PTH(1–84) Is Associated With Improved Quality of Life in Hypoparathyroidism Through 5 Years of Therapy

Abstract

Context:

In hypoparathyroidism, quality of life (QOL) is compromised as compared to normal subjects. We previously reported our results showing an association with recombinant human PTH(1–84) therapy in hypoparathyroidism and improvement in QOL measures for 1 year.

Objective:

We tested the hypothesis that PTH(1–84) therapy in hypoparathyroidism through 5 years would be associated with continued improvement in QOL measures.

Design:

Sixty-nine hypoparathyroid subjects received open-label PTH(1–84). Before and during therapy, subjects completed the RAND 36-Item Short Form (SF-36) Health Survey, a measure of health-related QOL covering eight domains of physical and mental health.

Results:

At baseline, subjects scored significantly lower than the normative reference range in all 8 domains (T-scores −1.4 to −0.9; P < .001 for all). With PTH therapy, intention-to-treat analysis showed significant improvement in the overall score at 2 months that persisted through 5 years (386 ± 19 to 482 ± 25; P < .0001). The mental component summary score improved at 2 months and was sustained through 5 years (199 ± 11 to 246 ± 14; P = .001), as did all four individual mental health domains and T-scores (vitality, social functioning, role emotional, mental health). The physical component summary score improved at 2 months and was sustained through 5 years (187 ± 10 to 237 ± 13; P < .0001), as did 3 physical health domains and T-scores (physical functioning, role physical, general health).

Conclusions:

PTH(1–84) therapy is not only associated with improvement in biochemical and skeletal indices, previously well-documented, but also in mental and physical health as determined by the SF-36 metric.

Hypoparathyroidism is a rare disease characterized by hypocalcemia and absent or deficient parathyroid hormone. It is the only classic endocrine deficiency disorder for which the missing hormone, PTH, is not yet an approved therapy. Standard treatment consists of calcium and active vitamin D supplementation, but with this standard approach, serum calcium is often difficult to manage and there are attendant concerns about long-term complications from large doses of these supplements (1–4). PTH treatment, an attractive alternative, reduces supplemental calcium and vitamin D requirements and improves skeletal parameters (5–12).

Complaints of cognitive dysfunction in hypoparathyroid patients are common. Our group and others have shown that hypoparathyroidism is associated with reduced quality of life (QOL) (13–15). We previously reported our results showing an association with recombinant human (rh) PTH(1–84) in hypoparathyroidism and improvement in QOL measures through 1 year of therapy (14). We now extend these results investigating the effect of PTH(1–84) therapy on QOL in hypoparathyroid subjects through 5 years.

Materials and Methods

Study design

We conducted an open-label uncontrolled study of rh PTH(1–84) (NPS Pharmaceuticals, Bedminster, NJ). The earliest subjects enrolled were initially treated with a dose of 100 μg every other day (7). Alternative dosing regimens of 25, 50, and 75 μg daily were made available during the study period. The PTH dose and calcium and active vitamin D supplementation regimen were titrated for each subject based on biochemical parameters. The original trial period was set at 2 years, however, an extension protocol was initiated and subjects were allowed to remain in the study indefinitely.

Subjects

The diagnosis of hypoparathyroidism in men and women was established by supplemental calcium and/or active vitamin D requirements to maintain serum calcium in the intended low-normal range with a low or insufficient PTH concentration. Hypoparathyroidism was present for at least 1 year in order to define a chronic hypoparathyroid state. All subjects had to be on stable regimens of supplemental calcium and/or vitamin D intake for at least 6 months before enrollment. Subjects were excluded if they (a) had been treated with a bisphosphonate within 5 years or for more than 6 months' duration at any time (b) were women within 5 years of menopause (c) were using any of the following medications: estrogens, progestins, raloxifene, calcitonin, systemic corticosteroids, fluoride, lithium, statins, loop diuretics, or methotrexate. The following potentially confounding disorders were also exclusionary criteria: Paget's disease of the bone, diabetes mellitus, chronic liver or renal disease, acromegaly, Cushing's syndrome, rheumatoid arthritis (RA), or multiple myeloma.

Patients were recruited from the Metabolic Bone Diseases Unit of Columbia University Medical Center and from the Hypoparathyroidism Association. The study was approved by the Institutional Review Board of Columbia University Medical Center. All subjects gave written informed consent. All subjects from our prior analysis are included in this report, in addition to subjects that enrolled after its publication (14).

Biochemical evaluation

The average of two or three pretreatment serum calcium values was used for the baseline calcium value. Blood sampling was performed 24 h after the last PTH injection for daily dosing or 48 h after injection for every other day dosing. Biochemistries were measured by automated techniques. The normal ranges for the assays are provided in Table 2 below.

Table 2.

Baseline Biochemistries of the Hypoparathyroid Population

	Mean ± se (n = 69)	Range (Median)	Normal Range
Serum calcium (mg/dL)a	8.7 ± 0.1	6.6–10.4 (8.8)	8.6–10.2
PTH (pg/mL)	2 ± 0.6	<3–24.5 (<3)	10–65
Creatinine (mg/dL)	0.93 ± 0.03	0.60–1.80 (0.90)	0.50–1.30
Phosphate (mg/dL)	4.4 ± 0.8	3.0–6.7 (4.3)	2.5–4.5
Total alkaline phosphatase activity (U/L)	62 ± 2	35–106 (60)	33–96
Urinary calcium excretion (mg/day)	255 ± 14	37–564 (240)	50–250b
25-hydroxyvitamin D (ng/mL)	51 ± 9	12–571 (35)	30–100
1,25-dihydroxyvitamin D (pg/mL) [n = 53]	35 ± 2	9–145 (30)	15–60

^aSerum calcium concentration was typically normal as a result of calcium and vitamin D supplementation.

^bFor men, 50–300 mg/day.

Quality of life evaluation

The RAND 36-Item Short Form (SF-36) Health Survey (version 1.0) was developed as part of the Medical Outcomes Study (16, 17). It is one of the most widely used measures of health-related QOL and has been applied in various populations (16–21). It consists of 36 items covering 8 domains of physical and mental health: physical functioning (PF), role limitations caused by physical health problems (RF), bodily pain (BP), perception of general health (GH), vitality (VT), social functioning (SF), role limitations due to emotional health problems (RE), and mental health (MH). Scores are placed on a scale of 0–100. Higher scores indicate more favorable physical functioning and psychological well-being. The eight domains may be further grouped into two summary measures: the physical component summary (PCS) comprised of PF, RF, BP, and GH and the mental component summary (MCS) comprised of VT, SF, RE, and MH (16, 17). Subjects were measured at baseline and following treatment with PTH(1–84) at months 2, 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60. We have baseline data from all subjects and data from at least one follow-up for all but two subjects. Follow-up data were not available from subjects after discontinuation from the protocol.

Statistical analysis

A linear mixed model for repeated measures approach was applied with a single fixed effect of time and baseline level of the outcome entered as a continuous covariate. The autoregressive covariance structure [AR(1)] was determined prior to inferential testing to provide the best covariance model fit across all of the outcomes to be tested. This analysis assesses the reliability of the within-subject change from baseline (SAS Proc MIXED, Version 9.2; SAS Institute). Our primary analysis investigated the change in RAND SF-36 scores from baseline through 5 years of therapy with PTH(1–84). T-scores were calculated from the normal ranges for healthy US men and women using the same instrument (16, 17). As secondary analyses, we investigated changes at other time points; proportions of subjects that continued PTH(1–84) therapy at defined T-score categories at baseline and annual time points; whether there were differences in scores due to age of onset, duration of hypoparathyroidism or etiology of hypoparathyroidism; and whether there were differences at 1 year in scores between subjects who discontinued therapy vs those who remain in the study. We compared baseline characteristics for subjects who discontinued therapy before 5 years to subjects who continued treatment using t-tests for continuous variables and Χ² for discrete variables. The reported analyses are intention-to-treat, save for the proportions of subjects who continued PTH therapy at defined T-score categories and the comparison between subjects who discontinued therapy vs those who remain in the study. Data are reported as model-estimated means and standard errors, and differences between baseline and subsequent times were tested by simultaneous confidence intervals. P-values <0.05 were used to establish significance.

Results

Baseline characteristics and adherence to treatment

Table 1 shows the baseline characteristics of the 69 hypoparathyroid subjects. The mean age was 46 ± 2 years (range 18–72 y) and 80% were female, consistent with the demographics of the disease. The two major etiologies of hypoparathyroidism were surgical and idiopathic. The mean duration of hypoparathyroidism was 12 ± 1 year (range 1–46 years).

Table 1.

Baseline Characteristics of the Hypoparathyroid Population

	Mean ± se (n = 69)	Range (Median)
Age (y)	46 ± 2	18–72 (45)
Sex	Female 55
	Male 14
Etiology	Postoperative 42
	Idiopathic 26
	DiGeorge 1
Duration of hypoparathyroidism (years)	12 ± 1	1–46 (7)
Elemental calcium supplement dose (g/d)	2.55 ± 0.2	0–11.0 (1.9)
Calcitriol supplement dose (μg/d)	0.69 ± 0.07	0–3.0 (0.5)
Daily parent vitamin D dose (IU/d)	4882 ± 1,837	0–100 000 (400)

The data over time are available from baseline (n = 69) and months 2, 6, 12 (n = 58), 18, 24 (n = 42), 30, 36 (n = 33), 42, 48 (n = 26), 54 and 60 (n = 25) of treatment. Twenty-seven subjects discontinued the intervention within the 5 year period (mean 21 ± 3 months) due to adverse events [depression, renal cancer, renal failure, vestibular neuritis, loss of bone density at the 1/3 radius, dizziness, gastrointestinal illness, headache; n = 8], withdrawn consent (n = 6), loss to follow-up (n = 5), nephrolithiasis (n = 2), unrelated health issues (n = 2), logistics of travel (n = 2), and recovery of parathyroid hormone function (n = 2). Some subjects have not yet reached 5 years of therapy (n = 17). Subjects who continued PTH were maintained on doses of 25 μg daily (n = 7), 50 μg daily (n = 16), 75 μg daily (n = 11), 100 μg daily (n = 7), and 100 μg every other day (n = 1). The average decrease in calcium supplementation was 41 ± 8% and the average decrease in active vitamin D supplementation was 58 ± 7%.

Biochemical evaluation

Baseline biochemistries are shown in Table 2. Most subjects maintained serum calcium values of at least 8.0 mg/dL throughout the study period (78.3% at baseline, ranging from 62.1 to 86.4% throughout the 5 years). The proportion of subjects with values within the reference range (8.6–10.2 mg/dL) was lower (59.4% at baseline, ranging from 34.6 to 59.1% throughout the 5 years). Hypercalcemia was rare (2.1% of values).

Quality of life evaluation

The results of the RAND SF-36 survey at baseline and following treatment with PTH(1–84) at months 2, 6, 12, 24, 36, 48, and 60 are shown in Table 3. Intention-to-treat analysis showed an improvement in the overall score at 2 months (386 ± 19 to 468 ± 21; P < .0001) that persisted through 5 years (482 ± 25; P < .0001). The MCS score improved at 2 months and remained significantly improved through 5 years (199 ± 11 to 246 ± 14; P = .001), as did each of the four individual mental health domains (VT, SF, RE, MH). The PCS score improved at 2 months and remained significantly improved through 5 years (187 ± 10 to 237 ± 13; P < .0001), as did three of the physical health domains (PF, RF, GH). Using T-scores, 7 of 8 domains improved early with sustained effects at 5 years: VT, −1.4 to −0.9 (P = .001); SF, −1.1 to −0.7 (P = .003); RE, −0.9 to −0.4 (P = .011); MH, −0.9 to −0.4 (P = .001); PF, −0.9 to −0.3 (P < .0001); RF, −1.2 to −0.5 (P = .002); GH, −1.3 to −0.9 (P = .001) (Figure 1).

Table 3.

RAND 36-Item Health Survey Total, Component, and Individual Domain Scores at Baseline and Through 5 year of PTH(1–84) Therapy

Time	n	Total	MCS	VT	SF	RE	MH	PCS	PF	RF	BP	GH
Baseline	69	386 ± 19	199 ± 11	32 ± 3	57 ± 3	51 ± 5	59 ± 2	187 ± 10	62 ± 3	40 ± 5	43 ± 2	45 ± 3
2 months	51	468 ± 21c	248 ± 11c	46 ± 3c	70 ± 3c	63 ± 5a	69 ± 2c	221 ± 11c	72 ± 3b	52 ± 5a	46 ± 2	55 ± 3c
6 months	57	482 ± 20c	250 ± 11c	45 ± 3c	70 ± 3c	68 ± 5b	69 ± 2c	233 ± 11c	74 ± 3c	59 ± 5c	46 ± 2	54 ± 3c
1 y	58	462 ± 20c	235 ± 11c	44 ± 3c	67 ± 3c	57 ± 5	69 ± 2c	227 ± 11c	74 ± 3c	53 ± 5a	47 ± 2	54 ± 3c
2 y	42	472 ± 22c	241 ± 12c	45 ± 3c	68 ± 4b	61 ± 6	68 ± 2c	233 ± 11c	73 ± 3c	57 ± 6b	50 ± 2a	54 ± 3c
3 y	33	440 ± 23b	226 ± 13a	41 ± 3b	63 ± 4	57 ± 6	65 ± 3b	215 ± 12b	68 ± 4	53 ± 6	41 ± 3	53 ± 3b
4 y	26	448 ± 25b	225 ± 14a	43 ± 3c	65 ± 4a	55 ± 7	63 ± 3	224 ± 13b	70 ± 4a	61 ± 7b	44 ± 3	51 ± 3a
5 y	25	482 ± 25c	246 ± 14c	42 ± 3b	68 ± 4b	69 ± 7a	68 ± 3b	237 ± 13c	76 ± 4c	62 ± 7b	45 ± 3	54 ± 3b

Values are mean ± se.

^aP < .05 compared to baseline.

^bP < .01 compared to baseline.

^cP < .001 compared to baseline.

Figure 1.

RAND 36-item health survey domain T-scores at baseline and 5 years of PTH(1–84) therapy. Values are mean ± SE. ^#, P < .001 compared to normal population. *, P < .05 compared to baseline. ^†, P < .01 compared to baseline. ^‡, P < .001 compared to baseline.

Secondary analyses

Figure 2 shows the proportions of subjects who continued PTH(1–84) therapy (n = 42) with RAND SF-36 T-scores for the MCS and PCS scores in the normal, below normal, low, and very low range at baseline and months 12, 24, 36, 48, and 60 of PTH(1–84) therapy. Normal was defined as a T-score ≥ 0, below normal as −1 SD ≥ T-score < 0, low as −2 SD ≥ T-score < −1, and very low as T-score < −2 SD. Subjects with full 5-year data and subjects who have not yet reached the 5-year time point but remain in the study protocol were included. The proportion of subjects with normal T-scores was lowest at baseline and increased at the other time points (23.8% at baseline to 48.0% at 5 years for the MCS and 33.3% at baseline to 60.0% at 5 years for the PCS). In addition, there were 21.4% of subjects with T-scores in the very low range for the PCS at baseline and 0.0% in the very low range at 5 years.

Figure 2.

Proportions of subjects that continued PTH(1–84) therapy with RAND SF-36 T-scores in the normal, below normal, low, and very low range at baseline and months 12, 24, 36, 48, and 60 of PTH(1–84) therapy. Normal: T-score ≥ 0, below normal: −1 SD ≥ T-score < 0, low: −2 SD ≥ T-score < −1, very low: T-score < −2 SD.

Age of onset, duration of hypoparathyroidism, and etiology of hypoparathyroidism were not significant predictors of the total or component summary scores or individual domains. There were no differences between subjects who continued or discontinued therapy during the study period with respect to baseline age, gender, etiology, duration of hypoparathyroidism, calcium or 1,25-dihydroxyvitamin D supplementation, or serum or urine calcium. As compared to those who continued therapy, the 27 subjects who discontinued PTH before 5 years had significantly lower values for the total (392 ± 35 vs 503 ± 25 at 1 y; P = .011) and MCS score (203 ± 19 vs 255 ± 13 at 1 year; P = .024) as well as RP (34 ± 9 vs 63 ± 6 at 1 year; P = .012), SF (58 ± 5 vs 80 ± 4 at 2 months; P = .001), and RE (36 ± 9 vs 68 ± 6 at 1 year; P = .005) domains. The overall results were similar when analyzed excluding those who discontinued PTH (data not shown).

Discussion

We investigated the effect of PTH(1–84) therapy on QOL in hypoparathyroid subjects though 5 years using the RAND 36-Item Health Survey. At baseline, subjects scored significantly lower than the normative reference range in all eight domains of mental and physical health. PTH(1–84) therapy was associated with improvement in the total score, MCS, PCS, and 7 out of the 8 domains, the four mental health domains (VT, SF, RE, and MH) and three of the physical health domains (PF, RF, and GH). In addition, the proportions of subjects with positive T-scores increased with therapy. Beneficial effects were noted early and persisted through 5 years. Serum calcium was maintained in the intended low-normal range (≥8.0 mg/dL) for most subjects. However, the proportion of subjects with serum calcium values within the reference range (8.6–10.2 mg/dL) was lower.

Complaints of cognitive dysfunction in hypoparathyroid patients are common. Our group and others have shown that hypoparathyroidism is associated with reduced QOL using standardized measures (13–15). We previously reported our results showing that PTH(1–84) therapy was associated with an improvement in QOL measures through 1 year of therapy (14). In that smaller group of subjects, improvement in QOL was noted in the total score, MCS, PCS, three of the mental health domains (VT, SF, and MH) and two of the physical health domains (PF and GH). There is some evidence that PTH may have central nervous system (CNS) effects (22–26), which may provide an explanation for reduced QOL in hypoparathyroid subjects despite relative eucalcemia and the capacity of PTH therapy to alleviate some of these complaints.

Sikjaer et al published the results of a randomized clinical trial investigating the effect of PTH(1–84) 100 μg daily vs placebo on QOL over 6 months (15). They found an improvement in QOL measures in both the placebo and PTH arms but no between-group differences. Mean serum calcium levels in the PTH-treated group were significantly increased during their study and there was a relatively high incidence of hypercalcemia. The authors noted that the large fluctuations in serum calcium might have negated any potential advantage of the PTH therapy. Considering that hypoparathyroid subjects may acclimate to relatively lower serum calcium values, these results may indicate that the reference range for serum calcium in normal subjects may not be suitable for all hypoparathyroid subjects with regard to their mental and physical well-being.

The strengths of this study include the remarkably large cohort of subjects with hypoparathyroidism followed longitudinally through 5 years of therapy. These long-term QOL data with PTH(1–84) in the therapy of hypoparathyroidism are unique. Among the limitations is the absence of a placebo control. While the persistence of the findings through 5 years is reassuring against the results being solely due to a placebo effect, this does not remove the possibility of confounding. A majority of the subjects remained in the study protocol, although subjects who discontinued PTH therapy may not have benefited to the same extent and this may have resulted in attrition bias despite our use of an intention-to-treat analysis. It should also be noted that the SF-36 instrument is a generalized one and not tailored to the specific QOL measures that subjects with hypoparathyroidism typically experience. It is impressive, nevertheless, that this general measurement tool would so clearly demonstrate improvements in QOL among subjects with hypoparathyroidism. A QOL instrument more specifically designed to a hypoparathyroid cohort might conceivably demonstrable even more dramatic improvements with PTH (1–84) therapy. Since our study design called for serum measurements after the first 24 h of PTH administration, earlier changes, if they occurred, would not have been captured. We do not believe our subjects would have experienced significant elevations in serum calcium in the time period preceding our measurement at the administered doses titrated to subjects' biochemistries based on the results of pharmacologic studies in other subjects (27, 28). In addition, a number of subjects discontinued the intervention due to adverse events that may or may not have been related to study drug. Our clinical trial subjects may not be representative of the hypoparathyroid population in general and the results of this trial may not reflect a common use experience. PTH therapy may not be appropriate for all patients.

PTH(1–84) therapy has previously been shown to be associated with improvement in biochemical and skeletal indices (7, 8, 10–12). The results of this study now show an association with improvement in mental and physical health over a substantial period of time. Further study in a randomized, placebo-controlled manner using PTH doses titrated by biochemical parameters would help to confirm these observations. The effect of a more physiologic mode of PTH delivery on QOL remains of interest.