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Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institute of Deafness and other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Dr. Karen K. Winer, National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Boulevard, Room 4B11, Bethesda, Maryland 20892-7510. E-mail: winerk{at}mail.nih.gov.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Treatment of hypoparathyroidism with bovine PTH was first attempted approximately 35 yr ago, but failed due to rapid development of resistance (11). In 1996, a 5-month randomized crossover trial showed that once daily PTH maintained mean serum calcium in the normal range over a 24-h period, with decreased urinary calcium excretion compared with calcitriol and calcium supplements (12). Subsequently, a 6-month randomized crossover trial supported twice daily dosing as the preferred dose schedule compared with once daily PTH to normalize serum and urinary calcium levels (13).
The effect of PTH on bone mineral density (BMD) in animals and humans has been studied extensively over the past 25 yr. Once daily PTH treatment of adults with osteoporosis produces a rapid rise in bone mineralization (14, 15, 16, 17, 18, 19, 20). However, adults with hypoparathyroidism typically have increased BMD (21), and the effects of long-term PTH on bone density in these patients have not been examined.
To establish the long-term efficacy of PTH compared with conventional treatment, we conducted a 3-yr randomized trial comparing PTH to calcitriol and calcium therapy. This is the longest study to date of PTH treatment in hypoparathyroidism and the first study to examine long-term effects on mineral metabolism, markers of bone turnover, and BMD. The results reported here provide essential insight into both treatment regimens.
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Subjects and Methods |
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The study was a randomized, parallel group, open-label trial conducted at the National Institute of Child Health and Human Development (NICHD), NIH (Bethesda, MD). The NICHD institutional review board approved the study. Study subjects provided written informed consent. Patients were randomly assigned to receive either twice daily sc PTH or conventional therapy (oral calcitriol and calcium supplementation). Patients were evaluated semiannually in the NICHD outpatient clinic.
Study subjects
We studied 27 adults with hypoparathyroidism, aged 18–70 yr (Table 1
). Hypoparathyroidism was confirmed in all subjects by low levels of intact PTH during hypocalcemia. At study baseline, only six patients (no. 2, 4, 5, 11, 15, and 26) had not been exposed to PTH therapy through participation in a previous NICHD study. Subjects 3, 8, and 22–25 participated in a prior randomized crossover study comparing calcitriol and PTH (12). After completing this 20-wk pilot study, patients 3, 8, 22, and 25 received PTH, and patients 23 and 24 received calcitriol for the 9–12 months before entry into this long-term study. The remaining subjects participated in a 6-month randomized crossover study comparing once daily with twice daily PTH injections (13). Those subjects continued directly from the dose study to the current study. Thus, 19 patients (10 randomized to PTH, nine randomized to calcitriol and calcium) were receiving PTH before entering this study, and eight patients (four randomized to PTH and four randomized to calcitriol and calcium) were receiving vitamin D and calcium before study entry. Eligible subjects showed no evidence of hepatic disease or severe renal insufficiency (creatinine clearance, <25 ml/min).
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). Subjects 6, 7, 10, and 21 were from a family with a gain of function mutation in the calcium-sensing receptor (CaR) (22), and all had severe renal insufficiency, with creatinine clearances ranging from 18–40 ml/min. Subject 10 entered the study, as a single exception to the exclusion criteria, with a creatinine clearance of 18 ml/min. Subjects 12 and 24–26 were from a second family that showed no evidence of a CaR defect. The mean height, weight, and body mass index of the two treatment arms did not differ significantly. Subjects 5 and 6 discontinued the study after 1 and 2 yr, respectively, due to pregnancy. Subject 4 discontinued the study after 2 yr due to recurrent lower extremity pain. Outcome measures
The primary outcome measures were calcium levels in serum and urine. Secondary outcome measures were serum phosphorus and magnesium levels, markers of bone remodeling in the blood and urine, serum vitamin D, and kidney function as measured by urinary creatinine clearance. All blood and urine samples were measured at the NIH Clinical Center with the exception of serum 25- and 1,25-hydroxyvitamin D, and osteocalcin and urinary pyridinoline and deoxypyridinoline, which were measured at Quest Diagnostics (San Juan Capistrano, CA). BMD measurements of the spine (L1–L4), proximal femur, whole body, and radius were performed on a QDR 2000 scanner using dual energy x-ray absorptiometry (Hologic, Inc., Bedford, MA). BMD measurements of an anthropomorphic spine phantom over a 6-month period gave a precision of less than 0.5%. In seven subjects (no. 2, 4, 5, 11, 15, 16, and 22), fatigue and physical endurance were assessed at baseline and at the semiannual follow-up visits to the NIH (23, 24).
Treatment protocol
Subcutaneous PTH or oral calcitriol was administered every 12 h. Synthetic human PTH-(1–34) was purchased from Bachem California (Torrance, CA) in lyophilized form. The Pharmaceutical Development Service of the NIH prepared aqueous solutions for sc injection. Oral calcium carbonate supplementation (1000 mg/d elemental calcium) was given four times daily (with meals and at bedtime). All subjects were instructed to maintain a diet containing 1000 mg elemental calcium. A food frequency questionnaire was administered by a nutritionist at the beginning of the study and at each clinic visit to determine the level of dietary calcium intake.
Study participants entering directly into this study (without prior participation in either the pilot study or the PTH dose frequency protocol), were admitted to the Clinical Center for a 2-wk dose adjustment period. During this time, daily blood and 24-h urine collections for calcium, phosphorus, and magnesium determinations were obtained to select the dose of calcitriol or PTH that most nearly normalized the levels of calcium in both blood and urine.
Serum samples were obtained 1 h before the (0900 h) morning dose. The dose of each agent, PTH or calcitriol, was adjusted to achieve a serum calcium level within or just below the normal range, 1.9–2.2 mmol/liter (7.6–8.8 mg/dl; normal range, 2.05–2.50 mmol/liter; 8.22–10.02 mg/dl). Patients with CaR defects usually required serum calcium levels maintained below the normal range to avoid markedly elevated urinary calcium excretion levels. Magnesium supplementation was provided to subjects in both study arms who developed hypomagnesemia (normal, 0.75–1.00 mmol/liter) with two levels below 0.7 mmol/liter. Therefore, mild hypomagnesemia was tolerated to avoid gastrointestinal symptoms that may develop in some patients who require high doses of magnesium supplementation.
Clinical monitoring
Blood and urine samples were obtained weekly during the first 3 months of the study and biweekly thereafter and were sent to the Clinical Center to assess the adequacy of metabolic control. The timing of blood samples was before the morning dose of calcitriol or PTH. Dose adjustments were based upon the subject’s serum and urinary calcium levels and symptoms of hypocalcemia. Each patient kept a diary of symptoms and concurrent medications, and completed questionnaires at each semiannual visit on the duration and severity of symptoms of hypo- and hypercalcemia. In a subset of subjects, physical endurance was measured with a 9-min walk at baseline and at two follow-up visits to determine whether PTH had an effect on strength and endurance, as several patients had reported.
Statistical analysis
Semiannual measurements from baseline to 3 yr were used for analysis. Data from the two study arms (PTH vs. calcitriol and calcium) were compared by mixed model analysis for repeated measures, which is similar to repeated measures ANOVA, but with additional adjustment for random effects due to different longitudinal profiles between subjects. Treatment effect and time effect were modeled as the between- and within-subjects factors, respectively. Time trend was assessed per treatment group for BMD parameters. The percentages of patients who reported adverse events were compared by two-sample test for equality of proportions with continuity correction. Physical endurance data were available from seven patients (four from the PTH arm), and the significance level for comparing PTH and calcitriol groups was based on the exact distribution of the Mann-Whitney U test statistics. Data are presented as the mean ± SE unless stated otherwise. Two-sided P < 0.05 was considered significant.
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Results |
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A mean ± SD PTH dose of 37 ± 2.6 µg (0.5 µg/kg·dose) and a mean ± SD calcitriol dose of 0.91 ± 0.2 µg were required to maintain serum calcium in the low normal or just below the normal range. Seventeen subjects (12 from the PTH group and five from the calcitriol group) required magnesium supplementation to maintain serum magnesium levels just below the normal range. All patients with known CaR defects required magnesium supplementation (mean daily dose, 324 ± 77 mg), which was usually divided into three doses.
Serum mineral and vitamin D levels
Throughout the 3-yr study, PTH and calcitriol therapy maintained similar levels of serum calcium, phosphorus, and magnesium, which did not differ significantly between the treatment arms (Fig. 1). Mean serum calcium levels were 1.92 ± 0.02 for the PTH-treated group and 2.0 ± 0.01 mmol/liter for the calcitriol-treated group. Mean serum phosphorus levels were 4.6 ± 0.08 and 4.5 ± 0.05 mg/dl for the PTH- and calcitriol-treated groups, respectively. Mean serum magnesium levels were 0.73 ± 0.02 and 0.75 ± 0.01 mmol/liter for the PTH- and calcitriol-treated groups, respectively. Additionally, mean serum 25-hydroxyvitamin D levels were 28 ± 4 and 31 ± 5 ng/ml, and mean serum 1,25-dihydroxyvitamin D levels were 43 ± 5 and 40 ± 5 pg/ml in the PTH- and calcitriol-treated groups, respectively.
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PTH-(1–34) normalized mean 24-h urine calcium excretion throughout the study, whereas calcitriol treatment produced elevated mean levels (5.8 ± 0.27 vs. 8.2 ± 0.51 mmol/24 h, respectively; normal, 1.25–6.25 mmol/24 h). Twenty-four-hour urinary phosphorus and magnesium excretion levels were equivalent in both study arms. Creatinine clearance levels were also similar in both treatment groups and showed no significant change over time. At baseline and 3 yr, mean creatinine clearance levels were 80 ± 10 and 84 ± 13 ml/min, respectively, for the PTH group, and 91 ± 12 and 95 ± 12 ml/min for the calcitriol group. Additionally, the patients with severe renal insufficiency (subjects 7, 8, 10, 21, and 22) showed no change in creatinine clearance.
Markers of bone remodeling
PTH treatment produced a significant increase in markers of bone turnover (Fig. 2). Mean serum alkaline phosphatase and osteocalcin levels and mean urinary deoxypyridinoline and pyridinoline excretion levels were significantly higher throughout the 3-yr study period in the PTH-treated group compared with the calcitriol-treated group (P < 0.001). Markers of bone turnover in serum and urine rose gradually during PTH therapy, with a peak at 2–2.5 yr. At 3 yr, serum osteocalcin and urinary pyridinium cross-links showed an apparent decrease compared with the values at 2.5 yr.
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Bone mineral content (BMC) and BMD of the lumbar spine, femoral neck, radius, and whole body, measured twice yearly, showed no significant between-group differences over the 3-yr study period (Fig. 3). Nonetheless, although the PTH group maintained stable whole body and antero-posterior spine BMD and BMC throughout the 3 yr, the calcitriol group demonstrated a gradual rise in these values (P = 0.003 and P = 0.005 for time-related trends in whole body BMD and antero-posterior spine BMC, respectively). The BMD and BMC values of the distal one third radius remained unchanged during the 3 yr for the calcitriol group and showed a nonsignificant downward trend in the PTH-treated group (P = 0.06). The density results from the femoral neck showed a rise in BMD and BMC values for both treatment groups, with a significant BMD trend effect in the PTH-treated group (P = 0.04). Table 2 shows the BMD and BMC data for all areas measured.
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Most subjects considered PTH injections a welcome change to the multiple pill regimen typically required during calcitriol and calcium therapy. This was especially true for the patients with type 1 autoimmune polyglandular syndrome and with mutations of the CaR, who usually require high dosages of calcitriol and calcium. Episodes of upper and lower extremity cramping, numbness, and tingling occurred unpredictably during both treatment arms, often when there was no apparent fluctuation in serum calcium levels. For most patients, these symptoms were transient and did not interfere with daily functioning.
There was no significant difference in the incidence of adverse events, such as neuromuscular irritability, bone pain, fatigue, or arthralgias. Mild intermittent lower extremity pain, consistent with bone pain, occurred in seven subjects receiving PTH and in three subjects receiving calcitriol therapy. No skeletal malignancies occurred in protocol participants. One subject (no. 18), enrolled in the calcitriol arm, had a recurrence of thyroid cancer. Nephrolithiasis in a patient with long-standing nephrocalcinosis occurred in one subject (no. 3) treated with PTH. Fatigue was a common complaint of patients in the calcitriol group. Several patients described less fatigue and greater endurance with PTH treatment. However, preliminary studies using a 9-min walk-run test (23) of seven patients showed no difference between PTH-treated and calcitriol-treated patients or between baseline and later values in the PTH-treated patients (data not shown). Additionally, the same seven subjects had a mean baseline score of 16%, indicating mild fatigue on the Multifaceted Assessment of Fatigue self-report questionnaire (24). Two of the four subjects in the PTH group showed a 50% improvement in self-reported fatigue assessment after 6 months of PTH therapy.
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Discussion |
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Although urinary calcium excretion persistently decreased with PTH vs. calcitriol therapy, this decrease did not produce a significant improvement in renal function over the 3-yr duration of this study. Furthermore, the chronic mild hypercalciuria in the calcitriol-treated group did not cause a decrease in renal function. The reduction of urinary calcium was achieved in the PTH arm despite the greater number of patients with gain of function mutations, who tend to produce greater elevations of urinary calcium.
Both treatments produced similar bone mineral changes despite increased levels in bone turnover markers in the PTH arm. The bone mineral response to PTH in patients with hypoparathyroidism, who have high normal or above normal bone density at baseline, contrasts with that of osteoporotic patients to once daily PTH administration, which is associated with high bone turnover and a rapid rise in BMD (25, 26). However, the increase in femoral neck BMD and the decrease in the distal radius density in the PTH arm may reflect changes in bone similar to the effects of PTH in patients with osteoporosis (18, 27). A closer examination of the PTH effect on cortical bone, as measured in the distal radius, in humans with osteoporosis using volumetric analysis by pQCT shows an overall positive effect with significant increases in cortical bone area, mineral content, and periosteal and endocortical circumferences (28). These observations suggest that PTH treatment of hypoparathyroidism, as in treatment of osteoporosis, may be associated with some increased cortical porosity accompanied by concurrent increases in new bone at the periosteal and endocortical surfaces.
In this study the calcitriol-treated group experienced a rise in BMD over time, which to our knowledge represents the first longitudinal data showing increasing BMD in calcitriol-treated adult patients with this disorder. This rise in bone density presumably results from decreased bone resorption due to hypoparathyroidism and/or an anabolic effect of calcitriol and calcium supplementation.
At the time of study entry, 19 subjects were receiving PTH therapy associated with their participation in prior studies. This explains the elevated bone markers at the initial time point in this study. For those patients in the calcitriol arm, the decrease in bone markers suggests that the acute PTH effect had largely disappeared within the initial 6 months of the study. For most subjects mean levels of bone markers remained elevated in the PTH-treated group at the end of the 3-yr study period. However, three patients demonstrated normalization of these markers at the end of the PTH treatment period, and the 3-yr study period may have been insufficient to observe normalization in the other subjects.
The safety of long-term PTH treatment in humans has been questioned recently due to a report of increased dose-dependent osteosarcoma risk in PTH-treated rats (29). However, our 3-yr study of twice daily PTH as replacement therapy showed a rise in markers of bone turnover, but no apparent adverse changes in the bone or in BMD. To achieve more physiological replacement and further minimize the potential adverse effects on the bone, other treatment options may be considered in the future, such as long-acting PTH, PTH pump therapy, or three times daily PTH injection.
Although subjects described an improved quality of life and greater physical endurance with PTH therapy, preliminary studies of physical endurance showed no difference between the two treatment groups. A double-blind, placebo-controlled trial would be necessary to definitively investigate the quality of life issues.
In conclusion, PTH is a safe and effective alternative to calcitriol therapy that can produce long-term normalization of serum and urinary calcium levels. This benefit may reduce the risk of nephrocalcinosis and renal insufficiency during long-term treatment of chronic hypoparathyroidism, although further study is needed to confirm this hypothesis.
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Acknowledgments |
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Footnotes |
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C.W.K. is affiliated with the Clinical Trial, Epidemiology, and Biostatistics Branch, National Institute of Deafness and Other Communication Disorders, NIH.
Abbreviations: BMC, Bone mineral content; BMD, bone mineral density; CaR, calcium-sensing receptor.
Received November 6, 2002.
Accepted May 19, 2003.
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