Vitamin D therapy

It is important to monitor vitamin D therapy aggressively to assure that PTH levels are not oversuppressed. Oversuppression of PTH levels can induce adynamic bone disease, which manifests as decreased osteoblast and osteoclast activity, decreased bone formation, and low bone turnover. 

Cinacalcet is a calcimimetic that increases the sensitivity of receptors on the parathyroid gland to serum calcium levels to reduce PTH secretion. Cinacalcet maybe beneficial in patients with an increased Ca-P product who have elevated PTH levels and cannot use vitamin D therapy. Because the effects of cinacalcet on PTH can reduce serum calcium levels and result in hypocalcemia, cinacalcet should not be used if serum calcium levels are below normal. 

Calcium (less than 9.5 mg/dL) and phosphorus (less than 4.6 mg/dL) must be controlled before vitamin D therapy is initiated. 

Adequate dietary calcium is necessary for clinical response to vitamin D therapy... 

Patients with nephrotic syndrome can lose vitamin D metabolites in the urine, presumably by loss of the vitamin D-binding protein. Such patients may have very low 25(OH)D levels. Some of them develop bone disease. It is not yet clear what value vitamin D therapy has in such patients, because therapeutic trials with vitamin D (or any other vitamin D metabolite) have not yet been carried out. Because the problem is not related to vitamin D metabolism, one would not anticipate any advantage in using the more expensive vitamin D metabolites in place of vitamin D itself. 

Ishida M et al Management of calcium, phosphorus, and bone metabolism in dialysis patients using sevalamer hydrochloride and vitamin D therapy. Ther Apher Dial 2005 9(Suppl 1) S16. 

T FIGURE 10-20 Vitamin D3 production and metabolism, (a) Cholecalciferol (vitamin D3) is produced in the skin by UV irradiation of 7-dehydrocholesterol, which breaks the bond shaded pink. In the liver, a hydroxyl group is added at C-25 (pink) in the kidney, a second hydroxylation at C-1 (pink) produces the active hormone, 1,25-dihydroxycholecalciferol. This hormone regulates the metabolism of Ca2+ in kidney, intestine, and bone, (b) Dietary vitamin D prevents rickets, a disease once common in cold climates where heavy clothing blocks the UV component of sunlight necessary for the production of vitamin D3 in skin. On the left is a 21/2-year-old boy with severe rickets on the right, the same boy at age 5, after 14 months of vitamin D therapy. 

Albright F, Butler AM, Bloom E. Rickets resistant to vitamin D therapy. Am J Dis Child 1937 54 529 14. 

Much clinical and experimental experience has been obtained about the manifestation of bone diseases, especially in renal patients. Many patients with Al-induced bone disease remain asymptomatic. There are two distinct forms of Al bone disease. The most severe form is osteomalacia, with recurrent fractures and resistance to vitamin D therapy. This disease is characterized by an increase of osteoid due to a mineralization defect induced by Al that is localized at a critical site in the bone, i.e., the osteoid calcification front [250]. The adynamic bone disease is another form of Al-related bone disease, characterized by a reduced bone turnover [97]. Al can have a direct negative effect on the bone by deposition at the mineralization front, causing a defective calcification. This is due to the influence of Al on calcium-phosphorus precipitation, crystal formation and crystal growth [251]. There might also be a toxic effect on the proliferation of osteoblasts and on mature osteoblasts with a time- and dose-dependent effect on osteoblast growth and function [143]. 

Alfacalcidol or calcitriol, but not ergocalciferol, should be prescribed if patients with severe renal impairment require vitamin D therapy (see above). 

Adachi JD, loannidis G. Calcium and vitamin D therapy in corticosteroid-induced bone loss what is the evidence Calcif Tissue Int 1999 65(4) 332-6. 

Bosch B, Plank C, Rascher W, Dbtsch J. Hyperkalzamie als Folge einer hoch dosierten Vitamin-D-Therapie bei terminaler Niereninsuffizienz. Monatsschr Kinderheilk 2002 150 1508-12. 

Management of hyperphosphatemia, calcium balance, and secondary hyperparathyroidism includes dietary phosphorus restriction, use of phosphate binding agents, and vitamin D therapy. 

A multiphcity of metabolic disorders in patients with CKD contributes to worsening sHPT and the consequences associated with elevated PTH (Fig. 44-4). The continuous production of PTH by the parathyroid glands leads to parathyroid hyperplasia (nodular or diffuse). Nodular tissue demonstrates more rapid growth potential and appears to be associated with fewer vitamin D and calcium-sensing receptors, which results in resistance to the effects of calcium and vitamin D therapy and subsequent development of ROD. Bone loss can be detected in patients with early stages of kidney disease and multiple types of bone lesions have been identified from bone biopsies of patients on dialysis. The skeletal complications associated with ROD... 

I Adverse Effects. While all agents are effective in suppressing PTH levels, they differ in the degree to which they cause other metabolic abnormalities. Adverse effects of note with vitamin D therapy in patients treated for sHPT include hypercalcemia and hyperphosphatemia. Differences in calcitriol and vitamin D analogs have been demonstrated in animal studies and in clinical trials evaluating the effect on reduction of PTH while minimizing the risk of these adverse consequences. 

Active vitamin D therapy should be initiated in patients with Stage 3 or 4 CKD with oral calcitriol 0.25 meg per day or oral doxercalciferol 2.5 meg three times per week. Prior to starting therapy the serum calcium aud phosphorus should be well coutrolled (serum calcium <9.5 mg/dL aud phosphorus <4.6 mg/dL) to minimize the risk of hypercalcemia and an elevated Ca x P. In patients with Stage 5 CKD there is a clearly defined role for treatment with active vitamin D or a vitamin D analog since the conversion of precursors to active vitamin D is impaired. Dosing recommendations based on PTH are provided in Table 44—8. Serum calcium and Ca x P should be monitored regularly while the patient is receiving therapy. ... 

Medications are another cause of hyperphosphatemia. Excessive intravenous or oral administration of phosphorus is an obvious potential cause of elevated serum phosphate concentrations. Phosphate-containing enemas increase concentrations, especially in those with renal insufficiency. Intravenous or oral vitamin D therapy can increase absorption of phosphorus in the gastrointestinal tract by up to 50%. Bisphosphonate therapy is associated with increased serum phosphate concentrations. Acute phosphorus poisoning as a result of ingestion of laundry detergents is a rare and often unrecognized cause of elevated phosphate concentrations. 

Treatment of osteomalacia from vitamin D deficiency is vitamin D therapy, with dose depending on severity. Supplements of 800 to 4000 units/day or 50,000 units weekly for 8 weeks may be necessary. For sprue, a gluten-free diet is necessary. With intestinal malabsorption, high oral doses (50,000 to 100,000 units/day) or daily intramuscular injections of 10,000 units of vitamin D may be initially required. With disordered vitamin D metabohsm caused by anticonvulsants or rifampin, supplemental vitamin D (4000 units/day) can be effective. Sun exposure can also be useful. Serum calcium and 25(OH) vitamin D monitoring is necessary with high vitamin D doses. 

In recent years, several reports have appeared, particularly from Britain, concerning vitamin D-responsive osteomalacia due to nutritional causes (C29, H16, S76, W27). Most of the patients described were immigrants from India or Pakistan whose diet contained a high content of phytic acid (W27). Serum alkaline phosphatase activities in these patients ranged from normal to 20 times the upper reference limit for adults. After the commencement of therapy, activities fell to half the mean pretreatment values within approximately 4 months (C30, S76), although in some patients, this fall was difficult to distinguish from that normally seen in the peripubertal period (C29). In patients with very high serum alkaline phosphatase values, vitamin D therapy produced more spectacular reductions than in patients with mild elevations (H16, S76). 

Riancho, J.A. et al. (1993) Vitamin D therapy modulates cytokine secretion in patients with renal failure. Nephron, 65, 364-368. 

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