From Medscape Nephrology

Expert Interview - Bone Metabolism and Chronic Kidney Disease: An

Expert Interview With Hartmut H. Malluche, MD, FACP

Hartmut H Malluche, MD

Authors and Disclosures

Posted: 06/30/2006

Editor's Note:

Renal osteodystrophy, a common consequence of hyperphosphatemia and abnormal

vitamin D status and an early complication during the course of chronic kidney disease
(CKD), can result in fractures, bone pain, deformities, and, ultimately, mortality.
Prevention and treatment of this metabolic bone disease are therefore essential in patients
with CKD. With their ability to accurately determine the nature of abnormalities of bone
turnover, bone biopsies are the gold standard for diagnosis and classification of renal
osteodystrophy, but they are rarely used, namely due to the overall complexities of this
invasive procedure. The role of bone biopsies should be clearly defined and strategies
undertaken to help normalize bone disease. Imbalances in serum levels of calcium,
phosphorus, and plasma parathyroid hormone are known contributors to bone disease and
should be monitored in all patients with CKD. Unfortunately, uncontrolled blood calcium
levels in patients with CKD can be worsened by currently available calcium-based
phosphate binders. Recently, newer phosphate binders such as lanthanum carbonate have
been shown to normalize markers of bone disease , and, to date, bone toxicity has not been
seen with lanthanum. Anne G. Le, PharmD, Editorial Director of Medscape Nephrology,
interviewed Hartmut H. Malluche, MD, FACP, Professor of Medicine, Division Chief,
Robert G. "Robin" Luke Chair in Nephrology, Division of Nephrology, Bone and Mineral
Metabolism, University of Kentucky Medical Center, Lexington, Kentucky, about the issues
surrounding bone metabolism in patients with CKD.

Medscape: Can you explain how kidney disease and bone mineral metabolism are
interrelated in patients with CKD?

Dr. Malluche: When patients lose kidney function, there is a reduction in the number of
functioning nephrons, which are the smallest operating units in the kidney. For example, if
50% of kidney function is lost, there will then be a reduction of nephrons by 50%, and this
reduced number of nephrons will face the same challenge of excreting the total amount of
phosphorus if the patient maintains the same phosphorus intake. In order to accomplish
this, compensatory mechanisms increase parathyroid hormone (PTH), which increases the
fractional excretion per individual nephron, and thereby avoid hyperphosphatemia. In
addition, another useful consequence of the increase in PTH is a stimulation of C1 alpha-
hydroxylase in the kidney to increase conversion from 25 (OH) D to 1,25 (OH)2 D.
Therefore, the 1,25 vitamin D deficiency seen with reduced kidney function can be
avoided, at least in the beginning. This compensatory mechanism takes place for the
duration of the underlying kidney disease. When patients reach a glomerular filtration rate
of about 25 mL/min, this compensatory mechanism is insufficient, resulting in frank
hyperphosphatemia combined with hypocalcemia and other abnormalities. Therefore, with
chronic reduction in kidney function, there is an increase in the levels of PTH and
eventually a decrease in levels of 1,25 vitamin D. These 2 processes obviously affect the
bone. Increased PTH level affects bone turnover and decreased 1,25 vitamin D, which is
normally associated with abnormal bone mineralization.

Medscape: What complications are associated with bone and mineral abnormalities,
and what goals and strategies should be used to help normalize bone turnover and
prevent soft-tissue calcification?

Dr. Malluche: Patients with stage 5 CKD have elevated levels of phosphorus, hyperactive
parathyroid glands, and suppressed 1,25 vitamin D production. Patients with chronic
hyperphosphatemia receiving calcium-containing phosphate binders have a number of
abnormalities, the worst being soft-tissue calcifications and, most importantly, vascular
calcifications. Therefore, a strategy should be designed to manage serum phosphorus
without calcium administration. The next step would be to replace the missing 1,25 vitamin
D hormone. However, one has to be careful not to overtreat patients with vitamin D. In a
state of low turnover, the propensity of bone to pick up calcium is decreased and, therefore,
patients are prone to develop hypercalcemia. Furthermore, clinical trials demonstrate that
the lower the bone turnover, the higher the risk for tissue calcification. To avoid low
turnover, one has to be judicious in dosing vitamin D, being careful not exceed the daily
intake of calcium of about 1500 mg to a maximum of 2000 mg per day to avoid
oversuppression.

Medscape: How important is it for physicians to check laboratory values in patients

with CKD and why? What laboratory values are the most important, and how
frequent should these parameters be measured?

Dr. Malluche: Physicians should refer to the National Kidney Foundation Kidney Disease
Outcomes Quality Initiative guidelines[1] for detailed recommendations. Briefly, physicians
should monitor calcium and phosphorus and also PTH levels periodically. In addition,
parameters of bone turnover might be valuable also; specifically, bone-specific alkaline
phosphatase. In terms of frequency, in most dialysis units, it is standard to perform monthly
laboratory tests for routine parameters including calcium and phosphorus, and certainly
PTH should be measured at least twice a year. PTH may need to be more frequently
monitored immediately after changing therapies. One has to keep in mind, though, that
results of total PTH levels (intact) do not only include the active PTH (1.84 PTH), but also
inhibitory fragments. Therefore, regardless of which assay you're using, you need to have
an idea of how much of the PTH results reflect active vs antagonistic fragments.[2]

Medscape: Bone biopsies are the gold standard for diagnosis and classification of
renal osteodystrophy in patients with CKD but are rarely utilized for various reasons.
When and why should bone biopsies be performed, and can you describe the benefits
of the new interactive nomenclature for renal osteodystrophy that you helped
develop?

Dr. Malluche: Well, it is correct that bone biopsies are the gold standard. The reason why
they are rarely utilized is mainly related to 3 factors. First, it's an invasive procedure, and
patients obviously try to avoid invasive procedures for as long as they can. The second
reason/problem is related to logistics. Relatively few nephrologists are trained in
performing bone biopsies, and, unfortunately, some are doing them in a way that causes
patients to suffer or have discomfort. Bone biopsies should be done by physicians who are
well trained in this procedure. It is equally important to use a biopsy technique that is
acceptable to the patient and has the lowest degree of invasiveness and the least associated
discomfort. Finally, the third reason/problem might be related to the fact that there aren't
that many laboratories equipped to handle bone biopsies for appropriate processing and
interpretation, and, also, the technique of processing the bone samples is rather time
consuming.

The new nomenclature for renal osteodystrophy should help increase awareness of the
problem and should help us understand what the abnormalities are.[3] It is uncertain whether
the new nomenclature will have a direct effect on the number of biopsies being done, but
what it does do is help increase the understanding of the bone histologic results (whether
there is high, normal, or low bone turnover; bone loss or bone gain; osteoporosis; or the
presence of mineralization defect). The new nomenclature also has the potential to help
increase understanding of the communication between the laboratories and clinicians and
their researchers.

Medscape: The recent 307 Study by Finn and colleagues[4] demonstrated that at 2
years, lanthanum carbonate, a non-calcium-containing phosphate binder, was safe
and effective as standard therapy; moreover, lower serum calcium levels and
increased PTH levels were observed in the lanthanum carbonate group. What is the
clinical significance of these results?

Dr. Malluche: These results are very encouraging and present another alternative for the
management of the severe clinical consequences of abnormal mineral metabolism.
Aluminum-containing phosphate binders, which are potent and effective, were found to be
associated with a number of severe complications. Calcium-containing binders were found
to be effective, but it was learned that if you exceed the daily recommended dose of
calcium over an extended period of time, particularly in a patient who does not have kidney
function and abnormal bone turnover, the body can no longer compensate for the excessive
calcium intake. The increased calcium load is associated with an increased risk of
calcification and, therefore, the non-aluminum, non-calcium-containing binders were
introduced. The first was sevelamer, a resin that binds phosphate in exchange for hydrogen
ions. Recently, lanthanum, a separate entity that directly binds phosphorus, was introduced.
The difference with lanthanum as compared with aluminum is that it is not excreted by the
kidney, but instead by the liver and the bile. There is a very low intestinal absorption of
lanthanum, and patients with reduced kidney function can still excrete lanthanum, thus
reducing the risk for toxicities due to accumulation. Lanthanum is also heavily protein-
bound in the blood and, therefore, doesn't cross the blood-brain barrier.
Lanthanum is an important addition to the clinically active nephrologist's armamentarium.
It is available as chewable tablets, making it easier for patients to take. Patients can take it
with minimal fluid and/or with meals, which helps simplify the overall management of
hyperphosphatemia and, more importantly, reduces the number of pills the patient has to
take in a day. Patient compliance is related, among other things, to the number of pills they
must take; thus, lanthanum has a great advantage. In addition, as demonstrated in the 307
study, lower serum calcium and higher PTH levels are seen with lanthanum.

Medscape: How safe and effective are the available phosphate binders, and what are
the differences among them?

Dr. Malluche: There are no head-to-head data available comparing the 2 non-calcium,
non-aluminum-containing binders. In terms of effectiveness, experimental or animal data
show that lanthanum is as effective as calcium-based phosphate binders and that lanthanum
and aluminum-based phosphate binders are clearly the most potent agents.[5] Recently,
sevelamer has been associated with bowel obstruction leading to death in a few patients.[6]
In my opinion, this observation is very anecdotal. It's not very scientific, but it does deserve
attention, and one should keep an eye on it. To be fair, gastrointestinal (GI) side effects are
common in patients on dialysis no matter what phosphate binders they are on. Obviously,
any mortality rate associated with intestinal obstruction is of concern, but one would need
to know more about the associated morbidity of those patients with GI abnormalities to
help interpret these data. In terms of safety, non-aluminum, non-calcium-containing binders
should be safer than the calcium-containing binders based on the Treat-to-Goal data, which
showed that long-term doses of calcium-containing phosphate binders have the potential to
increase progression of coronary and aortic calcification.[7] There has been some recent
concern regarding the potential accumulation of lanthanum in the liver, but one should keep
in mind that lanthanum is excreted through the liver, so obviously there has to be increased
concentration in the liver. The increase of lanthanum in the liver could simply reflect the
process by which lanthanum is being handled by the liver through the lysosomes; basically,
it appears to be the same metabolic handling or excretion as you see with iron. Liver
histology data are not available at this point, but what are available are liver function tests.
In clinical trials, after years of lanthanum use, there was no difference in liver function tests
between patients receiving lanthanum vs standard therapy.[8]

Medscape: In closing, was there anything else you would like to share?

Dr. Malluche: Yes, it is important to note that lanthanum is now available as 1 g tablets,
which decreases pill count even more, an advantage not seen with the other medications.
Again, to re-emphasize, a very important factor in the management of hyperphosphatemia
is the compliance of the patient. If the patient doesn't want to take the medications, there is
not much doctors can do. It is the patient who has to make up his or her mind that, yes, I'm
going to take these medications. Therefore the more options we have and the more choices
we have that we can give to the patient, the better our success rate will be in the
management of the complications of CKD.

References
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the PTH-(1-84)/large C-PTH fragments ratio in ESRD patients. Kidney Int. 2001;60:1460-
1468. Abstract
3. Malluche HH, Monier-Faugere MC. Renal osteodystrophy: what's in a name? Presentation
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therapy for the treatment of hyperphosphatemia: safety and efficacy in chronic
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