Secondary hyperparathyroidism

Cole, D. E. C., Janicic, N., Salisbury, S. R., and Hendy, G. N. (1997) Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and famdial hypocalciuric hypercalcemia multiple different phenotypes associated with an inactivating alu insertion mutation of the calcium-sensing receptor gene. Am. J. Med Genet. 71, 202-210. 

Osteitis fibrosa (hyperparathyroid bone disease) is the most common high-turnover bone disease. This disorder is caused by the high concentrations of serum PTH in secondary hyperparathyroidism. Secondary hyperparathyroidism is a consequence of the hypocalcemia associated with hyperphosphatemia and l,25(OH)2D deficiency. Hyperphosphatemia is a result of the kidneys inability to excrete phosphate. l,25(OH)2D deficiency results from the inability of the kidneys to synthesize l,25(OH)2 because of decreased renal mass and suppression of 25(OH)D-la-hydroxylase activity by high concentrations of phosphate. Deficiency of l,25(OH)2D leads to reduced intestinal absorption of calcium and reduced inhibition of PTH secretion by l,25(OH)2D. Skeletal resistance to PTH also contributes to the hypocalcemia and secondary hyperparathyroidism. 

Block GA, Martin KJ, de Francisco AL et al (2004) Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med 350 1516-1525... 

Primary hyperparathyroidism occurs as a result of hyperplasia or the occurrence of adenoma. Secondary hyperparathyroidism may result from renal failure because of the associated phosphate retention, resistance to the metabolic actions of PTH, or impaired vitamin D metabolism. The last-mentioned factor is primarily responsible for the development of osteomalacia. Muscle symptoms are much more common in patients with osteomalacia than in primary hyperparathyroidism. Muscle biopsy has revealed disseminated atrophy, sometimes confined to type 2 fibers, but in other cases involving both fiber types. Clinical features of osteomalacic myopathy are proximal limb weakness and associated bone pain the condition responds well to treatment with vitamin D. 

Insulin is a powerful anabolic hormone but it is unlikely that insulin deficiency causes skeletal muscle atrophy by direct action on muscle fibers (as opposed to neurogenic atrophy) except in chronic untreated cases. There is however a close parallel between the catabolic states induced by glucocorticoid excess and by insulin deficiency. Moreover, impaired insulin action is implicated in other endocrine myopathies as a contributory cause of muscle wasting. Both acromegaly and thyrotoxicosis are associated with insulin resistance due to a postreceptor defect, and secondary hyperparathyroidism due to hypophosphatemia also gives rise to insulin insensitivity. 

It has been shown that in postmenopausal women habitually high intakes of dietary isoflavones are associated with higher bone mineral density (BMD) values at both the spine and hip region (Mei et al, 2001). It is conceivable that an isoflavone-rich diet may help to reverse the state of secondary hyperparathyroidism associated with estrogen withdrawal and hence lower the rate of bone turnover in postmenopausal women, thus reducing the risk of osteoporosis (Valtuena et al, 2003). Phytoestrogens could be used as natural SERMs (Brzezinski and Debi, 1999) and some studies (Setchell, 2001 and refs therein) support such an idea since the molecular targets of... 

The management of secondary hyperparathyroidism involves correction of serum calcium and phosphorus levels, and decreasing parathyroid hormone secretion. 

What signs are consistent with secondary hyperparathyroidism ... 

As kidney function continues to decline and the GFR falls less than 60 mL/minute/1.73 m2, phosphorus excretion continues to decrease and calcitriol production decreases, causing PTH levels to begin to rise significantly, leading to secondary hyperparathyroidism (sHPT). The excessive production of PTH leads to hyperplasia of the parathyroid glands, which decreases the sensitivity of the parathyroid glands to serum calcium levels and calcitriol feedback, further promoting sHPT. 

FIGURE 23-5. Pathogenesis of secondary hyperparathyroidism and renal osteodystrophy in patients with CKD. 

Clinical Presentation of Secondary Hyperparathyroidism and Renal Osteodystrophy ... 

Determine if the patient requires medical intervention to prevent the development of or treatment for secondary hyperparathyroidism. 

Renal osteodystrophy Altered bone turnover that results from sustained metabolic conditions that occur in chronic kidney disease, including secondary hyperparathyroidism, hyperphosphatemia, hypocalcemia, and vitamin D deficiency. 

Secondary hyperparathyroidism Increased secretion of parathyroid hormone from the parathyroid glands caused by hyperphosphatemia, hypocalcemia, and vitamin D deficiency that result from decreased kidney function. It can lead to bone disease (renal osteodystrophy). 

Calcium should be ingested in adequate amounts to prevent secondary hyperparathyroidism and bone destruction. Although calcium increases BMD, fracture prevention is minimal. It should be combined with vitamin D and osteoporosis medications when needed. 

Glucocorticoids decrease bone formation through decreased proliferation and differentiation, and enhanced apoptosis of osteoblasts. They also increase bone resorption, decrease calcium absorption, increase renal calcium excretion, and result in secondary hyperparathyroidism. 

CKD development and progression is insidious. Patients with stage 1 or 2 CKD usually do not have symptoms or metabolic derangements seen with stages 3 to 5, such as anemia, secondary hyperparathyroidism, cardiovascular disease, malnutrition, and fluid and electrolyte abnormalities that are more common as kidney function deteriorates. 

Secondary hyperparathyroidism can cause altered lipid metabolism, altered insulin secretin, resistance to erythropoietic therapy, impaired neurologic and immune functions, and increased mortality. 

FIGURE 76-7. Pathogenesis of secondary hyperparathyroidism and renal osteodystrophy in patients with chronic kidney disease. These adaptations are lost as renal failure progresses. (Ca, calcium, P04 phosphate PTH, parathyroid hormone.)... 

Pruritus is a common problem in patients with ESRD. The pathogenesis is poorly understood but has been attributed to inadequate dialysis, skin dryness, secondary hyperparathyroidism, increased concentrations of vitamin A and histamine, and increased sensitivity to histamine. 

Zemplar (paricalcitol) injection is a synthetically manufactured selective vitamin D receptor activator (SVDRA) indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) stage 5. The U.S. Food Drug Administration (FDA) approved a capsule form of Zemplar for development to satisfy a need for an oral formulation. The objective of study M04-693 was to assess the bioequivalencies of several dosage strengths of paricalcitol capsules under fasting conditions. 

Calcium and magnesium deficiency also occur in some patients with the malabsorption syndrome and this may lead to tetany or bone changes. Low blood calcium levels may result from decreased absorption associated with lack of effective compensatory parathyroid activity. In patients in whom secondary hyperparathyroidism is effective, extensive loss of calcium from the bones may occur. The cause of the defective absorption of calcium in patients of the sprue group is complex and not yet fully understood (B3, Dl, Jl, M7, Nl). It is important that complications such as calcium or magnesium deficiency should be corrected before the final steps of definitive diagnosis are attempted. If this is not done, the secondary effects may obscure the results of other tests. 

High phosphate diets cause decreased Ca absorption, secondary hyperparathyroidism, accelerated bone resorption and soft tissue calcification in some animals, but not in normal humans. Although phosphates may decrease Ca absorption in man at very high (> 2000 mg/day) Ca intakes, they do not do so at more moderate Ca levels and enhance Ca absorption at very low levels (< 500 mg/day). Phosphates increase renal tubular reabsorption and net retention of Ca. At low Ca intakes, phosphates stimulate parathyroid hormone (PTH) secretion without causing net bone resorption. 

Patients with advanced renal insufficiency (Ccr less than 30 mL/min) exhibit phosphate retention and some degree of hyperphosphatemia. The retention of phosphate plays a role in causing secondary hyperparathyroidism associated with osteodystrophy and soft-tissue calcification. Calcium acetate, when taken with meals, combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in the feces. 

Bone marrow fibrosis Bone marrow fibrosis is a complication of CRF and may be related to secondary hyperparathyroidism or unknown factors. 

Paricalcitol is a synthetically manufactured analogue of calcitriol. It is indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease. Cinacalcet, a drug that acts as a calcimimetic, can be added if the effects on PTH levels are isufficient. 

Renal osteodystrophy is a complex disorder with several pathogenic factors. Histological evidence of bone disease is common in early renal failure and deficits in calcitriol synthesis seems to be an important factor in the pathogenesis of secondary hyperparathyroidism in early CRF. The most common component is osteitis fibrosa manifested as subperiosteal resorption of bone. This is due to decreased excretion as well as increased secretion of parathyroid hormone. In CRF small increments of serum phosphorus cause small decreases in serum calcium. 

Patients with chronic renal failure develop hyperphosphatemia, hypocalcemia, secondary hyperparathyroidism, and severe metabolic bone disease. The secondary hyperparathyroidism is thought to be due to hyperphosphatemia and decreased 1, 25-(OH)2 formation. Oral or intravenous l,25-(OH)2D3 (calcitriol) therapy along with oral phosphate-binding agents and calcium supplementation is effective in reducing the effects of renal osteodystrophy. 

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