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Nephrology & Hypertension. Vol. 14(4) (pp 355-360), 2005.

Purpose of review: Cinacalcet is a


calcimimetic agent that is now available for use clinically to manage SHPT among
patients undergoing dialysis regularly. It acts as an allosteric activator of the calcium-
sensing receptor, the molecular mechanism that controls PTH secretion. This

mechanism of action differs fundamentally


from that of the vitamin D sterols, which
heretofore have been the only definitive
pharmacological intervention for treating
SHPT. Recent findings: The ability of

calcimimetic agents to enhance signaling


through the calcium-sensing receptor in
parathyroid cells affects several important
components of parathyroid gland function.
Results: from several large clinical trials
demonstrate that cinacalcet effectively

lowers plasma PTH levels in dialysis


patients with SHPT when used either alone or together with vitamin D. Unlike the vitamin D sterols, which generally raise serum
calcium and phosphorus levels, treatment with cinacalcet is associated with modest reductions in serum calcium and

phosphorus concentrations. The impact of


these biochemical changes on renal bone
disease and on soft-tissue and vascular

calcification during long-term treatment has yet to be characterized fully. Cinacalcet

diminishes PTH gene expression, and studies in experimental animals indicate that its use retards the progression of

parathyroid gland hyperplasia and increases bone mass. If confirmed in future clinical

trials in patients with SHPT, these features represent potentially important ancillary

therapeutic benefits. Summary: Calcimimetic agents have diverse effects on parathyroid gland function that may enhance the overall medical management of SHPT in patients undergoing dialysis regularly.


Byrnes CA, Shepler BM.
Cinacalcet: A new treatment for

secondary hyperparathyroidism in patients receiving hemodialysis. Pharmacotherapy. Vol. 25(5 I)(pp 709-716), 2005.

Cinacalcet is the first calcimimetic drug
approved by the United States Food and
Drug Administration for the treatment of
SHPT in patients with chronic kidney

disease. A literature search, performed by








using PubMed and MEDLINE from January 1997-June 2004, identified articles

concerning the efficacy and safety of
cinacalcet in this patient population.

Currently, Vitamin D and its analogs are


considered first-line therapy for SHPT.
However, use of these agents is often
accompanied by an increase in serum

calcium and phosphorus concentrations, a problem that often limits their use.

Cinacalcet's mechanism of action decreases PTH, calcium, and phosphorus levels,

offering potential advantages over the other


treatments for SHPT. Additional clinical trials
are needed to evaluate the long-term safety
and efficacy of the drug as a first-line agent.
Phosphate Binders

Anonymous (2007).


Lanthanum: new drug.

Hyperphosphataemia in dialysis patients: more potential problems than benefits. Prescrire Int 16(88): 47-50, 2007.

In dialysis patients with CRF,

hyperphosphataemia can cause osteorenal dystrophy, leading to bone pain, fractures and excess cardiovascular mortality. In

addition to a low-phosphorus diet and
dialysis, phosphorus chelators are usually needed to control blood phosphorus levels. The first choice is calcium carbonate, and sevelamer is an alternative. Lanthanum carbonate, a phosphorus chelator, is now also licensed for the treatment of

hyperphosphataemia in dialysis patients with CRF. In addition to three dose-finding

placebo-controlled studies, clinical
evaluation includes 2 comparative

randomised unblinded trials: one 6-month trial versus calcium carbonate and a 2-year trial versus other phosphorus chelators.

During these trials, lanthanum was no more
effective than the comparators in terms of
effects on the mortality rate, incidence of

fractures, or blood phosphorus level. During these trials, adverse events attributed to

treatment were more frequent with
lanthanum than with the other phosphorus
chelators. The main problems were
gastrointestinal disorders (nausea, vomiting,
diarrhoea, constipation and abdominal pain),
headaches, seizures, and encephalopathy.
The accumulation of lanthanum in the bones
and brain is troubling. The known long-term adverse effects of aluminium, another

trivalent cation with weak gastrointestinal


absorption, suggest that caution is also

required with lanthanum. In practice, when a phosphorus chelator is needed to treat

hyperphosphataemia in dialysis patients with
CRF, calcium carbonate is the first choice
and sevelamer remains the best alternative.

Freemont AJ.

Lanthanum carbonate. Drugs of
Today. Vol. 42(12)(pp 759-770),
2006.

Controlling hyperphosphatemia in patients with CRF on renal dialysis is a major

problem. None of the available calcium- or
aluminum-based phosphate binders match
the requirements for an ideal agent, each
having its own limitations. The introduction
of sevelamer hydrochloride represented a
step change in management. Lanthanum
carbonate is an alternative nonaluminium,
noncalcium phosphate binder. Taken with

food, it is well tolerated. It is poorly absorbed and does not require functioning kidneys to be removed from the body. There is no

evidence from current studies that it
accumulates to biologically significant levels in tissues, but despite the large numbers of patients included in clinical trials, experience with long-term dosing is limited and, as with every new drug used in this type of clinical setting, patients should be carefully
monitored as experience with the drug
increases. Lanthanum carbonate binds
phosphate effectively across the

physiological pH range of the upper


gastrointestinal tract, and has no detrimental
effect on calcium, vitamin D or PTH
metabolism. From the extensive trial data it
seems that lanthanum carbonate is an
effective and practical phosphate binder.
Lanthanum carbonate and sevelamer are
two new oral phosphate binding agents that
with others currently in preclinical trials, such
as stabilized polynuclear iron idroxide, could
well represent a significant breakthrough in
the management of hyperphosphatemia in
patients with CRF in whom dietary
phosphate restriction and cheaper oral
phosphate binding agents prove

unsatisfactory. Comparative trials and


enhanced clinical experience are needed
before the exact place of these competing






and complementary therapies can be


properly identified in patient management.

Cozzolino M, Brancaccio D.


Lanthanum carbonate - New data

on parathyroid hormone control without liver damage. Nephrology Dialysis Transplantation. Vol.

22(2)(pp 316-318), 2007. No abstract available.
Brancaccio D, Cozzolino M.
Lanthanum carbonate: Time to

abandon prejudices? Kidney International. Vol. 71(3)(pp 190-


192), 2007.

Since lanthanum carbonate has become


available there has been much interest in its
use as a non-calcium-containing phosphate
binder, but also much speculation among
scientists about possible aluminum-like
toxicity. This Commentary focuses on the
major aspects of this scientific controversy,
confirming the safety and efficacy of this
new phosphate binder

Nikolov IG, Joki N, Maizel J, et al.


Pleiotropic effects of the non-

calcium phosphate binder


sevelamer. Kidney International.
Vol. 70(SUPPL. 105)(pp S16-S23),
2006.

The number of CKD patients and related adverse outcomes has dramatically

increased worldwide in the past decade.
Therefore, numerous experimental and

clinical studies have recently addressed the underlying mechanisms, in particular the

marked increase in cardiovascular mortality. Hyperphosphatemia is a major problem in these patients with advanced stage of CKD. Its control by calcium-containing phosphate binders is effective, but at the price of

potentially noxious calcium overload.


Sevelamer hydrochloride is a phosphate
binder that offers an effective control of
hyperphosphatemia as calcium-rich binders but without increase of calcium load. Beyond the control of phosphate, sevelamer seems to exert pleiotropic effects which include the correction of lipid abnormalities and the
clearance of some uremic toxins.

Nolan CR, Qunibi WY.

Treatment of hyperphosphatemia in
patients with chronic kidney disease
on maintenance hemodialysis. Kidney International. Vol.

67(SUPPL. 95)(pp S-13-S-20),


2005.

Hyperphosphatemia in patients with ESRD leads to SHPT, renal osteodystrophy, and is independently associated with mortality risk. The exact mechanism by which

hyperphosphatemia increases mortality risk
is unknown, but it may relate to enhanced
cardiovascular calcification. National Kidney
Foundation K/DOQI bone metabolism and
disease guidelines recommend maintenance
of serum phosphorus (P) below 5.5 mg/dL,
and calcium-phosphate product less than 55
mg2/dL2. Although calcium-based phosphate
binders (CBPB) are cost effective, long-term
safety concerns relate to their postulated

role in progression of cardiovascular


calcification. Sevelamer hydrochloride has
been recommended as an alternative
noncalcium phosphate binder. Results from
the Calcium Acetate Renagel Evaluation
(CARE study) indicate that calcium acetate
is more effective than sevelamer in
controlling serum phosphorous and calcium-
phosphate product in hemodialysis patients.
In the Treat-to-Goal study, dialysis patients
treated with sevelamer had slower
progression of coronary and aortic
calcification than patients treated with
CBPB. The mechanism underlying the
beneficial effect of sevelamer is unknown,
but may relate to decreased calcium loading
or to dramatic reductions in LDL cholesterol
in sevelamer-treated patients. At present,
evidence incriminating CBPB in the
progression of cardiovascular calcification in
ESRD remains largely circumstantial. As
calcium acetate is more efficacious and cost
effective than sevelamer, it remains an
accepted first-line phosphate binder. In this
review, we will examine these issues and
provide rational guidelines for the use of
calcium-based phosphate binders in patients
on maintenance hemodialysis.
Monge M, Shahapuni I, Oprisiu R, et al.
Reappraisal of 2003 NKF-K/DOQI

guidelines for management of


hyperparathyroidism in chronic
kidney disease patients. Nature

Clinical Practice Nephrology. Vol. 2(6) (pp 326-336), 2006.

The 2003 guidelines for the management of
hyperparathyroidism in CKD compiled by the






Kidney Disease Outcomes Quality Initiative of the National Kidney Foundation (NKF-


K/DOQI) were formulated on the basis of work published up until 2001. Since then, new drugs (e.g. calcimimetics and

lanthanum carbonate) have become


available, and others (e.g. sevelamer,

nicotinamide and paricalcitol) have been more stringently clinically evaluated.

Because of these advancements, a
reappraisal of the 2003 guidelines is

justified. In this article we critically review the following recommendations of the NKF-

K/DOQI: (i) routine use of 1.25 mmol/l (5.0
mg/dl) dialysate calcium and 1aOH-vitamin
D derivatives; (ii) limitation of the maximal
daily dose of calcium-based oral phosphate
binders to 1.5 g of elemental calcium; and
(iii) not correcting vitamin D insufficiency in
dialysis patients.

Albaaj F, Hutchison AJ.

Lanthanum carbonate (Fosrenol): A novel agent for the treatment of

hyperphosphataemia in renal failure and dialysis patients. International Journal of Clinical Practice. Vol.

59(9)(pp 1091-1096), 2005.

Approximately 70% of patients with ESRD and dialysis have hyperphosphataemia, which is associated with renal

osteodystrophy, metastatic calcification and
increased mortality and morbidity. Despite
dietary restriction and dialysis, most patients
will require a phosphate-binding agent to

treat this condition. However, phosphate


control has not significantly improved over

the last two decades, mainly because of the lack of an ideal phosphate-binding agent.

Aluminium-based and calcium-based agents are associated with major side-effects

despite their efficacy. Although sevelamer


hydrochloride represents a step forward in
the management of hyperphosphataemia, it
has drawbacks and therefore is not the ideal
phosphate binder. Lanthanum carbonate is
a non-calcium, non-aluminium phosphate-
binding agent. It has shown to be effective,
well-tolerated and has a positive effect on
bone histology.
Nadin C.

Sevelamer as a phosphate binder in adult hemodialysis patients: An

evidence-based review of its
therapeutic value.Core Evidence. Vol. 1(1)(pp 43-63), 2005.

Introduction: Patients on hemodialysis


require phosphate binders to reduce dietary
phosphate absorption and control serum
phosphate. The standard therapy, calcium
salts, can be associated with elevated
serum calcium (hypercalcemia). Concern
has been raised that hypercalcemia,
especially combined with elevated serum
phosphate, may be associated with arterial
calcification, and this may contribute to
increased risk of cardiovascular mortality
and morbidity. Sevelamer is a nonmetal,
nonabsorbed phosphate binder. Aims: This
review assesses the evidence for the
therapeutic value of sevelamer as a
phosphate binder in adult hemodialysis
patients. Evidence review: Strong evidence
shows that sevelamer is as effective as
calcium salts in controlling serum phosphate
and calcium-phosphate product, has less
risk of inducing hypercalcemia and is more
effective at lowering lipid levels. Some
evidence indicates that sevelamer reduces
arterial calcification progression and loss of
bone mineral density, but it may be more
likely to induce metabolic acidosis,
compared with calcium salts. Sevelamer-
containing regimens may improve calcific
uremic arteriolopathy, although the evidence
is weak. Evidence is divided on whether the
incidence of gastrointestinal adverse events
with sevelamer is similar to or higher than
that with calcium salts. Retrospective and
modeling studies suggest lower

cardiovascular morbidity and mortality with sevelamer than with calcium salts, with

incremental cost-effectiveness of $US1100-
2200 per life-year gained. Further direct

evidence is needed on mortality, quality of life, and cost-effectiveness. Place in therapy: Sevelamer is effective in controlling serum phosphate and lowering lipid levels in

hemodialysis patients without inducing hypercalcemia, and may have beneficial effects on arterial calcification.

Cheng CM.

Lanthanum carbonate treatment of
hyperphosphatemia in end-stage
renal disease. Journal of Pharmacy
Technology. Vol. 22(2)(pp 99-104),
2006.

Objective: To review the literature on the


safety and efficacy of lanthanum carbonate






for the treatment of hyperphosphatemia in


patients with ESRD (ESRD). Data Sources:
Primary literature was obtained through a
PubMed search (1966-September 2005)

using the key terms Fosrenol and lanthanum


carbonate. The FDA review, manufacturer-
provided data, and published abstracts on
lanthanum carbonate were also reviewed

and evaluated. Study Selection and Data Extraction: Human studies in which

lanthanum carbonate was compared with placebo or active control for the treatment of hyperphosphatemia secondary to renal

disease were included. Dose-titration


studies were excluded. Data Synthesis:
Phosphate-lowering agents and dietary

phosphate restriction are currently the first-


line therapies for initial treatment of

hyperphosphatemia associated with ESRD. Lanthanum carbonate is a highly effective non-aluminum, non-calcium-containing

phosphate binder. It is the only FDA-
approved phosphate binder that is available
as an unflavored chewable tablet that may
be taken without water. Conclusions: Clinical
studies demonstrate that lanthanum
carbonate is more effective than placebo but
as or less effective than standard therapies
in lowering serum phosphate to target
levels. When compared with calcium salts,
lanthanum carbonate had a lower incidence
of hypercalcemia and a lower risk of patients
developing bone disease. However, in
clinical trials, patients receiving lanthanum
carbonate had greater discontinuation rates,
some due to adverse events. The long-term
safety data (>5 y), including the potential for
lanthanum accumulation in the bone with
subsequent development of osteodystrophy,
remain unknown.
Joy MS, Kshirsagar A, Candiani C, et al.
Annals of Pharmacotherapy. Vol.

40(2)(pp 234-240), 2006.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and

safety profile of lanthanum carbonate, a phosphate binder for CKD. DATA

SOURCES: Information was selected from PubMed (1965-October 2005). All studies presented as scientific posters and abstracts from nephrology meetings from 1999 to

2005 were also included. STUDY


SELECTION AND DATA EXTRACTION: All published articles regarding lanthanum carbonate were included. In addition,
abstracts and presentations from scientific
meeting symposia were also considered for
inclusion. DATA SYNTHESIS: Lanthanum
carbonate has been recently approved as
non-calcium-based therapy for phosphate
reduction in patients with stage 5 CKD

requiring dialysis. The recommended dose


is 250-500 mg with meals, for a maximum of
1500 mg daily. Clinical studies have shown
short- and long-term safety with lanthanum
carbonate administration. Adverse effects
were primarily gastrointestinal in nature.

Clinical trials have also shown reductions in serum phosphorus to target concentrations, reductions in associated calcium-phosphate product, and minimal effects on serum

calcium and PTH concentrations.
CONCLUSIONS: Lanthanum carbonate is
an effective phosphate-binding agent
without significant risk of hypercalcemia or
worsening metabolic acidosis. Lanthanum
carbonate is a safe and effective drug for
reduction of elevated serum phosphorus
levels associated with stage 5 CKD. The
role of lanthanum carbonate relative to other
phosphate-binding drugs, such as calcium
salts and sevelamer, remains to be
determined.
Qunibi WY, Nolan CR.

Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis:

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