Elevations in Serum and Urinary Calcium with Parathyroid Hormone (1–84) with and without Alendronate for Osteoporosis

Abstract

Context

The effect of PTH therapy on serum and urinary calcium levels and the risk of hypercalcemia or hypercalciuria has not been formally evaluated.

Objective

The objective was to examine changes in serum and urinary calcium associated with PTH(1–84) therapy in the PaTH trial and the extent to which a defined algorithm resolved the elevated values.

Design, Setting, Participants, and Intervention

A total of 178 postmenopausal women were randomized to PTH(1–84) either alone or in combination with alendronate during the first year of the PaTH study.

Main Outcome Measure(s)

The main outcome measures were fasting serum calcium at baseline and 1, 3, and 12 months and 24-h urinary calcium at baseline and 3 months.

Results

In 14% of participants, serum calcium more than 10.5 mg/dl (>2.6 mmol/liter) developed. Following the defined algorithm, 58% of elevated measurements were normal on repeat testing; 38% required discontinuation of calcium and vitamin D supplementation, and one necessitated a decrease in PTH injection frequency to normalize serum calcium. One participant developed transient hypercalcemia between study visits and required hospitalization; the episode resolved with iv hydration and PTH discontinuation. Baseline characteristics associated with the development of hypercalcemia were serum calcium [relative hazards = 1.9 per 0.5 mg/dl (0.12 mmol/liter); 95% confidence interval = 1.1–3.2] and serum 1,25-dihydroxyvitamin D [relative hazard = 1.9 per 10 pg/ml (26 pmol/liter); 95% confidence interval = 1.2–3.1]. Fifteen women (8%) developed hypercalciuria [urinary calcium > 400 mg (100 mmol)/24 h or calcium/creatinine ratio > 0.4]; 80% of cases resolved after discontinuing calcium and vitamin D, 13% without intervention, and one after PTH injection frequency was decreased. Higher baseline urinary calcium excretion was associated with development of hypercalciuria [relative hazard = 1.5 per 50 mg/d (12.5 mmol/d); 95% confidence interval = 1.2–4.0]. Proportions of patients with elevated serum and urinary calcium were similar on single and combination therapy.

Conclusions

The frequency of episodic hypercalcemia or hypercalciuria in the PaTH trial was 21%. Episodes were generally mild, and nearly all cases resolved spontaneously or with discontinuation of calcium and vitamin D. The algorithms used to address hypercalcemia and hypercalciuria in the PaTH trial proved effective in safely resolving clinical episodes of increased urinary or serum calcium and might therefore be helpful to clinicians caring for patients on PTH.

Daily injections of PTH(1–34) and PTH(1–84) are associated with improvements in bone mineral density (BMD) (1–5), and PTH(1–34) therapy decreases fracture risk (6). As PTH therapy for osteoporosis becomes more common, there is a need to understand more fully the changes in serum and urinary calcium that may occur. Little information is available regarding the frequency of hypercalcemia and hypercalciuria events during PTH therapy or the ideal management of these problems when they arise. To address this issue, we examined changes in serum and urinary calcium levels associated with PTH(1–84) therapy in the Parathyroid Hormone and Alendronate for Osteoporosis (PaTH) trial and the extent to which a defined algorithm was successful in resolving the problem.

Subjects and Methods

Study population

We analyzed data from the first year of the PaTH study, a multicenter double-blind trial of PTH(1–84) alone, alendronate alone, or PTH(1–84) in combination with alendronate in postmenopausal osteoporosis. Study population details have been previously published (1). Briefly, PaTH studied 238 postmenopausal women with low BMD. Women were excluded if they had risk factors for hypercalcemia or hypercalciuria, such as renal disease (creatinine clearance < 40 ml/min, or 0.67 ml/sec), nephrolithiasis, granulomatous disease, hypercalcemia [a value above the upper normal limit of the reference laboratory (10.3 mg/dl, or 2.6 mmol/liter)], hypercalciuria [24-h urinary calcium/creatinine ratio > 0.3 mg/mg (>0.85 mmol/mmol)], or 25-hydroxyvitamin D less than 15 ng/ml (37.4 nmol/liter). Women were also excluded if they had been treated with bisphosphonates or had diseases or used medications known to affect bone metabolism, including more than 1000 IU/d of vitamin D or vitamin D analogs.

The study protocol was approved by the institutional review board at each clinical center, and all participants provided written informed consent.

The current study includes the 178 participants who were on PTH(1–84) either alone or in combination with alendronate in the first year of the study. We did not include data from participants taking only alendronate because this agent does not cause hypercalcemia and there were no cases of hypercalcemia or hypercalcuria among the women who received alendronate alone. This analysis is limited to the first year; in the second year of PaTH, no subjects received PTH.

Treatment

Participants were randomly assigned to either PTH(1–84) 100µg daily (NPS Pharmaceuticals, Parsippany, NJ) and alendronate 10 mg daily (Merck, Whitehouse Station, NJ) (PTH/alendronate combination group), or PTH(1–84) 100 µg daily and placebo tablet matching alendronate (PTH group) for 12 months. All participants received 500 mg/d elemental calcium as calcium carbonate (Tums; SmithKline Beecham, Philadelphia, PA), and a multivitamin containing 400 IU of vitamin D (Rugby Laboratories, Norcross, GA).

Study design

A total of 119 women were assigned to the PTH group and 59 to the PTH/alendronate combination group. Participants and investigators remained blinded to the treatment group assignments, except for one clinician at the coordinating center, who provided reports to the Data and Safety Monitoring Board. Although medications were provided by pharmaceutical companies, they had no role in the design, implementation, or interpretation of the study. All data were evaluated at the coordinating center by the study investigators.

Biochemical assessment

Fasting serum specimens obtained at baseline were analyzed for calcium, 25-hydroxyvitamin D, C-terminal telopeptide of type I collagen (CTX), N-propeptide of type I collagen (P1NP), and bone-specific alkaline phosphatase (BSAP) concentrations. Baseline serum samples were frozen at −70 C, and later assayed in a batch for 1,25-dihydroxyvitamin D [1,25(OH)₂D] in the PTH treatment group.

Serum 25-hydroxyvitamin D concentration was measured centrally by radioimmunoassay (DiaSorin, Stillwater, MN) with an interassay coefficient of variation between 2.7 and 6.0%. The limit of detection was 3.2 ng/ml (8 nmol/liter). CTX and P1NP were measured centrally (Synarc, Lyons, France) with two-site immunoassays on an automatic analyzer (Eleccys; Roche Diagnostics, Basal, Switzerland). Intraassay and interassay coefficients of variation for serum P1NP and CTX are approximately 4 and 6%, respectively. BSAP was measured with the Ostase assay (Beckman Coulter, Fullerton, CA). Serum 1,25(OH)₂D concentrations were measured by Dr. Michael Holick (Boston University School of Medicine, Boston, MA) using a radioreceptor assay that uses a 1,25(OH)₂D receptor from calf thymus after serum extraction, as previously described in detail (7). The detection limit of the assay is 5 pg/ml (13 pmol/liter); the intraassay coefficient of variation is 8%, whereas the interassay coefficient of variation is 12%.

Safety assessment and adverse events

Fasting serum calcium concentrations were measured at baseline and at 1, 3, and 12 months. Serum calcium concentrations were also checked at the 6- and 9-month visits if the participant had been in either the hypercalcemia or hypercalciuria algorithm, or if a participant had had a serum calcium concentration 10.2 mg/dl or more (≥2.6 mmol/liter) with a rise in serum calcium from baseline to that value of 0.4 mg/dl or more (≥0.1 mmol/liter). The indications for adding a 6- or 9-month calcium measurement were selected based on analysis of serum calcium patterns in participants who developed hypercalcemia in the first 6 months of the study. Participants were instructed not to take the PTH injection the morning of these clinic visits. The 24-h urine calcium and creatinine were assessed at baseline and at 3 months. At each visit, participants were asked about adverse events, which were coded using preferred terms from the Medical Dictionary for Regulatory Activities (MedDRA) and classified by a clinician at the University of California, San Francisco, who was blinded to treatment-group assignments.

Hypercalcemia and hypercalciuria algorithms

The study protocol included algorithms for use when a serum or urinary calcium level was elevated. Elevations were defined as a serum calcium greater than 10.5 mg/dl or a urinary calcium excretion greater than 400 mg per 24 h, or a ratio of urinary calcium to creatinine concentration more than 0.4.

The hypercalcemia algorithm (Fig. 1) called for repeat assessment of the elevated value within 1 wk without any change in treatment (step 1), followed by discontinuation of the calcium and vitamin D supplementation (step 2), then a reduction of PTH dose (step 3), and lastly discontinuation of PTH treatment if serum calcium remained above 10.5 mg/dl (step 4). If serum calcium concentration was above 11.2 mg/dl, investigators were asked to repeat a serum calcium measurement immediately, and then institute the same stepwise algorithm as noted.

Fig. 1.

Algorithm provided to all study investigators who were to follow steps in this algorithm in case a participant had an elevated serum calcium level. To convert serum calcium to millimoles per liter, multiply by 0.25.

The hypercalciuria algorithm called for discontinuation of the calcium and vitamin D supplementation (step 1), followed by reduction of the dose of PTH to every other day (step 2) if the hypercalciuria persisted 6 wk later, and then discontinuation of PTH treatment if the urinary calcium remained elevated 6 wk after the reduction in PTH dose (step 3).

BMD assessment

Areal BMD was assessed using dual-energy x-ray absorptiometry (Hologic QDR-4500A or Delphi densitometer, Hologic, Inc., Bedford, MA). BMD was measured at the hip (femoral neck and total hip), the lumbar spine (L1–L4), and the radius (distal third of the radial shaft) at baseline and at 12 months. The coefficient of variation for these measurements is 1 to 2% (8).

Statistical analyses

Three participants were excluded from analyses because of missing calcium data. ANOVA was used to compare differences in means for continuous variables. We defined hypercalcemia as the first episode of a serum calcium more than 10.5 mg/dl (>2.6 mmol/liter) and hypercalciuria as the first episode of a urinary calcium excretion more than 400 mg/d (>100 mmol/d) or a urinary calcium/creatinine ratio more than 0.4 during a routine study visit after randomization. Concentrations of turnover markers were not normally distributed; therefore, they were log transformed for analysis, and their geometric means are presented. To analyze predictors of hypercalcemia, Cox proportional hazards models were used with time to first event of hypercalcemia or hypercalciuria; treatment-adjusted hazards ratios and 95% confidence intervals are reported. All statistical analyses were performed using SAS Software, version 9.2 (SAS Institute Inc., Cary, NC). All statistical tests were twosided, and we considered P < 0.05 (not adjusted for multiple comparisons) statistically significant.

Primary analyses were performed using total serum calcium, uncorrected for albumin. Adjusting the serum calcium for serum albumin [total calcium = measured calcium + 0.8 mg/dl (0.2 mmol/liter) × 4.0 g/dl (40 g/liter) − measured albumin] did not alter the results (9).

Results

Baseline characteristics

At baseline, participants who developed hypercalcemia (n = 24) and those who did not develop either hypercalcemia or hypercalciuria (n = 141) did not differ significantly with regard to age, body mass index (BMI), urinary calcium, creatinine clearance, serum 25-hydroxyvitamin D, or bone turnover markers (Table 1). Baseline serum calcium and 1,25(OH)₂D, however, were higher in those women who subsequently developed hypercalcemia compared with those who did not develop either hypercalcemia or hypercalciuria during PTH treatment (Table 1). The women who developed hypercalcemia also had somewhat higher BMD at the spine compared with those who did not. BMD at the total hip and radius did not differ between the two groups. Seventy-one percent of the women who developed hypercalcemia had baseline serum calcium values between 9.5 and 10.4 mg/dl (2.4 and 2.6 mmol/liter), 25% had a baseline serum calcium less than 9.5 mg/dl (2.4 mmol/liter), and one participant (4%) had a baseline serum calcium between 10.5 and 10.9 mg/dl (2.6 –2.7 mmol/liter) in the central laboratory. This participant had a repeat serum calcium measurement locally that was normal and qualified her for study entry.

TABLE 1.

Baseline characteristics of participants according to whether hypercalcemia or hypercalciuria developed while they were using PTH and PTH plus alendronate

Characteristic	Normal calcium (n = 141)	Hypercalcemia (n = 24)	P vs. normal	Hypercalciuria (n = 15)	P vs. normal
Age (yr)	69.6 ± 7.2	69.5 ± 7.8	0.9	68.7 ± 6.8	0.6
BMI (kg/m2)	26.3 ± 5.3	25.3 ± 3.5	0.4	25.1 ± 3.6	0.4
Total hip BMD (g/cm2)	0.72 ± 0.10	0.72 ± 0.07	0.8	0.73 ± 0.07	0.6
Total spine BMD (g/cm2)	0.78 ± 0.10	0.83 ± 0.15	0.03	0.76 ± 0.10	0.5
Radial BMD (g/cm2)	0.56 ± 0.07	0.58 ± 0.07	0.2	0.56 ± 0.08	0.9
Serum calcium (mg/dl)	9.5 ± 0.4	9.7 ± 0.4	0.02	9.5 ± 0.4	0.8
Serum 25OHD (ng/ml)	37.4 ± 13.4	40.8 ± 15.8	0.3	41.7 ± 11.5	0.2
Serum calcitriol (pg/ml)	49.0 ± 10.6	57.6 ± 15.7	0.01	50 ± 10.7	0.8
Urinary calcium (mg/d)	131 ± 70	126 ± 59	0.8	181 ± 69	<0.01
Urinary Ca/Cr ratio (mg/mg)	0.14 ± 0.07	0.14 ± 0.08	0.9	0.20 ± 0.08	<0.01
CrCl (ml/min)	92.4 ± 29	86.7 ± 28	0.4	95.1 ± 16	0.7
P1NP (ng/ml)	49.7 ± 25.6	46.8 ± 21.9	0.5	58.2 ± 24.6	0.2
BSAP (ng/ml)	16.7 ± 6.3	16.3 ± 5.6	0.6	17.8 ± 4.9	0.5
CTX (pg/ml)	331 ± 234	283 ± 234	0.2	415 ± 301	0.1

25OHD, 25-Hydroxyvitamin D; Ca, calcium; Cr, creatinine; CrCl, creatinine clearance. Normal calcium indicates participants who did not have any elevation of urine or serum calcium during PaTH. Hypercalcemia indicates participants who had at least one serum calcium concentration less than 10.5 mg/dl at a routine study visit. Hypercalciuria indicates participants with at least one episode of 24-h urinary calcium excretion greater than 400 mg or urinary Ca/Cr greater than 0.4 at a routine study visit. To convert serum calcium to mmol/liter, multiply by 0.25; to convert urinary calcium to mmol/d, multiply by 0.25; to convert CrCl to ml/sec, multiply by 0.0167; to convert serum 25OHD to nmol/liter, multiply by 2.496; to convert serum calcitriol to pmol/liter, multiply by 2.6; and to convert serum PTH to ng/liter, multiply by 1.0.

At baseline, participants who developed hypercalciuria (n = 15) and those who did not (n = 141) did not differ significantly with regard to age, BMI, total hip, or spine BMD, serum calcium, 25-hydroxyvitaminDor 1,25(OH)₂D, or bone turnover markers (Table 1). However, women who developed hypercalciuria had higher 24-h urinary calcium excretion (181 ± 69 vs. 131 ± 70 mg/d, or 45.2 ± 17.3 vs. 32.8 ± 17.5 mmol/d; P < 0.01), and higher calcium/creatinine ratios (0.20 ± 0.08 vs. 0.14 ± 0.07 mg/mg; P < 0.01) at baseline, compared with those participants who did not develop elevated urinary calcium.

Serum calcium

One month after initiation of therapy, mean serum calcium concentration had increased by 0.14 mg/dl (0.04 mmol/liter) on PTH alone (P = 0.004 compared with baseline), and by 0.08 mg/dl (0.02 mmol/liter) on PTH/alendronate combination therapy (P = 0.25 compared with baseline) (Fig. 2). These changes were not significantly different from each other (P = 0.45). Three months after initiation of therapy, mean serum calcium had increased by 0.25 mg/dl (0.06 mmol/liter) on PTH alone (P < 0.0001 compared with baseline), a change significantly different from the nonsignificant 0.01 mg/dl (0.003 mmol/liter) difference on PTH/alendronate combination therapy (P = 0.009, between group comparison). After 12 months of therapy, there was no difference in the mean change in serum calcium among those on PTH alone (−0.03 mg/dl, or −0.008 mmol/liter) and those on combination therapy (0.02 mg/dl, or 0.005 mmol/liter) (P = 0.44).

Fig. 2.

Mean serum calcium concentration at each study visit in participants assigned to PTH alone (■) or to PTH and alendronate combination therapy (●). To convert serum calcium to millimoles per liter, multiply by 0.25.

Hypercalcemia

During the study, 25 women (14%) developed hypercalcemia on at least one occasion; 12 values were between 10.5 and 10.7 mg/dl (2.63 and 2.68 mmol/liter), five between 10.8 and 11.0 mg/dl (2.70 and 2.75 mmol/liter), two between 11.1 and 11.3 mg/dl (2.78 and 2.83 mmol/liter), three between 11.7 and 11.9 mg/dl (2.93 and 2.98 mmol/liter), and three were greater than 12 mg/dl (3.0 mmol/liter). In the PTH alone group, 13% of women developed hypercalcemia; 4% had values more than 11.2 mg/dl (2.8 mmol/liter). In the PTH/alendronate combination group, 16% of women developed hypercalcemia; 3.4% had values more than 11.2 mg/dl (2.8 mmol/liter). Serum calcium concentrations were normal in 14 women (58%) after a repeat measurement (step 1 of the algorithm). In nine additional participants (38%), serum calcium elevations resolved after discontinuation of calcium and vitamin D supplementation (step 2). PTH injection frequency was decreased to every other day (step 3) in one participant, with prompt resolution of the elevated serum calcium level. One other study participant met criteria for decreasing PTH injection frequency because of a repeat serum calcium of 11.1 mg/dl (2.8 mmol/liter), but her hypercalcemia resolved after discontinuing calcium and vitamin D supplementation alone. Lastly, one participant using PTH alone had normal serum calcium at all study visits, but presented to a local hospital with nausea and had a serum calcium of 14.3 mg/dl (3.6 mmol/liter) 9 months after beginning PTH. The hypercalcemia episode had no identifiable precipitating event and resolved within 24 h with iv hydration and discontinuation of PTH, calcium, and vitamin D supplements. In three of the seven participants who had a serum calcium more than 11.2 mg/dl (2.8 mmol/liter), serum calcium levels were normal at the repeat measurement. Eleven of the cases (46%) of elevated serum calcium occurred within 1 month of starting PTH therapy, six were noted at the 3-month visit, three at 6 months, and four at 12 months (Fig. 3). Hypercalcemia recurred in four participants; in three cases, serum calcium concentrations were normal after a repeat measurement, whereas in one case, the serum calcium elevation resolved after discontinuation of calcium supplementation.

Fig. 3.

Percentage of participants on PTH or PTH/alendronate combination therapy who had hypercalcemia at each study month after randomization.

Among the women with hypercalcemia, two discontinued PTH for an adverse event unrelated to the hypercalcemia; one discontinued therapy temporarily, and the other discontinued PTH therapy permanently 2 wk before her serum calcium was found to be elevated.

Urine calcium

At 3 months, the mean urine calcium was 207.2 ± 110.1 mg/dl (51.8 ± 27.5 mmol/liter) on PTH alone and 193.3 ± 144.2 mg/dl (48.3 ± 36.1 mmol/liter) on PTH/alendronate combination therapy; these values were not significantly different from each other. Compared with baseline, mean urine calcium concentration had increased by 68.6 ± 106.7 mg/dl (17.2 ± 26.7 mmol/liter) on PTH alone (P < 0.001 compared with baseline), and by 73.1 ± 120.5 mg/dl (18.3 ± 30.1 mmol/liter) on PTH/alendronate combination therapy (P < 0.001 compared with baseline). The changes in urine calcium were not significantly different between the treatment groups (P = 0.81).

Hypercalciuria

During the study, 15 women (9%) developed hypercalciuria, reflecting 8% of the PTH alone group and 11% of the PTH/alendronate group. In 12 participants (80%), hypercalciuria resolved after discontinuing calcium and vitamin D supplementation (step 1). PTH injection frequency was decreased to every other day (step 2) in one participant, with resolution of the hypercalciuria. In one case the site investigator implemented step 2 of the algorithm before step 1, with resolution of the hypercalciuria. When PTH frequency was resumed, hypercalciuria did not recur. In the remainder of cases, hypercalciuria resolved without intervention. Among women with hypercalciuria, two had a temporary suspension of PTH therapy related to an adverse event other than hypercalciuria, and three women discontinued PTH altogether because of adverse events other than hypercalciuria. Two participants in the PTH-only group had concurrent serum and urinary calcium elevations, both of which resolved with discontinuation of calcium and vitamin D supplementation.

Predictors of hypercalcemia

The risk for hypercalcemia doubled for each 0.5 mg/dl (0.13 mmol/liter) increase in baseline serum calcium (relative hazard = 1.9; 95% confidence interval = 1.1–3.1). Similarly, the risk for hypercalcemia doubled for each increase in baseline serum 1,25(OH)₂D concentration of 10 pg/ml (26 pmol/liter) (relative hazard = 1.9; 95% confidence interval = 1.2–3.1). The risk for hypercalcemia while using PTH(1–84) was not associated with other baseline characteristics such as age, BMI, markers of bone turnover, or baseline BMD (Table 2).

TABLE 2.

Relative hazards and 95% confidence intervals for the development of hypercalciuria or hypercalcemia based on baseline patient characteristics

Predictor	Hypercalcemia		Hypercalciuria
	RH	95% CI	RH	95% CI
Age (per 5 yr)	1.0	0.7–1.3	0.9	0.6–1.3
BMI (per 5.0 kg/m2)	0.8	0.5–1.3	0.8	0.4–1.4
Total hip BMD (per 0.09 g/cm2)	1.0	0.7–1.5	1.1	0.7–1.9
Spine total BMD (per 0.11 g/cm2)	1.6	1.1–2.5	0.7	0.4–1.3
Radial BMD (per 0.07 g/cm2)	1.3	0.9–2.0	0.9	0.6–1.6
Serum calcium (per 0.5 mg/dl)	1.9	1.1–3.1	0.8	0.4–1.7
Serum 25OHD (per 5 ng/ml)	1.1	0.9–1.3	1.1	0.9–1.3
Serum calcitriol (per 10 pg/ml)	1.9	1.2–3.1	1.0	0.5–2.0
Urinary calcium (per 50 mg/d)	0.9	0.6–1.2	1.5	1.1–2.0
Urinary Ca/Cr ratio (per 50 mg/mg)	1.0	0.7–1.3	1.6	1.2–2.2
CrCl (per 28.5 ml/min)	0.8	0.5–1.2	1.1	0.7–1.8
P1NP (per 26 ng/ml)	0.8	0.5–1.3	1.4	0.9–2.3
BSAP (per 6 ng/ml)	0.9	0.6–1.3	1.2	0.7–1.9
CTX (per 234 pg/ml)	0.8	0.5–1.1	1.6	0.9–2.8

Serum calcitriol measured only in PTH group (n = 85). CI, Confidence interval; RH, relative hazard.

Predictors of hypercalciuria

The risk for hypercalciuria increased by 50% for each 50 mg/d increase in baseline urinary calcium excretion (relative hazard = 1.5; 95% confidence interval = 1.1–2.0) (Table 2). Similarly, the risk for hypercalciuria increased by 60% for each increase in baseline urinary calcium/creatinine ratio of 50 mg/mg (relative hazard = 1.6; 95% confidence interval = 1.2–2.2). The risk for hypercalciuria while using PTH(1–84) was not associated with other baseline characteristics, such as age, BMI, baseline BMD, markers of bone turnover, serum concentrations of vitamin D metabolites, or calcium.

Discussion

The primary mechanism involved in PTH-mediated hypercalcemia is thought to be increased bone remodeling. Intermittent PTH administration increases bone turnover with formation predominating over resorption, particularly early in therapy (10, 11). Therapeutic use of PTH may lead to hypercalcemia via activation of bone remodeling, through activation of the renal 1-α-hydroxylase and subsequent increase in 1,25(OH)₂D concentration, resulting in increased intestinal calcium absorption, or by increasing renal tubular reabsorption of filtered calcium. In our study, therapy with PTH(1–84) for osteoporosis was associated with a relatively low rate of elevations in serum or urinary calcium.

The frequency of at least one episode of hypercalcemia in PaTH was 14%, a rate very similar to the 11% rate observed in the teriparatide phase 3 fracture trial that used 20 µg/d of PTH(1–34) (6). Although these two studies had differences that limit precise comparisons, 20 µg of PTH(1–34) has been found to have similar effects on BMD at the spine and hip to those of 100 µg of PTH(1–84), the dose used in PaTH (4, 12). However, it should be noted that in the teriparatide trial, the 11% rate of hypercalcemia was noted when serum calcium was measured 4 to 6 h after PTH injection, which is when serum calcium concentration is likely to peak after PTH therapy, whereas the 14% rate observed in PaTH was noted when serum calcium measurements were made 24 h after the last PTH injection. In the teriparatide trial, serum calcium measurements obtained 16 to 24 h after the previous injection were “usually normal” (6). Furthermore, hypercalcemia was defined as a serum calcium concentration more than 10.6 mg/dl (>2.7 mmol/liter) in the teriparatide trial, whereas in PaTH, hypercalcemia was defined as a serum calcium more than 10.5 mg/dl (>2.6 mmol/liter). In addition, PaTH included a formal algorithm for hypercalcemia, whereas in the teriparatide trial the study protocol required “permanently halving the injected dose of medication in women with persistent hypercalcemia after a reduction in calcium intake” (6). This approach was somewhat similar to the algorithm applied in PaTH, in which the first step was to repeat the serum calcium measurement, followed by discontinuation of supplementation of calcium and vitamin D, and only if this failed to resolve the hypercalcemia was the PTH dose halved. In PaTH, PTH injections were decreased in frequency due to hypercalcemia in only one participant (0.8%), and PTH injections were discontinued in a second participant, whereas all other cases resolved either on repeat measurement or with discontinuation of calcium and vitamin D supplementation. In the teriparatide trial, 15 women (3%) in the 20-µg teriparatide dose group needed PTH dose reduction, and one participant required discontinuation of treatment with PTH. Eight percent of PaTH participants developed one episode of hypercalciuria, although no placebo group is available for comparison of hypercalciuria rates; however, with teriparatide, the incidence of hypercalciuria was not increased among patients on treatment compared with those using placebo, although a rate is not provided (6). The phase 3 fracture trial for PTH(1–84) has been reported in abstract form, relating a rate of hypercalcemia of 28.3% in the PTH group vs. 4.7% in the placebo group (13). This rate would appear to be higher than the rate we observed in PaTH; however, participants in the fracture study received a higher dose of calcium supplements (700 mg/d), and the definition of hypercalcemia in the fracture trial was not described.

In the current study, the incidence of elevations in serum or urinary calcium was similar between women using PTH alone and women using PTH/alendronate in combination. Although concomitant alendronate blunts some of the therapeutic effects of PTH(1–84) on bone (1), its effects on the hypercalcemic response appear to be minimal.

The exclusion criteria in PaTH were selected to minimize the participants’ risk for hypercalcemia or hypercalciuria. Therefore, the study population of PaTH may not reflect populations who are on PTH therapy in clinical practice. During the course of PaTH, participants took a calcium and vitamin D supplement of modest size (500 mg elemental calcium and 400 IU of vitamin D daily), yet the discontinuation of this supplement appeared to impact on subsequent serum calcium measurements. In this study, we did not assess dietary calcium intake, so we are unable to draw conclusions as to whether women with higher dietary calcium intake at baseline were more likely to develop hypercalcemia, or to have resolution of hypercalcemia with the discontinuation of supplemental calcium. It is possible that higher calcium and vitamin D supplementation doses than the doses used in PaTH may increase the rate of hypercalcemia and/or hypercalciuria in women treated with PTH.

Approximately half of the episodes of hypercalcemia noted in PaTH occurred within 1 month of treatment initiation; however, approximately half of participants who developed hypercalcemia during the study had normal serum calcium concentrations at the 1-month visit but developed hypercalcemia at the 3-, 6-, or 12-month visits. Because of this and because we did observe one case of hypercalcemia in a patient who had normal serum calcium concentrations at all study visits, it seems that hypercalcemia tends to occur early but could develop at any time during PTH therapy. It is therefore imperative that clinicians prescribing and patients using therapeutic PTH are aware of the clinical signs and symptoms of hypercalcemia, as well as potential precipitating factors (such as dehydration, vomiting, diarrhea, or febrile illnesses). Based on our findings that the risk for hypercalcemia doubled for each 0.5-mg/dl (0.125 mmol/liter) increase in serum calcium at the initiation of therapy, it might also be advisable to monitor more closely patients who start PTH therapy with higher serum calcium concentrations.

Therapy with PTH(1–34) or PTH(1–84) poses a risk of hypercalcemia or hypercalciuria during therapy. The frequency of developing either hypercalcemia or hypercalciuria in the PaTH trial was 21%, although episodes were generally mild, and almost all (88%) readily resolved spontaneously or with discontinuation of calcium and vitamin D supplementation. Episodes occurred early in treatment and were successfully managed by the algorithm used in PaTH. None of the episodes of hypercalcemia had any clinical sequelae, except for the case of the participant who presented with symptomatic hypercalcemia. Even in her case, however, there were no lasting sequelae. The algorithms used to address hypercalcemia and hypercalciuria in the PaTH trial proved effective in safely resolving clinical episodes of increased urinary or serum calcium. These algorithms might therefore be helpful to clinicians caring for patients on PTH therapy.

Abbreviations

BMD

Bone mineral density

BMI

body mass index

BSAP

bone-specific alkaline phosphatase

CTX

C-terminal telopeptide of type I collagen

1,25(OH)₂D

1,25-dihydroxyvitamin D

P1NP

N-propeptide of type I collagen

PaTH

Parathyroid Hormone and Alendronate for Osteoporosis Trial