Calcium-Regulating Hormones and Other Agents Affecting Bone

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Chapter 44 Calcium-Regulating Hormones and Other Agents Affecting Bone

Abbreviations
EDTA Ethylenediamine tetraacetic acid
GI Gastrointestinal
OPG Osteoprotegerin
PTH Parathyroid hormone
RANK Receptor activator of nuclear factor-κB
RANKL Receptor activator of nuclear factor-κB ligand
SERM Selective estrogen receptor modulator

Therapeutic Overview

The plasma Ca++ concentration is normally maintained within narrow limits of 8.5 to 10.4 mg/dL. Approximately 45% of the plasma Ca++ (~ 2 mM) is bound to plasma proteins and fatty acid anionic groups, and approximately 10% is complexed with inorganic anions. Intracellular Ca++ (200 nM) is maintained by low membrane permeability to passive Ca++ transport and exists unbound or stored in the mitochondria and endoplasmic (sarcomella) reticulum. When ionized Ca++ levels fall outside the normal physiological range, compensatory mechanisms occur. Failure to restore normal levels adversely affects cellular and whole body physiology. Calcium levels less than 8.5 mg/dL are indicative of hypocalcemia, which can lead to increased neuromuscular excitability and tetany and impairment of mineralization of the skeleton. Calcium levels exceeding 10.5 mg/dL are indicative of hypercalcemia and can precipitate life-threatening cardiac dysrhythmias, soft tissue calcification (e.g., kidney stones), and central nervous system abnormalities.

The primary sites of regulation of Ca++ levels are the kidney, gastrointestinal (GI) tract, and bone (Fig. 44-1). The GI tract can normally absorb 10% to 20% of dietary Ca++, and effectiveness is directly dependent on vitamin D levels. Renal tubular reabsorption is highly efficient (99%) and recovers 10 to 20 gm of Ca++ filtered per day. Skeletal bone is the major site of Ca++ storage, containing approximately 1 kg in a 70-kg human. Of this, more than 99% is normally in a stable state, and 1% is in an exchangeable pool that turns over at a rate of approximately 20 g of Ca++ per day.

The loss of normal bone structure and integrity can result from drugs, disease, or nutritional deprivation. Among diseases affecting bone integrity are disorders of Ca++ metabolism and bone diseases, which are associated with increased morbidity and mortality associated with fractures. Pharmacological treatments of diseases

associated with Ca++ or bone metabolism are dependent on the cause and severity of the disease and are summarized in the Therapeutic Overview Box (See page 501).

Hypocalcemia commonly results from the onset of hypoparathyroidism (low levels of parathyroid hormone, PTH) or pseudohypoparathyroidism (resistance to PTH). Regardless of the cause, the resulting imbalances of Ca++ metabolism are predictable and include increased renal excretion of Ca++, decreased formation of calcitriol (1,25-dihydroxyvitamin D, the hormonally active form of vitamin D), decreased bone resorption, and/or decreased intestinal absorption of Ca++. Therapeutic strategies include supplementation with Ca++ salts or Ca++ gluconate, the most appropriate form of vitamin D, or both. The selection of a vitamin D preparation depends on the effective production of calcitriol, which is dependent on adequate levels of PTH. For hypocalcemia resulting from decreased PTH synthesis as a consequence of Mg++ deficiency, Mg++ sulfate is administered.

Hypercalcemia can result from a variety of diverse disorders including primary hyperparathyroidism, hyperparathyroidism caused by chronic renal disease, PTH-secreting parathyroid carcinoma, PTH-related protein producing-malignancy (bronchogenic carcinoma), and bone-wasting neoplasia. Management of mild hypercalcemia (10.5 to 11.4 mg/dL) usually involves dietary restriction of Ca++ and maintenance of hydration. Moderate hypercalcemia (11.5 to 14 mg/dL) has the same considerations as the mild form but requires a more aggressive and timely management plan. Specifically, it is necessary to rapidly reduce blood Ca++ levels using saline infusion and a diuretic, if renal function is intact, or dialysis, if renal function is impaired. The loop diuretics such as furosemide increase both Ca++ and Na+ excretion (see Chapter 21). Severe hypercalcemia (> 14 mg/dL) is a life-threatening condition often involving serious bone or renal pathology and requires immediate and intensive treatment. High Ca++ levels, dehydration, and volume depletion must be addressed. To rapidly reduce Ca++, intravenous administration of bisphosphonates with or without calcitonin is the safest option. Other agents and approaches have been used but are associated with frequent and severe side effects that reduce their desirability.

Disorders of bone turnover, which are not usually associated with abnormal serum Ca++ and PO4−3 concentrations, are also amenable to therapy. Rickets (inadequate bone mineralization during development) or osteomalacia (inadequate bone mineralization in adults) can result from inadequate dietary intake or in situ formation of vitamin D or its active metabolite, calcitriol, or resistance to the action of these hormones. Treatment of these disorders involves administration of vitamin D, Ca++, or both. Again, the form of vitamin D chosen will depend on the ability to make calcitriol and, as needed, PO4−3.

Paget’s disease of bone is characterized by excessive bone resorption and formation, leading to areas of structurally abnormal bone microstructure (Pagetic or sclerotic bone), which appear more radiopaque than normal bone. Although the milder form is usually asymptomatic, the more severe forms can be characterized by skeletal deformities that are painful and can lead to deficits such as spinal cord depression, thickening of long bones, osteoarthritic changes in joints, skull thickening, and hearing impairment. Treatment strategies include the use of agents to decrease bone resorption and facilitate more normal bone formation such as calcitonin, the bisphosphonates, or estrogen and the selective estrogen receptor modulators (SERMs); Ca++ and vitamin D may also be included.

Osteopenia and osteoporosis are skeletal disorders characterized by compromised bone strength predisposing to an increased risk of fracture. Indicators for development include decreased estrogen levels in women and men, low initial skeletal bone thickness, small stature, family or personal history of osteopenia or osteoporosis, chronic hyperparathyroidism, sustained immunosuppression with adrenocorticosteroids, or periods of immobility. The diagnosis of osteopenia or osteoporosis is made by measuring bone mineral density as determined by scans of multiple regions of the skeleton. Therapeutic interventions are dictated by the severity of bone mineral density losses and include both nonpharmacological and pharmacological approaches. For the former, weight-bearing and muscle-strengthening exercises within tolerance and reduction of situations with high risk of falling are recommended. Pharmacological management includes administration of Ca++ or vitamin D, antiresorptive agents, and bone anabolic agents. Over-the-counter Ca++ salts (lactate, carbonate, gluconate, or citrate) that provide 1 to 1.5 g Ca++/day are recommended. A split dose of 3 × 500 mg/day reduces side effects and improves absorption. Antiresorptive agents, which interfere with osteopenia or osteoporosis by reducing bone resorption mediated by osteoclasts, include calcitonin, bisphosphonates, and SERMs. One anabolic agent, teriparatide, is approved for promoting new bone growth.

Therapeutic Overview
Hypocalcemia
Disorders:
Hypoparathyroidism; pseudohypoparathyroidism; renal failure; inadequate calcium intake or absorption; abnormal vitamin D metabolism, ingestion, or absorption; tissue resistance
Management:
Soluble Ca++ salts and/or vitamin D or its analogs
Hypercalcemia
Disorders:
Hyperparathyroidism, hypervitaminosis D, neoplasia, sarcoidosis, hyperthyroidism
Management (based on cause and severity):
Mild hypercalcemia: dietary restriction of calcium
Moderate hypercalcemia: loop diuretics and intravenous saline
Severe hypercalcemia: intravenous bisphosphonates, replace phosphate as needed, calcitonin, glucocorticoids
Abnormal Bone Remodeling
Disorders:
Paget’s disease of bone, rickets (osteomalacia), drug-induced, osteopenia, osteoporosis
Management:
Oral/intravenous bisphosphonates, calcitonin, Ca++, vitamin D, selective estrogen receptor modulators (SERMs) teriparatide

Mechanisms of Action

Vitamin D, Metabolites, and Analogs

The structure and metabolism of vitamin D is shown in Figure 44-2. Vitamin D is a secosteroid, a steroid in which the B ring is cleaved and the A ring rotated. Vitamin D3, cholecalciferol, is the natural form of vitamin D in humans and is synthesized from cholesterol in the skin in response to solar ultraviolet light. Vitamin D2, ergocalciferol, is the plant-derived form of vitamin D; both vitamins D2 and D3 are present in the diet and equally effective in adults. The activation of vitamin D requires enzymatic hydroxylation by the liver and the kidney. In the endoplasmic reticulum and mitochondria of the liver, vitamin D is hydroxylated to form 25-hydroxyvitamin D (calcifediol), which becomes the primary circulating metabolite. Renal metabolism of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol) involves mitochondrial P450-catalyzed hydroxylation by the enzyme 1α-hydroxylase (CYP27B1), whose activity is stimulated by PTH and low plasma PO4 concentrations.

Calcitriol and active vitamin D analogs bind primarily to nuclear receptors in target cells and act as ligand-activated transcription factors by binding to response elements on genes and modulating synthesis of specific proteins. Among the protein products resulting from actions of vitamin D on the intestine are two high-affinity Ca++-binding proteins, the calbindins, which play a role in stimulation of intestinal Ca++ transport. Vitamin D metabolites increase absorption of dietary Ca++ and PO4−3 by stimulating uptake across the GI mucosa, leading to an increase in serum Ca++ concentration (Fig. 44-3). The antirachitic effect of vitamin D on bone mineralization is an indirect result of this increased Ca++ and PO4−3 absorption, which also results in deposition of more mineral in bone.

Vitamin D metabolites, especially at higher concentrations, stimulate the release of Ca++ from bone. The synthesis of a membrane-associated cytokine, receptor activator of nuclear factor-κB ligand (RANKL), is activated. Interaction of RANKL with receptor activator of nuclear factor-κB (RANK) receptors on osteoclasts stimulates osteoclast differentiation, survival, and activity, resulting in Ca++ release (Fig. 44-4). A decoy receptor, osteoprotegerin (OPG), is produced by bone marrow stromal cells and can competitively antagonize the effects of RANKL. Increased RANKL is a general mechanism by which many factors, including PTH, prostaglandins, and inflammatory cytokines, stimulate bone resorption. Vitamin D metabolites inhibit PTH synthesis and secretion. Vitamin D also affects differentiation of other cell types, including keratinocytes.

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