13Specific complications of CKD – renal bone disease

Publication Details

13.1. Monitoring of calcium, phosphate, vitamin D and parathyroid hormone levels in people with CKD

13.1.1. Clinical introduction

Alterations in the control mechanisms for calcium and phosphate homeostasis occur early in the course of CKD and progress as kidney function decreases. Changes that occur include abnormalities of calcium, phosphate, parathyroid hormone (PTH), and vitamin D metabolism; together with abnormalities of bone turnover, mineralisation, volume, linear growth, and strength; plus vascular or soft tissue calcification.323 A wide variety of disturbances of bone metabolism may occur in the setting of CKD necessitating an understanding of the changes that occur in order to design a treatment strategy. However, an in-depth discussion of metabolic bone disease in CKD is beyond the scope of this guideline. This section is focussed on the changes that occur early in the course of CKD. The aim is to prevent metabolic bone disease by maintaining the blood levels of calcium and phosphate as close to normal as possible, and preventing the development of established hyperparathyroidism and parathyroid hyperplasia.

Central to the prevention of these disturbances is an ability to intervene early, recognising that bone disease in people with kidney disease is often asymptomatic, and symptoms appear only late in its course, long after the opportunity for early intervention has passed. Whilst bone biopsy may be the gold standard for assessment of metabolic bone disease it is neither widely available nor widely used. Biochemical assessment is the mainstay of diagnosis and treatment. In addition to measurements of calcium and phosphate it is essential to obtain a direct index of parathyroid activity by measurement of PTH. Under certain circumstances measurement of vitamin D may also be necessary. When should these parameters be measured and at what frequency should they be repeated?

13.1.2. Methodology

Serum calcium, phosphate, intact parathyroid hormone (iPTH), and vitamin D levels were assessed in adults with various stages of CKD in five cross-sectional studies and one observational study.

Two reports from the cross-sectional US NHANES III study (N=14,679) examined changes in serum calcium and phosphate324 and 25-hydroxyvitamin D325 by level of renal function. Hsu et al. also reported the prevalence of hyperphosphataemia.

A cross-sectional study compared levels of serum calcium, phosphate, iPTH, and vitamin D amongst stage 3, 4, and 5 CKD. The prevalence of vitamin D deficiency, hyperphosphataemia, and hypocalcaemia was examined in people with stages 3 and 4 CKD.326

A cross-sectional analysis of CKD patients (N=1836) was performed to ascertain levels of serum calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D within each stage of CKD.327

A cross-sectional analysis at baseline of the Study for the Evaluation of Early Kidney disease participants (SEEK, N=1814, mean age 70 years)328 examined serum calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D within decreasing deciles of eGFR. This study also reported the prevalence of abnormal calcium, phosphate, iPTH, and vitamin D with decreasing eGFR.

All of these studies were limited by the use of one serum creatinine measurement to estimate renal function.

GFR was measured by 99Tc-DTPA clearance in one small observational study and levels of serum calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in people with ‘mild CRF’ (N=27) or ‘moderate CRF’ (N=12) were compared with healthy people (N=12).329

Calcium, phosphate, iPTH, and vitamin D levels with decreasing renal function are summarised in Table 13.1 at the end of the evidence statements.

Table 13.1. Summary of serum calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D levels according to level of renal function (95% CI).

Table 13.1

Summary of serum calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D levels according to level of renal function (95% CI).

13.1.3. Health economics methodology

There were no health economics papers found to review.

13.1.4. Evidence statements

Serum calcium

Five studies showed that serum calcium levels decreased only in advanced renal disease. Two of these studies reported the prevalence of hypocalcaemia in a CKD population.

Of people with GFR <20 ml/min, 15% had abnormal Ca levels (Ca <2.1 mmol/l).328 (Level 3)

43% of people with stage 3 CKD and 71% of people with stage 4 CKD had serum Ca <2.37 mmol/l.326 (Level 3)

Two studies showed that people with stage 4 CKD had significantly lower serum calcium than people with stage 3 CKD.326,327 (Level 3)

People with moderate CRF (GFR 20–39 ml/min/1.73m2) had significantly lower Ca levels than people with mild CRF (GFR 40–90 ml/min/1.73m2).329 (Level 3)

Compared to men with CrCl >80 ml/min, men with CrCl <20 ml/min had a significant decrease in ionised serum Ca.324 (Level 3)

Serum phosphate

Five studies showed that serum phosphate levels increased with advanced renal disease. Three of these studies showed that abnormal phosphate levels were highly prevalent when eGFR was <20 ml/min.

Of people with eGFR 20–29 ml/min, 15% had abnormal phosphorus levels (P >1.49 mmol/l). Of people with GFR <20 ml/min, 40% had abnormal phosphorus levels.328 (Level 3)

The prevalence of hyperphosphataemia (serum P >1.45 mmol/l) increased with declining CrCl: 7% of people with CrCl 20–30 ml/min, and 30% of people with CrCl <20 ml/min had hyperphosphataemia.324 (Level 3)

3% of people with stage 3 CKD and 22% of people with stage 4 CKD had serum P >1.52 mmol/l.326 (Level 3)

Two studies showed that people with stage 4 CKD had significantly higher serum phosphate levels than people with stage 3 CKD.326,327 (Level 3)

People with stage 5 CKD had significantly higher serum phosphate than people with stage 4 CKD.327 (Level 3)

Serum intact parathyroid hormone (iPTH)

Four studies showed that iPTH increased in early stages of CKD. One of these studies reported the prevalence of hyperparathyroidism in the CKD population.

Levin et al. showed hyperparathyroidism (iPTH >65 ng/ml) was prevalent in approximately 20%, 30%, 40%, 55%, and 70% of people with eGFR 69–60, 59–50, 49–40, 39–30, and 29–20 ml/min/1.73 m2, respectively.329 The increase in iPTH above reference values began at GFR <60 ml/min/1.73 m2. People with mild CRF (GFR 40–90 ml/min/1.73 m2) had significantly higher levels of iPTH than healthy people. People with moderate CRF (GFR 20–39 ml/min/1.73 m2) had significantly higher iPTH levels than people with mild CRF. (Level 3)

Craver et al. showed that serum iPTH increased across all stages of CKD. (Level 3)

Serum 1,25-dihydroxyvitamin D

Four studies reported decreases in 1,25-dihydroxyvitamin D in early stages of CKD.

23% of people with CRF were below the reference range of serum 1,25-dihydroxyvitamin D at GFR <60 ml/min/1.73m2. People with mild CKD (GFR 40–90 ml/min/1.73m2) had significantly lower levels of 1,25-dihydroxyvitamin D compared with healthy people.329 (Level 3)

Deficiency of 1,25-dihydroxyvitamin D (<22 pg/ml) was seen as GFR decreased to approximately 45 ml/min/1.73 m2. The prevalence of 1,25-dihydroxyvitamin D deficiency was approximately 15%, 15%, 20%, 30%, 45%, 50%, and 65% in people with eGFR 70–79, 60–69, 50–59, 40–49, 30–39, 20–29, and <20 ml/min/1.73 m2, respectively.328 (Level 3)

Two studies showed that people with stage 4 CKD had significantly lower serum 1,25-dihydroxyvitamin D levels compared with people with stage 3 CKD.326,327 (Level 3)

Serum 25-hydroxyvitamin D

Two studies showed NS differences in serum 25-hydroxyvitamin D with worsening renal function.327,329 (Level 3)

There was NS difference in serum 25-hydroxyvitamin D for people with GFR 30–59 ml/min/1.73 m2 compared with people with GFR 90 ml/min/1.73m2. Compared with people with GFR 90 ml/min/1.73 m2, people with GFR 15–29 ml/min/1.73 m2 had significantly lower serum 25-hydroxyvitamin D.325 (Level 3)

Multiple regression analysis showed NS relationship between eGFR and serum 25-hydroxyvitamin D (p=0.8932). The prevalence of deficiency in serum 25-hydroxyvitamin D (<15 ng/ml) remained stable until GFR <30 ml/min/1.73 m2, when the prevalence of serum 25-hydroxyvitamin D deficiency increased. The prevalence of serum 25-hydroxyvitamin D deficiency was approximately 15%, 20%, and 25% in people with eGFR 39–30, 29–20, and <20 ml/min/1.73 m2, respectively.328 (Level 3)

57% of people with stage 3 CKD and 58% of people with stage 4 CKD had serum 25-hydroxyvitamin D insufficiency (10–30 ng/ml). 14% of people with stage 3 CKD and 26% of people with stage 4 CKD had serum 25-hydroxyvitamin D deficiency (<10 ng/ml).326 (Level 3)

13.1.5. From evidence to recommendations

The GDG noted that in many of the studies the results were not broken down by stage of CKD or level of GFR.

Although there were statistically significant differences in mean calcium concentrations at different levels of GFR these were unlikely to be clinically significant differences. On the basis of the evidence the GDG agreed that there was no need to routinely measure serum calcium concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD.

The GDG noted that although there were statistically significant differences in mean phosphate concentrations at different levels of GFR these values were all within the normal range. Serum phosphate concentrations generally fell within the normal range unless the GFR level was below 20 ml/min/1.73 m2. On the basis of the evidence the GDG agreed that there was no need to routinely measure serum phosphate concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD.

The prevalence of hyperparathyroidism in people with a reduced GFR was higher than in healthy individuals; however, the significance of modestly elevated PTH concentrations was thought unclear and there was no consensus on whether people with concentrations elevated to this extent benefit from treatment. On the basis of the evidence the GDG agreed that there was no requirement to routinely measure serum PTH concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD in the absence of specific indications. Specific indications to measure serum PTH would include unexplained hypercalcaemia and symptoms suggestive of hyperparathyroidism.

The prevalence of abnormally low vitamin D concentrations increased once the GFR fell below 45 ml/min/1.73 m2;328 however, there was no information in this study on the prevalence of low vitamin D concentrations in the general population.

Most laboratories do not measure 1,25 dihydroxyvitamin D concentrations.

On the basis of the evidence the GDG agreed that there was no need to routinely measure serum vitamin D concentrations in people with stage 1, 2 and 3A CKD and that it was not usually necessary to measure it in people with stage 3B CKD except where there are specific indications such as unexplained hypocalcaemia or symptoms suggestive of vitamin D deficiency.

Because of the increased prevalence of abnormal serum calcium, phosphate, PTH and vitamin D concentrations in people with stage 4 and 5 CKD and the fact that these people may require treatment for renal bone disease it was recommended that calcium, phosphate and PTH concentrations should be measured in people with stage 4 and 5 CKD.

There was no evidence to guide a recommendation about how frequently the calcium, phosphate, PTH and vitamin D concentrations should be measured in people with stage 4 and 5 CKD and the GDG agreed that this would be determined by the clinical circumstances.

13.1.6. RECOMMENDATIONS

R64.

The routine measurement of calcium, phosphate, parathyroid hormone (PTH) and vitamin D levels in people with stage 1, 2, 3A or 3B CKD is not recommended.

R65.

Measure serum calcium, phosphate and PTH concentrations in people with stage 4 or 5 CKD (glomerular filtration rate (GFR) <30 ml/min/1.73 m2). Determine the subsequent frequency of testing by the measured values and the clinical circumstances. Where doubt exists seek specialist opinion.

13.2. Risks and benefits of bisphosphonates for preventing osteoporosis in adults with CKD

13.2.1. Clinical introduction

Osteoporosis is caused by the cumulative effect of bone resorption in excess of bone formation. Bisphosphonates inhibit bone resorption with relatively few side effects and are widely used for the prevention and treatment of osteoporosis. Osteoporosis can also develop in people with CKD and ESRD for many reasons beyond age-related bone loss and postmenopausal bone loss. People with CKD are far more likely than the general population to have conditions putting them at risk of osteoporosis and are much more likely to be prescribed medication promoting development of osteoporosis. The diagnosis of osteoporosis in people with advanced CKD is not as straightforward as it is in people with postmenopausal osteoporosis. Neither fragility fractures nor the World Health Organization bone mineral density criteria can be used to diagnose osteoporosis in this population since all forms of renal bone disease may fracture or have low ‘T scores’. The diagnosis of osteoporosis in people with CKD must be done by first excluding the other forms of renal osteodystrophy.330

Bisphosphonates are poorly absorbed orally (1–5% of an oral dose), and absorption is best when the drug is given on an empty stomach. Approximately 80% of the absorbed bisphosphonate is usually cleared by the kidney, the remaining 20% being taken up by bone. Relative bone uptake is increased in conditions of high bone turnover, with less of the drug being excreted by the kidneys. The plasma half-life is approximately one hour, while the bisphosphonate may persist in bone for the lifetime of the patient.

Product data sheets do not recommend bisphosphonates for people with stage 4 or 5 CKD. What is the evidence for this and what is the evidence for the routine use of bisphosphonates in the prevention and treatment of osteoporosis in people with CKD?

13.2.2. Methodology

There were very few papers that examined the effect of bisphosphonates on bone mineral density (BMD) and fracture outcomes in a CKD population.

One open-label RCT was excluded due to limitations in randomisation.331

One RCT (N=38, 1 year follow-up) investigated the effects of risedronate with and without vitamin D in people with CKD (mean eGFR 78 ml/min) with high dose corticosteroid-induced bone loss.332 Corticosteroids are frequently used in the treatment of kidney disease and even at low doses may cause osteoporosis and bone fractures. Limitations of this study include the small sample size, although there was no loss to follow-up.

A meta-analysis of data from nine phase III trials (N=9883, 2 years follow-up, mean age 75 years) investigated the effects of risedronate in osteoporotic women with varying levels of renal function.333 Although this was not a systematic review and included only phase III trials, due to lack of other evidence, this paper was included. 91% of the pooled cases had some degree of renal impairment and the analyses were conducted in categories of patients with mild (CrCl 50–80 ml/min), moderate (CrCl 30–50 ml/min) or severe (CrCl <30 ml/min) renal dysfunction.

A post-hoc analysis of the Fracture Intervention Trial (FIT, N=6458, 3 year follow-up, mean age 68 years)334 investigated the effects of alendronate on BMD and fracture in osteoporotic women with moderate/normal renal function (eGFR 45 ml/min, N=5877) or severe renal dysfunction (eGFR <45 ml/min, N=581).

The safety and efficacy of bisphosphonates in preventing osteoporosis in people with CKD are summarised in Table 13.2, at the end of the evidence statements.

Table 13.2. Summary of the safety and efficacy of bisphosphonates in preventing osteoporosis in people with CKD (95% confidence intervals).

Table 13.2

Summary of the safety and efficacy of bisphosphonates in preventing osteoporosis in people with CKD (95% confidence intervals).

13.2.3. Health economics methodology

There were no health economics papers found to review.

13.2.4. Evidence statements

Risedronate

Change in BMD

Combination therapy of risedronate (2.5 mg/day) and vitamin D together resulted in a significant increase in BMD, whereas BMD significantly decreased in the vitamin D alone group. There was a NS decline in BMD in the risedronate group. The difference between BMD changes in the risedronate and vitamin D combination therapy group and the vitamin D alone group were statistically significant.332 (Level 1+)

The mean percent increase from baseline to endpoint in BMD at the lumbar spine, femoral neck and trochanter was significantly greater in the risedronate (5 mg/day) arm than in the placebo arm in all mild, moderate and severe renal impairment subgroups, with the exception of the femoral neck in the severe renal impairment subgroup.333 (Level 1+)

Fractures

In one RCT, no fractures occurred over 1 year of follow-up.332 (Level 1+)

The incidence of new vertebral fractures was significantly lower in the risedronate (5 mg/day) group than placebo groups within mild, moderate and severe renal impairment subgroups.333 Within the risedronate treatment group, the incidence of new vertebral fractures was similar across renal impairment subgroups (p=0.124). Within the placebo group, new vertebral fractures increased significantly with increasing severity of renal impairment (p<0.001). (Level 1+)

Adverse events

There were no adverse events in any of the treatment arms in the Kikuchi et al. RCT. (Level 1+)

The incidence of overall, urinary and renal function related adverse events were similar between risedronate (5 mg/day) and placebo groups in the subgroups of patients with severe, moderate and mild renal impairment.333 (Level 1+)

Alendronate

Change in BMD

Alendronate increased BMD at the total hip, femoral neck and spine to a greater extent in postmenopausal women with eGFR <45 ml/min, than in women with eGFR 45 ml/min. There was a significant interaction between renal function and the increase in total hip BMD (p=0.04). Among women with osteoporosis (N=3214), alendronate produced a greater increase in BMD at the hip and femoral neck in the group with eGFR <45 ml/min than women with eGFR 45 ml/min. However at the spine the increase in BMD was greater in women with eGFR 45 ml/min. There was no significant interaction between renal function and increase in BMD.334 (Level 1+)

Fractures

Overall, alendronate significantly reduced the risk of clinical fractures (OR 0.8, 95% CI 0.7–0.9) and spine factures (OR 0.54, 95% CI 0.37–0.87) compared with placebo. The risk reduction was significant in women with eGFR 45 ml/min for both clinical and spine fractures, but NS in women with eGFR <45 ml/min. (Level 1+)

Women with a reduced eGFR <45 ml/min had an increased risk of any clinical fracture (OR 1.3, 95% CI 1.0–1.6) and of spine fractures (OR 2.5, 95% CI 1.6–3.9) compared with women with an eGFR 45 ml/min.334 (Level 1+)

Adverse events

There was no difference for adverse events among women with reduced renal function compared with women without reduced renal function (p=0.189).334 (Level 1+)

13.2.5. From evidence to recommendations

The GDG concluded that from the studies presented there was no evidence of an increased risk of drug related adverse events in people with CKD. Bisphosphonates appeared to have benefits on bone mineral density in people with CKD.

The studies did not include prevention of osteoporosis in people with a GFR <30 ml/min/1.73 m2 and therefore there is no evidence about either the effectiveness or the safety of bisphosphonates in this group.

Guidelines on the management of osteoporosis do not make recommendations that relate to people with CKD.

The dose of bisphosphonate may need adjusting according to the GFR and clinicians should refer to the drugs’ Summary of Product Characteristics (SPC) for guidance on this.

13.2.6. RECOMMENDATIONS

R66.

Offer bisphosphonates if indicated for the prevention and treatment of osteoporosis in people with stage 1, 2, 3A or 3B CKD.

13.3. Vitamin D supplementation in people with CKD

13.3.1. Clinical introduction

Vitamin D is normally either ingested or synthesised in the skin under the influence of sunlight. It is then hydroxylated in the liver to form 25-hydroxyvitamin D (calcidiol) and then hydroxylated in the kidney to 1,25-dihydroxyvitamin D (calcitriol), which is the most active form. Vitamin D deficiency can therefore occur as a result of decreased intake or absorption, reduced sun exposure, increased hepatic catabolism, or decreased endogenous synthesis (via 25-hydroxylation in the liver and subsequent 1-hydroxylation in the kidney). Active vitamin D has a variety of actions on calcium, phosphate, and bone metabolism. By increasing intestinal calcium and phosphate reabsorption and increasing the effect of parathyroid hormone (PTH) on bone, in health vitamin D has the net effect of increasing the serum calcium and phosphate concentrations. Vitamin D deficiency or resistance interferes with these processes, sometimes causing hypocalcaemia and hypophosphataemia. Since hypocalcaemia stimulates the release of PTH, however, the development of hypocalcaemia is often masked. The secondary hyperparathyroidism, via its actions on bone and the kidney, partially corrects the hypocalcaemia but enhances urinary phosphate excretion, thereby contributing to the development of hypophosphataemia. In people with CKD the kidney component of this loop is increasingly compromised as CKD advances.

As renal function declines, the hydroxylating activity of renal 1α-hydroxylase on 25-hydroxyvitamin D3 also decreases, resulting in decreased production of active vitamin D (1,25-dihydroxyvitamin D3) and decreased intestinal absorption of calcium. The decrease in calcium and active vitamin D3 alleviates the repression of parathyroid hormone (PTH) production, resulting in hyperproliferation of parathyroid cells. High PTH levels cause an increase in bone remodelling, leading to high bone-turnover (osteitis fibrosa), loss of bone density and structure. This excess bone remodelling liberates calcium and phosphorus from bone, resulting in hypercalcaemia and hyperphosphataemia and increasing the risk for vascular calcification.

Vitamin D supplementation in people with CKD should therefore be driven by the underlying metabolic abnormality. This in turn will depend on the stage of CKD but is complicated by the fact that in the population with the highest prevalence of CKD, the older population, vitamin D deficiency is common. Cutaneous vitamin D production and vitamin D stores decline with age coupled with the fact that intake is often low in older subjects. Furthermore, even in those with adequate vitamin D intake, achlorhydria, which is common in older people, limits vitamin D absorption. Nutritional forms of vitamin D include ergocalciferol and cholecalciferol; active forms of vitamin D include alfacalcidol, calcitriol and paricalcitol. Elderly patients are likely to be vitamin D deficient from diet, lack of sunlight and poor absorption for which they will need nutritional vitamin D. However as CKD progresses (particularly in stages 4 and 5), renal function is impaired to such a degree that active vitamin D may also be required.

What type of vitamin D supplementation, if any, should be used in adults with CKD?

13.3.2. Methodology

Eight RCTs and one case series investigated the safety and efficacy of various natural and synthetic vitamin D metabolites to treat secondary hyperparathyroidism and to prevent bone loss in people with pre-dialysis CKD. Outcomes of interest included adverse events, fractures, changes in serum calcium, phosphorus, PTH, osteocalcin, alkaline phosphatase, GFR, and bone mineral density. All of these studies are limited by small sample sizes (N=25–220), and very few presented intention to treat analyses. There were no studies of acceptable methodological quality that compared different vitamin D metabolites head-to-head.

Four RCTs335–338 compared calcitriol supplementation to placebo in people with CKD. Two of these RCTs titrated the dose of calcitriol from 0.25 μg/day up to 0.5 μg/day.335,336 In the RCT of Przedlacki et al., treatment with calcitriol (0.25 μg/day, N=13, 12 months follow-up) was compared with placebo (N=12) in people with eGFR <51.2 ml/min. In the RCT of Ritz et al., a low dose of calcitriol (0.125 μg/day, N=28, follow-up 1 year) was compared with placebo (N=24) in people with nondiabetic CKD and abnormal iPTH levels (iPTH >6 pmol/l on 3 separate occasions). The Baker et al. study (N=13, follow-up 12 months) was excluded due to small sample size, high dropout rate, and lack of baseline data comparison between the two trial arms.

One RCT compared 6 months of treatment with calcitrol (N=8, 1 μg/day) or calcidiol (N=9, 4000 IU/day) in people with chronic renal failure.339 This study was rejected because there was no indication of blinding, concealment, intention to treat, and statistical power to detect differences between the two groups.

Two RCTs investigated the effects of treatment with alfacalcidol (1-α-hydroxycholecalciferol) compared to placebo in people with mild to moderate CKD (creatinine clearance 10–60 ml/min).340,341 The Hamdy et al. RCT (N=89 alfacalcidol and N=87 placebo, 24 months follow-up) titrated the dose of alfacalcidol from 0.25 to 1 μg/day. Most of the participants had abnormal bone histology at baseline (NS difference between the trial arms). The smaller RCT of Rix et al. (N=36, 18 months follow-up) titrated alfacalcidol from 0.25 to 0.75 μg/day.

A pooled analysis of 3 RCTs with identical inclusion/exclusion criteria and different dosing regimens (3 times weekly or once daily) compared paricalcitol (N=107, 6 months follow-up, mean dose was 1.3 to 1.4 μg/day) with placebo (N=113) in people with CKD and hyperparathyroidism (iPTH 150 pg/ml). Although this study was not a systematic review, it was included as an RCT (albeit pooled) due to lack of studies of non-dialysis CKD populations.342

One retrospective case series examined changes in serum calcium, phosphate, iPTH, and adverse events before and after 6 months’ treatment with ergocalciferol (vitamin D2) in men with stage 3 CKD and plasma iPTH >70 ng/l (N=44) or stage 4 CKD and plasma iPTH >110 ng/l (N=22).343

13.3.3. Health economics methodology

There were no health economics papers found to review.

13.3.4. Evidence statements

Calcitrol versus placebo

Refer to Table 13.3 for summary of studies.

Table 13.3. Summary of studies comparing calcitrol with placebo.

Table 13.3

Summary of studies comparing calcitrol with placebo.

Serum calcium

One RCT showed that serum calcium significantly increased with calcitrol (0.25 titrated to 0.5 μg/day) compared with placebo.336 (Level 1+)

Two RCTs showed NS changes in mean serum calcium in people taking calcitrol (0.25 μg/day steady or 0.125 μg/day) or placebo.337,338 (Level 1 +)

Serum phosphorus

Three RCTs showed that mean serum phosphate did NS change in either the placebo or calcitrol groups.336–338 (Level 1 +)

Serum parathyroid hormone (PTH)

Two RCTs showed that iPTH significantly decreased in people receiving calcitrol, whereas in the placebo groups, iPTH levels either increased significantly336 or did not significantly change.337 (Level 1 +)

One RCT showed that iPTH decreased from baseline in the calcitrol group whereas iPTH increased from baseline in those taking placebo (p<0.05 between placebo and calcitrol groups).338 (Level 1 +)

Serum alkaline phosphatase (ALP)

Two RCTs showed that serum ALP decreased significantly in people taking calcitrol, whereas there were NS changes in ALP in people taking placebo.336,337 (Level 1 +)

Serum osteocalcin

One RCT showed that mean serum osteocalcin significantly decreased in the calcitrol group, whereas osteocalcin significantly increased in the placebo group.337 (Level 1 +)

Change in eGFR or creatinine clearance

Two RCTs showed that creatinine clearance or GFR significantly decreased in both the calcitrol and the placebo groups, but there were NS differences between the groups.336,337 (Level 1)

Bone mineral density (BMD)

BMD of the lumbar spine (L2–L4), femoral neck, and trochanter significantly increased in the calcitrol group. By contrast BMD of the lumbar spine (L2–L4), femoral neck, and trochanter significantly decreased in the placebo group (p<0.01 between groups).337 (Level 1+)

Indices of bone formation, remodelling and structure

There were NS changes in bone volume in placebo or calcitrol groups.336 (Level 1+)

Indices of bone formation, remodelling and structure (osteoid volume, osteoid thickness, osteoid surface, eroded surface, osteoclast surface, bone formation rate, mineralisation surface, and mineral apposition rate, singly labelled trabecular surfaces) significantly decreased in the calcitrol group, whereas there were NS changes in the placebo group.336 (Level 1+)

There were NS changes in doubly labelled trabecular surfaces in calcitrol or placebo groups. (Level 1+)

Adverse events

Hypercalcaemia (>2.6 mmol/l) was observed in 2/13 people receiving calcitrol and 0/12 receiving placebo. Hyperionised calcaemia (blood ionised Ca >1.29 mmol/l) occurred in 5/13 on calcitrol and 3/12 in the placebo group.337

There was no hypercalcaemia (>2.7 mmol/l on three consecutive occasions) in either calcitrol (0.125 μg/day) or placebo groups.338

There was no hyperphosphataemia (>2.2 mmol/l on 3 consecutive occasions) in either calcitrol (0.125 μg/day) or placebo groups.338

Hyperphosphataemia (P >1.5 mmol/l) occurred in 3/12 placebo and 10/13 randomised to calcitrol (NS between groups).337 (Level 1+)

Alfacalcidol (1α-hydroxycholecalciferol) versus placebo

Refer to Table 13.4 at the end of the evidence statements for a summary of studies.

Table 13.4. Summary of studies comparing alfacalcidol with placebo.

Table 13.4

Summary of studies comparing alfacalcidol with placebo.

Serum calcium

Two RCTs showed that mean serum calcium increased significantly in people taking alfacalcidol, while there were NS changes in calcium in people taking placebo, p<0.001 between groups.340,341 (Level 1 +)

Serum phosphorus

Two RCTs showed that there were NS changes in serum P in the alfacalcidol or placebo groups.340,341 (Level 1+)

Serum parathyroid hormone (PTH)

The RCT of Hamdy et al. showed a NS decrease in iPTH with alfacalcidol treatment and a significant increase in iPTH in the placebo group. At 24 months, iPTH returned to baseline levels in those with alfacalcidol treatment. (Level 1+)

The RCT of Rix et al. showed a significant decrease in iPTH with treatment with alfacalcidol, whereas there were NS changes in iPTH in the placebo group, p<0.05 between groups. (Level 1+)

Serum alkaline phosphatase (ALP)

Bone-specific ALP significantly decreased in the alfacalcidol group, whereas there was NS change in ALP in the placebo group.341 (Level 1+)

Serum osteocalcin

Osteocalcin significantly decreased in the alfacalcidol group, whereas there was NS change in osteocalcin in the placebo group. At the end of the study only 1 person in the alfacalcidol group had osteocalcin levels above the reference range (4.2–31.4 ng/ml), whereas 6 people in the placebo group had osteocalcin levels exceeding reference ranges.341 (Level 1+)

Change in creatinine clearance

Two RCTs showed that CrCl decreased significantly in both placebo and alfacalcidol groups, but there were NS differences between treatments.340,341 (Level 1+)

Bone mineral density (BMD)

There was a significant difference for BMD of the spine in the alfacalcidol versus placebo group (4.2%, p<0.05).341 (Level 1+)

There was a significant difference for BMD of the femoral neck in the alfacalcidol versus placebo group (4.9%, p<0.05).341 (Level 1+)

There were NS changes in total body BMD or forearm BMD in the placebo or the alfacalcidol groups.341 (Level 1+)

Indices of bone formation, remodelling and structure

In people with histological bone abnormalities at baseline (N=100), there were NS differences in bone volume in the placebo (N=45) or alfacalcidol (N=55). (Level 1+)

Osteomalacia improved in people taking alfacalcidol as the number of osteoid lamellae decreased whereas the number of osteoid lamellae increased in the placebo group, p=0.002 between groups. (Level 1+)

The proportion of people with bone abnormalities at the beginning of the study was similar between the placebo (73%) and alfacalcidol (76%) groups. After 24 months treatment, 54% of people taking alfacalcidol and 82% on placebo had bone abnormalities (no p given). (Level 1+)

Fibrosis significantly decreased in people taking alfacalcidol, while fibrosis increased in the placebo group, p=0.0002 between groups. (Level 1+)

Osteoid volume, osteoid surface, osteoblast surface, and osteoclast surface all decreased significantly in the alfacalcidol group, whereas there were NS changes in any of these parameters in the placebo group, p<0.05 between groups for each outcome. (Level 1+)

There were NS differences in mineral apposition rate between placebo or alfacalcidol groups. (Level 1+)

Bone formation rate decreased significantly in alfacalcidol group, but there was NS change in placebo and NS difference between groups. (Level 1+)

Bone resorption decreased in people taking alfacalcidol compared with placebo. The eroded bone surface significantly decreased in the alfacalcidol group while it increased in the placebo group, p=0.04 between groups. Also, alfacalcidol was associated with a significant decrease of active eroded surface compared with placebo, p=0.0006 between groups.340 (Level 1+)

Adverse events

Mild hypercalcaemia (>2.63 mmol/l on 2 occasions) was seen in 10/89 patients receiving alfacalcidol and 3/87 patients receiving placebo (p=0.09, NS). Severe hypercalcaemia (>3.00 mmol/l on 1 occasion) was observed in 4 people taking alfacalcidol and 0 people on placebo.340 (Level 1+)

Hypercalcaemia occurred in 1/18 people on alfacalidol.341 (Level 1+)

Mild GI disturbances were reported in 6/89 people on alfacalcidol and 1/87 on placebo.340 (Level 1+)

Pseudogout was reported by 2/89 people on alfacalcidol.340,340 (Level 1+)

Paricalcitol versus placebo

Refer to Table 13.5 for a summary of studies.

Table 13.5. Summary of studies comparing paricalcitol with placebo.

Table 13.5

Summary of studies comparing paricalcitol with placebo.

Serum calcium

Mean serum calcium increased slightly in people taking paricalcitol, while there were small decreases in serum calcium in the placebo group, NS between groups.342 (Level 1+)

Serum phosphorus

There were NS changes in serum phosphate in the paricalcitol or placebo groups.342 (Level 1 +)

Serum parathyroid hormone (PTH)

Serum iPTH decreased significantly from baseline to 6 months treatment with paricalcitol, whereas iPTH increased in the placebo group (p<0.001 between groups).342 (Level 1+)

Serum alkaline phosphatase (ALP)

Bone-specific ALP significantly decreased from baseline to 6 months in the paricalcitol group, compared with a smaller decrease in bone ALP in the placebo group, p<0.001 between groups.342 (Level 1+)

Serum osteocalcin

Serum osteocalcin significantly decreased in the paricalcitol group, compared with an increase in osteocalcin in the placebo group (p<0.001 between groups).342 (Level 1+)

Change in GFR

After 6 months, eGFR decreased in both placebo and paricalcitol groups, but there were NS differences between treatments.342 (Level 1+)

Two consecutive reductions in iPTH ≥30% from baseline

Significantly more people taking paricalcitol achieved 2 consecutive ≥30% decreases in serum iPTH from baseline compared with people taking placebo (p<0.001 between groups). Significantly more people taking paricalcitol achieved iPTH <110 ng/l compared with those on placebo.342 (Level 1+)

Four consecutive reductions in iPTH ≥30% from baseline

Significantly more people taking paricalcitol achieved 4 consecutive ≥30% decreases in serum iPTH from baseline compared with the placebo group (p<0.001 between groups).342 (Level 1+)

Urinary deoxypryidinoline

There were NS differences between paricalcitol or placebo groups for changes in urinary deoxypryidinoline.342 (Level 1+)

Urinary pyridinoline

Urinary pyridinoline decreased significantly in the paricalcitol group, compared with an increase in the placebo group (p=0.006 between groups).342 (Level 1+)

Adverse events

Hypercalcaemia (2 consecutive Ca >2.62 mmol/l) occurred in 2 people on paricalcitol and no people on placebo (NS).

Hyperphosphataemia (2 consecutive PO4 >1.78 mmol/l) occurred in 11 people on paricalcitol and 13 people on placebo (NS).342 (Level 1+)

Before versus after treatment with ergocalciferol (vitamin D2)

Serum calcium

Mean serum calcium did NS change after 6 months treatment with ergocalciferol in the whole group (N=66), stage 3 CKD alone (N=44) or stage 4 CKD alone (N=22).343 (Level 3)

Serum phosphate

Mean serum phosphate did NS change after 6 months treatment with ergocalciferol in the whole group, stage 3 CKD alone or stage 4 CKD alone.343 (Level 3)

Serum parathyroid hormone (PTH)

In those with stage 3 CKD (N=44), iPTH significantly decreased after 6 months of ergocalciferol treatment (−22%, p<0.005). In the stage 4 CKD group (N=22) there was NS change in iPTH.343 (Level 3)

Adverse events

There were no cases of hypercalcaemia or hyperphosphataemia before or after ergocalciferol.343 (Level 3)

13.3.5. From evidence to recommendations

The classification in the BNF344 of the forms of vitamin D available as pharmacological supplementation can be confusing. Both preparations containing ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) are listed under the heading ‘ergocalciferol’.

Tablets of ergocalciferol combined with calcium are the cheapest form of vitamin D, but preparations of cholecalciferol combined with calcium are also cheaper than alfacalcidol and calcitriol. The GDG observed that cholecalciferol is the most commonly prescribed form used to treat simple vitamin D deficiency in primary care.

The GDG noted that the costs of 1-α-hydroxyvitamin D (alfacalcidol) and 1,25-dihydroxy-vitamin D (calcitrol) are very similar.

There is no evidence as to whether one form of vitamin D is more effective than another as all the studies were comparisons with placebo and there were no trials that looked at 25-hydroxyvitamin D.

The GDG noted that all forms of vitamin D will suppress PTH secretion.

It was agreed that given the similar prevalence of vitamin D deficiency in people with stage 1, 2, 3A and 3B CKD it was most likely that the deficiency was related to poor dietary intake or limited sunlight exposure. Renal hydroxylation was likely to be normal in these people. They therefore recommended that ergocalciferol or cholecalciferol should be the first treatment used to treat vitamin D deficiency in these people.

Because of reduced renal hydroxylation in people with stage 4 and 5 CKD the GDG recommended that when vitamin D supplementation was necessary in these people, it should be with the 1-α-hydroxylated or 1,25-dihydroxylated forms.

Although no statistically significant increase in the overall frequency of hypercalcaemia was observed in people with CKD given vitamin D, severe hypercalcaemia occurred in 4 people on calcitriol versus 0 people in the placebo group in one study of calcitriol. The GDG also noted that the BNF suggests that ‘all people receiving pharmacological doses of vitamin D should have the plasma calcium concentration checked at intervals (initially weekly) and whenever nausea or vomiting are present’. The GDG recommended that further research should be undertaken on the occurrence of hypercalcaemia in people with CKD treated with different vitamin D preparations.

13.3.6. RECOMMENDATIONS

R67.

When vitamin D supplementation is indicated in people with CKD, offer:

  • cholecalciferol or ergocalciferol to people with stage 1, 2, 3A or 3B CKD
  • 1-α-hydroxycholecalciferol (alfacalcidol) or 1,25-dihydroxycholecalciferol (calcitriol) to people with stage 4 or 5 CKD.
R68.

Monitor serum calcium and phosphate concentrations in people receiving 1-α-hydroxycholecalciferol or 1,25-dihydroxycholecalciferol supplementation.*

Footnotes

*

Detailed advice concerning management of bone and mineral disorders in CKD is beyond the scope of this guideline. Where uncertainty exists seek advice from your local renal service.