Changes in vitamin D metabolites during teriparatide treatment

Bone 50 (2012) 1368–1371

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Original Full Length Article

Changes in vitamin D metabolites during teriparatide treatment Felicia Cosman a, b,⁎, Bess Dawson-Hughes c, Xiaohai Wan d, John H. Krege d a

Clinical Research Center, Helen Hayes Hospital, West Haverstraw, NY 10993, USA Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032, USA c Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, MA 02111, USA d Lilly USA LLC, Lilly Corporate Center, Indianapolis, IN 46285, USA b

a r t i c l e

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Article history: Received 5 January 2012 Revised 28 February 2012 Accepted 29 February 2012 Available online 9 March 2012 Edited by: R. Baron Keywords: Teriparatide 25-hydroxyvitamin D 1,25-dihydroxyvitamin D Vitamin D Osteoporosis

a b s t r a c t Parathyroid hormone (PTH) increases the conversion of 25-hydroxyvitamin D [25(OH)D] to 1,25 dihydroxyvitamin D [1,25(OH)2D]. The purpose of this study was to assess the changes in serum concentration of vitamin D metabolites 1,25 dihydroxyvitamin D [1,25(OH)2D] and 25-hydroxyvitamin D [25(OH)D] during teriparatide 20 μg/day (teriparatide) therapy in the double-blind Fracture Prevention Trial of postmenopausal women with osteoporosis and in the male study of men with osteoporosis. Patients were randomized to teriparatide or placebo and received daily supplements of calcium 1000 mg and vitamin D 400–1200 IU. Serum concentrations of 1,25(OH)2D and 25(OH)D were measured. In women (N =336), median 1,25(OH)2D concentrations at 1 month increased from baseline by 27% (P b 0.0001) in the teriparatide group versus −3% (P =0.87) in the placebo group (between group P b 0.0001). At 12 months, the increase was 19% (P b 0.0001) in the teriparatide group versus −2% (P =0.23) in the placebo group (Pb 0.0001). Median 25(OH)D concentrations at 12 months decreased by 19% (P b 0.0001) in the teriparatide group versus 0% (P =0.13) in the placebo group (P b 0.0001). In men (N =287), median 1,25(OH)2D concentrations at 1 month increased by 22% (Pb 0.0001) in the teriparatide group versus 0% (P=0.99) in the placebo group (P b 0.0001). At 12 months, the increase was 14% (Pb 0.0001) in the teriparatide group versus 5% (P =0.004) in the placebo group (P =0.17). Median 25(OH)D concentrations at 12 months decreased by 11% (P =0.001) in the teriparatide group versus an increase of 1% (P= 0.20) in the placebo group (P =0.003). Therefore, treatment with teriparatide increases 1,25(OH)2D concentrations and decreases 25(OH)D concentrations. © 2012 Elsevier Inc. All rights reserved.

Introduction Parathyroid hormone (PTH) stimulates renal 1α-hydroxylase activity resulting in the conversion of vitamin D metabolite 25-hydroxyvitamin D [25(OH)D] to the main biologically active form 1,25-dihydroxyvitamin D [1,25(OH)2D]. In turn, 1,25(OH)2D promotes intestinal calcium absorption, renal conservation of calcium, and skeletal calcium release to increase serum calcium concentrations [1–3]. Deficiency in the ability to generate 1,25(OH)2D has been reported in elderly patients with osteoporosis [4]. Teriparatide is recombinant human PTH (1–34), which has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone. Teriparatide 20 μg/day (teriparatide) is approved for use in both Abbreviations: 1,25OH2(D), 1,25 dihydroxyvitamin D; 25OH(D), 25-hydroxyvitamin D; BMD, bone mineral density; BMI, body mass index; CV, coefficient of variation; IQR, interquartile range; PTH, parathyroid hormone. ⁎ Corresponding author at: Helen Hayes Hospital, West Haverstraw, NY 10993, USA. Fax: + 1 845 786 4878. E-mail addresses: [email protected] (F. Cosman), [email protected] (B. Dawson-Hughes), [email protected] (X. Wan), [email protected] (J.H. Krege). 8756-3282/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2012.02.635

men and postmenopausal women with osteoporosis at high risk of fracture. The anabolic actions of teriparatide result in an increase in skeletal mass, markers of bone formation and resorption, and bone strength [5–10]. In postmenopausal women with osteoporosis, teriparatide reduces the risk of both vertebral and nonvertebral fractures [11,12]. In a letter, Licata [13] reported that 1,25(OH)2D concentrations increased and 25(OH)D concentrations decreased in 12 patients treated with teriparatide. These findings require confirmation, and details of the changes including the time course during teriparatide therapy compared with placebo may provide useful information for clinicians caring for patients treated with teriparatide. Previously completed phase 3 clinical trials of teriparatide included prospective assessments of serum 1,25(OH)2D and 25(OH)D. Here, we report the changes in concentrations of these vitamin D metabolites during teriparatide therapy in placebo-controlled clinical trials of men and postmenopausal women with osteoporosis. Materials and methods Details of the study design and populations for the prospective, double-blind, randomized, placebo-controlled Fracture Prevention

F. Cosman et al. / Bone 50 (2012) 1368–1371

Trial and the male osteoporosis trial of teriparatide have been previously described [11,14]. Both studies were conducted in accordance with the principles of the Declaration of Helsinki (current amendment at time of study) regarding ethics of medical research involving human subjects. The Fracture Prevention Trial enrolled ambulatory postmenopausal women with osteoporosis, defined as having ≥1 moderate or 2 mild atraumatic vertebral fractures, or with b2 moderate vertebral fractures and a hip or lumbar spine bone mineral density (BMD) T-score of ≤ −1.0 [11]. The male osteoporosis trial enrolled ambulatory men with hypogonadal or idiopathic osteoporosis and a spine or hip BMD T-score ≤ −2.0 [14]. In both trials, participants were supplemented daily with 1000 mg calcium and 400 to 1200 IU vitamin D for at least 1 month before baseline serum samples were obtained, and supplementation was continued for the duration of the trials. Vitamin D dosage was regionally determined. The supplements could be changed, reduced, or eliminated based on gastrointestinal or other symptoms. Participants were randomized to placebo or teriparatide. Vitamin D metabolite findings for a non-approved teriparatide 40 μg/day dose group were similar to those for the approved teriparatide 20 μg/day dose group (data not shown). The vitamin D metabolite assessments were prespecified in the study protocols and the assays were performed during the conduct of the trials. In all men and a subset of postmenopausal women, serum samples for 1,25(OH)2D were collected prior to the daily dose of study medication at the baseline visit and at 1, 3, 6, and 12 months. For this assay, serum samples were extracted with acetonitrile, purified on a Sep-Pak C-18 column, and assayed using a radioreceptor assay using calf thymus receptor and 3H-1,25 (OH)2D (Quest Diagnostics, San Juan Capistrano, CA; interassay coefficient of variation [CV] b10%). Serum concentrations of 25(OH)D after an acetonitrile extraction step were measured at the baseline visit and at 12 months in all patients in both studies, using a radioimmunoassay (Diasorin, Stillwater, MN; interassay CV between 2.7% and 6.0%). Theory/calculation In each trial, both actual and percent changes in serum concentrations of 1,25(OH)2D and 25(OH)D were compared between the placebo and teriparatide groups using the nonparametric Wilcoxon rank-sum test. The effects of either placebo or teriparatide on 1,25(OH)2D and 25(OH)D serum concentrations were assessed by comparing postbaseline values with baseline values using the signed-rank test. Statistical inferences were based on a 2-sided significance level of 0.05. No adjustment for multiplicity was made. Results Within each trial, there were no statistically significant differences between the placebo and teriparatide groups for any baseline

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characteristic (Table 1). Median levels of both vitamin D metabolites were within acceptable normal ranges. At all postbaseline timepoints, concentrations of 1,25(OH)2D were significantly increased in the teriparatide group compared with placebo group in each study (Fig. 1). In both trials, peak 1,25(OH)2D concentrations occurred at 1 month in the teriparatide group, with smaller increments persisting throughout the subsequent months of treatment. In both trials (Fig. 2), the 25(OH)D concentrations were unchanged in the placebo group and significantly decreased from baseline in the teriparatide treatment group (P b 0.05 between groups within each trial). In both trials, the 25(OH)D differences between the placebo and teriparatide groups were statistically significant for analyses by percent change, absolute change, and absolute value at 12 months (all P b 0.05). Discussion In summary, data from 2 teriparatide clinical trials showed that teriparatide therapy increased 1,25(OH)2D with the peak effect occurring at 1 month, and a persistent increase over the course of 1 year. The mechanism for the changes in vitamin D concentrations may be related to teriparatide-induced stimulation of 1α­hydroxylase, resulting in conversion of 25(OH)D to 1,25(OH)2D [1–3]. In support of this theory, 25(OH)D concentrations decreased during teriparatide therapy suggesting a conversion of 25(OH)D to the active 1,25(OH)2D metabolite. Serum concentrations of 25(OH)D were much higher than serum concentrations of 1,25(OH)2D suggesting the presence of a large reservoir of 25(OH)D [15]. As such, decreased serum concentration of 25(OH)D during teriparatide therapy because of the conversion of 25(OH)D to 1,25(OH)2D is somewhat unexpected. However, the half life of 1,25(OH)2D is approximately 20 times shorter than that of 25(OH)D [16], requiring the consumption of a significant amount of 25(OH)D for the maintenance of a small increase in 1,25(OH)2D. It is also possible that teriparatide may increase the conversion of 25(OH)D to other vitamin D metabolites which were not measured in this study. The increase in 1,25(OH)2D may contribute to the biological effects of teriparatide. For example, the effect of 1,25(OH)2D to increase calcium balance by increasing intestinal calcium absorption and renal calcium conservation may help contribute to the increase in skeletal mass during teriparatide therapy [17]. Additionally, an increase in 1,25(OH)2D concentration during teriparatide therapy might potentiate osteoblastic function [18–20]. An increase in active vitamin D may contribute to the observed increase in serum calcium during teriparatide therapy [11]. Furthermore, a PTH-induced reduction in 25(OH)D may be of clinical importance in the management of patients treated with teriparatide. However, in the clinical trial of postmenopausal women treated with teriparatide and supplemented with calcium and vitamin D, outcomes in subjects with baseline 25(OH)D sufficiency versus insufficiency were not notably different [21]. An area of potential investigation would be to assess whether patients with significant

Table 1 Baseline characteristics. Characteristic

Fracture Prevention Trial Placebo(n = 492)

Age (years) BMI (kg/m2) Lumbar Spine BMD(g/cm2) T-score 1,25-Dihydroxyvitamin D(pg/mL) 25-Hydroxyvitamin D(ng/mL) a,c

a,b

68.9 ± 7.0 26.6 ± 4.7 0.82 ± 0.17 − 2.4 ± 1.5 42.0(40.0, 44.0) 31.3(30.0, 32.1)

Male Osteoporosis Trial Teriparatide(n = 490) 69.4 ± 7.0 26.8 ± 4.1 0.82 ± 0.17 − 2.5 ± 1.5 42.0(40.0, 43.0) 30.8(29.2, 32.1)

Placebo(n = 145) 58.7 ± 12.9 25.2 ± 3.6 0.85 ± 0.14 − 2.4 ± 1.2 43.0(41.0, 45.0) 31.6(29.2, 36.0)

Teriparatide(n = 146) 59.4 ± 13.4 25.4 ± 3.7 0.89 ± 0.15 − 2.0 ± 1.4 39.0(37.0, 43.0) 31.6(28.4, 34.0)

Abbreviations: BMD = bone mineral density; BMI = body mass index; n = number of subjects. Vitamin D metabolites data include patients with both baseline and at least 1 postbaseline serum measurement of either 25(OH)D or 1,25(OH)2D. Values are mean ± standard deviation and median values (interquartile range). a Covance reference intervals: 1,25(OH)2D 15–60 pg/mL, 25(OH)D 10–61.2 ng/mL. b Concentrations of 1,25(OH)2D were obtained in 336 women (placebo [n = 169], teriparatide [n = 167]) and 287 men (placebo [n = 143], teriparatide [n = 144]). c Concentrations of 25(OH)D were obtained in 950 women (placebo [n = 479],teriparatide [n = 471]) and 279 men (placebo [n = 140], teriparatide [n = 139]).

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25(OH)D % Change from Baseline (medianIQR)

1,25(OH)2D % Change from Baseline (median IQR)

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60 55 50 45 40 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25

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Months Fig. 1. A. Postmenopausal women with osteoporosis. B. Men with Osteoporosis Percent changes in 1,25(OH)2D concentration over time from baseline to 12 months in the Fracture Prevention Trial [9] (A: N = 336 [placebo 169, teriparatide 167]) and male osteoporosis trial [12] (B: N = 287[placebo 143, teriparatide 144]). Note: Absolute levels of 1,25(OH)2D in the male study were included in Orwoll et. al. [12]. Abbreviation: IQR = interquartile range.

25(OH)D % Change from Baseline (medianIQR)

1,25(OH)2D % Change from Baseline (Median IQR)

Men with Osteoporosis 30

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25 20 15 10 5 0 -5 -10 -15

* P<0.05 vs.Placebo † P<0.05 vs. Baseline

-20 -25

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Teriparatide

Fig. 2. A. Postmenopausal women with osteoporosis. B. Men with Osteoporosis Percent changes in 25(OH)D concentration from baseline to 12 months in the Fracture Prevention Trial [9] (A: N = 950 [placebo 479, teriparatide 471]) and male osteoporosis trial [12] (B: N = 279 [placebo 140, teriparatide 139]). Abbreviation: IQR = interquartile range.

(25(OH)D concentration more than 30 ng/mL) increased similarly in all treatment groups [21].

decreases in 25(OH)D during teriparatide therapy might benefit from an increase in vitamin D supplementation. Patients with vitamin D deficiency (25(OH)D b10 ng/mL) were excluded from both trials, and the effect of teriparatide in such patients is unknown. The use of teriparatide in these patients should be delayed until the correction of their vitamin D deficiency. Limitations of these studies included that 25(OH)D was only assessed at baseline and at 12 months. Since the peak effect on the 1,25(OH)2D metabolite was at 1 month, it is possible that this analysis did not assess the 25(OH)D metabolite at the actual time of the peak effect. Additionally, individual data regarding the level of vitamin D supplementation and compliance with the vitamin D supplement were not collected. However, compliance with vitamin D supplementation would not be expected to differ by treatment group in these double-blind studies. Indeed, vitamin D supplementation in the trial of postmenopausal women appeared to impact 25(OH)D concentrations similarly in all groups. Patients were supplemented for the month between the enrollment and randomization visits, and during this interval, the proportion of patients who were vitamin D sufficient

Conclusions In conclusion, teriparatide therapy resulted in an increase in 1,25(OH)2D and a decrease in 25(OH)D concentrations in both men and postmenopausal women with osteoporosis. Disclosure Statement Cosman is a grant recipient and/or consultant/speaker for Novartis, Amgen, Lilly, and Merck; Dawson-Hughes is a consultant for Cytochroma, Lilly, Merck, Pfizer, Servier, and Wright Medical Technology; Wan and Krege are employed by and have financial interest in Eli Lilly and Company. The studies were funded and conducted by Eli Lilly. Acknowledgments The authors acknowledge David Meats and Fuad Mehraban at i3 Statprobe for support of this manuscript.

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