Prevention of Secondary Hyperparathyroidism With Vitamin D in Stage II/III Chronic Kidney Disease

Vitamin D is important to maintain normal calcium homeostasis and optimal bone health (1,
2). The synthesis of vitamin D and its metabolism to 1,25(OH)2D is regulated by parathyroid
hormone (PTH), serum calcium, and phosphorus levels. In response to low serum calcium level,
serum PTH activates alpha-1-hydroxylase for increased 1,25(OH)2D production in the kidney
and also enhances tubular reabsorption of calcium (3). The higher levels of 1, 25(OH)2D
results in increased intestinal calcium absorption (4). Increased serum phosphorus levels
which occurs in the early stages of chronic kidney disease (CKD) results in inhibition of
the 1-alpha-hydroxylase, which results in decreased 1, 25(OH)2 D production, decreased
intestinal calcium absorption leading to secondary hyperparathyroidism with increased PTH
levels. Circulating 1,25(OH)2D levels begin to fall when the glomerular filtration rate is
less than 40 mL/min occasionally even less than 80 mL/min (11) and almost always
significantly reduced in subjects with end-stage renal failure (12). Furthermore, in CKD,
decreased renal mass also results in decreased expression of 1-alpha-hydroxlase and less
production of 1,25(OH)2D which also exacerbates secondary hyperparathyroidism (5-7).

Therefore, in CKD there are three processes that lead to secondary hyperparathyroidism. 1)
decreased renal mass leading to decreased production of 1,25(OH)2D leading to a compensatory
rise in PTH to further enhance production of 1,25(OH)2D 2) inhibition of the renal
1-alpha-hydroxylase by accumulating phosphorus levels leading to decreased 1,25(OH)2D which
also leads to secondary hyperparathyroidism. 3) increased phosphorus leads to lower ionized
calcium leading to increased parathyroid hormone secretion.

Untreated secondary hyperparathyroidism can lead to renal osteodystrophy (9) and increased
mortality due to cardiovascular disease (10). Prolonged secondary hyperparathyroidism can
lead to bone resorption and eventually autonomous parathyroid hormone secretion termed
tertiary hyperparathyroidism.

Vitamin D status is one of the major factors that may prevent progression of secondary
hyperparathyroidism in patients with CKD. Insufficient levels of 25-hydroxyvitamin D
further exacerbate secondary hyperparathyroidism by not providing adequate substrate for the
renal 1-alpha-hydroxylase for conversion to the active form of vitamin D, 1,25(OH)2D. A
recent cross-sectional study on patients with moderate to severe CKD not yet on dialysis
therapy from 12 geographically diverse regions of the United States has shown that only 29%
and 17% of them had sufficient level, respectively (13). Vitamin D status is easily
corrected. In our previous study we concluded that weekly cholecalciferol supplementation
was an effective treatment to correct vitamin D status in patients with CKD stages III and
IV (14). However, PTH levels did not return to normal. Therefore, it is likely that
earlier intervention with vitamin D is necessary to prevent rather than to treat secondary
hyperparathyroidism. This is the major question that is being evaluated in this study. Can
intervening with vitamin D at an earlier stage of chronic kidney disease result in decreased
incidence of secondary hyperparathyroidism?

2.0 Objectives

2.1 Overall Objective

The primary objective of this study is to assess that if improving and maintaining an
optimal 25(OH) D level ( by National Kidney Foundation should be greater than 30ng/ml) (15)
in people with stage II/III Chronic Kidney disease would delay the progression of secondary
hyperparathyroidism and translate into improved markers of bone turnover

2.2 Specific Aims

Primary: 1) To determine in a double blind, randomized study whether supplementation with
50,000 IU of cholecalciferol (vitamin D3) given weekly for 12 weeks followed by maintenance
cholecalciferol 50,000 IU every other week would improve and maintain vitamin D status in
CKD patients stage 2/3 compared to placebo at 12 months.

2) To determine whether early intervention with vitamin D therapy further decreases PTH
levels after 12 weeks of therapy and 12 months of therapy.

Secondary: 1) To determine whether early treatment with vitamin D results in improving
levels of bone turnover markers- tartrate-resistant acid phosphatase isoform 5b(TRAP5b),
procollagen Type 1 N-Terminal propeptide (PINP), serum C-Telopeptide and Alkaline
phosphatase.