Hypercalciuria

Hypercalciuria, or excessive urinary calcium excretion, occurs in about 5-10% of the population[7] and is the most common identifiable cause of calcium kidney stone disease. Indeed, about 80% of all kidney stones contain calcium, and at least one third of all calcium stone formers are found to have hypercalciuria when tested. Hypercalciuria also contributes to osteoporosis. (Other significant causes of kidney stones include hyperoxaluria, hyperuricosuria, low urinary volume, and hypocitraturia.)

Hypercalciuria can be classified as idiopathic or secondary. Idiopathic hypercalciuria can be diagnosed when clinical, laboratory, and radiographic investigations fail to delineate an underlying cause. Secondary hypercalciuria occurs when a known process produces excessive urinary calcium. (See Pathophysiology, Etiology, and Workup.)

Elevated urinary calcium occurs by 1 of 3 primary mechanisms, as follows:

• The filtered load of calcium is abnormally increased without an adequate compensatory increase in tubular calcium reabsorption

• The filtered calcium load is normal but tubular calcium reabsorption is reduced

• The filtered load is increased and the reabsorbed load is reduced

A good screening test for hypercalciuria compares the ratio of urinary calcium to creatinine. To validate the screening test, an accurately timed urinalysis should be used to confirm any positive screens. (See Workup.)

Definitions

Hypercalciuria is defined as urinary excretion of more than 250 mg of calcium per day in women or more than 275-300 mg of calcium per day in men while on a regular unrestricted diet. It can also be defined as the excretion of urinary calcium in excess of 4 mg/kg of body weight per day or as a urinary concentration of more than 200 mg of calcium per liter.

An alternate definition of hypercalciuria is daily urinary excretion of more than 3 mg of calcium per kilogram of body weight or more than 200 mg of calcium per day, while on a restricted diet (400 mg calcium and 100 milliequivalent [mEq] sodium). Table 1, below, outlines the various definitions of hypercalciuria based on a regular or restricted diet.

Table 1. Definitions of Hypercalciuria (Open Table in a new window)

Limitations of hypercalciuria definitions

Optimal levels of urinary calcium have not been determined. Several experts, including the author of this article and Dr. Gary Curhan of Harvard University, have suggested that the current definitions of hypercalciuria and several other 24-hour urinary chemistries are inadequate and may not be reliable when applied to nephrolithiasis. Available definitions are limited by the occasional inclusion in research investigations of recurrent stone formers in the healthy group of study subjects and by poorly defined controls.[8] In addition, the parameters and ranges are not optimized from the point of view of kidney stone disease or production.

The data from several large databases (including the Nurses' Health Study and the Health Professional Follow-up Study) indicate that, with the current definition of hypercalciuria, a substantial proportion of controls would be defined as abnormal. The relative risk of stone production appears to be continuous, along a sliding scale, rather than dichotomous with a single arbitrary level that differentiates healthy people from those who form stones.

Therefore, although the gross total 24-hour urinary calcium excretion remains useful, the urinary calcium concentration is probably a more reliable dynamic indicator of stone formation risk.[8] Further study is needed to confirm these conclusions and to possibly establish better 24-hour urine reference ranges for calcium and other metabolic stone–risk chemistries. (See Workup.)

Clinically significant hypercalciuria

The following are the most common types of clinically significant hypercalciuria, although evidence suggests that this classic differentiation is insufficient to explain all of the cellular and genetic variations that have been noted in the condition[7] :

• Absorptive hypercalciuria
• Renal phosphate leak hypercalciuria (also known as absorptive hypercalciuria type III)
• Renal leak hypercalciuria
• Resorptive hypercalciuria

It is uncertain whether these different types of hypercalciuria are truly separate and distinct entities or are instead just the extremes of a single, unified process. Although the answer to this question is not currently known, the evidence and the consensus opinion lean toward the unified theory. In reality, other than for research purposes, this question has little impact clinically, because ultimately whatever therapy works is required. Table 2, below, provides simple test guidelines for specific diagnoses of hypercalciuria. (See Treatment and Medication.)

Table 2. Hypercalciuria Simplified Test Guideline (Open Table in a new window)

Absorptive hypercalciuria

Absorptive hypercalciuria is by far the most common cause of excessive urinary calcium. About 50% of all calcium stone formers have some form of absorptive hypercalciuria, which is caused by an increase in the normal gastrointestinal absorption of calcium, overly aggressive vitamin-D supplementation, or excessive ingestion of calcium-containing foods (milk-alkali syndrome). Calcium absorption occurs mainly in the duodenum and normally represents only about 20% of the ingested dietary calcium load.[9]

Increased intestinal calcium absorption produces a corresponding increase in serum calcium levels. Typically, serum parathyroid hormone (PTH) is low or in the low-normal range in absorptive hypercalciuria, because the serum calcium level is generally high.

Mild or moderate absorptive hypercalciuria can usually be controlled solely with dietary measures, but medical therapy is required in severe and resistant cases.

Type I

Absorptive hypercalciuria type I is a relatively rare condition, generally characterized by elevated urinary calcium and calcium/creatinine levels except while fasting.

A variant of absorptive hypercalciuria type I exists in which fasting hypercalciuria can occur due to excess serum vitamin D3. This vitamin D–dependent variant can be diagnosed with the finding of increased serum vitamin-D levels and with correction of the fasting hypercalciuria with a trial of ketoconazole therapy. (Ketoconazole is a potent P450 3A4 cytochrome inhibitor that reduces circulating vitamin D3 levels by 30-40%.)

As many as 50% of all patients with absorptive hypercalciuria type I may have increased levels of vitamin D3. Other causes of fasting hypercalciuria can be identified by elevated PTH levels (renal leak and resorptive hypercalciuria) or by increased urinary phosphate levels with hypophosphaturia (renal phosphate leak calciuria, also called absorptive hypercalciuria type III).

Absorptive hypercalciuria type I represents an extremely efficient intestinal calcium absorption mechanism. Bone density is usually normal, because abundant calcium is available for bone deposition, and PTH levels are normal or low. In some cases, however, the urinary calcium excretion is even greater than the amount absorbed, resulting in a net negative calcium balance and possible decrease in bone density, which is the opposite of what would be expected. Researchers think that this could be due to elevated serum vitamin-D levels or may be the result of an increased sensitivity to vitamin D and its metabolites.

Type II

This is a less severe form, and most common variety, of absorptive hypercalciuria. It usually responds to moderate dietary calcium restriction. Fasting hypercalciuria is not present in this disorder.

Type III

Absorptive hypercalciuria type III, also called renal phosphate leak hypercalciuria, is a vitamin D–dependent variant of absorptive hypercalciuria. This condition, a relatively uncommon cause of hypercalciuria, should be suspected in any patient with hypercalciuria who has a low serum phosphate level. A serum phosphate level of less than 2.9 mg/dL has been suggested as sufficient to raise the suspicion of renal phosphate leak hypercalciuria.

The etiology is an obligatory and uncontrolled loss of phosphate in the urine due to a renal defect, with a low ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate.[10]  This produces hypophosphatemia, which stimulates the renal conversion of 25-hydroxyvitamin D to the much more active 1,25-dihydroxyvitamin D3 (calcitriol, vitamin D3). Vitamin D3 increases intestinal phosphate absorption to correct the low serum phosphate levels. However, it also simultaneously increases intestinal calcium absorption. This extra calcium eventually is excreted in the urine. The diagnosis is confirmed by the following findings:

• Low serum phosphate
• Hypercalciuria
• High urinary phosphate
• High serum vitamin D3
• Normocalcemia and normal PTH levels

Renal leak hypercalciuria

Renal leak hypercalciuria occurs in about 5-10% of calcium-stone formers and is characterized by fasting hypercalciuria with secondary hyperparathyroidism but without hypercalcemia.

The etiology is a defect in calcium reabsorption from the renal tubule that causes an obligatory, excessive urinary calcium loss. This results in hypocalcemia, which causes an elevation in the serum PTH. This secondary hyperparathyroidism raises vitamin-D levels and increases intestinal calcium absorption. Essentially, this means that, even in cases of undeniable renal leak hypercalciuria, an element of absorptive hypercalciuria can be present.

The diagnosis is relatively easy. Any patient who fails to control their excessive urinary calcium on dietary measures alone and who demonstrates relatively high serum PTH levels without hypercalcemia or hypophosphatemia probably has renal leak hypercalciuria.

The ratio of calcium to creatinine (in mg/dL) tends to be high in renal leak hypercalciuria (> 0.20), and the occurrence of medullary sponge kidney is more likely than in other types of hypercalciuria.

Renal leak hypercalciuria is generally not amenable to therapy with dietary calcium restrictions, because of the obligatory calcium loss, which can easily lead to bone demineralization, especially if oral calcium intake is restricted.

Resorptive hypercalciuria

Resorptive hypercalciuria is almost always due to hyperparathyroidism. This generally accounts for 3-5% of all cases of hypercalciuria, although some reports have indicated an incidence as high as 8%. Increased PTH levels cause a release of calcium from bone stores.

In addition, resorptive hypercalciuria increases calcium absorption from the digestive tract by raising vitamin D3 levels and decreases renal excretion of calcium by stimulating calcium reabsorption in the distal renal tubule. Eventually, the hypercalcemia overcomes this renal calcium–conserving quality and results in an increased net loss of calcium through the urine (hypercalciuria).

Hyperparathyroidism does not always result in calcium-stone disease. The reason for this is unclear but may reflect urinary volume and optimal levels of other urinary metabolites, such as oxalate, uric acid, sodium, phosphate, citrate, urinary volume, and serum vitamin D3. In some cases, the vitamin D3 level has been suggested to be responsible for determining which patients with hyperparathyroidism actually develop kidney stones. This apparently reasonable hypothesis remains unproved, however, and the current evidence suggests that vitamin-D levels cannot be the only reason that some patients with hyperparathyroidism do not develop stones.

Hyperparathyroidism produces a lower urinary calcium excretion for the patient’s serum calcium level than does hypercalcemia from other causes. In other words, for any level of serum calcium, patients with hyperparathyroidism have lower urinary calcium excretion than do patients with hypercalcemia who have normal PTH levels. This is due to the calcium-conserving effect of PTH on the kidneys.

Diagnosis and treatment

Hyperparathyroidism should be suspected in calcium stone–forming patients with significant hypercalciuria, even in those with only mild hypercalcemia. Failure to identify a curable cause of osteoporosis and calcium nephrolithiasis can be easily avoided just by checking the parathyroid hormone level routinely in hypercalciuric patients with relatively high serum calcium levels.[11]

Patients with hyperparathyroidism who have parathyroid surgery and subsequently demonstrate normal urinary calcium levels are still at risk for developing stones at about the same rate as other calcium-stone formers. Therefore, retesting with 24-hour urine determinations is recommended for calcium-stone formers even after successful parathyroid surgery has normalized their serum calcium levels. Urinary cyclic adenosine monophosphate (cAMP) can be used as a substitute for serum PTH level determinations to monitor patients who have already been diagnosed.

Urinary excretion of calcium is the result of the complex interplay of the gastrointestinal tract, the kidney, and bone and is regulated by multiple hormones. Hypercalciuria is believed to be a polygenic trait and is significantly influenced by diet.

Idiopathic hypercalciuria is the most common metabolic abnormality in patients with calcium kidney stones. Subjects with idiopathic hypercalciuria have a generalized increase in calcium turnover, which includes increased gut calcium absorption, decreased renal calcium reabsorption, and a tendency to lose calcium from bone. Despite the increase in intestinal calcium absorption, a negative calcium balance is commonly seen in balance studies, especially in patients on a low-calcium diet. The mediator of decreased renal calcium reabsorption is unclear; it is not associated with either an increase in filtered renal calcium or altered parathyroid hormone (PTH) levels.

An increased incidence of hypercalciuria is observed in first-degree relatives of individuals with idiopathic hypercalciuria, but it appears to be a complex polygenic trait with a large contribution from diet to expression of increased calcium excretion.

Increased tissue vitamin D response may be responsible for manifestations of idiopathic hypercalciuria in at least some patients.[12, 13] Moreover, deficiency in the enzyme that inactivates 1,25(OH)2D, 1,25(OH)2D-24 hydroxylase causes elevated vitamin D, hypercalciuria, nephrocalcinosis, and kidney stones.[14] Furthermore, dysregulation of the calcium-sensing receptor ̶ Claudin-14 axis likely contributes to the development of hypercalciuria.[15, 16, 17]

Intestinal adaptation

Intestinal adaptation occurs with long-term, consistent calcium intake. This means that patients with persistently low dietary calcium increase their intestinal calcium absorption, and those with a high calcium intake show a corresponding decrease in intestinal absorption.

Fractional calcium absorption decreases with larger calcium loads, probably due to saturation of active absorption pathways. It plateaus at about 500 mg of calcium for most people. This means that an oral calcium dose is absorbed better if administered in small, divided portions rather than in a single large calcium bolus. In general, each additional 100 mg of daily dietary calcium ingestion increases urinary calcium levels by 8 mg/day in a healthy population but raises urinary calcium levels by 20 mg/day in hypercalciuric patients.

When properly evaluated, 97% of hypercalciuric patients can be classified according to etiology. Causes of hypercalciuria that need to be considered include the following:

• Hyperthyroidism
• Renal tubular acidosis
• Sarcoidosis and other granulomatous diseases
• Vitamin D intoxication
• Glucocorticoid excess
• Paget disease
• Albright tubular acidosis
• Various paraneoplastic syndromes
• Prolonged immobilization
• Induced hypophosphatemic states
• Multiple myeloma
• Lymphoma
• Leukemia
• Metastatic tumors (especially to bone)
• Addison disease
• Milk-alkali syndrome

Wong and colleagues reported that hypercalciuria was present in 91.9% of subjects on deferasirox, an oral iron chelator used widely in the treatment of thalassemia major and other transfusion-dependent hemoglobinopathies but was not present in a control group taking an alternative iron chelator, deferoxamine.[18]

Mahyar et al reported a significantly higher frequency of hypercalciuria and hyperuricosuria in children with vesicoureteral reflux (VUR) than in a control group. These authors also observed a positive correlation between hypercalciuria and hyperuricosuria and severity of VUR (P < 0.05).[19]

As the name implies, the cause of idiopathic hypercalciuria is not known. Several theories have been published, and some data supports certain aspects of these theories; however, these theories cannot yet be uniformly applied to a large patient population. Studies that examined metabolic balance have reported increased absorption of calcium from the intestine. In some instances, this process has been shown to be independent of vitamin D or a result of increased gut sensitivity to vitamin D.

In other patients with hypercalciuria, the proportion of calcium excreted into the urine is higher than normal, regardless of dietary intake of calcium. In fact, some patients have been found to have higher than normal urinary calcium despite lower than normal dietary intake, suggesting decreased renal tubular reabsorption. This renal tubular leak is possibly a result of a mutational defect in 1 or more ion channels.

Another proposed mechanism involves an imbalance of calcium deposition and reabsorption in bone that is independent of PTH or vitamin D. In addition, a combination of these factors may contribute to the high amounts of urinary calcium observed in patients with idiopathic hypercalciuria.

Genetics

Molecular genetics and other research have indicated potential lines of future investigation into the nature of hypercalciuria. For example, dysregulation of the calcium-sensing receptor–claudin-14 axis, as well as polymorphism in the regulatory region controlling expression of the calcium-sensing–receptor gene, may contribute to increased calcium excretion.[15, 16] More than 60 activating mutations in the calcium-sensing receptor have been identified to cause autosomal dominant hypocalcemic hypercalciuria.[20]

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive disorder caused by mutations in the tight junction proteins claudin-16 and claudin-19, which are encoded by the CLDN16 and CLDN19 genes, respectively. Over 60 mutations in CLDN16 have been described in FHHNC. The disorder is characterized by excessive urinary losses of magnesium and calcium, bilateral nephrocalcinosis, and progressive chronic renal failure.[21]

Claudin-2 is abundantly expressed in the proximal tubule and mediates paracellular reabsorption of calcium.  In a family with missense CLDN2 mutations, five males had a history of hypercalciuria and kidney stones while four males without the mutation did not.[22]

An interesting study in specially prepared transgenic mice suggests the possible importance of the gene CLCN5, which encodes ClC5 (a renal chloride channel located exclusively in the kidney), to the development of hypercalciuria. The transgenic mice were produced using an antisense ribozyme targeted against ClC5 so that these mice lacked ClC5 activity.[23] This mouse model is similar to Dent disease in humans, which is a rare, heritable X-linked disorder with reduced ClC5 activity that is characterized by absorptive hypercalciuria, nephrocalcinosis, nephrolithiasis, low ̶ molecular weight proteinuria, Fanconi syndrome, and renal failure. In Dent disease, the nephrolithiasis, hypercalciuria, and nephrocalcinosis are eliminated with a renal transplant from a healthy individual, confirming the renal cause of these problems.[23]

Other promising lines of research involve overexpression of vitamin D receptors and deficiencies in various renal tubular enzymes.

Obesity

The association between obesity and kidney stones has been well documented in the literature.[24, 25]

Pregnancy

Pregnancy has long been thought to increase the incidence of urinary stones and hypercalciuria. Healthy, non–stone-producing pregnant women have been found to have hypercalciuria during all 3 trimesters. In addition, urinary oxalate, magnesium, and citrate levels have been found to increase during pregnancy. This suggests that the overall risk of nephrolithiasis during pregnancy may not be increased substantially, as levels of urinary stone promotors and inhibitors have both been found to rise.

Calcium supplementation

A study suggests that calcium supplementation, with or without calcitriol, does not increase the risk of calcium urolithiasis significantly in healthy (non–stone-forming) postmenopausal women even if they have increased urinary calcium excretion.[26] The study, which involved healthy postmenopausal women (not calcium-stone formers), showed that those women who were administered calcium supplements alone did not demonstrate any significant increase in their urinary calcium excretion.

Those who were administered calcium and calcitriol did have a significant increase in their urinary calcium levels. However, this did not result in any increase in overall stone risk or calcium oxalate activity product, due in part to a simultaneous decrease of about 20% in urinary oxalate levels. Theoretically, a thiazide diuretic would reduce the urinary excretion of calcium and could be of some therapeutic benefit for this group at risk for osteoporosis.

Vitamin D

Many cases of absorptive hypercalciuria involve elevated vitamin-D levels.[9] Vitamin D increases small-bowel absorption of calcium and phosphate, enhances renal filtration, decreases PTH levels, and reduces renal tubular calcium absorption, which ultimately leads to hypercalciuria. An elevated vitamin-D level accounts for the finding of fasting hypercalciuria in some cases of absorptive hypercalciuria type I. About 30-40%, and possibly as many as 50%, of patients with absorptive hypercalciuria demonstrate abnormally elevated vitamin D3 levels.

It has been suggested that some patients have an exaggerated response to, affinity for, or sensitivity to normal levels of vitamin D and its metabolites. Activation of vitamin D3 takes place in the proximal renal convoluted tubule. This activation can be reduced by ketoconazole therapy.

Serum vitamin-D determinations can be helpful in determining the etiology of hypercalciuria in difficult or resistant cases, but these tests are probably are unnecessary in most hypercalciuric patients except as part of a research study or other standardized protocol.

Sarcoidosis and hypervitaminosis D

Sarcoidosis is a chronic disease that causes granulomas in various parts of the body but most often in the lungs. Although the exact cause is unknown, this condition is thought to arise from an exaggerated cellular immune response. The prevalence in the United States is about 1-4 cases per 10,000 population.

In some patients with sarcoidosis, 1,25-dihydroxyvitamin D is synthesized in an uncontrolled fashion by macrophages in the sarcoid granulomas. This produces a hypervitaminosis-D state with hypercalcemia and, frequently, hypercalciuria. Rarely, hypercalciuria is found without the hypercalcemia. This vitamin-D overproduction is not controlled by increased serum calcium, PTH, or phosphate administration.

Limiting sunlight exposure and reducing vitamin D ingestion are recommended. Glucocorticoid therapy usually controls the hypercalcemia and hypercalciuria. Primary hyperparathyroidism has been reported in some patients with sarcoidosis.[27]

More than 30 million Americans experience kidney stone disease, with 1.2 million new cases each year. The percentage of people with hypercalciuria has been estimated to be at least 1 in 3 among people who form kidney stones, although some investigators have suggested that hypercalciuria can be found in as many as 60% of all calcium-stone formers. It is the most common metabolic abnormality found with calcium nephrolithiasis.

Despite a higher incidence of stone disease in the "stone belt," which is primarily the southeast portion of the United States, no clear biochemical difference was found when risk factors were compared among various regions of the country. Although nutritional and environmental influences would be expected to produce some variability, stone formers in all of the regions tested showed a striking similarity in urinary chemical risk factor profiles, with no significant biochemical differences noted that could be attributable to geographic factors.

International occurrence

Globally, the overall risk of forming stones differs in various regions. The probability is 1-5% in Asia, 5-9% in Europe, 13% in North America, and 20% in Saudi Arabia. Upper-tract stone disease is associated with an affluent lifestyle in developed countries where diets are high in animal protein, whereas bladder stones are predominant in developing countries and are related to poor socioeconomic conditions.

Race-related demographics

White persons tend to have stones more often than do Black individuals. Whether this is due to genetic differences or is secondary to dietary and socioeconomic factors is unclear, although the latter explanation is suggested by the increasing incidence of nephrolithiasis in the nonwhite population.

A study by Whalley and associates from Johannesburg, South Africa, found that Black male stone formers had similar chemistry profiles to those of the White male stone formers, although the risk factors were generally less severe.[28] The investigators compared lithogenic risk factors in healthy Black male volunteers, Black males who were recurrent stone formers, and White male recurrent stone formers. The subjects were observed over a 10-year period and were assessed with a thorough history, dietary analysis, and serum and urinary chemistry evaluation. No significant family history of stone disease was present in the Black population studied, which suggests that genetic factors may be of more importance in the etiology of stone formation among Wwhites.[28]

Similar findings were reported by Maloney and associates, who found that all racial groups tested (White, Black, Asian, Hispanic) demonstrated remarkable similarity in the incidence of underlying metabolic abnormalities.[29]

A study by Rodgers and Lewandowski found that a low-calcium diet caused a statistically significant increase in urinary oxalate in Black subjects but not in White subjects.[30] The results of a high-oxalate diet also differed between the Black and White groups.[30]

Sex-related demographics

The reference range of urinary calcium excretion for men generally is 275 mg or less per day, whereas in women the usual daily limit is only 250 mg. These reference values were created using large numbers of people (not calcium kidney-stone formers) to establish a reference range. The most likely reason for the discrepancy is that men are generally larger physically than women and have a correspondingly larger amount of material, such as calcium and uric acid, to excrete.

Clearly, stone development occurs when the chemical conditions are favorable, regardless of what any arbitrary reference range might be. For most practical purposes, the 250-mg/day limit for 24-hour urinary calcium excretion or a concentration of no more than 200 mg of calcium/liter of urine is used regardless of sex when the relative severity of hypercalciuria and overall risk of calcium kidney stone production are considered (see Table 1).

Postmenopausal women are more likely than men to demonstrate hypercalciuria. Hyperparathyroidism, which produces hypercalciuria, is more common in older women, and, because of concerns about their risk for osteoporosis, calcium supplementation is more popular with women.

In a study, women who developed calcium kidney stones had an average calcium intake that was 250 mg/day less than that of non–stone-forming women. This finding agrees with other studies that suggest that calcium stone formers should not restrict their calcium intake too aggressively.

When urinary chemistry and stone formation rate data were analyzed with the demographic information from a large national database of kidney stone formers, investigators found that obesity is a risk factor for kidney stone disease in women but not in men.

This finding is similar to that found in 2 large studies involving 81,000 women in the Nurses' Health Study and 51,000 men in the Health Professionals Follow-up Study. Investigators at Harvard who conducted these studies found that body size was a positive risk factor for kidney stone disease in women, but the correlation was much less significant in men.[8] The reason for this finding is unclear, but it may be related to estrogen levels. Whether this increased risk in women disappears when the excess body weight is lost is also unclear.

High-dose vitamin B6 appears to be beneficial in women with calcium oxalate stone disease but probably not in men. Using data from more than 85,000 women with no history of kidney stones whose cases were monitored for 14 years, investigators found that those who took large amounts of vitamin B6 had a significantly lower incidence of new calcium oxalate stone formation. A similar benefit of reduced calcium stone production from increased vitamin B6 intake was not evident in an equivalent male study group. Similarly, carbohydrate intake was found to be a kidney stone dietary risk factor for women but not for men. (Incidentally, these studies found no benefit to dietary vitamin-C modifications in either men or women.)

As previously mentioned, pregnancy has long been thought to increase the incidence of urinary stones and hypercalciuria. Healthy, non–stone-producing pregnant women have been found to have hypercalciuria during all 3 trimesters.

Age-related demographics

The peak age range for calcium kidney stone production is generally 35-45 years. Another peak incidence of hypercalciuria occurs in postmenopausal women. In this older age group, many women are taking supplemental calcium for osteoporosis prophylaxis or therapy. The excess absorbed calcium eventually is released into the urine. In addition, postmenopausal women are at an increased risk of hyperparathyroidism, which can cause hypercalciuria.

Geriatric stone disease is relatively uncommon. The risk for newly formed stones in patients older than 65 years is quite low, although once a stone has formed the number and types of risk factors, as well as the risk of recurrent stones, are similar to those for younger stone formers. In particular, the incidence of hyperparathyroidism is higher in older persons and should be considered whenever an older patient presents with a first calcium kidney stone, particularly if the patient is female.

Children

Hypercalciuria can occur at any age, including in newborns. The peak incidence of idiopathic hypercalciuria in children occurs at age 4-8 years.

The morbidity of hypercalciuria is related to 2 separate factors; ie, kidney stone disease and bone demineralization leading to osteopenia and osteoporosis.

Kidney stones are extremely painful because of the stretching, dilating, and spasm of the ureter and kidney caused by the acute obstruction. The pain is unrelated to the size of the stone or its composition and is related only to the rapidity and degree of the obstruction. Although normally functioning kidneys are quite resistant to damage from acute obstruction, aggressive surgical treatment is necessary in certain situations, such as a solitary kidney, renal transplantation, pyonephrosis (infection proximal to the obstruction), and intractable pain not relieved by parenteral analgesics.

Bone-density loss

Hypercalciuric stone formers have been demonstrated to have a lower average bone mineral density than non–stone formers matched for age and sex. Moreover, compared with normocalciuric stone formers, hypercalciuric patients have an average bone density that is 5-15% lower.[2] (In children with idiopathic hypercalciuria, bone mineral ̶ density measurements have consistently demonstrated Z-score reductions at the lumbar spine and, to a lesser extent, the femoral neck.[31] )

Bone loss is worsened if patients are placed on a calcium-restricted diet, as 99% of the body's calcium is stored in the bones. Fortunately, significant clinical bone loss is relatively rare. However, female hypercalciuric stone formers who become menopausal are at significantly greater risk of osteoporosis than their healthy female counterparts. The higher the urinary calcium excretion is, the greater the risk.

Untreated patients with an obligatory urinary calcium loss relatively unaffected by diet, as in renal leak hypercalciuria, renal phosphate leak, and resorptive hypercalciuria, develop a negative calcium balance that can result in osteopenia or osteoporosis.

Some patients may have a primary altered bone metabolism, as occurs in postmenopausal women with an estrogen deficiency. Thirty percent of hypercalciuric children already show evidence of bone loss, which suggests a metabolic disorder is responsible. Strong evidence exists suggesting that the underlying disorder causing the hypercalciuria is responsible for the bone demineralization, but other factors, such as an overly zealous dietary calcium restriction, undoubtedly play a role.

Patient education is extremely important in the treatment of hypercalciuria. Only a very motivated patient with an understanding of the need for continuing treatment can be expected to maintain any long-term preventive program, which typically lasts years.

Additionally, no immediate penalty exists for cheating, such as occurs in a patient with diabetes who forgets to take his/her morning insulin. In a hypercalciuric patient who fails to follow the treatment regimen, the penalty (the next kidney stone) may not become apparent for many months or even years. This means that only a truly motivated and informed patient can be expected to follow any therapeutic program for hypercalciuria on a long-term basis.

For patient education information, see Kidney Stones. Other excellent sources of general patient information on kidney stones and hypercalciuria include PK Pietrow and ME Karellas’s " Medical Management of Common Urinary Calculi," available free online from American Family Physician, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Note that hypercalciuria has no significant physical examination findings and is purely a laboratory diagnosis. Important aspects of the patient’s history may include the following:

• Skeletal diseases (eg, osteoporosis, Paget disease) may produce hypercalciuria.

• Immobilization for various reasons (eg, postoperative, orthopedic injury, burns, intensive care, spinal cord injury, bone marrow transplants) can cause rapid bone remodeling and, hence, elevated calcium excretion; fortunately, this has become less common owing to the use of early mobilization strategies and physical therapy

• Nephrolithiasis is commonly associated with hypercalciuria

• Malignancy is a common cause of hypercalcemia and hypercalciuria in hospitalized patients; it usually results from bone destruction, bone reabsorption, or humoral factors such as PTH-related protein.

• Human immunodeficiency virus (HIV) infection or its treatment may be associated with a higher risk of hypercalciuria in children

Medications

Certain medications, such as vitamin-D supplements and furosemide, may contribute to hypercalciuria. All loop diuretics decrease the tubular reabsorption of calcium.[32]

Dietary and fluid intake

Many dietary factors can alter urinary calcium excretion, including the following:

• Sodium chloride

• Protein

• Glucose

• Sucrose

• Magnesium

• Phosphate

An inverse relationship between phosphate intake and urinary calcium excretion is observed; thus, phosphate-restricted diets result in an increase in urinary calcium excretion. With all of the other dietary items mentioned above, a direct relationship between dietary intake and urinary calcium excretion is observed.

Family history

Idiopathic hypercalciuria can run in families, as can diseases that are associated with secondary hypercalciuria. Approximately 50% of persons with kidney stones and hypercalciuria have a first-degree relative who also has hypercalciuria.

Signs and symptoms in children

In children, hypercalciuria is often associated with some degree of hematuria and back or abdominal pain, and is also sometimes associated with voiding symptoms. The standard treatment for pediatric hypercalciuria is limited to dietary or short-term medical therapy, because the patients become asymptomatic when the hypercalciuria is corrected and are often lost to follow-up.

A study involving 124 children with idiopathic hypercalciuria found that 50% of these patients had a family history of kidney stone disease. Fifty-two children developed clinical symptoms of flank or abdominal pain during the study period, but only 6 of these children had actual renal calculi. Twenty-seven children had hematuria, and 10 had incontinence. The children were treated with increased fluid intake and a reduction in dietary oxalate and sodium. Some required treatment with thiazides. All but 5 of the patients responded to therapy. Resolution of the hypercalciuria eliminated the recurrent pain in this patient population.[33]

Another study, looking at the long-term effects of hypercalciuria in children and several possible therapies over a 4- to 11-year period, concluded that, regardless of treatment, most children with hypercalciuria eventually become asymptomatic while remaining hypercalciuric.[34] Because limiting calcium intake in children is unwise, the recommended dietary therapy for hypercalciuria is to use a low-sodium/high-potassium diet, which normalizes the hypercalciuria in most pediatric patients.

In children with hypercalciuria, microcrystallization of calcium with urinary anions has been suggested to lead to injury of the uroepithelium. Consequently, when taking the history of the illness, attempt to identify symptoms relating to the urinary tract. Pay particular attention to the following signs and symptoms:

• Dysuria

• Abdominal pain

• Irritability (infants)

• Urinary frequency

• Urinary urgency

• Change of urinary appearance

• Colic

• Daytime incontinence

• Isolated or recurrent urinary tract infections[3]

• Vesicourethral reflux[4]

Some clinical manifestations are age dependent. For instance, irritability may be the only manifestation in infants, but a teenager may experience renal colic and hematuria.

Many different processes and disease states can produce overlapping symptoms and similar findings on urinalysis. A directed, stepwise approach is important in the evaluation of a patient with symptoms or a history compatible with hypercalciuria to avoid unnecessary expense, exposure to radiation, and patient discomfort. The first task is to document hypercalciuria. Looking for commonly associated urinary findings or problems that can produce similar symptoms is easy and inexpensive.

Two distinct approaches to the laboratory evaluation of hypercalciuric patients exist: the traditional approach and the simplified clinical approach. With both, initial blood tests, such as serum calcium, creatinine, and phosphate studies, should be performed to identify patients at risk for hyperparathyroidism, renal failure, and renal phosphate leak. Once hyperparathyroidism has been excluded, the 2 approaches differ.[5]

In the traditional approach, an effort is made to formally study the exact cause of the hypercalciuria, ultimately establishing a more precise diagnosis and leading directly to the most appropriate therapy based on etiology.

The simplified clinical approach uses a goal-oriented focus with therapeutic trials of therapy. A precise diagnosis may not be determined by this system.

Pediatric patient approach

A directed stepwise approach is important in the evaluation of a child with symptoms or a history compatible with hypercalciuria in order to avoid unnecessary expense, exposure to radiation, and patient discomfort. The first task is to document hypercalciuria. Looking for commonly associated urinary findings or problems that can produce similar symptoms is also easy and inexpensive. Consequently, the initial approach to any child with urgency, hematuria, or suspected hypercalciuria should include urinalysis, urinary calcium, creatinine, and uric acid.

Differentiation between absorptive hypercalciuria types I and II

The fasting and post–calcium-loading parameters are essentially the same in these 2 entities. The main difference is that patients with absorptive hypercalciuria type I still have hypercalciuria, defined as urinary excretion in excess of 200 mg of calcium per 24 hours, while on a 400-mg low-calcium diet. Patients with absorptive hypercalciuria type II have a less severe form of calcium hyperabsorption and are able to achieve normal urinary calcium levels while on the low-calcium diet.

Essentially, if the patient demonstrates normocalciuria on the restricted calcium diet, further testing is unnecessary because absorptive hypercalciuria type II is the only disorder that normalizes urinary calcium excretion on a limited oral calcium diet.

Differentiation of absorptive from renal leak hypercalciuria without a calcium-loading test

Patients with renal leak hypercalciuria tend to have relatively low serum calcium levels in relation to their serum parathyroid hormone (PTH) levels. Secondary hyperparathyroidism caused by an obligatory loss of serum calcium is a hallmark of renal leak hypercalciuria. The calcium/creatinine ratio tends to be high (> 0.20) in patients with renal calcium leak, and these individuals are more likely than other hypercalciuric patients to have medullary sponge kidney.

A trial of dietary therapy with a restricted calcium diet is relatively ineffective with renal leak hypercalciuria and is quite harmful in the long term because of possible bone decalcification, negative calcium balance, and osteoporosis. Alkaline phosphatase and cyclic adenosine monophosphate (cAMP) levels are often elevated in this condition.

Thiazide challenge

Thiazides, the mainstay of pharmacologic therapy for hypercalciuria, increase serum calcium levels. Therefore, they can be used in a thiazide challenge for cases of borderline or subtle hyperparathyroidism to confirm the diagnosis. This involves the temporary use of thiazide therapy to create a controlled hypercalcemia. If the PTH levels drop, the patient is responding properly and hyperparathyroidism is unlikely. If the PTH level does not diminish as the serum calcium level rises, hyperparathyroidism can be diagnosed.

In the traditional classification system, several distinct types of hypercalciuria exist, such as absorptive hypercalciuria types I, II, and III; renal leak hypercalciuria; and resorptive hypercalciuria. This classification system assumes that these hypercalciurias are separate and distinct entities that can and should be differentiated.

In clinical practice, these hypercalciuria types often overlap, and extensive testing to differentiate them is difficult, time consuming, and often clinically unnecessary, because such testing rarely affects therapy. In select cases in which a more extensive evaluation is necessary, the patient may benefit from a referral to a center with expertise in this area, but this is rarely required in routine clinical practice.

Calcium-loading test

In the traditional diagnostic approach, a calcium-loading test is performed, with the type of hypercalciuria determined in the following ways:

• Absorptive hypercalciuria - During a defined period of fasting, patients with absorptive hypercalciuria show a significant decrease in urinary calcium excretion; patients are then administered a large oral calcium meal, with urine samples obtained periodically afterwards tending to show a great increase in the patient’s urinary calcium excretion

• Renal leak hypercalciuria – In this type, the kidney has an obligatory calcium-losing defect, so patients are expected to show relatively little effect from dietary measures alone, including fasting; following a large oral calcium meal, patients with renal leak hypercalciuria do not demonstrate as large an increase in urinary calcium as do those with absorptive hypercalciuria

In practice, however, performing the calcium-loading test is difficult, tedious, and usually reserved for selected cases in a tertiary care center or for research purposes.

An alternate approach to the diagnosis of hypercalciuria is based on patients’ clinical responses. This simplified clinical approach is much easier and more practical for the vast majority of physicians and patients.

In this system, initial blood and 24-hour urine testing is performed, but the finding of hypercalciuria does not automatically require further testing, such as a calcium-loading test, to determine the exact etiology of the excess urinary calcium. Instead, a trial of therapy is instituted, usually based on dietary guidelines (after first screening the patient with blood tests for kidney failure, hyperuricemia, hypophosphatemia, and hypercalcemia).

The clinical response is evaluated with repeat 24-hour urine testing. If the hypercalciuria has resolved after dietary changes alone, the treatment plan is judged adequate and can be continued. If the response to dietary measures is insufficient, additional medical treatment is necessary. Blood and 24-hour urine testing is repeated at periodic intervals of 30-90 days. Longer intervals emphasize patient compliance, while shorter periods stress efficacy.

Appropriate treatment modifications are suggested until the results are stable, with acceptable urinary risk-factor levels.

Not only is the simplified clinical method much easier to perform and follow than the traditional workup, it also corresponds to what many experts actually carry out in their own clinical practices. The precise diagnosis may not always be clear, but the patient receives essentially the same treatment without the need for an inconvenient expensive test that is hard to interpret.

Advantages of the simplified approach

With the simplified approach, only a short-term trial of dietary therapy is needed to determine whether dietary modification is potentially adequate as a treatment. Medical treatment, usually beginning with thiazides, is used if dietary therapy alone is unsuccessful for any reason. Serum testing for PTH excess, hypercalcemia, and hypophosphatemia helps to identify those entities (hyperparathyroidism, renal leak hypercalciuria, renal phosphate leak) that should not be treated with dietary therapy alone.

The vast majority of hypercalciuric patients can be treated with this simplified plan. Ensuring that patients are retested while on the modified diet is important; otherwise, judging the effectiveness of the therapy or patient compliance is impossible.

Summary of the simplified approach

The simplified approach is carried out as follows:

• Complete a medical history

• Carry out initial blood and 24-hour urine testing

• Identify hypercalciuric patients

• Check hypercalcemic patients for hyperparathyroidism with PTH levels; consider a thiazide challenge test if the PTH level alone is inconclusive

• Check hypophosphatemic patients for hyperphosphaturia and possible absorptive hypercalciuria type III (renal phosphate leak hypercalciuria); verify the diagnosis by determining the vitamin D3 level or with a clinical trial of orthophosphate therapy

• Start a therapeutic trial of dietary modification treatment

• Repeat the blood and 24-hour urine tests

• If the hypercalciuria is controlled successfully with dietary modification, continue the therapy and repeat testing periodically; if dietary modification is unsuccessful, consider a trial of thiazide therapy

• Orthophosphates are typically recommended if thiazides are not tolerated well or fail to control urinary calcium levels adequately; they are particularly useful in hypercalciuric patients with elevated vitamin-D levels; patients whose hypercalciuria fails all of these therapies require further evaluation

A urinary tract infection is suggested by the presence of leukocyte esterase, white blood cells (WBCs), nitrite, or bacteria on microscopic examination findings. A urinalysis also can identify hematuria, a common, but insensitive and nonspecific, finding in children with hypercalciuria.

The urinary pH and the presence of crystals also may help to identify possible clues or an explanation of the observed symptoms. Uric acid and calcium oxalate crystals are usually seen in acidic urine, whereas calcium phosphate and carbonate crystals are usually seen in alkaline urine. Similarly to hematuria, however, the presence of crystals or an abnormal pH is neither sensitive nor specific for hypercalciuria.

Urinary calcium, creatinine, and uric acid

Not only does this study function as a reasonable screening test to document hypercalciuria, it also reveals hyperuricosuria. The calcium/creatinine and uric acid/creatinine ratios should be calculated to determine whether or not abnormalities are present. The normal calcium/creatinine ratio is less than 0.2; if the calculated ratio is higher than 0.2, repeat testing is indicated. If the follow-up results are normal, then no additional testing for hypercalciuria is needed. On the other hand, if the ratio remains elevated, a timed 24-hour urine collection should be obtained and the calcium excretion calculated.

The 24-hour calcium excretion test is the criterion standard for the diagnosis of hypercalciuria. If the calcium excretion is higher than 4 mg/kg/day, the diagnosis of hypercalciuria is confirmed and further evaluation is warranted.

Similarly, if hyperuricosuria is detected (through the uric acid ̶ to-creatinine ratio), the appropriate evaluation for this condition should be initiated.

Urinary calcium/osmolality ratio

In children with decreased muscle mass, urinary calcium/osmolality ratio has been suggested as a more specific and sensitive screening test than calcium/creatinine ratio because of decreased urinary creatinine excretion in those patients. A urinary calcium/osmolality ratio (X 10) of less than 0.25 is considered to be suggestive of hypercalciuria.

Additional studies

Freshly voided urine should be measured for bicarbonate and pH. A 24-hour urine collection also should be collected, for measurement of calcium, phosphorus, sodium, and magnesium.

The obvious initial laboratory evaluation for hypercalciuria is the 24-hour urinary calcium determination, which is generally recommended when patients are feeling well and on their usual diet. A 24-hour urine test is of little value when patients are hospitalized with acute stone attacks or other medical problems, since their diet and activity levels are different from the home conditions under which they formed the stones. The 24-hour urine sample should be collected in a standardized fashion.

In addition to calcium, other 24-hour urine chemistries that are usually performed in stone formers include the following (if possible, these chemistries should be performed together):

• Oxalate
• pH
• Volume
• Creatinine
• Specific gravity
• Phosphorus or phosphate
• Citrate
• Sodium
• Uric acid
• Magnesium
• Urea nitrogen or sulfate - These are increased in cases of high protein ingestion

Ensure that the laboratory performing the studies has a reliable methodology for urinary chemistry testing. In the United States, this most often requires sending most 24-hour urine tests to an outside reference laboratory. Because usually only a small portion of the total sample is actually sent, some potential errors are introduced if the urine sample is not handled properly or if the total volume is not measured and recorded accurately.

Instructions for proper 24-hour urine collection procedures must be reviewed carefully with every patient. (The most intelligent patients are often the ones who rush through the instructions and misunderstand, delivering grossly inaccurate specimens.)

One easy way to determine the accuracy of urine collection is to compare the total urinary creatinine collected with the expected levels. A properly performed 24-hour urine collection should show a mean urinary creatinine of 22.1 mg/kg in men and 17.2 mg/kg in women. Any values that are significantly different from the predicted ones probably represent improper or inaccurate collections.

The theoretical advantage of a formal calcium-loading test is a more precise diagnosis, which leads more quickly to definitive therapy. This is particularly useful in differentiating absorptive hypercalciuria type I and type II from renal leak hypercalciuria.

Usually, 2 separate 24-hour urine collections are gathered and analyzed for calcium while the patient is on a regular diet. This is undertaken to confirm the diagnosis of hypercalciuria, establish the baseline urinary calcium level, and determine if the degree of hypercalciuria is consistent and reproducible.

The patient is placed on a strict low-calcium diet of 400 mg of calcium and 100 mEq of sodium per day for 1 week. At the end of the week, an additional 24-hour urine sample is taken and tested for calcium and creatinine.

Fasting sample

The fasting phase begins at 9 pm and continues until 7 am the following morning. The patient voids at 7 am, and the specimen is discarded. He or she is provided with an additional 400-600 mL of water to drink. For the next 2 hours, the patient continues fasting but does not urinate again until 9 am, when he/she is asked to void. The urine is collected and analyzed for calcium and creatinine. This specimen is called the fasting sample.

Post-calcium load sample

Next, the patient is administered a 1-g oral calcium load, which usually consists of an appropriate amount of calcium gluconate. All urine that is passed from this point until 1 pm, 4 hours later, is collected and analyzed for calcium and creatinine. This specimen is called the post–calcium load sample.

Measuring calcium/creatinine ratios

The calcium/creatinine ratio is measured in the urine specimen taken on the 400-mg calcium-restricted diet and in the fasting and post–calcium load samples. In healthy people, the calcium/creatinine ratio is no more than 0.11 for the fasting sample and no more than 0.20 for the post–calcium load sample.

Interpreting the calcium-loading test

Note that in this testing series, hypercalciuria is defined as the excretion of more than 200 mg of urinary calcium per 24 hours on the 400-mg calcium-restricted diet.

Absorptive hypercalciuria

Patients with absorptive hypercalciuria normalize their urinary calcium excretion while on a fasting diet but greatly increase their urinary calcium excretion after the calcium load. Therefore, their fasting calcium/creatinine ratio is 0.11 or less, but their post–calcium load samples are greater than 0.20, demonstrating an exaggerated calcium absorption and subsequent excretion.

Patients with absorptive hypercalciuria type I typically do not normalize their urinary calcium excretion to less than 200 mg per 24 hours on the 400-mg calcium restricted diet, whereas patients with type 2 hypercalciuria do demonstrate less than 200 mg of urinary calcium per day while on that same diet.

Renal leak and resorptive hypercalciuria

Patients with either renal leak or resorptive hypercalciuria are hypercalciuric regardless of oral calcium intake. Consequently, they show more than 200 mg of urinary calcium excretion per 24 hours on the calcium-restricted diet and demonstrate high calcium/creatinine ratios in both phases of the calcium-loading test.

The serum calcium level, however, can be used to differentiate between these 2 diagnoses. Patients with renal leak hypercalciuria have low serum calcium levels, whereas those with resorptive hypercalciuria, which occurs in patients with hyperparathyroidism, are hypercalcemic. Table 3, below, provides a guide to interpreting calcium-loading tests.

Table 3. Calcium-Loading Test Interpretation Guide (Open Table in a new window)

 

Ideally, serum laboratory studies should be drawn at the same time that the 24-hour urine sample is being collected. In this way, the action of the kidneys can be viewed in the context of serum levels of these same parameters.

Minimum blood tests currently recommended for stone formers include the following:

• Calcium
• Phosphorus
• Electrolytes
• Uric acid
• Creatinine

Serum calcium studies should be repeated when initial levels are high, along with PTH levels to check for hyperparathyroidism. Serum intact PTH and ionized calcium are the most reliable in borderline cases. (Vitamin D and vitamin D3 levels are available in some laboratories and, although useful in select cases, are still considered investigational.)

Once hypercalciuria has been diagnosed, several follow-up tests should be considered to search for an underlying etiology. If excess dietary intake or gut absorption of calcium is a concern, a simple way to verify or refute this notion is to temporarily limit dietary calcium intake and retest.

After initial history and laboratory testing, including serum and 24-hour urinary chemistries as outlined previously, patients with hypercalciuria undergo a short-term trial of dietary modification. (Patients with hypercalcemia and elevated PTH levels probably have hyperparathyroidism and should be treated appropriately.)

The test diet includes a moderate dietary calcium intake of about 600-800 mg/day. This corresponds to roughly 1 good calcium meal per day and possibly 1 additional dairy snack (eg, 1 glass of milk with a second small dairy serving). Restricting dietary salt, which can increase hypercalciuria, is important. Animal protein should be ingested in moderation (< 1.7 g/kg of body weight daily), and dietary fiber should be increased. Limiting dietary oxalate is also advantageous, to avoid an increase in oxaluria due to the loss of intestinal oxalate-binding sites from the reduction in dietary calcium.

The 24-hour urinary chemistries are repeated while the patient is on this modified diet. The author tests all of the urinary chemistries and not just calcium, because of the possibility of finding new chemical risk factors caused by the dietary changes. If patients have normalized their urinary calcium solely with dietary modifications, they can then be treated successfully with this method. If they still have significant hypercalciuria, patients need medical therapy, such as with thiazides, orthophosphates, sodium cellulose phosphate, or bisphosphonates.

The cause of the failure to control urinary calcium with dietary therapy is not particularly important at this point in therapy, although it most likely is a lack of effectiveness of the prescribed diet or a lack of patient compliance.

Testing should be repeated at periodic intervals to ascertain continued patient compliance and effectiveness. Once a stable, satisfactory urinary calcium level is established, periodic 24-hour urinary testing is not necessary more often than perhaps once a year for monitoring. Difficult or unresponsive cases can be referred to an appropriate expert or tertiary care center for further evaluation and treatment.

Pediatric patients

The American Academy of Pediatrics (AAP) policy statement recommends that the daily calcium intake equal 800 mg in healthy children aged 4-8 years and 1300 mg in healthy children aged 9-18 years. If hypercalciuria is detected, place the child on a diet consisting of one-half the recommended daily allowance of calcium for 5 days and remeasure the urinary calcium excretion. If the calcium excretion normalizes, allow the child to resume a diet with an appropriate calcium content and reassess. If the urinary calcium excretion is still elevated despite reduced dietary intake, further testing is indicated.

Several imaging studies may be helpful in identifying underlying renal abnormalities or nephrolithiasis. Follow-up imaging may be needed to assess new formation, progression, or resolution of stones.

Ultrasonography

A good place to start is with ultrasonography of the urinary tract. This reveals most major malformations, nephrocalcinosis, and many stones.

Renal calyceal microlithiasis is seen as hyperechoic spots smaller than 3 mm in diameter in the renal calyces. In one study, renal calyceal microlithiasis was suggested to be present in as many as 85% of children with idiopathic hypercalciuria and did not seem to indicate an increased risk of lithiasis.[35]

CT scanning

If urinary tract stones are still a strong consideration despite normal ultrasonographic findings, a noncontrast helical CT scan is indicated. This has been shown to be a very sensitive and specific modality for identifying renal stones. The scan may also identify low mineral bone density, based o attenuation measured in Hounsfield units at the L1 vertebral body.[36]  

Radiography

A large proportion of stones is calcified; the stones may be revealed using plain radiography of the abdomen, but this technique may miss a significant number of those that are small or uncalcified.

Other radiographic studies may be indicated if metabolic bone disease is suspected or if a need to determine bone density exists.[31]

Intravenous pyelography

Medullary sponge kidney is a congenital condition that is most easily diagnosed by intravenous (IV) pyelography; no specific treatment for it exists. The condition appears as a whitish blush in the renal papilla, which is caused by the cystic dilatation of the distal collecting ducts before they empty into the renal pelvis. On CT scan, the diagnosis may require IV contrast.

Patients with medullary sponge kidney are quite likely to produce kidney stones, with about 60% developing nephrolithiasis at some point. About 12% of all stone formers are thought to have medullary sponge kidney (although the exact incidence is uncertain, ranging from 2.6-21% in various studies). Renal leak hypercalciuria is more frequently found in patients with medullary sponge kidney than in other hypercalciuric calcium-stone formers.

Histopathologic and ultrastructural examinations using light and electron microscopy have shown significant changes in the lower urinary tracts and kidneys in chronic hypercalciuria specimens.

Transitional epithelial cells of the ureters and bladder demonstrate increased cell proliferation and apical cytoplasmic vacuole formation. These effects were found to be more prominent in the proximal urinary tract epithelial cells. Deeper structures have shown increased mitotic activity, edema, vasodilatation, and separation of collagen fibers.

In the kidney, findings include interstitial edema, vasodilatation, tubular degeneration, and vacuolization of the proximal and distal convoluted tubules.

Although optimal levels of urinary calcium have not been determined, less than 125 mg of calcium per liter of urine has been suggested as a reasonable optimal goal for most calcium-stone formers.

Dietary modifications have long been the mainstay of initial therapy for hypercalciuria. All hypercalciuric patients are advised to follow reasonable dietary changes to help limit their urinary calcium loss, reduce stone recurrences, and improve the effectiveness of medical therapy. Although dietary changes alone may not always be a successful or adequate treatment, dietary excesses possibly can undermine or defeat even optimal medical therapies.

On the other hand, patients who normalize their urinary calcium excretion with dietary changes alone may still benefit from thiazides or other therapies to avoid or treat bone demineralization and osteoporosis or osteopenia.[37]

Reducing intestinal calcium inadvertently may increase oxalate absorption and contribute to hyperoxaluria, resulting in a net increase in stone formation risk rather than a reduction. This is why dietary oxalate is limited whenever calcium intake is reduced.

Vitamin D levels

As previously mentioned, many cases of absorptive hypercalciuria involve elevated vitamin D levels.[9] Vitamin D increases small-bowel absorption of calcium and phosphate, enhances renal filtration, decreases parathyroid hormone (PTH) levels, and reduces renal tubular calcium absorption, which ultimately leads to hypercalciuria.

It has been suggested that some patients have an exaggerated response to, affinity for, or sensitivity to normal levels of vitamin D and its metabolites.

Reduction

Activation of vitamin D3 takes place in the proximal renal convoluted tubule. This activation can be reduced by ketoconazole therapy.

Oral neutral phosphate therapy, limitation of vitamin D and calcium intake, and reduction of sunlight exposure can also be useful in treating excess vitamin-D levels and hypervitaminosis D (usually caused by chronic ingestion of excessive amounts of vitamin D). Dipyridamole (Persantine) reduces renal phosphate excretion and may also be useful in controlling excessive vitamin D levels and reducing vitamin D–dependent hypercalciuria.

Vitamin D is stored in fat, which means that in some cases vitamin D intoxication may persist for weeks after vitamin D ingestion has ceased. In these cases, glucocorticoids (roughly 100 mg of hydrocortisone per day or the equivalent) usually return calcium levels to normal within a few days.

The following are recommendations in the dietary treatment of hypercalciuria:

• Limit daily calcium intake to 600-800 mg/day unless otherwise instructed

• Limit dietary oxalate, especially when calcium intake is reduced; high oxalate levels are found in strong teas; nuts; chocolate; coffee; colas; green, leafy vegetables (eg, spinach); and other plant and vegetable products

• Avoid excessive purines and animal protein (< 1.7 g/kg of body weight)

• Reduce sodium (salt) and refined sugar to the minimum possible

• Increase dietary fiber (12-24 g/day)

• Limit alcohol and caffeine intake

• Increase fluid intake, especially water (sufficient to produce at least 2 L of urine per day)

Dietary modifications involving reasonable restrictions of dietary calcium, oxalate, meat (purines) and sodium, have been useful in reducing the urinary supersaturation of calcium oxalate. This effect is more pronounced in calcium oxalate ̶ stone formers with hypercalciuria than in calcium nephrolithiasis patients who are normocalciuric.

Some have suggested that the following 3 criteria need to be fulfilled for any dietary factor to be implicated in kidney stone disease:

• Intake of the dietary constituent should be increased in patients with stones compared with controls

• Restriction of the dietary factor should decrease stone formation rates

• The reason the dietary factor causes stones needs to be understood

The main dietary contributions of calcium, sodium, potassium, animal protein, fiber, alcohol, caffeine, water, oxalate, and carbohydrates are reviewed individually below. No relationship between dietary fat and hypercalciuria has been found.

Calcium intake

Avoidance of an excessively high-calcium diet is an obvious recommendation for calcium-stone formers. (See the image below for a list of calcium-rich foods.) Stone formers as a group are much more sensitive to dietary calcium than non–stone formers. For any given change in dietary calcium, urinary calcium has been shown to increase an average of only 6% in healthy controls, but it can increase 20% in calcium-stone formers. Ingestion of more than 2000 mg of calcium per day generally results in hypercalciuria and/or hypercalcemia in calcium-stone formers.

The recommended dietary calcium intake for most calcium-stone formers is about 600-800 mg/day. Avoiding a diet that is too severely limited in calcium is important, however, because otherwise a negative calcium balance may occur, with subsequent osteopenia or actual osteoporosis.

Moreover, when calcium is removed from the diet without also restricting oxalate intake, the lack of intestinal oxalate-binding sites may too much intestinal oxalate unbound and available for easy absorption. When this occurs, urinary oxalate levels rise. Proportionately, oxalate is 15 times stronger than calcium in promoting nephrolithiasis, so the net stone formation rate may actually increase if dietary oxalate intake and hyperoxaluria are not controlled. In 2 large population studies involving men and women, patients with the highest daily calcium intake were demonstrated to have significantly fewer stones (within reasonable limits) than did patients with the lowest dietary calcium levels.

Calcium citrate is recommended if calcium supplements are needed. This combination has been shown to be the most effective in limiting the new stone formation rate for those who require calcium supplements.

Any patient with kidney stones who is placed on a long-term, reduced calcium diet for any reason should have his/her bone density measured periodically, preferably in the spine. Urinary oxalate levels should also be checked regularly.

Pediatric patients

Children with hypercalciuria should be referred to a dietitian to accurately assess daily calcium, animal protein, and sodium intake. A trial low-calcium diet can be administered transiently to determine if exogenous calcium intake is contributing to the high urinary calcium. However, great caution should be used when trying to restrict calcium intake for long periods.

Because of concerns regarding poor bone matrix calcification and subsequent osteoporosis, no child should receive less than the daily recommended intake (DRI) of calcium for long periods without careful monitoring. If the dietary calcium is restricted to less than the DRI, bone density measurements and growth parameters should be taken at regular intervals to monitor the development of osteoporosis and growth retardation.

Reducing sodium and animal protein to the DRI may facilitate lowering of urinary calcium. However, the authors recommend that great caution be used when placing any child on a diet with less than the DRI of calcium and that a dietitian be consulted for assistance. If dietary changes do not provide the desired results of symptom relief, prevention of nephrolithiasis, and normalization of calcium excretion (< 4 mg/kg/day), pharmacotherapy should be initiated.

Sodium intake

A high sodium intake promotes various effects that enhance urinary calcium excretion and increase overall kidney stone formation rates. These effects include a rise in urinary pH, as well as in urinary calcium and cystine levels, and a decrease in urinary citrate excretion. Sodium and calcium share common sites for reabsorption in the renal tubules.

Urinary calcium levels

In healthy adults, high sodium intake has been associated with increased fractional intestinal calcium absorption and a rise in PTH and vitamin D3 levels. Each 100-mEq increase in daily dietary sodium raises the urinary calcium level by about 50 mg.

Enhanced renal calcium excretion from high dietary sodium consumption is thought result from an increase in extracellular fluid volume, which ultimately results in inhibition of renal tubular calcium reabsorption.

Sodium intake among stone formers has been found to be equal to or higher than the intake in control groups of non–stone formers. Moreover, patients with recurrent nephrolithiasis and hypercalciuria have been found to be particularly sensitive to the hypercalciuric actions of a high-sodium diet.

Urinary pH levels

The rise in urinary pH is caused by an increase in serum and urinary bicarbonate levels. High serum bicarbonate lowers urinary citrate excretion by a direct effect on citrate metabolism in proximal renal tubular cells.

Dietary sodium reduction

Dietary sodium reduction has been shown to decrease urinary calcium excretion in stone formers with hypercalciuria, whereas high dietary sodium is associated with increased urinary calcium excretion and low bone density. (In postmenopausal women, high sodium intake has been directly associated with low bone density in calcium-stone formers.)

Patients should be aware that most restaurant meals and fast food items, such as pizza, contain a considerable amount of sodium. In addition, ketchup, mustard, teriyaki sauce, Worcestershire sauce, soy sauce, canned soups, cold cuts, prepared vegetables, and TV dinners have large amounts of sodium. However, many prepared foods have low-sodium varieties available.

Daily dietary salt intake should be restricted to levels sufficient to keep the urinary sodium excretion below 150-200 mEq/day. Most experts recommend limiting dietary sodium (salt) in calcium-stone formers to about 100 mEq/day, but this is difficult because many people find that salt enhances the taste of food. In children, a good target range for dietary sodium intake is 2-3 mEq/kg/day.

Recommendations to reduce sodium (salt) intake include the following:

• Remove the saltshaker from the dining table; other spices, such as pepper, salt substitutes, or Mrs. Dash, can be used instead

• Use little or no salt in food preparation or cooking

• Avoid eating foods with high salt content whenever possible; most fast food is high in sodium.

• Do not add any additional salt to foods that already contain it; this would apply to most prepared or canned foods, such as soups, gravies, TV dinners, and canned vegetables

• Use fresh or frozen vegetables whenever possible; to reduce the salt content of canned vegetables, they should be drained and then rinsed with water before cooking

• Use one half or less of the specified amount of salt when following cooking recipes

• Everyone in the family should participate in the low-sodium diet so that the patient does not feel singled out

Dietary sodium needs to be controlled during any calcium testing, such as a calcium-loading test, to avoid affecting the results.

Potassium intake

Some evidence suggests that low potassium intake may be a risk factor for stones, but this has not been confirmed in all studies.[38, 39, 40] The potential influence of a low-potassium diet may be due to its relationship to sodium intake in stone formers, who generally have a higher sodium/potassium ratio than do non–stone formers.

Potassium decreases urinary calcium excretion by inducing transient sodium diuresis, which results in a temporary contraction of the extracellular fluid volume and an increase in renal tubular calcium reabsorption. Potassium also increases renal phosphate absorption, raising serum phosphate levels, which reduces serum vitamin D3, resulting in decreased intestinal calcium absorption.

Animal protein intake

High protein intake has been judged second only to vitamin D ingestion in its ability to increase intestinal calcium absorption. Other effects of a high animal protein diet include an increase in urinary oxalate and uric acid, as well as a reduction in urinary citrate.

Urinary sulfate levels can be used as a general marker of oral animal protein intake. Generally, up to 40 mg of sulfate per day is considered normal, whereas in calcium-stone formers, optimal levels would be below 25-30 mg daily.

The possible link between high animal protein intake and kidney stones has been known since at least 1973. This link was found in epidemiologic studies first in India and then in England, Germany, Austria, Japan, Italy, and, finally, the United States.[41] Known stone formers appear to be more sensitive to the stone-enhancing effects of high–animal protein diets than do non–stone forming control populations.

Animal protein affects urinary calcium mainly through its acid-loading ability. Animal protein is high in purines, which are metabolized to uric acid, contributing to the acid load. Animal protein also increases the body's acid load directly. Methionine and cystine, which contain relatively high levels of sulfur, are more common in animal protein than plant protein. When the sulfur is oxidized to sulfate, additional acid is generated. (Sulfate also can form a soluble complex with calcium in the renal tubules, reducing calcium reabsorption and contributing to hypercalciuria.)

Excess acid needs to be neutralized. This often occurs in the bone, where the extra acid is buffered, releasing calcium from the bony stores. The released calcium eventually contributes to increased urinary calcium. Moreover, acid loading directly inhibits calcium reabsorption in the distal renal tubule, which further exacerbates any hypercalciuria. The extra acid also reduces urinary citrate excretion, by enhancing citrate reabsorption in the proximal renal tubule.

Dietary animal protein reduction

Each 75 g of additional dietary animal protein raises the urinary calcium level by 100 mg/day. In one study, increasing methionine ingestion by just 6 g/day was found to raise the daily urinary calcium excretion by 80 mg. Dietary animal protein intake should be less than 1.7 g/kg of body weight per day.

An intriguing randomized study that compared the stone production rates in about 100 known calcium oxalate stone formers who differed in their dietary protein and fiber intakes found significantly fewer stones in the group with the high-fiber, low–animal protein diet.[42] Of course, the possibility exists that the fiber or just the combination of the high fiber and animal protein restriction was effective.

The first group in the study was instructed just to increase fluid intake, whereas the second group was told to increase fluid intake and consume a high-fiber, low–animal protein diet; both groups were observed for 4.5 years.[42] Additional studies are needed to determine exactly which dietary modifications are most efficacious and to eliminate variables, such as uncontrolled sodium and calcium intake, that might influence the outcome.

Oxalate excretion

An association may also exist between high animal protein ingestion and increased oxalate excretion.[43] For example, the production of glycolate, an oxalate precursor, is strongly linked to animal protein intake. However, although some investigators have found a link between high animal protein intake and increased urinary oxalate, others have not. Further studies are needed to determine the presence and significance of any such correlation.

Fiber intake

Calcium-stone formers as a group have a lower intake of dietary fiber than do healthy control populations. Dietary fiber, including oat, wheat, and rice bran, can reduce hypercalciuria and lower intestinal calcium absorption by 20-33%. As much as 24 g of dietary fiber per day may be necessary. Wheat bran, for example, is rich in oxalate, which accounts in part for its ability to bind and absorb free intestinal calcium.

However, although no significant adverse effects from increased dietary fiber have been reported, some potential risks exist. For example, dietary fiber may reduce intestinal magnesium, resulting in a deficit. Patients on a very high-fiber diet should be checked periodically for magnesium deficiency. A magnesium supplement, such as magnesium oxide, can be added if necessary.

Another potential problem is reactive enteric hyperoxaluria. Whenever intestinal calcium is reduced, fewer intestinal oxalate-binding sites are available. This leads to more free intestinal oxalate, which is absorbed more easily than oxalate bound to calcium or other agents. The increased free intestinal oxalate is absorbed and is eventually excreted in the urine, increasing urinary oxalate levels.

Because oxalate is proportionately about 15 times stronger than calcium with regard to stone promotion, limiting oxalate absorption in known stone formers makes sense. The easiest way to accomplish this is to limit dietary oxalate any time that intestinal oxalate-binding sites are reduced (such as when dietary calcium intake is reduced). Dietary oxalate can be lowered by limiting such foods as iced tea, coffee, colas, collard greens, spinach, chocolate, nuts, rhubarb, and green, leafy vegetables. Another approach is to use an alternate oxalate-binding agent, such as an iron supplement.

Alcohol intake

Acute alcohol ingestion causes hypoparathyroidism with hypercalciuria and hypocalcemia. PTH levels can drop by 70% after acute alcohol intoxication. Prolonged, moderate alcohol intake, however, eventually raises PTH levels. People with chronic alcoholism develop low serum vitamin D levels, which cause impaired intestinal calcium absorption and hypocalciuria.

A direct inhibitory effect on osteoblast activity by alcohol ingestion also appears to exist. This effect is enhanced in smokers. Urinary calcium excretion during periods of alcohol consumption can increase by more than 200% over control subjects. Osteopenia has also been linked to alcohol consumption.

Caffeine intake

Caffeine has been shown to increase urinary calcium excretion, but the clinical importance is relatively small unless very large amounts of caffeine are ingested. Ingestion of 34 ounces of caffeine is necessary to cause the loss of 1.6 mmol of total calcium. This caffeine-induced hypercalciuria seems to parallel changes in urinary prostaglandin F2-alpha (PGF2-alpha), which suggests that prostaglandins may play a role in hypercalciuria.

Fluid intake

Several studies have shown that on average, stone formers have a lower overall fluid intake than do non–stone formers. Not surprisingly, the highest incidence of kidney stone formation was in the group with the lowest overall fluid intake.

The need for a high fluid intake to increase urinary fluid volume seems obvious, because extra water decreases urinary concentration and reduces the likelihood of stones, even if the total calcium excretion is unchanged. The amount of extra water to be consumed is variable. In general, the author suggests an amount of water that produces a 24-hour urinary volume of 2000 mL or more. This amount may need to be increased in selected cases.

Citrus intake

Potassium-rich citrus fruits and juices, such as oranges, grapefruit, and cranberries, are recommended. Orange juice, for example, has natural potassium citrate. Lemon juice also has a very high citrate content, so lemonade made from real lemon juice is recommended. In contrast, lime juice contains mostly citric acid and does not increase urinary citrate substantially.

Oxalate intake

Oxalate is an organic acid found primarily in the leaves, bark, and fruit of plants. Its only known function in plants is to bind tightly with calcium. This is useful because it allows the plant to extract unwanted calcium from the internal circulation. The leaves containing the calcium-oxalate complex then can be discarded or shed by the plant. Humans absorb oxalate when oxalate-containing leaves and other vegetable products are eaten. Oxalate has no known useful function in human nutrition.

A relatively mild restriction of foods that contain high amounts of oxalate enables the body to avoid a reactive hyperoxaluria when intestinal oxalate-binding sites are reduced from a drop in oral calcium intake. Common foods with relatively high oxalate content include nuts, chocolate, colas, vegetables, rhubarb, spinach, collard greens, tea, and green, leafy vegetables.

Refined carbohydrate intake

Several large population studies have investigated the issue of the potential contribution of a high-carbohydrate diet to stone production. For example, Curhan found that carbohydrates were not a significant risk factor for stone formation in men but that they were associated with increased stone production in women. Some investigators found that stone formers tend to have a higher carbohydrate intake than non ̶ stone formers, but other researchers have failed to confirm this association.

Good evidence indicates that a high-carbohydrate diet causes an increase in urinary calcium excretion because of decreased distal renal tubular calcium reabsorption and an increase in intestinal calcium absorption. There is also evidence to indicate that excessive carbohydrate loading can increase endogenous oxalate production. This seems reasonable, because glucose is involved in oxalate metabolism through a series of chemical interactions with glyoxylate. (Glyoxylate is involved not only in the metabolism of endogenous oxalate but also in the gluconeogenesis pathway and urea metabolism.)

Ketogenic diet

The ketogenic diet is sometimes used to treat intractable seizure disorders in children. It involves an initial period of fluid restriction and starvation until ketone bodies appear in the urine. This is followed by a low-protein, low-carbohydrate, fluid-restricted diet, which tends to cause chronic metabolic acidosis with hypocitraturia and relatively low urinary volumes, which, in turn, induce kidney stone formation. Elevated uric acid levels have also been reported.

The average time from initiation of the diet until stone presentation is about 18 months, so patients who are started on this diet should be checked for stone formation at about 12 months after diet application. Fluid liberalization and citrate supplements can be used to prevent kidney stone formation in these patients.

Medical therapy is used to treat hypercalciuria whenever dietary treatment alone is inadequate, ineffective, unsustainable, or intolerable for the patient.[6] Generally, medical therapy should be used together with dietary treatment for optimal results and health.

Medications used in the treatment of hypercalciuria include the following:

• Diuretics - Thiazides, indapamide, and amiloride
• Orthophosphates - Neutral phosphate
• Bisphosphonates - Alendronate
• Calcium-binding agents - Sodium cellulose phosphate; rarely used

Combination therapy with multiple medicines is possible and recommended in unusual or difficult cases.[44] Occasionally, ketoconazole and dipyridamole are useful in lowering vitamin-D levels in selected patients.

Pharmacologic therapy in children

Dietary modification alone may not be enough to improve bone mineral density in children with idiopathic hypercalciuria.[17] Children with idiopathic hypercalciuria may have improvement in the bone mineral density z-score after treatment with potassium citrate and thiazides.[20] Thus, the indication for starting medications is evidence of bone demineralization or history of previous renal stone formation. Hydrochlorothiazide (HCTZ) and other thiazide-type diuretics are the agents most frequently used to treat hypercalciuria.

Thiazides

Thiazides are currently the mainstay of medical therapy for hypercalciuria. These agents do not directly affect intestinal calcium absorption but instead stimulate calcium reabsorption in the distal renal tubule. In addition, thiazides decrease extracellular fluid volume and increase proximal renal tubular calcium reabsorption. They generally lower urinary calcium levels by about one third, but reductions of as much as 50% or 400 mg/day have been reported. (Their hypocalciuric effect is reduced, however, if sodium intake is not limited.)[45]

Even when used in a nonselective fashion, thiazides can reduce stone recurrences from 50% (untreated) to 20% (treated) over 5 years. Thiazides are particularly well suited for hypercalciuric patients with hypertension, especially when dietary control measures alone fail to adequately normalize urinary calcium excretion.

Renal leak hypercalciuria

Thiazides are specifically indicated for renal leak hypercalciuria, in which case they not only reduce the inappropriate renal calcium loss but also lower PTH levels and correct other metabolic problems. When used appropriately in renal leak hypercalciuria, thiazides prevent secondary hyperparathyroidism and normalize vitamin D3 synthesis, calcium absorption, and urinary calcium excretion. Stone formation rates drop more than 90% in patients with renal calcium leak who are placed on long-term thiazide therapy.

Absorptive hypercalciuria

When used for absorptive hypercalciuria, thiazides are still effective, but their long-term usefulness may diminish over time as the bone stores become filled, allowing the hypercalciuria to return. Until then, bone density on thiazide therapy has been shown to increase by about 1.5% or more per year. When thiazides lose their hypocalciuric effect, which has been reported to occur, on average, about 2 years after therapy initiation, the use of an alternate regimen for a period of approximately 6 months usually restores the efficacy of the thiazide medication for use in hypercalciuria.

Other thiazide effects

Thiazides have many other effects on the body. These drugs increase serum calcium and uric acid levels while decreasing urinary citrate levels. Hyperuricemia and acute gout rarely develop in individuals receiving thiazides.

However, adverse effects occur in about one third of patients, although they are usually mild. For example, a risk of hypokalemia, hyponatremia, hypocitraturia, and magnesium loss, as well as of cholesterol level increase, exists. Moreover, thiazides tend to increase urinary volume because of their diuretic effect, a useful feature in kidney stone formers but one that can also easily lead to dehydration if oral fluid intake is not maintained.

The most bothersome clinical adverse effect is lethargy, but muscle aches, depression, decreased libido, generalized weakness, and malaise also can occur. About 20% of patients stop thiazide therapy because of these adverse effects.

Chemically, thiazides are sulfonamides and generally should not be used or should be used cautiously in patients with a history of sulfa allergy. Drug interactions have been reported when thiazides are used together with alcohol, barbiturates, narcotics, antidiabetic drugs, steroids, pressor amines, muscle relaxants, lithium, and nonsteroidal anti-inflammatory agents (NSAIDs).

Most patients on thiazides do not need any potassium supplementation, but potassium and electrolyte levels need to be checked periodically. Because of the risk of hypokalemia and hypocitraturia, potassium citrate supplements are often prescribed along with thiazides in calcium-stone formers.

Thiazide dosing

Thiazide dosage depends on the specific medication used. Once-a-day drug preparations are usually preferred because of better patient compliance and tolerability. Trichlormethiazide (Naqua) is administered as a 2- or 4-mg daily tablet. Indapamide (Lozol) can be administered in either 1.25- or 2.5-mg doses once a day.[46]

If a potassium-sparing combination is desired, those that contain triamterene, such as Dyazide, should be avoided, because triamterene can form its own stones. Moduretic, which uses amiloride as a potassium-sparing diuretic, would be recommended. Amiloride does not form stones and has a mild hypocalciuric effect of its own.

Orthophosphates

In 1962, Howard et al first suggested the use of orthophosphate therapy (K-Phos Neutral, Neutra-Phos K, Uro-KP-Neutral) as a preventive treatment for kidney stones.[47] Stone cessation rates of more than 90% have been reported with this agent.

Orthophosphate therapy has been shown to decrease urinary calcium excretion by lowering serum vitamin D3 levels (which reduces intestinal calcium absorption) and by increasing renal tubular calcium reabsorption. Orthophosphates may also have some intestinal calcium-binding capability, but the limited studies conducted on this issue have not confirmed this effect.

Overall, orthophosphates lower 24-hour urinary calcium excretion by about 50% in patents with absorptive hypercalciuria and by about 25% in patients with other hypercalciuric states. No apparent effect on PTH levels exists in healthy individuals. Uncontrolled studies have shown kidney stone remission rates of 75-91% in recurrent stone formers on long-term orthophosphate therapy.

Orthophosphates also increase urinary stone inhibitors such as citrate and, particularly, pyrophosphate. Many patients (40% in one series) have even noted a loss of stone mass while on orthophosphate therapy. Orthophosphates are particularly useful in cases of absorptive hypercalciuria type III (renal phosphate leak) and when thiazides cannot be used or are ineffective.

The use of orthophosphates with thiazides is extremely effective in controlling urinary calcium excretion and reducing new kidney stone formation rates, particularly in hypercalciuric calcium oxalate stone formers.

About 60% of all dietary phosphate is absorbed in the duodenum and jejunum; 65% percent of the absorbed phosphate is excreted by the kidneys, and the rest is eliminated through the intestinal tract by secretion in the ileum and colon.

Adverse effects of orthophosphates

Side effects of orthophosphate therapy include diarrhea, bloating, and gastrointestinal upset. These usually are worst during the first 2 weeks of therapy, after which they tend to diminish. The medication must be taken 3-4 times per day, which reduces patient compliance.

Do not administer to patients with struvite (magnesium ammonium phosphate) stones or to patients with renal failure, because they can develop soft-tissue calcifications. Use cautiously in patients with a history of predominantly calcium phosphate stones or in whom the urinary pH is consistently alkaline (which promotes calcium phosphate precipitation and stone formation). In addition, patients with a previous history of gastrointestinal problems generally do not tolerate orthophosphate therapy well.

Currently available orthophosphate preparations tend to be rapidly dissolving, which increases the gastrointestinal upset and diarrhea. A slow-release form of potassium phosphate (UroPhos-K) is currently awaiting United States Food and Drug Administration (FDA) approval. This new preparation uses a wax matrix to slow the release of phosphate, reducing its adverse effects. It contains no sodium and is designed to modify urinary pH to 7.0, which discourages the formation of calcium phosphate crystals and calculi.

In a randomized, double-blind study, patients with absorptive hypercalciuria type I who were administered the slow-release phosphate preparation had an average daily urinary calcium level of only 171 mg; controls averaged levels of 288 mg/day.[48] Urinary inhibitor levels of citrate and pyrophosphate were increased in the group treated with orthophosphate, and no gastrointestinal adverse effects were reported.[48]

Orthophosphate dosing

To be effective, orthophosphates must be taken at regular intervals and in sufficient amounts. The neutral salt tends to have fewer adverse effects and is more effective than other preparations. Optimal levels of neutral orthophosphate are 1-2.5 g/day. Orthophosphate preparations for calcium-stone formers should be sodium free.

Bisphosphonates

Bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), and ibandronate (Boniva) have become useful in the treatment of hypercalciuria and hypercalcemia. These agents are particularly helpful in cases of hyperparathyroidism in which parathyroid surgery cannot be performed or medical therapy is desired.

Bisphosphonates are analogues of pyrophosphate with a high affinity for the hydroxyapatite of bone, especially in areas of rapid turnover and bone resorption. These drugs inhibit osteoclast activity, which causes a net increase in bone density, calcium deposition, and mineralization. Preferential binding to osteoclasts is roughly 10 times greater than osteoblastic binding.

Although bisphosphonates are clearly helpful in cases of overt hypercalcemia and hyperparathyroidism, their usefulness in the long-term treatment of hypercalciuria in recurrent stone formers is unproved. These agents may be most useful in hypercalciuric stone formers in whom a history of decreased bone density or other evidence of osteoporosis, such as elevated osteocalcin levels, is present. Combination therapy with thiazides would be expected to be particularly beneficial. Bisphosphonates can also be helpful in difficult cases of hypercalciuria when other measures are unsuccessful or poorly tolerated.

Bisphosphonate with thiazide

In a study of 70 patients with recurrent lithiasis, hypercalciuria, and bone-density loss, Arrabal-Polo et al found that after 2 years of treatment the patients receiving a combination of bisphosphonate and thiazide had a significantly greater decrease in calciuria and improvement in bone density than did patients treated with bisphosphonate alone. Half of the patients in the study were treated with 70 mg/wk of alendronate, while the other 35 patients were treated with a combination of 70 mg/wk of alendronate and 50 mg/day of hydrochlorothiazide.[37]

Sodium cellulose phosphate

Sodium cellulose phosphate (Calcibind) is an extremely effective intestinal calcium-binding agent. This agent removes about 85% of the available intestinal calcium from the digestive tract and prevents its absorption. Sodium cellulose phosphate is about 11% sodium and has a calcium-binding capacity of 1.8 mmol of calcium per gram of cellulose phosphate. In the digestive tract, the sodium ion is exchanged for calcium, which is then excreted bound to the cellulose in the stool.

When sodium cellulose phosphate is used as a therapy, supplemental magnesium and dietary oxalate restriction are recommended, because the cellulose phosphate binds magnesium as well as calcium and results in a magnesium deficiency if supplemental magnesium is not supplied.

The need for the dietary oxalate restriction (primarily of tea, cola, coffee, chocolate, nuts, and green, leafy vegetables) is due to the lack of available intestinal calcium that the cellulose therapy creates. With so much intestinal calcium bound to the cellulose, intestinal oxalate-binding sites are severely lacking. This leaves an excess of free, unbound intestinal oxalate available for absorption, which then increases oxaluria.

Unfortunately, sodium cellulose phosphate causes a reduction in absorbed calcium, which makes it useful against hypercalciuria but may cause a negative calcium balance and subsequent reduction in bone density.

The drug may nonetheless have a role in the diagnosis of hypercalciuria if used in a brief therapeutic trial and it may be useful in selected cases of absorptive hypercalciuria type I when other therapies are ineffective. The benefits of its use must be judged sufficient to justify the risks. Other treatments, such as thiazides and bisphosphonates, can be used to prevent unnecessary bone demineralization and limit the dosage of cellulose required, minimizing the adverse effects and complications associated with sodium cellulose phosphate.

Dipyridamole

Dipyridamole (Persantine) is a platelet adhesion inhibitor and vasodilator. It is usually used to lengthen platelet survival time and reduce the incidence of thromboembolic phenomenon after heart valve replacement surgery. Researchers have found that dipyridamole reduces renal phosphate excretion, which increases the serum phosphate level, resulting in decreased activation of vitamin D3 and then in reduced hypercalciuria. This is useful in patients with vitamin D–dependent hypercalciuria, such as the renal phosphate leak (absorptive hypercalciuria type III) form, especially when orthophosphates are not tolerated or cannot be used.

No direct effect on urinary calcium excretion is present. Adverse effects are minimal, but the medication must be taken frequently. Dipyridamole has been shown to reduce urinary calcium excretion in patients with vitamin D–dependent renal phosphate leak on a long-term basis.[49, 50]

Parathyroid hormone

PTH or its amino-terminal fragment has been shown stimulate bone formation and resorption without causing hypercalcemia. Once-daily injections of PTH tend to maximize the osteoblastic activity while minimizing bone resorption for a net gain in bone mass. This treatment was tested in a large, multicenter trial of 9347 postmenopausal women with osteoporosis. All of the patients received vitamin D and calcium supplementation.[51]

The group that received the PTH injections had reductions in fracture rates of 65-86%.[51] Urinary calcium excretion was increased only slightly (roughly by 30 mg of calcium per day in the treated group), but the overall incidence of hypercalciuria was no different between the PTH-treated group and the patients who received placebo. This most likely was due to the single daily dosing of the PTH, which minimized the hypercalcemic and hypercalciuric responses.[51]

In short, this is a promising avenue of research for osteoporosis and osteopenia that appears to have no significant effect on hypercalciuria or calcium stone formation. Further research on this and other osteoblast-enhancing therapies holds promise in treating osteoporosis and, possibly, select cases of hypercalciuria.

Absorptive hypercalciuria type I

Treatment of absorptive hypercalciuria type I can be very difficult due to the severity of the intestinal calcium hyperabsorption. Therapy primarily consists of moderate dietary calcium restriction, thiazides, and orthophosphates.

Thiazides

Thiazides, such as trichlormethiazide (Naqua) or indapamide (Lozol), substantially reduce urinary calcium excretion, but they do not correct the primary defect, which is increased, uncontrolled intestinal calcium absorption. Thiazides may lose their hypocalciuric effect over time and cause hypokalemia, hypocitraturia, and increased uric acid levels.

Orthophosphates

Orthophosphates, such as K-Phos Neutral, Neutra-Phos K, and Uro-KP-Neutral, lower serum vitamin D3 levels and reduce urinary calcium excretion. These agents are roughly equal to thiazides in their ability to reduce urinary calcium and prevent recurrent calcium stone formation. Because of the need for frequent dosing and various gastrointestinal adverse effects, orthophosphates are not the preferred agents when thiazides alone are sufficient and well tolerated. The combination of thiazides and orthophosphates used together may be necessary in difficult or resistant cases of absorptive hypercalciuria type I.

Sodium cellulose phosphate

Sodium cellulose phosphate is an extremely potent intestinal calcium-binding agent that was previously recommended as a primary therapy for absorptive hypercalciuria type I. Concerns about creating a negative calcium balance, bone demineralization, and other adverse effects currently limit its usefulness. These risks have shifted therapy away from this agent in favor of thiazides and orthophosphates.

When sodium cellulose phosphate therapy is used, supplemental magnesium is recommended. This is because the cellulose phosphate binds intestinal magnesium as well as calcium. Supplemental magnesium, therefore, must be administered to patients on cellulose phosphate to avoid magnesium depletion.

Oxalate

Dietary oxalate restriction is also recommended, due to the lack of free intestinal calcium that is created with cellulose phosphate therapy. This removes the primary intestinal oxalate-binding agent (calcium) from the digestive tract and leads directly to increased free intestinal oxalate absorption with subsequent hyperoxaluria.

Additional treatments

Other therapies include the use of increased dietary fiber, such as rice, oat, and wheat bran supplements, as relatively mild intestinal calcium binders. Bisphosphonates, such as alendronate (Fosamax), increase bone deposition of calcium, thus removing it from the circulation before it can be excreted. This improves bone calcium density and helps to reduce urinary calcium levels.

Optimization of all other urinary stone risk factors is highly recommended. This would include increasing urinary volume, reducing dietary oxalate, and using potassium citrate as needed. Purine intake should be restricted if uric acid levels are elevated.

Pentosan polysulphate (Elmiron) may potentially have use in difficult calcium oxalate stone cases. Although it has no effect specifically on calcium excretion, pentosan polysulphate appears to reduce calcium oxalate crystallization and crystal aggregation, which reduces new kidney stone formation rates.[52, 53, 54]

Absorptive hypercalciuria type II

Treatment is generally with dietary modifications, whenever possible, including restriction to a moderate calcium intake. Overly strict dietary calcium reductions are discouraged, however, because of the possibility of creating a negative calcium balance and osteoporosis. Moreover, dietary calcium reduction causes a lack of oxalate-binding sites in the intestinal tract, increasing urinary oxalate levels and potentially negating the benefit of urinary calcium reductions.

If patients decide that they cannot follow the recommended calcium diet or if the dietary changes are ineffective, orthophosphate and/or thiazide therapy is recommended. Some concern exists that when thiazides are used in these cases on a long-term basis, the hypocalciuric effect may become attenuated as the calcium stores in the bones become filled. If this problem occurs, it generally arises at least 2 years after treatment initiation. A period of alternate therapy, such as treatment with sodium cellulose phosphate or orthophosphates, can be used temporarily for approximately 6 months, and then the thiazides can be restarted.

No such problem exists with orthophosphate therapy, but current formulations need to be taken frequently and often have gastrointestinal adverse effects, such as diarrhea, bloating, and indigestion.

Absorptive hypercalciuria type III

Because the specific renal defect cannot be corrected in this condition, which is also known as renal phosphate leak hypercalcemia, the most effective treatment is oral orthophosphate therapy. This corrects the hypophosphatemia and limits the amount of vitamin D3 activation that occurs.

The optimal orthophosphate supplement may be a slow-release neutral potassium phosphate (UroPhos-K), which has not yet been approved by the FDA. Dipyridamole (Persantine) also has been shown to increase the renal phosphate excretion threshold, which raises serum phosphate, normalizes high vitamin-D levels, and reduces hypercalciuria.[49]

Treatment of renal leak hypercalciuria is primarily with thiazides. These medications specifically return calcium from the renal tubule to the serum, generally reduce urinary calcium levels by 30-40%, and eliminate secondary hyperparathyroidism. This hypocalciuric effect of thiazides is diminished or eliminated if dietary sodium is not restricted.

Adverse effects of thiazides include an increase in uric acid and a decrease in urinary citrate; they also can cause hypokalemia. To correct these potential problems, potassium citrate often is administered to patients on long-term thiazide therapy. When used appropriately in renal leak hypercalciuria, thiazides work extremely well and do not appear to attenuate their hypocalciuric effect over time. Chemically, thiazides are sulfonamides and should be used cautiously, if at all, in patients with a known sulfa allergy.

Preferred forms of thiazide therapy include trichlormethiazide (Naqua) 2-4 mg/day and indapamide (Lozol) 1.25-2.5 mg/day. These 2 medications can be administered just once a day and tend to carry fewer adverse effects than do shorter-acting thiazides. Potassium citrate is often added to the thiazide therapy to prevent hypokalemia and to increase urinary citrate levels. The dosage of potassium citrate should be adjusted based on serum potassium and 24-hour urinary citrate levels.

The recommended treatment for patients with hyperparathyroidism who produce calcium stones is parathyroid surgery. For individuals who are unable or unwilling to undergo the surgery, medical treatment is available. Bisphosphonates are the medical agents of choice, because they correct the hypercalcemia, reduce bone resorption, and lower urinary calcium excretion. Orthophosphates and calcitonin can be used for these patients as well.

Thiazides should not be used in patients with hyperparathyroidism, even when hypercalciuria is present, because of the risk of increasing the hypercalcemia. (The only exception would be a short course for testing purposes in carefully selected patients, inducing a mild, controlled increase in serum calcium while monitoring the PTH level to see if it drops appropriately or is autonomous.)

Estrogens should be used in postmenopausal women with hypercalciuria whenever possible. Their action is similar to that of the bisphosphonates.

PTH actually stimulates osteoblastic and osteoclastic cells. High, sustained levels of PTH result in a net loss of calcium and bone mass, but research indicates that intermittent injections of PTH in animals and humans produce a net increase in osteoblastic activity and bone mass. This intermittent therapy, which appears promising as a potential treatment for osteoporosis, does not seem to significantly affect hypercalciuria or serum calcium levels.

Calcimimetic drugs

Calcimimetic agents, such as cinacalcet (Sensipar), are a new and exciting modality being studied for the medical treatment of hyperparathyroidism.[55, 56, 57, 58, 59] Activation of specific calcium receptors on parathyroid cells by these calcimimetic agents inhibits PTH secretion. Essentially, the drug increases the sensitivity of calcium-sensing receptors.

Therapy with calcimimetic agents has already been used successfully in hyperparathyroid patients, particularly in those with chronic renal failure who were on dialysis and had secondary hyperparathyroidism. A 50-60% decrease in circulating PTH and a mild decrease in serum calcium levels have been reported, but the hypercalciuria is not significantly affected. The agents may be also useful in resistant hypercalcemias and parathyroid cancers, as well as in the medical treatment of hyperparathyroidism.

Vitamin D

Paricalcitol is a vitamin-D analogue that was developed to help prevent and treat secondary hyperparathyroidism in patients with chronic renal failure. Actual vitamin D also suppresses parathyroid hormone levels but tends to cause hypercalcemia and hyperphosphatemia. Vitamin-D analogues such as paricalcitol are able to significantly reduce PTH levels without significantly changing serum levels or urinary excretion of either calcium or phosphorus.

The issue of hypercalciuria treatment can be complicated by the presence of osteoporosis or osteopenia. A serum calcium determination is the first step in identifying patients with possible hyperparathyroidism. The identification of elevated serum calcium levels should be followed up with a simultaneous PTH level to diagnose hyperparathyroidism.

Even without a history of calcium kidney stones, a 24-hour urine test to check urinary calcium excretion can be useful in the management of osteoporosis. If the patient has hypercalciuria (and hyperparathyroidism has been eliminated by serum testing), the patient will benefit from thiazide therapy, which increases serum calcium and reduces excessive urinary calcium excretion.

Estrogen should be used, if appropriate, in postmenopausal women. Bisphosphonates, such as alendronate (Fosamax), risedronate (Actonel), or ibandronate (Boniva), should be used in men and in women when estrogen cannot be used.

Calcium supplementation can be helpful in osteoporosis, but urinary calcium levels need to be monitored carefully in calcium stone–forming patients, especially if they demonstrate overt hypercalciuria.

Studies have shown that, for most postmenopausal women with osteoporosis but with no previous history of calcium kidney stone disease, the overall risk of calcium nephrolithiasis does not increase significantly with the use of supplemental calcium or of combined calcium with calcitriol, despite an increase in urinary calcium excretion.[26]

Calcium citrate is recommended for calcium-stone formers in this situation, because its citrate component limits any increase in stone formation rate. Medical therapy, including thiazides, should be started first; calcium citrate can then be added until the urinary calcium level reaches the normal upper limit (250 mg of calcium per 24 hours or 4 mg of calcium per kilogram of body weight).

Other treatment for possible urinary stone risk factors, such as uric acid, citrate, volume, phosphate, sodium, magnesium, and oxalate, should be optimized.

The treatment of hypercalciuria is important not only in the reduction of future kidney stone formation and the diagnosis of possible underlying metabolic disease but also in the prevention of bone demineralization and osteoporosis.

Every physician who treats patients with hypercalciuria may not be able to become an expert on this condition or its therapy. Physicians who are uncomfortable treating such patients should not hesitate to refer them, especially if the patients are highly motivated and interested in treating their calcium problem. A difficult or high-risk case that is resistant to dietary and standard medical therapy in a motivated patient would be a good case to refer to a physician expert or tertiary care center with expertise in this area.

Patients with hyperparathyroidism should be referred to a physician skilled in dealing with this condition. Patients with overt renal failure need the assistance of a nephrologist.

Every patient with at least 1 kidney stone should be offered the opportunity for stone prevention testing and prophylactic therapy. This is most critical in children and in patients with renal failure or a single functioning kidney. For most adult patients, this is optional, but testing and preventive treatment needs to be offered and the consequences of additional preventable stones reviewed.

Even if patients refuse preventive testing and prophylactic therapy, they should be advised of the potential risks of recurrent stones and be provided with general dietary advice regarding moderation of calcium, animal protein, sodium, purines, and oxalate ingestion. All patients with history of kidney stones need to increase their fluid intake. Patients with hypercalciuria must be cautioned about the risks of an overly severe reduction in oral calcium intake, which actually can increase their risk of new stone formation.

Osteocalcin monitoring

An intriguing suggestion has been made that osteocalcin levels be used before and after dietary calcium restriction.[60] Osteocalcin is released during periods of bone resorption, which would be expected with renal leak hypercalciuria, hyperparathyroidism, or any dietary calcium ̶ resistant hypercalciuria. Patients with elevated osteocalcin levels theoretically would benefit from thiazide and/or bisphosphonate therapy to prevent bone demineralization over time, even if their hypercalciuria is well controlled with dietary therapy alone. Estrogen can be added in women.

Repeat 24-hour urine testing and appropriate blood determinations are needed until the patient’s hypercalciuria is controlled and stable. Once this occurs, repeat testing can be performed less often. Testing once per year is considered reasonable for patients whose stone production and level of hypercalciuria are controlled. If hypercalciuria is not well controlled, appropriate adjustments can be suggested and testing should be repeated more frequently.

As patients modify their diets, they may substitute new foods and beverages for the ones previously restricted. These new dietary items can have an unpredictable effect on the various stone risk factors. Therefore, follow-up 24-hour urine tests should include all of the major stone risk factors and not just calcium.

Routine radiographs, such as an abdominal flat plate (also called KUB [for kidneys, ureters, and bladder]) or plain renal tomograms, are useful for finding any newly formed stones. This is particularly important and helpful in patients whose hypercalciuria is poorly controlled.

Some patients pass additional stones and assume their treatment plan is not working when, actually, these stones had already formed before testing or treatment began. Establishing the number, size, and location of any existing calculi before testing or treatment begins is important. In this way, patients can be reassured that their treatment plan is successfully controlling their hypercalciuria.

Patients with hypercalciuria who have known osteopenia, osteoporosis, or bone demineralization and those with untreated or unresponsive hypercalciuria should have periodic bone density measurements, especially if they are aged 50 years or older.

Pediatric patients

Children with hypercalciuria should be followed at regular intervals by a pediatric nephrologist. Twenty-four–hour urine collections for calcium clearance should be monitored at 6-month intervals. Growth parameters should be followed in all children, and bone mineralization should be measured if less than the DRI of calcium is consumed. Serum electrolytes, uric acid, and lipid panels should be monitored in children on thiazide therapy.

Parathyroidectomy should be considered for patients with primary hyperparathyroidism. In a retrospective cohort study of 100 patients with primary hperparathyroidism who underwent curative parathyroidectomy, 84 patients (76.4%) experienced a 24-hour urinary calcium level reduction of at least 20%. Of the patients who had confirmed hypercalciuria, 79% had urinary calcium levels return to normal range postoperatively.[61]  

Thiazides are specifically indicated for patients with renal leak hypercalciuria, in whom they not only reduce the inappropriate renal calcium loss but also lower parathyroid hormone (PTH) levels and normalize other metabolic processes.[62, 63]

These agents can also be used to treat absorptive hypercalciuria, but their long-term usefulness may diminish over time, requiring approximately 6 months of an alternative regimen before they are effective again.

Thiazides also increase serum calcium and uric acid levels while decreasing urinary citrate levels. Hyperuricemia and acute gout rarely develop in individuals receiving thiazides.

Because thiazide therapy carries the risk of inducing hypokalemia and hypocitraturia, potassium citrate supplements are often prescribed with thiazides in calcium-stone formers.

Class Summary

Thiazide diuretics are used in patients with hypercalciuria that is not adequately controlled with dietary modifications alone. Thiazide diuretics are also used upon evidence of bone demineralization if a patient’s diet includes less than the DRI of calcium.

Thiazides work by increasing calcium reabsorption at the level of the distal renal tubule and, thus, lowering urinary calcium. Hydrochlorothiazide (HCTZ) is the agent most commonly used, but other thiazide or thiazide-type diuretics can be administered, including trichlormethiazide and chlorthalidone.

Despite the common use of thiazides, no long-term clinical trials have been performed documenting their efficacy and safety in children. Parents should be notified of this and understand the risks and benefits before initiating therapy.

Hydrochlorothiazide (Microzide)

HCTZ is the most frequently used thiazide in the reduction of urinary calcium levels.

Chlorthalidone

This agent reduces calcium excretion through direct tubular effects.

Class Summary

Potassium citrate is metabolized to bicarbonates, which increase urinary pH levels by increasing the excretion of free bicarbonate ions without producing systemic alkalosis when administered in recommended doses.

Potassium citrate (Urocit K)

This is an alkalinizing agent indicated for the treatment of systemic metabolic acidosis, urinary alkalinization, and hypocitraturia. Potassium citrate is administered orally and metabolized to bicarbonate in the liver.

Class Summary

Drugs in this class increase bone deposition of calcium, thus removing it from the circulation before it can be excreted. This improves bone calcium density and helps to reduce urinary calcium levels. Bisphosphonates, such as alendronate (Fosamax), risedronate (Actonel), or ibandronate (Boniva), should be used in men and in women when estrogen cannot be used.

Pamidronate (Aredia)

The main action of pamidronate is to inhibit the resorption of bone. The mechanism by which this inhibition occurs is not fully known. The drug is adsorbed onto calcium pyrophosphate crystals and may block the dissolution of these crystals, also known as hydroxyapatite, which are an important mineral component of bone. Evidence also suggests that pamidronate directly inhibits osteoclasts.

Alendronate (Fosamax)

Alendronate is a potent third-generation bisphosphonate that principally acts by inhibiting osteoclastic bone resorption.

Ibandronate (Boniva)

Ibandronate inhibits the resorption of bone, increases bone mineral density, and reduces the incidence of vertebral fractures.

Risedronate (Actonel, Atelvia)

Risedronate is a potent aminobisphosphonate that principally acts by inhibiting osteoclastic bone resorption. It is recommended for the treatment of Paget disease.

Etidronate (Didronel)

Etidronate was the first bisphosphonate studied in humans and approved in the United States (1978) for the treatment of Paget disease. It is the least potent of currently available bisphosphonate drugs.

Tiludronate (Skelid)

Tiludronate is a sulfur-containing bisphosphonate of intermediate potency between etidronate and newer nitrogen-containing bisphosphonates. No food, indomethacin, or calcium should be ingested within 2 hours before and 2 hours after. A 3-month posttreatment evaluation follows.

Class Summary

Estrogens should be used in postmenopausal women with hypercalciuria whenever possible. Their action is similar to that of the bisphosphonates.

Estrogens are used to increase the serum estrogen level, which, in turn, decreases the rate of bone resorption. The lowest effective dose at the shortest duration necessary should be used. Estrogen therapy reduces bone resorption and retards or halts postmenopausal bone loss. Estrogen therapy is no longer a first-line approach for the treatment of osteoporosis in postmenopausal women because of increased risk of breast cancer, stroke, venous thromboembolism, and coronary disease. The FDA recommends that other approved nonestrogen treatments be considered first for osteoporosis prevention.

Conjugated estrogens (Premarin)

Estrogens can directly affect bone mass through estrogen receptors in bone, reducing bone turnover and bone loss. Estrogens can also indirectly increase intestinal calcium absorption and renal calcium conservation and, therefore, improve calcium balance. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom nonestrogen medications need to be carefully considered.

Estradiol (Estrace, Estraderm, Menostar, Vivelle-Dot, Climara, Estraderm, Alora)

Estradiol restores estrogen levels to concentrations that induce negative feedback at gonadotropic regulatory centers; this, in turn, reduces the release of gonadotropins from the pituitary. Estradiol increases the synthesis of DNA, RNA, and many proteins in target tissues; it also inhibits osteoclastic activity and delays bone loss. In addition, evidence suggests a reduced incidence of fractures.

Estropipate (Ortho-Ext 0.625, Ortho-Est 1.25)

Estropipate is indicated for the prevention of osteoporosis. When estrogen therapy is discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal period. No evidence suggests that estrogen replacement therapy restores bone mass to premenopausal levels.