Therapy of Hypoparathyroidism With rhPTH(1-84): A Prospective, 8-Year Investigation of Efficacy and Safety

Abstract

Context

Conventional treatment of hypoparathyroidism is associated with decreased renal function and increased bone mineral density (BMD).

Objective

To evaluate the effects of 8 years of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] therapy on key biochemical and densitometric indices.

Design

Prospective open-label trial.

Setting

Tertiary medical center.

Participants

Twenty-four subjects with hypoparathyroidism.

Intervention

Treatment with rhPTH(1-84) for 8 years.

Main Outcome Measures

Supplemental calcium and vitamin D requirements, serum calcium and phosphorus levels, calcium-phosphate product, urinary calcium excretion, estimated glomerular filtration rate (eGFR) and BMD.

Results

PTH therapy was associated with progressive reduction in supplemental calcium (57%; P < 0.01) and active vitamin D (76%; P < 0.001) requirements over 8 years. Serum calcium concentration was stable; urinary calcium excretion declined 38% (P < 0.01). eGFR remained stable and was related to baseline eGFR and serum calcium levels. Calcium-phosphate product was below the recommended limit; serum phosphorus remained within normal range. Lumbar spine and total hip BMD increased, peaking at 4 (mean ± SE, 4.6% ± 1.5%; P = 0.01) and 8 years (2.6% ± 1.1%; P = 0.02), whereas femoral neck BMD did not change and one-third radius BMD decreased (mean ± SE, −3.5% ± 1.1%; P = 0.001). BMD at all sites was higher throughout the 8 years than in the age- and sex-matched reference population. Hypercalcemia and hypocalcemia were uncommon.

Conclusion

rhPTH(1-84) is a safe and effective treatment for hypoparathyroidism for 8 years. Long-term reductions in supplemental requirements and biochemical improvements with stable renal function are maintained.

rhPTH(1-84) therapy is safe and effective in hypoparathyroidism. Supplemental calcium and active vitamin D requirements decrease and serum calcium is maintained; renal function is stable.

Hypoparathyroidism is a rare disorder characterized by hypocalcemia with insufficient or absent PTH levels and abnormal bone remodeling. The biochemical profile also includes hyperphosphatemia and hypercalciuria (1–5). In January 2015, the Food and Drug Administration approved the use of recombinant human PTH (1-84) [rhPTH(1-84)] for the management of hypoparathyroidism that could not be controlled by conventional means (6). Different from the use of PTH analogs for osteoporosis, no limit was placed on the duration of therapy for the treatment of hypoparathyroidism. Therefore, long-term efficacy and safety data are needed.

We previously reported that treatment with rhPTH(1-84) for up to 6 years in hypoparathyroid subjects led to reduced supplemental calcium and 1,25-dihydroxyvitamin D requirements (7, 8). However, given the chronic nature of hypoparathyroidism, and the expectation that rhPTH(1-84) will be used indefinitely, even longer-term data on the safety and efficacy of PTH are essential. We now report the effects of rhPTH(1-84) treatment in hypoparathyroidism on key biochemical and densitometric parameters for up to 8 years. To our knowledge, this experience represents the longest experience to date in a cohort with the use of PTH or any PTH analog for any condition.

Material and Methods

Subjects

The diagnosis of hypoparathyroidism in women and men was established by undetectable or insufficient PTH concentration in association with hypocalcemia and an absolute requirement for supplemental calcium and/or active vitamin D to maintain serum calcium in the low-normal range. Hypoparathyroidism was present for at least 1 year to establish a chronic state. All subjects had to be taking a stable regimen of supplemental calcium and vitamin D intake for at least 6 months before enrollment. Subjects were excluded if they had ever been treated with PTH (1-34) or rhPTH(1-84) or if they had been taking a bisphosphonate within 5 years prior to study entry or for >6 months at any time. Patients with a history consistent with a calcium-sensing receptor mutation were excluded, as were those who used any of the following medications: estrogen, progestins, raloxifene, calcitonin, systemic corticosteroids, fluoride, lithium, statins, loop diuretics, or methotrexate. The following potentially confounding disorders were also exclusionary criteria: Paget disease of bone, diabetes mellitus, chronic liver or renal disease, acromegaly, Cushing syndrome, rheumatoid arthritis, or multiple myeloma. Patients were recruited from the Metabolic Bone Disease 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.

This report presents our findings for 24 subjects who reached the 8-year point. The original study included 82 patients who provided written informed consent. The other subjects are not part of this analysis for the following reasons: three withdrew consent before administration of study drug, 14 have not yet reached the 8-year point, 14 withdrew because of logistics of travel or for personal reasons, 12 for noncompliance or were lost to follow-up, four for adverse events not attributed to the study drug (gastrointestinal illness, vestibular neuritis, depression, and headache/syncope), four for unrelated health issues, five for apparent recovery from hypoparathyroidism, and two for nephrolithiasis.

Protocol

rhPTH(1-84) (NPS/Shire Pharmaceuticals Lexington, MA) was used to treat hypoparathyroid subjects for 8 years. rhPTH(1-84) was administered by a pen injector with a multiple dose, dual-chamber glass cartridge. At the initiation of the study, rhPTH(1-84) was only available at the 100-µg dose; we initially used 100 µg every other day in all subjects. The drug was self- administered as a subcutaneous injection in the thigh, with the frequency depending on the individual regimen. The availability of lower doses of rhPTH(1-84) during the course of the study made it possible to follow a titration schedule during which the dose could be adjusted. Titration was determined with the following goals: avoidance of hyper- and hypocalcemic symptoms and maintenance of serum calcium levels between 8.5 mg/dL and 7.5 mg/dL with calcium supplementation ≤1.5 g/d and calcitriol dose ≤0.25 µg/d. The rhPTH(1-84) dose was individualized to achieve a serum calcium level in the lower half of the normal range along with minimal symptoms. In general, the rhPTH(1-84) dose was increased by an increment of 25 µg/d if the serum calcium level was ≤7.5 mg/dL while the subject was taking at least calcium 1.5 gm/d and calcitriol 0.25 µg/d; the dose was decreased by an increment of 25 µg/d if the serum calcium level was >8.5 mg/dL and the subject was not taking calcium supplementation or calcitriol. All patients were receiving daily dosing at the end of the study, with the predominant dose being 50 µg (54%; n = 13) followed by 100 µg (21%; n = 5), 75 µg (17%; n = 4), and 25 µg (8%; n = 2). Based on a count of the number of returned cartridges, mean compliance was 97%.

Subjects initially continued their established individual regimens of calcium and active vitamin D. Calcium citrate and calcium carbonate were used. Monitoring was accomplished by review of symptoms and regular measurements of serum and urine calcium. Serum calcium was checked within 1 week of rhPTH(1-84) initiation and within 1 week of any subsequent change in calcium or active vitamin D supplementation or rhPTH(1-84) dosing. If the serum calcium level was >9 mg/dL, the active vitamin D was decreased by 50%, or discontinued if the subject was already taking the lowest dose. If active vitamin D was discontinued and serum calcium level was still >9 mg/dL, calcium supplements were decreased on the basis of serum calcium value and clinical assessment for signs and symptoms of hypercalcemia. If the serum calcium level was <8 mg/dL, calcium supplementation and/or active vitamin D was increased if signs and symptoms of hypocalcemia were present. If the serum calcium level was <7 mg/dL, calcium supplementation and/or active vitamin D was increased. These steps were repeated until serum calcium levels were within the lower half of the normal range. High-dose ergocalciferol or cholecalciferol adjustments were also made with the goal of maintaining serum calcium levels within the lower half of the normal range.

Biochemical evaluation

Blood samples were obtained at baseline three times before treatment and at months 1, 2, 3, 4, 5, 6, 9, and 12, and at 6-month intervals thereafter. Serum calcium levels were corrected for albumin. The average of three pretreatment serum calcium values was used as the baseline calcium value; the annual values are reported here. Blood sampling was performed immediately before the next PTH injection. Blood was obtained 48 hours after rhPTH(1-84) dosing with the every-other-day regimen; if a patient was following a daily dosing regimen, a serum sample was obtained 24 hours after injection. Biochemical values were measured by automated techniques. Glomerular filtration rate was estimated using the abbreviated Modification of Diet in Renal Disease study equation. Subjects’ 24-hour urinary calcium excretion was measured at baseline and yearly intervals. Urine was initially obtained 24 to 48 hours after rhPTH(1-84) dosing; if a patient was following a daily dosing regimen, urine was obtained immediately after injection.

Safety outcomes

Study visits occurred at months 0, 1, 2, 3, 4, 5, 6, 9, 12, and at 6-month intervals until month 96. Patients informed study staff between visits of any symptoms, adverse events, or changes in regimen. Additional blood and urine samples were obtained between study visits if there were symptoms of hypo- or hypercalcemia and at 1 week (for serum calcium level) and 1 month (for serum and urinary calcium levels) after any adjustment in calcium supplementation, active vitamin D, or rhPTH(1-84) dose. In addition to these time points, serum calcium concentration was measured 1 and 2 weeks after initiation of rhPTH(1-84) treatment. If symptoms of hypocalcemia, such as numbness or paresthesia, developed, upward adjustments in calcium or 1,25-dihydroxyvitamin D dosing were made. Serum calcium was measured 1 week after each change in calcium or 1,25-dihydroxyvitamin D supplementation or rhPTH(1-84) dose to ensure stability of the serum calcium concentration; urinary calcium level was measured 1 month after any change in regimen. Information regarding adverse events was recorded at each study visit.

Bone mineral density

Areal bone mineral density (BMD) was measured at the lumbar spine (L1–4), total hip, femoral neck, and one-third radius by dual-energy x-ray absorptiometry (Hologic). Subjects were measured on the same densitometer, using the same software, scan speed, and technologist, certified by the International Society for Clinical Densitometry. Short-term in vivo precision error (root-mean-square SD) was 0.026 g/cm² for L1–4 (1.1%), 0.041 g/cm² for the femoral neck (2.4%), and 0.033 g/cm² (1.8%) for the forearm.

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. This method accounts for the within-person correlation of repeated measures. The χ² test or Fischer exact test (where appropriate) was used for between-group comparisons for categorical variables and the independent t tests for between-group comparisons for continuous variables. All statistical tests were two-tailed and a P < 0.05 was considered significant. The statistical software R, version 3.3.2 (http://www.r-project.org/) and SPSS 23.0 for Windows (IBM Corp., Armonk, NY) were used for the analyses. The data are presented as model-estimated mean ± SE for continuous variables. Data for categorical variables are presented as frequency and percentage.

Results

Baseline characteristics

Table 1 lists the baseline characteristics of the 24 subjects. The mean serum calcium concentration was just below the lower limit of the normal range. BMD was normal or above average for a young, normal population.

Table 1.

Baseline Characteristics

	Total Cohort (N = 24)	Range (Median)	Normal Range
Age, y	46.2 ± 2.8	26–72 (45.3)
Sex
Female	18
Premenopausal	12
Postmenopausal	6
Male	6
Etiology
Postsurgical	13
Autoimmune	10
DiGeorge syndrome	1
Duration of hypoparathyroidism, y	29.9 ± 3.3	13–58 (24.5)
Fractures in adulthood, no. of patients	10a
Kidney stones, no. of patients	4
Basal ganglia calcifications, no. of patients	2
Calcium supplement dose, mg/d	2961 ± 472	0–11,000 (2400)
1,25-dihydroxyvitamin D supplement dose, μg/d	0.76 ± 0.13	0–3 (0.50)
Daily vitamin D dose, IU/d (n = 16)	20,898 ± 8858b	133–100,000 (667)
Thiazide dose, mg/d (n = 9)	36.6 ± 8.0	12.5–100.0 (25.0)
Serum calcium, mg/dL	8.46 ± 0.2	6.9–10.1 (8.49)	8.6–10.2
Albumin, g/dL	4.4 ± 0.4	3.9–5.6	3.6–5.1
Corrected serum calcium, mg/dL	8.15 ± 0.9	6.7–10.0 (8.10)	8.6–10.2
PTH, pg/mL	4.0 ± 0.6	<3–14 (3)	10–64
Undetectable, no. patients	20	8–14
Detectable, no. of patients	3
Creatinine, mg/dL	0.95 ± 0.04	0.70–1.50 (0.90)	0.5–1.3
eGFR, mL/min	88.4 ± 4.4	45–123 (88.2)	>60
Phosphate, mg/dL	4.50 ± 0.20	2.6–6.7 (4.70)	2.5–4.5
Magnesium, mg/dL	1.84 ± 0.03	1.5–2.1 (1.90)	1.8–3.6
Total alkaline phosphatase activity, U/L	63.9 ± 2.6	47–89 (62.0)	33–96
Urinary calcium excretion, mg/d	256.9 ± 23.0	99–450 (250.0)
25-hydroxyvitamin D, ng/mL	81.5 ± 26.6	8.8–571 (43.6)	30–100
1,25-dihydroxyvitamin D, pg/mL	45.9 ± 6.3	20.6–145.2 (36.0)	15–60
P1NP, μg/L	37.4 ± 3.2	16.1–72.6 (37.6)	16–96
Serum CTX, ng/mL	0.28 ± 0.09	0.08–2.19 (0.16)	0.12–1.35
Weight, kg	78.0 ± 3.4	61.2–113.4 (77.6)
Lumbar spine
BMD, g/cm2	1.242 ± 0.04	0.934–1.912 (1.188)
T-score	+1.68 ± 0.30	−1.02 to +7.87 (0.88)
Z-score	+2.25 ± 0.41	+0.13 to +9.35 (1.58)
Femoral neck
BMD, g/cm2	0.992 ± 0.03	0.717–1.278 (0.984)
T-score	+1.08 ± 0.30	−1.19 to +3.63 (0.88)
Z-score	+1.69 ± 0.27	−0.59 to +3.64 (1.58)
Total hip
BMD, g/cm2	1.105 ± 0.03	0.893–1.463 (1.091)
T-score	+1.10 ± 0.24	−0.40 to +4.27 (0.98)
Z-score	+1.49 ± 0.23	−0.33 to +4.36 (1.34)
One third radius
BMD, g/cm2	0.735 ± 0.01	0.639–0.861 (0.730)
T-score	+0.16 ± 0.17	−1.73 to +1.54 (0.15)
Z-score	+0.80 ± 0.19	−1.70 to +2.78 (0.66)

Values are expressed as mean ± SEM unless described otherwise.

^aAmong the 10 patients, there were four digit fractures, one metatarsal, one facial, two rib, one tibia, one skull fracture, and one Colles fracture. There were no hip or vertebral fractures.

^bFive patients were taking ergocalciferol or cholecalciferol dosages >1000 IU/d.

Calcium and vitamin D supplementation

Supplemental calcium requirements were reduced significantly within the first year of initiation with rhPTH(1-84) replacement and remained lower than baseline up to 8 years of treatment. The average reduction in calcium supplementation was 57%, from 3.0 ± 0.3 g/d at baseline to 1.3 ± 0.3 g/d at 8 years (P < 0.01; Fig. 1). The number of subjects who required more than 1.5 g/d of calcium supplementation decreased from 19 (79%) at study entry to eight (33%) at study conclusion. Requirements for 1,25-dihydroxyvitamin D also had a sustained and significant decrease throughout the 8 years. Over the entire study period, 1,25-dihydroxyvitamin D requirements decreased by 76%, from 0.76 ± 0.1 µg/d at baseline to 0.18 ± 0.1 µg/d at study conclusion (P < 0.001; Fig. 1). Twelve subjects (50%) were able to discontinue 1,25-dihydroxyvitamin D supplementation. Of the nine subjects who were taking thiazide diuretics at the start of the study, the mean dosage decreased significantly by 51% from 37 ± 8 mg/d to 19 ± 7 mg/d (P = 0.01; Fig. 1); two subjects (22%) were able to eliminate thiazides from their treatment regimen. Eight patients who were not taking ergo- or cholecalciferol at the start of the study received daily parent vitamin D supplementation during the course of the 8 years. The mean daily doses of parent vitamin D (for participants who were taking it at baseline; n = 16) decreased by 61%, from 20,898 ± 8858 IU/d at baseline to 8096 ± 6175 IU/d at the end of the study (P = 0.09).

Figure 1.

Annual changes in key clinical and biochemical indices. Changes are shown in serum calcium and phosphate levels, calcium-phosphate product, calcium supplemental dose, calcitriol supplemental dose, and hydrochlorothiazide dose over the 8-y study duration. *P < 0.05 vs baseline; **P < 0.01 vs baseline. HCTZ, hydrochlorothiazide.

Serum corrected calcium levels and other indices of mineral metabolism

Serum calcium levels were relatively stable and maintained slightly below the lower limit of the normal range throughout the 8 years. There was a transient decrease in the second year of treatment (7.8 ± 0.2 mg/dL vs baseline; P = 0.05; Fig. 1). Pretreatment serum phosphate levels were near the upper limit of the normal range and decreased significantly from baseline at years 4 and 5 (both P < 0.01), but subsequent values were not different than baseline values (Fig. 1). The calcium-phosphate product decreased from a pretreatment level of 38 ± 2 mg²/dL² to 34 ± 2 mg²/dL² (P = 0.02) at year 1, 34 ± 2 mg²/dL² (P = 0.01 at year 3), 33 ± 2 mg²/dL² (P < 0.01) at year 4, and 34 ± 2 mg²/dL² (P = 0.03) at year 5 of the study (Fig. 1); levels during years 6 to 8 did not differ from baseline. Serum magnesium concentration decreased slightly within the first year of treatment (baseline, 1.8 ± 0.1 mg/dL) to 7 years (1.7 ± 0.1 mg/dL; P < 0.01) but was not different than pretreatment levels at year 8 (1.8 ± 0.1 mg/dL; P = 0.18). Total alkaline phosphatase activity increased significantly from pretreatment levels (63 ± 4 U/L) within the first year of treatment (to 87 ± 4 U/L; P < 0.01) and with the exceptions of year 3 and 4, this increase persisted until the end of the study (to 76 ± 4 U/L; P < 0.01).

Urinary calcium and renal indices

Urinary calcium excretion tended to be lower than pretreatment level in year 1 (baseline: 254 ± 29 mg/d, to year 1: 185 ± 37 mg/d; P = 0.06) and year 3 (178 ± 39 mg/d; P = 0.05) and was significantly lower than pretreatment level in year 7 (156 ± 36 mg/d; P < 0.01) and year 8 (157 ± 37 mg/d; P < 0.01; Fig. 2). Of note, there was no correlation between change in urinary calcium excretion over 8 years and change in calcium supplementation over 8 years (r = −0.29; P = 0.26) or between change in urinary calcium excretion over 8 years and change in PTH dose over 8 years (r = 0.3; P = 0.25).

Figure 2.

Annual changes in renal indices. Changes are shown in serum creatinine level, estimated glomerular filtration rate (eGFR; according to the Modification of Diet in Renal Disease equation), and urinary calcium excretion over the 8-year study duration. *P < 0.05 vs baseline; **P < 0.01 vs baseline.

Renal function was stable throughout the entire treatment duration. There was no correlation between change in urinary calcium excretion over 8 years and change in eGFR over 8 years (r = −0.04; P = 0.87). Serum creatinine was within the normal range, with only a slight and transient decrease from baseline at year 2 (0.87 ± 0.04 mg/dL; P = 0.03; Fig. 2). Correspondingly, there was a transient increase in estimated glomerular filtration rate (eGFR) from baseline at year 2 (96 ± 3 mL/min/1.73m²; P = 0.02). The 2-year decrease in serum creatinine directly correlated with the 2-year decrease in serum calcium levels (r = 0.48; P = 0.02) and the 2-year increase in eGFR levels inversely correlated with the 2-year decrease in serum calcium levels (r = −0.43, P = 0.04). Mean eGFR was maintained well above 60 mL/min/1.73m² throughout the study period (Fig. 2). At baseline, 41.5% of our subjects had eGFR >90 mL/min and 46% had an eGFR between 60 and 90 mL/min (stage 2 chronic kidney disease). A few subjects (n = 3; 12.5% of the cohort) had an eGFR commensurate with stage 3 chronic kidney disease at baseline. This subgroup had a baseline eGFR of 50 ± 10 mL/min, which improved transiently at year 2 (74 ± 10 mL/min; P = 0.04) to year 3 (73 ± 10 mL/min; P = 0.04) but was not different from baseline thereafter (at 8 years: 57 ± 10 mL/min; P = 0.49).

Effect of serum calcium on renal function

There was a significant interaction with serum calcium and eGFR over time. For every 1 mg/dL increase in serum calcium, there was a 5-mL/min decrease in eGFR (P < 0.01). There were no associations between eGFR and age, duration of disease, serum phosphate levels, calcium-phosphate product, PTH, calcium, and vitamin D doses.

Bone mineral density

Lumbar spine BMD increased by 3.8% ± 1.6% (P = 0.02) at year 3 and remained significantly higher than baseline up to year 8, with a maximal increase at year 4 (4.6% ± 1.5%; P < 0.01; Fig. 3; Table 2). Femoral neck BMD did not change throughout the study period. Total hip BMD was significantly higher at year 8 than at baseline, with a gain of 2.6% ± 1.1% (P = 0.03; Fig. 3; Table 2). One-third radius BMD trended lower than baseline in the first 6 years and was significantly reduced at year 7 (−2.8% ± 1.1%; P < 0.01) and year 8 (−3.5% ± 1.1%; P < 0.01; Fig. 3; Table 2).

Figure 3.

Annual changes in skeletal densitometric indices. Changes are shown in lumbar spine, total hip, femoral neck, and one-third radius over the 8-y study duration. *P < 0.05 vs baseline; **P < 0.01 vs baseline.

Table 2.

BMD Measurements Over 8 Years of rhPTH(1-84) Therapy

	Baseline	Year
		1	2	3	4	5	6	7	8
Lumbar spine, g/cm2	1.242 ± 0.04	1.246 ± 0.05	1.275 ± 0.05	1.289 ± 0.05a	1.300 ± 0.05b	1.292 ± 0.05a	1.294 ± 0.05b	1.282 ± 0.05a	1.277 ± 0.05a
T-score	1.68 ± 0.4	1.72 ± 0.4	1.98 ± 0.5	2.06 ± 0.5b	2.23 ± 0.5b	2.16 ± 0.5b	2.17 ± 0.5b	2.05 ± 0.5a	1.98 ± 0.5
Z-score	2.25 ± 0.4	2.32 ± 0.5a	2.61 ± 0.5b	2.72 ± 0.5b	2.94 ± 0.5b	2.92 ± 0.5b	2.96 ± 0.5b	2.90 ± 0.5b	2.87 ± 0.5b
Femoral neck, g/cm2	0.992 ± 0.03	0.991 ± 0.03	0.989 ± 0.03	1.015 ± 0.04	1.007 ± 0.04	1.006 ± 0.04	1.007 ± 0.04	1.008 ± 0.04	1.008 ± 0.04
T-score	1.08 ± 0.3	1.06 ± 0.3	1.09 ± 0.3	1.21 ± 0.3	1.14 ± 0.3	1.14 ± 0.3	1.24 ± 0.4	1.18 ± 0.4	1.19 ± 0.4
Z-score	1.69 ± 0.3	1.71 ± 0.3	1.77 ± 0.3	1.92 ± 0.3a	1.87 ± 0.3a	1.90 ± 0.3a	2.01 ± 0.3b	2.03 ± 0.3b	2.06 ± 0.3b
Total hip, g/cm2	1.105 ± 0.03	1.094 ± 0.03	1.111 ± 0.03	1.127 ± 0.03	1.120 ± 0.03	1.125 ± 0.03	1.127 ± 0.03	1.117 ± 0.03	1.130 ± 0.03b
T-score	1.10 ± 0.2	1.01 ± 0.2	1.17 ± 0.2	1.27 ± 0.3	1.17 ± 0.2	1.20 ± 0.2	1.30 ± 0.3	1.15 ± 0.2	1.31 ± 0.3 a
Z-score	1.49 ± 0.2	1.43 ± 0.2	1.61 ± 0.2	1.73 ± 0.3a	1.63 ± 0.2a	1.69 ± 0.2b	1.81 ± 0.2b	1.70 ± 0.2b	1.88 ± 0.2b
1/3 radius, g/cm2	0.735 ± 0.01	0.725 ± 0.01	0.727 ± 0.01	0.729 ± 0.01	0.723 ± 0.01	0.728 ± 0.02	0.724 ± 0.02	0.716 ± 0.02b	0.711 ± 0.02b
T-score	0.16 ± 0.2	−0.01 ± 0.2	0.00 ± 0.2	0.14 ± 0.2	−0.04 ± 0.2	0.04 ± 0.2	0.07 ± 0.2	−0.16 ± 0.3b	−0.26 ± 0.3b
Z-score	0.80 ± 0.2	0.66 ± 0.2	0.70 ± 0.2	0.89 ± 0.2	0.76 ± 0.2	0.89 ± 0.2	0.95 ± 0.2	0.78 ± 0.3	0.73 ± 0.3

Values are expressed as mean ± SEM.

^a P < 0.05 compared with baseline.

^b P < 0.01 compared with baseline.

Adverse events

Documented hypercalcemia was rare, with only three hypercalcemic events (serum calcium >10.2 mg/dL) at 1, 4, and 7 years noted in three different patients, none of whom required hospitalization. The most common serious adverse event was hypocalcemia, which occurred five times in year 2 in three patients who required hospitalization. After year 2, no additional documented hypocalcemia was observed in any subject. Other adverse events included eight fractures in six patients (year 1, elbow; year 2, toe; year 3, metatarsal; year 5, wrist; year 6, wrist, leg; year 8, metacarpal, wrist) and one episode of nephrolithiasis at year 4 (24-hour urinary calcium excretion, 378 mg/d).

Discussion

In this report, we describe our 8-year clinical experience with PTH treatment of hypoparathyroidism. Administration of rhPTH(1-84) led to sustained reductions in supplemental calcium and 1,25-dihydroxyvitamin D requirements and in urinary calcium excretion, while maintaining key biochemical parameters such as serum calcium and phosphate levels and calcium-phosphate product well within the recommended therapeutic ranges (9, 10). The persistent efficacy of PTH therapy in this hypoparathyroid cohort over this prolonged period of administration is an important addition to our knowledge about long-term efficacy of rhPTH(1-84) in this disease.

Another important outcome of this study is the stable renal function throughout the 8 years of rhPTH(1-84) administration. The maintenance of stable renal function with rhPTH(1-84) contrasts with conventional therapy with calcium supplementation and active vitamin D, in which renal complications have been demonstrated (5, 11–13). Conventional therapy involves the frequent administration of high doses of supplemental calcium and active vitamin D, increasing the risk of hypercalciuria, renal stones, and renal insufficiency. Progressive compromise of renal function is of concern, particularly because at baseline, renal function in hypoparathyroidism is frequently compromised. In our cohort, not different from others, baseline renal function was decreased and similar to that in a large Danish registry of patients receiving conventional therapy. In that Danish cohort, 45% had stage 2 chronic kidney disease (eGFR, 60 to 90 mL/min), 21% had stage 3 chronic kidney disease or worse (eGFR <60 mL/min), and only 34% had normal renal function (eGFR >90 mL/min) (13). Moreover, in a retrospective review of patients with hypoparathyroidism identified from an electronic hospital-based registry, hypercalciuria was present in 38%, and 31% had evidence of renal calcifications (5). In that report, 41% had evidence of stage 3 chronic kidney disease; this rate was twofold to 17-fold higher compared with a normative age-based reference population (5). Our baseline data confirm the expectations in a representative sampling of patients with hypoparathyroidism: 41% of the cohort had hypercalciuria (>250 mg/d) and 46% and 12.5% had stage 2 and 3 chronic kidney disease, respectively.

Specific risk factors predispose patients with chronic hypoparathyroidism who are receiving standard therapy to a heightened risk of renal disease. Mitchell et al. (5) showed that age, duration of disease, and proportion of time with relative hypercalcemia (calcium >9.5 mg/dL) were negative predictors of eGFR. Underbjerg et al. (13) showed that the calcium- phosphate product (>2.8 mmol²/L² or 0.2 mg²/dL²), duration of disease (>12.7 years), and number of hypercalcemic episodes (one or more) were significant predictors of renal disease in patients receiving standard therapy. We similarly found that serum calcium levels were a significant negative predictor of eGFR. Notably, the 2-year decrease in serum calcium levels correlated directly with the 2-year decrease in serum creatinine levels and inversely with the 2-year increase in eGFR levels. It is possible that a trend toward a decrease in filtered calcium load at 2 years had a salutary effect on renal function. This may suggest that goals for serum calcium levels should be kept as low as possible while avoiding symptoms of hypocalcemia. These data confirm published guidelines that recommend levels typically lower than the laboratory range for the serum calcium (9, 14, 15).

We observed a decrease in urinary calcium excretion with rhPTH(1-84). In previous studies that used PTH(1-34) given twice daily for up to 3 years, authors observed maintenance of urinary calcium in the normal range (16), whereas continuous administration of PTH(1-34) via pump delivery system for 3 months reduced urinary calcium excretion by 59% (17). In contrast, in a 6-month randomized study of rhPTH(1-84), 24-hour urinary calcium excretion did not decrease, but this was probably due to the fixed dose of 100 μg/d that was used (18). Sustained reduction of urinary calcium excretion is difficult to achieve in conventionally treated patients with hypoparathyroidism (5), but achievement of this outcome is an important goal in the care of these patients. Of note, our study did not include assessment of 24-hour urine profiles and it is possible that we missed transient increases in urinary calcium excretion that may increase renal morbidity. Additional pharmacokinetic assessment would be needed to address this point.

When PTH or its analogs are administered as monotherapy for any disease, BMD by dual energy x-ray absorptiometry typically reflects the known site-specific effects of PTH, namely, increases in lumbar spine and declines in one-third radius BMD. In hypoparathyroidism, as shown by us and others (2, 19), baseline BMD at the lumbar spine and total hip is higher than age- and sex-matched reference standards. We now show that lumbar spine BMD increased in the early years and plateaued after 4 years of rhPTH(1-84) therapy, and the increase in total hip BMD was seen in the later years of PTH therapy. Femoral neck BMD remained unchanged throughout the study. One-third radial BMD declined modestly. These densitometric results are compatible with the differential effects of PTH at sites that are predominantly cortical (distal one-third radius) or trabecular (lumbar spine) bone. The microstructural basis for the increase at the lumbar spine and total hip is not certain. Our histomorphometric analysis of bone biopsy specimens from 13 subjects with hypoparathyroidism who were treated with rhPTH(1-84) showed that after 8 years, intratrabecular tunneling was present, with increases in cancellous bone volume and trabecular number (20). Whether these changes in trabecular microstructure and BMD are associated with fewer classical, fragility fractures remains to be determined.

The effects on cortical bone are unclear. The decrease we observed at the one-third radius is consistent with the known effects of PTH to increase cortical porosity and endosteal resorption. Our 8-year histomorphometric analysis showed an increase in cortical porosity (20). It is noteworthy that the fractures we observed, although not classical fragility fractures, all occurred at cortical sites. Fracture data are needed to determine whether cortical bone fragility is present. It is unknown whether the fractures we observed might be part of the natural history of hypoparathyroidism rather than attributable to rhPTH(1-84) treatment per se. It seems unlikely that the normal one-third radial T-score of −0.26 at 8 years was related to the observed fractures, but we are limited in this assumption by the lack of a control group. The increase at the trabecular-enriched lumbar spine and the decrease at the cortical one-third radius are reminiscent of the patterns observed with intermittent PTH treatment of osteoporosis. In the context of intermittent PTH therapy for osteoporosis (21), nonvertebral fracture risk is reduced, even with a similar decline in cortical bone density that we observed in this study. The only way to resolve this issue will be to obtain important fracture-risk data in the context of long-term rhPTH(1-84). This goal will only be achieved by a multinational consortium, because no one investigative site will ever have enough subjects with hypoparathyroidism to draw any key conclusions in this regard.

Our long-term experience documents that treatment with rhPTH(1-84) was associated with relatively few adverse events. In particular, hypercalcemia, hypocalcemia, and nephrolithiasis were uncommon. Although this report only includes patients who chose to continue long-term therapy, this safety information is reassuring, given the expected long-term use of PTH replacement in this disease. None of the subjects withdrew from the study because of these adverse effects, with the exception of two who withdrew because of nephrolithiasis.

The strengths of this investigation include the unusually large cohort of subjects with hypoparathyroidism that was followed longitudinally over 8 years of rhPTH(1-84) therapy. The limitations of the study include the open-label design and, importantly, the lack of a control group. For ethical reasons, however, it would have been unacceptable to follow up over such a long time subjects who were eligible for rhPTH(1-84) but did not receive it. However, each patient served as his or her own control, with careful monitoring of specific changes. Although the variability in dosing might be considered a limitation of the study, such dosing reflects the real-life experience of using this drug for hypoparathyroidism. Titration of rhPTH(1-84) in hypoparathyroidism is an accepted and necessary standard of care. The most common dose at 8 years was 50 μg daily (54% of patients), consistent with the recommended starting dose.

This study demonstrates that rhPTH(1-84) is safe and effective as a long-term treatment of hypoparathyroidism for at least 8 years. It permits major reductions in the need for supplemental calcium and active vitamin D while maintaining serum calcium levels in the low-normal range. It reduces urinary calcium excretion and is notably associated with stable renal function. Larger and longer-term studies are needed to determine whether the classical comorbidities associated with hypoparathyroidism at the kidney and bone are reduced or reversed with long-term rhPTH(1-84) therapy.

Glossary

Abbreviations:

BMD

bone mineral density

eGFR

estimated glomerular filtration rate

rhPTH(1-84)

recombinant human parathyroid hormone (1-84)

Additional Information

Disclosure Summary: J.P.B. is a consultant for Amgen, Radius, Ultragenyx, Regeneron, and Shire Pharmaceuticals. N.E.C. is on the speaker’s bureau for Shire Pharmaceuticals. M.R.R. receives research support from Shire Pharmaceuticals and Amgen.

Data Availability: Restrictions apply to the availability of data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.