Major trial is key to future treatment: CKD and bone loss

Major trial is key to future treatment: CKD and bone loss
July 7, 2011 By Gary Culliton

'Patients want to know whether they will live, whether they will have bone fractures, or if they’ll have other mineral or bone disease complications’
Two groups of drugs have a role in combating mineral and bone disorder in patients with chronic kidney disease, Prof John Cunningham told Gary Culliton.
Chronic kidney disease (CKD) causes mineral and bone disorder, according to an expert nephrologist. “Everybody who has bad CKD will get bad bone disease — almost without exception,” said Prof John Cunningham, Professor of Nephrology at the Royal Free Hospital and University College London, who addressed the Irish Nephrology Society’s Annual Scientific Meeting at the Dublin Convention Centre recently.
“There are two groups of drugs that are most likely to have a role here,” he said. “One is the non-calcium phosphate binders. These are given to try to limit the build-up of phosphorus in the blood. This is a problem that all kidney patients encounter. There’s some evidence that they’re effective in that sense.
“The other group of drugs is the calcimimetic group of drugs. They work very well indeed in kidney patients. Laboratory results are impressive. The early signs are that they probably limit the amount of calcium that forms in the arteries, too.”
The randomised, placebo-controlled Evaluation of Cinacalcet HCl Therapy to Lower CV Events (EVOLVE) trial is currently examining this area.
“This study is big enough at the end of the day to probably tell us whether the drug does or doesn’t reduce complications and whether it prolongs life,” said Prof Cunningham. “It’s a very important avenue.”
At the Scientific Meeting, Prof Cunningham spoke about cinacalcet, as well as both native and activated vitamin D therapy. ‘Active vitamin D’ refers to compounds that directly activate the nuclear vitamin D receptor (VDR).
Mineral and bone disorder
Therapies have been designed to try to prevent or to ameliorate mineral and bone disorder in CKD. “The therapies, however, are not perfect in many cases and debate has centred around this,” Prof Cunningham said. “Ways are being sought to refine the therapies, minimise the side-effects and to ensure that the outcomes are ones which matter to patients.”
Patients with progressive chronic kidney disease experience alterations of calcium and phosphorus homeostasis and active vitamin D deficiency, resulting in prolonged stimulation of the parathyroid glands, increased synthesis and release of parathyroid hormone (PTH). Ultimately, this can lead to secondary hyperparathyroidism (SHPT). When SHPT is treated with vitamin D in CKD patients, this will have both beneficial and potentially adverse effects. Most of the adverse effects relate to increases in serum calcium and/or phosphorus levels.
A study in animals (Lopez I et al, 2006) demonstrated that treatment with vitamin D alone significantly increased aortic calcium and phosphorus, whereas aortic calcium and phosphorus content were not increased with calcimimetic treatment. This study demonstrated that calcimimetic treatment reduced elevated PTH levels without inducing vascular calcification and prevented vitamin D-induced vascular calcification and mortality.
The EVOLVE trial is investigating the effect of treatment with cinacalcet on all-cause mortality and cardiovascular events in approximately 4,000 haemodialysis patients around the world (Chertow GM, 2006). A second randomised clinical trial (ADVANCE) is investigating the ability of cinacalcet in combination with reduced-dose vitamin D to attenuate the progression of coronary artery calcification in haemodialysis patients.
By increasing the sensitivity of the calcium-sensing receptor (CaR) to calcium, cinacalcet treatment predictably results in simultaneous reduction of both calcium and PTH in patients with primary or secondary hyperparathyroidism (Dong BJ, 2005).
“Historically, there has been a tendency in some areas of medicine to see good laboratory test results as a satisfactory outcome,” said Prof Cunningham. “Patients aren’t concerned with that. They want to know whether they will live, whether they will have bone fractures, or if they’ll have other mineral or bone disease complications. If these can be stopped, then you’re doing something worthwhile.”
Controlled studies
A series of controlled studies has evaluated the clinical usefulness of cinacalcet treatment. Patients with moderate and severe SHPT — despite receiving standard care with active vitamin D compounds and phosphate binders, as appropriate — were randomised to receive either cinacalcet or a placebo, in addition to standard care (Block GA, 2004 and Lindberg JS, 2003, 2004).

Patient undergoing dialysis for chronic kidney disease
Treatment with cinacalcet enables much higher compliance with Kidney Disease Outcomes Quality Initiative (KDOQI) biochemical targets than does standard care, in Prof Cunningham’s view. “The results of these studies were substantially consistent and showed a marked reduction in serum PTH, with moderate — although still highly significant — reductions in serum calcium, phosphate and calcium-phosphorus product,” he said. These biochemical changes led to “striking increases” in the proportion of patients who became compliant with KDOQI targets for serum PTH, calcium, phosphorus and calcium-phosphorus products, he added.
In addition, extensive analyses of safety-related outcomes data suggest that the addition of cinacalcet to standard care may have a significant salutary effect on the parathyroidectomy rate and fracture rates, cardiovascular-related hospitalisation and some aspects of health-related quality of life (HR-QOL).
Patients who have chronic kidney disease, as a group, have a much higher fracture risk than normal people do. Osteoporosis is a danger. “Fracture risk in normal people as they get older is quite high anyway. If they have CKD as well, the risk is considerably higher still. That’s an outcome that really matters to patients,” said Prof Cunningham.
PTH secretion is increased in response to low serum calcium and it is likely that calcimimetics lessen the need for parathyroidectomy by rendering parathyroid cells more calcium sensitive, thus decreasing PTH synthesis and parathyroid cell proliferation, according to one 2005 study (Colloton M, 2005). The same year, Prof Cunningham himself demonstrated that the probability of a parathyroidectomy was substantially diminished in patients treated with cinacalcet. By increasing sensitivity of the calcium-sensing receptor to serum calcium, calcimimetics enhance signal transduction by the CaR and suppress PTH production.
Calcium complications
Calcium causes particular difficulties when it enters and hardens the arteries. This is associated with complications and early death. “There’s evidence in the non-renal population that a shift in body calcium from the bones to soft-tissue areas is associated with reduced survival,” said Prof Cunningham. “That phenomenon is massively exaggerated in the renal population — there is a shift of calcium on a grand scale. The calcification in arteries we see in kidney patients is hundreds of times greater. It’s very serious indeed.”
Elevated concentrations of PTH and calcium-phosphorous product have been shown to be associated with an increased number of hospitalisations in haemodialysis patients (Block GA, 2004).
In a pooled analysis of three studies, Moe SM et al (2004) demonstrated that significantly more cinacalcet-treated dialysis patients with SHPT achieved KDOQI targets, compared with patients receiving standard therapy. In the combined database study of patients with CKD, a greater proportion of patients receiving cinacalcet (26 per cent) versus standard care (20 per cent) had a large improvement in physical function.
“Not everybody is afflicted in that way,” Prof Cunningham said. “This is an area which is being researched very actively. The hope is that it will be possible to pick out people who are heading for trouble at an early stage.”

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