Download CALCIUM METABOLISM Regulation of calcium homeostasis is of

CALCIUM METABOLISM
Regulation of calcium homeostasis is of critical importance for maintenance of normal
physiology. Ionized calcium serves as an important intracellular signal, particularly for
neuromuscular function. Inert complexed calcium, in contrast, is the major structural
component of the skeleton. The skeleton serves as the major reservoir for extracellular
calcium in the setting of calcium deficiency, and mineralization of the skeleton partly depends
on the extracellular concentration of calcium and phosphate. Extracellular calcium levels are
precisely regulated. Several systems preserve body calcium stores and the extracellular
calcium concentration. The normal serum calcium concentration ranges from 9 to 10 mg/dL.
The distribution of calcium is that 40% is bound to plasma proteins, mainly albumin, and to
globulins to a lesser extent; 10% is complexed to anions; and the remaining 50% is ionized or
free calcium, which is the physiologically active fraction and is tightly regulated. The total
serum calcium concentration is affected by variations in the plasma protein concentration. In
hypoalbuminemic states, the measured serum calcium should be corrected by adding 0.8
mg/dL for every 1-g/dL reduction in albumin from the normal level of 4 g/dL. Acidosis
decreases protein binding and increases the ionized calcium, conversely, alkalosis increases
protein binding and decreases the ionized calcium level. However, current technology allows
for direct measurement of the ionized calcium level.
Proper evaluation and treatment of patients with disorders of calcium metabolism requires
knowledge of the normal control mechanisms involved in the maintenance of calcium
homeostasis. The parathyroid glands are the major regulators of body calcium. They secrete
parathyroid hormone (PTH), which serves to increase serum calcium concentrations. This
effect occurs via three main actions. First, PTH decreases calcium excretion in the urine by
increasing the renal tubular reabsorption of calcium. Second, PTH stimulates osteoclastmediated resorption, thereby mobilizing calcium from bone. Lastly, PTH upregulates the 1
alpha-hydroxylase enzyme, thereby increasing the production of 1,25-dihydroxyvitamin D3
from 25-hydroxyvitamin D in proximal renal tubular cells. 1,25-dihydroxyvitamin D3 then
increases intestinal calcium absorption. Hypocalcemia and hypophosphatemia also increase
the formation of 1,25-dihydroxyvitamin D3.
PTH secretion is modulated through the calcium-sensing receptor, which lies in the cell
membrane of parathyroid cells. An increase in the serum ionized calcium level stimulates the
calcium-sensing receptor, which causes a consequent decrease in PTH secretion. High
concentrations of magnesium can also stimulate the calcium-sensing receptor and cause a
decrease in PTH secretion. Hypocalcemia leads to less calcium binding to the calcium-sensing
receptor, which leads to an increase in PTH secretion.
PTH is also phosphaturic – it increases the renal loss of phosphate by decreasing the renal
threshold of phosphate clearance. This action causes a decrease in serum phosphate levels.
Figure 12 shows an overview of the regulation of calcium metabolism.
Figure 12. Regulation of calcium metabolism.
GI = gastrointestinal; PTH = parathyroid hormone.
The vitamin D axis is the second important regulator of calcium homeostasis. Vitamin D3 is
derived from dietary sources. Additionally, exposure of the dermis to ultraviolet light leads to
conversion of cholesterol precursors to vitamin D3. Vitamin D3 is converted to 25hydroxyvitamin D3 in the liver, which is then converted to the more potent 1,25dihydroxyvitamin D3 in the proximal renal tubular cells under the effect of PTH. 1,25dihydroxyvitamin D3 is the biologically active form and causes an increase of calcium and
phosphate absorption in the gut. It can also directly suppress parathyroid cell function and
stimulate bone turnover to a lesser degree.
25-hydroxyvitamin D3 levels are measured to assess body stores of the vitamin. 1,25
hydroxyvitamin D3 levels can be assayed, but, because of the low levels in blood (about 30
pg/mL), extensive purification of the metabolite prior to assay must be performed and then
measured using the naturally occurring cellular receptor in radioligand assays or by
radioimmunoassay
HYPERCALCEMIA
Hypercalcemia occurs when calcium influx from the gastrointestinal tract and bone
overwhelms the excretory capacity of the kidneys. A directed clinical examination and several
simple biochemical tests can usually determine the cause of the hypercalcemia. The most
common cause of hypercalcemia in outpatients is primary hyperparathyroidism with increased
PTH secretion. In hospitalized patients, cancer is frequently the cause of the hypercalcemia.
Hypercalcemia is classically categorized into parathyroid-mediated and nonparathyroid–
mediated forms. This division highlights the central role that PTH plays in calcium
homeostasis.
Parathyroid-mediated hypercalcemia is generally referred to as hyperparathyroidism. In this
situation, the PTH level is elevated or inappropriately normal for the level of hypercalcemia.
There are three forms of hyperparathyroidism: primary, secondary, and tertiary. Primary
hyperparathyroidism results from dysregulated autonomous secretion of PTH from one or
more parathyroid glands. Secondary hyperparathyroidism is not a cause of hypercalcemia. It
occurs in the setting of vitamin D deficiency, chronic renal insufficiency, and intestinal
malabsorption states such as celiac disease. In these situations the ionized calcium level is
low. The hypocalcemia causes a normal physiologic stimulation of PTH secretion from the
parathyroid glands, in an attempt to revert the ionized calcium level to normal. The
biochemical profile shows an elevated PTH level with a low or low-normal calcium level.
Tertiary hyperparathyroidism is rare and usually occurs following many years of chronic renal
insufficiency and secondary hyperparathyroidism. The long-standing secondary
hyperparathyroidism results in four-gland parathyroid hyperplasia. Relative autonomous PTH
production by the hyperplastic glands then leads to hypercalcemia because they no longer
respond physiologically to the elevation in ionized calcium levels.
Benign familial hypercalcemia (also known as benign familial hypocalciuric hypercalcemia)
is a rare autosomal dominant disorder characterized by lifelong, mild, asymptomatic
hypercalcemia. It is caused by an inactivating mutation of the calcium-sensing receptor. It is
imperative to distinguish this condition from primary hyperparathyroidism because the
patients with benign familial hypercalcemia do not require parathyroid surgery. This
syndrome is diagnosed by a urinary calcium/creatinine clearance ratio less than 0.01,
measured in a fasting morning urine spot collection. Additionally, hypercalcemia can be
found in first-degree relatives, 50% of whom carry the trait.
Non-PTH mediated hypercalcemia is characterized by suppressed PTH levels (lower than 20
pg/mL in an intact PTH immunoradiometric assay, normal ranges between 10 to 65 pg/mL.)
The most common cause is cancer. Humoral factors, cytokines, or local osteolysis cause an
unregulated release of calcium from bone.
Table 36 shows the causes of hypercalcemia. Table 36. Causes of Hypercalcemia
Parathyroid hormone–mediated
Primary hyperparathyroidism
Tertiary hyperparathyroidism
Benign familial hypercalcemia
Non–parathyroid hormone-mediated
Cancer
Drug-induced (thiazides, lithium*, milk-alkali syndrome†, vitamin D or A intoxication)
Granulomatous diseases (sarcoidosis, tuberculosis)
Thyrotoxicosis
Adrenal insufficiency
Immobilization
Rhabdomyolysis
*
Parathyroid hormone levels are normal to slightly elevated in lithium-induced hypercalcemia
because of the effects of lithium on the calcium-sensing receptor; therefore, the inclusion of
lithium in this list can be disputed.
†
Milk-alkali syndrome results from ingestion of large amounts of calcium-containing
nonabsorbable antacids.
Granulomatous diseases are associated with the unregulated production of 1,25dihydroxyvitamin D3 within the granulomas. Lithium affects the parathyroid calcium-sensing
receptor and causes normal to slightly elevated PTG levels with relatively mild
hypercalcemia.
SYMPTOMS AND SIGNS
Symptoms and signs of hypercalcemia are related to the degree of elevation of the serum
calcium concentration, the rapidity of its development, and its cause. Mild hypercalcemia
(serum calcium 10 to 11.5 mg/dL) is usually asymptomatic and well tolerated. Occasionally,
mild neurocognitive impairment can occur. Moderate hypercalcemia (11.5 to 13.5 mg/dL) and
severe hypercalcemia (more than 13.5 mg/dL, called hypercalcemic crisis), are associated
with progressive symptoms of fatigue, polyuria, weakness, anorexia, nausea, vomiting,
constipation, abdominal pain, change in mental status, lethargy and, if left untreated, coma.
Calcium levels greater than 14 to 15 mg/dL can cause life-threatening cardiac arrhythmias.
Hypercalcemia also worsens digitalis toxicity. Dyspepsia often occurs in patients with
primary hyperparathyroidism.
EVALUATION
The widespread use of automated blood chemistry analyzers had lead to primary
hyperparathyroidism being diagnosed at an early, asymptomatic stage with mild
hypercalcemia. The classic presentation with band keratopathy (corneal calcifications), bone
pain, and kidney stones (“stones, moans, abdominal groans”) is rarely seen. Hypertension has
been associated with primary hyperparathyroidism.
A complete history and physical examination are important. Close attention should be paid to the
duration of hypercalcemia. An acute, sudden onset of hypercalcemia is suggestive of cancer, whereas
chronicity suggests a cause such as primary hyperparathyroidism. Signs and symptoms of
hypercalcemia, cancer, or hyperparathyroidism should be elicited. The initial step is to measure the
intact PTH level by a immunoradiometric assay. Serum electrolytes, serum phosphate, renal function,
and calculation of the fractional excretion of calcium are very helpful. If the clinical assessment is
suggestive, vitamin D metabolites and PTH-related protein, can also be measured. Figure 13 shows
the work-up of hypercalcemia. (Open the interactive tutorial.) Figure 13. Evaluation of
Hypercalcemia.
Ca+ = calcium; PTH = parathyroid hormone; PTHrP = parathyroid hormone–related protein.
PRIMARY HYPERPARATHYROIDISM
Primary hyperparathyroidism is the most common cause of hypercalcemia in an outpatient
setting. A single parathyroid adenoma is the cause in 85% of patients. In 15% of patients, a
double adenoma or multigland hyperplasia is noted, usually in the setting of the multiple
endocrine neoplasia (MEN) type 1 or 2 syndromes. The genetic mutations involved in these
syndromes have been defined. Parathyroid carcinoma is very rare and is usually associated
with severe hypercalcemia.
Primary hyperparathyroidism commonly presents as asymptomatic hypercalcemia (1). A
history of renal stones is very significant. These stones are composed of calcium oxalate and
are formed consequent to hypercalciuria. Although the action of PTH is to increase the renal
tubular reabsorption of calcium, hypercalcemia causes an increase in the filtered load of
calcium. This increase overwhelms the ability of PTH to reabsorb calcium in the renal tubule
with resultant hypercalciuria (calcium excretion >4 mg/kg per day). PTH causes renal
phosphate and bicarbonate wasting; therefore, a nonanion–gap metabolic acidosis and
hypophosphatemia can occur. Cortical bone loss occurs in sites such as the distal radius.
Osteopenia or osteoporosis is common (2).
The only definitive curative therapy for primary hyperparathyroidism is parathyroidectomy.
This surgery is usually recommended if the patient has evidence of end-organ damage related
to the hypercalcemia or if a specific symptom complex exists because in these settings the
greatest benefit from parathyroidectomy is likely to be obtained. The optimum approach to
asymptomatic patients is controversial. Table 37 shows the 2002 National Institutes of Health
consensus conference guidelines for the management of asymptomatic primary
hyperparathyroidism.
A single or double adenoma can be excised, however multigland hyperplasia requires subtotal
parathyroidectomy. Preoperative radiographic localization techniques have improved greatly
over the past few years and have altered the surgical approach. Technetium-99m sestamibi
parathyroid scanning can detect solitary adenomas in 70% to 80% of cases. Following a
positive scan, high-resolution neck ultrasonography can further define the anatomy. Not all
patients need these studies because, in the hands of experienced parathyroid surgeons, the
operative cure rate was 90% to 95% before the availability of localization studies; however,
preoperative localization may decrease operative time. Localization techniques are most
helpful in persistent or recurrent hyperparathyroidism. These surgeries are more complex
because anatomic boundaries are altered by prior surgical intervention and the adenoma
frequently resides in an atypical site.
Bilateral exploration of the neck was standard practice in parathyroid surgery 15 years ago.
Minimal-access or minimally invasive parathyroidectomy is replacing a bilateral neck
exploration as the surgical approach of choice in primary hyperparathyroidism. When a
parathyroid adenoma is localized preoperatively, ideally with technetium-99m sestamibi
combined with ultrasonography, results equivalent to a bilateral neck exploration can be
achieved through an incision less than 2.5 cm. Minimal-access techniques with a handheld
gamma probe can be used for intraoperative detection of high-uptake lesions, and videoassisted endoscopic surgery has been used successfully. These techniques offer the advantage
of cure under local anesthesia with a smaller incision (cosmetically more feasible) and no
overnight hospital stay. Intraoperative measurement of PTH is a valuable adjunct to
confirmation of parathyroid adenoma removal. The rapid intraoperative PTH assay relies on
the very short half-life of the hormone (3 to 4 minutes). It has a unique ability to detect even
an occult residuum of hyperfunctioning parathyroid tissue. PTH levels are measured before
and after the removal of the adenoma. Successful removal of a parathyroid adenoma causes at
least a 50% decrease in the PTH concentration. If this decrease does not occur, then further
neck exploration is required.
Oral cinacalcet hydrochloride is the first in a new class of therapeutic agents, the
calcimimetics, and has a novel mechanism of action. It directly modulates the calciumsensing receptor on the chief cells in the parathyroid gland and reduces circulating PTH levels
by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. In three
pivotal phase III, 26-week, randomized, double-blind, multicenter trials in 1136 chronic
kidney disease patients on dialysis with uncontrolled secondary hyperparathyroidism, a
significantly higher proportion of oral cinacalcet recipients (30 to 180 mg/d) achieved a
reduction in intact PTH levels to less than 250 pg/mL compared with placebo recipients.
Cinacalcet treatment also simultaneously lowered serum calcium and phosphorus and
calcium-phosphorus product levels. Notably, cinacalcet proved effective in a broad range of
patients with chronic kidney disease on dialysis with uncontrolled secondary
hyperparathyroidism, regardless of disease severity, duration of dialysis treatment, dialysis
modality, race, age, gender, or concurrent phosphate binder or vitamin D sterol use (3).
Cinacalcet also reduced elevated serum calcium levels by greater than 1 mg/dL in 15 of 21
patients (71%) with parathyroid carcinoma in an open-label, multicenter, dose-titration trial
(4). A recent study assessed the ability of cinacalcet to achieve long-term reductions in serum
calcium and PTH concentrations in patients with primary hyperparathyroidism (5). Seventyeight patients with primary hyperparathyroidism, with serum calcium greater than 10.3 mg/dL
but less than 12.5 mg/dL, were randomized to cinacalcet or placebo. The primary end-point
was the achievement of normocalcemia (serum calcium less than 10.3 mg/dL) with at least a
0.5 mg/dL reduction from baseline. Of cinacalcet-treated patients, 73% achieved the primary
endpoint versus only 5% of placebo-treated patients (P < 0.001). Bone mineral density was
unchanged by cinacalcet. Adverse events consisting of nausea and headache were mild and
similar between the two groups. Cinacalcet is FDA approved for the therapy of uncontrolled
secondary hyperparathyroidism, but not for the medical therapy of primary
hyperparathyroidism.
Antiresorptive therapy should be considered in all patients with demonstrable bone loss and
hyperparathyroidism. Patients with primary hyperparathyroidism who are not surgical
candidates and are being managed medically should avoid dehydration, thiazide diuretics, and
lithium because these conditions can worsen hypercalcemia. Periodic follow-up is necessary
because 25% of patients eventually develop an indication for surgery.
Table 37. 2002 National Institutes of Health Recommendations for Patients with
Asymptomatic Primary Hyperparathyroidism
Indications for surgery
Serum calcium level >1 mg/d above upper limit of normal
24-Hour urine calcium excretion > 400 mg
Creatinine clearance reduced by ≥ 30%
Bone mineral density: T-score <−2.5 at any site
Age younger than 50 years
Recommended follow-up measurements for patients not undergoing surgery
Biannual serum calcium
Annual serum creatinine
Annual bone mineral density (lumbar spine, proximal femur, distal forearm)
Adapted from: Bilezikian JP, Potts JT Jr., Fuleihan Gel-H, et al. Summary statement from a
Workshop on Asymptomatic primary hyperparathyroidism: A perspective for the 21st
century. J Clin Endocrinol Metab. 2002 Dec;87:5353-5361.
CANCER
Cancer is the second most common cause of hypercalcemia but is the most common cause in
the hospital. The term humoral hypercalcemia of malignancy refers to the production of
humoral factors by the tumor that cause hypercalcemia. PTH-related protein is the most
common such factor. PTH-related protein is produced by various tumors including squamous
cell carcinomas, ovarian cancer, breast cancer, and renal cell cancer. The protein has
significant structural homology to PTH, and therefore, PTH-related protein mimics many of
the metabolic actions of PTH. B-cell lymphomas can produce 1,25-dihydroxyvitamin D3 with
resultant hypercalcemia. Tumors such as multiple myeloma lead to hypercalcemia through
local invasion into bone (local osteolytic hypercalemia). In this situation, the tumor cells
within bone produce locally active cytokines that upregulate osteoclastic resorption of bone
with systemic release of calcium and resultant hypercalcemia. Table 38 shows tumors
associated with hypercalemia (6).
Table 38. Neoplasms Associated with Non–Parathyroid Hormone–Mediated Hypercalcemia
Humoral hypercalcemia of malignancy
Parathyroid hormone–related protein
Squamous cell carcinoma (lung, esophagus, larynx, oropharynx, nasopharynx, cervix, penis,
skin)
Ovarian cancer
Breast cancer
Renal-cell carcinoma
Transitional-cell carcinoma of the bladder, ureter
Pancreatic islet-cell neoplasms
T-cell lymphoma
Pheochromocytoma
Carcinoid
Others
1,25-Dihydroxyvitamin D3
B-cell lymphoma
Local osteolytic hypercalcemia
Multiple myeloma
Breast cancer
Lymphomas
Others
MANAGEMENT OF HYPERCALCAEMIA
Treatment of the underlying cause of hypercalcemia is an obvious, but frequently overlooked
goal, especially in patients with malignancy-associated hypercalcemia. In these patients
antitumor therapy should be planned and initiated early in the hospital course because other
measures are effective only transiently and may be associated with toxicity. Usually,
hypercalcemia is an end-stage manifestation of the tumor and can only be controlled with
successful antitumor therapy or tumor extirpation. Most patients with acute hypercalcemia are
volume-depleted, and expansion of the extracellular space with intravenous crystalloid,
preferably 0.9% saline, is necessary. Renal calcium excretion is enhanced by saline infusion,
secondary to the increase in the glomerular filtration rate and the role of the filtered load of
sodium in blocking proximal tubular calcium reabsorption. Infusion rates of 200 to 400 mL/h
are commonly used, but clinical discretion is advised to avoid fluid overload in these patients,
many of whom are elderly with a fragile cardiovascular status. Only when the patients are
euvolemic, a loop diuretic such as furosemide can be added to enhance calciuresis. Loop
diuretics appear to inhibit calcium reabsorption in the thick ascending limb of Henle's loop.
Bisphosphonates inhibit osteoclastic bone resorption and are particularly effective in
hypercalcemia of malignancy. Normocalcemia may last from 1 to 8 weeks following
intravenous pamidronate. Zoledronate is a newer, long-acting, intravenous nitrogencontaining bisphosphonate that is indicated for the treatment of hypercalcemia of malignancy.
The recommended dose is 4 mg by slow intravenous infusion over 15 minutes or more every
3 to 4 weeks. Compared with pamidronate 90 mg, zoledronate 4 mg and 8 mg provided a
higher complete response rate for hypercalcemia of malignancy after 10 days and had a longer
duration of action (median time to relapse 30 and 40 days versus 17 days). Furthermore,
zoledronate normalizes serum calcium levels significantly faster than pamidronate. Other
drugs used to treat hypercalcemia include calcitonin, plicamycin, and gallium nitrate (Table
39). Calcitonin inhibits osteoclast function and causes a rapid fall in serum calcium levels,
within 2 to 4 hours after subcutaneous injection. Calcitonin can be used as an intermediary
measure to “take the tip off the hypercalcemia,” while waiting for the intravenous
bisphosphonates to exert their hypocalcemic effects. Tachyphylaxis to the effect of calcitonin
has been documented. Corticosteroids have classically been used in hypercalcemic states
associated with production of 1,25 dihydroxyvitamin D3, such as lymphoma or granulomatous
disorders. The oral doses have been approximately 25 mg of cortisone acetate, to as high as
20 mg of prednisone, or their parenteral equivalents given three to four times a day. The
hypocalcemic response may take 7 to 10 days to become apparent.
In patients with renal failure and hypercalcemia, dialysis against a low calcium bath can be
performed. Aggressive therapy in all patients with malignancy-associated hypercalcemia may
not be advisable because the hypercalcemia is often a terminal event.
HYPOCALCEMIA:
Table 40 shows the causes of hypocalcemia. Table 40. Causes of Hypocalcemia
Abnormal supply of or response to parathyroid hormone
Hypoparathyroidism
Pseudohypoparathyroidism
Abnormal supply of or response to vitamin D
Nutritional vitamin D deficiency
Vitamin D pseudodeficiency (vitamin D-dependent rickets, type I)
Abnormal vitamin D receptor (vitamin D-dependent rickets, type II)
Vitamin D-resistant rickets (hypophosphatemic rickets)
Malabsorption
Chronic renal insufficiency
Cirrhosis
Anticonvulsant therapy
Other
Hypoalbuminemia (ionized calcium levels are normal)
Hypomagnesemia
Hyperphosphatemia
Drugs (phosphate, bisphosphonates, calcitonin, plicamycin)
Acute pancreatitis
Rhabdomyolysis
Large-volume transfusions of citrate-containing blood products
Osteoblastic metastases (breast, prostate cancers)
Gain of function mutation in calcium-sensing receptor gene
©2006 American College of Physicians. MKSAP®14. All rights reserved.
In patients with chronic illnesses or malnutrition, hypoalbuminemia causes the total calcium
level to fall; however, the ionized calcium level is normal and the patients are asymptomatic.
During neck surgery, excision of or vascular compromise to the parathyroid glands can lead to
hypoparathyroidism with hypocalcemia and hyperphosphatemia. In this situation the
hypocalcemia is usually short-lived, lasting for weeks to (rarely) months, and can be treated
with oral calcium supplementation and oral calcitriol as necessary. Irreversible postsurgical
hypoparathyroidism is unlikely, unless all four parathyroid glands have been removed or the
vascular supply irreversibly damaged. Autoimmune destruction of the parathyroid glands is
usually associated with other autoimmune phenomena such as Hashimoto's thyroiditis or
Addison's disease (the polyglandular autoimmune syndromes). Infiltrative diseases such as
hemochromatosis can affect the parathyroid glands. Hypomagnesemia is a common cause of
“functional hypoparathyroidism” in hospitalized patients. Hypomagnesemia inhibits the
release and action of PTH. The “hungry bone syndrome” occurs after parathyroidectomy in
patients who have had long-standing primary hyperparathyroidism with severe bone disease.
Large amounts of calcium and phosphate are deposited in the bone after removal of the
parathyroid adenoma. Hypocalcemia and hypophosphatemia occur, thereby differentiating
this condition from transient hypoparathyroidism in which hyperphosphatemia and
hypocalcemia are the hallmarks. Pseudohypoparathyroidism is congenital and characterized
by dysmorphic features, hypocalcemia, and a resistance to PTH (PTH levels are very high).
Deficiency of vitamin D or resistance to its action can lead to mild hypocalcemia (7). The
most common cause is nutritional vitamin D deficiency, which is characterized by rickets in
children and osteomalacia in adults. Acute or chronic renal failure, rhabdomyolysis, and the
tumor lysis syndrome lead to hyperphosphatemia and hypocalcemia because the phosphate
complexes with calcium. Acute pancreatitis can result in hypocalcemia because pancreatic
lipase locally liberates free fatty acids, which form complexes with calcium.
The cause of hypocalcemia can be ascertained by obtaining a careful history and measuring
circulating concentrations of serum calcium, phosphate, PTH, and vitamin D metabolites (25
hydroxyvitamin D3 and 1,25 dihydroxyvitamin D3).
Mild hypocalcemia is usually well tolerated, especially if the decrease in ionized calcium has
been gradual. If the serum calcium level is less than 7 mg/dL, however, especially if it has
decreased precipitously, then signs and symptoms of hypocalcemia can occur. These include
tremor, muscle spasm, laryngospasm, Trousseau's sign, Chvostek's sign, paresthesias, tetany,
and even seizures. Dangerous prolongation of the QTc interval can occur with deterioration
into ventricular tachycardia and fibrillation.
The severity, acuity, and presence of symptoms of hypocalcemia guide the therapy. Patients
with acute symptoms of hypocalcemia can be repleted with an intravenous infusion of
calcium salts such as 10% calcium gluconate or 10% calcium chloride. Calcium chloride
should be infused via central venous access because extravasation into the subcutaneous
tissues is very irritating. Hypocalcemic emergency in the presence of tetany, seizures, or
electrocardiographic changes can be treated with one ampoule of calcium gluconate
administered intravenously over 10 to 15 minutes. This administration should be followed by
a slower infusion to provide elemental calcium 0.5 to 2 mg/kg bodyweight per hour.
Hypomagnesemia should also be treated parenterally. Alkalosis should be avoided because it
increases protein binding of calcium, thereby lowering the ionized calcium level.
Oral supplementation of calcium is sufficient in less severe cases of hypocalcemia. Calcium
carbonate or calcium citrate can be used to provide 1000 to 2500 mg of elemental calcium
daily. Vitamin D supplementation is usually recommended as well. In nutritional vitamin D
deficiency 400 to 800 IU/d of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) is
sufficient. Malabsorptive states may require higher doses of vitamin D. These vitamin D
preparations have a slow elimination and can accumulate in adipose tissue, and therefore, care
should be exerted to avoid prolonged vitamin D toxicity. Hypoparathyroidism or renal failure
is treated with the end hormone 1,25 dihydroxyvitamin D3 in the form of calcitriol (0.5 to 1
µg/d). In patients with hypoparathyroidism the goal is to maintain the serum calcium level in
the range 8 to 8.5 mg/dL. Normalization of the serum calcium concentration is associated
with hypercalciuria and the tendency to develop kidney stones, nephrocalcinosis, and
potential renal failure. This effect occurs because renal tubular reabsorption of calcium cannot
be increased because of the absence of PTH action.
METABOLIC BONE DISEASES
Metabolic bone diseases are generalized skeletal disorders. The two most common bone disorders,
osteoporosis and Paget's disease of the bone, have generalized symptoms and may not be clinically
apparent in all patients. Bone loss in association with osteoporosis is generalized; however, the
diagnosis of osteoporosis is often made only when fractures of the hip, spine, or forearm have
occurred. Paget's disease may affect any bone in the skeleton, but it is localized (monostotic) in 20%
of patients.
OSTEOPOROSIS
MEASUREMENT OF BONE DENSITY
Bone mineral densitometry is used to measure bone mass to establish the diagnosis of
osteoporosis and to determine the severity of bone loss. Standard radiographs are not sensitive
indicators of bone loss because 30% to 40% of bone mineral density has already been lost by
the time osteoporosis appears on radiographs. Today dual-energy X-ray absorptiometry
(DEXA) is the gold standard for measuring bone mass. This technique has the best correlation
with fracture risk, requires a short scanning time of 5 minutes, and measures the bone mineral
density of all areas of the skeleton with high accuracy and reproducibility and low exposure to
radiation. However, it does not assess the plasticity or connectivity of bone. Other techniques
to measure bone mass include quantitative CT, single-photon absorptiometry, radiographic
absorptiometry, and quantitative ultrasonography. Results vary highly among these
techniques. Table 42 shows the indications for measurement of bone mass.
Table 42. Indications for Measurement of Bone Mass
Women age ≥ 65 years (regardless of risk factors)
Postmenopausal women age < 65 years who have at least one risk factor for osteoporosis
other than menopause
Postmenopausal women who present with fractures
Women who are considering therapy for osteoporosis and for whom bone mineral
densitometry tests results would influence this decision
Women who have been receiving hormone replacement therapy for a prolonged period
Radiographic findings suggestive of osteoporosis or vertebral deformity
Corticosteroid therapy for more than 3 months
Primary hyperparathyroidism
Treatment for osteoporosis (to monitor therapeutic response)
DEXA scan results are reported in terms of T scores (the standard deviation from the mean
bone mineral density of a young healthy population) and Z scores (the standard deviation
from the bone mineral density of an age- and sex-matched group). At the spine, a T score of –
1 represents approximately 10% bone loss. The T score is used to diagnose osteoporosis.
In 1994, the World Health Organization developed criteria for the diagnosis of osteoporosis
and osteopenia in white women by using T scores from any skeletal site (Table 43). Table 43.
World Health Organization Definitions of Bone Mass
Normal bone mass: T score > −1
Low bone mass: T score –1 to −2.5
Osteoporosis: T score < −2.5
Established (severe) osteoporosis: T score < −2.5 and one or more osteoporotic fractures
Since the definitions were obtained from data in white postmenopausal women, however,
these definitions should be used with caution in men, other ethnic groups, and premenopausal
women. The criteria were developed from studies using bone densitometry and therefore
should not be applied to bone density assessments by other techniques such as quantitative CT
or ultrasound. These criteria are epidemiologic definitions and not intended as treatment
guidelines. Clinical assessment of the patient's medical condition and history should be
incorporated with the results of the bone mineral density assessment to determine the best
treatment plan.
EVALUATION During the evaluation it is important to assess a patient's risk for the disease.
Certain medical conditions can lead to osteoporosis (Table 44). able 44. Causes of Secondary
Osteoporosis
Endocrine disorders: hyperparathyroidism, Cushing's syndrome, hypogonadism,
hyperthyroidism, prolactinoma, acromegaly, osteomalacia
Hematopoietic disorders: multiple myeloma, sickle-cell disease, thalassemia minor, leukemia,
lymphoma, polycythemia vera
Connective tissue disorders: osteogenesis imperfecta, homocystinuria
Medications: corticosteriods, anticonvulsants, heparin
Renal disease: chronic renal failure, renal tubular acidosis, hypercalciuria
Nutritional: malabsorption, total parenteral nutrition
Gastrointestinal: gastrectomy, primary biliary cirrhosis, celiac disease
Genetic: Turner's syndrome, Klinefelter's syndrome
The use of markers of bone formation (alkaline phosphatase, osteocalcin, procollagen) and
bone resorption (hydroxyproline, pyridinoline and deoxypyridinoline) is controversial. Use of
these markers is limited by a wide range of normal values, their circadian rhythm, and large
intra-assay and inter-assay variability. Bone biopsy is rarely indicated and should be limited
to patients with unusual skeletal lesions, patients with renal osteodystrophy, and young men
or women who have severe osteoporosis or fracture without an obvious secondary cause.
Prevention of bone loss in postmenopausal women should be considered when the T score is
less than –1 and risk factors are present. Preventive measures for osteoporosis include an
adequate calcium and vitamin D intake, exercise, cessation of smoking, fall prevention,
limitation of alcohol and caffeine, and use of medications (bisphosphonates and raloxifene).
The recommended goals for calcium intake depend on sex and age (Table 45). Vitamin D
supplementation should be approximately 400 to 800 IU orally once a day.
Table 45. Recommended Calcium Requirements
Patient/Age Group (years)
Adolescents/young adults: 11 – 24
Optimal Daily Intake of Calcium (mg)
1200 – 1500
Men
25 – 65
1000
> 65
1500
Women
25 – 50
1000
Pregnant or nursing
1200 – 1500
THERAPY.
The National Osteoporosis Foundation has recommended treatment for women with a T score
less than –2 in the absence of risk factors, women with a T score of less than –1.5 who have
risk factors, and women older than age 70 years with multiple risk factors. All women with a
prior vertebral or hip fracture should be treated. The treatment plan should include preventive
measures (8).
Exercise and physical therapy increase bone formation, improve balance, and decrease the
frequency of falls and fractures. Inactivity worsens osteoporosis as does exercise that is
strenuous enough to cause amenorrhea in premenopausal women. However, there is no
consensus about the type, duration, and frequency of exercise that is optimal for bone health.
Most experts recommend 30 minutes of weight-bearing or resistance exercise at least four
times a week.
Medical therapy includes bisphosphonates. These drugs are pyrophosphate derivatives that
bind to the bone surface and inhibit osteoclastic bone resorption. They are poorly absorbed
and must be taken in the fasting state to optimize absorption. The two FDA-approved
bisphosphonates, alendronate and risedronate (9), have significant antifracture efficacy at the
spine, hip, and other sites. Antifracture efficacy has been examined in patients with severe
osteoporosis (alendronate and risedronate) and in those with low bone mass (alendronate).
Alendronate appears to be more effective in lowering fracture risk in severely osteoporotic
patients than in those with osteopenia. For alendronate and risedronate, the FDA has approved
once-weekly dosing on the basis that it gives the same bone mineral density response as daily
dosing. The optimal duration of treatment with these drugs is not known. Patients have been
treated for 5 to 7 years with continued small gains in bone mineral density and no apparent ill
effects (10).
Zoledronate is one of several newer bisphosphonates that is being evaluated for the treatment
of osteoporosis. In postmenopausal women with osteoporosis, a single injected dose of
zoledronate suppressed bone turnover markers for a full year and induced significant gains in
bone mineral density over the same period (11). The effect of zoledronate on fracture
incidence is not yet known.
Hormone replacement therapy is no longer regarded as the mainstay of therapy for
osteoporosis. In the Women's Health Initiative, the use of conjugated estrogens and
medroxyprogesterone in postmenopausal women increased the risk of cardiovascular disease,
invasive breast cancer, stroke, deep venous thrombosis, and pulmonary embolism (12).
In view of these findings consideration of other medications before estrogen is prudent.
Raloxifene is a selective estrogen receptor modulator that has estrogen-like effects on bone,
but inhibits the effects of estrogen in the breast and uterus. Raloxifene increases bone mass
and decreases the risk of vertebral fractures in postmenopausal women but does not affect the
incidence of hip fractures. Raloxifene is not associated with adverse cardiovascular events and
decreases the risk of breast cancer in high-risk women. Side effects include hot flushes and an
increase in the risk of thromboembolism.
Calcitonin nasal spray increases bone mass in the spine and decreases vertebral fractures but
does not affect the incidence of hip fractures. This drug is indicated for women who are more
than 5 years postmenopausal.
Teriparatide (recombinant human PTH [1-34]) is the only anabolic agent, whereas all the
other medications are antiresorptive. When given intermittently, teriparatide stimulates
osteoblastic bone formation. It is given as a subcutaneous injection and should not be used for
more than 2 years. Teriparatide significantly increases bone mass and can decrease the
incidence of both vertebral and nonvertebral fractures (13). Animal studies have shown an
increased risk of osteosarcoma; therefore, this agent should be avoided in patients with Paget's
disease of bone, previous radiation involving the skeleton, and a history of skeletal cancer.
Because of its expense it should not be used as a first-line agent. Teriparatide should be
considered in patients who are intolerant of other medications and in those with the greatest
fracture risk.
Combination therapy with teriparatide and alendronate has been investigated in women with
postmenopausal osteoporosis and in men with osteoporosis (14, 15). There was no evidence
of synergy between the two agents; in fact, the concurrent use of alendronate appeared to
blunt the anabolic effects of teriparatide. Another study assessed the effect of teriparatide on
bone mineral density after treatment with raloxifene or alendronate. Prior treatment with
raloxifene allowed for the expected teriparatide-induced increase in bone mineral density.
However, prior treatment with alendronate prevented increases in bone mineral density,
particularly in the first 6 months. Long-term studies of fractures are needed to determine
whether and how antiresorptive agents can be optimally used in conjunction with PTH. Table
46 shows the FDA-approved indications of the medications for the treatment of osteoporosis.
Table 46. Medications for Osteoporosis and United States Food and Drug AdministrationApproved Indications
Medication
Postmenopausal
Osteoporosis
CorticosteroidInduced Osteoporosis
Males
Once Weekly
Administration
Prevention Treatment Prevention Treatment Treatment
Estrogens
Yes
No
No
No
No
No
Calcitonin
No
Yes*
No
No
No
No
Raloxifene
Yes
Yes
No
No
No
No
Alendronate Yes
Yes
No
Yes
Yes
Yes
Risedronate Yes
Yes
Yes
Yes
No
Yes
Teriparatide No
Yes
No
No
Yes
No
*More than 5 years after menopause.
OSTEOPOROSIS IN MAN
Between 250,000 and 2,000,000 men have osteoporosis. The lifetime risk for an osteoporotic
fracture in a man is approximately one-third that for women. Hip fractures in men occur later
in life than in women, especially in the eighth decade. In contrast, vertebral fractures in men
can occur as early as the third to fourth decade. In men with chronic obstructive pulmonary
disease, almost 50% will have documented vertebral fractures regardless of corticosteroid
therapy. This data supports bone mineral densitometry screening of men by the sixth decade,
particularly those at high risk of fracture.
Risk factors in men include a low body mass index (less than 18), a history of smoking or
excessive alcohol consumption, a family history of osteoporotic fractures, hypogonadism, a
history of corticosteroid use, vitamin D deficiency, medications causing osteomalacia or
hypogonadism such as phenytoin or GnRH agonists, and an increased risk factor for falls
(e.g., stroke, movement disorder). Approximately 40% of men have no medical condition or
risk factors for bone loss (16).
Hypogonadism is a prevalent secondary cause of male osteoporosis. Testosterone increases
the periosteal apposition of bone and suppresses the recruitment of osteoclasts from their
progenitors. Hypogonadism increases the skeletal sensitivity to PTH and decreases intestinal
calcium absorption. As men age, the free testosterone level falls in as many as 25% of men. In
cross-sectional studies, low bone mass correlated to total estradiol rather than testosterone;
additionally severe osteoporosis is seen in men with aromatase deficiency. This finding
supports the theory that estradiol is the main hormone responsible for maintaining bone mass.
Because testosterone is aromatized to estradiol it can be regarded as a pro-hormone for
estradiol in the bone.
Vitamin D deficiency is associated with a 30-fold increased risk of fractures and with
concurrent osteomalacia. Of men older than age 50 years, 4% to 6% have 25-hydroxyvitamin
D3 levels less than 15 ng/mL. Hypercalciuria is seen in 10% of men with osteoporosis.
Treatment with thiazide diuretics can increase bone mass by 3% to 5% in this situation.
Men experience fracture less often than do women, but the mortality associated with hip
fractures is higher (30% vs 15% for women in the year after a hip fracture). Men are 1.6 times
more likely to die of a hip fracture while hospitalized. For patients with pulmonary disease,
each vertebral crush fracture is associated with a 10% reduction in total lung capacity.
The treatment of men with osteoporosis includes calcium and vitamin D supplementation:
1500 mg of oral elemental calcium and 800 IU of oral vitamin D daily. Low bone mass in
hypogonadal men is increased with androgen replacement, and bisphosphonates are effective
in men regardless of gonadal status. Anabolic therapy with teriparatide can increase bone
mineral density, but no fracture risk trials are available.
CORTICOSTEROID INDUCED OSTEOPOROSIS
Bone loss induced by exogenous corticosteroids is the most common form of secondary
osteoporosis. There is a generalized decrease of bone mineral density, and 30% to 50% of
patients develop vertebral fractures. The effect is determined by the dose and duration of
therapy. Trabecular bone loss primarily occurs and is significant in the spine. After the
initiation of corticosteroid therapy, there is a rapid phase of bone loss, followed by a slow
continuous decline. A decrease in bone markers such as serum osteocalcin and alkaline
phosphatase occurs.
Corticosteroids also cause a decrease in calcium absorption, and an increase in urinary
calcium excretion. Secondary hyperparathyroidism occurs. There is a modest increase in bone
resorption but a marked decrease in osteoblastic function. The fundamental action on bone is
to decrease bone formation. When corticosteroids are administered, there is an early increase
in bone resorption with rapid bone loss (explaining the effectiveness of antiresorptive agents),
after which the loss is sustained and slower.
The prevention and treatment includes oral calcium supplementation 1500 mg/d and oral
vitamin D 800 IU/d. A DEXA scan should be performed at the initiation of corticosteroid
therapy in addition to patient education and treatment of underlying risk factors.
Bisphosphonates are recommended for the prevention of bone loss if prednisone, 5 mg/d or
more (or its equivalent), is to be used for more than 3 months. Gonadal sex steroids should be
replaced if hypogonadism is present. Calcitonin can be used if bisphosphonates are
contraindicated or not tolerated. Bisphosphonates should be started in patients with T scores
less than –1 who are receiving long-term corticosteroid therapy. In addition, patients with a
history of fractures on corticosteroid therapy should be started on bisphosphonates. A 24-hour
urine calcium measurement is recommended 1 month after corticosteroids have been started.
If the urine calcium excretion is greater than 300 mg/d, a thiazide diuretic can be initiated
unless it is contraindicated. A repeat DEXA scan should be done at 6 to 12 months of therapy.
If the bone mineral density is stable, has improved, or decreased less than 5%, then the current
therapy can be continued. However, if the bone mineral density has decreased more than 5%,
then a change in the medication or addition of medications should be undertaken.
OSTEOMALACIA/VIT D DEFICIENCY
RADIOGRAPHIC APPEARANCE
Looser's zones (also called pseudofractures) are pathognomonic of osteomalacia. These
findings are caused by defects in bone and on radiograph appear as radiolucent bands,
perpendicular to the bone surface, and usually symmetric and bilateral. Characteristic
locations include the inner aspects of the femur, the pubic rami, and the outer edges of the
scapula. Pseudofractures occur where major arteries cross bones. The trauma caused by
arterial pulsations may be responsible for their location and symmetry. Vertebrae may show
loss of trabeculae and blurring of trabecular markings. Bones may show decreased
mineralization or a coarsened texture. Rugger-jersey spine sign may be apparent in addition to
bowed long bones. Most of these patients have chronic renal disease.
LAB EVALUATION
Hypocalcemia and hypophosphatemia (which can be quite profound) are seen, except in renal
osteodystrophy in which the phosphorus level is invariably high and the calcium level low. The
alkaline phosphatase is usually elevated in all forms of osteomalacia (except hypophosphatasia).
Bone biopsy is sometimes necessary to establish the diagnosis and allow assessment of the number
and thickness of osteoid seams per unit area. Widened osteoid seams are present with less
mineralized bone per unit volume. Tetracycline labeling helps confirm decreased mineralization of
osteoid seams.
TREATMENT
Simple dietary deficiency of vitamin D or lack of exposure to sunlight responds to small daily
supplements of ergocalciferol and calcium or regular periods of exposure to ultraviolet light.
Administration of 1000 to 2000 IU/d of oral ergocalciferol will heal the bone disease in several
months. Oral calcium supplementation includes 1 g/d of elemental calcium for adults and 2 g/d for
children. Patients with malabsorption need higher doses of oral calcium and oral ergocalciferol
(200,000 IU/d) or 40,000-80,000 IU of ergocalciferol given intravenously or intramuscularly. Patients
with impaired synthesis of or target cell resistance to 1,25 dihydroxyvitamin D3 should be treated
with calcitriol. The serum calcium should be kept in the low normal range to avoid hypercalcemia and
hypercalciuria ; in addition, the calcium, phosphate, and alkaline phosphatase levels should be
followed every 3 to 4 months.
ONCOGENIC OSTEOMALACIA
Oncogenic osteomalacia may be associated with benign, vascular, small mesenchymal tumors such as
hemangiomas, which are difficult to locate. These tumors are frequently found in the area of the
sinuses; some are in bone or skin. A humoral factor causes the osteomalacia because the bone
disease resolves when the tumors are resected. The factor appears to be a phosphaturic peptide
(phosphatonin), which acts at the level of the proximal renal tubule, inhibiting sodium-dependent
phosphate transport with resultant phosphate wasting and profound hypophosphatemia. Supportive
therapy with calcitriol (up to 3 µg/d) and phosphate (2 to 4 g/d) alleviates the osteomalacia and
muscle weakness. A complete resection of the tumor will result in cure.
PAGET’S DISEASE
Paget's disease is a focal disorder of bone remodeling that leads to greatly accelerated rates of bone
turnover, disruption of the normal architecture of bone and sometimes to gross deformities of bone
(enlargement of the skull, bowing of the femur or tibia). The exact cause is not known but the
primary abnormality appears to be in the osteoclast. A viral cause has been suggested as well as a
genetic predisposition. Most patients with Paget's disease are asymptomatic. The diagnosis is often
suspected from radiographs obtained for other reasons or from an isolated elevation of the serum
alkaline phosphatase. The most common symptom is a dull, aching bone or joint pain. Headache,
bone deformity, fracture, warmth of skin over involved bone, high-output cardiac failure, or
entrapment neuropathies causing loss of hearing are less common. Table 47 shows complications of
Paget's disease.
Table 47. Complications Associated with Paget's Disease of Bone
Bone pain
Bone deformity
Secondary arthritis adjacent to pagetic bone
Neurologic abnormalities
Spinal stenosis
Hearing loss and other cranial nerve palsies
Radiculopathy
Obstructive hydrocephalus
Cardiovascular complications
Increased blood flow to involved bone
Increased cardiac output
Vascular and aortic valve calcifications
Fracture
Malignant transformation
Immobilization hypercalcemia
The primary indication for treatment of Paget's disease is the presence of symptoms. Bone
pain usually responds to therapy, as do some of the neurologic compression syndromes.
However, hearing loss, bone deformity, and mechanically dysfunctional joints are unlikely to
improve with treatment. Treatment of asymptomatic patients with Paget's disease is
controversial. Untreated Paget's disease appears to progress. Thus, many physicians treat
patients with osteolytic Paget's disease or asymptomatic patients with active disease involving
weight-bearing bones, vertebral bodies, the skull, or areas adjacent to major joints (Table 48).
Table 48. Indications for Treatment of Paget's Disease of Bone
Symptoms: bone pain, headache, most neurologic abnormalities
Osteolytic bone disease
Active asymptomatic disease in weight-bearing bones, areas adjacent to major joints,
vertebral bodies, or skull
Young age
Before orthopedic surgery on pagetic bone
Immobilization hypercalcemia
There is no cure for Paget's disease, but several medications decrease the accelerated rate of
osteoclastic bone resorption. Bisphosphonates such as alendronate, risedronate, tiludronate,
pamidronate, and etidronate are available in the United States for the therapy of Paget's
disease. Other than pamidronate, all of these drugs are orally administered. These agents are
usually given for several months, and the duration of therapy varies for each agent.
Salmon calcitonin is also effective in the treatment of Paget's disease. It requires subcutaneous
or intramuscular injection. Resistance to the effect of calcitonin is associated with the
formation of neutralizing antibodies. Calcitonin nasal spray is not effective in the therapy of
Paget's disease because of its low bioavailability. After treatment with bisphosphonates
suppression of disease activity may last for several years, whereas the response to calcitonin is
generally short-lived once the calcitonin has been discontinued. Thus, for the therapy of
uncomplicated Paget's disease an oral bisphosphonate is the agent of choice (17). Calcitonin
should be reserved for patients with primarily lytic disease or those in whom a rapid response
is required, such as patients with high-output cardiac failure or symptomatic disease of the
spine, or those who are having elective surgery on pagetic bone. Treatment of symptomatic
patients should also include other options such as analgesics, nonsteroidal anti-inflammatory
drugs, canes, shoe lifts, hearing aids, and surgery.