treatment of chronic hypoparathyroidism in adults...1 1 european society of endocrinology clinical...
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European Society of Endocrinology Clinical Guideline on: 1
Treatment of Chronic Hypoparathyroidism in Adults 2
3
Abstract 4
Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and 5
inappropriately low (insufficient) circulating PTH levels, most often in adults secondary to 6
thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplement 7
and not replacement with the lacking hormone, as in other hormonal deficiency states. 8
The purpose of this guideline is to provide clinicians with guidance on the treatment and 9
monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend 10
to draft a practical guideline, focusing on operationalized recommendations deemed to be 11
useful in the daily management of patients. 12
This guideline was developed and solely sponsored by The European Society of 13
Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based 14
on the GRADE principles as methodological base. The clinical question on which the 15
systematic literature search was based and for which available evidence was synthesized was: 16
What is the best treatment for adult patients with chronic HypoPT? This systematic search 17
found 1,100 articles, reduced to 312 based on title and abstract. The working group assessed 18
these for eligibility in more details, 32 articles were assessed in full-text. Of note, for the final 19
recommendations also other literature was taken into account. 20
Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk 21
of complications have just started to emerge, and clinical trials on how to optimize therapy is 22
essentially non-existent. Most studies are of limited sample size, hampering firm conclusion. 23
No studies are available relating target calcium levels to clinically relevant endpoints. Hence 24
it is not possible to formulate recommendations based on strict evidence. This guideline is 25
therefore mainly based on how patients are managed in clinical practice, as reported in small 26
case series and based on the experiences of the authors. 27
28
29
30
31
2
1. Summary of Recommendations 32
1.1. Diagnosis 33
1.1.1 We recommend considering a diagnosis of chronic hypoparathyroidism (HypoPT) in a 34
patient with hypocalcaemia and inappropriately low PTH levels. 35
1.1.2 We suggest considering genetic testing and/or family screening in a patient with 36
HypoPT of unknown etiology. 37
1.2. General goals of management in chronic hypoparathyroidism 38
1.2.1 We suggest treatment targeted to maintain serum calcium level (albumin adjusted total 39
calcium or ionized calcium) in the lower part or slightly below the lower limit of the reference 40
range (target range) with patients being free of symptoms or signs of hypocalcaemia. 41
1.2.2 We suggest that 24-hour urinary calcium excretion should be within the sex-specific 42
reference range. 43
1.2.3 We suggest that serum phosphate levels should be within the reference range. 44
1.2.4 We suggest that the serum calcium–phosphate product should be below 4.4 mmol2/L
2 45
(55 mg2/dL
2). 46
1.2.5 We suggest that serum magnesium levels should be within the reference range. 47
1.2.6 We suggest aiming at an adequate vitamin D status. 48
1.2.7 We recommend that treatment be personalized and focused on the overall well-being 49
and quality of life (QoL) of the patient when implementing different therapeutic efforts, 50
aiming to achieve the therapeutic goals. 51
1.2.8 We recommend providing information/education that enables patients to know the 52
possible symptoms of hypo- or hypercalcaemia and/or complications of their disease. 53
1.3. Treatment 54
1.3.1 We recommend treatment of all patients with chronic HypoPT with symptoms of 55
hypocalcaemia and/or an albumin adjusted serum calcium level < 2.0 mmol/L (< 8.0 mg/dL / 56
ionized serum calcium (S-Ca2+
) levels < 1.00 mmol/L). 57
1.3.2 We suggest offering treatment to asymptomatic patients with chronic HypoPT and an 58
albumin adjusted calcium level between 2.0 mmol/L (8.0 mg/dL / S-Ca2+
1.10 mmol/L) and 59
the lower limit of the reference range in order to assess whether this may improve their well-60
being. 61
1.3.3 We recommend the use of activated vitamin D analogues plus calcium supplements in 62
divided doses as the primary therapy. 63
3
1.3.4 If activated vitamin D analogues are not available, we recommend treatment with 64
calciferol (preferentially cholecalciferol). 65
1.3.5 We recommend that the doses of activated vitamin D analogues or cholecalciferol are 66
titrated in such a manner that patients are without symptoms of hypocalcaemia and serum 67
calcium levels are maintained within the target range. 68
1.3.6 We recommend vitamin D supplementations in a daily dose of 1000-2000 IU to patients 69
treated with activated vitamin D analogues. 70
1.3.7 In a patient with hypercalciuria, we suggest considering a reduction in calcium intake, a 71
sodium-restricted diet, and treatment with a thiazide diuretic. 72
1.3.8 In a patient with renal stones, we recommend evaluation of renal stone risk factors and 73
management according to relevant international guidelines. 74
1.3.9 In a patient with hyperphosphataemia and/or an elevated calcium-phosphate product, we 75
suggest considering dietary interventions and/or adjustment of treatment with calcium and 76
vitamin D analogues. 77
1.3.10 In a patient with hypomagnesaemia, we suggest considering measures that may 78
increase serum magnesium levels. 79
1.3.11 We recommend against the routine use of replacement therapy with PTH or PTH 80
analogues. 81
1.4. Monitoring 82
1.4.1 We recommend routine biochemical monitoring of serum levels ionized or albumin 83
adjusted total calcium, phosphate, magnesium and creatinine (estimated glomerular filtration 84
rate, eGFR), as well as assessment of symptoms of hypocalcaemia and hypercalcaemia at 85
regular time intervals (e.g., every 3-6 months). 86
1.4.2 Following changes in therapy, we recommend biochemical monitoring weekly or every 87
other week. 88
1.4.3 We suggest considering monitoring of 24-hour urinary calcium excretion at regular, but 89
longer time intervals (e.g., once a year or every second year). 90
1.4.4 We recommend renal imaging if a patient has symptoms of renal stone disease or if 91
serum creatinine levels start to rise. 92
1.4.5 We suggest monitoring for development of signs or symptoms of co-morbidities at 93
regular time intervals (e.g., yearly). 94
1.4.6 We advise against routine monitoring of bone mineral density by dual energy X-ray 95
absorptiometry (DXA) scans. 96
1.5. Special circumstances 97
4
Autosomal dominant hypocalcaemia (ADH): 98
1.5.1 We recommend frequent monitoring of patients with ADH, who are being treated with 99
calcium and/or activated vitamin D analogues, as such patients may be at high risk of 100
hypercalciuria and renal complications. 101
Pregnancy and breastfeeding: 102
1.5.2 We suggest treatment with activated vitamin D analogues and calcium supplements as in 103
non-pregnant patients. 104
1.5.3 We suggest monitoring serum ionized calcium regularly (every 2nd
or 3rd
week) during 105
pregnancy and breastfeeding with levels to be kept at the lower end of the normal range 106
(serum albumin adjusted total calcium is also acceptable). 107
108
2. Methods 109
2.1. Guideline working group 110
This guideline was developed and solely sponsored by The European Society of 111
Endocrinology (ESE), supported by CBO (Dutch Institute for health care improvement). The 112
working group was chaired by Jens Bollerslev (clinical) and Olaf Dekkers (methodology) and 113
included Claudio Marcocci, Lars Rejnmark, and Dolores Shoback (endocrinologists), Wim 114
van Biesen (nephrologist), and Antonio Sitges Sierra (endocrine surgeon). The working group 115
had two in-person meetings (January and December, 2014) and communicated by phone and 116
email. Consensus was reached upon discussion, minority positions were taken into account in 117
the rationale behind recommendations. Prior to the process, conflict of interest forms were 118
completed by all participants. 119
120
2.2 Target group 121
This guideline was developed for European based healthcare providers of adult patients with 122
chronic HypoPT, ie, primarily endocrinologists and specialists in internal medicine. However, 123
general practitioners with a special interest in calcium metabolism might also find the 124
guideline useful, as might our patients. Patient leaflets were developed in collaboration with 125
patients and patient associations (xxx, xxx, and xxx) based on the guideline recommendations. 126
A draft of the guideline was reviewed by an expert in the field1, before submitted for external 127
review and comments by ESE-members, and was presented and discussed at the European 128
Congress of Endocrinology, May 18th
, 2015 in Dublin. 129
130
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2.3 Summary of Methods used for guideline Development 131
The current guideline has the GRADE (Grading of Recommendations Assessment, 132
Development and Evaluation) principles as methodological base. GRADE is a systematic 133
approach for synthesizing evidence and grading of recommendations (1). The main advantage 134
of the system is the aim for transparency at all stages of the guideline development process. 135
This to provide the reader with all information required to understand the underlying rationale 136
of the provided recommendations. 137
The first methodological step for the guideline development group is to define the clinical 138
question(s) to be addressed in the guideline (see section 2.4). These clinical questions are 139
formulated in such ways that their answering can directly inform management decisions. An 140
answer to the question: What is the best treatment in HypoPT to prevent renal complications, 141
can inform treatment decisions. Whereas the question: Is hydrochlorothiazide better than 142
PTH for treatment in HypoPT to prevent renal complications, is too restricted if other 143
alternatives are available but not considered. Importantly, the clinical questions should be 144
specific in terms of populations; for this guideline: chronic HypoPT in adults who do not have 145
end-stage renal disease. Prior to synthesizing and rating available evidence, the guideline 146
development group rated clinical outcomes either as critical, important but non-critical, and 147
not important (2), see Section 2.4. 148
The clinical questions subsequently formed the base for a systematic literature search, see 149
Section 2.5. After including all relevant articles, synthesis of the evidence was made in two 150
directions: 1) Estimation of an average effect for specific outcomes (if possible): 2) Rating the 151
quality of the evidence. The quality rating is standardized (3) and is provided as summary 152
rating (using four categories: high, moderate, low, very low) across studies for each outcome, 153
as it may be that quality differs for different outcomes. See the evidence tables in Appendix 1. 154
Evidence synthesis and quality rating were performed by the guideline methodologist. 155
For the final recommendations, three elements importantly were taken into account: 1) 156
Quality of the evidence, 2) Balance of desirable and undesirable outcomes, 3) Values and 157
preferences (patient preferences, goals for health, costs, management inconvenience, 158
feasibility of implementation, etc) (4). The recommendations are worded as recommend 159
(strong recommendation) and suggest (weak recommendation). The meaning of a strong 160
recommendation can be stated as follows: reasonably informed persons (clinicians, 161
politicians, patients) would want the management in accordance with the recommendation. 162
For a weak recommendation, most persons would still act in accordance with the guideline, 163
6
but a substantial number would not (4). Only for recommendations regarding treatment we 164
aimed for formal evidence synthesis; this was not the case for recommendations on diagnosis, 165
monitoring and special circumstances. . 166
Importantly, there is no automatic step from evidence to recommendations. Often available 167
evidence is of poor quality hampering strong recommendations, but even high quality 168
evidence may not directly translate into a strong recommendation if, for example, the outcome 169
under study is judged as not important or if a management strategy cannot be implemented on 170
a large scale. This highlights the fact that standardized quality judgement still does not 171
eliminate the need for clinical judgement (1). Another consideration is that you cannot abstain 172
from recommendations when there is no evidence, as treatment decisions need to be made any 173
way. For the ESE guidelines, recommendations are achieved by majority reports of the 174
guideline development committee, but if members have substantive disagreements, this will 175
be acknowledged in the manuscript. To optimize transparency, all recommendations provided 176
are accompanied by text explaining why specific recommendations were made. 177
178
2.4. Clinical question, eligibility criteria and endpoint definition 179
The clinical question on which the literature search was based and for which available 180
evidence was synthesized was: What is the best treatment for adult patients with chronic 181
HypoPT? 182
Exclusion criteria for the studies considered were: 183
Patients with HypoPT for < 6 months 184
Intervention < 4 week duration 185
Age < 18 years 186
Case series 187
End-stage renal disease 188
The following outcomes were rated by the guideline working group as critical: 189
Mortality 190
Quality of life 191
Calcium levels in serum or plasma and urine, including incidence of hypercalcaemia 192
Chronic kidney disease and renal calcifications defined as symptoms or episodes of 193
nephrolithiasis or nephrocalcinosis 194
Cramps, tetany and seizures 195
7
Cardiovascular disease defined as the incidence of major adverse cardiovascular 196
events 197
Disability or sick leave 198
199
2.5 Description of search and selection of literature 200
A systematic search was done using the database Ovid MEDLINE to find literature from 1970 201
onward. Systematic reviews, randomized controlled trials (RCTs), cohort studies and case-202
control studies were eligible; only articles in Dutch, English, German and French were 203
considered. Articles were searched that included adult, human patients with chronic HypoPT 204
(>6 months) as well as the relevant interventions and outcome measures. Only interventions 205
with duration > 4 weeks were considered. Articles identified by the working group as relevant 206
were used to optimize the search strategy. Articles found by “snowballing” were also 207
considered. For the full search strategy, see Appendix 2. 208
This systematic search found 1,100 articles, reduced to 312 based on title and abstract. The 209
working group members assessed 312 articles for eligibility in more detail, of which 32 210
articles were assessed in full-text. One article (5) could not be located in full-text and was 211
excluded. The final literature selection included 16 articles. Of note, for the final 212
recommendations also other literature (basic literature, physiologic studies) was also taken 213
into account. 214
215
3. Clinical considerations in Chronic Hypoparathyroidism 216
3.1 Etiology and epidemiology 217
HypoPT is an endocrine disease with low calcium and inappropriately low (insufficient) 218
circulating parathyroid hormone (PTH) levels (6-9). It is a rare condition, designated as an 219
orphan disease by the European Commission in January, 2014, (EU/3/13/1210) 220
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/orphans/2014/01/hum221
an_orphan_001301.jsp&mid=WC0b01ac058001d12b and the only major endocrine condition 222
today, where the hormonal insufficiency in general is not treated by substitution of the 223
missing hormone (PTH). The most common cause of chronic HypoPT is neck surgery i.e., 224
secondary to thyroid or parathyroid surgery (10), but the disease also has an autoimmune 225
basis (11) and/or a genetic etiology, like DiGeorge syndrome (12). 226
The prevalence of postsurgical HypoPT has recently been systematically studied in Denmark, 227
where a total of more than 2000 patients were identified giving a prevalence of approximately 228
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24/100,000 inhabitants, among whom only a minority (2/100,000) had HypoPT due to non-229
surgical causes (13;14). These estimates are in agreement with recent data from USA, 230
showing a prevalence of the same magnitude for patients with chronic HypoPT (15). 231
232
3.2 Postsurgical Hypoparathyroidism 233
Chronic HypoPT in adults of more than 6 months duration is usually secondary to previous 234
thyroid surgery, but may also occur following parathyroidectomy or other cervical surgical 235
procedures. Completion thyroidectomy (after previous partial thyroidectomy) or lymph node 236
dissection of the central neck compartment for locally recurrent cancer may also lead to 237
HypoPT. Overall, between 2-10% of patients submitted to total thyroidectomy (often 238
associated with central/lateral lymph node dissection in cases of thyroid cancer) will develop 239
chronic HypoPT (16). 240
The initial manifestation of postoperative parathyroid failure is hypocalcaemia detected 241
within 24 hours of thyroidectomy, which occurs in 30-60% of patients undergoing total 242
thyroidectomy. Predisposing factors involved are young age, female gender, Graves’ disease, 243
lymphadenectomy, accidental parathyroidectomy (including biopsies during surgery for 244
hyperparathyroidism), parathyroid auto-transplantation and, most importantly, the number of 245
functioning parathyroid glands remaining in situ (17;18). All these factors contribute to 246
reduced PTH secretion immediately after surgery resulting in hypocalcaemia (19;20). If 247
hypercalcaemia was present prior to surgery (e.g., in a patient with hyperparathyroidism), it 248
may take a few days before serum calcium levels have normalized, during which PTH levels 249
may be very low. 250
About 60-70% of cases of postoperative hypocalcaemia resolve within four to six weeks after 251
surgery (transient HypoPT); the rest will progress to protracted HypoPT characterized by low 252
serum PTH levels and the need for continued treatment. The most relevant factor leading to 253
protracted HypoPT is the number of functioning parathyroid glands remaining in situ; clinical 254
and disease-related variables lose significance at this stage (21). 255
Finally, about 15-25% of patients with protracted HypoPT will develop chronic HypoPT. The 256
significant variables favouring recovery from protracted HypoPT are the number of 257
parathyroid glands remaining in situ and the serum calcium level at this stage: Normal to high 258
calcium levels at one month after thyroidectomy appears to increase the chance of parathyroid 259
gland recovery. The clinical and disease-related variables do not seem to influence 260
parathyroid function recovery. The risk of chronic HypoPT is closely related to the number of 261
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parathyroid glands remaining in situ at operation: 16% for cases with 1-2 preserved glands, 262
6% for 3 glands and 2.5% for 4 glands (21). 263
3.3 Complications and Renal Implications of Chronic Hypoparathyroidism in Adults 264
Patients with chronic HypoPT seem to have lower quality of life (QoL), muscle complaints, 265
including fatigue and weakness, more anxiety and tendency to depression (22-25). In support 266
of these issues, large cohort studies from Denmark have shown increased risk of 267
hospitalization for depression and affective disorders, renal impairment, and infections, 268
whereas the risk for cancer and overall mortality was not increased (13;26). Risks of ischemic 269
heart disease and of cataract are increased in non-surgical HypoPT, but not among patients 270
with postsurgical HypoPT (13;14;26). 271
HypoPT has traditionally been associated with calcium-containing urolithiasis and renal 272
impairment, because of an increased calcium‐phosphate product. Loss of renal PTH action 273
decreases renal tubular reabsorption of calcium and excretion of phosphate causing 274
hypercalciuria and hyperphosphataemia, respectively (9). Thus, patients with chronic HypoPT 275
have been found to have an increased risk of renal complications, such as renal stones, renal 276
insufficiency and a higher risk for needing dialysis (13). Impaired renal function has been 277
associated with age of the patient, duration of the disease, and relative time with 278
hypercalcaemia (27). In agreement, two smaller cross-sectional studies in patients with mainly 279
postsurgical HypoPT have found renal complication rates in the same magnitude (22;28). 280
Moreover, two thirds of subjects included in an early intervention trial had decreased 281
creatinine clearance values at baseline, and 40% had verified renal calcinosis (29). However, 282
despite keen interest in improving the management of HypoPT, large cohort studies 283
describing typical treatment patterns, optimized target laboratory parameters and rates of 284
complications are scarce. 285
3.4 Pregnancy and breastfeeding 286
Pregnancy and lactation pose substantial short-term challenges to maternal calcium 287
homeostasis, due to the need to mineralize the fetal skeleton and to provide this essential 288
mineral to the breast milk to sustain postnatal skeletal development and well-being in the 289
newborn (30-34). These challenges to the mother are met by vigorous placental production of 290
1,25-dihydroxyvitamin D (1,25(OH)2D), which stimulates intestinal calcium and phosphate 291
absorption during pregnancy, resulting in higher levels of urinary calcium and low to 292
suppressed endogenous PTH secretion. As pregnancy progresses, parathyroid hormone-293
related protein (PTHrP) production increases in many tissues. PTHrP synthesis rises even 294
further during nursing, because it is abundantly produced in lactating mammary tissue. 295
10
PTHrP increases bone resorption substantially and renal calcium reabsorption, which together 296
provides a steady supply of calcium for milk production. PTHrP’s effects on the kidney 297
prompt urinary calcium levels to fall during lactation. Because of the changes in PTHrP and 298
1,25(OH)2D during pregnancy and lactation, levels of endogenous PTH are suppressed. 299
Although PTH plays a negligible role in regulating calcium homeostasis in pregnancy and 300
lactation in normal women, those with chronic HypoPT, whose serum calcium levels are 301
being maintained by supplemental calcium intake and therapy with vitamin D metabolites or 302
analogues, are at considerable risk for both hypercalcaemia and hypocalcaemia when 303
pregnant or nursing. Poor control of maternal HypoPT and resulting hypocalcaemia during 304
pregnancy can cause miscarriage, stillbirth, premature labor and even neonatal death (34-37). 305
Maternal hypocalcaemia can affect neonatal skeletal development and cause compensatory 306
hyperparathyroidism in the newborn. Skeletal deformities, fractures, parathyroid hyperplasia, 307
and clinical complications (e.g., respiratory distress, poor feeding, hypotonia) may result 308
(32;34-41). Conversely, maternal overtreatment resulting in hypercalcaemia can suppress 309
fetal parathyroid development causing neonatal hypocalcaemia. To avoid these potential 310
complications, pregnant and nursing women with HypoPT need careful monitoring and 311
medication adjustment by their physicians. The clinical literature on which summary is based 312
is detailed in Appendix 4. 313
3.5 Treatment 314
The aim of treatment of chronic HypoPT is to relieve symptoms of hypocalcaemia and 315
improve the patient’s QoL (9;42). The treatment should aim to maintain serum calcium levels 316
in the low normal range, serum phosphate within the normal range, total calcium-phosphate 317
product below 4.4 mmol2/L
2 (55 mg
2/dL
2), and to avoid hypercalciuria. 318
Standard treatment includes oral calcium salts and active vitamin D metabolites. 319
Hyperphosphataemia should be addressed by decreasing dietary phosphate intake and by 320
eventually using phosphate binders (9;42;43). In the event of hypercalciuria, a thiazide 321
diuretic accompanied by a low salt diet may be advised (44). Replacement therapy with PTH 322
(synthetic human PTH1-34 and intact PTH1-84) is an attractive option for those patients who do 323
not stably and safely maintain their serum and urinary calcium in the target range (43;45). 324
Both compounds have shown to be effective (43) and the American Food and Drug 325
Administration has very recently approved the use recombinant human PTH1-84 as a 326
supplement to conventional treatment (FDA 2015: 327
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm431358.htm ). 328
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Patients with mild hypocalcaemia should be given oral therapy even if they have only 329
nonspecific symptoms (fatigue, brain fog, anxiety), since they may improve with treatment. 330
Dietary calcium intake should be optimized, according to the guidelines for the general 331
population (46;47). Magnesium-depleted patients should be replete with this mineral. 332
In cases of symptomatic severe hypocalcaemia, the use of intravenous calcium should be 333
considered for a limited period of time. Serum calcium and phosphate should be monitored 334
weekly or twice weekly during the initial dose adjustment period and every third to sixth 335
month when serum levels are stable. 24-hour urinary calcium excretion is suggested to be 336
measured yearly or every other year. 337
338
The overall purpose of this guideline is to provide clinicians with guidance on the treatment of 339
chronic HypoPT. We intended to draft a practical clinical guideline, focusing on 340
operationalized recommendations that are supposed to be useful in the daily management of 341
adult patients with chronic HypoPT. 342
343
5. Conclusions from scientific literature and directions for further research 344
5.1 Summary and interpretation of the main findings 345
Sixteen studies on treatment on chronic HypoPT were included based on eligibility criteria 346
and endpoint definition (see 2.5). Only one study (48) had a sample size of > 100 patients. 347
Most of the (few) available randomized studies investigated effects of PTH replacement 348
therapy. Details of included studies are shown in appendix 1. A more extensive summary, the 349
formal conclusions, and the GRADE scoring per endpoint and evidence synthesis are 350
provided in appendix 2 and 3. 351
Study endpoints 352
Mortality 353
Only one study reported data on mortality (48). No deaths were reported in this randomized 354
study with 134 patients comparing PTH to placebo. The follow-up was short (24 weeks), not 355
allowing conclusions regarding long-term effects on mortality. 356
Quality of life, disability and sick leave 357
In two studies QoL was studied. Whereas a cohort study showed improvement in QoL 358
compared to baseline after treatment with PTH (49), an advantage in QoL of therapy with 359
PTH compared to placebo could not be shown in a RCT (50). No studies reported on 360
disability or sick leave. 361
12
Cardiovascular events 362
Two studies (25;48) reported one serious cardiovascular event in the PTH-treated group, 363
compared to none in the placebo group. Sample sizes were too small and follow-up too short 364
to draw meaningful conclusions regarding cardiovascular events. 365
Cramps, tetany and seizures 366
Occurrence of cramps, tetany or seizures was not quantitatively reported in the majority of 367
studies. In one RCT the reported frequency of tetany did not differ materially between PTH 368
and placebo group (48). 369
Renal function, kidney stones and calcifications 370
Although nephrocalcinosis or nephrolithiasis is described in HypoPT, no study adequately 371
investigated the occurrence of these conditions under different treatment regimens. 372
Serum and urinary calcium levels 373
Many studies reported in various ways on serum calcium levels. In general, calcium levels 374
within the target range can be achieved with different treatment (combinations), and the risk 375
of severe hypo- or hypercalcaemia is low. 376
5.2 Study results in perspective 377
Very little evidence is available on how best to treat HypoPT. Data on QoL and the risk of 378
complications have just started to emerge in recent years, and clinical trials on how to 379
optimize therapy are essentially non-existent. Importantly, the majority of studies are of 380
limited sample size, which hampers firm conclusion especially regarding dichotomous 381
outcomes (mortality, cardiovascular events). Also no studies are available that relate target 382
calcium levels to clinical relevant endpoints. Thus, we do not know what the optimal calcium 383
target is. Because of this remarkable lack of data, it is not possible to formulate 384
recommendations based on strict evidence. This ESE guideline on treatment of chronic 385
HypoPT in adults is, therefore, mainly based on how patients are managed in clinical practice, 386
as reported in small case series and based on the experiences of the authors of the guideline. 387
Noticeably, HypoPT is one of the last endocrine deficiency diseases not treated by hormone 388
replacement. In recent years, a number of studies have been published showing that 389
normocalcaemia can be maintained with PTH (rhPTH1-84) or a PTH fragment (rhPTH1-34). In 390
most of the studies, PTH has been administered in an unphysiologic manner (once-daily 391
injection), compared to its continuous episodic endogenous pattern of secretion. Due to the 392
short plasma half-life of PTH, once-daily injections do not cause sustained increased PTH 393
levels. In other words, the physiology of calcium-phosphate homeostasis is not restored by 394
13
this schedule of replacement therapy. Recently, a National Institutes of Health (NIH) 395
sponsored study in the USA showed an almost normalization of the diurnal rhythm of PTH, 396
calcium and phosphate levels in response to rhPTH therapy delivered by an (insulin) infusion 397
pump (51). So far, no data are available on whether continuous infusions of rhPTH will 398
improve QoL and reduce the risk of complications. If so, this may be a feasible way forward 399
to improve the treatment of chronic HypoPT in adults. As HypoPT recently has been 400
acknowledged as an orphan disease in Europe and the USA, further systematic and 401
prospective studies on how to optimize therapy and avoid complications will hopefully be 402
initiated. 403
404
6. Recommendations, Rationale for the Recommendations 405
6.1. Diagnosis 406
6.1.1 We recommend considering a diagnosis of HypoPT in a patient with hypocalcaemia and 407
inappropriately low PTH levels. 408
Reasoning: 409
Hypocalcaemia is defined as an ionized or albumin adjusted serum total calcium level below 410
the lower limit of the reference interval. Measurements of ionized or total calcium mostly 411
reflects local traditions, however, ionized calcium measurements might improve diagnostic 412
accuracy (52), and is preferred in pregnancy, see 6.5.3. A specific cut-off limit for PTH levels 413
in the presence of hypocalcaemia cannot be defined. If parathyroid function is intact, 414
hypocalcaemia is normally associated with (markedly) increased PTH levels (secondary 415
hyperparathyroidism). In accordance, a diagnosis of HypoPT may be considered in a patient 416
with hypocalcaemia even though PTH levels are within the reference interval (inappropriate 417
normal PTH levels) (6-9). 418
Remarks 419
Magnesium depletion impairs the secretion of PTH causing a state of “functional HypoPT” 420
and impairs effective PTH actions in target tissues. If magnesium levels are low, this should 421
be corrected before diagnosing a patient with chronic HypoPT (53). 422
6.1.2 We suggest considering genetic testing and/or family screening in a patient with 423
HypoPT of unknown etiology. 424
Reasoning: 425
Non-surgical HypoPT may be due to various reasons (43;54). If no obvious cause can be 426
established, we suggest considering genetic testing and/or family screening. This may be of 427
14
specific importance to younger individuals, as a genetic diagnosis may allow for genetic 428
counseling in relation to pregnancy plans and for monitoring for other possible complications 429
that may accompany the HypoPT (e.g., renal and hearing abnormalities due to GATA3 430
mutation). 431
6.2. Goals of management in chronic hypoparathyroidism 432
6.2.1 We suggest treatment targeted to maintain calcium level (albumin adjusted total 433
calcium or ionized calcium) in the lower part or slightly below the lower limit of the reference 434
range (target range) with patients being free of symptoms or signs of hypocalcaemia. 435
Reasoning: 436
No data exist on optimal serum calcium levels during treatment of HypoPT. Aiming at low 437
normal or slightly below the lower limit of normal for serum calcium levels seems reasonable, 438
as this may help to lower renal calcium excretion and avoid risk of hypercalcaemia (55). 439
Some patients may, however, need higher serum calcium levels to be free of symptoms. If the 440
patient’s well-being is improved by titrating treatment in such a manner that serum calcium 441
levels are in the upper part of the reference interval, this may be accepted as no data exist on 442
whether relatively high normal serum calcium levels are of specific harm to patients. 443
6.2.2 We suggest that 24-hour urinary calcium excretion should be within reference range. 444
Reasoning: 445
In a patient with intact parathyroid function, hypercalciuria is considered a risk factor for 446
renal stone formation. Because PTH increases the renal tubular reabsorption of calcium, 447
chronically low PTH levels make hypercalciuria a common feature of HypoPT. Risk of renal 448
stone disease is increased in HypoPT (13;27), but no evidence exists as to whether the risk of 449
forming or passing renal stones is associated with the amount of urinary calcium excreted in 450
patients with HypoPT. However, if it is assumed that the pathogenesis of renal stone disease 451
is similar in HypoPT as in hypercalciuric individuals with normal parathyroid function, it 452
seems reasonable to aim at keeping 24-hour urinary calcium within the sex-specific reference 453
range (55) in order to prevent renal stone formation (56). 454
Remark 455
If sex-specific reference ranges are available we suggest using them, as the urinary calcium 456
excretion in higher in men compared to women. 457
6.2.3 We suggest that serum phosphate levels should be within the reference range. 458
6.2.4 We suggest that the serum calcium–phosphate product should be below 4.4 mmol2/L2 459
(55 mg2/dL2). 460
Reasoning: 461
15
HypoPT is characterized by a relatively high serum phosphate level and a higher than normal 462
calcium-phosphate product. This is attributable to the lack of the phosphaturic effect of PTH, 463
as well as an increased intestinal absorption of phosphorus due to activated vitamin D 464
treatment (9;27;43). Risk of extra-skeletal calcifications, including nephrocalcinosis and 465
cataract, is increased in HypoPT. It is generally assumed that this is related to high serum 466
phosphate levels and an increased serum calcium-phosphate product, why it seems reasonable 467
to aim at keeping phosphate levels within the normal range (57). 468
6.2.5 We suggest that serum magnesium levels should be within the reference range. 469
Reasoning: 470
Magnesium is central for several physiological processes, including secretion and actions of 471
PTH. Low magnesium levels may cause functional HypoPT by blunting the (residual) 472
capacity of the parathyroid glands to secrete PTH (58). Moreover, low magnesium levels may 473
cause symptoms similar to hypocalcaemia. Accordingly, it seems reasonable to aim at 474
keeping serum magnesium levels within the reference range. 475
6.2.6 We suggest aiming at an adequate vitamin D status. 476
Reasoning: 477
Vitamin D insufficiency has been associated with adverse effects on skeletal as well as extra-478
skeletal health (59). Severe vitamin D deficiency is associated with symptoms of myopathy, 479
and patients with HypoPT often have neuromuscular complains (9;43;50). To ensure that 480
symptoms are not caused by low vitamin D levels, it seems reasonable to ensure an adequate 481
vitamin D status (53). A serum concentration of 25-hydroxyvitamin D (25OHD) between 75-482
125 nmol/L (30 – 50 ng/mL) may be considered as adequate (60). 483
Remarks: 484
Treatment with activated vitamin D analogues does not ensure an adequate vitamin D status 485
in terms of serum 25-hydroxyvitamin D levels. As calciferol itself may be of importance to a 486
number of cellular processes and may undergo hydroxylation to 1,25(OH)2D catalyzed by 487
local hydroxylases in different tissues (61), it seem reasonable to ensure sufficient 25OHD 488
levels, despite treatment with activated vitamin D analogues. 489
6.2.7 We recommend to personalize treatment and focus on the overall well being and QoL of 490
the patient when implementing different therapeutic efforts, aiming to achieve the therapeutic 491
goals. 492
Reasoning: 493
The therapeutic goals (albumin adjusted serum calcium levels 2.1 - 2.3 mmol/L or S-Ca2+
494
levels 1.10 – 1.25 mmol/L) are mainly based on reasoning according to normal physiology, 495
16
assuming that normalization of biochemical indices may be advantageous to patients. 496
However, it has to be emphasized that no firm evidence exists on long-term benefits (or 497
harms) of achieving these therapeutic goals. Accordingly, patients cannot be ensured long-498
term beneficial effects, when accepting potential side-effects to drug treatment or 499
(troublesome) changes in lifestyle (dietary habits). Thus, we consider it inappropriate 500
management, if therapeutic efforts have immediate negative impact on a patient’s well-being 501
or QoL. 502
6.2.8 We recommend providing information/education that enables patients to know the 503
possible symptoms of hypo- or hypercalcaemia and/or complications to their disease. 504
Reasoning: 505
As stated in Section 6.4, we suggest monitoring of patients at regular time intervals. Serum 506
calcium levels may, however, change, and complications may emerge at any time, with or 507
without any apparent reasons. Thus, we find it of importance to empower patients with 508
knowledge of symptoms and co-morbidities and drugs that may be related to changes in the 509
course of their disease. 510
Table 1 shows typical symptoms of hypo- and hypercalcaemia, which patients should be 511
informed of. 512
Table 2 shows co-morbidities which may occur with an increased prevalence in HypoPT. 513
Table 3 list drugs, conditions and diseases which may interfere with calcium homeostasis. If a 514
patient is diagnosed with one of the diseases or initiates treatment with one of the drugs, this 515
may necessitate changes in the medical treatment of HypoPT in order to maintain 516
normocalcaemia. 517
6.3. Treatment 518
6.3.1 We recommend treatment of all patients with chronic HypoPT with symptoms of 519
hypocalcaemia and/or an albumin adjusted serum calcium level < 2.0 mmol/L (< 8.0 mg/dL / 520
ionized serum calcium (S-Ca2+) levels < 1.00 mmol/L) . 521
6.3.2 We suggest offering treatment to asymptomatic patients with chronic HypoPT and an 522
albumin adjusted calcium level between 2.0 mmol/L (8.0 mg/dL / S-Ca2+ 1.10 mmol/L) and 523
the lower limit of the reference range in order to assess whether this may improve their well-524
being. 525
Reasoning: 526
In chronic HypoPT, symptoms of hypocalcaemia may vary widely, from an asymptomatic 527
state to life-threatening conditions, such as seizures, cardiac failure, bronchospasm and 528
laryngospasm etc. (7;9;27;43). While it is obvious to recommend treatment of patients with 529
17
severe symptoms of hypocalcaemia, no evidence exists on whether asymptomatic patients 530
with biochemical hypocalcaemia should be treated. No limit of serum calcium levels have 531
been defined below which, treatment is unquestionably needed. Symptoms of hypocalcaemia 532
do not translate directly to serum calcium levels. Sudden fluctuations in serum calcium levels 533
may cause symptoms, even if calcium levels are (almost) normal. On the other hand, no 534
apparent symptoms may be present, despite low calcium levels, if the hypocalcaemia has 535
developed slowly. In a patient with intact parathyroid function, serum calcium levels are 536
tightly regulated within a narrow range (62;63). It seems likely that patients with no 537
complaints of hypocalcaemia, despite (very) low serum calcium levels, have adapted to a new 538
calcium homeostasis which may have blunted their hypocalcaemic symptoms. We, therefore, 539
consider it reasonable to offer treatment to asymptomatic patients with chronic HypoPT, since 540
treatment might improve their well-being (Figure 1). If no improvements occur following 6-541
12 months of therapy, the need for treatment may be reconsidered, especially if 542
hypocalcaemia is only mild. However, vitamin D levels should be optimised. 543
6.3.3 We recommend the use of activated vitamin D analogues plus calcium supplements in 544
divided doses as the primary therapy. 545
6.3.4 If activated vitamin D analogues are not available, we recommend treatment with 546
calciferol (preferentially cholecalciferol). 547
6.3.5 We recommend that the doses of activated vitamin D analogues or cholecalciferol are 548
titrated in such a manner that patients are without symptoms of hypocalcaemia and serum 549
calcium levels are maintained within the target range. 550
Reasoning: 551
No evidence exists from direct comparisons within clinical trials as to the best way to treat 552
HypoPT. Prior to the development of activated vitamin D analogues, calciferol (ergocalciferol 553
[vitamin D2] or cholecalciferol [vitamin D3]) was used in the treatment of HypoPT and 554
supraphysiological doses of calciferol (typical 25,000 – 200,000 IU/day) were needed to 555
maintain normocalcaemia, usually resulting in very high plasma concentrations of 25OHD 556
(typically 500-1000 nmol/l). Following the development of activated vitamin D analogues, 557
small case-series showed that normocalcaemia could be achieved in HypoPT treated with 558
activated vitamin D analogues (64;65). Today, activated vitamin D analogues are preferred 559
due to a shorter plasma half-life, allowing for dose titration at shorter time-intervals compared 560
with calciferol. Moreover, in case of intoxication, serum calcium levels will normalize faster 561
if patients are treated with activated vitamin D analogues (66;67). 562
18
Either alfacalcidol (1α-hydroxyvitamin D) or calcitriol (1,25(OH)2D) may be used. Effects of 563
the different analogues have not been compared head-to-head in HypoPT. In terms of 564
calcaemic effects, calcitriol is approximately twice as potent as alfacalcidol. To maintain 565
serum calcium levels within the target range, the daily dose must be carefully titrated, as the 566
dose needed varies between patients. Daily doses of calcitriol are typically 0.25 to 2.0 μg, 567
equal to a daily dose of 0.5 to 4.0 μg of alfacalcidol (68). 568
If serum calcium levels are slightly outside the target range, or a patient is complaining of 569
symptoms, the daily dose of activated vitamin D analogue may be gradually changed (Figure 570
1) i.e., daily dose of alfacalcidol may be changed by 0.5 (or 0.25) μg corresponding to a 0.25 571
μg change in dose of calcitriol. Larger changes in dose may be needed in case of severe 572
hypo- or hypercalcaemia. In order to allow for a new steady-state, dose adjustments should (if 573
possible) not be performed more frequently than at 2-3 days’ time intervals (69). If only 574
minor symptoms or biochemical disturbances are to be adjusted, weeks may be allowed to 575
pass between dose adjustments. If a patient is on treatment with high doses of calciferol, 2-3 576
months are needed between dose adjustments, before a new steady state has emerged. 577
Intake of calcium from supplements (or diet) causes only a relatively transient increase in 578
serum calcium levels. Extra intake of calcium may be recommended pro re nata (PRN) if a 579
patient is only experiencing symptoms of hypocalcaemia once in a while. 580
Calcium intake: An adequate daily intake of calcium from diet and supplements is advisable. 581
Intake of calcium from dietary sources (mainly dairy products) is considered equivalent to 582
intake from supplements (70). Patients with HypoPT are most often recommended to use 583
calcium supplements in a total daily dose of 800-2000 mg of elemental calcium, although 584
sometimes higher doses are used. The absorptive capacity of the intestine is probably 585
saturated by intake of a dose of approximately 500 mg of calcium in one ingestion. Thus, a 586
higher amount per dose is unlikely to be of benefit to the patient (71;72). Accordingly, intake 587
of calcium should be divided into smaller doses and spread throughout the day. Different 588
calcium salts are available as supplements. Calcium carbonate is most often used and less 589
expensive than other calcium preparations. However, calcium carbonate requires an acidic 590
environment for absorption and should, therefore, be taken together with a meal (70). Calcium 591
citrate should be recommended to patients with achlorhydria or on treatment with proton 592
pump inhibitors (PPI), as well as to patients who preferred to take supplements outside 593
mealtimes (72). 594
19
A high intake of calcium from diet and supplements may lower the dose of vitamin D needed 595
to maintain serum calcium levels within the target range. It is unknown whether a relatively 596
high intake of calcium from supplements (> 1000 mg/d) is of advantage, as it may cause 597
hypercalciuria. On the other hand calcium binds phosphorus in the intestine and may thereby 598
lower plasma phosphate levels (73). Thus, in selected cases high doses of calcium supplement 599
may be needed. 600
6.3.6 We recommend vitamin D supplementations in a daily dose of 1000-2000 IU to patients 601
treated with activated vitamin D analogues. 602
Reasoning: 603
In order to ensure an adequate vitamin D status, a daily cholecalciferol dose of 1000-2000 IU 604
(25-50 g) will most likely ensure a serum 25OHD level within the suggested target range of 605
75-125 nmol/L (30 – 50 ng/mL), Figure 1. 606
6.3.7 In a patient with hypercalciuria, we suggest considering a reduction in calcium intake, a 607
sodium-restricted diet, and treatment with a thiazide diuretic. 608
Reasoning: 609
In HypoPT, the risk of renal complications is increased (13;27;43), but no data are available 610
on whether a high renal calcium excretion is associated with the increased risk. However, as 611
HypoPT causes pathological high renal calcium excretion it is reasonable to aim to normalize 612
the 24-hour urinary calcium, Figure 1. 613
No data exist on whether dietary recommendations are useful in reducing urinary calcium in 614
HypoPT. In patients with intact parathyroid function, urinary calcium is positively associated 615
with intake of calcium and sodium (74;75). Accordingly, it may be helpful to reduce the 616
intake of sodium (Figure 1). If patients are on treatment with a high daily dose of calcium 617
supplements, daily dose of (activated) vitamin D may be increased in order to allow for a 618
reduced dose of calcium supplements. 619
If dietary recommendations or changes in the daily dose of calcium supplements and/or 620
activated vitamin D analogue do not reduce urinary calcium, treatment with a thiazide diuretic 621
may be considered, Figure 1. Thiazide diuretics have been shown to reduce urinary calcium 622
in patients with HypoPT (44;76-79). By lowering renal calcium excretion, thiazides may exert 623
a calcium-sparing effect, allowing for reduced doses of calcium supplements. Addition of 624
amiloride to treatment with a thiazide may further lower urinary calcium losses and decrease 625
the risk of hypokalemia. Moreover, amiloride may lower renal magnesium excretion (80). 626
However, no data are available on whether thiazides reduce risk of renal complications in 627
HypoPT. 628
20
If a thiazide diuretic is prescribed, it should be noted that the hypocalciuric effect is dose-629
dependent, and treatment should preferably be combined with sodium restriction (81). A 630
relatively high dose administered twice a day is often needed in order to lower 24 hour 631
urinary calcium i.e., hydrochlorothiazide 50 mg twice daily or bendroflumethiazide 5 mg 632
twice daily. Thiazide-like diuretics (e.g., chlorthalidone and indapamide) may, however, be 633
administered only once daily as they have a longer duration of action. 634
Risk of side-effects increases with dose, and potential side-effects should be monitored 635
closely during treatment, including blood electrolyte disturbances and blood pressure. 636
6.3.8 In a patient with renal stones, we recommend evaluation of renal stone risk factors and 637
management according to relevant international guidelines. 638
Reasoning: 639
Although calcium-containing stones are likely to be the most frequent type of stones in 640
HypoPT, patients with renal stones should receive a full evaluation of possible causes, and 641
treatment should be advised according to relevant guidelines (82;83), Figure 1. 642
6.3.9 In a patient with hyperphosphataemia and/or an elevated calcium-phosphate product, 643
we suggest considering dietary interventions and/or adjustment of treatment with calcium and 644
vitamin D analogues. 645
Reasoning: 646
As high serum phosphate levels and/or a high calcium-phosphate product are presumed to 647
increase risk of extra-skeletal calcifications, interventions aiming at normalizing these 648
biochemical indices may be considered (84) (Figure 1), although evidence from trials are 649
lacking. Patients may be advised to reduce intake of dietary sources rich in phosphate. As 650
calcium binds phosphate in the intestine and calcitriol increases intestinal absorption of 651
phosphorous, it may be considered to titrate therapy so that the daily dose of calcium 652
supplements is increased, which may allow for a decrease in daily dose of activated vitamin D 653
analogue. Following such changes, 24-hour urinary calcium should be measured in order to 654
ensure that patients have not developed severe hypercalciuria. No data exist on use of 655
phosphate binders in HypoPT. Of notice, however, recent studies in patients with chronic 656
kidney diseases (mostly not on dialysis) have suggested an increased mortality and risk of 657
vascular calcifications in those on treatment with calcium-containing vs. calcium-free 658
phosphate binders (85). It is unknown whether lowering phosphate levels in HypoPT by 659
increasing calcium intake is of benefit or harm to patients, which is why no firm 660
recommendation can be stated on this matter. 661
21
6.3.10 In a patient with hypomagnesaemia, we suggest considering measures that may 662
increase serum magnesium levels. 663
Reasoning: 664
Low magnesium levels are often reported in HypoPT. In addition to HypoPT as an 665
explanation for hypomagnesaemia, other causes should be considered such as treatment with 666
diuretics and PPI (86). In order to normalize magnesium levels, treatment with magnesium 667
supplements or amiloride may be considered (80;87), Figure 1. 668
Magnesium supplements are, however, not always well tolerated due to gastrointestinal 669
adverse events. 670
In addition to lowering renal potassium excretion, amiloride has also been shown (in patients 671
with an intact parathyroid function) to work as a magnesium-sparing diuretic (24). 672
If magnesium levels are chronically low, a magnesium infusion test (0.5 mmol of magnesium 673
per kg of body weight, in a saline solution of 500 mL, administered as an intravenous infusion 674
over 6 hours) may be considered. If renal function is mildly impaired, the dose should be 675
reduced. If renal function is severely impaired, this test should not be done. The results of this 676
test will provide information on whether the patient has intracellular magnesium depletion. If 677
24-hour urinary magnesium excretion is < 50% of the amount infused, this signifies 678
magnesium depletion, and the infusion itself will treat the magnesium deficiency (88). 679
6.3.11 We recommend against routine use of replacement therapy with PTH or PTH 680
analogues 681
Reasoning: 682
Normocalcaemia can be achieved in response to subcutaneous injections with intact PTH or 683
the N-terminal fragment of PTH (PTH1-34; teriparatide) (25;29;48). Treatment with PTH 684
reduces the dose of activated vitamin D analogues and calcium supplements needed to remain 685
at target levels of biochemical indices. However, long-term beneficial effects have so far not 686
been shown in RCTs examining other outcomes such as hypercalciuria, renal complications, 687
or QoL (29;48;50). A markedly improved well-being has, nevertheless, been reported in 688
response to PTH therapy in case reports and in sub-groups of patients included in trials on 689
PTH therapy (29;49;89). Accordingly, it is possible that PTH therapy may be of benefit for 690
certain patients. 691
Remarks 692
Injection therapy with PTH is currently not marketed for the treatment of HypoPT in Europe. 693
Recombinant human intact parathyroid hormone (rhPTH1-84) (Natpara®, Shire) has recently 694
been approved by the U.S. Food and Drug Administration for long-term treatment of 695
22
HypoPT. Marketing authorization application for rhPTH1-84 has been submitted to the 696
European Medicines Agency. 697
6.4. Monitoring 698
6.4.1 We recommend routine biochemical monitoring of serum levels ionized or albumin 699
adjusted total calcium, phosphate, magnesium and creatinine (eGFR), as well as assessment 700
of symptoms of hypocalcaemia and hypercalcaemia at regular time intervals (e.g., every 3-6 701
months). 702
Reasoning: 703
In a patient with HypoPT on stable therapy, serum calcium and renal function may change 704
without obvious causes and without causing noticeable symptoms. Although no data exist on 705
how best to monitor patients with HypoPT, it seems reasonable to offer biochemical screening 706
to patients at regular time intervals, Figure 1. 707
As no straightforward relationship exists between serum calcium levels and hypocalcemic 708
symptoms, occurrence of hypocalcemic symptoms should also be assessed at regular time 709
intervals, in order to assure that the treatment provides relief of symptoms, without causing 710
side-effects. 711
6.4.2 Following changes in therapy, we recommend biochemical monitoring weekly or every 712
other week. 713
Reasoning: 714
If the daily dose of activated vitamin D or calcium is changed or if new drug treatment is 715
introduced (such as thiazide diuretics), serum levels of calcium, phosphate, magnesium and 716
creatinine (eGFR) should be closely monitored for the first weeks, Figure 1. In case of severe 717
hypo- or hypercalcaemia, more frequent monitoring (several times a week) may be needed. 718
6.4.3 We suggest considering monitoring of 24-hour urinary calcium excretion at regular 719
time intervals (e.g., once a year or every second year). 720
Reasoning: 721
As hypercalciuria is considered a risk factor for renal calcifications, assessment of 24-hour 722
urinary calcium at regular time intervals may allow for early intervention if hypercalciuria is 723
present. No data are, however, available on whether this will help to reduce long-term 724
morbidity. 725
6.4.4 We recommend renal imaging if a patient has symptoms of renal stone disease or if 726
serum creatinine levels start to rise. 727
Reasoning: 728
23
Risks of renal complications are significantly increased in HypoPT (13). Deterioration of 729
renal function, as detected by increased creatinine levels, or symptoms compatible with renal 730
stone disease should be carefully investigated, Figure 1. It is unknown whether screening for 731
renal calcifications by use of routine renal imaging at certain time intervals is advantageous. 732
6.4.5 We suggest monitoring for development of signs or symptoms of co-morbidities at 733
regular time intervals (e.g., yearly). 734
Reasoning: 735
HypoPT is associated with a number of co-morbidities (Table 2). Early detection of such 736
complications may be of importance which is why it seems reasonable to assess, in a 737
systematic manner, whether patients are experiencing symptoms which may indicate 738
emerging complications. Of note, no study in patients with HypoPT has shown the beneficial 739
effect of screening for these co-morbidities. 740
As certain drugs/diseases and conditions may interfere with the treatment of HypoPT, 741
awareness of concomitant treatment with other drugs is also needed (Table 3). 742
6.4.6 We advise against routine monitoring of bone mineral density by dual energy X-ray 743
absorptiometry (DXA) scans. 744
Reasoning: 745
HypoPT is a state of very low bone turnover and bone mineral density (BMD) is not expected 746
to decrease during the course of HypoPT (90) unless other disorders or drug therapies occur 747
(e.g., glucocorticoids). 748
6.5. Special circumstances 749
6.5.1 Autosomal dominant hypocalcaemia (ADH): We recommend frequent monitoring of 750
patients with ADH, who are being treated with calcium and/or activated vitamin D 751
analogues, as such patients may be at high risk of hypercalciuria and renal complications. 752
Reasoning: 753
ADH is caused by an activating mutation in the calcium-sensing receptor (CaSR). A diagnosis 754
of ADH can be established through genetic testing (OMIM 601198). The gain of function 755
mutation causes a lowering of the calcium set-point in the parathyroid glands. At equivalent 756
serum calcium levels, patients with ADH have lower PTH levels than normal individuals. In a 757
strict sense, this is not a state of HypoPT, as the parathyroid glands are well preserved 758
although less responsive to a hypocalcemic challenge (91). The CaSR is also expressed in the 759
renal tubule, and renal calcium excretion is often markedly increased in patients with ADH 760
who are at increased risk of renal complications (54;92). In case reports, thiazide diuretics 761
have been reported to reduce urinary calcium in patients with ADH (44;77;93). 762
24
6.5.2 Pregnancy and breastfeeding: We suggest treatment with activated vitamin D analogues 763
and calcium supplements as in non-pregnant patients. 764
Reasoning: 765
Although pregnancy-related increases in 1,25(OH)2D initially and in PTHrP later would 766
suggest that calcium and vitamin D analogues may need reducing during pregnancy, this is 767
often not the case. Especially after the 20th
week of pregnancy, many women with HypoPT 768
actually need gradually higher doses of activated vitamin D analogues to maintain serum 769
calcium levels in the target range and avoid symptoms of hypocalcaemia (94-96). 770
There are relatively few case reports and no trials that test management strategies for women 771
with chronic HypoPT during pregnancy and lactation. The largest series included 12 pregnant 772
women who were treated with oral calcium and calcitriol and reported a high level of overall 773
safety during pregnancy (35) (see Appendix 4). These and other authors have recommended 774
oral calcium supplements to be combined with calcitriol (doses of 0.25 to 3.0 ug per day) for 775
treatment of chronic HypoPT during pregnancy (32;35). Other reports support the 776
recommendation to use calcitriol in pregnancy and lactation, due to it potency and short half-777
life, compared to other forms of vitamin D (94-96), but the amount of evidence is low. 778
During lactation, PTHrP levels rise and many women develop hypercalcaemia if calcium and 779
activated vitamin D supplements are not often dramatically reduced. Then, gradually after 780
weaning, these changes in maternal hormones regress, and a new steady-state is achieved. 781
Generally, patients with hypoparathyroidism stabilize on a similar if not the same medical 782
regimen as pre-pregnancy, but careful adjustment and monitoring of these patients are needed 783
to assure smooth transition. 784
6.5.3 We suggest monitoring serum ionized calcium regularly (every 2nd or 3rd week) during 785
pregnancy and breastfeeding with levels to be kept at the lower end of the normal range 786
(serum albumin adjusted total calcium is also acceptable). 787
Reasoning: Serum total calcium falls in normal pregnancy due to haemodilution-induced 788
reductions in serum albumin levels, but ionized calcium remains stable (34;97). Thus, in 789
pregnant women with HypoPT, serum ionized calcium is the preferred parameter that should 790
be frequently monitored (e.g., every 2 or 3 weeks) (30;32). Alternatively, albumin-corrected 791
total serum is an acceptable parameter to follow (30). Levels of serum calcium are 792
recommended to be kept at the lower end of the normal range in pregnant women with 793
chronic HypoPT. During lactation, there are high rates of bone resorption due to breast tissue 794
production of PTHrP (98). These events mandate careful monitoring of serum calcium levels 795
in women with HypoPT who are nursing because hypercalcaemia is commonly encountered if 796
25
vitamin D analogue therapy is not quickly adjusted. The onset of hypercalcaemia during 797
breastfeeding can be immediate (94;98-102) and has even been reported when treating women 798
with HypoPT with longer-acting ergocalciferol, who did not breast-feed (103). Gradually after 799
weaning, the above changes in maternal hormones regress, and a new steady-state is achieved. 800
801
802
803
804
26
Acknowledgement1 805
The authors of the guideline want to thank and acknowledge Kari Lima, MD. Ph.D, Akershus 806
University Hospital, Norway for expert review before sending the Guideline out to ESE 807
Members 808
27
Table 1. Symptoms patients should be informed of to allow for early detection of hypo- or 809
hypercalcaemia. 810
Hypocalcaemia Hypercalcaemia
CNS Depression Irritability Confusion or disorientation Seizures
Weakness Headache Drowsiness Confusion or disorientation Poor memory Reduced concentration
Neuromuscular Numbness and tingling (paraesthesia) in circumoral and acral areas (fingers, toes) Spasms / twitches Cramps
Muscle weakness
Cardiovascular Fast, slow, or uneven heart rate Symptoms of congestive heart failure
Fast, slow, or uneven heart rate Hypertension
Gastrointestinal Abdominal cramps Loss of appetite Nausea / vomiting Abdominal pain Constipation
Renal Polyuria Dry mouth and or increased thirst
Respiratory Shortness of breath Wheezing Throat tightness
811
812
28
Table 2. Co-morbidities which may occur with an increased prevalence in patients with 813
HypoPT (13;14;22;23;26;27;50;104). 814
Organ system Co-morbidity
Renal
Renal stone disease and impaired renal function Renal calcifications
Immunological Infections
Neuropsychiatric Neuropsychiatric diseases Depression Impaired quality of life
Musculoskeletal Muscle stiffness / pain Seizures Proximal humerus fractures*
Cardiovascular Ischemic heart disease*
CNS Intracerebral calcifications *
Eyes Cataract *
* An increased risk has only been documented in nonsurgical HypoPT. 815
816
817
29
Table 3. Drug therapy and diseases which may interfere with calcium homeostasis and 818
necessitate changes in monitoring and therapy 819
820
* Changes in the free (ionized) fraction of serum calcium (Ca2+) cannot be monitored by measuring total calcium levels. Many laboratories 821
report serum Ca2+ levels adjusted to a neutral pH value (pH 7.4), which does not reflect the actual serum Ca2+ level in a patient with 822
disturbances in acid-base balance. If so, patients may have symptoms despite (apparently) normal calcium levels and Ca2+ levels at actual 823
pH should be requested. 824
825
826
827
828
829
Drug / disease Mechanism Possible adverse effects in
HypoPT
Action
Loop diuretics Increased urinary calcium losses
May aggravate hypercalciuria and lower serum calcium levels
Avoid if possible
Thiazide diuretics Decreased urinary calcium losses
May increase serum calcium levels
May be used in a patient with HypoPT (see text, section 3.7)
Systemic glucocorticoids Decreased intestinal calcium absorption and increased urinary calcium losses
May cause hypocalcaemia Avoid if possible
Antiresorptive drugs Decreased bone turnover May cause hypocalcaemia Rarely needed, as HypoPT is a state of (very) low bone turnover
Proton pump inhibitors (PPI) May cause hypomagnesaemia
May lower serum calcium levels and cause symptoms similar to hypocalcaemia
Avoid if possible – otherwise magnesium supplements as needed
Chemotherapy: Cisplatin, 5-Fluorouracil, Leucovorin
May cause hypomagnesaemia
May lower serum calcium levels and cause symptoms similar to hypocalcaemia
Magnesium supplements, as needed
Cardiac glycosides (e.g., digoxin)
Hypercalcaemia may predispose to digoxin toxicity Hypocalcaemia may reduce the efficacy of digoxin
Arrhythmias Avoid if possible. If needed, close monitoring by a cardiologist
Diarrhea / gastrointestinal disease
May reduce intestinal absorption of calcium and vitamin D
May cause hypocalcaemia Close monitoring of serum calcium levels with dose adjustments as needed
Changes in (correction of) acid-base balance*
The affinity of calcium to bind to proteins in serum is highly pH dependent – only the free fraction in physiological active
Correction of metabolic acidosis may cause hypocalcaemia Correction of metabolic alkalosis may cause hypercalcaemia
Immobilization Increased bone resorption. In healthy individuals, PTH and 1,25-dihydroxyvitamin D levels are suppressed.
May cause hypercalcaemia
30
Figure 1 830
831 832
31
Reference List 833
834
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