Efficacy of Calcium Citrate Versus Calcium Carbonate for the Management of Chronic Hypoparathyroidism
Condition: Chronic Hypoparathyroidism
MeSH terms: Hypoparathyroidism
Study type: Interventional
Phase: Phase 4

Summary: 
      Hypoparathyroidism is an endocrinopathy characterized by a deficient secretion or action of
      PTH associated with low calcium level. According to the European guideline (2015), standard
      treatment includes oral calcium salts and active vitamin D metabolites to relieve symptoms of
      hypocalcaemia, maintain serum calcium levels in the low normal range and improve the
      patient's QoL Calcium carbonate is most often used and less expensive than other calcium
      preparations and contains the highest concentration of elemental calcium per gram (42%). It
      requires gastric hydrochloric acid to form carbonic acid (H2CO3) that immediately decomposes
      into water (H2O) and carbon dioxide (CO2). CO2 is responsible for its side effects such as
      flatulence, constipation and general gastrointestinal disorders. Therefore, in some patients
      it is better to find an alternative to calcium carbonate. Calcium citrate should be
      recommended to patients with achlorhydria or on treatment with proton pump inhibitors (PPI)
      as well as to patients who preferred to take supplements outside mealtimes. furthermore,
      patients with hypoparathyroidism have an increased risk of kidney stones. Kidney stones are
      formed by calcium salts, among which the most frequent ones are calcium-oxalate (70-80%),
      followed by calcium-phosphate and uric acid. Citrate salts are widely used in the treatmentof
      nephrolithiasis, since have shown an inhibitory effect on kidney stone formation. Up to now,
      there are no studies aimed to investigate the efficacy of calcium citrate in the management
      of subjects with chronic hypoparathyroidism. In particular, we will investigate if calcium
      citrate compared to calcium carbonate does not affect the risk of renal stones, if it is able
      to maintain normal calcium levels and, if it has an impact on QOL, in subjects with chronic
      hypoparathyroidism.
    

Detailed description: 
      BACKGROUND Hypoparathyroidism is an endocrinopathy characterized by a deficient secretion or
      action of PTH associated with low calcium level. It can be primary (inadequate PTH activity),
      or secondary (peripheral resistance to PTH).

      The most common cause of chronic Hypoparathyroidism is the postsurgical one: it is usually
      secondary to previous thyroid surgery but may also occur following parathyroidectomy or other
      cervical surgical procedures. Transient Hypoparathyroidism occurs in 30-60% of patients
      undergoing total or subtotal thyroidectomy. About 60-70% of cases of postoperative
      hypocalcaemia resolve within 4-6 weeks after surgery. About 15-25% of patients will develop
      chronic Hypoparathyroidism. The risk of chronic Hypoparathyroidism is closely related to the
      number of parathyroid glands remaining in situ at operation.

      Hypocalcemia is defined as serum calcium level (albumin adjusted total calcium or ionized
      calcium) below the lower limit of the reference range (target range).

      In literature there are not data that suggest which is the best serum calcium level to
      maintain during treatment, but the aim is to maintain serum calcium level in the lower part
      or slightly below the lower limit of the reference range (adjusted serum calcium level
      <2.1-2.3 or S-Ca2+ between 1.05-1.15mmol/L), serum phosphate levels within the reference
      range, serum calcium-phosphate product below 4.4 mmol2/l2 (55 mg2/dl2), 24-hurinary calcium
      excretion <7.5 mmol/2h (300 mg/24h) in men, <6.25 mmol/24h (250 mg/24h) in women, or <0.1
      mmol/kg per 24 h (4 mg/kg per 24h) in both sexes.

      In addition to hypocalcemia, patients affected by chronic hypoparathyroidism have a higher
      risk of renal implications such as urolithiasis and renal impairment because lack of PTH
      reduces calcium absorption and phosphate excretion causing hypercalciuria and
      hyperphosphatemia.

      Moreover, many patients with hypoparathyroidism complain of reduced quality of life (QOL) in
      ways that are difficult to quantify but that are nevertheless of concern. Biochemical control
      with standard therapy is rarely accompanied by improved functioning or sense of well-being.
      Complaints of cognitive dysfunction are common, with the term brain fog typically described
      by patients. In support of these issues, large cohort studies from Denmark have shown
      increased risk of hospitalization for depression and affective disorders, renal impairment
      and infections, whereas the risk for cancer and overall mortality was not increased.

      According to the European guideline (2015), standard treatment includes oral calcium salts
      and active vitamin D metabolites to relieve symptoms of hypocalcaemia, maintain serum calcium
      levels in the low normal range and improve the patient's QoL An adequate daily intake of
      calcium from diet and supplements is advisable. Different calcium salts are available as
      supplements because elemental calcium is highly reactive so it has to be combined with other
      substances. These preparations differ in the concentration of elemental calcium per gram.

      Calcium carbonate is most often used and less expensive than other calcium preparations and
      contains the highest concentration of elemental calcium per gram (42%). It requires gastric
      hydrochloric acid to form carbonic acid (H2CO3) that immediately decomposes into water (H2O)
      and carbon dioxide (CO2). CO2 is responsible for its side effects such as flatulence,
      constipation and general gastrointestinal disorders. Therefore, in some patients it is better
      to find an alternative to calcium carbonate. Calcium citrate, for example, should be
      recommended to patients with achlorhydria or on treatment with proton pump inhibitors (PPI)
      as well as to patients who preferred to take supplements outside mealtimes.

      Previous studies showed that calcium citrate, in comparison to calcium carbonate, causes
      greater increment in serum calcium concentration and urinary calcium excretion in parallel
      with greater suppression of serum PTH, after Roux-en-Y Gastric bypass and this datum suggests
      both the pharmacokinetic and pharmacodynamic superiority of calcium citrate.

      Calcium citrate is also better adsorbed than calcium carbonate after panproctocolectomy, so
      in a condition of a general enteric malabsorption.

      Up to now, there are no studies aimed to investigate the efficacy of calcium citrate in the
      management of subjects with chronic hypoparathyroidism. In particular, the investigators will
      test the efficacy of calcium citrate in maintaining normal calcium level compared to
      carbonate calcium in subjects with chronic hypoparathyroidism. Moreover, the investigators
      will evaluate the impact of calcium citrate on QOL in this kind of patients compared to the
      gold standard therapy (carbonate calcium).

      MATERIALS AND METHODS Each subject will participate in two phases of the study and each phase
      will last one month. Once every 2 weeks blood and a morning urine sample will be drawn. For
      all the study period, participants will be instructed to maintain a predetermined dietary
      calcium intake (800 mg/day) with sodium (100 mEq/day) restrictions. All subjects will
      complete a questionnaire on quality of life at 0, +2, +4 week, during both phases. The
      investigators will use the Rand 36-Item Short Form Health Survey (version 1.0) to evaluate
      the QOL.

      Phase 1: According to a block randomization scheme, subjects will be assigned to a calcium
      supplement (Drug A or Drug B) at the same total amount of elemental calcium that they had
      taken before the study enrollment. The dose of Vitamin D will be equal to the daily dose
      taken prior to the study, and will not be changed during the study period.

      Phase 2: subjects will be shift to the opposite Drug (from drug A to drug B or from drug B to
      drug A) at the same total amount of elemental calcium that they had taken during the last
      week of the phase 1.

      SAMPLE SIZE CALCULATION

        1. Based on the assumption that the within-patient standard deviation of the calcium
           oxalate saturation is 0.5, to demonstrate that calcium citrate does not affect the
           calcium oxalate saturation, a total of 24 patients need to be enrolled in this study.
           This sample size will allow to detect a difference of 0.43 points at a two-sided 5%
           significance level with a probability of type II error of 20%.

        2. to demonstrate that calcium citrate is as effective as calcium carbonate in maintaining
           serum Ca within the acceptable clinical range. To this end, we will study a sample of 21
           people already treated with calcium and vitamin D supplementation. Our hypothesis is
           that at the end of the study period, the mean Ca concentration will not be different
           from the ideal value (9 mg/dl), accepting a 10% variation as the equivalence limit
           (i.e., accepting as equivalent values between 8.1 and 9.9 mg/dl). Under these
           assumptions, we would need 11 patients to show equivalence between the two treatments,
           with a alpha error probability of 5% and a beta error probability of 10%20. With the
           available sample size, we will be able to establish equivalence with an equivalence
           limit of 0.7 (i.e., values between 8.3 and 9.7 mg/dl).
    

Intervention name(s): Calcium Carbonate; Calcium Citrate
Intervention type(s): Drug; Drug
Intervention description(s): subjects will be assigned to a calcium supplement (Carbonate or Citrate) at the same total amount of elemental calcium that they had taken before the study enrolment.; subjects will be assigned to a calcium supplement (Carbonate or Citrate) at the same total amount of elemental calcium that they had taken before the study enrolment.
Intervention MeSH terms: Calcium, Dietary; Calcium Carbonate; Calcium
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: calcium carbonate; calcium citrate; quality of life; hypoparathyroidism; hypocalcemia; calicum oxalate saturation; kydney stone