PTH 1-34 Replacement Therapy has Minimal Effect on Quality of Life in Patients with Hypoparathyroidism

Abstract

In addition to hypocalcemia, patients with hypoparathyroidism report poor quality of life (QOL), complaining of fatigue and “brain fog.” Parathyroid hormone (PTH) therapy can effectively manage hypocalcemia; however, the effects of PTH treatment on QOL are unclear. Thirty-one patients with hypoparathyroidism were treated in an open-label study with full replacement subcutaneous PTH 1-34 twice daily for up to 5.3 years, with individualized fine dosing titration. Prior to initiation of PTH 1-34, conventional therapy was optimized. The SF-36 Health Survey, Fatigue Symptom Inventory (FSI), and 6-minute walk test (6MWT) were assessed at PTH start (baseline), every 6 months on PTH, and after PTH discontinuation. The SF-36 assesses physical function (PF), physical role limitations (RP), bodily pain (BP), general health (GH), vitality (VT), emotional role limitations (RE), social function (SF) and mental health (MH). Compared to population norms, patients at baseline had lower scores in RP, GH, VT, and MH (p<0.05), consistent with impaired quality of life. With PTH therapy, only GH at 6 months and VT at 12 months improved (p<0.05). At the last treatment timepoint, RP, VT, and SF improved compared to baseline (P<0.05). However, follow-up scores were unchanged from baseline or last PTH treatment, except for SF, which had decreased at follow-up compared to on-PTH (P<0.05). On the FSI, there were no changes in fatigue frequency; perceived interference was improved at 12 and 18-months and composite severity was improved only at 60 months (p<0.05). The 6MWT measures did not change. In conclusion, hypoparathyroidism is associated with decreased QOL. Despite the bias in open-label studies to predict improvements in QOL, PTH therapy had limited and non-sustained effects on QOL, inconclusive changes in fatigue experience, and no change in the 6MWT. While PTH 1-34 can adequately manage the hypocalcemia in hypoparathyroidism, its effects on QOL appear to be minimal.

Introduction

Hypoparathyroidism is a condition of hypocalcemia due to inadequate secretion of parathyroid hormone (PTH). PTH is an 84-amino acid peptide hormone (PTH 1-84 or intact PTH) produced by the parathyroid glands, with biological activity residing in the first 34 amino acids (PTH 1-34 or teriparatide)⁽¹⁾. Typically, low calcium signals the parathyroid glands via the calcium sensing receptor (CaSR), causing release of PTH, which acts at the kidney to increase reabsorption of calcium at the distal tubule and bone to release calcium. In the proximal tubule, PTH increases 1α-hydroxylase activity, converting 25-OH-vitamin D to its active form, 1,25(OH)₂-Vitamin D, which promotes gastrointestinal calcium absorption⁽²⁾. Taken together, PTH acts to restore blood calcium levels to normal. PTH also plays a role in regulating blood phosphate levels by promoting renal phosphate excretion at the proximal tubule.

The most common etiology for hypoparathyroidism is parathyroid gland damage during neck surgery. Hypoparathyroidism can also be due to autoimmune parathyroid disease and genetic disorders affecting parathyroid gland formation or function⁽³⁾. PTH deficiency causes hypocalcemia and hyperphosphatemia⁽⁴⁾. Symptoms include neuromuscular excitability that can range from twitching to tetany. Patients also develop increased bone mass, intracranial calcifications, cataracts, psychological effects and decreased quality of life (QOL)⁽⁵⁾. When surveyed, most patients reported moderate or severe symptoms, illustrating the lack of adequate disease control on conventional therapy⁽⁶⁾, which typically includes calcium and active vitamin D in multiple divided doses.

The effects of hypoparathyroidism on QOL are significant, with many patients reporting fatigue, a lack of focus that patients refer to as “brain fog,” and impaired memory (Table 1). A study of 688 patients with post-surgical hypoparathyroidism showed an increase risk of depression and bipolar affective disorders⁽⁷⁾. QOL, including physical functioning, was reduced in patients with both post-surgical hypothyroidism and hypoparathyroidism as compared to those who developed hypothyroidism alone⁽⁸⁾. Another study showed reduced QOL in 57 patients with non-surgical hypoparathyroidism⁽⁹⁾. Neuropsychological dysfunction was present in up to one-third of a cohort with idiopathic hypoparathyroidism, a finding which was not correlated to intracranial calcifications⁽¹⁰⁾. In another cohort, patients with nonsurgical hypoparathyroidism also had an increased risk of depression or hospitalization due to a neuropsychiatric disorder⁽¹¹⁾. When 374 adults with a diagnosis of hypoparathyroidism for at least 6 months were surveyed using an online questionnaire, 45% felt hypoparathyroidism interfered with their lives, 85% felt an inability to perform household activities, and 20% had a change in employment status based on the diagnosis⁽¹²⁾. In a study of 37 hypoparathyroid patients on conventional therapy and 20 control patients who underwent thyroidectomy, in which psychological symptoms were self-reported by the Symptom Checklist-90-R (SCL-90-R), patients with hypoparathyroidism had a significantly higher Global Severity Index (thought to reflect general quality of life) than control patients⁽¹³⁾. There were no significant differences in the other two indices of the SCL-90-R-Positive Symptom Total (PST) or Positive Symptom Distress Index (PSDI) and no correlation between GSI score and serum calcium level⁽¹³⁾. Similarly, in a study of 25 women with postsurgical hypoparathyroidism, patients reported significantly higher complaint scores on the SCL-90-R, Giessen Complaint List (GBB-24), and von Zerssen Symptom List (B-L Zerssen), reflecting worse QOL even though serum calcium was largely in the normal range⁽¹⁴⁾.

Table 1.

Quality of life outcomes in studies of patients with hypoparathyroidism

Patients	Evaluation	Results	Comments	Ref
N=25 Post-surgical hypoparathyroidism N=25 Post thyroid surgery	Surveys: SCL-90-R, GBB-24, B-L Zerssen	Hypoparathyroid pts ↑ GBB-24 scores, B-L Zerssen, SCL-90-R, specifically: ↑ anxiety, phobic anxiety, their physical equivalents	lower quality of life in patients with hypoparathyroidism	(14)
N=62 Idiopathic hypoparathyroidism N= 70 Controls	Psychologist: HMSE, BPRS, TMT-A/B, AIMS, PGIMS, BGT, FTT, VAIS, BVRT, Stroop test	↑ neuropsychological dysfunction	No relationship to intracranial calcification	(10)
N=374 Hypoparathyroidism	Survey	45%- significant interference with lives 85%- inability to perform household activities 20%- disease associated change in employment		(12)
N=688 Post-surgical hypoparathyroidism N = 2064 Controls	Chart Review	↑ incidence of diagnosis of depression, bipolar disorder		(7)
N=180 Nonsurgical hypoparathyroidism N = 540 Controls	Chart Review	↑ risk of being hospitalized due to any neuropsychiatric disorder ↑ risk of developing depression		(11)
N=57 Nonsurgical hypoparathyroidism N=55 Postsurgical hypoparathyroidism	Survey: SF-36v2, WHO-5	↓ 8 domains of SF-36 at baseline vs normal population ↓ PF, SF, MH, MCS non- vs postsurgical hypoparathyroidism ↔ WHO-5 scores		(9)
N=22 Hypoparathyroid + Hypothyroid N=22 Hypothyroid N=22 Healthy controls	Survey: SF-36v2, WHO-5	Mental:  ↓ VT, SF, MH vs controls Physical:  ↓GH, PP, RF, BP, PCS vs controls; ↓PF, RP, PCS vs Hypothyroid WHO-5 index ↓ in Hypothyroid+hypoparathyroid pts ↔ hypoparathyroid pts vs hypothyroid pts	Hypoparathyroid pts ↑ Timed up and Go, ↑ time repeated chair stands vs controls or hypothyroid pts	(8)
N=37 Hypoparathyroidism (31-postsurgical, 6-autoimmune) N=20 Post-thyroidectomy	Survey: SCL-90-R: GSI, PST, PSDI	↑ GSI Score in hypoparathyroid pts vs control ↑ GSI when comparing n=31 postsurgical pts vs control ↔ PST ↔ PSDI	No correlation between GSI and Ca level	(13)
N=398 Inadequately controlled hypoparathyroidism	Anonymous survey: SF-36 EQ-5D-5L	↓ PCS & MCS (Significance not reported) VT and GH most impacted		(6)

Abbreviations: months (mo), year (yr) weeks (wks), Symptom Checklist 90 (SCL-90-R), Giessen Complaint List (GBB-24), Von Zerssen Symptom List (B-L Zerssen), Global Severity Index (GSI), Positive Symptoms Total (PST), Positive Symptom Distress Index (PSDI), Hindi Mental State Examination (HMSE), Brief Psychiatric Rating Scale (BPRS), Trail Making Test (TMT-A/B), Abnormal Involuntary Movement Scale (AIMS), PGI-Memory scale (PGIMS), Bender Gestalt Test (BGT), Finger Tapping test (FTT), Verbal Adult Intelligence Sxale (VAIS), Benton Visual Retention Test (BVRT), Five-Level EuroQoL 5 Dimensions (EQ-5D-5L), calcium (ca). SF-36 abbreviations: physical functioning (PF), role-physical (RP), bodily pain (BP), general healthy (GH), vitality (VT), social functioning (SF), role-emotional (RE), mental health (MH), physical component summary (PCS) mental health component summary (MCS).

As QOL complaints often persist even in the presence of eucalcemia, it has been suggested that the lack of PTH itself may have a direct role on well-being, independent of blood calcium. Consistent with a direct effect of PTH on the central nervous system, PTH receptors have been reported in the brain ⁽¹⁵⁾. PTH, however, does not appear to cross the blood-brain barrier⁽¹⁶⁾.

Hormone replacement options include recombinant PTH 1-84, which has been approved for hypoparathyroid patients not well-controlled on conventional treatment, and PTH 1-34, which has been approved for osteoporosis but could be used off-label in hypoparathyroidism^(17,18). Studies of the effect of PTH replacement on QOL in hypoparathyroidism have been conflicting^(5,19). While some reports show improvements, persisting for up to 8 years of PTH 1-84 treatment^(20–23), others show no benefit⁽²⁴⁾, or variable results of PTH treatment^(25,26). We therefore aimed to compare QOL before, during, and after treatment with twice daily PTH 1-34 full replacement therapy, which was carefully individualized and titrated to achieve a blood calcium of 7.6–9.0 mg/dL, in a cohort of 31 patients with hypoparathyroidism studied for up to five years.

Methods

Study Design

This was a longitudinal open-label, uncontrolled study of synthetic human PTH 1-34 (hPTH) replacement therapy in 31 patients with hypoparathyroidism (25 women, 6 men), ages 16–60 years old⁽²⁷⁾. Included patients had physician-diagnosed hypoparathyroidism for at least 1-year, confirmed by an intact PTH <30 pg/mL with concomitant blood calcium below the normal range upon screening. The majority of patients (20) had postsurgical hypoparathyroidism; four had activating pathogenic variants of the calcium-sensing receptor, two had 22q11.2 deletion syndrome, 1 had hypoparathyroidism-deafness-renal syndrome, and four had idiopathic/acquired autoimmune disease. Patients were excluded if they had significant liver or kidney disease, other chronic diseases affecting mineral metabolism, a history of chronic steroid or bisphosphonate use, active thyroid cancer, or pregnancy. The primary objective of the study was to evaluate the skeletal effects of hPTH replacement; secondary objectives included the assessment of quality of life, biochemical parameters, markers of bone metabolism, and nephrocalcinosis. The protocol was approved by the Institutional Review Board of the National Institute of Dental and Craniofacial Research (NIDCR) and written informed consent was obtained from adult patients. Written assent and parental consent were obtained from patients less than 18 years old.

Following a screening visit to establish eligibility, patients were managed with calcium and calcitriol supplements which were adjusted to target a blood calcium of 7.6–9.0 mg/dL. Then, just prior to initiation of PTH, calcitriol was discontinued. Twenty-nine patients were started on twice daily (BID) PTH dosing and two were started on thrice daily (TID) dosing. Due to a study redesign, these two patients were switched to twice daily dosing 30 months into the study.

Synthetic human PTH 1-34 was purchased from Bachem, Inc. (Torrance, CA, USA) as a lyophilized powder and prepared by the NIH Pharmaceutical Development Service. The mean starting doses were 0.40 +/− 0.06 ug/kg/day in two doses or 0.47 +/− 0.04 ug/kg/day in three doses. The PTH doses were titrated by as little as 0.5 microgram per dose to maintain the blood calcium level between 7.6–9 mg/dL. A daily calcium intake of 1000 to 2000 mg/day through either diet or supplementation was targeted, and calcium supplements were weaned off as tolerated. 25-OH Vitamin D levels were maintained above 25 ng/mL with supplementation, if necessary. Patients remained off calcitriol while receiving PTH replacement therapy. Patients visited the NIH Clinical Center (Bethesda, MD) every six months. After a maximum of 64 months on hPTH 1-34, conventional therapy was restarted as patients were weaned off hPTH.

QOL Evaluation

QOL was assessed using the SF-36 Health Survey (SF-36), Fatigue Symptom Inventory (FSI), and Six-minute Walk Test (6MWT) at baseline, every six months while on hPTH, and 6 months after discontinuation. The SF-36 Health Survey is a 36-item survey which assesses physical and mental health. This assessment addresses 8 components of health that are scored with u=50, sigma=10 based on US population norms. The four physical components are physical function (PF), physical role limitations (RP), bodily pain (BP), and general health (GH). The four mental components are vitality (VT), emotional role limitations (RE), social function (SF), and mental health (MH). A higher SF-36 score reflects better QOL.

The Fatigue Symptom Inventory (FSI) is a 13-item survey that assesses fatigue severity, frequency, and perceived interference of fatigue with daily activities. A lower score on the FSI indicates better QOL. Finally, patients performed the 6MWT, a self-paced walk on flat ground. The total distance walked in 6 minutes is recorded. The test reflects a patient’s general ability to function in day-to-day activities.

Duration of therapy varied, so data was analyzed both in 6-month increments, and using the groups of baseline, treatment, and post-treatment, where treatment reflects the last treatment time point for each patient.

Statistical Analyses

Repeated measures were analyzed with ANOVA and post-hoc comparisons of Fisher’s protected LSD, and Dunnett-Hsu adjustment. The duration of treatment varied for patients, so analyses were made using the last treatment time point. Covariates for baseline intact PTH (<15 or ≥15 pg/mL), duration of hPTH 1-34 treatment, and cause of hypoparathyroidism (post-surgical vs other) were assessed separately for impact on outcome.

Results

The mean (range) duration of hPTH 1-34 therapy was 37.1 months (7.5 – 63.9); eight patients completed five years of treatment. Reasons for study discontinuation included: pregnancy (1 patient), bone pain (3 patients), decreased radial BMD (2 patients), noncompliance with study (1 patient), acquired lack of responsiveness to therapy (1 patient), inconvenience (1 patient), partial parathyroid recovery (1 patient), and early termination due to unanticipated closure of the NIH Pharmaceutical Development Service (13 patients). Twenty-five patients returned for the follow-up visit. The mean baseline fasting calcium was 8.27 +/− 1.04 mg/dL (normal range: 8.5–10.2 mg/dL); there was no significant change in blood calcium across time points⁽²⁷⁾. At baseline, prior to starting hPTH 1-34, the mean daily dose of calcium supplementation was 1,584.2±813.0 mg (mean±SD), and at the last time point, prior to restarting conventional therapy, the mean daily dose was significantly lower at 164.5±463.7 mg (mean±SD). Within subjects, the change in calcium dose from baseline to the last time point on PTH was significant (p<0.0001). In fact, only four patients still required daily calcium supplementation while on full replacement doses of hPTH 1-34. Some patients took an occasional dose of calcium as needed, but this is not included in the daily dose.

The SF-36 data were analyzed and reported in two ways: first, cross sectionally by comparing grouped patient data pre-PTH, at the patient’s last time point on PTH, and 6 months post-PTH treatment (Figure 1); and next, all data on all patients as assessed prospectively every six months (Figure 2). At baseline, patients’ QOL scores were lower than the US population in physical role limitations, general health, vitality, social functioning, and physical component score (p<0.05). When adjusted for baseline PTH (<15 or ≥15 pg/mL), duration of hPTH 1-34 treatment, or cause of hypoparathyroidism (post-surgical vs other), there was only one noteworthy difference: social functioning was no longer different from the population norm when adjusted for baseline PTH level. At the last treatment point on hPTH 1-34, the mean scores for physical role limitations, vitality, and social functioning had improved compared to baseline (p<0.05, Figure 1). At follow-up, 6 months after discontinuation of PTH therapy, scores were not different from baseline. Only social functioning was decreased at follow-up compared to the last point on treatment (p<0.05), and all other components were unchanged at follow-up compared to scores at the last treatment time point (Figure 1). This was the case even when analyses were adjusted for baseline PTH (<15 or ≥15 pg/mL), duration of hPTH 1-34 treatment, or cause of hypoparathyroidism (post-surgical vs other).

Figure 1.

Mean SF-36 scores before starting hPTH 1-34 (blue), at last visit on hPTH 1-34 (red), and at follow-up (green). hPTH 1-34 treatment was associated with a significant improvement in QOL compared to baseline only in Role Physical (RP), Vitality (VT), and Social Functioning (SF), *p<0.05. At follow-up, 6 months post-PTH therapy, only Social Functioning (SF) decreased from the on-treatment measurement. Compared to the US population norm of 50 (horizontal dashed line), patients reported significantly lower quality of life at baseline in Role Physical (RP), General Health (GH), Vitality (VT), and Social Functioning (SF). Error bars denote 95% confidence intervals. Abbreviations: Physical functioning (PF), Bodily pain (BP), Role limitations due to emotional healthy (RE), Mental health (MH), Physical component score (PCS), Mental component score (MCS).

Figure 2.

SF-36 component scores at each study visit (mean +/− SD). There were improvements in General Health (GH) at 6 months, and in Vitality (VT) at 12 months on hPTH 1-34 therapy compared to the baseline (*p<0.05), but these improvements did not persist across later time points. Numbers in parentheses above bars reflect the number of patients completing the QOL assessment.

No changes were present during hPTH treatment in the domains of physical functioning, bodily pain, general health, emotional role, and mental health. There were only improvements in mean scores of general health at 6 months and vitality at 12 months compared to baseline (p<0.05), but these improvements did not persist across later time points (Figure 2). Again, when the analyses were adjusted for either baseline PTH (<15 or ≥15 pg/mL), duration of hPTH 1-34 treatment, or cause of hypoparathyroidism (post-surgical vs other), the results persisted, showing improvement from baseline only in general health at 6 months and vitality at 12 months.

Fatigue frequency, as measured by the FSI, was unchanged through the study (Figure 3). Perceived interference with activities was improved at the 12 and 18-month time points only (p<0.05). Only composite severity was improved at 60 months (p<0.05). When adjusted for baseline PTH (<15 or ≥15 pg/mL) and duration of hPTH 1-34 treatment, the covariates did not significantly alter the data.

Figure 3.

The Fatigue Symptom Inventory (FSI) was used to assess frequency and severity of fatigue as well as perceived interference with daily activities. A lower score indicates less symptoms. A. The fatigue frequency in days per week (blue dots) and in hours per day (red squares) at baseline and at 6-month intervals while on PTH treatment. There were no significant differences in fatigue frequency at baseline, while on treatment, or at follow up. B. The FSI Score representing the perceived interference of fatigue on daily activities (green line) and the composite severity of fatigue (red line). The perceived interference of fatigue on daily activities was significantly decreased at 12 and 18 months (*p<0.05). The composite severity was significantly improved at 60 months (*p<0.05). Numbers in parentheses above bars reflect the number of patients completing the FSI.

When the analyses were adjusted for cause of hypoparathyroidism, there were significant differences in the fatigue experienced by patients with post-surgical hypoparathyroidism compared to patients with other causes of hypoparathyroidism. Specifically, patients with post-surgical hypoparathyroidism had a greater perceived interference of fatigue with daily activities (p=0.0456), and experienced fatigue more days per week (p=0.0307) and more hours per day (p=0.0242).

Across the 60 months on treatment, there were no significant changes in the average distance walked during the 6MWT at any time point on hPTH 1-34 or at follow-up (Figure 4).

Figure 4.

Distance walked, expressed as a percentage of normal, in six minutes at each six-month time point on PTH therapy. There were no significant differences in the distance walked at baseline, at six-month intervals, or at follow-up. Numbers in parentheses above bars reflect the number of patients completing the six-minute walk test.

Discussion

In this study, patients with hypoparathyroidism were treated with individually titrated, full replacement hPTH 1-34 therapy for up to 60 months. QOL was assessed using three scales, the SF-36, the FSI, and the 6MWT. We found minimal, but unsustained improvements in QOL on the SF-36. In the prospective analyses, general health and vitality were improved at 6 and 12 months respectively, but these changes were transient (Figure 2). In the cross-sectional analysis, improvements at the last time point of hPTH 1-34 treatment compared to baseline were present in three of the ten domains: physical role limitations, vitality, and social function, spanning both the physical and mental components of well-being. The expectation is that a PTH treatment effect would have dissipated by 6 months after discontinuation, which is what occurred with social function. Therefore, changes in physical role limitations and vitality that persisted off treatment suggest that effect may not be directly related to PTH treatment and could represent a placebo effect.

Improvements on the FSI in perceived interference of fatigue on daily activity, only occurred at the 12- and 18-month time points and thus also not sustained. Likewise, composite severity was only improved at 60 months, and it is unclear if this improvement would persist if the study continued past 60 months. There were no changes in the 6MWT at any visit from 6 to 60 months or at follow-up, reflecting largely unchanged day-to-day physical functioning while on hPTH 1-34 therapy. Interestingly, patients with post-surgical hypoparathyroidism experienced more fatigue and perceived greater interference of fatigue on their daily activities. This likely represents the difference between patients who are accustomed to eucalcemia and then experience abrupt-onset hypoparathyroidism compared with those who have hypoparathyroidism from birth or acquire the disease slowly.

The results of our study are in contrast to a series of reports from a single hypoparathyroid cohort treated with recombinant human PTH 1-84 evaluated with the SF-36. At baseline, they found lower scores in 54 hypoparathyroid patients and a significant improvement at one month, which remained at one year⁽²⁰⁾. In an extension of the study that included a subset of 25 patients who completed five years of treatment, improvements in the overall score and seven of the eight component scores were reported⁽²¹⁾. A further subset of 20 of the 25 completed eight years of treatment and showed improvement in the physical component for six years and a sustained improvement in the mental component for eight years⁽²²⁾. It is possible that the group that chose to continue treatment for 5 or 8 years was enriched for those who had improved QOL. Similar SF-36 results were reported in a different cohort treated with fixed doses of subcutaneous PTH 1-34 20 ug twice daily, finding that patients had improvements in all 8 domains at six months⁽²³⁾, which persisted for 2 years⁽²⁸⁾. A possible cause of a type 1 error in these studies is that patients had poor control and more symptoms and complications on conventional treatment and thus sought entry into this non-randomized open-label trial that included increased clinical monitoring compared to pre-study, thus yielding better quality of life. If this were the case, the improved quality of life would not be due to the effect of the drug, per se, but the effect of better control and care in general. In the PTH 1-34 studies, patients had a mean baseline calcium=7.6 mg/dL, which increased significantly to 9.1 mg/dL at 15 days on PTH therapy after which it remained stable during the study^(23,28). This was not the case in PTH 1-84 studies, in which the mean calcium at baseline and after one year of PTH were not different (8.6 mg/dL and 8.3 mg/dL respectively)^(20–22). Our study differed from these in that there was a run-in period during which patients were optimized on conventional treatment, with baseline QOL assessments performed after the optimization period and prior to starting PTH treatment.

Other studies have yielded variable results. Sikjaer et al studied 62 patients with hypoparathyroidism who received either a fixed dose 100 ug/day PTH 1-84 or placebo. Assessment of the SF-36 and the WHO-5 Well-Being Index at baseline and at 6 months and did not find a benefit of PTH (1-84) on QOL⁽²⁴⁾. A percentage of patients did, however, become hypercalcemic while taking PTH 1-84, which could have accounted for the lack of improvement in QOL.

Vokes et al studied 122 patients in a double-blind study in which 83 were randomized to PTH 1-84, and 39 received placebo injection for 24 weeks. The PTH dose could be increased twice, at weeks 2 and 4, and calcium and vitamin D were adjusted throughout the study to maintain serum calcium and reduce hypercalcemia. This study included an optimization period prior to randomization. There were no statistically significant differences in QOL between the PTH treatment and placebo groups. Within the PTH-treated group, however, there were improvements over time in four domains (bodily pain, general health, vitality, and the physical component score) when compared to the group’s baseline, while there were no improvements over time within the placebo group⁽²⁵⁾. Winer et al performed a three-year open label trial of conventional treatment vs PTH 1-34 of 27 patients, and seven of these patients were assessed with a 9-minute walk-run test. In the subset of seven patients, there was no difference between PTH-treated (n=4) and calcitriol-treated (n=3) patients, nor was there a difference between baseline and later measurements in the PTH group. These patients had mild fatigue at baseline as measured by the Multi-faceted Assessment of Fatigue questionnaire, and two of the four patients receiving PTH therapy showed a 50% improvement in fatigue⁽²⁶⁾.

In studies that have shown improvements in QOL due to PTH therapy, the improvement has been greatest in patients with lower QOL scores at baseline. Perhaps our patients did not show robust QOL improvements because their baseline, post-optimization with conventional therapy and pre-PTH treatment QOL scores were relatively high; they scored below the mean US population at baseline in only four of the eight components measured on the SF-36 (physical role limitations, general healthy, vitality, and mental health). In several other studies, patients scored below baseline in all eight components^(20–22). While it is possible that the patients in this study had higher baseline QOL scores because their conventional treatment had been optimized in a run-in period prior to the baseline of the study, some studies have shown decreases in QOL persist in hypoparathyroidism despite optimized conventional treatment^(13,14). One variable not directly assessed was the effect of daily injections and pill burden on QOL. In our study, hPTH 1-34 was given as full-replacement therapy by subcutaneous injection twice daily; patients did not receive calcitriol and took only minimal calcium supplementation when dietary intake was insufficient. This contrasts with some of the PTH 1-84 studies where patients received one daily injection and often continued calcium and calcitriol supplementation^(21,22,24). Stability of calcium levels and medication routines over time is an additional factor which might impact QOL. Perhaps patients who had fluctuating calcium levels and required multiple medication adjustments felt more burdened by their need to change medication routines; on the other hand, these patients could have also felt an improvement in QOL due to more personalized and precise medication adjustments. Another limitation of this study is that it only addressed hPTH 1-34 treatment; therefore, we cannot exclude the possibility that PTH 1-84 or the fragments of the PTH 35-84 region affect quality of life differently than hPTH 1-34.

Another variable in studying QOL is the tools used to assess the patients. The SF-36 Health Survey is a powerful, well-validated measure of QOL that has been used in other studies of hypoparathyroidism. However, this survey is not specific to hypoparathyroidism. Over the past year, two new disease-specific scales have been developed for hypoparathyroidism, the Hypoparathyroidism Patient Experience Scale-Symptom (HPES-Symptom)⁽²⁹⁾ and the Hypoparathyroidism Patient Questionnaire (HPQ 40)⁽³⁰⁾. In the future, these surveys could be utilized and compared to each other and to the SF-36 to determine if specific factors affecting hypoparathyroid patients have been missed in past evaluations of QOL.

Finally, as this was an open-label study, one might expect an inherent bias toward positive effects reported by highly motivated clinical trial participants. Despite this potential bias, hPTH 1-34 therapy had limited and not-sustained effects on QOL, further supporting the lack of an effect of PTH replacement on QOL in hypoparathyroidism.

In summary, this study of 31 patients with hypoparathyroidism treated with individually titrated, full replacement hPTH 1-34 in an open-label design for up to 5 years, found there were minor, non-sustained effects on QOL. These results are consistent with a negligible effect of PTH replacement on QOL in patients with hypoparathyroidism.

Table 2.

Summary of PTH treatment studies on quality of life in patients with hypoparathyroidism.

PTH Preparation	Study Design	n	Baseline	Time	QOL Result	Mental Components	Physical Components	Comments	Ref
PTH (1-84)	Randomized Placebo-Control*	PTH n=32 Placebo n=30	↓ PF, RP, BP, GH, VT, RE, SF, PCS (not MCS)	6 mo	↔ QOL or muscle function- PTH vs placebo	Placebo group: ↑ MCS, VT, RE	Placebo group: ↑ RP, BP PTH group: ↑BP	-WHO-5 Well-Being Index: ↔ in % from baseline to post-rx -Hypercalcemia during the study might complicate these results. -Double blinded	(24)
PTH (1-84)	Randomized Placebo-Control	PTH n=83 Placebo n=39	↓GH, RP, BP, SF, PF	24 wks	↔ between placebo and PTH treated	Placebo group: ↔ vs baseline PTH group: ↑VT	Placebo group: ↔ vs baseline PTH group: ↑PCS, BP, GH	-Optimization period, then PTH or placebo -Patients with ↓ baseline– more likely to improve -Double blinded	(25)
PTH (1-34)	Randomized Open label vs conventional	n=7** with QOL data	Mild fatigue		9 min walk-run: ↔ PTH vs Calcitriol ↔ Baseline vs PTH rx	2 of 4 PTH pts – improved fatigue after 6 mo of PTH		-Total study n=27, but only 7 pts assessed for QOL -Open label	(26)
PTH (1-84)	Open label	n=54#	↓ in all 8 domains	1 mo n=52	↑ Total Score	↑MCS, VT, SF, MH	↑PCS, GH		(20)
				1 yr n=42	↑ Total Score	↑MCS, VT, SF, MH	↑PCS, GH, PF
PTH (1-84)	Open label	n=69#	↓ in all 8 domains	2 mo n=51	↑ Total Score	↑MCS, VT, SF, RE, MH	↑PCS, GH, PF, RP		(21)
				5 yrs n=25	↑ Total Score	↑MCS, VT, SF, RE, MH	↑PCS, GH, PF, RP
PTH (1-84)	Open label	n=20#	↓ in all 8 domains	8 yrs		↑MCS, VT, SF, MH	↑BP, GH (PCS only ↑ for 6 yrs)	-↓ baseline QOL associated with ↑ improvement. -28 subjects discontinued PTH within 8-year study.	(22)
PTH (1-34)	Open label	n=42		6 mo		↑MCS, VT, SF, RE, MH	↑PCS, GH, PF, RP, BP	-No optimization period	(23)
PTH (1-34)	Open label	N=42		6 mo		↑MCS, VT, SF, RE, MH	↑PCS, GH, PF, BP, RP	-Twice-daily PTH (1-34) -Post-surgical hypoparathyroidism -PF, RE, GH, PCS decreased from 6 to 24 mo	(28)
				24 mo		↑MCS, VT, SF, RE, MH	↑PCS, GH, PF, BP, RP

As summarized in this table, there are three randomized studies (two double blinded and one open label) followed by five open label studies that asses QOL with PTH treatment in hypoparathyroidisim. Three studies indicated by ^# are the same cohort followed for various lengths of time. All studies used the SF-36, except for the following:

^*Sikjaer et al (ref 24) used the SF-36 and the WHO-5. They also studied muscle function, postural stability by dynamometer chair, stadiometer platform, repeated chair stands, timed up and go test, and electromyography. At baseline, they found no myopathy, and after treatment, the maximum force decreased 30% at elbow flexion in the PTH group vs placebo, and no change in postural stability.

^**Winer et al (ref 26) was a study of 27 patients, but only 7 were assessed for quality of life with the 9-minute walk test and the multifaceted assessment of fatigue questionnaire. How patients were selected is not indicated. Four patients treated with PTH were assessed on Multi-faceted assessment of fatigue after 6 months of PTH therapy; two of them improved. On the 9-minute walk-run test, there was no change in the PTH vs calcitriol groups and no change in the baseline vs PTH groups.

Abbreviations: mo=months, yr= year, wks= weeks; SF-36 abbreviations: physical functioning (PF), role-physical (RP), bodily pain (BP), general healthy (GH), vitality (VT), social functioning (SF), role-emotional (RE), mental health (MH), physical component summary (PCS) mental health component summary (MCS).