Elizabeth H. Holt MD, PHD1
Silvio E. Inzucchi MD2
1Assistant Professor of Internal Medicine/Endocrinology and Metabolism, Yale University School of Medicine
2Associate Professor of Medicine, Section of Endocrinology, Yale University School of Medicine
Elizabeth H. Holt, M.D., Ph.D., has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Silvio E. Inzucchi, M.D., has received research funding from Eli Lilly Co. and speakers' honoraria from Merck & Co., Inc.
The precise regulation of body calcium stores and of the calcium concentration in both extracellular and intracellular compartments is critically important, for the following reasons: calcium is the chief mineral component of the skeleton; calcium serves major roles in neurologic transmission, muscle contraction, and blood coagulation; and it is a ubiquitous intracellular signal. A typical laboratory range for serum calcium concentration is between 8.8 and 10.5 mg/dl; 50% to 60% of the calcium in the blood is bound to plasma proteins or is complexed with citrate and phosphate. The remaining ionized (free) calcium controls physiologic actions. The body regulates not only ionized calcium concentrations but also the entry and exit of calcium into its main storage site, bone, through the activity of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) [see Figure 1]. PTH, secreted by the parathyroid glands, is an 84-amino acid peptide with a very short plasma half-life (2 to 4 minutes). Cholecalciferol (vitamin D3) is generated by the skin, upon exposure to ultraviolet light; it is also supplied by dietary sources (chiefly fortified liquid milk products). In the liver, vitamin D3 is hydroxylated to 25-(OH)D3, which is in turn hydroxylated in the kidney to 1,25-(OH)2D3 (calcitriol), markedly increasing its potency. In concert, this hormonal system expresses its action at the level of the gastrointestinal tract, bone, and the kidney and maintains circulating ionized calcium concentrations under extremely tight control (variation < 0.1 mg/dl), despite significant variations in calcium supply.
Figure 1. Mechanism of calcium metabolism
Circulating concentrations of ionized calcium are maintained under extremely tight control by parathyroid hormone (PTH) and the vitamin D axis. Absorption of dietary calcium by the gastrointestinal tract, reduction of calcium excretion by the kidneys, and release of stored calcium from bones serve as sources for circulating calcium. Decreases in circulating calcium trigger the release of PTH, which promotes release of calcium into the extracellular space by increasing bone resorption; the release of PTH also causes an increase in calcium reabsorption in the distal nephron, resulting in a decrease in urinary calcium loss. PTH also augments renal production of 1,25-dihydroxyvitamin D, which secondarily increases calcium absorption in the gut.
Under normal conditions, despite ranges in dietary calcium consumption that can vary from 400 to 2,000 mg daily, net calcium absorption from the GI tract averages about 150 to 200 mg/day. In steady state, this equals the amount of calcium excreted by the kidneys. Ongoing remodeling of bone results in the consumption and release of approximately 500 mg of calcium a day. Through humoral regulation, this calcium reservoir can be exploited to maintain extracellular calcium levels in a narrow range despite increased physiologic need or decreased intake, such as results from severe curtailment of the dietary calcium supply or from impairment of intestinal calcium absorption.
Changes in the extracellular ionized calcium concentration are registered by parathyroid cells via the cell surface calcium-sensing receptor (CaSR).1 Interaction of calcium ions with the extracellular domain of the CaSR triggers a series of intracellular signaling events, which ultimately govern PTH secretion. As circulating concentrations of calcium fall, PTH secretion rises, and vice versa.
PTH increases bone resorption and distal nephron calcium reabsorption, the former promoting calcium release into the extracellular space and the latter decreasing urinary calcium losses. PTH also augments renal production of calcitriol, which then increases fractional calcium absorption in the gut. If calcium intake increases beyond the body's needs, PTH secretion decreases, leading to decreased calcitriol production and decreased calcium absorption by the gut. If calcium is absorbed in excess of requirements, it will be promptly excreted. In this elegant manner, circulating ionized calcium concentration is guarded closely, albeit sometimes at the expense of skeletal calcium stores. Disturbances of PTH, vitamin D action, or both are most often manifested by altered serum calcium or phosphate concentration and by abnormal bone turnover. In some cases, bone mineral density (BMD) is decreased.
Measurement of Calcium
Diagnosis of a calcium disorder depends first on accurate measurement of serum or ionized calcium or both. Serum measurements are usually performed by spectrophotometry or by atomic absorption spectrophotometry, which yields more accurate measurements. Spurious readings may occur with tourniquet stasis (i.e., if the tourniquet is in place too long before the blood is drawn), which can elevate serum calcium values by up to 1 mg/dl. Dilution of blood by drawing samples from indwelling intravenous catheters is a common error that leads to spuriously low calcium readings. Ionized calcium measurements should be considered accurate only when performed on samples collected anaerobically (i.e., in a blood gas syringe) and placed on ice, with immediate analysis.
Hypercalcemia is a common metabolic abnormality. Signs and symptoms of hypercalcemia vary significantly from patient to patient and correlate somewhat with the degree of calcium elevation and its rate of change. The diagnostic workup of hypercalcemia is straightforward [see Figure 2].2 The etiology of hypercalcemia is usually discovered after a comprehensive history, physical examination, focused laboratory assessment, and, occasionally, diagnostic imaging studies.3
Figure 2. Evaluation and management of hypercalcemia
Evaluation and management of hypercalcemia. (DXA—dual-energy x-ray absorptiometry; FHH—familial hypocalciuric hypercalcemia; MEN—multiple endocrine neoplasia; PTH—parathyroid hormone; PTHrP—parathyroid hormone—related protein)
Most patients with mild hypercalcemia (serum calcium level < 11 mg/dl) are asymptomatic, although some may experience mild fatigue, vague changes in cognitive function, depression, or polyuria and polydipsia (from decreased urine concentrating ability caused by a high calcium level). Those with moderate hypercalcemia (serum calcium levels of 11 to 14 mg/dl) are more likely to be symptomatic. The likelihood of classic manifestations of hypercalcemia increases sharply when calcium levels rise to 12 to 14 mg/dl. These symptoms include anorexia, nausea, vomiting, abdominal pain, constipation, muscle weakness, and altered mental status. Severe hypercalcemia (i.e., serum calcium levels greater than 14 mg/dl) may cause progressive lethargy, disorientation, and even coma.
In addition to the degree of elevation, the rate of increase in serum calcium may influence the clinical picture. Chronically hypercalcemic patients can function and feel reasonably well with serum calcium values even as high as 15 to 16 mg/dl. In contrast, patients whose calcium level has risen abruptly will often experience symptoms at lesser calcium elevations. Elderly or debilitated patients are also more likely to be symptomatic.
HISTORY AND PHYSICAL EXAMINATION
The history and physical examination are directed at uncovering signs or symptoms of hypercalcemia, as well as signs of the most common causes of hypercalcemia: hyperparathyroidism, malignancy, granulomatous diseases, and certain endocrinopathies. Evidence of any related condition, such as osteoporosis or urinary tract stones, should also be sought. The medical record should be reviewed to determine the duration of the hypercalcemia. The most common cause of hypercalcemia, primary hyperparathyroidism, presents as stable or gradually progressive elevation of the serum calcium level over a period of years. In contrast, malignancy typically causes a more acute rise in serum calcium. All recent medications, foods, and nutritional supplements should be thoroughly reviewed for possible culprits. A careful family history should be performed to identify disorders of calcium metabolism; renal stones; fragility fractures; and any related endocrinopathies, such as diseases of the pituitary, adrenal, thyroid, or endocrine pancreas.
Aside from mental status deficits and signs of dehydration, physical examination findings are generally normal in patients with hypercalcemia, especially if calcium levels are only mildly to moderately elevated. Rarely, severe and prolonged hypercalcemia results in a visible horizontal calcium deposit on the cornea, a condition known as band keratopathy. Other signs and symptoms depend on the etiology of the elevation [see Table 1]. Patients with hyperparathyroidism classically have osteopenia, bone pain, or nephrolithiasis. Currently, however, most cases of primary hyperparathyroidism are identified before the patient becomes symptomatic. Patients whose hyperparathyroidism is associated with multiple endocrine neoplasia (MEN) syndromes may have specific manifestations of the other conditions that are part of these syndromes. Patients with sarcoidosis may present with fever, lymphadenopathy, skin rashes, or pulmonary symptoms. Hypercalcemia of malignancy develops only when a substantial tumor burden is present; consequently, most of these patients have an established cancer diagnosis and clinical features associated with the specific tumor type and extent of disease.
Table 1 Differential Diagnosis of Hypercalcemia
The first step in the laboratory assessment is to exclude factitious hypercalcemia, which may result from an increase in circulating concentrations of plasma proteins. About 50% to 60% of circulating calcium is bound to these proteins, so elevation in their concentrations (as occurs in HIV infection, chronic viral hepatitis, and multiple myeloma) will produce a proportionate rise in the total calcium concentration. The ionized calcium concentration, however, remains normal. To adjust for elevations in plasma protein, the serum calcium level should be lowered by 0.8 mg/dl for every 1 g/dl of albumin (or protein) above the normal range. When performed correctly, ionized calcium measurement is more accurate than adjusted total calcium. Because acute renal failure may occasionally lead to hypercalcemia, renal function should also be assessed.
Once hypercalcemia is confirmed, the next step is measurement of the serum PTH concentration. This is the most important test for determining the cause of hypercalcemia.3 Several PTH assays are commercially available. The most commonly utilized is the two-site immunochemiluminometric assay (ICMA, or so-called bio-intact PTH). Earlier assays could not distinguish between full-length PTH and inactive molecular fragments that circulate in significant concentrations. The ICMA measures only the intact PTH molecule and is therefore the preferred test in most instances, especially in patients whose serum creatinine level is elevated.
Other helpful tests include measurement of serum creatinine and alkaline phosphatase, as well as inorganic phosphorus assays and an electrolyte panel. Assessment of 24-hour urinary calcium excretion is usually performed. Serum creatinine may be elevated in patients with nephrocalcinosis secondary to prolonged hypercalcemia. The alkaline phosphatase level may be elevated in patients with hypercalcemic states involving increased bone turnover. Patients with hypercalcemia caused by malignancy may demonstrate biochemical or hematologic findings consistent with the site of neoplasia and the degree of its dissemination. Most causes of hypercalcemia are also accompanied by hypercalciuria (24-hour urinary calcium excretion > 4 mg/kg/day), which may lead to nephrocalcinosis or renal stone formation. A serum calcium × phosphate product greater than 70 suggests the patient is at risk for calciphylaxis, and efforts to lower the serum phosphate level (e.g., with phosphate binders) should accompany the interventions to lower serum calcium.
Other diagnostic studies may be dictated by clinical circumstances. Electrocardiographic abnormalities of severe hypercalcemia include shortening of the QTc interval and, rarely, atrioventricular blocks. In addition, many hypercalcemic conditions cause a decrease in BMD, which may be noted on plain x-rays but is best quantified by measurement of bone density (see below). Abdominal x-rays may identify renal stones or nephrocalcinosis. Specific bone radiographic findings are few, and in primary hyperaparathyroidism, specific bony abnormalities are now rare, thanks to early detection of hypercalcemia.
The results of PTH measurement indicate whether hypercalcemia is or is not mediated by PTH and thus provide a broad indication of the cause of hypercalcemia [see Table 1]. When PTH levels are high or, in some cases, inappropriately normal, the hypercalcemia is PTH mediated; this is commonly referred to as hyperparathyroidism. When PTH levels are suppressed, the hypercalcemia is said to be non-PTH mediated, or PTH independent. In turn, this distinction guides subsequent patient assessment.
HYPERPARATHYROIDISM (PTH-MEDIATED HYPERCALCEMIA)
Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients. Current estimates place the annual incidence at approximately four per 100,000 population; the incidence peaks in the fifth to sixth decade of life, and there is a female-to-male ratio of 3:2.4 The most common clinical presentation is that of asymptomatic mild hypercalcemia. Pathologically, a solitary parathyroid adenoma is present in 80% to 85% of cases; hyperplasia involving multiple glands is found in 15% to 20% of cases, and parathyroid carcinoma is found in less than 1%. Occasionally, double adenomas are found. Patients with type I MEN (MEN I) or MEN II usually have parathyroid hyperplasia.5
Lithium therapy can change the set point for the calcium-sensing receptor such that a higher serum calcium concentration is needed to inhibit PTH secretion. This can lead to biochemical abnormalities (e.g., high levels of calcium and high-normal to elevated PTH levels) that mimic primary hyperparathyroidism. Patients on lithium will often have very low urinary calcium excretion.
Conditions that tend to decrease serum calcium increase PTH secretion as a corrective measure. This increase of PTH secretion is termed secondary hyperparathyroidism. Once circulating PTH is elevated, the serum calcium may return to normal or remain low. Common causes of secondary hyperparathyroidism include chronic renal insufficiency, vitamin D deficiency, intestinal malabsorption, renal calcium losses, and severe dietary inadequacy. Correction of the underlying calcium abnormality will return serum PTH concentrations to normal.
Familial hypocalciuric hypercalcemia
Familial hypocalciuric hypercalcemia (FHH), also referred to as benign familial hypercalcemia, is a rare inherited condition caused by various inactivating mutations in the CaSR. This results in inappropriately increased PTH secretion and a higher set point for the extracellular ionized calcium concentration. Patients with FHH have chronic asymptomatic hypercalcemia associated with relatively depressed urinary calcium excretion.
In some patients with prolonged secondary hyperparathyroidism, hyperplasia or neoplasia of the parathyroid glands develops. These parathyroids no longer respond appropriately to serum calcium; instead, they produce excess PTH at all times, leading to chronic hypercalcemia. This is most often seen in patients with chronic kidney disease. More than one parathyroid gland is usually affected.
The clinical manifestations of hyperparathyroidism depend, in part, on the severity of the hypercalcemia. When hyperparathyroidism was first described more than 50 years ago, most patients presented with late-stage complications of prolonged and severe hypercalcemia, such as abnormalities of bone (osteitis fibrosa cystica)6 or kidneys (nephrocalcinosis, renal failure). Since the development more than 30 years ago of laboratory equipment for measuring serum chemistry, hyperparathyroidism is often diagnosed by routine blood testing, before the development of symptoms. It also may be uncovered during the evaluation of osteoporosis or during the workup of renal stone disease.
When symptomatic, patients with hyperparathyroidism demonstrate clinical manifestations of hypercalcemia (see above).
In general, parathyroid tumors are too small to be palpable. Indeed, a palpable parathyroid tumor should be suspected as a malignancy until proved otherwise. Evidence of the consequences of hyperparathyroidism should be sought, such as osteoporosis (kyphosis) or nephrolithiasis (costovertebral angle tenderness).
Currently, most patients with hyperparathyroidism have a serum calcium concentration of less than 12 mg/dl (unless coexisting volume contraction is present), and they may have mild to moderate hypophosphatemia and a non-anion gap metabolic acidosis (from renal tubular acidosis). Urinary calcium excretion is often increased; in these patients, the reduction of fractional calcium excretion by PTH is overcome by the high filtered calcium load. This may result in nephrocalcinosis or nephrolithiasis.
Renal stones in patients with hyperparathyroidism are usually composed of calcium oxalate and tend to occur bilaterally, especially when urinary calcium excretion is high. Rarely, nephrocalcinosis and azotemia develop, usually in those with the most severe and protracted hypercalcemia, especially if dehydration or other renal insult is superimposed. Because PTH increases both osteoclast and osteoblast activity, there are increases in serum and urinary concentrations of biochemical markers of bone turnover, including bone alkaline phosphatase.
Elevation of both the serum calcium and the PTH concentrations (in the absence of low urinary calcium excretion) supports a diagnosis of primary hyperparathyroidism. PTH levels are usually increased to less than five times the upper limit of normal. In certain mild cases, the calcium level is only slightly high, and the PTH is minimally elevated or inappropriately normal. Rarely, patients with primary hyperparathyroidism have serum calcium levels in only the high-normal range. In fact, most such patients have elevated serum ionized calcium values and therefore are not actually normocalcemic. The diagnosis in such patients can be extremely challenging.
When the PTH level is normal or mildly elevated and the 24-hour urinary calcium level is low, consideration should be given to the possibility of FHH.7 The relatively low urinary calcium output seen in FHH may help distinguish this condition from primary hyperparathyroidism, although low urinary calcium excretion may also occur in hyperparathyroidism.
The possibility of FHH is raised when there is a strong family history of symptomatic, stable hypercalcemia, especially in patients younger than 40 years; when family members have undergone unsuccessful parathyroid surgery; or when the patient's urinary calcium output is unexpectedly low. When this diagnosis is suspected, further evaluation is necessary, such as the screening of other family members. Unfortunately, specific genetic testing is not currently widely available from commercial laboratories. In some cases, FHH cannot be distinguished confidently from primary hyperparathyroidism. However, in most such patients, expectant management is safe and avoids unnecessary parathyroid exploration. When there is trouble distinguishing between primary hyperparathyroidism and FHH, parathyroid imaging is sometimes useful. In primary hyperparathyroidism, enlarged parathyroid glands are easily found, whereas parathyroid size is usually normal in FHH.
Once the diagnosis of primary hyperparathyroidism is secured, it will usually already be apparent whether the patient is a candidate for parathyroidectomy. If the patient does not meet criteria for surgery on the basis of age, renal function, urinary calcium excretion, history of fractures, or renal stones/nephrocalcinosis, then measurement of bone density with a dual-energy x-ray absorptiometry (DXA) scan may be useful. In addition to the standard left hip and lumbar spine measurements, assessment at the distal radius may be particularly helpful, because hyperparathyroidism may affect this predominantly cortical site more than the other locations, which have a greater percentage of trabecular bone.6
Other diagnostic studies are usually not necessary. Consideration should also be given to the possibility of one of the MEN syndromes, particularly if the patient is young or has a personal or family history of a related endocrinopathy.5 This information will be helpful to the surgeon, because the patient with primary hyperparathyroidism in the setting of a MEN syndrome usually has multigland parathyroid hyperplasia, and in such patients a surgical procedure beyond a single parathyroidectomy is necessary. If MEN II is suspected, medullary thyroid cancer should be considered, and pheochromocytoma must be excluded before the patient goes to surgery.
Previous controversy over which patients with hyperparathyroidism require surgical intervention has been largely resolved. Those without symptoms or complications clearly related to hyperparathyroidism can be followed safely for long periods. Treatment of the patient with primary hyperparathyroidism must take into account the degree of the hypercalcemia, the presence of symptoms, and the severity of any end-organ damage.8 Understandably, it is widely agreed that patients with symptoms clearly attributable to hypercalcemia should undergo surgery.
Guidelines for surgical intervention in patients with primary hyperparathyroidism were developed at a National Institutes of Health workshop in 2002.9 The indications for surgical intervention are as follows:
Those patients with mild hypercalcemia who are truly asymptomatic can be followed clinically for the subsequent development of surgical indications. Most will likely remain asymptomatic and will not require intervention.9
Imaging studies to locate parathyroid adenomas have become more widely used, particularly as more centers have started offering minimally invasive surgery with intraoperative PTH assays (see below).10,11 In most cases of adenoma in a single gland, precise knowledge of the location of the adenoma may decrease operative time by allowing the surgeon to direct attention to the area of suspicion. It is important to remember, however, that in good hands, parathyroidectomy for primary hyperparathyroidism has a cure rate in the range of 90% to 95%, even without such localization studies. Thus, it is unlikely that preoperative localization will ever be demonstrated to improve overall surgical outcomes. Localization studies are mandatory before minimally invasive parathyroidectomy, in the setting of a second neck exploration for persistent or recurrent hyperparathyroidism, or if previous thyroid surgery has been performed. The localization test of choice is technetium-99m sestamibi scintigraphy.12,13 This is often followed by a neck ultrasound of the region demonstrating scintigraphic activity to confirm the location of an enlarged parathyroid gland. An additional benefit of ultrasound at this stage in the evaluation is to provide the opportunity for any coexisting thyroid abnormalities to be addressed.
The surgical procedure required in patients with hyperparathyroidism resulting from a solitary parathyroid adenoma is resection of that gland. If intraoperative PTH assays show a drop in the PTH level by more than 50% a few minutes after resection, no further neck exploration is required. Intraoperative measurement of PTH is considered by some experts to be critical in the case of ectopic parathyroid adenoma (which would not be easily found during routine neck exploration) and in reoperations. If an intraoperative PTH assay is not used, the other three glands must be directly inspected to ensure that a second adenoma or generalized hyperplasia is not present.14 If a second adenoma is found, it too should be excised. If hyperplasia is encountered, the surgeon performs a subtotal parathyroidectomy: removal of approximately three to three and one half glands. In some centers, this is followed by autotransplantation of remaining parathyroid tissue to the forearm, which may simplify follow-up surgical exploration in the event of recurrent hypercalcemia. Additional parathyroid tissue may be frozen in case future need develops. Parathyroid autotransplantation is a controversial treatment, because some patients experience aggressive regrowth of parathyroid tissue within the forearm muscles. This can require challenging and disfiguring surgery to correct.
At certain centers, so-called minimally invasive parathyroidectomy is being offered in conjunction with intraoperative PTH measurements.11This approach is best suited for a good surgical candidate in whom both history and preoperative imaging studies suggest a single adenoma (which is, in fact, the most common situation in primary hyperparathyroidism). With information from scintigraphy and ultrasound already in hand, the diseased gland can be excised through a smaller, unilateral incision, under local nerve block, in an ambulatory setting. Success is gauged by the drop in PTH levels intraoperatively. This approach usually provides a better cosmetic result, quicker recovery time, and a lower incidence of postoperative hypocalcemia. Minimally invasive surgery may not be appropriate in suboptimal surgical candidates, in patients who may have multigland disease, and in reoperative cases. However, it is quite likely that the majority of parathyroidectomies will be performed in this fashion in the future.
Hyperparathyroidism occasionally persists after operative intervention, usually because of failure to identify the culprit gland, occasionally because of undiagnosed multigland hyperplasia, and rarely because of undiagnosed parathyroid carcinoma.15,16,17 Scar tissue and the sometimes unexpected location of remaining pathologic parathyroid tissue make second surgeries notoriously more challenging and prone to complications. Consequently, preoperative imaging studies are invaluable in patients undergoing repeat surgery for persistent hyperparathyroidism. Catheterization studies with venous sampling may also be helpful in certain difficult cases. The identity of putative parathyroid glands can be confirmed by fine-needle aspiration with real-time PTH assay.
Although there is as yet no recognized medical therapy for primary hyperparathyroidism, patients who do not meet the criteria for surgical intervention or who refuse surgery can be followed expectantly. This involves periodic monitoring of serum and urine calcium levels, renal function, and BMD, as well as evaluation for nephrocalcinosis or nephrolithiasis. The extent and frequency of this monitoring should be tailored to the individual patient's disease and comorbidities. [see Table 2].9 Drugs that have a tendency to raise serum calcium levels, such as thiazides and lithium, should be avoided. Calcium and excessive vitamin D supplementation should generally be avoided. Dietary calcium should not be restricted, because such restriction may lead to further elevation of PTH and may possibly have detrimental effects on bone mass. Vitamin D deficiency should be identified and treated with gradual supplementation, because vitamin D deficiency will enhance the adverse effects of hyperparathyroidism on bone. Good hydration should be maintained at all times to avoid the development of renal insufficiency and renal stones, especially in patients with hypercalciuria. In patients with low BMD, a bisphosphonate will help to slow bone loss. In patients who are very hypercalcemic but cannot or will not have surgery, calcimimetic agents have been used to control hypercalcemia, although they are not approved by the Food and Drug Administration for use in this particular setting. For example, the calcimimetic agent cinacalcet is approved for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease who are on dialysis, as well as for the treatment of hypercalcemia in patients with parathyroid cancer. Calcimimetic agents activate the CaSR and thus diminish PTH production. The high cost of these agents and the relative ease of parathyroid surgery make their widespread use in the future unlikely.18
Table 2 2002 NIH Working Group Recommendations Regarding Follow-up Testing for Patients with Primary Hyperparathyroidism Who Do Not Undergo Surgery9
Cancer remains the most common cause of PTH-independent, persistent, substantial hypercalcemia and is most frequently to blame when an acutely elevated calcium level is discovered in a hospitalized patient. Other causes include sarcoidosis, certain endocrine disorders, and various drugs and supplements.
Malignancy-associated hypercalcemia has two forms: humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia (LOH).
HHM results from the elaboration by the tumor of a circulating factor that has systemic effects on skeletal calcium release, renal calcium handling, or GI calcium absorption. Rarely, it can be caused by the unregulated production of calcitriol (usually by B cell lymphomas). However, the best-recognized mediator responsible for HHM is parathyroid hormone-related protein (PTHrP).19 Normally, PTHrP appears to serve as a paracrine factor in a variety of tissues (e.g., bone, skin, breast, uterus, and blood vessels); it is involved in cellular calcium handling, smooth muscle contraction, and growth and development. The amino terminus of PTHrP is homologous with that of PTH, and they share a common receptor. When PTHrP circulates in supraphysiologic concentrations, it induces most of the metabolic effects of PTH, such as osteoclast activation, decreased renal calcium output, and increased renal phosphate clearance.
Tumors that produce HHM by secreting PTHrP are usually squamous cell carcinomas (e.g., lung, esophageal, laryngeal, oropharyngeal, nasopharyngeal, or cervical carcinomas).20 Other tumor types that occasionally produce PTHrP include adenocarcinoma of the breast and ovary, renal cell carcinoma, transitional cell carcinoma of the bladder, islet cell tumors of the pancreas, T cell lymphomas, and pheochromocytoma. All tumors that elaborate PTHrP do so in relatively small amounts; thus, the syndrome typically develops in patients with a large tumor burden. It is also unusual for HHM to be the presenting feature of the cancer.
LOH occurs when a tumor growing within bone itself causes the local release of calcium through the production of cytokines that activate osteoclasts; there is no production of a systemic factor in these cases. The classic tumor associated with this syndrome is multiple myeloma, although other neoplasms, such as adenocarcinoma of the breast and various lymphomas, may also cause LOH. Local factors produced by bone cells may further enhance the growth of such tumors; this results in the skeleton inadvertently working in concert with the tumor to promote progressive bone resorption and calcium release and further advancement of the cancer. (This is the basis of the success of bisphosphonates in the treatment of multiple myeloma.)
PTH-independent hypercalcemia may be caused by sarcoidosis and other granulomatous diseases, such as tuberculosis, in which granulomas produce calcitriol. Endocrine conditions that may occasionally lead to hypercalcemia include hyperthyroidism (which stimulates bone turnover) and Addison disease (in which volume contraction reduces calcium clearance). Immobilization may increase calcium levels, usually in persons with active bone turnover, such as adolescents or those with previously unrecognized hyperparathyroidism or Paget disease of bone (see below). Use of drugs and dietary supplements (e.g., vitamin D and vitamin A) may be associated with hypercalcemia. The association of thiazides with hypercalcemia is now thought to occur when a thiazide-induced reduction in calcium excretion unmasks previously unrecognized primary hyperparathyroidism. Although only rarely encountered today, the so-called milk-alkali syndrome results from the long-term consumption of large quantities of milk and antacids; milk and antacids were the standard treatment of peptic ulcers in the days before the development of H2 receptor blockers and proton pump inhibitors.
If the serum calcium concentration is elevated but the PTH level is very low, the patient has PTH-independent hypercalcemia. Possible causes include malignancy, granulomatous disease, thyrotoxicosis, and vitamin D intoxication. These cases require further laboratory assessment, with the choice of tests depending on the clinical situation.
In malignancy-associated hypercalcemia, the degree of calcium elevation is usually moderate or severe. Evidence of significant volume depletion and generalized debility may dominate the clinical picture, along with other cancer-related symptoms. Typically, the diagnosis of malignancy has already been established. The diagnosis of malignancy-associated hypercalcemia should be suspected in cancer patients with hypercalcemia who have abnormally low PTH concentrations. In patients with tumors associated with HHM, measurement of PTHrP is indicated. Radioimmunoassays for PTHrP are commercially available; an elevation of PTHrP concentration will essentially confirm the diagnosis of most cases of HHM. Special care should be taken to ensure that blood for PTHrP levels is drawn and handled correctly to avoid spuriously low results. In HHM from B cell lymphomas, circulating plasma concentrations of calcitriol are increased. In local osteolytic disease, PTHrP and calcitriol are within normal ranges, and there is definitive evidence of bony metastases.
When the PTH is low and the patient is not known to have a malignancy, diagnostic possibilities include granulomatous diseases, other endocrine disorders, drugs or dietary supplements, and immobilization. Possible laboratory studies in such patients might include measurement of vitamin D metabolites, thyroid hormone levels, or 24-hour urine calcium excretion. If investigation of these diagnoses proves unrewarding, the very rare possibility of unrecognized malignancy may be considered, especially if measurement of PTHrP is performed and shows elevated values. Further imaging studies are indicated in such cases, including a plain chest radiograph or a computed tomographic scan of the thorax as the initial study. If the results are negative, consideration should be given to a comprehensive otolaryngoscopic examination, esophagoscopy, or CT of the abdomen. Should such further assessment be unrevealing, radiographic or endoscopic assessment of the genitourinary tract should be considered.
A nonparathyroid disorder, often a malignancy, is responsible for most cases of acute hypercalcemia [see Table 1]. When the serum calcium level is substantially elevated, treatment includes attempts to increase renal calcium excretion while simultaneously attenuating either bone resorption or intestinal calcium absorption, depending on which is the primary source of calcium. Because most patients have at least moderate volume contraction, which further exacerbates their ability to excrete calcium, the initial intervention should be expansion of the intravascular volume with an intravenous infusion of normal saline [see Table 3]. This will augment the delivery of sodium and water to the distal nephron, both of which will, in turn, increase urinary calcium excretion. Once the intravascular volume is repleted, adding a loop diuretic such as furosemide will allow continued aggressive saline hydration and may further increase calcium excretion. If the serum calcium concentration does not normalize quickly with intravenous fluid and diuresis, pharmacologic therapy is indicated.21 Because almost all causes of severe hypercalcemia involve some degree of increased osteoclast activation, drugs that decrease bone turnover are favored. The treatment of choice is a bisphosphonate, such as pamidronate or zoledronic acid, both of which are available for intravenous infusion. Pamidronate is given in a dosage of 60 to 90 mg intravenously over several hours; it is generally well tolerated. Typically, serum calcium levels begin to decrease within 24 to 48 hours of the infusion, although the peak effect may not occur for several days. The action of pamidronate may persist for up to several weeks; treatment can be repeated as needed if renal function will allow. Zoledronic acid is given at a dosage of 4 mg intravenously over no less than 15 minutes. It appears to have a higher potency and an even longer duration of action than pamidronate. A repeat dose may be provided after 7 days. Use of intravenous bisphophonates, especially zoledronic acid, is often associated with an acute-phase response after the first dose, with flulike symptoms. Caution should be employed with these agents in the setting of renal dysfunction. In addition, if parathyroidectomy is planned, use of bisphosphonates should be considered carefully, because they may make postoperative hypocalcemia management more difficult. When more rapid action is desired, subcutaneous injection of calcitonin can be tried, either alone or in conjunction with a bisphosphonate. Calcitonin is given at a dosage of 4 IU/kg twice daily. Calcitonin is a relatively weak hypocalcemic agent; tachyphylaxis to the effects of calcitonin is common and limits its use to a few days. Other possible therapies are plicamycin and gallium nitrate, although certain toxicities limit their use as first-line agents. In severe or refractory cases, hemodialysis against a low-calcium bath may also be undertaken.
Table 3 Therapy for Acute Hypercalcemia
In the more unusual situation of hypercalcemia resulting from an increase in gut calcium absorption, such as in vitamin D intoxication or granulomatous diseases, glucocorticoid therapy may have an integral role. Glucocorticoids directly impede intestinal calcium transport and also decrease renal or granulomatous 1α-hydroxylase activity, which results in a decrease in concentrations of calcitriol. In patients with lymphoma, steroids may also have an antineoplastic effect.
Contributing factors to hypercalcemia, such as the use of oral calcium or vitamin D supplements, diuretic therapy, or immobilization, should be corrected, if possible.
In malignancy-associated hypercalcemia, effective surgery, chemotherapy, or radiotherapy targeted at the tumor itself will reduce the hypercalcemia. However, because hypercalcemia is often an end-stage complication, further chemotherapy or radiotherapy may be neither possible nor desired.
Hypocalcemia is defined as a serum calcium level below the reference range for the laboratory. As with hypercalcemia, an ionized calcium determination on a correctly collected sample is the best way to confirm hypocalcemia.
An abnormally low level of serum calcium on laboratory testing is most often factitious, resulting from a decrease in plasma protein concentration secondary to decreased protein synthesis or hemodilution. Because circulating calcium is so highly protein bound, decreases in serum albumin concentrations—such as occurs with malnourishment, liver disease, or nephrotic syndrome—produce proportionate reductions in total serum calcium. In such situations, the serum calcium level may be corrected by adding 0.8 mg/dl for each 1 g/dl reduction in the serum albumin level below 4 g/dl. An accurate ionized calcium measurement will circumvent many of these pitfalls.
True hypocalcemia is most often related to vitamin D deficiency or impaired parathyroid gland function. Removal of or vascular injury to the parathyroids during neck surgery can result in hypoparathyroidism, which is manifested by hypocalcemia, hyperphosphatemia, and inappropriately low concentrations of PTH. However, unless all four parathyroids are removed or their blood supply is severely impaired, hypocalcemia after parathyroidectomy is usually a transient phenomenon. Normal parathyroid function typically returns after a period of several days to weeks. Patients who experience prolonged, severe primary hyperparathyroidism and significant bone resorption before undergoing parathyroidectomy may experience protracted hypocalcemia and hypophosphatemia after surgery, as a result of the deposition of large quantities of mineral into the skeleton. This is referred to as the “hungry bone syndrome.”
Automimmune destruction of the parathyroid glands may be seen in certain conditions, including autoimmune polyglandular syndrome type 1, a condition marked by hypoparathyroidism, premature ovarian failure, Addison disease, and mucocutaneous candidiasis.22 Certain infiltrative diseases, such as hemochromatosis, may also adversely affect parathyroid function, as may external-beam irradiation of the neck. Functional hypoparathyroidism may also result from hypomagnesemia, because magnesium is necessary for both PTH release and PTH action. This is often seen in hospitalized alcoholic patients. Pseudohypoparathyroidism is caused by inherited PTH resistance, which results in hypocalcemia and secondary marked elevations of PTH levels.
Because vitamin D ultimately regulates intestinal calcium absorption, disorders of its supply, production, or activity may lead to hypocalcemia. In such conditions, serum calcium concentrations are usually not severely affected, thanks to compensatory increases in PTH levels. Indeed, the primary clinical manifestations are in the skeleton (e.g., rickets in children and osteomalacia in adults). Dietary vitamin D deficiency in the elderly is common, but it is often overlooked.23 At-risk adults include the elderly and darker-skinned persons with poor dietary habits who avoid liquid milk products and have little sun exposure, particularly in northern climates. However, recent reports suggest that vitamin D deficiency may be more frequent than traditionally considered, even in persons not previously thought to be at risk.24
Hypocalcemia may occur in patients with acute pancreatitis, when fatty acids released through the action of pancreatic lipase complex with calcium. The complexing of phosphate with calcium also occurs in severely hyperphosphatemic states, such as acute renal failure, rhabdomyolysis, and the tumor lysis syndrome, and it may result in a decrease in serum calcium concentrations. Hypocalcemia may also be caused by large-volume blood transfusions using red blood cells to which calcium chelators have been added to prevent clotting.
Chronic mild to moderate hypocalcemia is usually well tolerated. However, when the serum calcium level falls below 7.5 to 8 mg/dl (assuming that plasma protein levels are normal), the patient may develop symptoms of neuromuscular irritability, such as tremor, muscle spasms, or paresthesias. On examination, Chvostek and Trousseau signs may be present. If the serum calcium level drops further, tetany or seizures may result. Prolongation of the QTc interval may also occur, predisposing the patient to cardiac arrhythmias.
As with hypercalcemia, the cause of hypocalcemia can usually be discerned after a careful history (including a review of medications, previous surgeries, and dietary and social habits) and by the measurement of the circulating concentrations of calcium, phosphorus, PTH, and 25-(OH)D3. The differential diagnosis consists principally of conditions that result in an abnormal supply or the abnormal action of PTH or vitamin D, but the use of medications or supplements and the presence of other conditions must be considered [see Table 4].
Table 4 Differential Diagnosis of Hypocalcemia
In patients with symptoms of marked hypocalcemia (e.g., neuromuscular irritability), calcium should be infused slowly (e.g., as calcium gluconate) to raise the serum calcium level until symptoms are relieved. Individual boluses of intravenous calcium will not achieve this effect. Concurrently, any deficiency in magnesium stores should be corrected. In severe cases, hypocalcemia may recur quickly after discontinuance of calcium infusion, so oral calcium should be administered concurrently. In less severe cases, calcium can be administered orally as calcium carbonate or calcium citrate in doses of 1,000 to 2,000 mg of elemental calcium daily in divided doses. If appropriate, vitamin D should also be provided. If dietary deficiency of vitamin D is suspected, cholecalciferol (vitamin D3) or, if cholecalciferol is unavailable, ergocalciferol (vitamin D2), may be adequate. Because hydroxylation of cholecalciferol may take several days, however, a brief course of calcitriol may also be necessary. In cases of hypoparathyroidism, long-term administration of calcitriol is needed, because renal 1α-hydroxylase may not be active in the absence of PTH. In hypoparathyroid patients, it is important to not fully normalize the serum calcium level, because this often results in hypercalciuria and hyperphosphaturia, increasing the risk of nephrocalcinosis or renal stones. Instead, serum calcium should be kept around the lower limit of the normal range, at a level sufficient to relieve symptoms and reverse tetanic signs (e.g., Trousseau sign). Periodic monitoring for nephrocalcinosis in these patients may be appropriate.
Metabolic Bone Disease
Osteoporosis is defined as a loss of bone mass, including loss of trabecular bone microarchitecture and connectivity and a thinning of cortical bone, leading to an increased risk of fracture. Clinically, osteoporosis is usually diagnosed by measuring BMD, which reflects the bone calcium content and is a surrogate for bone mass. The diagnostic criteria of the World Health Organization are based on the results of standardized bone density measurements: osteoporosis is present when the BMD is more than 2.5 standard deviations (SDs) below that of a normal, young adult control population (in whom bone density is at its peak). Osteopenia is present when the BMD falls between -1.0 and -2.5 SDs from peak bone density.
Peak bone mass occurs in persons who are in their late 20s or early 30s; after this age, bone density decreases slowly. Consequently, the incidence of osteoporosis increases with age, becoming most common in persons older than 60 years. Because peak bone mass is lower in women than in men, women generally have lower bone density at each succeeding stage of life.25 Therefore, women experience higher rates of fracture. The most common sites of so-called fragility fractures are the hip, the distal forearm, and vertebrae.
The lifetime risk of experiencing any fragility fracture for white women is 40%, whereas for white men it is 13%. By site, the respective risks for women and men are as follows: 18% and 6% for hip fracture, 16% and 3% for distal radius fracture, and 18% and 6% for vertebral fracture.26 The incidence of hip fracture in women and men aged 65 years is approximately 300 and 150 per 100,000 person-years, respectively. These rates increase to approximately 3,000 and 2,000 per 100,000, respectively, by 85 years of age.25 African Americans generally have higher BMD and are at lower risk for fracture than their white, Hispanic, or Asian counterparts.
Osteoporosis produces enormous burdens, both for patients and for society at large. In the United States, the direct costs of treatment of osteoporotic fractures alone are estimated to be $10 billion to $15 billion annually. Hip fracture carries the highest morbidity and mortality of all fractures. Deaths may occur from associated complications, such as pulmonary embolism or pneumonia. Only one third of patients with hip fracture return to their previous level of functioning. Of the remainder, one third will be placed in long-term nursing care facilities. Rates of depression and anxiety also increase after osteoporotic fracture.10 Because of the high cost to patients and the insurance system, prevention of hip fracture has been a major focus of osteoporosis prevention and treatment.
Bone remodeling occurs continuously in adults; at any given time, as much as 5% to 10% of the skeleton is in a state of turnover. The cells involved in this remodeling process are the osteoclasts, which resorb bone, and the osteoblasts, which form new bone. A cycle of bone remodeling begins with the recruitment of osteoclasts. Osteoclast-mediated resorption of bone from the site releases mineral and collagen breakdown products into the circulation. Through local osteoclast-derived cytokine signals, osteoblasts are then recruited to the site and create new bone matrix to fill the resorption pit left behind by the osteoclasts. The matrix is then mineralized through the physiochemical crystallization of hydroxyapatite. Each bone turnover cycle lasts approximately 3 months.
Through the process of bone remodeling, the skeleton is constantly rejuvenated. In an accelerated form, the bone remodeling process allows for the healing of fractures. In addition, the massive mineral stores of the skeleton are continuously made available to the body for systemic needs, especially during times of decreased calcium supply.
With advancing age, slightly less bone is formed than was resorbed during each remodeling cycle, presumably because of a gradual decline in osteoblast activity. As a result, net bone loss occurs with each cycle, resulting in the gradual decline in bone mass with aging. Therefore, bone loss is to some degree linked to the rate of bone turnover. Any process that increases bone resorption without increasing bone formation will result in a decrease in bone mass and in a concomitant increase in the risk of fracture.
Bone mass accumulates during the first 2 decades of life, achieves its peak in the late third or early fourth decade, stabilizes during the next 1 or 2 decades, and then declines slowly. The age-related decline in bone mass occurs at a rate of approximately 0.1% to 0.5% a year in both sexes. In women, however, the rate of bone loss accelerates during the relatively abrupt loss of gonadal steroids during menopause, especially just before and during the first 6 or 7 years after the cessation of menses. During this period, bone mass may actually fall by up to 4% a year. Thus, by the end of this period, a woman may have lost one quarter to one third of her total skeletal mass.26,27 Subsequently, bone loss tends to slow to a rate similar to that seen in aging men.
Risk Factors and Pathologic Causes
The most important risk factors for decreased bone density and osteoporotic fracture are advanced age, female gender, postmenopausal status, white or Asian race, personal or family history of fragility fracture, and low body weight.28,29 These risk factors assist in identifying patients who are at increased risk for bone loss and consequent fracture. Those patients warrant prophylactic measures to help maintain bone mass, and they may benefit from formal bone density measurement to more precisely quantify risk. Other factors contributing to bone loss include cigarette smoking, ethanol abuse, insufficient dietary calcium, and lack of physical exercise.
Diseases or conditions associated with low bone density include Cushing syndrome, glucocorticoid therapy, thyrotoxicosis, excessive thyroid hormone replacement, primary hyperparathyroidism, hypogonadism, intestinal malabsorption, chronic obstructive pulmonary disease, chronic renal or hepatic failure, multiple myeloma and other malignancies, hypopituitarism (growth hormone deficiency), rheumatoid arthritis and other connective tissue diseases, and organ transplantation.
Although risk-factor analysis assists in determining which patients are at greatest risk for osteoporosis and fracture, the measurement of bone density remains an essential tool to assess risk. Several modalities for measuring bone density are currently in use, including DXA, quantitative CT (QCT), and ultrasound. QCT is not yet widely used clinically. Ultrasound is used for screening purposes, but selected patients must be followed with central DXA measurements. DXA has the highest accuracy and precision of any densitometric method and is currently the diagnostic tool preferred by most authorities.30,31 It is also the method most widely employed in large clinical trials of osteoporosis treatment regimens and is both widely available and safe. DXA should therefore be used for the initial screening and follow-up.
In a typical DXA report, the bone density measurements (expressed in g/cm2) are converted to T scores and Z scores. The T score is the number of SDs the patient's BMD falls above or below the mean value for young, healthy persons at peak bone density. The Z score represents the number of SDs the patient's BMD falls above or below the average value for persons of the patient's age and sex. The T score is the best indicator of fracture risk. Bone density reference databases are currently available only for whites and African Americans; this limits the value of the results obtained for other ethnic groups. The most common sites measured by DXA are the proximal femur and lumbar spine, although the distal nondominant radius can also be assessed. Pitfalls in the interpretation of DXA scans include incorrect patient positioning and improper selection of the region of interest for analysis. Degenerative disease or scoliosis in the lumbar spine can make the bones appear denser, leading to falsely reassuring results. Each SD below peak bone mass represents a loss of 10% to 12% of bone mineral content and corresponds to an approximate twofold to 2.5-fold increase in fracture risk at that site. It should be noted, however, that factors other than bone density play important roles in the risk of fracture. Recent attention has been directed to so-called bone quality, which refers to the microarchitecture and fracture resistance of the bone, and which may not correspond to BMD as measured by DXA.32 In elderly persons, in particular, additional factors that increase the risk of fractures include low visual acuity, impaired neuromuscular function, decreased mobility, cognitive decline, sedative drug use, and residence in a nursing home.33 In a review of the risk of fracture in almost 8,000 women enrolled in a longitudinal study of osteoporosis, the clinical factors found to be most important for risk of fracture included a history of fracture after 50 years of age, maternal history of hip fracture, weight less than 125 lb, current cigarette smoking, and the inability to raise oneself from the seated position without use of the arms. By combining these factors with the T score at the hip, these researchers were able to create a fracture risk index that predicted the patient's likelihood of hip fracture over the subsequent 5 years with greater accuracy than seen with the bone density result alone.34
In 1998, the National Osteoporosis Foundation recommended that DXA be used as a screening modality in women with established osteoporotic fractures (to establish a baseline for follow-up measurements) and in women without established osteoporotic fractures who are 65 years of age or older or who are younger than 65 years but have one or more accepted risk factors for fragility fracture. These risk factors include low body weight (< 128 lb); current smoking; and personal history of, or a first-degree family relative with, a low-trauma fracture.29 Indications for bone density measurement in any patient include fracture from mild or moderate trauma, evidence of osteopenia on plain radiography, pending organ transplant, and ongoing or anticipated long-term corticosteroid therapy. Bone density measurements are also useful in the evaluation of patients with conditions that might adversely affect bone mass (e.g., hyperparathyroidism) and for monitoring patients who are receiving therapy for osteoporosis. When follow-up bone density studies are performed, it is important that they be done in a reproducible fashion, so that an accurate comparison can be made. It is best to use the same densitometer at the same facility from one year to the next. Identical patient positioning for each scan will also help eliminate error.
Once the diagnosis of osteoporosis or osteopenia is made, the clinician may wish to undertake a selective evaluation to exclude causes of secondary osteoporosis (other than estrogen deficiency). In a premenopausal woman or a man with decreased bone density, such investigations are imperative. A comprehensive history and physical examination will reveal many of the causes of secondary bone loss. The evaluation should explore symptoms of chronic illness, hyperthyroidism, hyperparathyroidism, intestinal disease, and glucocorticoid use.35Lifelong calcium and vitamin D intake should be reviewed. In women, the menstrual history should also be discussed, because even relatively short periods of amenorrhea (reflecting estrogen deficiency) in the past may have a detrimental effect on bone mass.36 Lifestyle factors such as physical activity level, eating disorders, cigarette smoking, and alcohol abuse should also be addressed. In men, osteoporosis is more often associated with a secondary cause, the more common ones being alcoholism, steroid use, and hypogonadism.37However, in about half of men with osteoporosis, the disorder is idiopathic.
An extensive biochemical assessment of the patient, other than that indicated by the clinical evaluation, is not necessary. It is reasonable, however, to perform routine blood chemistry studies, including measurement of levels of serum calcium and phosphorus, serum creatinine, and alkaline phosphatase along with a complete blood count. Immunofixation electrophoresis can also be performed to rule out early myeloma if there is any suspicion of malignancy. Subclinical hyperthyroidism can be ruled out with a thyroid-stimulating hormone determination. Measurement of PTH and vitamin D levels is often helpful, because asymptomatic disease is common. Measurement of 24-hour urinary calcium excretion will evaluate for calcium malabsorption or excessive renal losses of calcium.
Modifiable risk factors
Lifestyle modification is the first step in the prevention or treatment of osteoporosis. Smoking cessation and moderation of alcohol consumption are important first steps. Exercise is an important aspect of osteoporosis management. Weight-bearing physical activity attenuates bone loss; exercise also helps maintain the proximal muscle strength and balance necessary to avoid falls.38 A physical therapy evaluation is appropriate for patients considered at high risk for falls. Physical therapists can conduct home safety evaluations to identify and address conditions that might promote falls (e.g., trailing electric cords, throw rugs). Physical therapy can also improve strength and gait stability, thus decreasing fall risk. For frail elderly patients, it is prudent to review medication lists and try to eliminate medications that may cause dizziness or sedation and thus predispose patients to falls. Hip protectors have been shown in some, but not all, studies to prevent hip fracture if a patient falls.39
Any patient being treated for bone loss must consume adequate amounts of both calcium and vitamin D. The recommended daily dietary intake of elemental calcium is 1,000 to 1,500 mg, depending on age and menopausal status [see Table 5],40 and recommended vitamin D intake ranges from 400 to 800 IU a day. Patients taking medications that increase vitamin D metabolism (e.g., phenytoin) may need higher vitamin D doses. Substantial and prolonged deficiencies in calcium intake may lead to secondary hyperparathyroidism with reduction of bone mass, as bone is resorbed to release calcium for systemic requirements. Several investigators have demonstrated that calcium and vitamin D supplementation has a beneficial effect on postmenopausal bone loss, although the effects are not as dramatic as those seen with antiresorptive or anabolic therapies.41 In addition, vitamin D supplementation in the elderly appears to be associated with as much as a 22% decreased risk of falls.42 Skeletal muscle has vitamin D receptors, and it is thought that vitamin D sufficiency is necessary for optimal muscle strength.
Table 5 Dietary Reference Intakes for Calcium*76
Preferably, calcium and vitamin D should be from dietary sources.40 Unless milk products are a major component of the diet, however, achieving adequate intake may be difficult; therefore, commercially available supplements should be used. In patients who are elderly, in patients who are taking proton pump inhibitors or H2-blockers, or in patients who have pernicious anemia, calcium citrate may be better absorbed than calcium carbonate. In all major clinical trials of osteoporosis therapies, participants were also provided basal calcium and vitamin D supplements. Thus, the efficacy of currently available pharmacologic agents for osteoporosis generally has been demonstrated only in persons with adequate calcium and vitamin D intake.
Osteoporosis is most often treated with antiresorptive agents. FDA-approved agents for the treatment of established osteoporosis include the bisphosphonates (e.g., alendronate, risedronate), selective estrogen receptor modulators (SERMs) (e.g., raloxifene), calcitonin,28 and estrogen.43,44,45,46 All of these agents reduce vertebral and nonvertebral fracture rates (on the order of 30% to 60%) over 2 to 3 years,28,37,40,43,44,47,48,49,50,51,52,53 but only estrogen54 and the bisphosphonates have been shown to reduce hip fracture risk.47,48,49 All of these agents tend to be more effective for increasing bone density and lowering fracture risk at the spine than at the hip. Estrogen is less widely used for prevention of postmenopausal bone loss since the publication of the Women's Health Initiative (WHI) results. The WHI studies showed an increased risk of cardiovascular disease, breast cancer, stroke, and pulmonary embolism in patients treated with estrogen in combination with progestin,55 as well as an increase in stroke risk for women treated with estrogen alone.56
Antiresorptive therapy should be considered for postmenopausal women for the prevention of osteoporosis, particularly in those with established fracture and those who are at high risk for fracture. For the prevention of osteoporosis, the antiresorptives currently approved by the FDA are alendronate, risedronate, raloxifene, and estrogen. These agents increase BMD at both the hip and the spine during the first 2 to 3 years of use, with subsequent stabilization.
Given their demonstrated safety record and their ability to prevent hip fractures, the bisphosphonates should be considered for initial prevention and treatment of osteoporosis. Bisphosphonates bind to skeletal hydroxyapatite and decrease osteoclast activity, thus slowing bone resorption while new bone formation continues. Over a period of 2 to 3 years, they produce a 6% increase in bone density and a 30% to 50% reduction in fracture risk at both vertebral and nonvertebral sites, with greater effectiveness at the former.48,49,50,51 Alendronate is dosed at 70 mg once weekly for osteoporosis treatment and at 35 mg once weekly for osteoporosis prevention.57 Risedronate is given at 35 mg once weekly for prevention or treatment of osteoporosis.58 Risks of bisphosphonate therapy include esophagitis; these agents are contraindicated in patients with active esophagitis, achalasia, or esophageal stricture, and they should be used with caution in anyone with a history of esophagitis or gastroesophageal reflux disease. Caution should be taken in prescribing these agents for women of childbearing age: they persist in bone matrix and can be measured in the blood for years after discontinuance, so there is a risk of passage to the fetus even in patients no longer taking them.
Because they are poorly absorbed, bisphosphonates should be taken on an empty stomach immediately upon awakening in the morning. After taking the agent, the patient should remain upright and should not consume food for at least 1 hour. How long bisphosphonate therapy should be provided is an area of active interest in osteoporosis research. Alendronate use for up to 10 years provides a sustained benefit and is well tolerated.59 The bone-preserving effects of alendronate may persist for up to 2 years after the drug is discontinued, presumably because it remains in bone matrix. There has been concern that prolonged therapy with bisphosphonates might lead to adynamic bone, a condition associated with low bone turnover, microfractures, and chronic pain. It may be appropriate to consider a 1- to 2-year drug holiday after 5 to 10 years of bisphosphonate therapy to avoid these theoretical risks, although no guidelines currently exist for duration of bisphosphonate therapy for osteoporosis.
Raloxifene, a SERM, can be used for osteoporosis prevention or treatment.60 Raloxifene acts as an estrogen agonist in bone, but it acts as an estrogen antagonist in breast and uterus. Thus, its use is not associated with endometrial hyperplasia, and concurrent treatment with progestins is not required. Raloxifene also does not increase the risk of breast cancer. In fact, it is under active investigation for its potential role in preventing breast cancer in high-risk patients.61 Raloxifene increases bone density by only about 1% over 12 to 24 months, but data on vertebral fracture are comparable to those of estrogen replacement therapy (ERT) or bisphosphonate therapy. Raloxifene has not been shown to reduce the incidence of hip fracture. It is generally well tolerated but may exacerbate menopausal hot flashes. Patients should be advised that raloxifene carries a threefold increased risk of thromboembolic disease, which is similar to that seen with estrogen. Preliminary reports suggest no detrimental effect on cardiovascular risk.62 Raloxifene is a good choice for patients who have bone loss primarily in the spine, for women with relatively low risk of hip fracture, and for patients who are unable to tolerate oral bisphosphonates. Raloxifene is not approved for use in premenopausal women or men.
Calcitonin has much less potent effects on BMD and fracture than do the bisphosphonates, raloxifene, or estrogen.63 This hormone, which is normally produced by the parafollicular cells (C cells) of the thyroid, typically circulates in low concentration in humans. The precise role of calcitonin in the body is not fully understood, but it appears to be a weak regulator of serum calcium concentrations and bone turnover. Commercially available products include calcitonin injections and nasal spray. Both are approved for the treatment of established osteoporosis but not for its prevention. In most of the calcitonin trials, the average increase in bone density was only 1% to 2% over 2 years. Calcitonin has been primarily shown to prevent vertebral fractures and has not been shown to prevent nonvertebral or hip fractures.52 Calcitonin is generally safe; occasional flushing, headaches, anosmia, or nasal irritation is observed with the nasal spray. There is a concern about tachyphylaxis, or decreased effectiveness over time, with calcitonin use. Because of the availability of other safe and more potent drugs for osteoporosis, calcitonin is rarely used except when other options are lacking.
Until recently, ERT was widely recommended as first-line therapy for both the prevention and treatment of osteoporosis, although it is approved by the FDA for prevention only.43 Advocates argued that estrogen directly corrected the chief pathophysiologic defect of the menopause: estrogen deficiency. However, use of ERT to maintain bone health has fallen out of favor because of data indicating that it may actually increase the risk of cardiovascular disease, as well as the risk of breast cancer and ovarian cancer. The multicenter WHI was created to study the effects of hormone replacement therapy in healthy postmenopausal women. Women receiving estrogen in combination with progestin had a lower incidence of fracture, but this arm of the study was stopped prematurely because of a 26% increase in the risk of breast cancer and a lack of overall benefit in this treatment group. The WHI also found that, compared with women taking a placebo, women taking the combination of estrogen and progestin had a 29% increase in myocardial infarction, a 41% increase in stroke, and a doubling of thromboembolic events. For hysterectomized women taking estrogen without progestin, the risk of stroke was increased compared with the group receiving placebo. As a result of the WHI findings, estrogen should probably no longer be considered the optimal first-line preventive or therapeutic agent for bone loss in postmenopausal women.55 On the basis of these data, the use of estrogen for osteoporosis prevention or treatment should be limited to women who require its beneficial effects for menopausal symptoms. For other women, there are equally effective and probably safer alternatives. When used, ERT should be accompanied by a comprehensive screening program consisting of regular lipid profiles, breast examinations, mammography, and gynecologic assessments.64
Anabolic therapy with recombinant human PTH (1–34)
Currently, PTH (1–34)—teriparatide—is the only available anabolic agent for osteoporosis in the United States, although other anabolic agents have been developed [see Future Therapies, below]. Teriparatide was approved by the FDA in late 2002 for use in osteoporosis. Although chronic elevation in PTH results in bone loss, brief increases in PTH have anabolic effects on bone. A daily injection of recombinant human PTH (hPTH) provides a brief rise in PTH, resulting in increased BMD. To date, teriparatide is the anabolic agent with the most potent effects on BMD. Its effects are particularly dramatic in the spine: in one study comparing teriparatide and alendronate treatment, at the end of 14 months, alendronate-treated patients had a 5.6% increase in lumbar spine BMD, whereas teriparatide-treated patients had a 12.2% increase.65 It should be noted, however, that teriparatide has not been demonstrated to prevent hip fracture, and it does not have FDA approval for that purpose.
Teriparatide is administered nightly in a standard subcutaneous dose by a pen delivery system. Side effects include flushing, hypercalcemia, and hypercalciuria. Patients must be monitored with measurement of serum calcium and 24-hour urine calcium levels, and calcium intake must be adjusted as needed to keep urine and serum calcium in a normal range. Teriparatide comes with a black-box warning from the FDA concerning an association with risk of sarcomas, based on its effects in rats. For this reason, it is administered for no longer than 2 years, and its use is contraindicated in patients with active malignancy. Unfortunately, the high cost of teriparatide has limited its use, because much of its target population is on Medicare and does not have prescription drug coverage.
Selection of patients for this costly and potent drug should be done with care. Osteoporosis experts have developed a consensus opinion, published in the spring of 2004, to help clinicians identify appropriate patients for teriparatide therapy. Indications for its use were as follows: (1) history of vertebral fracture, T score-3.0 or below, or age greater than 69 years; (2) fracture or unexplained bone loss in patients on antiresorptive therapy; and (3) intolerance of oral bisphosphonate therapy. Contraindications listed include hypercalcemia, Paget disease, history of irradiation to the skeleton, sarcoma, or malignancy involving bone.66
Combining teriparatide and bisphosphonates
Simultaneous administration of teriparatide and oral bisphosphonates impairs the anabolic effects of teriparatide.67 When these agents are given sequentially, however, the increase in BMD seen with initial teriparatide therapy is followed by additional gain during subsequent bisphosphonate treatment.68 This increase in BMD in the setting of bisphosphonate use is thought to reflect mineralization of bone matrix laid down during the teriparatide treatment. Interestingly, when teriparatide is administered to patients who have previously been treated with bisphosphonate, their response to teriparatide is blunted.69 This finding is of concern, because many patients currently being considered for teriparatide therapy have already been treated with bisphosphonates.
National Osteoporosis Foundation guidelines
The most comprehensive set of guidelines for the management of osteoporosis comes from the National Osteoporosis Foundation (NOF).70These guidelines, which were updated in 2004, recommend that any postmenopausal women with a prior vertebral or hip fracture should receive pharmacologic therapy to reduce fracture risk. Therapy should also be initiated in women with a hip T score lower than -1.5 and one or more of the following risk factors for osteoporotic fracture: (1) a family history of osteoporosis in a first-degree relative, (2) a personal history of any fracture as an adult, (3) low body weight (< 127 lb), (4) current smoking, or (5) use of oral corticosteroid therapy for more than 3 months. Women with no risk factors for osteoporotic fracture (other than age, gender, and menopausal status) should be treated if the hip T score is below -2.0. In the NOF guidelines, the choice of antiosteoporotic therapy follows current FDA indications, without specific recommendations of one agent over another [see Table 6 for other sources of information].
Table 6 Internet Resources for Osteoporosis and Bone Metabolism
For purposes of monitoring, a follow-up bone density study is indicated no sooner than 1 to 2 years after the initial determination, depending on the results and whether any therapy is initiated. Subsequent measurements may be made at similar or longer intervals, depending on the patient's progress and any further therapeutic alterations. For more precise comparison, follow-up studies should be performed using the same DXA unit, if possible. It should be borne in mind that with many of these therapies, the expected increase in BMD seen on follow-up DXA studies will be minimal in comparison with the improvement in fracture risk. However, patients who continue to lose bone despite ongoing antiresorptive therapy should be evaluated for previously unrecognized causes of secondary osteoporosis. Biochemical bone turnover markers (e.g., N-telopeptide, pyridinoline cross-links) may be helpful to document patient response to antiresorptive therapy, but they show significant variability within individuals, and therefore large changes are necessary for proper interpretation. In addition, their concentrations may be influenced by timing of collection, diet, and other factors. Accordingly, widespread consensus is lacking on their precise role in osteoporosis management.
Recombinant hPTH (1–84) is currently in phase III trials and appears to have effects similar to those of hPTH (1–34) (see above). Additional agents in the SERM class include lasofoxifene (currently being evaluated for FDA approval) and bazedoxifene (in phase III trials). Strontium ranelate is an anabolic agent that appears to act on the CaSR to induce osteoblast differentiation. It enhances both bone resorption and formation, with an emphasis on formation, resulting in significantly decreased risk of vertebral fracture.71 It was approved for use in Europe in late 2004. Preclinical studies of the anabolic effects of vitamin D on bone are under way72 and may lead to the development of vitamin D analogues for osteoporosis therapy.
Osteomalacia is a condition in which the bone matrix is normal in quantity but is weakened by insufficient mineral content. Osteomalacia in the growing skeleton is termed rickets. Causes of osteomalacia include nutritional deficiencies of calcium, phosphate, or vitamin D; intestinal disease affecting the absorption of these substances; abnormalities in vitamin D metabolism, such as occurs in liver disease, renal failure, or through the use of antiepileptic drugs; vitamin D resistance; renal phosphate leak; and oncogenic osteomalacia (a humoral syndrome of increased urinary phosphate loss associated with rare tumors of mesenchymal origin).73 In adults, severe osteomalacia presents as fatigue, proximal muscle weakness, and diffuse or focal skeletal pain. Mild osteomalacia is common and often asymptomatic.74Decreased or low-normal concentrations of both calcium and phosphorus are noted on biochemical testing, and the alkaline phosphatase concentration is elevated. Depending on the cause, decreased levels of either 25-(OH)D3 or calcitriol may be seen. Plain films may demonstrate osteopenia and pseudofractures. When necessary, the diagnosis can be confirmed with bone biopsy processed and analyzed by an experienced bone pathologist. The treatment of osteomalacia depends on the pathogenesis of the condition. For the majority of cases in which the problem is dietary insufficiency or malabsorption of vitamin D, administration of high doses of cholecalciferol and calcium will rapidly correct deficits and heal the bone. Underlying conditions such as celiac disease (which may be asymptomatic) should be identified and treated. Other conditions, such as tumor-induced osteomalacia, represent special cases and require a different approach (e.g., phosphate supplementation).
PAGET DISEASE OF BONE
Paget disease is a relatively common condition in which abnormal osteoclast function leads to accelerated and disordered bone remodeling, producing highly disorganized bone microarchitecture in affected areas. This sometimes leads to deformity of affected bones, increased vascularity, nerve impingement syndromes, and a propensity to fracture. Paget disease is commonly seen in the elderly and may be familial. The precise etiology is not yet known, although a viral origin is suspected. Many persons with Paget disease are asymptomatic. The sole manifestation may be increased serum alkaline phosphatase activity, detected incidentally on blood testing. If the disease is severe or extensive, pain syndromes may result. Very often, the discomfort originates not from bone itself but from arthritic changes in adjacent joints caused by altered biomechanics. The skull may be enlarged, or there may be significant bowing of the long bones of the legs. Bony overgrowth may lead to local impingement on spinal nerve roots, with pain or neurologic deficits; overgrowth in the inner ear can lead to sensorineural hearing loss. Rare complications include high-output chronic heart failure (from multiple vascular shunts in bone) and transformation to osteosarcoma.
The diagnosis of Paget disease is typically made after finding isolated elevation of the serum alkaline phosphatase level without evidence of liver disease. (Fractionation of alkaline phosphatase isoenzymes can confirm bone as the source). A nuclear bone scan is performed next to identify involved areas. The results of the bone scan will identify which bones should be evaluated by plain x-ray to exclude signs of metastatic disease and confirm pagetic findings.
Treatment of Paget disease is indicated for patients with bone pain; it is also indicated, regardless of symptoms, if there is involvement of a weight-bearing bone or a joint. Antiresorptive agents, such as high-dose oral or injectable bisphosphonates (see above) or injectable calcitonin, can be used to treat this disorder.75 Treatment of any vitamin D deficiency is essential before starting intravenous bisphosphonate therapy to avoid hypocalcemia. Disease activity and response to therapy are assessed with serial measurement of alkaline phosphatase or other bone turnover markers. The goal of treatment is normalization of alkaline phosphatase. Re-treatment is indicated if the alkaline phosphatase level begins to rise above normal. Patients with skull involvement should have periodic audiometry to exclude hearing loss.
Figure 1 Seward Hung.
Editors: Dale, David C.; Federman, Daniel D.