Hypoparathyroidism (HypoPT) stems from dysfunctional production and/or secretion of active parathormone (PTH) by the parathyroid glands.1 HypoPT has many causes, and the most frequent are parathyroidectomy and thyroidectomy surgeries.2 After total thyroidectomy, the incidence of postoperative HypoPT ranges from 0.5% to 6.6%.2 However, incidences as high as 20% have been reported3–6 depending on surgery extension and complexity, which are greater in malignant neoplasms, such as thyroid cancer, the main indication for total thyroidectomy.7–9 In these cases, central compartment neck dissection is a risk factor for permanent hypoparathyroidism.10

Permanent HypoPT after total thyroidectomy is characterized by persistent hypocalcemia and low or inappropriately normal levels of PTH for more than six months after surgery.11 Its treatment involves the supplement protocol of calcium and vitamin D1 to control the clinical manifestations of hypocalcemia, to maintain calcium (Ca) and phosphorus (P) levels, and adequate Ca×P product.12 For this treatment and in many other situations where Ca replacement is indicated, calcium carbonate (CaCO3) is the Ca salt most frequently prescribed because of its higher percentage of elemental Ca13 and better absorption in the normal or acidic pH of the stomach.2,14,15 Normal individuals should take CaCO3 with meals or a particular food to increase the bioavailability of the mineral.16 Yet, for HypoPT, where Ca supplement is associated with quality of life maintenance and patient survival, no studies have assessed the influence of CaCO3 intake protocol on certain parameters, such as calcemia and phosphatemia. Moreover, in normal individuals calcemia is rigorously controlled by a feedback system that involves many factors, especially PTH.1,17,18 This system maintains serum Ca levels constant, even when a Ca overload occurs, which impairs assessing the temporal effect of CaCO3 intake. In this sense, HypoPT patients could be a good model for assessing the real impact of CaCO3 intake protocols on calcemia and phosphatemia.

Thus, the present study investigated how the serum levels of Ca, P, and Ca×P vary over time after three different protocols of CaCO3 intake by women with permanent HypoPT secondary to total thyroidectomy.

HypoPT may be a consequence of total thyroidectomy,3,20 which is the most frequent treatment for DTC,21 a neoplasm whose incidence has increased considerably in the last years.22,23 Patients with permanent HypoPT require lifelong treatment with Ca salts to control calcemia, phosphatemia, and the Ca×P product.2,12,24 CaCO3 is the most common salt used for this purpose because of its higher elemental Ca percentage13 with good absorption.14 Studies that assessed calcemia, phosphatemia, and Ca×P product in different CaCO3 intake protocols, in HypoPT patients after thyroidectomy, were not found.

This study compared three different protocols of CaCO3 supplementation, equivalent to 500mg of elemental calcium. Serum Ca over time did not differ by protocol. The mean serum Ca levels remained in the lower limit of normality, as recommended for HypoPT patients.12 Calcemia of healthy women did not vary over time after CaCO3 supplementation.25 On the other hand, Ca serum of women with polycystic ovary syndrome increased significantly.26 However, comparison of the study results with individuals with normal PTH secretion is inappropriate. Additionally, although the therapeutic objectives seem to have been achieved, individual analysis of the three intake protocols showed that roughly 41% of serum Ca values were below the lower limit of normality. Hypocalcemia may have unknown health repercussions.

The calcemia peaks ranged from 8.6 to 8.9mg/dL, and the times-to-peak ranged from 152 to 202min, with an AUC of 2433–2577mg/dLmin regardless of CaCO3 intake protocol. The peaks remained in the lower half of normality, which is desirable in HypoPT patients because serum Ca in these patients should remain low, despite the adverse effects of hypocalcemia.12 These values differ from those reported by Tondapu and contributors27 who studied CaCO3 supplementation in patients submitted to the bariatric surgery Roux-en-Y and found a peak of 9.2mg/dL, time-to-peak of 126min, and AUC of 3240mg/dLmin. The different results are justified by the fact that both calcemia and AUC rely on PTH action, which was normal in the sample studied.27 PTH controls calcemia rigorously, as shown by a crossover study of healthy women that compared CaCO3 and placebo intakes and did not find differences in the Ca peak and AUC.25 Eventually, the age and vitamin D sufficiency of the patients could have influenced the results obtained. However, no significant associations were found between these parameters and Ca AUC.

The study time-to-peak means were higher than those reported elsewhere,27 which may also stem from low PTH. Still, Wang and contributors28 assessed healthy premenopausal women and found a Ca time-to-peak of 240min, higher than the study time-to-peak. On the other hand, Heller and contributors29 assessed healthy postmenopausal women and found a time-to-peak of 174min, similar to the study time-to-peak.

The phosphatemia of normal individuals has a circadian rhythm, with a nadir at around 10 in the morning and a peak at around 2 in the afternoon, generally ranging from 2.4 to 3.6mg/dL.30 Phosphatemia is affected by food intake. Valderas and contributors31 assessed phosphatemia for 3h after a standard meal and found mean phosphatemia values ranging from 3.1 to 3.5mg/dL. At eight in the morning, time of the first blood collection, the participants’ phosphatemia ranged from 2.7 to 5.7mg/dL. The last blood samples were collected at one o’clock in the afternoon, when normal individuals have a discrete elevation of serum phosphorus.30 Phosphatemia peak, time-to-peak, and AUC were similar in all three CaCO3 intake protocols, regardless of food intake. The mean peak values ranged from 4.03 to 4.12mg/dL, time-to-peak ranged from 135 to 167min, and AUC ranged from 1052 to 1203mg/dL.min. Although mean phosphatemia was within the reference range, roughly 10% of the participants had P levels beyond the recommended limits, especially above, which may negatively impact their metabolic control. In HypoPT hyperphosphatemia is almost as harmful as hypocalcemia. Hyperphosphatemia is associated with lower bone resorption32 and calcification of the basal ganglia33 and coronary artery.34,35 In normal individuals hyperphosphatemia decreases calcemia, which stimulates PTH secretion and consequently, increases calcemia. Thus, in HypoPT patients hyperphosphatemia worsens hypocalcemia even more because of PTH deficiency.36 Phosphatemia must be rigorously monitored to avoid significant fluctuations, since hypophosphatemia may also have negative effects, as it is associated, for example, with higher childhood mortality.37 Interestingly, because of hypocalcemia, CaCO3 may also be used for controlling hyperphosphatemia.38

In HypoPT the Ca×P product should stay below 55mg2/dL2,39 to avoid precipitation of Ca–P complexes in soft tissues, such as basal ganglia, lens, and kidneys,11 and vascular calcification,33,40,41 especially in the coronary arteries.35 In addition to organic processes, neuropsychological disorders have been associated with changes in the Ca×P product.42 In untreated HypoPT calcemia decreases and phosphatemia increases, so the Ca×P product should not change. In fact, this product did not change in rats submitted to parathyroidectomy.32 Nonetheless, when these patients take Ca supplements to correct hypocalcemia, Ca×P product may increase. In the present study, all Ca×P product values were below the recommended upper limit, and the mean Ca×P product values were similar in the three CaCO3 intake protocols.

This study has some limitations, such as the small sample size. Nevertheless, the sample size was calculated statistically based on the study design. Another limitation is the relatively low Ca dose used (500mg of elemental Ca), which may have contributed to the similar temporal variations of the study parameters in the three CaCO3 intake protocols. Still, other studies that used the same dose observed significant changes, with an increase in calcemia.26,29,43 Moreover, the study dose would be the recommended dose for HypoPT patients, given that the recommended 1–3g dose of elemental Ca per day is divided into two or three doses.2 As a matter of fact, once the maximum intestinal solubility of CaCO3 is reached, higher doses would not be absorbed.44 Another limitation would be the evaluation of total serum Ca instead of ionized Ca, which is effectively active in blood. However, the measurement of total Ca is more available in clinical practice and, since there were no differences between serum albumin levels in the three situations evaluated, it was considered that this measure could be used.2 Despite the limitations, the present study is the first to assess the temporal variation of calcemia and phosphatemia after CaCO3 supplementation in HypoPT patients. Furthermore, this endocrine disorder may be a model for the assessment of CaCO3 per se, without the influence of PTH on the temporal variations of calcemia and phosphatemia. Since our findings suggest that better Ca absorption in HypoPT patients does not require taking the salt after meals, perhaps this conclusion could be extrapolated to other conditions that require Ca supplementation.

The temporal variations of calcemia, phosphatemia, and the Ca×P product in women with permanent hypoparathyroidism secondary to total thyroidectomy are similar regardless of the CaCO3 supplementation protocol (water, juice or breakfast). Therefore, considering only calcemia and phosphatemia, these patients may take CaCO3 after an overnight fast with water or orange juice, or after breakfast.

This work was supported by the National Council for Scientific and Technological Development (CNPq – Conselho Nacional de Desenvolvimento Científico e Tecnológico), no. 130424/2013-7, and had no influence on the design of the study, or on the collection, analysis, and interpretation of data, or on the writing the manuscript.

The authors declare no conflicts of interest.