Alkaline phosphatase (abbreviated to ALP or Alk Phos) is an important lab result for the chronic hypophosphatemia community, but you don’t see it discussed much, at least outside of the more advanced meetings of bone-metabolism specialists. It’s worth getting to know the basics though, so you can spot concerning lab results or you can reassure your primary care provider that results that may look concerning are in fact normal for you (or your child).
Alkaline phosphatase is a group of enzymes that, in the XLH context, serves as a biomarker for when things are going wrong with bones. (One set of the enzymes is primarily a biomarker for liver disease, but the relevant set for us is bone-related, and there’s a separate, more advanced/complicated test that can confirm which type of ALP is elevated, but you don’t see it often.) ALP levels are high in untreated XLH patients, and low in the very different but similar-sounding condition, hypophosphatasia (HPP).
Unfortunately, much like the state of FGF23 knowledge, ALP isn’t well understood, other than the correlation with certain bone (or liver) conditions. According to the Cleveland Clinic, “Even though researchers know the function of several other types of enzymes and have studied alkaline phosphatase for decades, they don’t yet know the exact function of ALP. However, researchers believe it’s important for multiple different processes.”
For more advanced information about ALP, check out this NIH overview. One interesting tidbit that I didn’t know before: ALP tends to be higher in kids and seniors. It makes sense though, since it’s a biomarker for bone mineral turnover, and kids’ bones are growing, while seniors’ bones are un-growing (losing minerals). So make sure your lab is using age-appropriate “normal” ranges when reviewing the results.
Much of the NIH article is about liver-related issues, but for bone issues, it notes, “Elevated bone ALP levels can be observed in cases of bone metastasis, Paget disease, osteogenic sarcoma, healing fractures, hyperparathyroidism, hyperthyroidism, and osteomalacia.” XLH is included in that list only indirectly, via osteomalacia and hyperparathyroidism. The reference to fractures would explain why our already-elevated ALP might occasionally be even higher than usual. Given how often XLHers have fractures we don’t know about, a sudden blip in the ALP might signal the existence of one of those fractures, which can then be confirmed by x-ray if you can pinpoint a possible location.
I took a look at the journal articles reporting on the phase 3 clinical trials for burosumab for info about ALP (but remember I’m a patient, not a doctor), and it looks like, at least in kids, it took two years or more for the ALP to hit the Upper Level of Normal (ULN). There’s a big drop in the first year or so, then a slower, gradual decrease over a long period of time. This ongoing, gradual improvement is more evidence supporting the need for long-term treatment, since it confirms that it takes a long time for bone mineralization to fully stabilize. It would be useful to have similar data from patients who had to stop burosumab for unrelated reasons (as in the recent heartbreaking journal article where patients were forced to stop treatment due to government regulations), to see how long it took for the ALP to rise to pre-treatment levels again.
“Safety and Efficacy of Burosumab in Pediatric Patients With X-Linked Hypophosphatemia: A Phase 3/4 Open-Label Trial” reviewed 88 weeks of data. It shows a big drop in ALP by week 64, and then a slower drop to close to the ULN by week 88. Only about half of the patients were actually within the ULN.
A longer period (124 weeks) is covered in “Safety and Efficacy of Burosumab in Pediatric Patients With X-Linked Hypophosphatemia: A Phase 3/4 Open-Label Trial.” The same pattern held, with a big drop in the first year, and then patients generally reached ULN (or close to it) by a few months before the end.
An even longer period (160 weeks) is reviewed in “Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia.” The ALP was still dropping a little between week 112 and the end of the study. It’s interesting to note though that only about three-quarters of the patients fully reached the ULN at the end, more than three years since the start of treatment.
I couldn’t find a similar open-access article for adults, so I can’t say for sure that the same pattern applies to us, but my own improvement in ALP, without ever quite reaching the ULN, is consistent with the pediatric pattern.
As an aside, there is an article with some ALP data for TIO patients, but they used a slightly different measurement (bone-specific ALP) that I don’t understand, so I can’t comment on it. If you want to check it out, the article is “TIO: Interim Analysis of a Phase 2 Open Label Trial Assessing Burosumab Efficacy and Safety in Patients With Tumor Induced Osteomalacia.
So, with all of that in mind, I thought it might be interesting to take a look at my ALP test results over the course of the almost-ten years since starting burosumab. I started the trial in January 2016, but did not start burosumab until six months later, and have been on it consistently since then. The normal range for ALP from my lab is (using really rough numbers) about 50 to 100 U/L (or maybe that’s a percentage of ULN; I’m not sure, a consequence of my being just a patient, not a doctor!).
My pre-burosumab numbers (again, rounded to easy-to-remember numbers) were in the 150-170 range, well above normal. I’d broken my arm three months before the study began, so that could have been the cause of the elevation. In the first six months on burosumab, the ALP levels rose to about 200 (twice the upper normal). Over the next 18 months, the levels dropped gradually to about 120-140 (still above normal, but better than before I started). There’s a gap in data, but by year seven, the levels were hovering on either side of the upper limit of normal, between about 90 and just slightly above 100.
This is just one patient’s experience, of course, but it tracks what I would expect to happen, and seems like a good indicator of the patient experience. At first, the ALP gets worse, but it’s a good sign, even if the patient may feel worse in this timeframe. Bone change (which ALP is a biomarker for) can be good, not just bad, and in this case the bone is changing for a good reason, getting stronger. It’s “growing” in a sense (in terms of mineralization, not size), so you’d expect the ALP levels to be higher, just like in kids. Then, the levels stabilize, which, to my non-scientist mind, indicates that the bones have been stuffed with as much phosphorus as they need, so the turnover settles into a maintenance level.
What I find particularly interesting though is that my levels (and those of some of the patients in the journal articles) never quite dip consistently into the normal range. That suggests to me that there’s still something less-than-ideal going on with my bones. If so, it’s consistent with a number of other indications that the FGF23 excess, while the main cause of XLH, is not actually the whole story, and something else is also happening with our bone metabolism. It’s important to remember that there may be another factor while working on research toward a comprehensive cure, which may need to address something beyond just blocking FGF23.
I also wonder about interactions between excessive parathyroid activity (an issue for us) and ALP. A recent-ish test I did (spring of last year, which was year nine of treatment) was elevated again, perhaps because my parathyroids have been increasingly overactive in the last two or three years, and the NIH article linked above mentioned that hyperparathyroidism can elevate ALP levels. I expect to repeat the labs soon, so I’ll be looking to see if my parathyroids have settled down, and if so, whether the ALP has also dropped.
I’d love to hear about your experience with ALP levels over time. And I’m also shouting out to researchers studying ALP in general—consider looking into ALP in the XLH, HPP, and TIO communities! I bet we have a lot of useful data for you!
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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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