| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Medicine, Lawson Health Research Institute, University of Western Ontario (A.B.H.), London, Ontario, Canada N6A 4V2; Department of Medicine, University of Calgary (D.A.H.), Calgary, Alberta, Canada T2N 4N1; Regional Osteoporosis Center of South Florida and Radiant Research (M.P.E.), Stuart, Florida 34996; Bethesda Health Research (M.A.B.), Bethesda, Maryland 20817; NPS Pharmaceuticals, Inc. (J.F., A.J.M.), Salt Lake City, Utah 84108; and Regional Bone Center, Helen Hayes Hospital (R.L.), West Haverstraw, New York 10993
Address all correspondence and requests for reprints to: Anthony B. Hodsman, M.D., Department of Medicine, St. Joseph’s Health Center, Room F-215, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2. E-mail: anthony.hodsman{at}sjhc.london.on.ca.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Anabolic agents that directly stimulate bone formation have the potential to rapidly increase skeletal mass to levels at least equal to those seen in age- and sex-matched normal patients; conceivably, these agents can restore bone mass to young adult levels. Sodium fluoride, which was the first anabolic agent studied, increased BMD to a greater extent than antiresorptive agents (8). However, bone containing fluoride is weaker than naturally mineralized bone, and the antifracture efficacy of fluoride is inconsistent (9, 10, 11).
The anabolic activity of PTH and N-terminal fragment analogs of PTH has been investigated for many years. Although these agents increase both resorption and formation of bone, animal models have demonstrated that their primary effects when given by daily injection reflect their role as potent anabolic agents capable of inducing large and rapid increases in bone mass and strength (12, 13). Over the past 25 yr, the limited availability of these peptides has resulted in the performance of small, relatively uncontrolled clinical trials. Because of concerns that PTH also stimulates bone resorption, which might adversely affect the strength of cortical bone, many of these early studies used concurrent therapy with calcitriol or antiresorptive agents, either concomitantly or sequentially (14, 15, 16, 17, 18). In most of these trials, the PTH analog human PTH-(1–34) (teriparatide) was used; patients received concurrent estrogen replacement, whereas control groups received estrogen alone. Gains in lumbar spine BMD of up to 12% occurred over treatment intervals as short as 12 months, but in these small clinical trials, the therapeutic response was highly variable. Recently, a large, randomized, placebo-controlled trial of teriparatide reported dose-related increases in lumbar spine BMD of 9.7–13.7% after a median treatment period of 21 months (19). Significant gains of 2.8–5.1% also occurred at the femoral neck, but a decrease in BMD of 2.1–3.2% was seen at the radial shaft, which is primarily a cortical bone site. This trial, the only one to specifically address the antifracture efficacy of teriparatide, showed a significant reduction in both incident vertebral fractures (65–69%) and nonvertebral fractures (
53%).
PTH, an 84-amino acid peptide, is the major regulator of calcium homeostasis. However, the parathyroid glands also secrete C-terminal fragments of PTH, and secreted PTH is cleaved peripherally, releasing a variety of C-terminal fragments back into the circulation (20). There is no evidence that N-terminal fragments of PTH similar to teriparatide are either secreted by the parathyroid gland or enter the circulation after peripheral PTH metabolism (21). Because PTH and teriparatide are equipotent at the PTH-1 receptor, it has been assumed that teriparatide contains all of the known biological activity of PTH, and indeed, the far N-terminal region appears primarily responsible for the anabolic properties of PTH in bone (22). However, it is now apparent that the C-terminal region of PTH has biological functions in bone that are mediated by a novel receptor specific for this region of the hormone (23, 24). For example, PTH-(7–84) inhibits bone resorption, blocks the calcemic response to teriparatide infusion, and, in contrast to the antiapoptotic effects of teriparatide, increases osteocyte apoptosis (24, 25, 26, 27). Therefore, full-length PTH has biological properties distinct from those of N-terminal PTH analogs.
We now report a prospective, double-blind, placebo-controlled study that evaluated the effects of 12 months of treatment with full-length recombinant human PTH in postmenopausal women with osteoporosis. The primary objectives of the study were to assess the safety of this therapy and to establish the dose dependency of changes in BMD at the lumbar spine and hip.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Patients with postmenopausal osteoporosis were recruited at 18 sites across the United States and Canada. All women in the study were 50–75 yr old, were postmenopausal for at least 5 yr, and had lumbar spine BMD greater than 2.5 SD below the young adult mean (T-score 
-2.5). Women were excluded if they had significant medical problems that might affect skeletal homeostasis or vertebral abnormalities precluding measurement by dual energy x-ray absorptiometry (DXA) of 2 or more contiguous L1–L4 vertebrae. Also excluded were women who had taken estrogen within the previous 6 months and those who had used any bisphosphonates (except etidronate, for which maximum use could not be more than 2 cycles), fluoride (within 6 months), or calcitonin (within 4 months). Altogether 879 patients were screened, and 217 were enrolled, with each site recruiting between 1–27 patients. All women provided written informed consent, and the study protocol was approved by the institutional review board at each participating center.
Treatment
The full-length recombinant human PTH used in this study was obtained by expression of the human PTH gene in Escherichia coli and was manufactured by Chiron BV (Amsterdam, The Netherlands) in accordance with U.S. FDA Good Manufacturing Practices. Patients were randomly assigned to one of three doses of full-length PTH or placebo within each block of four consecutive patient numbers. The doses chosen (50, 75, and 100 µg) were based on data from a 7-d, dose-ranging, phase I study. Patients were taught the techniques of daily dilution of the lyophilized agent and self-injection (0.5 ml sc); they were asked to perform these each morning, except on clinic visit days, when they were instructed to inject after they had provided blood and urine samples. After assessment of their habitual dietary calcium intake, all patients were provided daily with one or two calcium carbonate tablets (each containing 500 mg elemental calcium) to ensure a dietary calcium intake of 1000–1500 mg/d; a vitamin D supplement (400 IU/d) was also given.
BMD, bone area, and bone mineral content (BMC)
BMD, bone area, and BMC were measured by DXA at the anterior-posterior lumbar spine (L1–L4) and hip with the use of either a Lunar (GE Medical Systems, Waukesha, WI; n = 70) or a Hologic (n = 136; Hologic, Inc., Bedford, MA) densitometer. One measurement was taken at screening, and a second at baseline. The median duration between scans was 20 d. The average of the two scans was used as the baseline BMD value unless they were more than 59 d apart, in which case only the later value was used; follow-up measurements were conducted after 3, 6, and 12 months of treatment. Whole body BMD and BMC (excluding the skull) were monitored in a subset (n = 120) of patients at baseline and at 12 months. Quality control and central analyses of the DXA scans and x-rays were performed by the University of California Osteoporosis and Arthritis Research Group/Quality Assurance Center under the guidance of Dr. H. Genant. The coefficient of variation (CV) for longitudinal measurements of BMD using a calibration phantom averaged 0.44% for the two machines. The precision of BMD measurements in patients was calculated using the two measurements at baseline; the CVs were 1.3% and 1.7% for lumbar spine and femoral neck, respectively. The CV for the lumbar spine bone area measurement was 1.0%.
Biochemistry
All clinical laboratory tests were performed at MDS Clinical Trials (Etobicoke, Ontario, Canada). Markers of bone formation (serum osteocalcin and bone-specific alkaline phosphatase) and bone resorption [urinary N-terminal collagen telopeptide (NTx) and deoxypyridinoline] were measured with the use of specific immunoassays at baseline and at 1, 3, 6, 9, and 12 months after the initiation of treatment. The assay CVs were all less than 10%. Routine safety parameters, including complete blood count; hepatic function; urinalysis; serum electrolytes, glucose, and creatinine; and urea nitrogen, were also measured. Urine measurements were taken on second morning void samples. For monitoring of creatinine clearance, 24-h urine samples were collected at baseline and at 6 and 12 months in a subset of patients (n = 127).
Adverse events (AE)
Patients were questioned at each visit about any adverse occurrences, defined as any unexpected or untoward events, including minor complaints such as upper respiratory infections and skin rashes, as well as any more serious events, regardless of association with the study or medication. AE requiring hospitalization or discontinuation from the study were included in the analysis.
The presence of antibodies to full-length PTH or E. coli-contaminating proteins was determined by analyzing the 12-month serum samples using two separate indirect ELISAs. In these assays, biotinylated antigen (full-length PTH or E. coli-contaminating proteins) was incubated with serum at final dilutions of 1:100 to 1:128,000, before capture and quantification on a streptavidin-coated microassay plate.
Statistical analysis
For the primary end point (percentage change from baseline in vertebral BMD), sample size was based on data provided by Dr. A. Hodsman, in which the SD of change from baseline in vertebral bone mass after 12 months of treatment with teriparatide was estimated to be 0.0361 g/cm2. With a level of significance set at 
= 0.025 for a two-sided test with 80% power (with an applied penalty for a 6-month interim analysis), the sample size to detect a between-group difference of 0.025 g/cm2 (roughly a 3% difference) was set at 40 patients/arm. With an expected attrition rate of 20%, the total number of recruited patients was set at 200, with equal distribution among treatment groups.
Intention to treat (ITT) analysis was used, with all participants analyzed according to randomization regardless of their continuation in the study or their adherence to the medication. All patients with at least one baseline and one postrandomization measurement were included in the ITT analysis, but no imputation of missing data (such as last value carried forward) was performed. Except where noted in the figures, all data are reported as the mean ± SD.
To account for systematic differences between instruments from different manufacturers, the change from baseline for BMD measurements was expressed as a percentage of the mean baseline value. Biochemical markers of bone turnover were also analyzed as percentage change from baseline. Tests of significance were based on one-way ANOVA and Fisher’s protected least significant difference procedure.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
A total of 217 women were randomly assigned in the study. Of these, a total of 206 patients were eligible for ITT analysis; 11 had no postrandomization data. The ages of the women ranged from 50–75 yr. Table 1
summarizes the demographics and clinical chemistries of the individual groups. At baseline, no significant differences among groups were noted in any parameter.
|
Treatment with full-length PTH produced dose- and time-related increases in BMD in the lumbar spine (Fig. 1A). After 3 months at the 100-µg dose, BMD was significantly higher than at baseline; in contrast to the effects of lower doses, no tendency for plateauing of the response was revealed over time. At the end of the study, the mean increases were 3.0%, 5.1%, and 7.8% for the 50-, 75-, and 100-µg doses, respectively; all increases were significantly greater than baseline. In contrast, the 0.9% increase in BMD in the placebo group, which received calcium and vitamin D supplements alone, was not significant. Differences between each treatment group and placebo at 12 months were all significant, and the difference between the 100-µg dose and the next highest dose (75 µg) was also statistically significant. Increased BMD with the 100-µg dose corresponded to an increase in mean lumbar spine T-score, from -3.26 at baseline to -2.81 at the end of the study.
|
). This increase in bone area in the 100-µg dose group was significant vs. both baseline and placebo control values after 6 months (1.1% increase); after 12 months, bone area was 2.0% greater. The 50-µg dose of full-length PTH significantly increased bone area vs. baseline at both 6 and 12 months, although at neither time was bone area increased significantly above that in the placebo group. In contrast, the 75-µg dose increased bone area at 12 months by an amount that was significantly greater than both baseline and placebo values.
Because of the increase in measured bone area, the effect of full-length PTH treatment on BMC of the lumbar spine was greater than the increase in BMD. The increase in BMC was also dose related, with the 100-µg dose increasing BMC at 12 months by 10.0% (Fig. 1C). The 75- and 100-µg doses increased BMC significantly by 3 months, whereas the 50-µg dose did not increase BMC significantly until after 6 months of treatment. At 12 months, the increase in BMC with the 100-µg dose was significantly greater than with all other doses.
Effect of baseline BMD T-score on lumbar spine BMD response to full-length PTH
The anabolic effect of full-length PTH tended to be greater in patients in whom the baseline lumbar spine T-score was the lowest. Thus, patients whose T-scores were greater than -3.0 or less than -4.0 had BMD increases that averaged 6.7% and 13.5%, respectively (Table 2). This difference just failed to achieve statistical significance (P = 0.053), probably because of the small number of patients with severe bone loss. A similarly nonsignificant pattern was seen when the increase in BMD was expressed in grams per centimeter squared; patients with the lowest BMD at baseline also tended to show a greater response.
|
In contrast to the lumbar spine, full-length PTH treatment induced changes in BMD at the total hip and femoral neck that were relatively small and inconsistent throughout the study. With the 75-µg dose, BMD of the total hip at both 6 and 12 months was significantly higher than at baseline and was higher than that in the placebo group at 12 months (Fig. 2A). In contrast, with the 100-µg dose, a nonsignificant small (0.9 ± 3.9%) decrease in BMD occurred during the first 6 months, but this was reversed during the second half of the study to a net gain from baseline of 0.7 ± 4.3% at 12 months. This 1.6 ± 3.4% increase in total hip BMD between 6 and 12 months was significantly greater than that in any other study arm, including placebo. Total hip bone area increased by 1.7 ± 5.4% in the 100-µg group at 12 months, an increase that was significantly greater vs. baseline but not vs. placebo. Total hip BMC was 2.4 ± 7.0% higher in the 100-µg group at 12 months, with most of the increase occurring between 6 and 12 months (not shown). The increase in BMC was significantly greater vs. baseline but not vs. placebo.
|
). None of the changes in femoral neck BMD with the 100-µg dose, either from baseline or from placebo controls, was statistically significant. As with the total hip, the 1.4 ± 3.7% increase in femoral neck BMD in the 100-µg group between 6 and 12 months was significantly greater than in all other groups across the same time period. The 75-µg dose increased femoral neck BMD significantly vs. baseline at 6, but not at 12, months. Whole body BMD and BMC
Whole body DXA analysis was performed at baseline and 12 months in a subgroup of patients. Changes in whole body BMD for 0-, 50-, 75-, and 100-µg doses of full-length PTH were 0.3 ± 1.9%, -0.5 ± 2.3%, -0.4 ± 1.9%, and -0.9 ± 2.4%, respectively. Corresponding changes for whole body BMC were, respectively, 0.2 ± 3.8%, -0.6 ± 4.8%, -0.7 ± 5.6%, and -1.5 ± 3.4%. None of these changes was statistically significant (P > 0.28).
Markers of bone turnover
The administration of full-length PTH produced a dose-related increase in all measured biochemical markers of bone remodeling. Osteocalcin levels were significantly higher vs. baseline and placebo in all groups after only 1 month of treatment (Fig. 3A). Most of the increase in osteocalcin levels had occurred by 3–6 months, with only relatively small additional increases during the last 6–9 months of the study. Full-length PTH treatment induced similar changes, both temporally and in magnitude, in bone-specific alkaline phosphatase levels (not shown).
|
). With the 75- and 100-µg doses, urinary NTx excretion reached a maximum (mean 4-fold increase) by 6 months. Similar temporal and dose-related changes occurred in deoxypyridinoline excretion, although the variability was even greater than for NTx, and the maximum mean increment was 2.8-fold with the 100-µg dose at 6 months (data not shown). Plasma and urinary calcium
The reported changes in predose serum total calcium levels and urinary calcium excretion are confounded by the failure of all study sites to control the timing of PTH injection and calcium supplement administration (Fig. 4). Thus, the data shown include values other than those for 24 h after the previous dose. Perhaps in part because of this inconsistency, a small, but statistically significant, dose-related increase in serum total calcium levels is seen in the PTH-treated groups, although mean values remain well below the upper limit of normal. This effect was most apparent during the first 6 months of the study, and with the 75- and 100-µg doses, it tended to resolve after 6–12 months (Fig. 4A).
|
). However, at no time was the calcium/creatinine ratio significantly different from that in the placebo group. No significant time- or treatment-dependent changes were noted in the fractional excretion of calcium (Fig. 4C). Compliance and safety
Compliance, which was calculated by dividing the number of used vials returned by the number of days in the study, was very high, at 94.8–97.6% in all PTH groups and 96.8% in the placebo group. Administration of full-length PTH was generally well tolerated throughout the study, with 31 patients (14%) discontinuing treatment over the duration of the study (Table 3). Reasons for discontinuation included study noncompliance (15 patients), AE (12 patients), intercurrent illness (2 patients), loss to follow-up (1 patient), and motor vehicle accident (1 patient). Adverse reactions that resulted in discontinuation from the study included 3 patients with localized irritation at the site of injection (2 in the placebo group and 1 in the 100-µg group), 2 patients with rashes (50-µg group), 1 patient in the 100-µg group with repeated hypercalcemia [serum total calcium, 
11.6 mg/dl (2.9 mmol/liter)], and 1 patient in the 100-µg group with elevated serum alkaline phosphatase (218 U/liter; upper limit of normal, 110 U/liter). The remaining patients withdrew or were withdrawn for a variety of reasons considered unrelated to study medication. These included single occurrences of dizziness, palpitations, and myocardial infarction (placebo group), 1 case of thrombocytopenia (50-µg group), and an abnormal electrocardiogram (100-µg group).
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Patients with the lowest lumbar spine BMD T-score at baseline tended to show the greatest increase in BMD, whether this increase was expressed as a percentage or as grams per centimeter squared. Similar findings have been reported recently in patients treated with teriparatide (29).
The 7.8% increase in BMD in the lumbar spine of the 100-µg group was associated with a significant 2% increase in measured bone area. This increase in bone area caused the BMD measurement to underestimate the anabolic effect of full-length PTH in the spine, as BMC increased by 10%. A similar change in lumbar spine bone area has been reported recently with teriparatide (28). Whether this increase in vertebral bone area is a result of increased periosteal bone apposition or is simply a DXA-related artifact of the increase in BMD remains unclear (30, 31, 32). However, a significant 5% increase in periosteal circumference of the 15% distal radius, measured by peripheral quantitative computed tomography (QCT), has been reported in postmenopausal osteoporotic women treated with teriparatide alone for a median of 18 months (33). Similarly, Rehman et al. (34) used QCT to show that 12-month teriparatide treatment of postmenopausal women with glucocorticoid-induced osteoporosis increased vertebral cross-sectional area. Resolution of this issue is important, because even small increases in bone area result in substantial improvements in bone strength (35).
Changes in total hip and femoral neck BMD were relatively modest and were seldom significantly different from those seen in placebo controls. As in the spine, it is difficult to compare the efficacy of full-length PTH in this study with that of teriparatide because of substantial variability in the experimental design of teriparatide trials. Thus, at 12 months, changes in total hip BMD with 40 µg teriparatide have ranged from 0% in women rendered estrogen deficient with nafarelin (16) to 4% in postmenopausal osteoporotic women treated with teriparatide alone (28). In this study there was a nonsignificant tendency for total hip BMD to decrease during the first 6 months of treatment with full-length PTH at 100 µg/d, which was followed by a significant rebound response during the second 6 months, such that there was a small (0.7%), but nonsignificant, net gain from baseline at 12 months.
Treatment with full-length PTH has disparate effects on trabecular and cortical bone. In trabecular bone, it is thought that new bone is added both by overfilling of the active bone remodeling units and by increased new bone formation on quiescent bone surfaces. Thus, in the lumbar spine (a predominantly trabecular bone site), BMD increased significantly within 3 months of initiation of treatment with full-length PTH. In cortical bone, full-length PTH increases new bone formation on the endocortical surface and, to a lesser extent, on the periosteal surface, but it also increases intracortical (haversian) remodeling, which increases cortical porosity and decreases cortical BMD. Because the hip contains roughly equal amounts of cortical and trabecular bone, and because DXA cannot discriminate between the two, measured BMD represents a composite of the two bone types. Thus, the smaller effect of treatment with full-length PTH at the hip compared with the spine suggests that it is the overall result of increased trabecular BMD and decreased cortical BMD. Indeed, studies in ovariectomized rhesus monkeys treated with full-length PTH daily for 16 months showed exactly those changes when trabecular and cortical BMD of the hip were measured separately with the use of peripheral QCT (36). As was seen in patients in this study, the effect of full-length PTH treatment on total hip BMD measured by DXA in monkeys was small.
Because the entire skeleton is approximately 80% cortical and 20% trabecular bone, these disparate effects of PTH on trabecular and cortical bone may also explain the small decrease in whole body BMD observed with full-length PTH treatment in this study. However, it is very important to emphasize that the femoral neck of monkeys treated with full-length PTH was stronger than that of controls when subjected to biomechanical testing despite an increase in cortical porosity and a decrease in cortical BMD. In a femoral neck shear test, the peak load and area under the stress-strain curve were 9.2% and 34% higher, respectively, in monkeys receiving 10 µg PTH/kg·d for 16 months. At the femoral diaphysis, a pure cortical bone site, peak load was unchanged, but the area under the stress-strain curve was 22% higher in PTH-treated animals (36). Thus, despite an apparent decrease in cortical BMD, which could predict an increased susceptibility to hip fracture, animal studies show that, on the contrary, treatment with full-length PTH confers a significant strength advantage. This hypothesis is being tested in a large phase III trial in postmenopausal women with osteoporosis that is evaluating the effects of 100 µg full-length PTH/d for 18–24 months.
We speculate that a transiently increased cortical remodeling space may lead to early reduction of cortical BMD, but that other competing effects within the periosteal, endocortical, and haversian systems gradually allow the anabolic effects of full-length PTH to predominate over the observed effects of an enlarged intracortical remodeling space. In this scenario, BMD measurements obtained during the second and third years of therapy should demonstrate net gains in BMD. This hypothesis is supported by a marked increase in hip BMD in the 100-µg group during the second 6 months of this study. To test this hypothesis, a subset of 66 subjects from the total cohort of postmenopausal women described in the current report were offered open label therapy with daily oral alendronate alone for a second 12-month interval (37). If early changes in cortical BMD were indeed due to transient increases in the remodeling space, then sequential therapy with a potent antiresorptive agent such as alendronate should induce a rapid reduction in bone turnover, closure of the remodeling space, and significant increments in BMD. This was exactly the outcome; subjects previously receiving 100 µg full-length PTH had significant increases in femoral neck BMD of 4.5% and in whole body BMD of 6.1% in the second year (37).
The changes in biochemical markers of bone turnover seen in this study were very similar to those reported when teriparatide (40-µg dose) was studied without a concomitant antiresorptive (28). With the 100-µg dose of full-length PTH, markers of bone formation increased approximately 2-fold within 3 months, and that increase was maintained throughout the remainder of the study. In contrast to the consistent changes in markers of bone formation, urinary markers of bone resorption were considerably more variable and seldom significantly different from changes in the placebo group.
Treatment with full-length PTH for 1 yr was generally safe and well tolerated. Despite the rigorous daily injection regimen, compliance (95–98%) was excellent. Hypercalcemia occurred in a dose-related fashion, with 11 patients in the 100-µg group having at least 1 incident of transient hypercalcemia. Hypercalcemia was sustained in only 1 patient, and this patient was discontinued from the study. No effects on creatinine clearance occurred as a result of the transient increases in serum calcium levels; in fact, creatinine clearance tended to increase more in full-length PTH-treated patients than in the placebo group during the study. In contrast to studies of teriparatide, no cardiovascular adverse effects, such as hypotension or tachycardia, were noted, and there was no detectable formation of antibodies to PTH (19).
In conclusion, daily treatment with full-length PTH for 12 months resulted in significant dose-dependent increases in BMD in the lumbar spine, with minimal and nonsignificant changes at sites containing a greater proportion of cortical bone (hip and whole body). The absence of significant BMD increases at primarily cortical bone sites can be ascribed to early transient effects of full-length PTH on cortical bone remodeling, which, according to the results of animal studies, do not affect bone strength. Changes in biochemical markers of bone turnover are consistent with the anabolic properties of other N-terminal PTH analogs. The safety of full-length PTH over 1 yr has been established; in particular, this study provided evidence for a low incidence of hypercalcemia, even at the highest dose used. An ongoing phase III trial will test the antifracture efficacy of full-length PTH in patients with established osteoporosis.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received April 30, 2003.
Accepted July 16, 2003.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  A. K. Abraham, D. E. Mager, X. Gao, M. Li, D. R. Healy, and T. S. Maurer Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Parathyroid Hormone-Calcium Homeostasis in Rats and Humans J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 169 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. E. McGee-Lawrence, H. V. Carey, and S. W. Donahue Mammalian hibernation as a model of disuse osteoporosis: the effects of physical inactivity on bone metabolism, structure, and strength Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2008; 295(6): R1999 - R2014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Tylavsky, K. M. Ryder, R. Li, V. Park, C. Womack, J. Norwood, L. D. Carbone, and S. Cheng Preliminary Findings: 25(OH)D Levels and PTH Are Indicators of Rapid Bone Accrual in Pubertal Children J. Am. Coll. Nutr., October 1, 2007; 26(5): 462 - 470. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Greenspan, H. G. Bone, M. P. Ettinger, D. A. Hanley, R. Lindsay, J. R. Zanchetta, C. M. Blosch, A. L. Mathisen, S. A. Morris, T. B. Marriott, et al. Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Randomized Trial Ann Intern Med, March 6, 2007; 146(5): 326 - 339. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Antoniucci, D. E. Sellmeyer, J. P. Bilezikian, L. Palermo, K. E. Ensrud, S. L. Greenspan, and D. M. Black Elevations in Serum and Urinary Calcium with Parathyroid Hormone (1-84) with and without Alendronate for Osteoporosis J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 942 - 947. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Cranney, A. Papaioannou, N. Zytaruk, D. Hanley, J. Adachi, D. Goltzman, T. Murray, A. Hodsman, and for the Clinical Guidelines Committee of Osteoporo Parathyroid hormone for the treatment of osteoporosis: a systematic review. Can. Med. Assoc. J., July 4, 2006; 175(1): 52 - 59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liu, K. Michaud, S. Nayak, D. B. Karpf, D. K. Owens, and A. M. Garber The Cost-effectiveness of Therapy With Teriparatide and Alendronate in Women With Severe Osteoporosis. Arch Intern Med, June 12, 2006; 166(11): 1209 - 1217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Olgaard and E. Lewin Can Hyperparathyroid Bone Disease Be Arrested or Reversed? Clin. J. Am. Soc. Nephrol., May 1, 2006; 1(3): 367 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Bauer, P. Garnero, J. P. Bilezikian, S. L. Greenspan, K. E. Ensrud, C. J. Rosen, L. Palermo, D. M. Black, and for the PTH and Alendronate (PaTH) Research Group Short-Term Changes in Bone Turnover Markers and Bone Mineral Density Response to Parathyroid Hormone in Postmenopausal Women with Osteoporosis J. Clin. Endocrinol. Metab., April 1, 2006; 91(4): 1370 - 1375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Hodsman, D. C. Bauer, D. W. Dempster, L. Dian, D. A. Hanley, S. T. Harris, D. L. Kendler, M. R. McClung, P. D. Miller, W. P. Olszynski, et al. Parathyroid Hormone and Teriparatide for the Treatment of Osteoporosis: A Review of the Evidence and Suggested Guidelines for Its Use Endocr. Rev., August 1, 2005; 26(5): 688 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Murray, L. G. Rao, P. Divieti, and F. R. Bringhurst Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl- Terminal Ligands Endocr. Rev., February 1, 2005; 26(1): 78 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 {blacktriangledown}Teriparatide for postmenopausal osteoporosis DTB, December 1, 2004; 42(12): 93 - 96. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
