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Understanding Bone Health in Children: Grand Rounds Episode · Pediatrics Now: Cases Updates and Discussions for the Busy Pediatric Practitioner

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Music.
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A fascinating talk. Let's listen in. So it is an absolute privilege to introduce Dr. Radhika Ply.
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She is a Pediatric Endocrine Fellow in her final year of fellowship.
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She earned her medical degree for a medical college of Georgia and Augusta and
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completed her residency at the Children's Hospital of San Antonio,
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Baylor College of Medicine.
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Her research has focused on cystic fibrosis, leading projects on obesity and
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cardiovascular health, which she has presented at local, regional,
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and national conferences.
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Last year, she was awarded third place for her oral presentation at Pediatric
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Research Day, which makes me so lucky to be her mentor.
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Dr. Pillai's clinical interests include calcium growth and puberty disorders,
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pediatric diabetes and obesity, and the use of diabetes technology to improve patient outcomes.
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Bone health is an important and often underappreciated pediatric concern.
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Bones are necessary not only for body structure and movement,
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but they also protect our organs, house bone marrow.
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Bone also serves as a reservoir for calcium and phosphorus and as an endocrine
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organ in its involvement with renal phosphate handling, glucose metabolism,
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and the vitamin D endocrine pathways.
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And so incorporating bone health considerations into routine clinical practice is important.
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This is a summary slide just to highlight the point that when we're evaluating
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for bone disorders, there are important aspects of the assessment that will
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help with uncovering the diagnosis.
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And it starts with getting a good history and exam.
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In terms of bone health history, you want to ask about birth history,
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an individual's diet and activity, through fertile development and growth?
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Are they meeting milestones?
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You want to ask about their dental health, whether there have been any delays
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or early dental eruptions, any concerns about enamel or frequent cavities.
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You want to ask about illnesses and current and previous medication use and
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fracture history, asking about the mechanism of fractures, the impact,
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and the healing process.
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And you also want to get a family history, understanding if there are a history
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of fractures in the family, osteoporosis, connective tissue disorders,
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or any underlying chronic illnesses.
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And on an exam, you want to assess for growth parameters, motor function.
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Limb deformities, spine asymmetry, and pubertal progression.
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So let's see what this looks like with a clinical case.
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It's after hours, and you're the on-call endocrinologist, and you receive a
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call from a community pediatrician regarding a 16-month-old African-American
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male with concerns for leg falling.
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And as you can see on the growth chart, there's concerns regarding the decline
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in growth trajectory, both for weight and for length.
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I just want to make a point about measurements for any of our learners in the audience.
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So it's really important to ask how the patient was measured and to make sure
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that the measurements were done accurately.
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So in the case of infants, to measure their length accurately on a stadiometer,
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you want to have them laying flat on their back on the measuring board.
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Ensure that their head is against the headboard in the vertical plane and that
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their feet are against the footboard.
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And this is usually going to be a two-person job, one person to secure the head
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in place and the other to make sure that the feet are touching the footboard.
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For ambulatory children, this means that there's a stadiometer that's attached
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to a wall so that the child can stand against it with their head,
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shoulders, and heels touching.
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You want to make sure there are no head accessories or shoes on and that their
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head is in the horizontal axis of vision.
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So if there is any concern about measurements, it's always important to ask
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how are the measurements done and to repeat them if there's concerns.
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So back to our patient, we learned that he was born term, yet an uncomplicated pregnancy.
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His parents noted Boeing at 11 months, with daily dental eruption at 12 months.
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He is meeting his developmental milestones.
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He was exclusively breastfed until 15 months, and so far he's a fairly picky
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eater, only eats certain foods in limited quantities.
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He was not on vitamin D supplementation, and you also learn that his brother,
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who's now three, had a similar history of leg bowing in infancy.
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They are a single-income household and there are concerns for food insecurity.
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On exam, you do confirm the bilateral leg bowing.
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You also notice metaphysial flaring in the long bones as seen in this forearm,
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frontal bossing, and prominence of the cosochondral junction.
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Or also referred to as rachytic rosary.
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And so based on the history and the exam, this helps to guide further evaluation.
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In terms of imaging, we think about getting a skeletal survey to assess for fractures.
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And if there's concern about bone mineral density, then we think about getting DEXA scans.
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And in terms of laboratory testing, we have a whole host of bone health labs
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that we like to assess, including parathyroid hormone levels,
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calcium, magnesium, phosphate,
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alkaline phosphatase.
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To vitamin D levels, the 25-hydroxy and 125-hydroxy, and then assessing renal
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function with electrolytes and urine studies.
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So in our patient, radiographic imaging does confirm the varus boning.
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There's also the prominent costochondral junction, and then there's broadening,
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cupping, and fraying of the long bone metathases.
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On laboratory testing, we see that there's marked hypotalsamia.
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Hypophosphatemia, elevated alkaline phosphatase, and parathyroid hormone levels,
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and that the 25- hydroxyvitamin D and 125-dihydroxyvitamin D are both low.
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And so this constellation of features from the history, the exam,
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our imaging, and laboratory testing leads us to suspected diagnosis of vitamin D deficiency rickets.
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Now I want to take a step back and discuss calcium and phosphate homeostasis
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and the role of vitamin D in this process.
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So vitamin D in an inactive pro-hormone form comes as vitamin D2 or ergocalciferol
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and vitamin D3, holycalciferol.
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And an easy way to remember which vitamin D is which is two Cs in ergocalciferol
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and three Cs in holycalciferol or vitamin D3.
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Now we can get vitamin D2 and D3 from our diet and we can also make vitamin
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D3 in our skin through exposure to UV sunlight.
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This vitamin D is then hydroxylated in the liver to become 25-hydroxyvitamin D or calcidiol.
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And this is the storage form of vitamin D that we most often are measuring on
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laboratory testing because it has a more stable half-life.
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It then is hydroxylated again in the kidney by 1-alpha-hydroxylase to become
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the active form, or 125-dihydroxyvitamin D, also referred to as calcitriol.
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And this calcitriol is involved in maintaining our calcium and phosphate levels
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within target range by stimulating calcium and phosphate absorption from the
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gut by regulating bone modeling and resorption,
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and also indirectly being involved in phosphate absorption and excretion in the kidney.
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It also feeds back to the parathyroid gland and serves as a modulator of parathyroid
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hormone release, which is involved in regulating this process of calcium and
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phosphate homeostasis as well.
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So when we look at our patients' labs in this pathway, due to the low vitamin D intake,
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this led to low levels of calcidiol and calcitriol.
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And because the body was not able to have the substrate of calcitriol to absorb
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adequate amounts of calcium and phosphate,
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the parathyroid hormone and alkaline phosphatase, which is a marker of bone turnover,
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were elevated to try to counter-regulate the insufficient quantities of calcitriol.
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And so because this system was not able to re-achieve homeostasis,
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this led to the findings of hypocalcemia and hypophosphatemia as well.
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So ribicates, what is it? It is a generalized bone disorder that's associated
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with decreased mineralization of the bone matrix.
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And again, this occurs because the body is trying to do all that it can to maintain
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calcium and phosphate levels within target range,
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and it comes at the expense of the mineralization process of the bony matrix.
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And so this leads to softer and weaker bones.
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This is occurring at the growth plates of the long bones in actively growing children,
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and this same process when it occurs after growth is complete or after the growth
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plate closes is referred to as osteomalacia.
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In terms of causes of rickets, we can classify them as either due to calcium
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deficiency and or phosphate deficiency.
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In terms of calcipenic rickets, we have vitamin D deficiency and calcium deficiency,
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which are globally the most common causes of nutritional rickets.
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And then there are rarer forms, calcipenic rickets, due to abnormalities of
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vitamin D metabolism or action, which are due to deficiencies in the 25-hydroxylase enzyme,
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1-alpha-hydroxylase enzyme,
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and end organ resistance due to mutations in the vitamin D receptor that lead
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to vitamin D-resistant rickets.
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So I want to take a minute to talk about nutritional rickets.
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There are certain risk factors that can predispose a child to develop nutritional
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rickets and are important to take into account.
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In preterm infants, because the in-utero mineralization process that is occurring
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in the third trimester is interrupted, as well as the increased nutritional demand,
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they are at a higher risk of developing rickets.
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In infants who are exclusively breastfed due to the low content of vitamin D
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in breast milk, as well as if there's maternal vitamin D deficiency,
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they are more likely to be at risk for Ricketts.
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Children who have darker skin pigmentation have higher melanin content,
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which reduces their skin's ability to produce vitamin D from sunlight.
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And this can be particularly problematic in countries at high latitudes or in
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colder climates where sunlight exposure might be limited,
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as well as with more frequent use of sunscreen, which impairs our skin's ability to make vitamin D.
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In terms of malabsorptive disorders, any disease processes that impair absorption,
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for example, celiac disease or inflammatory bowel disease, can lead to nutritional rickets as well.
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And if there are any dietary restrictions, whether that's being on a vegetarian
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or vegan diet or limiting dairy intake if there's, for example, lactose intolerance.
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And then it's also important to consider socioeconomic factors.
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So if there's limited access to health care or nutritional education or limited
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access to foods that are fortified,
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this can lead to a diet that's deficient in essential nutrients,
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which was a concern in our patient's case.
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There are recommended dietary allowances for both calcium, vitamin D,
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as well as phosphorus by age.
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It's fairly easy to achieve the amount of daily phosphorus that's needed because
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our diet is rich in phosphorus.
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However, it can be challenging to achieve the amount of calcium and vitamin
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D that's necessary on a daily basis.
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And as you can see, the required amount varies by age,
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reaching up to 1,300 milligrams per day for 9 to 18-year-olds and 400 to 600
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international units of vitamin D daily.
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And so just to put this into perspective in terms of the challenge,
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for vitamin D, there are foods that are fortified dairy products,
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cereals. there are various types of fish that have vitamin D.
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But to achieve that amount of 400 to 600 international units of vitamin D daily
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would require having at least four to five servings of high-rich vitamin D foods.
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For example, in a glass of milk that's vitamin D fortified, there's about 40%
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of that daily recommended amount.
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And so it can be challenging when we're counseling our patients to help them
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achieve that daily required amount.
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And the same with calcium. There are dairy products, fish, vegetables,
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fruits, again, that have calcium in them.
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But there is the added challenge with calcium that it's important to space out
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the intake over the day to optimize with absorption.
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And that adds a layer of added complexity in children who have active schedules
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or who might be on other medications that could have impaired absorption if taken with calcium.
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It is preferred for calcium to be obtained through the diet.
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There are some studies in adults that show adverse cardiovascular effects.
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And so we do try to reserve calcium supplementation if we're concerned that
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dietary intake is not sufficient.
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In terms of supplementation for vitamin D,
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either formulation of D2 or D3 are equally effective and the goal of vitamin
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D levels is to maintain within a range above 20 to 30.
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In terms of calcium supplementation, I wanted to just point out that there are
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many calcium formulations, and it's important to be mindful that these formulations
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have varying amounts of elemental calcium.
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One of the more common forms is calcium carbonate, which has about 40%,
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which has 40% of elemental calcium.
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And so as an example, if a 1,000 milligram calcium carbonate tablet has 40%
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elemental calcium, this amounts to 400 milligrams.
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And so being mindful of that when you're calculating the doses is important.
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In terms of Ricketts vitamin D management, it's recommended that oral treatment
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is done to restore vitamin D levels.
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And as I mentioned, either D2 or D3 are equally effective.
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The dosing ranges from 2,000 to 6,000 units, depending on the age,
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and it's advised to prescribe this regimen for a minimum of three months.
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At that time, it's important to assess for biochemical improvement,
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so checking labs, and some children may require longer treatment.
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During that time, it's also important to replace calcium in the diet or via
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supplementation because when the body starts to see the improved vitamin D,
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it will try to compensate for inadequate with calcium by continuing to pull from the bones.
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And so to avoid this hungry bone picture that we might encounter,
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we supplement with some calcium as well.
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And once the concern for rickets has resolved, it's recommended to continue
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maintenance dosing at anywhere from 400 to 600 international units daily.
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There are some studies that have looked at single-dose treatment with equivocal
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findings, but for ease of use and compliance, it is an option that can be considered.
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So, in terms of calcipedic rickets, we've talked about nutritional rickets.
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I just wanted to take a few minutes to talk about some of the rare abnormalities
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that can occur from vitamin D metabolism or action that can also lead to rickets.
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So, 25-hydroxylase deficiency is where there's a mutation in 25-hydroxylase that inactivates it.
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And as a result, there's a similar presentation as vitamin D deficiency rickets,
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where there's low levels of calcidiol and calcitriol, which lead to hypocalcemia
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and hypophosphatemia, and the counter-regulatory hormones,
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alkaline phosphatase, which is that marker for bone turn number,
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is elevated, as well as parathyroid hormone levels become elevated.
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In 1-alpha-hydroxylase deficiency, the loss of function mutation is in 1-alpha-hydroxylase,
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the enzyme in the kidney.
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And this leads to markedly low levels of calcitriol.
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The 25-hydroxyvitamin D or calcidiol levels may be normal.
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And again we see the hypocalcemia
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and hypophosphatemia at much
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significant levels and markedly elevated
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alkaline phosphatase and PTH and
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this is because that active vitamin D is
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not able to reach its target organs and
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so these counter-regulatory pathways
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are ramped up and in
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vitamin d resistant rickets this is
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an end organ resistance due to vitamin to
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vitamin d due to receptor mutation and
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so the body feels that there's not adequate 125 hydroxy vitamin d and so this
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leads to hypocalcemia and hypophosphatemia when in reality the calcidriol levels
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are actually markedly elevated,
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but not able to interact with the target organs.
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And again, alkaline phosphatase and PTH respond by ramping up,
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and calcidriol levels again can be normal.
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Another unique feature of vitamin D resistant rickets is that there can be varying
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degrees of alopecia with the bony deformities characteristic of rickets. Thank you.
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In addition to calcipenic rickets, there are also phosphopenic rickets.
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In developed countries, dietary phosphate deficiency or impaired bioavailability is fairly rare.
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However, it is important to be aware of, particularly in preterm infants who
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can be at risk for phosphate deficiency due to their increased nutritional needs,
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especially when they're breastfed.
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And also if there are antacids being used, which can bind to phosphate and lead to hypophosphatemia.
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In terms of renal defects, there's Fanconi syndrome,
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which is a generalized reabsorptive defect in proximal convoluted tubule,
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which leads to loss of amino acids, glucose,
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phosphate in the urine leads to proteinuria and hypophosphatemia and metabolic acidosis.
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There's also hereditary hypophosphatemic rickets with hypercalcinuria,
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which is due to a defect in the sodium phosphate transporter.
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And this leads to an early onset hypophosphatemia due to renal wasting along with the rickets.
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And the unique findings are there are elevated 125 vitamin D levels and increased
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urinary calcium excretion.
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The other category of phosphopenic brickets are those that involve FG23,
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whether that's an increase in fibroblast
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growth factor 23 secretion or an impairment and its degradation.
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What is fibroblast growth factor 23?
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It's made by the bone and the
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way it interacts in this vitamin D
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calcium phosphate homeostasis pathway is that it feeds back to the kidney when
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there are adequate levels of calcium and phosphorus to slow down 1-alpha hydroxylase
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and the production of 1-alpha hydroxylase.
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5-dihydroxyvitamin D.
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It also interacts in the kidney at the level of phosphate absorption and excretion.
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And there are various forms of XGF-mediated hypophosphatemic rickets.
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There's X-linked hypophosphatemia, autosomal recessive hypophosphatemic rickets,
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which are both due to increased FGF-23 secretion.
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There's also autosomal dominant hypophosphatemics due to impaired degradation of FGF-23.
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And then more rare entities, such as tumor-induced osteomalacia,
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where there are tumors that produce excess FGF-23, and fibrous dysplasia,
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such as McCune-Albright,
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which is associated with increased
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FGF secretion via the activation of the protein kinase A pathways.
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I want to talk about XLH, or X-linked dominant hypophosphatemic rickets, for just a moment.
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It's one of the most common causes of inherited hypophosphatemic rickets,
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occurring in one per every 20,000 live births.
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This is due to a mutation in the gene called FEX, which is located on the X
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chromosome, and it's normally expressed in osteoblasts.
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And its role is in inactivating phosphatonins, like FGF23, that promote phosphate excretion.
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And so when there is a loss of function mutation in FACs, this leads to an increased
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secretion and activity of FGF23.
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And as a result, in the kidney, there's impaired phosphate absorption and increased
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phosphate excretion in the urine.
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As I mentioned, XGF23 also has a role in down-regulating calcintriol production.
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And so, we have these two paths due to decreased absorption of phosphate at
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the kidney level and decreased phosphate absorption from the gut due to low levels of calcintriol.
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Overall, there's low serum phosphate, and this impairs bone mineralization.
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Conventionally, treatment has included supplementation with phosphate,
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calcitriol, and vitamin D to counteract this increased FGF activity.
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In 2018, the FDA approved gurosumab, which is a fully human monoclonal IDG1
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antibody that neutralizes FGF23 for children one year and older.
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And the way it works is that it blocks the FGF23 signaling, and this leads to
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improvement in phosphate absorption in the kidneys and improved production of calcitriol.
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And because these two paths are restored, there's improved phosphate absorption
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and improved voluminarization.
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And this has been really exciting in terms of prognosis for XLH.
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I now want to switch gears a bit and talk about osteoporosis in childhood.
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And I want to take a minute to first review bone anatomy.
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So bone is divided into three anatomic regions.
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We have the diaphysis, or the shaft of the bone, the metathesis,
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which includes the epiphyseal or growth plate, and then the epiphysis,
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which is the rounded articular surface of the bone.
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And it's at this epiphyseal growth
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plate where there's cartilage which
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is the site of bone formation and allows for
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long bone growth in childhood at a
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macroscopic level we have two types of bone trabecular
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bone or or spongy bone and cortical bone which is the majority of our skeleton
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it's found in the shaft of our long bones and it's more dense and offers mechanical
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support Our trabecular bone is found at the ends of the long bones,
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our vertebrae and flat bones, and it's metabolically active in hematopoiesis.
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There are two main players in terms of our at a microscopic level,
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and those are our osteoblasts and our osteoclasts.
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And these two cells are involved in bone formation and resorption.
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So our osteoglasts help with forming bone, and our osteoclasts are involved
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in releasing bone mineral for our bodily use.
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And we need both of these processes to occur in balance to achieve normal bone
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mass and bone mineral density.
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And this process of remodeling and modeling is going on throughout our lifetime,
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and it allows our bone to grow and change.
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If there's an imbalance in this process where there's inadequate bone formation
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and increased bone resorption,
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then this can lead to impaired bone strength and bone fragility and risk for osteoporosis.
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There are many intrinsic and extrinsic factors that influence our bone health.
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Our peak bone mass is achieved in adulthood, and it is heavily influenced by genetics, 60 to 80%.
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However, that remaining 20-40% of our peak bone mass is impacted by nutrition
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and diet, which we've talked about extensively, physical activity,
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hormones and pubertal progression,
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steroids, and chronic disease.
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And it's important for us to be mindful of these modifiable factors because
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these are things that we can address with our patients on a regular basis in clinic.
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In terms of physical activity, bone adapts to mechanical load,
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and so when muscle pulls on bone, this strengthens our bone,
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which is why weight-bearing exercise is important.
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In terms of our hormonal milieu and pubertal progression,
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our growth factors and sex hormones play a major role in our peak bone mass
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accrual, which is why 50% is accrued in adolescence.
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Estrogen plays a role in osteoblast survival and osteoclast apoptosis,
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which promotes bone mass formation.
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And our androgens, like testosterone, stimulate bone formation on the outer surface of bone as well.
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And then, of course, our growth hormone and growth hormone factors are anabolic
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agents that are important in skeletal growth.
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In individuals who are on steroid therapy, this can impair bone health by impairing
31:32
osteoblast function and increasing osteoclast activity.
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It can also suppress growth factors and affects hormones which can impair linear growth and bone mass.
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And in chronic disease, there are many ways that bone health can be affected
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through the inflammatory processes that can promote osteoclast activity,
31:55
malabsorption, which can lead to nutritional deficiencies, and immobility,
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which can reduce mechanical loading.
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And of course, chronic disease can also impact endocrine function in terms of
32:08
growth hormones, sex hormones, and the thyroid axis.
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Bone does have this intrinsic ability to model and remodel.
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And this is what allows us to repair our bone throughout life.
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In terms of normal bone growth or accretion, 39% of our total bone mineral is
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acquired during the four years that surround our peak in bone accretion.
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And in girls, this is occurring between the ages of 10 to 14.
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And in boys, this typically occurs between the ages of 12 to 14.
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By four years following that peak, 95% of bone mass has been achieved.
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And this is one of the reasons why it's so important for us to consider pediatric
33:03
bone health in our patients to ensure that we're doing everything we can to
33:08
prevent low bone mineral density in our at-risk patients.
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There is, as you can see, a delay between peak growth velocity and peak bone
33:20
mass accrual both in boys and girls.
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And it's due to this that there's an increased fracture risk in this window
33:29
between 11.5 and 12.5 in girls and 13.5 and 14.5 in boys.
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And it's thought that this increased fracture rate in childhood is due to this
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lag between the peak growth velocity and peak bone mass accrual.
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And so just to emphasize, cortical density and structural strength does continue
33:55
to increase into the third decade.
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So even after this four-year window, there is continued bone mass accrual into the third decade.
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And so optimizing accrual during that growth period is essential to prevent
34:12
current and future fractures.
34:15
So childhood fractures are common, as I mentioned. We see tons of kids with
34:19
fractures, and it can be very challenging to know as a pediatrician which ones to worry about.
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About 50% of children have at least one fracture prior to adulthood,
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and the most frequent sight is the forearm, which accounts for 50% of all fractures.
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So how do we know when to be concerned? And again, it goes back to that history
34:41
and asking important questions.
34:44
So you want to ask about fracture characteristics, the location of the fractures.
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Were they in the long bones or in the vertebrae? What was the mechanism of injury?
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Was it falling from a cliff or was it simply from climbing a flight of stairs.
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You want to ask about any unusual features, whether or not the healing process was impaired.
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And you also want to assess for clinical findings suggestive of an underlying
35:22
bone fragility disorder.
35:25
So looking for discoloration of the sclera, skeletal deformities,
35:32
dental appearance, any limb abnormalities.
35:39
Joint or skin laxity, and chest wall deformities,
35:45
and asking about family history, whether there were any early fractures,
35:51
frequent fractures, or known diagnosis of bone disorders in close relatives.
35:57
So what is osteoporosis? How do we define it?
36:00
It's characterized by low bone mineral density and impaired microarchitecture,
36:06
which leads to decreased bone strength and fragility fractures.
36:11
And it's being increasingly recognized, particularly in children with genetic
36:15
disorders causing bone fragility and in those with chronic illness.
36:20
And the way that we measure bone mineral density is through a DEXA scan, which looks like this.
36:27
So DEXA, or dual energy x-ray ulcer optometry, is the preferred method,
36:32
as I mentioned, for assessing aerial bone mineral density.
36:36
It's reproducible, inexpensive, and low radiation exposure.
36:42
However, it is important that the technicians are trained to work with children
36:47
and that comparisons of images over time are conducted on the same machine,
36:53
ideally with the same technician, and with pediatric software that has normative data for comparison.
37:01
The preferred sites for DEXA measurements are the lumbar spine and total body less head.
37:08
And in children who may not be able to be assessed at these sites,
37:14
the distal forearm, foxal hip, and lateral distal femur can be used.
37:20
And this is usually in the case where they might have hardware or reduced weight
37:26
bearing or are non-ambulatory.
37:29
The DEXA scan generates bone mineral density raw scores that are then converted
37:36
to age and sex-matched Z-scores.
37:39
And there are additional comparisons that can be made by race and ethnicity.
37:43
However, this is a limitation because the only reported race and ethnicity options
37:50
are white, black, and Hispanic.
37:52
And those clearly don't represent the depth of any person's identity.
37:59
Bone age is something that can be used in children who might have delayed or
38:06
advanced puberty to adjust for the age-adjusted disease scores.
38:11
So, for example, if there's a child who's chronologically 15 years of age,
38:17
but may have delayed puberty, and their bone age is close to that of a 12-year-old,
38:25
you would want to use their bone age for the age-adjusted Z-scores.
38:31
Similarly, the DEXA scan, because it's a 2D image of a 3D object,
38:37
has potential for calculation error in individuals who are taller or shorter for their age.
38:45
And so in individuals who are short, their bone mineral density may be falsely
38:51
low because they have smaller bones.
38:53
And taller individuals may have falsely elevated bone mineral density due to having larger bones.
39:01
And so adjusting for height is also important.
39:03
And the Children's Hospital of Pennsylvania has an excellent calculator that
39:08
can help with this if the software doesn't have it already built in.
39:14
This is just an example of a DEXA scan report.
39:18
On the left, you can see the total body left head where it is showing the parts
39:26
of the full body minus the skull is being assessed.
39:31
And the reason for that is because the skull is not considered a major osteoporotic
39:38
site, so it's excluded from the scan. and then age-matched percentiles and Z-scores are generated.
39:45
And the same for the lumbar spine. You can see that the area that is being scanned
39:51
as well as the age-matched percentiles and Z-scores.
39:55
In terms of diagnostic criteria for osteoporosis.
40:00
It's defined as having either one or more vertebral fractures or the presence
40:05
of a clinically significant fracture history and bone mineral density Z-score of less than minus two.
40:12
What is a clinically significant fracture history?
40:16
Having either having two or more long low trauma fractures by age 10 or three
40:23
or more low trauma long fractures by age 19.
40:28
It's important to note, however, that having a bone mineral density Z-score
40:33
that's above minus two does not preclude the possibility of skeletal fragility
40:39
or increased fracture risk.
40:41
And this is important to remember in patients who have bone fragility due to
40:47
an underlying disorder.
40:48
For example, patients who might have leukemia or chronic kidney disease or neuromuscular
40:55
disorders, and of course, osteogenesis imperfecta.
41:00
Where their bone marrow density score may be normal, but we know that they are
41:05
at an increased risk of sustaining fractures.
41:08
So what is low trauma fracture?
41:11
There are various definitions which create a bit of a challenge in terms of diagnosis.
41:17
One is fractures occurring outside motor vehicle accidents or falling from 10 feet or less.
41:24
Now 10 feet is quite a high height, And so this can create a bit of a gray zone
41:32
in terms of moderate and mild trauma.
41:36
With respect to falls in high-risk chronic illness setting, a more conservative
41:41
definition has been used of falling from a standing height or less at no more than walking speed.
41:48
And again, as I've mentioned, there are limitations to diagnosing osteoporosis
41:56
in addition to the challenge of defining low energy trauma,
42:01
the diagnostic criteria can also lead to under diagnosis.
42:05
The question arises of do we wait for two or three fractures if that first long
42:14
bone fracture was significant.
42:17
Also with the bone marrow density Z-scores, they can vary depending on the reference
42:23
database that was used to generate the Z-scores.
42:26
And so this can create challenge in terms of assessing the bone mineral density as well.
42:34
If that individual, for example, was not able to obtain the scan in the same machine.
42:42
So we've talked about osteoporosis. We've defined it.
42:46
We've reviewed the role of DEXA scans. How do we approach this clinically?
42:51
If we have a patient coming into our practice with fractures.
42:55
And so this is a summary slide. We've talked about rickets, but that first step
43:01
is to perform an evaluation for a biochemical assessment so that you can roll out rickets.
43:10
And it involves getting a good history and exam and laboratory testing.
43:18
And I want to make a note here that it's also important during this process
43:23
to consider non-occidental trauma on the differential because these conditions
43:30
are critical to ensure that appropriate intervention is provided.
43:36
They're not related with an underlying bone issue, and so the treatment is going
43:44
to be very different from osteoporosis.
43:46
So if you see a child who's not ambulatory or if there are delays in care or
43:53
unexplained bruising with fractures and various stages of healing or an unclear
44:00
mechanism of history of injury,
44:03
it's very important to involve our child abuse specialist to undergo the proper evaluation.
44:11
And so that leads to imaging consideration.
44:14
So getting a skeletal survey to assess for fractures.
44:19
In terms of bone fragility, this can also help identify skeletal deformities,
44:25
for example, like wormian bones, which are those extra skull bones that can
44:31
be seen in osteogenesis imperfecta.
44:34
You also want to think about getting lateral spine and radiographs to look for vertebral fractures.
44:41
And then we've talked about getting DEXA scans when we're concerned about one mineral density.
44:48
The next step is to determine whether there's a primary or a secondary cause of osteoporosis.
44:55
So again, this is where we look for features, the osteogenesis imperfecta,
45:02
such as blue blaze sclera, skin laxity, long bone deformities.
45:08
Chest wall deformities, and if there's a family history, that's suggested as well.
45:14
The majority of childhood osteoporosis, however, is going to fall under secondary
45:20
osteoporosis. And each one of these could really be a lecture in and of itself.
45:25
But some things to highlight, many of our patients will fall under overlapping
45:31
categories. For example, those with chronic disease who are also on long-term steroid therapy.
45:39
In the endocrine category, Adley discussed the role of growth hormone in terms
45:45
of osteoblast activity, our sex hormones in terms of osteoblast activity.
45:51
As well, and the parathyroid gland in modulating osteoblasts and osteoclastic activity.
45:59
Any impairments in these processes can affect bone fragility,
46:04
as well as thyroid dysfunction,
46:07
type 1 diabetes, and Cushing syndrome, which all lead to increased osteoclastic
46:13
activity and bone resorption.
46:18
The next step is to evaluate for spontaneous recovery,
46:21
so deciding whether or not aggressive medical intervention is needed or if the
46:30
patient has the potential to recover without more aggressive medical therapy.
46:35
And so individuals who might have less potential would be those who are on prolonged
46:41
steroid therapy of more than three months,
46:45
chronic impaired mobility, or an underlying disease that's poorly controlled
46:50
or due to a genetic condition.
46:52
Older age, because there's less growth potential, and having higher severity
46:59
vertebral fractures creates a risk for less potential for spontaneous recovery.
47:06
Conversely, being on short-term steroid therapy,
47:10
having short-term immobilization, and well-controlled underlying disease bode
47:15
for more potential as well as younger age and lower severity of vertebral fractures.
47:23
Now, I want to make a point about spontaneous recovery.
47:27
It's not this magical recovery that just happens. there are still supportive
47:34
measures that need to be put into place to assure that the patient recovers from the fracture.
47:41
So this includes prescribing calcium supplementation, vitamin supplementation,
47:47
and as ABLE, recommending physical therapy to help in the healing process.
47:53
And so in terms of drug therapy and osteoporosis, the sposphonates are the mainstay of therapy.
48:03
And the way that bisphosphonates work is that they impair osteoclast activity.
48:10
They deposit at the bone matrix and then are ingested by the osteoclast which
48:15
leads to impaired activity and apoptosis.
48:19
And there are two forms of IV bisphosphonates, a pomidronate and zoledronic
48:24
acid and it's been shown that the IV formulations are superior to oral in terms of bioavailability.
48:31
Important considerations in terms of preparing for infusion include making sure that eucalcemia.
48:43
Normal ranges of phosphate and vitamin D are achieved prior to the infusion.
48:50
During and after the infusion, there is risk, particularly with the first infusion,
48:56
of having flu-like symptoms and of precipitating hypocalcemia and hypophosphatemia.
49:02
So it's important to monitor calcium and phosphorus levels very closely after the infusion.
49:09
Additionally, in patients who might beyond chronic steroid therapy,
49:14
the infusion can precipitate an adrenal crisis type picture.
49:18
And so it's important to have these patients on stress dosing,
49:22
not only prior to the infusion, but to continue for the 24-48 hours after the infusion as well.
49:32
Just to quickly highlight There are two IV formulations. I won't go into all
49:37
the details, but the dosing varies by age as well as the frequency.
49:43
It's more frequent in the younger age because there's more bone turnover.
49:48
And the same for zoologonic acid. This zoologonic acid is more frequently used
49:53
in clinical care because of the ease of less frequent dosing intervals and the
49:59
shorter infusion time compared to primidronate.
50:02
And the dose varies by age as well as the intervals.
50:07
There are some rare side effects that have been reported.
50:11
Iriditis anecdotally, so it's important to have children who might have any
50:16
eye issues undergo ophthalmologic evaluation.
50:21
Atypical femoral fractures have been reported with the studies being more in the adult population,
50:27
and so it might not be drug-related in the pediatric population and is not necessarily
50:34
an indication for treatment cessation.
50:36
It's been shown to be a risk in adults with prolonged bisphosphonate therapy
50:42
of greater than five years.
50:46
And then osteonecrosis of the jaw, there aren't any published reports occurring in childhood.
50:53
However, it is important to emphasize routine dental care and to intervene if necessary.
51:02
And then in childbearing individuals, it's important to counsel on the importance
51:08
of avoiding pregnancy for at least 12 months after therapy.
51:12
And this is because bisphosphonates have a really long half-life of 10 years or more.
51:19
And so the risk for fetal development is not clearly understood,
51:25
and so it's important to counsel.
51:27
In terms of dose adjustments and duration, the duration of therapy in children
51:33
is not well-defined, but it's tailored to the individual patient's response
51:39
and their clinical condition.
51:42
So generally, treatment is continued until there's significant bone mineral
51:46
density improvement or until the patient reaches skeletal maturity.
51:52
So you start at osteoporosis stabilization doses, and then you titrate to achieve
51:59
normal bone mineral density Z-scores.
52:01
And if there are no new fractures, if there's evidence of improved bone mineral
52:07
density, improve functional mobility, then there is the option of reducing to maintenance therapy,
52:14
which includes reducing the frequency or the dose of infusions,
52:19
while continuing to ensure that there are abdominal density improvements and fracture prevention.
52:26
In individuals who might have transient conditions that have led to osteoporosis, for example,
52:33
patients who have leukemia, who are on cyclic glucocorticoids,
52:39
but may now be in remission and have improved bone mineral density and no new fractures,
52:47
consideration of discontinuing therapy is an option, usually after six to 12 months.
52:53
And in those who have permanent or persistent risk factors, like patients with
52:59
OI or chronic illnesses,
53:01
then you want to consider lowering to maintenance dosing if they're stable and
53:10
continuing until final height is achieved.
53:13
It's been shown that with fracture holidays where there's intermittent dysphosphonidate infusions,
53:20
this can lead to reoccurrence of fractures because of the juxtaposition of bisphosphatidated bone,
53:33
with new bone that's bisphosphatidate naive and weaker.
53:38
And this creates a site for fractures to occur.
53:43
And so, in conclusion, bone health is an essential consideration in pediatric care.
53:48
Optimizing bone mass accrual in the pediatric years is crucial in optimizing adult bone health.
53:56
And this is something that we all play a role in.
54:00
A thorough history and exam can often lead to the diagnosis of rickets and osteoporosis
54:06
with the goal of early identification and initiation of therapy to optimize functional outcomes.
54:14
And with that, I thank you all for listening, and I'm happy to take any questions.
54:19
Thank you, Dr. Pera, for that excellent presentation on bone health in children.
54:24
Let's see. Dr. Williams, you have a question? I have a statement,
54:29
but first I want to say thank you for that outstanding presentation.
54:33
It really warms the cockles of my heart because everybody,
54:38
my colleagues and house staff who have worked with me, know that I'm constantly
54:44
speaking about the 1,300 milligrams of calcium that adolescents need and are not getting.
54:52
I think that you're under what I've seen, a historic trend of dairy being.
55:03
And even other quality foods, although nobody's eating six cups of broccoli
55:09
a day or eating six cups of cheese a day and living to tell about it.
55:18
Anyway, that you're under this historic trend of dairy being replaced by sodas
55:26
and juice beverages that don't contribute at all.
55:30
As a matter of fact, they can be a detriment to calcium deposition.
55:34
And the other thing that I see more recently is somehow dairy,
55:40
milk, we'll say, but it's dairy type substance, a liquid, is getting a bad rap.
55:47
And someone is teaching our house staff to limit milk to one cup a day.
55:52
And I think that's really wrong. It is true that you can drink too much of a milk-type substance,
56:00
even formula, but there's nothing wrong with getting that extra two cups,
56:06
let's say, or possibly even three at times.
56:08
There's 200 milligrams, as you said, of calcium in there, and it's really,
56:13
really hard to get the 1,300 milligrams.
56:16
So what I recommend religiously is that all girls at adolescence,
56:23
if they can hopefully swallow a pill by age 10, which is where adolescence starts for me,
56:29
take a women's vitamin because a women's vitamin has a five to 600,
56:34
usually pretty religiously 600, which is the limit you can absorb at one time of calcium daily.
56:41
Now it's not that I don't like guys. So the boys and also girls who don't want
56:45
to do that can take Tums, which are generally doable, but you have to educate
56:51
them about turning the bottle around and how much they're going to get, right?
56:55
Because that's only going to be 400 or possibly 600, usually not, maybe less.
57:00
So anyway, I just want to say that.
57:04
You know, on your bandwagon. And I think it's critically important to educate
57:09
the adolescent and the family about calcium intake and to do it in a way that they can,
57:17
it's compatible with them and also affordable.
57:21
They don't need a fancy women's vitamin or fancy Tums.
57:25
They can buy the generic brand at H-E-B, Walmart, whatever, and it's really
57:30
affordable. So just want to say, Thank you so much.
57:34
Yes, thank you. Those are all excellent points. I agree.
57:37
I think it's so challenging to achieve that dietary amount of calcium and vitamin D.
57:44
And so I really like your approach. I think that's great.
57:49
Thank you. Thank you, Dr. Lynch. Dr. Lynch, go ahead and ask your question.
57:54
Oh, I just want to say that was absolutely fantastic. And as you know,
57:58
as those of you on the wards know, we've been struggling with a tough case of
58:03
bone disease. And so I learned some good things.
58:07
I'm just going to do a shout out for an article that came out in January through
58:11
the AAP that somehow got buried as an e-article, which is a shame because it was so good.
58:17
And I put it in the chat.
58:20
It's on evaluating factors in young children.
58:23
And we do often get endocrine consults and you need to have a really good history
58:31
and work up for that because when those cases end up in court,
58:36
the child abuse team is super appreciative if you've shown that there wasn't
58:41
an underlying reason for those fractures.
58:43
And this just walks you through it if you want to pull that up and put that in your resources.
58:48
Thank you. Don't forget to click on the link in this podcast for free credit.
58:53
That may include CME, MOC, or ethics credits.
58:56
Music.