Changes in treatment needs for chronic postoperative hypoparathyroidism during initiation of conventional treatment compared to stable phase of treatment

Abstract Introduction In our clinical experience, need for doses of active vitamin D and calcium supplements changes during the period following a diagnosis of postsurgical hypoparathyroidism (HypoPT), but only sparse data are available. In the present study, we aimed to investigate the magnitude of changes in need for activated vitamin D (alfacalcidol) and calcium supplements during initiation of therapy as well as time to be expected until a stable phase was achieved. Furthermore, we determined the frequency of (unexpected) episodes of hypo‐ and hypercalcaemia after reaching a steady state for alfacalcidol and calcium. Methods Retrospective study of twenty‐four patients with chronic postsurgical HypoPT (>6 months) diagnosed from 2016 to 2018. Data were extracted from medical records on doses of alfacalcidol and calcium as well as ionized plasma calcium levels (P‐Ca2+) from time of diagnosis and until 86 weeks after surgery. Results Patients were treated with alfacalcidol and calcium in order to maintain a stable concentration of P‐Ca2+. Our data demonstrated a great variation in treatment needs until 11 weeks after surgery, where the mean doses of alfacalcidol stabilize, while calcium doses stabilized a bit earlier. After the stable phase had emerged, 21 out of 24 patients continued to have one or more episodes of spontaneous hypo‐ or hypercalcaemia. Conclusions Patients with chronic HypoPT attain a steady state for alfacalcidol 11 weeks after the diagnosis. Continuous monitoring of P‐Ca2+ is of continued importance after reaching steady state due to a high frequency of spontaneous hypo‐ or hypercalcaemia.


| Measurements
Medical records were reviewed with focus on P-Ca 2+ and changes in doses of calcium supplements and alfacalcidol. Patients diagnosed with postoperative hypocalcaemia were initially admitted to our department for monitoring and treatment of calcium homeostasis. After initial stabilization, patients were followed up at our outpatient clinic for further titration with less frequent measurement of calcium levels on the discretion of the treating physician. After stabilization, calcium levels are measured routinely every 3 rd month, or more frequently, if needed (eg suspected hypo-or hypercalcaemia).
If dose adjustments were needed, calcium levels were re-measured 3-14 days later and the patient was followed closely until normocalcaemia was re-established. If a patient was not seen for a given week, normocalcaemia was assumed as well as unchanged doses were assumed since the last clinical visit with last values carried forward. Calcium levels were measured in blood drawn in the morning and prior to medication. In the beginning of the disease, levels were sometimes measured several times a day. However, for the purpose of this study, we only used fasting morning samples. Ionized plasma calcium was measured immediately by an automated electrochemical method (Nova 8), and levels were adjusted to a pH value of 7.4.
All patients were treated at our department according to the standard of care as detailed in the European guidelines for monitoring and treatment of chronic HypoPT, aiming at P-Ca 2+ levels in the lower half of the reference interval or slightly below the lower limit of normal. 7 The reference for ionized calcium in our laboratory is 1.18-1.32 mmol/L. In the context of guidelines allowing for a target range

| RE SULTS
24 patients were included in the study with a mean age of 54 years (from 21 to 72 years old).

| Changes in treatment needs
Mean doses of alfacalcidol per patient given per week are summa-  weekly change in alfacalcidol needs of more than ± 10%. In the first weeks after surgery, the changes in treatment needs were more than ± 10% for most of the patients, as alfacalcidol doses changed more than ± 10% from week 1 to week 2 for all of the patients.
From week 2 to 3, 70% had a change in alfacalcidol doses of more than ± 10%. Subsequently, less than 50% had a weekly change in alfacalcidol of more than ± 10%. Eleven weeks after surgery less than 20% of the patients had changes of more than ± 10% until week 51, which agrees with our interpretation of Figure 2, suggesting that 11 weeks after surgery the patients were relatively stable and remained stable for more than 3 months.
Treatment with calcium supplements is shown on Figure 5.
Patients were given high doses in the first weeks after surgery, where the mean dose of calcium was approximately 12 g/patient/ week. Subsequently, the mean dose of calcium decreased to around 6 g/patient/week 5-7 weeks after surgery and remained stable apart from 41 to 47 weeks after surgery where the mean dose increased.
This increase in needs for calcium was due to the same patient, who had a marked increase in needs for alfacalcidol in the same period.
Similar to alfacalcidol, the change in the needs for calcium supple-

| Measurement of serum calcium during treatment
The number of patients with hypocalcaemia, stratified by whether hypocalcaemia was mild or moderate to severe, are shown on Figure S1A. Moreover, the median number of days per week with hypocalcaemia is shown for patients suffering from hypocalcaemia.

| DISCUSS ION
Patients were treated with alfacalcidol and calcium supplements as recommended by guidelines 7,9 in order to obtain and maintain a stable concentration of P-Ca 2+ in the lower part of the reference range.
On a contrary to other studies, our data demonstrated that treatment needs varied greatly until 11 weeks after surgery, where the mean doses of alfacalcidol became more stable, which occurred a bit earlier for doses of calcium. The stable phase occurred much later than former studies. 5 Days with hypocalcaemia occurred randomly and were not only in the beginning of the treatment but also in the stable phase of treatment, although the number of patients experiencing hypocalcaemia decreased concurrently with the number of weeks after surgery.
The gender distribution seen in our study with 29% men and 71% women was in consistency with other studies investigating postsurgical hypoparathyroidism. 10  The mean maintenance dose of alfacalcidol in the study by Halabe et al 5 was 1 µg/day with a range of 0.5-2.5 µg/day. This was a much lower dose than the dose needed for patients in our study, that is 16 µg/week at 33 weeks after surgery. However, the needed amount of calcium in the first weeks of treatment (7-13 g/week in week 1-11) and at the end of this study (6 g/week) was similar to Halabe et al, 5 where the needed dose of calcium was 1.5-2.0 g/day in the beginning of treatment and 0.5-1.0 g/day as maintenance dose.
The population in this study is not quite comparable to the popu- A characteristic among HypoPT patients seen in this study was the sudden changes in treatment needs due to fluctuations in calcium levels in the blood, which also is well known from other studies suggesting biochemistry to be monitored at regular intervals (every 3-6 months) and weekly after changes in treatment. 7,10 It is poorly understood how some of the symptoms and long-term complications among HypoPT patients occur, but fluctuations in calcium and phosphate levels are presumably associated with an increased risk of long-term complications. 12 Increased levels of calcium and calciumphosphate product in the blood are associated with impaired renal function, nephrocalcinosis, nephrolithiasis and renal failure. [13][14][15] Moreover, a recent review by Mannstadt et al 16  Hypercalcaemia is not only associated with increased risk of renal diseases, but also with an increased mortality as well as high phosphate levels increase the risk of infections. 12 The risk of cardiovascular diseases increase when suffering from HypoPT for more than 20 years, when having more than 4 episodes of hypercalcaemia and when patients have adequately low levels of calcium corresponding to hypocalcaemia. 12 Therefore, it is relevant to investigate conventional treatment in order to determine whether the treatment needs change during the time patients suffer from HypoPT in order to reduce the long-term effects of inadequately treated HypoPT.
A major strength of this study is the systematic assessment of treatment needs in terms of active vitamin D and calcium supplements in a group of patients recently diagnosed with HypoPT and followed for more than one year after the diagnosis. To the best of our knowledge, no prior studies have reported this. However, our study has several limitations. First, we only included a relatively small group of patients. However, HypoPT is a rare disease, hence it is difficult to make studies with a larger group of patients.
Moreover, this is a retrospective study based on patient records, which is better than if depending on patient's memory due to recall bias. Nevertheless, a prospective design would have been better in order to investigate the reasons for sudden development of hypo-or hypercalcaemia, which often are unknown and therefore impossible to explore in a retrospective design. Moreover, a prospective design could have included measurements of plasma phosphate and urine calcium in order to investigate how the treatment influence on these. A final limitation is that this study only included patients suffering from chronic HypoPT, which means that patients suffering from HypoPT less than 6 months characterized as transient were excluded. It is unknown whether patients who reestablish their parathyroid function during the first 6 months have more or less fluctuations in P-Ca 2+ levels than patients with permanent HypoPT.
In conclusion, a steady state for doses of alfacalcidol occurred approximately 11 weeks after surgery. However, the patients continued to have unexpected episodes of hypo-and hypercalcaemia after becoming stable, which means that it is important to continue monitoring patients with chronic HypoPT after stabilization of the treatment. Hence, we reject our hypothesis that the patients attain a stable phase of treatment with calcium and active vitamin D as early as during the first month after surgery.

CO N FLI C T S O F I NTE R E S T
The authors declare that they have no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.