The human body contains approximately 1100 g of calcium, 99% of which is deposited in bones and teeth. The small amount found in plasma is divided into 3 fractions: ionized calcium (50%), protein-bound calcium (40%), and calcium complexed to citrate and phosphate forming soluble complexes (10%) (Figure 5–7). The complexed and ionized Ca2+ fractions (approximately 60% of plasma Ca2+) can cross the plasma membrane. The majority (80%–90%) of protein-bound Ca2+ is bound to albumin, and this interaction is sensitive to changes in blood pH. Acidosis leads to a decrease in protein binding of Ca2+ and an increase in “free” or ionized Ca2+ in the plasma. Alkalosis results in increased Ca2+ binding and a decrease in ionized Ca2+ in the plasma. A smaller fraction (10%–20%) of protein-bound Ca2+ is bound to globulins.
The resting intracellular (cytosolic) calcium concentration is approximately 100 nM, but this can increase to 1 μM by the release of Ca2+ from intracellular stores or by uptake of extracellular Ca2+ in response to cellular activation. In contrast, the extracellular ionized calcium concentration is approximately 10,000-fold higher than the intracellular calcium concentration and remains virtually constant at approximately 1 mM. Multiple physiologic functions involve calcium ions. Ca2+ is a key intracellular messenger and cofactor for various enzymes. Ca2+ also has diverse extracellular functions (eg, in the clotting of blood, maintenance of skeletal integrity, and modulation of neuromuscular excitability). Therefore, stable Ca2+ levels are critical for normal physiologic function. For example, Na+ channel voltage-gating is dependent on the extracellular Ca2+ concentration. Decreased plasma Ca2+ concentrations reduce the voltage threshold for the action potential firing, resulting in neuromuscular hyperexcitability. This can result in numbness and tingling of fingertips, toes, and the perioral region or muscle cramps. Clinically, neuromuscular irritability can be demonstrated by mechanical stimulation of the hyperexcitable nerve leading to tetanic-like muscle contraction by eliciting Chvostek (ipsilateral contraction of facial muscles elicited by tapping the skin over the facial nerve) or Trousseau (carpal spasm induced by inflation of the blood pressure cuff to 20 mm Hg above the patient’s systolic blood pressure for 3–5 minutes) sign.
Interaction of Bone, Kidney and Intestine in Maintaining Calcium Homeostasis
Normal plasma concentrations of Ca2+ range between 8.5 and 10.5 mg/dL and are mainly regulated by the actions of PTH, vitamin D, and calcitonin on 3 tissues: bone, kidney, and intestine.
Calcium in bone is distributed in a readily exchangeable pool and a stable pool. The readily exchangeable pool is involved in maintaining Ca2+ plasma levels by the daily exchange of 550 mg of calcium between the bone and ECF. The stable Ca2+ pool is involved in bone remodeling. Bone is metabolically active throughout life. After skeletal growth is complete, remodeling of both cortical and trabecular bone continues with an annual turnover rate of approximately 10% of the adult skeleton.
In the kidney, virtually all filtered Ca2+ is reabsorbed. Approximately 40% of the Ca2+ that is reabsorbed is under hormonal regulation by PTH. Most filtered Ca2+ is reabsorbed in the proximal tubules, mainly by passive transport processes independent of hormonal regulation. Ca2+ absorption in the cortical thick ascending limbs is mediated by a combination of active and passive absorption. Ca2+ absorption in the distal convoluted tubules is mediated by active cellular absorption, which is stimulated by PTH binding to PTHR1. Transcellular transport of Ca2+ is facilitated by vitamin D through the increase in the Ca2+-binding protein calbindin-D28K and in the expression of Ca2+ transporters in the basolateral membrane.
The availability of dietary calcium is a critical determinant of calcium homeostasis. Dietary intake of calcium averages 1000 mg/d, of which only 30% is absorbed in the intestinal tract (Figure 5–8). This percentage of dietary Ca2+ that is absorbed is significantly enhanced by vitamin D during growth, pregnancy, and lactation. During growth, there is a net bone accretion. After completion of the growth phase in the young and healthy individual, there is no net gain or loss of Ca2+ from bone despite a continuous turnover of bone mass; the amount of Ca2+ lost in urine is approximately equal to net Ca2+ absorption.
Calcium balance. Dietary intake of calcium averages 1 g/d and is a critical determinant of calcium homeostasis. A small fraction is absorbed in the intestinal tract, and this is significantly enhanced by vitamin D. Calcium in bone is distributed in a readily exchangeable pool and a stable pool. The readily exchangeable pool is involved in maintaining Ca2+ plasma levels. The stable Ca2+ pool is involved in bone remodeling. Virtually all filtered Ca2+ is reabsorbed, and approximately 40% of the Ca2+ that is reabsorbed is under hormonal regulation by PTH. ECF, extracellular fluid; PTH, parathyroid hormone.
Intestinal absorption of Ca2+ occurs by a saturable, transcellular process and a nonsaturable, paracellular pathway. The paracellular pathway predominates when dietary Ca2+ is abundant. The active transcellular pathway is vitamin D–dependent and plays a major role in absorption when the Ca2+ supply is limited. Intestinal transepithelial Ca2+ transport, similar to that in the distal tubule, is a 3-step process consisting of passive entry across the apical membrane, cytosolic diffusion facilitated by vitamin D–dependent calcium-binding proteins (calbindins), and active extrusion of Ca2+ across the opposing basolateral membrane mediated by a high-affinity Ca2+-ATPase and Na+/Ca2+ exchanger.
Hormonal Regulation of Calcium Homeostasis
As explained previously, a slight decrease in the free ionized Ca2+ level is sensed through the Ca2+ sensor in parathyroid chief cells, resulting in an increased release of PTH. PTH binds to receptors in osteoblasts leading to the recruitment of preosteoclasts and their maturation to active osteoclasts, which are responsible for increased bone resorption and release Ca2+ and inorganic phosphate (Pi) into the circulation. In the kidney, PTH promotes Ca2+ reabsorption and Pi excretion in urine. In addition, PTH stimulates the hydroxylation of 25-hydroxyvitamin D3 at the 1-position, leading to the formation of the active form of vitamin D (calcitriol). Vitamin D increases intestinal absorption of dietary Ca2+ and renal reabsorption of filtered Ca2+. In bone, vitamin D increases the number of osteoclasts and stimulates bone resorption, with a resulting increase in the release of Ca2+ into the circulation. An increase in free ionized Ca2+ levels decreases the release of PTH from the parathyroid gland, decreases the activation of vitamin D in the kidney, and stimulates parafollicular cells of the thyroid gland to release the hormone calcitonin.
Calcitonin counteracts the effects of PTH. Calcitonin inhibits osteoclast activity, decreasing bone resorption and increases renal Ca2+ excretion; the result is a decrease in free ionized Ca2+ levels. Overall, PTH, calcitriol, and calcitonin work together to maintain plasma Ca2+ levels within a normal range. The previous section described in detail the physiologic effects of PTH. The following section discusses the contributions of vitamin D and calcitonin to the regulation of Ca2+ homeostasis.
Role of Vitamin D in Calcium Homeostasis
Synthesis and Activation of Vitamin D
Vitamin D is a lipid-soluble vitamin that can be synthesized from plant-derived precursors or through the action of sunlight from cholesterol-derived precursors found in the skin (see Figure 5–7) or obtained from dietary intake of fortified milk, fatty fish, cod-liver oil, and, to a lesser extent, eggs. Active vitamin D (calcitriol) is the product of 2 consecutive hydroxylation steps, (first in the liver and then in the kidney) of its precursors, cholecalciferol (derived from skin) and ergocalciferol (derived from diet). Cholecalciferol is produced in the skin by ultraviolet radiation from 7-dehydrocholesterol, an inert precursor. This previtamin D3 (cholecalciferol) is isomerized to vitamin D3 and is transported in the circulation bound to vitamin D-binding protein; the major plasma carrier protein of vitamin D and its metabolites. Cholecalciferol (vitamin D3) and vitamin D2 (ergocalciferol from plants) are transported to the liver, where they undergo the first step in bioactivation, the hydroxylation at C-25 to 25-hydroxyvitamin D [25(OH)D]. The resulting prehormone, 25-hydroxyvitamin D, is the major circulating form of vitamin D (15–60 ng/mL). 25-hydroxyvitamin D is the principle storage form of vitamin D, has a half-life of 15 days, is in equilibrium with the storage pool in muscle and fat, and is the value measured by most clinical laboratories to assess levels of vitamin D in individuals.
25-hydroxyvitamin D circulates bound to vitamin D–binding protein. This protein can be filtered at the glomerulus and enter the proximal tubular facilitating the delivery of the precursor, 25-hydroxyvitamin D, to the 1α-hydroxylase. Renal 1α-hydroxylase (under regulation by PTH) is the enzyme responsible for the second step in the activation of the prehormone, the hydroxylation at C-1, resulting in the hormonally active vitamin D [1,25(OH)2D], also known as calcitriol. Calcitriol is released into the circulation (20–60 pg/mL), where it functions as an endocrine hormone, regulating cellular processes in a host of target tissues. This second hydroxylation step, the production of 1,25(OH)2D by 1α-hydroxylase in the kidney, is a tightly regulated process and is a central factor in the feedback regulation of calcium homeostasis. The production of the active form of vitamin D is under negative feedback regulation by plasma Ca2+ levels. An increase in plasma Ca2+ levels inhibits the hydroxylation at C-1 and favors hydroxylation at C-24, leading to the synthesis of an inactive metabolite of vitamin D [24,25(OH)2D].
In summary, PTH stimulates the activity of 1α-hydroxylase, favoring an increase in the synthesis of the active form of vitamin D. Vitamin D, as well as high Ca2+ levels, suppress the activity of 1α-hydroxylase, decreasing its own synthesis and favoring the synthesis of 24,25(OH2)D, the less active form of the hormone (Figure 5–9).
Vitamin D metabolism and physiologic effects at target organs. Provitamin D (7-dehydrocholesterol) in the skin is converted to cholecalciferol by ultraviolet (UV) light. Cholecalciferol and ergocalciferol (from plants) are transported to the liver, where they undergo the first step in bioactivation, the hydroxylation at C-25 to 25-hydroxyvitamin D3 [25(OH)D], the major circulating form of vitamin D. The second hydroxylation step, at C-1, occurs in the kidney and results in the hormonally active vitamin D [1,25(OH)2D], also known as calcitriol. This activation step, mediated by 1α-hydroxylase, is under tight regulation by parathyroid hormone (PTH), Ca2+ levels, and vitamin D [1,25(OH)2D]. The activity of 1α-hydroxylase is stimulated by PTH and inhibited by Ca2+ and 1,25(OH)2D. Decreased activity of 1α-hydroxylase favors formation of the inactive form of vitamin D by C-24 hydroxylation. Vitamin D increases bone resorption and formation, increases dietary Ca2+ absorption, facilitates renal Ca2+ reabsorption, and decreases the PTH synthesis by the parathyroid glands. The overall effect of vitamin D is to increase plasma Ca2+ concentrations.
Cellular Effects of Vitamin D
The principal physiologic effects mediated by vitamin D result from its binding to a vitamin D steroid receptor located in the principal target organs; intestine, bone, kidney, and parathyroid gland (see Figure 5–9). The receptor has high affinity for calcitriol and very low affinity for the metabolites of the hormone. The effects of active vitamin D are primarily to increase intestinal Ca2+ absorption, facilitate PTH-mediated calcium reabsorption in the distal renal tubules, and to suppress the synthesis and release of PTH from the parathyroid gland. Vitamin D also plays a role in regulation of bone resorption and formation. Additional tissues including skin, lymphocytes, skeletal and cardiac muscle, breast, and anterior pituitary express receptors for calcitriol. Thus, calcitriol has additional physiologic effects in modulating immune response, reproduction, cardiovascular function, and cellular differentiation and proliferation.
Vitamin D is able to generate biologic effects both by genomic mechanisms (changes in gene transcription) and rapid nongenomic mechanisms. The genomic effects are dependent on the interaction of 1,25(OH)2D with a cytosolic-nuclear receptor protein, followed by interaction of the steroid-receptor complex in the nucleus with selective regions of the promoters of genes that are either activated or repressed. The stimulation of rapid responses by 1,25(OH)2D may result from interaction of the vitamin with a cell membrane receptor for 1,25(OH)2D that activates a variety of signal transduction systems, including protein kinase C, phospholipase C, and adenylate cyclase, and modulates ion (ie, Ca2+ or Cl–) channels.
Abnormal Vitamin D Levels
The US recommended daily allowance of vitamin D is 200 U for adults and 400 U for children, pregnant women, and lactating women. Vitamin D belongs to the class of vitamins that are lipid soluble (ie, A, D, E, and K) and can be stored in tissues. Excess vitamin D may lead to problems such as calcinosis (calcification of soft tissues), deposition of Ca2+ and PO4 in the kidney, and increased plasma Ca2+ levels, resulting in cardiac arrhythmia.
Deficiency of vitamin D can be the result of decreased dietary intake or lack of sunlight and the resulting decreased conversion from the inactive precursor in skin to the active form of the vitamin. Vitamin D deficiency results in bone deformities (rickets) when it occurs in children and decreased bone mass (osteomalacia) in adults. Vitamin D deficiency is associated with weakness, bowing of the weight-bearing bones, dental defects, and hypocalcemia. Factors that may contribute to vitamin D deficiency include the use of sunscreen, particularly in the elderly population; lack of sunlight during November through March in certain latitudes (above 40 N and below 40 S); and use of clothing that covers most of the skin. Less frequently, people may have a mutation in 1α-hydroxylase, the enzyme that catalyzes the second and final step in vitamin D activation, or a resistance to vitamin D action in the tissues caused by mutations in the vitamin D receptor.
Role of Calcitonin in Calcium Homeostasis
A third hormone involved in calcium homeostasis, although to a lesser extent than PTH and vitamin D, is calcitonin. Calcitonin is a 32–amino acid peptide hormone derived from procalcitonin, produced by cells of neural crest origin (parafollicular or C cells) in the thyroid gland. Calcitonin belongs to a family of peptides including amylin, calcitonin gene-related peptides (CGRPs) and adrenomedullin. These are distributed in various peripheral tissues as well as in the central nervous system and induce multiple biologic effects including potent vasodilatation (CGRP and adrenomedullin), reduction in nutrient intake (amylin), and decreased bone resorption (calcitonin).
The release of calcitonin is regulated by plasma calcium levels through a Ca2+ receptor on the parafollicular cells. Elevations in plasma Ca2+ higher than 9 mg/dL stimulate the release of calcitonin. Calcitonin has a half-life of approximately 5 minutes and is metabolized and cleared by the kidney and the liver. The release of calcitonin is also stimulated by gastrin, a gastrointestinal hormone.
Cellular Effects of Calcitonin
The main physiologic function of calcitonin is to decrease plasma Ca2+ and phosphate concentrations, mainly by decreasing bone resorption. The 2 target organs for calcitonin’s physiologic effects are bone and kidney. The overall effect of calcitonin in bone is to inhibit bone resorption, predominantly by inhibition of osteoclast motility, differentiation, and ruffled border formation. Calcitonin inhibits osteoclast secretory activity (particularly of tartrate-resistant acid phosphatase), alters Na+-K+-ATPase activity, carbonic anhydrase localization, and inhibits H+-ATPase activity, reducing osteoclast acid secretion. In the kidney, calcitonin increases urinary Ca2+ excretion by inhibition of renal tubular calcium reabsorption. The mechanism involved is through opening of low affinity Ca2+ channels in the luminal membrane and the stimulation of the Na+/Ca2+ exchanger in the basolateral membrane, both actions depending on the activation of adenylate cyclase. In hypercalcemic patients with metastatic bone disease, the administration of calcitonin induces a rapid decrease in plasma calcium primarily through inhibition of renal tubular reabsorption.
The cellular effects of calcitonin are mediated through G protein (Gs, Gq, or Gi)–coupled receptors from the same receptor family as the PTH, PTHrP, calcitonin, adrenomedullin, secretin receptor superfamily. Several calcitonin receptor subtypes have been identified, and they all bind calcitonin with high affinity. Calcitonin binding to its receptor stimulates adenylate cyclase, increasing the formation of cAMP and activation of protein kinase A and phospholipase C, resulting in the release of Ca2+ from intracellular stores and influx of extracellular Ca2+.
Calcitonin does not appear to be critical for the regulation of calcium homeostasis; in fact, total removal of the thyroid does not produce major alterations in Ca2+ homeostasis. In addition, no significant clinical findings have been associated with calcitonin excess or deficiency.
However, calcitonin has been used therapeutically for the prevention of bone loss and for the short-term treatment of hypercalcemia of malignancy. Osteoporosis is a systemic skeletal disease characterized by low bone mass and deterioration of bone tissue, resulting in bone fragility and susceptibility to fracture (discussed in Chapter 10). The ability of calcitonin to inhibit osteoclast-mediated bone resorption has made it a useful agent for the treatment of osteoporosis; it also relieves pain in osteoporotic patients with vertebral crush fractures. Calcitonin is also used in the treatment of Paget disease, which is characterized by an abnormality in bone remodeling, with increased bone resorption and hypercalcemia.
Additional Regulators of Ca2+ and Bone Metabolism
Although PTH and vitamin D play central roles in the regulation of bone metabolism, the contribution of other hormones cannot be ignored (Table 5–2). Sex steroids (androgens and estrogens) have been shown to increase 1α-hydroxylase activity, decrease bone resorption, and increase osteoprotegerin synthesis. Estrogen stimulates the proliferation of osteoblasts and the expression of type I collagen and alkaline phosphatase; influences the expression of receptors for vitamin D, growth hormone, and progesterone; and modulates responsiveness of bone to PTH. Estrogen decreases the number and activity of osteoclasts, as well as the synthesis of cytokines affecting bone resorption.
Table 5–2. Factors Involved in the Regulation of Ca2+ and Bone Metabolism |Favorite Table|Download (.pdf)
Table 5–2. Factors Involved in the Regulation of Ca2+ and Bone Metabolism
|PTH||Increases bone resorption and plasma Ca2+|
|Vitamin D||Increases intestinal Ca2+ absorption, bone resorption, and plasma Ca2+|
|Calcitonin||Decreases bone resorption and plasma Ca2+|
|Sex steroids (androgens and estrogens)|
- Increase 1α-hydroxylase activity,
- Increase osteoprotegerin synthesis
- Net decrease in bone loss
|Growth hormone and insulinlike growth factor||Stimulate bone synthesis and growth|
|Thyroid hormone||Increases bone resorption|
|Prolactin||Increases renal Ca2+ reabsorption and 1α-hydroxylase activity|
|Glucocorticoids||Increase bone resorption, decrease bone synthesis|
|Inflammatory cytokines||Increase bone resorption|
Growth hormone and insulin-like growth factor-1 (IGF-1) both exert effects on bone metabolism. Growth hormone stimulates the proliferation and differentiation of osteoblasts and bone protein synthesis and growth. IGF-1 produced by the liver and locally by osteoblasts, stimulate bone formation by increasing the proliferation of osteoblast precursors and by enhancing the synthesis and inhibiting the degradation of type I collagen. Normal thyroid function is required for physiologic bone remodeling. However, excess thyroid hormone levels result in increased bone resorption. Prolactin increases Ca2+ reabsorption and 1α-hydroxylase activity, indirectly modulating bone metabolism. Glucocorticoids play an overall catabolic role in bone metabolism by increasing bone resorption and decreasing bone synthesis, resulting in an increase in the risk of fractures. The mechanisms by which glucocorticoids exert their effects are not fully understood, but inhibition of osteoprotegerin may help stimulate osteoclastic bone resorption. The cytokines tumor necrosis factor, interleukin 1, and interleukin 6 increase the proliferation and differentiation of osteoclast precursors and their osteoclastic activity and are therefore potent stimulators of bone resorption in vitro and in vivo. The overall interaction of these various factors during health and disease plays an important role in maintaining bone mass. Their specific contributions may vary depending on the disease and on the prevailing hormone and cytokine levels in bone.
Hormonal Regulation of Bone Metabolism
Bone remodeling results from the interactions of multiple elements, including osteoblasts, osteoclasts, hormones, growth factors, and cytokines, the result being a dynamic maintenance of the bone architecture and systemic preservation of calcium homeostasis. Quiescent bone is covered by flat bone-lining cells. During bone resorption, osteoclasts are recruited and activated to remove both organic matrix and mineral content of bone to produce a pit. During bone formation, osteoblasts deposit osteoid in the pit, which is then mineralized under osteoblastic control. Hormones can influence bone remodelling at any stage throughout the remodelling cycle through direct effects on either osteoblasts or osteoclasts to alter either bone resorption or bone formation. It is important to remember that, in vivo, normal bone structure is maintained by complex interactions between osteoblasts and osteoclasts.
In early life, a careful balance exists between bone formation by osteoblasts and bone resorption by osteoclasts. With aging, the process of coupled bone formation-resorption is affected by the reductions in osteoblast differentiation, activity, and life span, which are further potentiated in the perimenopausal years by hormone deprivation (estrogen, testosterone, and adrenal-derived androgens) and an increase in osteoclast activity.
Decreased calcium intake below obligatory calcium loss (through the urine, feces, and skin) mobilizes calcium from the skeleton to maintain the ionized calcium concentration in the ECF, resulting in bone destruction. Vitamin D deficiency lowers the concentration of ionized calcium in the ECF (from loss of the calcemic action of vitamin D on bone), resulting in stimulation of PTH release (secondary hyperparathyroidism), increased phosphate excretion leading to hypophosphatemia, and failure to mineralize new bone as it is being formed. Simple calcium deficiency is associated with compensatory increases in PTH and calcitriol, which together mobilize calcium from bone, potentially decreasing bone mass. True vitamin D deficiency, however, reduces the mineral content of the bony tissue itself and leads to abnormal bone composition. However, these 2 nutritional deficiencies cannot be completely separated because calcium malabsorption is the first manifestation of vitamin D deficiency.
Bone mass increases throughout childhood and adolescence. In girls, the rate of increase in bone mass decreases rapidly after menarche, whereas in boys, gains in bone mass persist up to 17 years of age and are closely linked to pubertal stage and androgen status. By age 17–23 years, the majority of peak bone mass has already been achieved in both sexes. Skeletal growth is achieved primarily through bone modeling and only partially through bone remodeling. These mechanisms involve interaction between osteoblasts and osteoclasts, which work cooperatively under the influence of the mechanical strain placed on bone by skeletal muscle force such as that exerted during exercise. The mechanical loading or strain oscillates within a given range in response to physical activity, leading to bone maintenance without loss or gain. Decreased mechanical strain (such as that associated with prolonged bed rest or immobilization) leads to bone loss, whereas increased mechanical strain (weight-bearing exercise) stimulates osteoblastic activity and bone formation. The loading on the bone cells is exerted primarily by muscles and to a lesser extent by body weight. Muscle force or tension applied on long bones increases the thickness of cortical bone through continuous subperiosteal accretion. This relationship between muscle tension exerted on bones and bone formation is positively affected during exercise.
Peak bone mass is attained in the third decade of life and is maintained until the fifth decade, when age-related bone loss begins both in men and women. Sex steroids play an important role in bone growth and the attainment of peak bone mass. They are also responsible for the sexual dimorphism of the skeleton, which emerges during adolescence and is characterized by larger bone size in males (even when corrected for body height and weight), with both a larger diameter and a greater cortical thickness in the long bones.
The uptake and release of calcium from the skeleton are increased during pregnancy, and the rate of calcium mobilization continues to be increased during the early months of lactation, returning to prepregnancy rates during or after weaning. Intestinal calcium absorption and bone mobilization are higher during pregnancy than before conception or after delivery. Urinary calcium excretion is increased during pregnancy, and may be a reflection of the increased glomerular filtration rate, exceeding calcium reabsorption capacity during that period. The increases are evident in early to midpregnancy and precede the increased demand for calcium by the fetus for skeletal growth. The alterations in calcium and bone metabolism during pregnancy are accompanied by increases in vitamin D, but without significant alterations in either intact PTH or calcitonin concentrations. The increase in intestinal calcium absorption is associated with a doubling of 1,25-dihydroxyvitamin D levels and increased intestinal expression of the vitamin D-dependent calcium-binding protein calbindin. Changes in maternal bone mineral content during this period may influence bone mineral status in the long term. After delivery, calcium absorption and urinary calcium excretion return to prepregnancy rates. However, lactating mothers have decreased urinary calcium output and higher bone turnover than at the end of pregnancy. During this period, approximately 5 mmol/d (200 mg/d) of calcium is provided to the infant through breast milk, and this can exceed 10 mmol/d (400 mg/d) in some women. Thus, requirements for calcium are significantly increased during pregnancy and lactation.
The acute loss of bone that accompanies menopause involves most of the skeleton but particularly affects the trabecular component. The associated biochemical changes include increases in the complexed fraction of plasma calcium (bicarbonate), increases in plasma alkaline phosphatase and urinary hydroxyproline (representing increased bone resorption followed by a compensatory increase in bone formation), increased obligatory calcium loss in the urine, and a small but significant decline in calcium absorption (Table 5–3). These changes are ameliorated by hormone treatment, calcium supplementation, thiazide administration (which reduces calcium excretion), and restriction of salt intake, which reduces obligatory calcium loss. In some (50%) cases of osteoporosis, calcium absorption is low, and high bone resorption can be suppressed by treatment with vitamin D which in turn leads to improvement in calcium absorption. In males, bone loss begins at approximately the age of 50 years, but it is not associated with an increase in bone resorption markers. Instead, bone loss in men is linked to an age-related decline in gonadal function and is caused by a decrease in bone formation, not so much as an increase in bone resorption.
Table 5–3. Parameters Used for Evaluation of Parathyroid Hormone Function, Bone Metabolism, or Ca2+ Homeostasis |Favorite Table|Download (.pdf)
Table 5–3. Parameters Used for Evaluation of Parathyroid Hormone Function, Bone Metabolism, or Ca2+ Homeostasis
|Ionized calcium||8.5–10.5 mg/dL||Elevated with ↑ PTH, ↑ vitamin D, ↑ bone resorption|
|Plasma phosphate||3–4.5 mg/dL||Decreased in hyperparathyroidism, vitamin D deficiency Increased in renal failure, hypoparathyroidism, vitamin D intoxication|
|Intact plasma PTH levels||10–65 pg/mL||Elevated in hyperparathyroidism; decreased in hypoparathyroidism|
|Alkaline phosphatase||30–120 U/L||High levels indicate increased osteoblastic activity (bone turnover)|
|Bone-specific alkaline phosphatase||17–48 U/L||High bone turnover, useful marker of active bone formation|
|N-telopeptide (NTX)||21–83 nM BCE/mM creatinine||Reflects collagen breakdown, marker of bone resorption|
|C-telopeptide (CTX)||60–780 pg/mL||Reflects collagen breakdown, marker of bone resorption|
|N-terminal propeptide of type I procollagen (PINP)||2.3–6.4 μg/L||By-product of type I collagen deposition, marker of bone formation|
|Osteocalcin (intact)||<1–23 ng/mL||Reflects activity of osteoblasts, marker for skeletal bone turnover|
|Tartrate-resistant acid phosphatase (TRAP)||<5 ng/mL||Marker for osteoclastic activity (bone resorption)|
Estrogen deficiency is a major pathogenic factor in the bone loss associated with menopause and the subsequent development of postmenopausal osteoporosis. Estrogen replacement at or after menopause, whether natural or induced, prevents menopausal bone loss and usually results in an increase in bone mineral density (BMD) during the first 12–18 months of treatment. Estrogen regulates osteoclast activity through effects on osteoclast number, resorptive activity, and life span of the cell. The process of bone loss is progressive, starting at approximately the age of 50 in men and at menopause in women, and loss proceeds at an average rate of 1% per year to the end of life. Bone loss is faster in women than in men and affects some bones more than others; the consequences include decreased BMD and increased risk of fractures.
Bone density determines the degree of osteoporosis and the fracture risk. The main determinants of peak bone density are genetics, calcium intake, and exercise. The most common test for measuring bone density is dual-energy x-ray absorptiometry (DEXA) scanning. Additional approaches include computed tomography, radiologic techniques (morphometry or densitometry), or bone biopsy. DEXA uses x-rays to measure bone density and provides 2 measures of how dense bone is: the T score and the Z score. The T score compares the person’s bone density with the average bone density of 25- to 30-year-olds of the same sex. This age group is used because it is when bone density is at its peak. A T score of 0 means that bone density is the same as the average bone density of 25- to 30-year-olds. A score above 0 (a positive score) means that bones are more dense than the average. A score below 0 (a negative score) means that bones are less dense than the average. The Z score compares a person’s bone density with that of people of the same age, sex, and weight, and is less valuable in making predictions of risk of fracture or in making decisions about treatment.
Prevention of Osteoporosis
Understanding of the hormonal and nutritional regulation of calcium balance has led to the implementation of several measures to reduce bone loss. The principal current approaches are the following.
Estrogen Replacement Therapy
Estrogen decreases bone loss in postmenopausal women by inhibiting bone resorption, resulting in a 5%–10% increase in BMD over 1–3 years. Estrogen treatment is approved for prevention of osteoporosis. Calcium supplements enhance the effect of estrogen on BMD.
Bisphosphonates have a strong affinity for bone apatite and are potent inhibitors of bone resorption. Bisphosphonates reduce the recruitment and activity of osteoclasts and increase their apoptosis.
Calcitonin reduces bone resorption by direct inhibition of osteoclast activity. Calcitonin is less effective in prevention of cortical bone loss than cancellous bone loss in postmenopausal women. Calcitonin is approved for treatment of osteoporosis in women who have been postmenopausal for 5 or more years.
Human recombinant PTH is approved for the treatment of osteoporosis in postmenopausal women and men who are at high risk for fracture. Intermittent PTH administration stimulates new bone formation at the periosteal (outer) and endosteal (inner) bone surfaces and thickening the cortices and existing trabeculae of the skeleton.
Selective Estrogen Receptor Modulators
Selective estrogen receptor modulators (SERMs) are compounds that exert estrogenic effects in specific tissues and antiestrogenic effects in others. Raloxifene, a SERM competitively inhibits the action of estrogen in the breast and the endometrium and acts as an estrogen agonist on bone and lipid metabolism. In early postmenopausal women, raloxifene prevents postmenopausal bone loss at all skeletal sites, reduces markers of bone turnover to premenopausal concentrations, and reduces the serum cholesterol concentration and its low-density lipoprotein fraction without stimulating proliferation in the endometrium. Because raloxifene does not have agonistic effects on the endometrium, unwanted vaginal bleeding and increased risk of endometrial cancer are avoided. Thus, it exerts the beneficial effects of estrogen in the skeleton and cardiovascular system without its adverse effects in the breast and endometrium.
Vitamin D analogs induce a small increase in BMD that seems to be limited to the spine.
Physical activity early in life contributes to high peak bone mass. Various activities, including walking, weight training, and high-impact exercises, induce a small (1%–2%) increase in BMD at some, but not all, skeletal sites. These effects disappear if the exercise program is stopped. Load-bearing exercise is more effective for increasing bone mass than are other types of exercise. Some of the benefits of exercise may be caused by increases in muscle mass and strength, plus a reduction in the risk of falls by approximately 25% in frail elderly individuals.