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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0239
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4630-4636
Copyright © 2007 by The Endocrine Society

Response to Teriparatide in Patients with Baseline 25-Hydroxyvitamin D Insufficiency or Sufficiency

Bess Dawson-Hughes, Peiqi Chen and John H. Krege

Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging (B.D.-H.), Tufts University, Boston, Massachusetts 02111; and Lilly Research Laboratories (P.C., J.H.K.), Eli Lilly and Company, Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Bess Dawson-Hughes, M.D., Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, Massachusetts 02111-1524. E-mail: bess.dawson-hughes{at}tufts.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Serum 25-hydroxyvitamin D (25OHD) concentrations greater than 30 ng/ml have been recommended for lowering fracture risk.

Objective: Our objective was to determine whether 25OHD sufficiency is a prerequisite for effective response to teriparatide (TPTD).

Design and Patients: Data were from 1620 osteoporotic postmenopausal women in the Fracture Prevention Trial. The response to TPTD was assessed in women subgrouped by having 25OHD insufficiency (>10 but ≤30 ng/ml) or 25OHD sufficiency (>30 but ≤183 ng/ml) at the baseline (randomization) visit. An abnormal intact PTH was exclusionary.

Interventions: At baseline, after at least 1 month of supplementation with calcium (1000 mg) and vitamin D (400–1200 IU) daily, women were randomized to placebo or 20 or 40 µg TPTD by daily sc injection for a median of 19 months. Observation was for a median of 21 months.

Main Outcome Measures: Main outcome measures included vertebral and nonvertebral fractures, change in bone mineral density at the lumbar spine and femoral neck, change in bone formation marker amino-terminal extension peptide of procollagen type 1, and the proportion of women with serum calcium at least 2.76 mmol/liter 4–6 h after dosing.

Results: TPTD reduced vertebral and nonvertebral fracture risk, increased lumbar spine and femoral neck bone mineral density, and increased amino-terminal extension peptide of procollagen type 1 relative to placebo in the two 25OHD subgroups. There were no significant differences in these endpoints between the subgroups (each treatment by subgroup interaction, P > 0.10). However, it should be noted that because of the limited number of fractures, this study does not exclude the possibility of differences in fracture outcome between the subgroups.

Conclusions: In postmenopausal women with osteoporosis and normal intact PTH, the responses to TPTD did not differ significantly in women with baseline 25OHD insufficiency or sufficiency.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
VITAMIN D IS ESSENTIAL for maintaining calcium homeostasis and optimizing bone health. Low concentrations of vitamin D lead to alterations in calcium and phosphorus homeostasis, secondary hyperparathyroidism, bone loss, osteoporosis, and an increase in fracture risk (1, 2, 3). More severe degrees of vitamin D deficiency may lead to impairment of bone mineralization and osteomalacia (4). Additionally, low serum concentrations of 25-hydroxyvitamin D (25OHD) have recently been associated with impaired lower extremity strength and performance (5). Adequate calcium and vitamin D intake is considered an essential component of osteoporosis management (6).

Numerous epidemiological studies have assessed the prevalence of low serum 25OHD (7, 8, 9, 10) and found that vitamin D inadequacy is a common problem worldwide. For example, more than half of North American women receiving therapy to treat or prevent osteoporosis have 25OHD inadequacy (10). Worldwide, over one billion people may have vitamin D deficiency or insufficiency (11).

Recently, it has been postulated that having vitamin D insufficiency might impair the therapeutic response to osteoporosis therapy. One study has suggested that without pharmacological vitamin D replacement, etidronate confers smaller increases in bone mineral density (BMD) in patients with vitamin D insufficiency vs. sufficiency (12). However, two recent studies showed raloxifene and alendronate, when coadministered with calcium and vitamin D supplementation, conferred similar increases in BMD in patients with vitamin D insufficiency vs. sufficiency (13, 14).

Teriparatide (TPTD), recombinant human PTH(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34), is a bone anabolic drug with an essentially opposite mechanism of action from that of antiresorptive drugs (15). Although antiresorptive drugs decrease bone turnover by inhibiting resorption, TPTD increases bone turnover with a positive balance of bone formation vs. resorption. In postmenopausal women with osteoporosis, the clinical effects of TPTD include increases in lumbar spine and femoral neck BMD and reduced vertebral and nonvertebral fracture risk (16). This analysis was conducted to determine whether it is important to normalize serum 25OHD before TPTD initiation or whether the same benefits of therapy can be achieved by initiating supplementation around the time that therapy is initiated. Given that women with osteoporosis commonly have inadequate vitamin D concentrations, the current analysis explores the fracture risk reduction, BMD, and bone turnover marker responses to TPTD in women with 25OHD sufficiency vs. insufficiency at baseline.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

Data from the multicenter Fracture Prevention Trial (FPT) were used in this analysis. The methods and results of the FPT have been previously published (16). Briefly, this double-blinded, placebo-controlled trial included ambulatory, postmenopausal women with osteoporosis ranging in age from 42–86 yr. Approximately 1000 mg/d of elemental calcium and approximately 400-1200 IU/d of vitamin D were supplied as open-label supplement(s) in which the dose of vitamin D was at the discretion of investigators; these were in the form of a calcium supplement and a vitamin D supplement, a combination calcium and vitamin D supplement, or contained within a multivitamin/multimineral supplement. The patients continued to take their calcium and vitamin D supplements at any time of the day throughout the study. At least 1 month after initiation of calcium and vitamin D supplementation, women were randomized to receive daily, self-administered, sc injections of placebo (n = 544), TPTD 20 µg/d (TPTD20; n = 541), or TPTD 40 µg/d (TPTD40; n = 552). Inclusion in the study required serum creatinine less than 2 mg/dl and other normal or clinically nonsignificant abnormal laboratory values, with specific requirements that serum calcium, serum endogenous PTH, and urinary calcium excretion be within normal limits. The number of women excluded because of elevated serum calcium or PTH levels is unknown. By protocol, patients with serum 25OHD less than 10 ng/ml or more than 183 ng/ml (three times the upper limit of the reference range) at randomization were excluded. Even so, six patients had serum 25OHD less than 10 ng/ml at baseline; these patients were excluded from the current analysis. The median duration of exposure to TPTD was 19 months, and the median duration of observation was 21 months.

Fracture assessment

Thoracic and lumbar spine radiographs were performed at baseline and study endpoint. Radiographs were assessed at a central site (Osteoporosis and Arthritis Research Center, University of California San Francisco, San Francisco, CA) by radiologists who were blinded to treatment, using a visual semiquantitative technique (17). A new vertebral fracture was reported for vertebrae not fractured at baseline with approximately 20% or greater height loss at follow-up. Nonvertebral fractures were documented by a review of the radiographs or radiological reports and were classified as fragility fractures if the associated trauma would not have resulted in the fracture of a normal bone, in the opinion of the local investigator. Protocol-specified nonvertebral sites included clavicle, scapula, rib, sacrum, humerus, forearm, carpus, pelvis, femur, patella, tibia, fibula, ankle, calcaneus, tarsus, and metatarsal.

BMD assessment

Lumbar spine and femoral neck BMD were assessed by dual-energy x-ray absorptiometry using Hologic (Hologic Corp., Bedford, MA), Norland (Norland Corp., Ft. Atkinson, WI), and GE-Lunar (Lunar Corp., Madison, WI) equipment. To eliminate differences attributable to densitometer manufacturer, BMD values were converted to standardized units (expressed as grams per square centimeter). BMD measurements were analyzed centrally by persons blinded to treatment. Vertebrae that could not be analyzed due to prevalent vertebral fractures apparent on the dual-energy x-ray absorptiometry screen, surgical artifact, excessive osteophytes, or other permanent artifact were excluded from the analysis. Serial measurements of a spine phantom at each center were used to adjust for minor changes in densitometer performance and to assess the consistency of measurements between centers.

Laboratory analyses

Bone formation marker amino-terminal propeptide of type I procollagen (PINP) was used for this analysis because this marker had the highest signal-to-noise ratio of those assessed in the FPT (18), and 3-month changes in this biomarker were correlated with lumbar spine BMD response at 18 months (19). Baseline and 3-month PINP assessments were performed on a subset of 771 patients. The baseline demographics of this PINP subset were not significantly different from those of the overall study population (19). Serum samples were stored at –20 C at Covance Central Laboratories, Inc. (Indianapolis, IN) and later shipped to SUPREME SA (Liege, Belgium) for testing using the UniQ assay (Orion Diagnostica, Espoo, Finland), with intraassay coefficient of variation (CV) of 4.8–13.7% and interassay CV of 3.1–8.2%, by persons blinded to group assignment.

Samples for serum calcium were collected at baseline and at approximately 4- 6 h after the previous injection (postdose) of study drug at 1, 3, 6, 12, and 18 months as well as at early discontinuation and study closeout visits from 1161 women. Patients were defined as having postdose hypercalcemia if they had serum concentrations of at least 2.76 mmol/liter. Previously serum calcium levels were found to be maximal at 4–6 h after TPTD injections (postdose) (16).

Fasting blood samples for assessment of 25OHD were obtained at a screening visit before initiation of calcium and vitamin D supplementation, at the baseline randomization visit at least 1 month after initiation of calcium and vitamin D supplements, and 12 months after randomization. Samples were centrifuged, and serum was frozen until analyzed. Serum 25OHD was measured by RIA (DiaSorin, Stillwater, MN) with an interassay CV of 2.7–6.0%.

Statistical analysis

25OHD concentrations at the baseline (randomization) visit were defined as insufficient if they were more 10 ng/ml (25 nmol/liter) and less than or equal to 30 ng/ml (75 nmol/liter) and were defined as sufficient if they were more than 30 ng/ml (75 nmol/liter). Binary variables (incidence of new vertebral fractures, nonvertebral fractures, and hypercalcemia) were compared using logistic regression models. Effects in the logistic regression model included treatment, subgroup defined by baseline 25OHD level, and treatment-by-subgroup interaction. No significant difference indicates that there is no statistically significant interaction of 25OHD subgroup with treatment difference in an outcome. Additional analyses were also performed when baseline 25OHD level was treated as a continuous variable in the logistic regression model. For the continuous variables including changes in BMD from baseline, subgroup analyses of baseline 25OHD status were performed using ANOVA. Effects in the model included treatment, 25OHD subgroup, and treatment-by-subgroup interaction. The distribution of PINP changes was skewed; therefore, ranked ANOVA was used to compare the actual changes in PINP from baseline to 3 months between the treatment groups.

The assessment of primary interest was the classification of vitamin D status at baseline, i.e. the randomization visit at which study drug was initiated; as noted, patients had taken calcium and vitamin D supplements for at least 1 month at this time point. Additionally, vitamin D status assessed at the screening visit approximately 1 month before initiation of study drug and before initiation of calcium and vitamin D supplementation as well as concentrations measured at 12 months after randomization were considered.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Demographics

Of 1620 women for whom 25OHD was measured at randomization, 767 (47.3%) had 25OHD insufficiency. There were no other significant differences in baseline characteristics between the treatment groups among the women with sufficient or insufficient 25OHD concentrations. Body mass index (BMI) values tended to be higher in women with sufficient 25OHD concentrations compared with those with insufficient 25OHD (Table 1Go), but these differences were not statistically significant.


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  		TABLE 1. Comparison of baseline characteristics (mean ± SD) at randomization of 1614 women by vitamin D status subgroup and randomization to placebo, TPTD 20 µg/d, or TPTD 40 µg/d

 
Change in vitamin D status

The vitamin D status of 1409 patients who had assessments at screening, randomization, and 12 months are provided in Table 2Go. At screening, 4–6% of participants were vitamin D deficient and 55–60% were insufficient. At randomization, after approximately 1 month of calcium and vitamin D supplementation, very few were deficient, but approximately 50% remained insufficient. After 12 months of vitamin D supplementation and study drug, there was no significant change in the proportion of patients with 25OHD deficiency and insufficiency vs. randomization in the placebo group, whereas in the TPTD20 and TPTD40 groups, about 67% of women were 25OHD insufficient. The proportions of women with 25OHD insufficiency were significantly greater at 12 months compared with values at baseline (randomization) (Table 2Go) in each TPTD group.


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  		TABLE 2. Percentage of participants who were vitamin D deficient, insufficient, or sufficient at study enrollment, after 1 month (randomization), and after 12 months of 400-1200 IU/d vitamin D supplements

 
Vertebral and nonvertebral fracture risks

Among women with baseline 25OHD sufficiency, vertebral fractures occurred in 17 of 447 women (3.8%) and 37 of 231 women (16.0%) in the combined TPTD- and placebo-treated groups, respectively [odds ratio (OR), 0.21; 95% confidence interval (CI), 0.11–0.38] (Fig. 1Go). Nonvertebral fractures occurred in 11 of 562 women (1.9%) in the TPTD group and 18 of 285 (6.3%) women in the placebo group (OR, 0.30; 95% CI, 0.14–0.64).


Figure 1
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  		FIG. 1. Fracture efficacy as a function of 25OHD insufficiency or sufficiency. 95% CI are shown in parentheses. TPTD20+40, Pooled TPTD20 and -40 groups.

 
Among women with baseline 25OHD insufficiency, vertebral fractures occurred in 23 of 420 women (5.5%) in the TPTD group and 27 of 209 women (12.9%) in the placebo group (OR, 0.39; 95% CI, 0.22–0.70) (Fig. 1Go). Nonvertebral fractures occurred in 17 of 517 women (3.3%) and 12 of 250 women (4.8%) in the TPTD- and placebo-treated groups, respectively (OR, 0.67; 95% CI, 0.32–1.43).

The ratios of OR for vertebral and nonvertebral fractures between the vitamin D sufficiency and insufficiency subgroups were 0.53 (95% CI, 0.23–1.22) and 0.44 (95% CI, 0.15–1.29), respectively. Although the difference between TPTD and placebo was numerically smaller in women with baseline 25OHD insufficiency compared with those with sufficiency, there were no significant differences in the incidence of vertebral and nonvertebral fractures between the subgroups (Fig. 1Go, treatment-by-subgroup interactions for vertebral fracture, P = 0.14, and nonvertebral fracture, P = 0.13)

Additional analyses of 25OHD treated as a continuous variable did not show any statistically significant effects of baseline 25OHD concentration (treatment-by-baseline 25OHD level interactions for vertebral fracture, P = 0.41, and nonvertebral fracture, P = 0.14). The results remained similar after adjusting for BMI.

BMD and bone turnover marker changes

The mean changes from baseline in lumbar spine BMD at 18 months and femoral neck BMD at 12 months in women with baseline 25OHD sufficiency or insufficiency are presented in Fig. 2Go. Compared with placebo, both TPTD20 and TPTD40 significantly increased mean lumbar spine BMD in women having either baseline 25OHD sufficiency or insufficiency. Both TPTD20 and TPTD40 significantly increased mean femoral neck BMD in women with either baseline 25OHD sufficiency or insufficiency. There were no significant differences in the increases in lumbar spine and femoral neck BMD across vitamin D subgroups (treatment-by-subgroup interactions for lumbar spine BMD, P = 0.29, and femoral neck BMD, P = 0.64). The results remained similar after adjusting for BMI.


Figure 2
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  		FIG. 2. BMD as a function of 25OHD insufficiency or sufficiency. *, P < 0.05 for both TPTD groups vs. placebo.

 
The changes in bone formation, as assessed by the median increases in PINP from baseline to 3 months, are shown in Fig. 3Go. Compared with placebo, both the TPTD20 and TPTD40 groups had similarly increased PINP, regardless of baseline 25OHD status (treatment-by-subgroup interaction P = 0.28).


Figure 3
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  		FIG. 3. PINP levels as a function of 25OHD insufficiency or sufficiency. *, P < 0.05 for both TPTD groups (TPTD20, n = 257; TPTD40, n = 254) vs. placebo (n = 260). IQR, Intraquartile range.

 
Incidence of elevated serum calcium levels

The effects of baseline 25OHD status on the incidence of at least one occurrence of elevated serum calcium concentrations of 2.76 mmol/liter or higher at 4–6 h after dose are presented in Fig. 4Go. In women with sufficient or insufficient 25OHD concentrations, there was a significantly higher incidence of elevated serum calcium with TPTD40 treatment compared with the placebo- and TPTD20-treated groups. There was no significant difference in the incidence of elevated serum calcium between the TPTD20 and placebo groups. There was no significant difference in the incidence of elevated serum calcium concentrations between women with baseline 25OHD sufficiency and insufficiency (treatment-by-subgroup interaction, P = 0.54).


Figure 4
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  		FIG. 4. Incidence of 4–6 h postdose serum calcium of 2.76 mmol/liter or higher as a function of 25OHD insufficiency or sufficiency. *, P < 0.05 for TPTD40 group vs. both placebo and TPTD20.

 
Vitamin D status at other time points

All above analyses were repeated defining the same vitamin D subgroups but considering the 25OHD concentration obtained at the screening visit (approximately 1 month before the baseline randomization visit and before initiation of sponsor-provided calcium and vitamin D supplementation) and again considering the 25OHD concentration obtained at 12 months after randomization. The results of these analyses (data not shown) were similar to those described above based on baseline vitamin D status.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Current standard of care for patients with osteoporosis includes provision of vitamin D. An important clinical question is whether 25OHD should be sufficient before initiation of osteoporosis therapy. If so, this could significantly delay the initiation of therapy because it takes about 3 months for the serum 25OHD level to come into steady state after increasing vitamin D intake (20). In postmenopausal women with low bone mass, the effects on BMD of alendronate (14) and raloxifene (13) were not impacted by vitamin D insufficiency or even deficiency. Furthermore, in patients with gastrectomy-induced vitamin D resistance, alendronate was still able to improve bone health (21). However, in a prospective cohort study, changes in lumbar spine BMD in patients treated with alendronate were strongly positively related to baseline serum 25OHD concentrations (r = 0.80), but no such relationships existed at the total hip and femoral neck (22). These data suggest that responses to antiresorptive therapy may not depend on the baseline vitamin D status as long as patients receive concomitant vitamin D and calcium supplementation.

The question addressed in the current analysis is whether the effects of the bone anabolic drug TPTD differed in patients with vitamin D insufficiency vs. sufficiency. There is no common definition of vitamin D sufficiency, and levels from 20–36 ng/ml have been suggested (4, 23, 24, 25). We used a cutoff point of 30 ng/ml because it is the level below which serum PTH has been found to rise (10, 24) and it reflects the opinions of five of six members of a recent expert panel (25). The 30-ng/ml cutoff point is similar to that used in previous analyses (10, 13, 14).

The baseline characteristics of the subgroups were well matched. Although BMI and serum 25OHD have been found to be inversely related in other studies (26), BMI tended to be higher in the vitamin D sufficient than in the insufficient group in this study. Possible explanations for this might be that per protocol, a disproportionate number of women with high BMI were excluded from participation on the basis of vitamin D deficiency and increased PTH levels (27, 28, 29).

There was no significant difference in the effect of TPTD to reduce the incidence of vertebral and nonvertebral fragility fractures, to increase bone formation as assessed by PINP, and to increase BMD at the lumbar spine and femoral neck in patients with baseline 25OHD sufficiency or insufficiency. The incidence of serum calcium concentrations of 2.76 mmol/liter or higher 4–6 h after dosing was consistent across treatment groups in the two 25OHD subgroups. Thus, the response to TPTD together with calcium and vitamin D was similar in women with baseline 25OHD sufficiency vs. insufficiency.

There were several limitations of the current analysis. Because of the entry criteria used in this study, the present findings apply only to patients having normal intact PTH concentrations and 25OHD levels above 10 ng/ml. The fracture data do show some numerical differences in the difference between TPTD and placebo in the two subgroups. Although the treatment-by-subgroup interaction is not statistically significant, the study may have included too few fractures to identify a real difference if one indeed existed. Examination of the CI for the ratio of the OR reveals the possible magnitude of the difference between the groups given the experimental findings. In this study, if the CI for the ratio of the ORs between the subgroups includes 1, then the results would not be statistically significant. For vertebral fracture, the 95% CI for the ratio of the OR was 0.23–1.22, so the results were not statistically significant. Similarly, the 95% CI for the ratio of OR between the subgroups for nonvertebral fracture was 0.15–1.29, so those results were also not statistically significant. However, the wide breadth of CI indicates that one need obviously be cautious about interpreting the nonsignificance. For the fracture outcome, this study does not exclude the possibility of clinically meaningful differences in fracture outcome in patients with vitamin D sufficiency vs. insufficiency. However, the similarity of the BMD and marker findings between these subgroups is reassuring that there is unlikely to be a large difference in fracture outcome.

In our view, patients with frank vitamin D deficiency (osteomalacia), should have their vitamin D deficiency corrected before initiation of other osteoporosis treatments. Normalization of serum 25OHD levels in these patients will usually normalize PTH concentrations within a few weeks, although elevated alkaline phosphatase concentrations may take longer to normalize (30). The prudent physician will probably delay initiation of osteoporosis treatments including TPTD in a patient with vitamin D deficiency until a normalized alkaline phosphatase concentration provides evidence of skeletal healing. In agreement with current labeling recommendations, we support the requirement to not initiate TPTD in patients with unexplained elevations in alkaline phosphatase or elevations in serum calcium before treatment. Also consistent with current labeling, we do not support routine measurement of serum PTH before treatment. We are aware of no evidence that measuring serum PTH before treatment adds value for patients with normal serum calcium and alkaline phosphatase levels. However, as always, physicians may sometimes find assessments of serum PTH concentrations useful in the management of specific patients.

The observation that at entry, 58% of the women in this study had 25OHD insufficiency is in agreement with reports that more than half of North American women receiving therapy to treat or prevent osteoporosis have 25OHD inadequacy (11). After 1 month of calcium and vitamin D supplementation and after 13 months of supplementation with 400-1200 IU vitamin D, 45% of patients in the placebo group remained vitamin D insufficient. Higher doses of vitamin D supplementation appear to be required to achieve vitamin D sufficiency in most older patients. Serum 25OHD has been estimated to change in direct proportion to the dose, with a slope of approximately 0.70 nmol/liter for each additional 1 µg/d cholecalciferol input (31).

Interestingly, during TPTD therapy, an increased incidence of vitamin D insufficiency was noted after 12 months of study drug. This apparent decrease in 25OHD during TPTD therapy is accompanied by an increase in 1,25-dihydroxyvitamin D, consistent with an expected effect of TPTD to increase the conversion of 25OHD to 1,25-dihydroxyvitamin D. These findings will be reported and discussed in detail in a subsequent publication.

Serum 25OHD assays are widely available from commercial laboratories. Results from assays for 25OHD are somewhat variable and dependent on the laboratory performing the analysis (32, 33). Most of the commercial assays tested substantially overestimated serum 25OHD when compared with a gold standard HPLC (33, 34). Serum 25OHD levels in this study were all measured using the DiaSorin RIA in a single centralized laboratory. This assay has compared well to the gold standard of HPLC (32, 35).

In postmenopausal women with osteoporosis and normal intact PTH supplemented with vitamin D, the response to TPTD was similar in patients with baseline 25OHD insufficiency or sufficiency.


   Acknowledgments
 
We gratefully acknowledge Mayme Wong and Armando G. Amador for scientific review and discussion of the manuscript and Susan M. Zeilinga for editorial assistance.


   Footnotes
 
This clinical study was funded by Eli Lilly and Co.

Disclosure Statement: The authors have nothing to disclose.

First Published Online October 2, 2007

Abbreviations: BMD, Bone mineral density; BMI, body mass index; CI, confidence interval; CV, coefficient of variation; FPT, Fracture Prevention Trial; 25OHD, 25-hydroxyvitamin D; OR, odds ratio; PINP, amino-terminal propeptide of type I procollagen; TPTD, teriparatide; TPTD20, TPTD 20 µg/d; TPTD40, TPTD 40 µg/d.

Received January 31, 2007.

Accepted September 25, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Kinyamu HK, Gallagher JC, Balhorn KE, Petranick KM, Rafferty KA 1997 Serum vitamin D metabolites and calcium absorption in normal young and elderly free-living women and in women living in nursing homes. Am J Clin Nutr 65:790–797[Abstract/Free Full Text]
  2. Aaron JE, Gallagher JC, Anderson J, Stasiak L, Longton EB, Nordin BE, Nicholson M 1974 Frequency of osteomalacia and osteoporosis in fractures of the proximal femur. Lancet 1:229–233[Medline]
  3. Holick MF 2004 Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 79:362–371[Abstract/Free Full Text]
  4. Malabanan A, Veronikis IE, Holick MF 1998 Redefining vitamin D insufficiency. Lancet 351:805–806[Medline]
  5. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Hu FB, Zhang Y, Karlson EW, Dawson-Hughes B 2004 Higher 25-hydroxyvitamin D concentrations are associated with better lower-extremity function in both active and inactive persons aged ≥60 y. Am J Clin Nutr 80:752–758[Abstract/Free Full Text]
  6. Gass M, Dawson-Hughes B 2006 Preventing osteoporosis-related fractures: on overview. Am J Med 119:3S–11S
  7. Bettica P, Bevilacqua M, Vago T, Norbiato G 1999 High prevalence of hypovitaminosis D among free-living postmenopausal women referred to an osteoporosis outpatient clinic in northern Italy for initial screening. Osteoporos Int 9:226–229[CrossRef][Medline]
  8. Aguado P, del Campo MT, Garces MV, Gonzalez-Casaus ML, Bernad M, Gijon-Banos J, Martin Mola E, Torrijos A, Martinez ME 2000 Low vitamin D levels in outpatient postmenopausal women from a rheumatology clinic in Madrid, Spain: their relationship with bone mineral density. Osteoporos Int 11:739–744[CrossRef][Medline]
  9. Chapuy MC, Schott AM, Garnero P, Hans D, Delmas PD, Meunier PJ 1996 Healthy elderly French women living at home have secondary hyperparathyroidism and high bone turnover in winter. EPIDOS Study Group. J Clin Endocrinol Metab 81:1129–1133[Abstract]
  10. Holick MF, Siris ES, Binkley N, Beard MK, Khan A, Katzer JT, Petruschke RA, Chen E, de Papp AE 2005 Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 90:3215–3224[Abstract/Free Full Text]
  11. Holick MF 2006 The role of vitamin D for bone health and fracture prevention. Curr Osteoporos Rep 4:96–102[Medline]
  12. Koster JC, Hackeng WH, Mulder H 1996 Diminished effect of etidronate in vitamin D deficient osteopenic postmenopausal women. Eur J Clin Pharmacol 51:145–147[CrossRef][Medline]
  13. Antoniucci DM, Vittinghoff E, Blackwell T, Black DM, Sellmeyer DE 2005 Vitamin D insufficiency does not affect bone mineral density response to raloxifene. J Clin Endocrinol Metab 90:4566–4572[Abstract/Free Full Text]
  14. Antoniucci DM, Vittinghoff E, Palermo L, Black DM, Sellmeyer DE, The bone density effects of alendronate therapy, co-administered with calcium and ergocalciferol, are not impaired by baseline vitamin D insufficiency. Program of the 88th Annual Meeting of The Endocrine Society, Boston, MA, 2006, pp 520–521 (Abstract P2-498)
  15. McClung MR, San Martin J, Miller PD, Civitelli R, Bandeira F, Omizo M, Donley DW, Dalsky GP, Eriksen EF 2005 Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass. Arch Intern Med 165:1762–1768[Abstract/Free Full Text]
  16. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH 2001 Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441[Abstract/Free Full Text]
  17. Genant HK, Wu CY, van Kuijk C, Nevitt MC 1993 Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8:1137–1148[Medline]
  18. Eastell R, Chen P, Krege JH 2005 Monitoring teriparatide therapy for osteoporosis with procollagen type I N-propeptide (PINP). Curr Med Res Opin 22:61–68
  19. Chen P, Satterwhite JH, Licata AA, Lewiecki EM, Sipos AA, Misurski DM, Watman RB 2005 Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res 20:962–970[CrossRef][Medline]
  20. Vieth R, Chan PCR, MacFarlane GD 2001 Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level. Am J Clin Nutr 73:288–294[Abstract/Free Full Text]
  21. Suzuki Y, Ishibashi Y, Omura N, Kawasaki N, Kashiwagi H, Yanaga K, Abo M, Urashima M 2005 Alendronate improves vitamin D-resistant osteopenia triggered by gastrectomy in patients with gastric cancer followed long term. J Gastrointest Surg 9:955–960[CrossRef][Medline]
  22. Lee P, Colman PG, Ebeling PR 2006 Higher serum 25(OH)D concentrations are related to larger BMD increases with alendronate therapy for osteoporosis. J Bone Miner Res 22(Suppl 1):T72
  23. Heaney RP, Dowell MS, Hale CA, Bendich A 2003 Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D. J Am Coll Nutr 22:142–146[Abstract/Free Full Text]
  24. Chapuy MC, Preziosi P, Maamer M, Arnaud S, Galan P, Hercberg S, Meunier PJ 1997 Prevalence of vitamin D insufficiency in an adult normal population. Osteoporos Int 7:439–443[CrossRef][Medline]
  25. Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R 2005 Estimates of optimal vitamin D status. Osteoporos Int 16:713–716[CrossRef][Medline]
  26. Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S 1985 Evidence for alteration of the vitamin D endocrine system in obese subjects. J Clin Invest 76:370–373[Medline]
  27. Thomas MK, Lloyd-Jones DM, Thadhani RI, Shaw AC, Deraska DJ, Kitch BT, Vamvakas EC, Dick IM, Prince RL, Finkelstein JS 1998 Hypovitaminosis D in medical inpatients. N Engl J Med 338:777–783[Abstract/Free Full Text]
  28. Saquib N, von Mühlen D, Garland CF, Barrett-Connor E 2006 Serum 25-hydroxyvitamin D, parathyroid hormone, and bone mineral density in men: the Rancho Bernardo study. Osteoporosis Int 17:1734–1741[CrossRef][Medline]
  29. Bolland MJ, Grey AB, Ames RW, Horne AM, Gamble GD, Reid IR 2006 Fat mass is an important predictor of parathyroid hormone levels in postmenopausal women. Bone 38:317–321[Medline]
  30. Pettifor JM 2006 Nutritional and drug-induced rickets and osteomalacia. In: Favus M, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. 6th ed. Washington, DC: American Society of Bone and Mineral Research; 330–338
  31. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ 2003 Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204–210[Abstract/Free Full Text]
  32. Lips P, Chapuy MC, Dawson-Hughes B, Pols HA, Holick MF 1999 An international comparison of serum 25-hydroxyvitamin D measurements. Osteoporos Int 9:394–397[CrossRef][Medline]
  33. Binkley N, Krueger D, Cowgill CS, Plum L, Lake E, Hansen KE, DeLuca HF, Drezner MK 2004 Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab 89:3152–3157[Abstract/Free Full Text]
  34. Gemar DM, Binkley N, Krueger D, Engelke J, Drezner MK 2004 Clinical assessment of vitamin D status: an imposing dilemma. J Bone Miner Res 19(Suppl 1):S343
  35. Hollis BW, Kamerud JQ, Selvaag SR, Lorenz JD, Napoli JL 1993 Determination of vitamin D status by radioimmunoassay with an 125I-labeled tracer. Clin Chem 39:529–533[Abstract/Free Full Text]




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