I intended to talk about Rare Disease Day (Feb. 28), but that can wait, and I’m too excited about a new journal article to wait to share it with you. I highly recommend that you read it and share it with anyone you think might be interested.
The article is “Potential influences on optimizing long-term musculoskeletal health in children and adolescents with X-linked hypophosphatemia,” published in January by the Orphanet Journal of Rare Disease.
Journal titles tend to be dense, and at first I thought this was just another article on pediatric treatment. Which it is, in part, but it’s so much more. What’s groundbreaking (from a patient perspective) is: 1) the focus on muscle function, and 2) the discussion of what is likely to happen when pediatric/adolescent treatment is terminated.
The whole article is simply excellent on so many levels. First, it gets the nomenclature right: XLH is a phosphate-wasting disorder (rickets is just a single symptom that doesn’t apply to approximately three-quarters of an average patient’s life). Second, it acknowledges both the whole-body (more than just bones) and whole-life (more than pediatric) nature of symptoms. And finally, it explicitly considers what happens to adults when their pediatric treatment ends. It should go without saying that the science is solid too (as best a non-scientist can tell), laying the groundwork that establishes the authors really know what they’re writing about.
I’m going to skip over the bulk of the article (which provides solid information on how and why kids and adolescents should be diagnosed and treated as soon as possible and with an eye to a whole range of symptoms) to the reasons why I think everyone in the XLH (and autosomal) community should read it.
After so many articles almost exclusively about XLH bones, it’s refreshing to see some consideration of the importance of our muscle function, which, in my experience, can cause more disability in adults than bone issues. I love that authors include not just expertise in the usual subjects (pediatrics, epidemiology, bones, and joints), but also in muscle biology! I love the new vocabulary and understanding I have from the article about how bone mineralization affects muscle function and vice versa (“bone-muscle cross-talk”), which isn’t something I’ve seen to any significant degree in journal articles about XLH before.
There have been references to muscle issues in prior publications (referenced in the article’s footnotes), but this article brings them all together and considers the consequences to the patient. They say outright what common sense suggests: “many patients may have muscle function defects, such as muscle weakness, that may be related to insufficient quantities of adenosine triphosphate due to chronic hypophosphatemia.” (If you don’t recall your high school biology, adenosine triphosphate = ATP = source of energy for all living cells.) And they lay out how, as I understand it, bone-muscle cross-talk means that XLHers can experience a vicious cycle of deteriorating muscle function: weak muscles (from the ATP issue) contribute to bone weakness (beyond the poor mineralization), and bone weakness can contribute to muscle weakness (apart from the ATP issue), so there’s a feedback loop, resulting in a worsening of both bone and muscle.
This article is so good in its review of pediatric/adolescent treatment, that I would have recommended it even if they’d stopped at the end of that section. We have all probably seen, either in the XLH or in general medicine, the virtual barrier between pediatric specialists and adult specialists, that it’s almost as if they’re working on different disorders and never talk to each other. (It’s part of the challenge for improving transition of care for XLHers from pediatric endocrinology to a specialist who treats adults). So I would have understood if the article had ended after laying out the importance of good pediatric/adolescent treatment. But unlike most authors, this group went on to consider what is actually happening to too many patients: their treatment is terminated as soon as their growth plates close (or sometimes a bit later, after peak bone mass is achieved a few years later).
The authors conclude, in scientific language, what patients have known for years (decades even) in the context of phosphate treatment: that there’s a “window of improved skeletal health and life quality in adulthood,” but “increasing poor skeletal mineralization, osteomalacia, and the impact on muscle function will lead to a return of clinical manifestations.”
I saw that exact pattern almost twenty years ago, when I managed the subscriptions for the XLH Network’s listserv. Very few patients joined in their early twenties, but quite a few joined in their late twenties and early thirties, and then they all had essentially the same reason for joining: they had phosphate supplements as kids, felt okay when the treatment was terminated after the growth plates closed, but gradually the bone pain increased, along with osteoarthritis and the beginning of enthesopathy, until it became unbearable and they sought out the emotional support that other patients could give them.
There hasn’t been enough time yet to see that pattern repeat with burosumab (no kids have been on it for more than about five or six years, and most have been on it for much less than that, nowhere near an entire childhood), but in theory, there’s no reason to think the pattern will be any different in terms of symptoms eventually returning. We need phosphorus for our entire lives, not just during bone formation.
But I do think there are two possible changes to the timing of the return of symptoms, based on the evidence that burosumab patients’ bones will be better mineralized on reaching adulthood, and it is also better at reducing bone pain, so pediatric patients will not have as much experience with that kind of pain. As a result, on the positive side, it’s possible that the better initial mineralization might lengthen the window of improved health, delaying the return of pain, muscle weakness, etc. sufficient for the patient to seek out treatment again. And that seems to be what some insurers/agencies are counting on.
There’s another possibility though, which is why I think will actually happen, and it has to do with patients on burosumab not having experienced as much fatigue or bone pain as patients have experienced historically. I think the pain and fatigue will manifest almost immediately after stopping burosumab, and, not having lived with these symptoms in the past, they’ll be less likely to suffer in silence before seeking out help. Kids who have been on burosumab even for the last few years of their childhood are likely to notice the returning bone pain much faster, judging by how adults on burosumab have reported noticing almost immediately the return of pain and fatigue if a dose is late or even in the days immediately before the next dose is due. It comes back to my favorite take-away from the Symposium on Hypophosphatamia: that patients often don’t know how bad they feel until they start to feel better. But once we know what “normal” feels like, we’re less likely to suffer in silence. I think pediatric patients coming off burosumab will notice right away that they’re suffering, and will be demanding treatment, not waiting for the symptoms to become extreme and irreversible.
In any event, this article has a great deal of thought-provoking material, for the medical community. None of it is particularly surprising for patients (although I love the concept of bone-muscle cross-talk, which I hadn’t considered before). But as we’ve seen in the past, it’s not enough for patients to know and talk about our issues; the medical community will only listen when the information comes from other, appropriately qualified members of the medical community. That’s why it’s so exciting to see these issues in a journal article written by qualified members of the medical community. While the conclusions seem self-evident to us, they needed to be laid out in the right format, by qualified experts: XLHers still need phosphorus as adults, or else we’re at elevated risk of muscle weakness and fatigue, osteoarthritis, enthesopathy and renewed softening of our bones with additional/new bowing of lower limbs.
Seriously. Here’s the link again. Read it! Share it! Tell your clinicians about it! Send flowers and chocolate to the authors. (Just kidding about that last one, although I have reached out to the authors to let them know how great I think the article is. I’ll update if I hear back from them.)
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Please note that the author is a well-read patient, not a doctor, and is not offering medical or legal advice.
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