosphorus. Like we said, it's really difficult to figure out exactly what is needed and really how much of it is good. But we know that in modern cohorts, so babies born more recently that were given these fortified feeds have a much lower rate of rickets compared to babies kind of 20 years ago, like I was saying. Sometimes even with fortification, babies will still have a phosphorus deficiency. And if this is in a setting of an increased alkaline phosphatase as well, then we will probably want to add additional phosphorus supplementation. Remember what I said in the last video as well, that if the phosphorus is low, then the kidneys will basically dump more calcium trying to get the phosphorus up. So we really don't want a low phosphorus in blood just to help the whole preservation of the calcium as well. We usually give the additional phosphorus supplementation in salts naturally, normally of potassium phosphate or sodium phosphate. And it really depends on what everybody has in their hospital. Babies generally tolerate it pretty well. They are pretty high osmolarity. So just consider that if your baby is still very creamy and you want not to kind of irritate the gut too much. We especially want to supplement babies if the phosphorus level is less than four. And really, you're trying to get the phosphorus level to about a 5.5 mgs per deciliter. So this is something that you should be following, especially like we said, if the babies are receiving donor breast milk because they don't breast milk does have a much lower phosphorus level than mommy's milk. If a baby is on TPN, it's much harder to get the calcium and the phosphorus in because as the calcium and phosphorus is increased in the TPN, then you run into solubility issues and they're all just going to crystallize out and cause salts. So you're really maxed out with how much calcium and phosphorus that you're giving. When you're giving TPN, though, in it and when you're giving calcium, you're aiming for between three to four mil equivalents per kilo per day, which is only 60 to 80 milligrams per kilogram per day. So obviously much lower than really about half what we're getting when we're trying to give the baby enteral calcium. So you can see already why it's such a big issue when babies are on TPN. With phosphorus, we're aiming for between two to 2.5 millimoles per kilo per day. Also much lower than what we would be giving if the baby was fed enteral. Also realize that the ratios that you give calcium and phosphorus also really affects the baby's ability to use both of the minerals. And your ideal ratio mass to mass is calcium to phosphorus of 1.7 to one. So this is also something that you should be following when you're typing in your TPN and something that obviously the nutritionists are all over as well. Also realize that if we are giving calcium through an IV, then we really want to be using central access only. So one of the reasons is, is if you're giving calcium through a peripheral IV, then and the IV comes out, you could end up with a very, very severe calcium burn. And babies have lost digits from or even like the ends of limbs from having such severe calcium burns. So we actually avoid giving calcium peripherally at all. But the other reason why you want to use central access is that you can go up on the amount of calcium that you've got in your TPN without worrying about osmolarities and everything as much. So you really want to give calcium through an umbilical venous catheter, through a PICC line or through a Broviac. Also, interestingly, research has shown that babies are much more likely to maintain the calcium that you're giving them if the calcium is given continuously rather than in boluses. So it's much better for a baby to be on continuous TPN versus for the baby to be given extra doses of calcium every six hours or whatever. And this has been shown in studies where babies that were on continuous calcium had actually slightly lower alkaline phosphatase. So try to get continuous calcium wherever you can. There is a subset of babies on TPN that if they have hyperparathyroidism, so an elevated parathyroid hormone, they might benefit from receiving the activated form of vitamin D. So the vitamin D has been metabolized in the liver, been metabolized in the kidney, and it's now the activated form. This is called calcitriol. Like we've said already, PTH goes up if the baby's serum doesn't have a lot of calcium in it. And generally, if babies are on TPN, as we already said, they're not getting nearly the calcium that they need. Generally, a lot of them will end up with an elevated parathyroid hormone level. And this could be one of the times that you do actually want to check the PTH hormone just to see if maybe this would be a baby that would benefit from the calcitriol. Calcitriol in this situation may help suppress the parathyroid hormone. And parathyroid hormone in this situation will kind of help phosphorus dumping. So if we can suppress the parathyroid hormone, then we will prevent more phosphorus dumping. But like we also said in the first video, calcitriol helps the absorption of calcium and phosphorus from the gut. So in a situation where a baby is on prolonged TPN with a high parathyroid hormone, they may benefit from calcitriol. And the dose that we give is between 0.05 microns per kilo per day, all the way up to 0.2 microns per kilo per day. Again, you can do this with the lovely nutritionist in the unit. Going back to what we were saying earlier, nobody really recommends checking vitamin D levels unless you really have issues like short gut syndrome or whatever. But the AAP recommends that all preemie babies should receive between 200 to 400 international units of vitamin D a day. And that's what we do in our unit. We are supplementing them with extra vitamin D and even a little bit more than what's given in the multivitamin. If babies do have a reason where they really could have a vitamin D deficiency, again, prolonged TPN or NEC or whatever, then babies might need up to 800 to a thousand international units of vitamin D a day. Another big part of prevention and treatment of metabolic bone disease of prematurity is non-pharmacological therapy. So obviously, if a baby does have weak bones or even has a fracture, then they should be handled extra carefully, just very gently moved, very carefully, just be very aware that the bones are fragile. But on top of that, there may also be a place for physical therapy for babies with metabolic bone disease. Like we said already, one of the problems of the babies being born prematurely is that they have nothing to push against. They don't have the uterine wall to push against. And it's important to have a weight bearing exercise to build bones. We know that from adults. We should all be lifting weights all the time, right? So there may also be a role for actually kind of physical therapy in getting these babies to move. And some studies have shown that the bone mass is better when babies are put through these like physical therapy exercises for just five to 15 minutes a day. These exercises are like passive range of motion exercises, as well as just like joint compression exercises, really just getting the babies to move, preferably against a little bit of force is thought at least to really help the development of these bones, as well as to help in their overall growth, their length development, as well as their own like physical development in the future. So we have these babies on fortified breast milk feed with extra phosphorus and extra calcium, or they're going home on some sort of transitional formula with extra calcium and phosphorus. We're making sure that they get enough vitamin D. We're hoping that we are treating them gently, but also kind of making them do a little bit of physical therapy. The question is, how long does this have to continue for? How long do we have to continue the fortified feed for? Again, experts aren't really sure, with people saying anywhere between 40 to 52 weeks post-menstrual age. This should be even longer if there is poor growth. And if babies are sent home on exclusive breast milk feeds, which a lot of institutions do, then that is fine. But somebody should be following up the alkaline phosphatase levels after discharge to make sure that we are actually getting adequate bone deposition after the babies are going home. In the first few months of life, especially the first few months that preemie babies go home, bone mineralization improves rapidly. And often it reaches the level of full term babies within a few months. So this is not a long term problem, as long as we are not stopping adequate growth because the bones are so bad. But just to summarize everything, prevention is definitely the best thing in metabolic bone disease management. So we want to start enteral feeds early and advance with enteral feed, because as we keep saying, we can get a lot more calcium and phosphorus in enterally rather than parenterally. We need to fortify the breast milk feeds or make sure that the babies are getting enough calcium and phosphorus. We need to make sure that we are giving extra vitamin D supplementation and we need to minimize prolonged TPN. We need to make sure that babies are on steroids for a long period of time. And we want to avoid loop diuretics when we can. Again, I'll emphasize this. Prevention is so much easier than treatment in these little babies. Right. I hope that was helpful. If you learn anything, then please give this a like this video. If you're interested in more neonatal education, then please subscribe to our channel. We really do love having you here. Thank you.