NDT Advance Access originally published online on November 15, 2005
Nephrology Dialysis Transplantation 2006 21(1):29-32; doi:10.1093/ndt/gfi268
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What serum calcium can tell us and what it can't
Paris-Descartes University and School of Medicine, Paris, F75006 France, INSERM U652, Paris, F75006; and Department of Physiology, Hôpital Européen Georges Pompidou, Paris, F75015 France
Correspondence and offprint requests to: Pascal Houillier, MD, PhD, Département de Physiologie, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France. Email: pascal.houillier{at}egp.aphp.fr
Keywords: calcium balance; extracellular fluid; serum calcium
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Introduction |
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Top
Introduction
Calcium metabolism in healthy...Disorders in serum [and extracellular fluid (ECF)] calcium concentration are frequent events in clinical practice. Even more frequent are the disorders in calcium balance that occur in a large variety of diseases or pathological conditions. However, whereas it is easy to measure serum calcium concentrations, it is far more difficult to measure calcium balance and body calcium content; therefore, many clinicians are tempted to evaluate the status of calcium balance from the value of serum calcium concentration. As explained in this review, not only is it impossible to predict calcium balance based on serum calcium, but doing so may lead to inadequate and, sometimes, deleterious decisions for the patient.
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Calcium metabolism in healthy adults |
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The body of a healthy adult contains
25 000 mmol (1 kg) of calcium, of which >99% is part of the mineral component of bone and <1% (20 mmol) is in the ECF. The calcium homeostatic system targets not so much the total body calcium content but rather the concentration of ECF calcium. In a given healthy individual, this value is remarkably stable over time, never deviating by >2% from its set point [1]. Under normal conditions, both ECF calcium concentration and body calcium content are maintained at fixed values; however, under pathological conditions, the maintenance of ECF calcium concentration may require an alteration in calcium balance and body calcium content. |
Calcium fluxes in normal adults |
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Three organs can create calcium movement into or out of the ECF: the intestine, the bone and the kidney. However, intestinal calcium absorption after a meal does not contribute to maintaining serum calcium at its set point. On the contrary, it induces a transient increase in serum calcium. Nevertheless, adequate dietary calcium intake and normal intestinal calcium absorption are essential to maintain normal calcium balance and normal bone stores. On Western diets, faecal loss due to non-reabsorbed intestinal fluid calcium never falls below
150 mg (3.75 mmol) daily [1] and urinary loss never falls below 100 mg (2.5 mmol) daily. Because of such significant obligatory losses, the minimal dietary calcium requirement, based on balance studies in normal subjects, is 600 mg (15 mmol) per day [2].
The ECF calcium concentration is dependent, in the fasting state, on an amount of calcium released from bone that matches the obligatory loss of calcium in urine. When dietary calcium intake is inadequate (<600 mg/day in young adults) and/or intestinal calcium absorption abnormal, the serum calcium level can be kept stable only at the cost of a gradual depletion of bone calcium stores. For instance, a daily calcium intake of 
400 mg (10 mmol) results in a loss of 1–4 mmol (40–160 mg) of calcium from the body each day [1]. Thus, although intestinal calcium absorption does not regulate serum calcium levels, it provides the calcium needed to maintain bone calcium mass within the normal range: the calcium lost in the fasting state is replaced by absorption of an identical amount of calcium from the gut lumen. Consequently, in healthy individuals who have completed their growth, and with the exception of pregnant or breastfeeding women, when dietary calcium intake and intestinal calcium absorption are normal, the amount of calcium excreted in urine is equal to the net amount absorbed by the intestine.
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Maintaining serum calcium at its equilibrium value |
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The regulation of serum calcium involves mechanisms that keep the calcium level at its set point and mechanisms that correct variations from the set point.
The bone and kidney are the two organs that determine the serum calcium level in the fasting state. To maintain serum calcium levels constant under this condition, the bone releases an amount of calcium identical to the amount excreted in the urine during a given period of time. The calcium equilibrium level (set point) is the value for which the net calcium inflow, from the bone pool to the extracellular compartment, matches the net outflow, from the extracellular compartment to the urine. This match is primarily achieved by an adequate release of parathyroid hormone (PTH) that increases the release of calcium from bone tissue and limits the renal loss of calcium through an enhancement of the tubular reabsorption of filtered calcium in the ascending loop of Henle and in the distal tubule [3].
Importantly, this system also provides an efficient means to correct deviations from the calcium set-point. In the fasting state, serum calcium tends to decrease below its set point because calcium is lost in the urine. The parathyroid glands respond immediately by releasing larger amounts of PTH, which, in turn, stimulates calcium release from bone tissue and calcium reabsorption from the renal tubule, allowing serum calcium to return to the set point. Bone calcium release is rapid, of marked amplitude, but of limited capacity since only superficial bone layers are supposed to be involved. These characteristics are well suited to the rapid correction of serum calcium levels [4]. Calcium release is different from bone remodelling, which involves tight coupling between synthesis of organic bone matrix by osteoblasts and destruction of mature bone by osteoclasts: at the scale of the entire skeleton, and at a given point in time under normal conditions, the amount of newly formed bone is equal to the amount of destroyed bone. It follows that bone remodelling does not produce a net inflow of calcium from the bone pool to the extracellular compartment and, therefore, does not help to maintain the serum calcium level at the set point. Finally, bone remodelling is a slow process of limited amplitude but considerable capacity, since it potentially involves the entire skeleton.
Conversely, a rise in serum calcium decreases the secretion of PTH, leading to a reduction in the amounts of calcium released from bone and reabsorbed in the kidney and, finally, to the normalization of serum calcium.
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Mechanisms underlying abnormalities in serum calcium |
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As indicated above, the equilibrium value of ECF calcium depends on the balance between the amount of calcium entering the ECF (mainly from bone) and the amount of calcium leaving the ECF (in urine). Consequently, an increase in the ECF calcium value may result from (i) a decrease in the ability of the kidney to excrete calcium entering the ECF, the amount of calcium entering the ECF being normal or slightly increased and (ii) an increase in the inflow of calcium into ECF of sufficient magnitude to overwhelm the ability of the kidney to excrete the required amount of calcium in the urine.
Schematically, the first condition is typical of calcium disorders related to a primary alteration in PTH secretion (primary hyperparathyroidism, familial benign hypercalcaemia). Under this condition, the main determinant of the change in ECF calcium concentration is the increase in renal tubular calcium reabsorption [5,6]. The second condition depicts what occurs in patients with malignancy-related hypercalcaemia in whom an increased net bone calcium release is the main determinant of hypercalcaemia. The increase in net bone resorption may be very severe and responsible for a major increase in serum calcium concentration. Usually, a serum calcium concentration >3.5 mmol/l is more suggestive of malignancy than of a parathyroid disorder, this latter condition being usually responsible for mild to moderate hypercalcaemia.
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ECF calcium concentration does not depend on calcium balance |
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From what is described above, it appears that ECF calcium concentration and calcium balance (or body calcium content) are largely independent variables. At least two reasons may explain this independence.
The first one is that intestinal calcium inflow does not determine the equilibrium ECF calcium concentration, but is a very important determinant of calcium balance and body (bone) calcium content. In fact, any defect in net intestinal calcium inflow into ECF is associated with a negative calcium balance which, if sustained, may be responsible for a significant and measurable loss in bone (and, therefore, body) calcium content. Conversely, an increase in calcium intake and intestinal calcium inflow can make the calcium balance positive and exert a protective action on mineral bone content. Many randomized clinical studies have assessed the effect of an increase in calcium intake in patients with post-menopausal osteoporosis (reviewed in [7,8]). The result of these studies is unequivocal: increasing calcium intake is able to maintain bone mineral content, at variance with what is observed in control subjects of the same age in whom bone mineral content is steadily declining. In other words, the increase in calcium intake induces a relatively positive calcium balance. It is worth noting that the positive balance occurs without any measurable change in ECF calcium concentration.
The second reason is that bone remodelling does not determine the equilibrium ECF calcium concentration, whereas it is a major determinant of bone (and body) calcium content. A good example, again, is post-menopausal osteoporosis: this condition is characterized, among other disorders, by an increase in bone remodelling together with a loss of coupling, with bone resorption increasing more than bone formation. As a consequence, a calcium loss estimated at 20–40 mg daily (that is 8–16 g yearly) accounts for osteoporosis. However, no consistent change in ECF calcium concentration occurs in post-menopausal women.
Many other conditions illustrate the independence between changes in ECF calcium concentration and calcium balance (Table 1). Consistently with what is mentioned above, high or low values of serum calcium concentration can coexist with negative, zero or positive values for calcium balance. The state of calcium balance is clearly unpredictable by the mere examination of ECF calcium concentration.
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ECF calcium concentration and calcium balance in patients with altered renal function |
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The situation is much more complex in patients with decreased renal function for many reasons. First, the decline in glomerular filtration rate that characterizes renal failure is responsible for a decrease in the filtered load of calcium that tends to limit the ability to excrete calcium and tends to render the calcium balance positive. However, chronic renal failure is also associated with a decrease in renal tubular calcium reabsorption [9] and intestinal calcium absorption that are expected to have opposite effects on calcium balance. In addition, chronic renal failure is responsible for progressive secondary hyperparathyroidism with expected effects on bone metabolism. Finally, in patients with metabolic acidosis, the buffering of hydrogen ions by bone causes a net efflux of calcium from bone and a progressive reduction of skeletal calcium stores [10]. The integrated consequence of these various changes on calcium balance is highly unpredictable. Unfortunately, only a limited number of studies have measured total body calcium in patients with chronic renal failure [11,12]. It appears to be widely scattered, ranging from lower to higher values than normal. Consistently, low values have been observed in patients with osteomalacia, whereas normal to high values have been observed in patients with osteitis fibrosa. Interestingly, serum calcium concentrations are very similar in patients with either normal, high or low body calcium content [11,12]. Furthermore, in uraemic patients who have been prospectively followed-up, the changes in bony calcium content (induced by a change in dialysate calcium concentration, calcium supply and/or vitamin D metabolites) were not associated with consistent modifications in serum calcium concentration. Therefore, under the particular condition of chronic renal failure, serum calcium concentration is also unable to predict calcium balance.
The measurement of serum calcium is a matter of debate. The K/DOQI guidelines state that total calcium levels need to be adjusted for the level of albumin in order to better reflect the free calcium and suggest the use of the following simple formula [13]:
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Notwithstanding, significant changes in calcium balance may occur in the absence of an overt abnormality in serum calcium concentration. For example, in these patients who have a very limited capacity to excrete calcium in the urine, the ingestion of large amounts of calcium is expected to lead to a high intestinal absorption of calcium, to promote a positive calcium balance and to favour calcium salt deposition in soft tissues [15–20], especially in those with adynamic bone disease whose bones are unable to buffer excessive amount of calcium [21]. Accordingly, several studies have reported a positive link between the prescribed dose of calcium salts and arterial wall stiffness [22] or the occurrence or worsening of arterial calcification [23–26]. Therefore, the recent recommendation that the dose of elemental calcium (including calcium-containing phosphate binders) should not exceed 2 g per day is probably safe [13]. In many patients with chronic renal failure, this dose of elemental calcium is not enough to bind the required amount of phosphate. The use of non-calcium-based phosphate binders provides an additional means to control hyperphosphataemia without inducing a calcium overload and arterial calcifications [24,27].
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Conclusion |
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As in normal subjects and patients with normal renal function, the calcium balance may be positive, normal or negative in patients with chronic kidney disease in the absence of any overt abnormality in serum calcium concentration. Therefore, the mere consideration of the serum calcium concentration is of no help to predict calcium balance in these patients.
Conflict of interest statement. None declared.
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