Alastair J. Hutchison

Long-Term Efficacy and Safety Profile of Lanthanum Carbonate: Results for up to 6 Years of Treatment

Background/Aims: Lanthanum carbonate (LC, FOSRENOL®) is an effective phosphate binder for which tolerability and a safety profile have been reported in haemodialysis patients. Patients from previous studies entered a 2-year extension, enabling assessment of efficacy and safety for up to 6 years of LC monotherapy. Methods: Patients from four previous trials entered this study. Results: Ninety-three patients started the extension, with 22 entering a sixth year of LC treatment. Two-thirds of all patients received LC doses of 2,250 or 3,000 mg/day. Reductions in serum phosphate and calcium × phosphate product were maintained for up to 6 years. There were no new or unexpected adverse events (AEs), and no increase in the incidence of events with increasing treatment exposure. Over the complete duration of therapy, treatment-related AEs occurred in 25.8% of patients and were primarily gastrointestinal in nature. No clinically relevant changes in liver function tests were observed and there was no evidence of adverse effects on the liver, bone or the central nervous system. Conclusions: LC monotherapy was effective and well tolerated for up to 6 years with no evidence of safety concerns or increased frequency of AEs.

Oral phosphate binders

Hyperphosphatemia is an inevitable consequence of end-stage chronic kidney disease and is present in the majority of dialysis patients. Hyperphosphatemia is observationally and statistically associated with increased cardiovascular mortality among dialysis patients. Dietary restriction of phosphate and current dialysis modalities are not sufficiently effective to maintain serum phosphate levels within the recommended range, so the majority of dialysis patients require oral phosphate binders. However, the benefits of achieving the recommended range have yet to be shown prospectively. Unfortunately, conventional phosphate binders are not reliably effective and are associated with a range of limitations and side effects. Aluminum-containing agents are highly efficient but no longer widely used because of proven toxicity. Calcium-based salts are inexpensive, effective, and most widely used, but there is now concern about their association with hypercalcemia and vascular calcification. Sevelamer hydrochloride is associated with fewer adverse effects, but a large pill burden and high cost are limiting factors to its wider use. Lanthanum carbonate is another non-aluminum, calcium-free phosphate binder. Preclinical and clinical studies have shown a good safety profile, and it appears to be well tolerated and effective in reducing phosphate levels in dialysis patients; however, it is similarly expensive. Data on its safety profile over 6 years of treatment are now published. Achievement of opinion-based guidelines appears to have become an end in itself. Dialysis patient outcomes are worse than outcomes for many types of cancer, yet prospective, outcome-based randomized controlled trials are not being undertaken for reasons that are difficult to explain.

Effect of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation

To investigate the effect of calcitriol plus calcium carbonate on the bone loss associated with long-term renal transplantation, 30 patients with serum creatinine levels less than 2.0 mg/dL were randomly allocated to a control (n = 14) or treatment group (n = 16) and studied with bone biopsy and densitometry at baseline and after 1 year of follow-up. Calcitriol (0.25 microg/d) plus calcium carbonate (500 mg/d of elemental calcium) were administered to patients in the treatment group. Comparing the baseline and final data of each group at a time, no change in bone mineral density (BMD) z score was observed at the distal radius (control, -0.8 +/- 0.8 versus -0.6 +/- 0.9; treatment, -1.0 +/- 1.0 versus -1.0 +/- 1.1). However, a significant increase (P < 0.05) was found at the lumbar spine in both groups (control, 0.1 +/- 1.6 versus 0.4 +/- 1.6; treatment, -0.1 +/- 1.5 versus 0.3 +/- 1.5) and only in the treatment group at the femoral neck (control, -0.9 +/- 1.0 versus -0.8 +/- 1.0; treatment, -0.5 +/- 0.9 versus -0.3 +/- 1.1). When BMD was compared between groups, no significant differences were observed at the evaluated anatomic sites at baseline or after 1 year of follow-up. After 1 year of follow-up, adjusting for age and sex (z score), the control group showed a trend to reduce the value of several histomorphometric parameters, including osteoblast surface (-2.2 +/- 6.1 versus -3.4 +/- 3.9), osteoid surface (-2.3 +/- 3.5 versus -3.1 +/- 3.9), and osteoclast surface (0.2 +/- 5.0 versus -1.3 +/- 3.3). Consequently, there was a significant reduction (P < 0.05) in mineralizing surface (-9.8 +/- 11.0 versus -15.8 +/- 12.3) and appositional rate (-5.8 +/- 2.7 versus -7.6 +/- 2.2). In the treatment group, a significant reduction (P < 0.05) in osteoclast surface was observed at the end of the study (3.9 +/- 6.8 versus -1.2 +/- 4.1), and although a trend to reduce osteoblast surface (-2.5 +/- 2.6 versus -3.2 +/- 5.7) and osteoid surface (-2.1 +/- 2.5 versus -3.2 +/- 2.8) was also found, patients maintained approximately the same level of wall thickness (-5.2 +/- 5.3 versus -5.3 +/- 3.3) and bone volume (-2.7 +/- 1.8 versus -2.5 +/- 1.7). However, there was no improvement in mineralizing surface (-4.2 +/- 2.9 versus -10.4 +/- 3.6) or appositional rate (-5.8 +/- 3.1 versus -8.1 +/- 2.6). No significant differences in bone histomorphometric variables were observed between groups after 1 year of follow-up. In conclusion, 1,25-dihydroxyvitamin D3 and calcium carbonate did not significantly improve bone loss in long-term renal transplant recipients. However, significant osteoclast suppression and a trend to maintain trabecular bone volume and wall thickness as well as improve the axial BMD were observed in the treatment group.

Biochemical markers for non-invasive diagnosis of hyperparathyroid bone disease and adynamic bone in patients on haemodialysis

UNLABELLED The diagnostic and predictive value of serum intact parathyroid hormone (iPTH) and osteocalcin (bone Gla protein, BGP), alone or in combination, have been examined in only a small number of haemodialysis patients. METHODS We studied prospectively 114 patients (46 women, 68 men; mean age 52 +/- 12 years) on regular haemodialysis for a mean of 55 (6-185) months. All patients underwent labelled transiliac bone biopsy, and serum levels of iPTH, BGP and alkaline phosphatase were determined. RESULTS Seventy-one patients (62%) showed histological findings of hyperparathyroid bone disease, 24 (21%) mixed bone disease, six (5.5%) osteomalacia and 13 (11.5%) adynamic bone. Bone aluminium deposition over more than 25% of the trabecular bone interface was found in 66 patients (58%). Serum iPTH and BGP correlated with the majority of histomorphometric indices of bone formation, mineralization and resorption (r > 0.5, P < 0.01). iPTH levels > or = 200 pg/ml and BGP > or = 50 ng/ml were found to be indicative of hyperparathyroid bone disease, whilst iPTH levels < 65 pg/ml and BGP < 20 ng/ml were indicative of adynamic bone. However, the positive predictive value of these indices was limited (less than 80%), although their negative predictive value, especially when used in combination, was good (more than 90%) and the exclusion of hyperparathyroid bone disease and adynamic bone was possible. The diagnostic and predictive value of these bone markers were improved when patients with bone aluminium deposition were excluded. CONCLUSIONS Diagnosis of hyperparathyroid bone disease and adynamic bone is difficult on the basis of iPTH and BGP, especially when bone aluminium deposition is prevalent. However, using these bone markers, preferably in combination, the exclusion of these lesions is feasible.

Hyperphosphataemia in renal failure: causes, consequences and current management.

Hyperphosphataemia is prevalent among chronic renal failure and dialysis patients. It is known to stimulate parathyroid hormone and suppress vitamin D3 production, thereby inducing hyperparathyroid bone disease. In addition, it may independently contribute to cardiac causes of death through increased myocardial calcification and enhanced vascular calcification. Hyperphosphataemia is also associated with cardiac microcirculatory abnormalities. Therefore, phosphate control is of prime importance.It is important to control phosphate levels early in the course of chronic renal failure in order to avoid and treat secondary hyperparathyroidism, and cardiovascular and soft tissue calcifications. Dietetic restrictions are often difficult to follow long term. Because of its large sphere of hydration and the complex kinetics of phosphate elimination, phosphate is not easily removed by dialysis. Long, slow dialysis may be effective, but this needs logistics and acceptance by patients. Thus, oral phosphate binders are generally required to control serum levels. None of the existing phosphate binding agents is truly satisfactory. Aluminium-containing agents are highly efficient but many clinicians have abandoned their use because of the potential toxicity. Despite of the wide use of calcium-containing agents, there was a link with hypercalcaemia and soft tissue calcifications. Novel phosphate binders in the form of polyallylamine hydrochloride, polyuronic acid derivatives and lanthanum carbonate appear promising. In this review, we discuss causes of hyperphosphataemia, pathological consequences and modalities of treatment.Hyperphosphataemia is prevalent among chronic renal failure and dialysis patients. It is known to stimulate parathyroid hormone and suppress vitamin D3 production, thereby inducing hyperparathyroid bone disease. In addition, it may independently contribute to cardiac causes of death through increased myocardial calcification and enhanced vascular calcification. Hyperphosphataemia is also associated with cardiac microcirculatory abnormalities. Therefore, phosphate control is of prime importance. It is important to control phosphate levels early in the course of chronic renal failure in order to avoid and treat secondary hyperparathyroidism, and cardiovascular and soft tissue calcifications. Dietetic restrictions are often difficult to follow long term. Because of its large sphere of hydration and the complex kinetics of phosphate elimination, phosphate is not easily removed by dialysis. Long, slow dialysis may be effective, but this needs logistics and acceptance by patients. Thus, oral phosphate binders are generally required to control serum levels. None of the existing phosphate binding agents is truly satisfactory. Aluminium-containing agents are highly efficient but many clinicians have abandoned their use because of the potential toxicity. Despite of the wide use of calcium-containing agents, there was a link with hypercalcaemia and soft tissue calcifications. Novel phosphate binders in the form of polyallylamine hydrochloride, polyuronic acid derivatives and lanthanum carbonate appear promising. In this review, we discuss causes of hyperphosphataemia, pathological consequences and modalities of treatment.

Pharmacology, efficacy and safety of oral phosphate binders

The ideal serum level of phosphate in patients on dialysis, and the benefits of controlling levels of phosphate in serum remain unclear despite observational studies that associate phosphate levels with mortality. In the absence of robust data from trials, current guidelines are necessarily based on opinion. Oral phosphate binders are required by the majority of patients on dialysis, and all of these binders can control serum levels of phosphate to similar degrees. Patient preference and adherence to prescribed therapy is at least as important as the efficacy of the prescribed binder. Avoidance of calcium-containing binders has become accepted practice where the alternatives are affordable, but incontrovertible evidence in favor of this approach is lacking. Use of sevelamer and lanthanum avoids calcium loading, but at considerable financial cost and with no reliable patient outcome data to prove their value. Additional approaches to aid control of serum levels of phosphate include blockade of gastrointestinal phosphate absorption and possibly binding of salivary phosphate. Importantly, the role of phosphate control in determining patient outcomes must be quantified, which is likely to require a large randomized, controlled study of two levels of phosphate control. Without such a study we will continue to rely on observational data with all its uncertainties and potential to mislead.

Histological, radiological, and biochemical features of the adynamic bone lesion in continuous ambulatory peritoneal dialysis patients.

Adynamic bone is being found with increasing frequency in dialysis patients. Little is known about its aetiology, and even less about its natural history. We found 10 cases of asymptomatic adynamic bone among a group of 32 continuous ambulatory peritoneal dialysis patients, most of whom had never been exposed to aluminium-containing phosphate binders. Compared to the remaining 22 patients, they had an older mean age (54 +/- 11.4 vs. 42 +/- 11.8 years; p < 0.05), probably a longer pre-dialysis duration of renal failure (10.9 vs. 7.1 years), higher mean ionized calcium (1.30 +/- 0.04 vs. 1.15 +/- 0.02 mmol/l; p < 0.01), and lower mean intact parathyroid hormone (31.5 vs. 200.3 pg/ml; p < 0.001). The bone density was not different between the two groups, but 9 of the 10 adynamic patients had significant vascular calcification seen on plain radiology as compared with only 7 of 20 in the comparison group (p < 0.05). Follow-up of the adynamic patients showed a close association with serum intact parathyroid hormone and ionized calcium levels. With one exception, adynamic bone did not appear to be associated with lower bone density than other types of osteodystrophy, but a longer-term study is required to determine the complete natural history of this lesion.

Lanthanum carbonate (Fosrenol®): a novel agent for the treatment of hyperphosphataemia in renal failure and dialysis patients

Approximately 70% of patients with end‐stage renal disease 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.

Lanthanum carbonate for the treatment of hyperphosphataemia in renal failure and dialysis patients.

Hyperphosphataemia is a usual accompaniment of end stage renal disease and dialysis, in the absence of dietary phosphate restriction or supplemental phosphate binders. It 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 oral phosphate-binding agent. Aluminium- and calcium-based agents are associated with major side effects, despite their undoubted efficacy. Although sevel-amer hydrochloride represents a step forward in the management of hyperphosphataemia, it is not an ideal phosphate binder due to its cost and tablet burden. Lanthanum carbonate is the most recent non-calcium, non-aluminium, phosphate-binding agent. It is effective and well-tolerated, and no n-egative effects on bone histology have been observed.

Bone histopathology and densitometry comparison between cyclosporine a monotherapy and prednisolone plus azathioprine dual immunosuppression in renal transplant patients.

Background. No study has compared the bone histopathologic findings in renal transplant patients receiving cyclosporine A (CsA) monotherapy with those in patients receiving a non-CsA regimen. The aim of this study was to compare bone densitometry and histomorphometry findings in patients receiving CsA monotherapy versus those receiving azathioprine + prednisolone dual therapy. Methods. A bone biopsy and densitometry were performed in 13 patients receiving CsA monotherapy and 12 patients receiving azathioprine + prednisolone, who had been on these regimens since the time of transplantation. Fourteen men and 11 women, age 51±12 years, with 140±75 months since transplantation, were included. Results. A low bone mineral density (BMD) was observed in patients on both immunosuppressive schemes—most notably at the distal radius and less significantly at the lumbar spine. No significant differences in BMD were observed between immunosuppressive groups. Histopathologic analysis of the group as a whole revealed mixed uremic bone disease in 42%, adynamic bone in 29%, hyperparathyroid disease in 17%, and normal bone in 12%. Patients showed a slight increase in osteoclast number and function, decreased osteoblast number and function, and retardation of dynamic parameters. No differences in histopathologic diagnosis or histomorphometric findings were observed between the immunosuppressive therapy groups. In addition to the immunosuppressive drugs, male gender and old age negatively affected bone mass. Conclusions. Both prednisolone and CsA were associated with slight osteoclast stimulation and osteoblast suppression and marked retardation of mineral apposition and bone formation rates. Both drugs were also associated with reduced BMD at the axial and appendicular skeleton, even though a nonsignificant trend to a better-preserved lumbar spine BMD was observed in the CsA group.