PTH - how do I find the right balance?

Hi Dr. Agar,

My nephrologist and I have struggled to keep my PTH within normal limits. However, we have had only limited, short term success. We have been juggling with the Calcium level in the dialysate, Calcitriol and Cinacalcet to try and keep this under control. For a few months, things seem to be under control and then suddenly, the PTH either shoots up or plummets!

For the last couple of months, it was stable around 150 pg/ml (normal in the lab is 15 to 68 pg/ml) and I was using a 2.5 mEq/l Calcium bath and was on calcitriol 0.25 mcg alternate day and cinacalcet 30 mg alternate day. However a few days back, I noticed that I was having a little bone pain in my back and got a PTH test done and it was 30 pg/ml which I believe is low for dialysis patients.

I wanted to get your thoughts on this. Do dialysis patients generally have fluctuating PTHs? Is there anything else that can be done to control it?

Thanks so much!


Dear Kamal

Calcium, phosphate and PTH control and balance is, I think, the most difficult biochemical area for any dialysis patient … and for their physician! It is also the area we seem to have most trouble with and know the least about. There are a variety of opinions (and a significant pile of conflicting evidence too) about what exactly IS the right thing to do and the right balance to strike. One of the problems is that the blood tests that measure all this stuff are poor mirrors to the target organ = bone.

While the best way to understand and target bone-modifying therapy is almost certainly via bone-monitoring with serial bone biopsies, have you ever had a bone biopsy? Probably not! Most dialysis patients haven’t … and won’t. Why? … well, I can think of few tests less pleasant to have and as most who have had one biopsy politely reuse another, serial studies to gather the kind of data we really need to know if we are to be certain of exactly what the hell we are doing, are just not there.

So … we test secondary markers like Ca++ (total adjusted or ionized - and there are supporters of and arguments for both), PTH (and again there are those who support and argue the merits of the various ways to do this: intact molecule, mid-molecule, n-terminal, c-terminal etc), phosphate and alkaline phosphatase (bone-originating as opposed to liver-generated) … and at the end of the day, try to make sense of it all!

Normal bone renews itself constantly through a process of bone re(ab)sorption and new bone production.

Bone resorption is dependent on cells at the growth edge of bone called osteoclasts … I imagine them as like little Pac-Men that nibble away at old ‘dead’ bone and, in the process, liberate bone calcium into the circulation.

On the other hand, new bone growth is orchestrated by a different population of cells - cells that make new bone - called osteoblasts, which lay down new healthy layers of fresh bone to replace that which has been resorbed.

Healthy bone requires a balance between these two factors. This balance of removal and renewal is known as ‘bone turnover’. New for old. New for old.

In the broadest of terms, over-active bone with high turnover is seen at high levels of PTH … where it’s all going too fast. If you like, it’s like bone destruction and production in fast forward, the new bone being destroyed almost as fast as it can be made and with little time for any strength and solidity to result from the production of mature bone. PTH drives this frenetic process and the higher the PTH, the more frenetic is the turnover and the less stable mature bone gets formed and stablised. We call that state hyperparathyroidism - where high levels of PTH are resulting in lots of hyperactive but immature and ‘soft’ bone.

At the other end of the spectrum of bone function is bone that has stopped turning over at all … a state called adynamic bone - or adynamic bone disease, though it is not truly a ‘disease’ but rather a ‘state’. This is where there is little or no PTH production and all bone metabolism kind of grinds to a halt. Here, there is lots of old and rather brittle but essentially ‘dead’ bone, doing nothing much at all.

At both ends of this spectrum, bone is ‘unwell’ … it is either brittle and breakable, or soft, bendable and painful.

Somewhere in the middle is nice … the sweet spot, where there is not too much PTH, but enough … not too much turnover, but enough.

The best way to assess the ‘state’ of bone is under the microscope … but I have been there already, haven’t I, when I talked about bone biopsy … and most patients won’t have a bar of it. Nor do I blame them, tough the lack of bone studies hampers our real understanding of this most difficult or areas.

So, instead, we use blood levels of calcium and PTH and more ‘researchy stuff’ like osteopontin and other more esoteric bone enzymes and receptors … but these are simply NOT GOOD MARKERS. They are very blunt tools indeed.

Even more importantly … and perhaps in the context of your question, most importantly of all … there is a significant issue with ‘lag time’.

Bone, like Rome, is not built in a day, but blood calcium, and PTH levels etc. can change rapidly. This means that as the things we are measure in the blood (Ca++, PTH, PO4) and that we are using to try and interpret what is happening in the bones may be changing quite quickly in one direction, the bone itself (the bit that matters) may still going tortoise-like in the opposite direction. We use medication (or dialysis) to change the Ca++ level or the PTH, and zam … the blood levels turn around and head in the opposite direction. Meanwhile, the bone itself, like the Titanic, keeps on and on, for ages in the opposite direction till it finally turns round. But, by this time, we may have changed the medication yet again … always trying to head back towards the middle ground.

To make matters more difficult still, bone itself becomes less ‘responsive’ to (or, if you like, more resistant to) any given level of PTH as kidney function falls and/or a patient starts on dialysis. Further - and as a rule - the longer the period of renal dysfunction has been, the less responsive the bone becomes. This results in a higher ‘level’ of PTH being needed to get the same amount of ‘kick’ out of the bone. This is why you will often hear of levels of 2-3 times normal being ‘the ideal target level’ in advanced CKD or dialysis patients … they simply need more PTH to get the same bone bang for its buck … but … and it gets even messier here … even 2-3 times the ‘normal’ level of PTH may be insufficient in some patients. The ‘normal’ PTH for any given patient (= that level of PTH at which a normal bone response occurs) may be up to 4, 5, 6 or even 7 times the upper limits of the laboratory normal. And the problem is, no-one can really tell … not you, not us.

As you can see, it really gets hard to know what the hell we should do for any given patient … short of serial bone samples … and there aren’t many who will permit that!

Because of all this - and magnified by the ‘lag time’ problem - we are often left chasing our tails up and down the slippery slope from adynamia to over-activity and back, adding and subtracting medication as we always try to head back towards the mid-point … though even that mid-point is a moving feast and may change with dialysis vintage = time (years) on dialysis.

As for treatment, cinacalcet turns down bone activity by switching off PTH production … it will slide you towards adynamia … as does calcitriol, while a high phosphate will push the PTH higher as it binds calcium as calcium phosphate, lowers the calcium level and promotes PTH production.

Oh, Kamal, it is so very complicated … and to get it right is often more by good luck than smart management!

Patients (and doctors) get so (a) confused and (b) upset that it is natural to ask the question: “hey, does the doctor know what he’s doing” … as the medications chase their tails up and down the seesaw.

That chase is as much to do with the lag time problem as anything, and … as blood changes rapidly and bone is bone and take ages to reverse (in either direction), I can’t see the confusion lessening any time soon.

The best I can say is …

Don’t give up the battle.

Don’t be put off by the back and forth chase - it will always be that way, by the very nature of the disconnect between the speed of the changes in blood and the tortoise-like speed of change that governs bone metabolism.

I am not sure if that answers your question, but I hope it makes it a bit clearer.

Keep up the battle … and stick by your nephrologist … but remember: he is suffering as much frustration with this as you.

Thanks so much Dr. Agar for that lucid, detailed explanation. It is heartening to know that we on the right track, if you can call it that!

One more question - how often do you check the PTH levels in your patients who have problems with their PTH?

At a pinch, we might do them at each of our routine 6 weekly bloods till we have a feel, but usually not more than 3rd monthly.

Sure Dr. Agar, thanks! I think I have been checking too frequently (monthly). Maybe I need to wait and watch after making any change to see the long term effect it is having.