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From the Clinical Research Centers |
Departments of Medicine (E.S.K., F.C., R.L., J.P.B.) and Pharmacology (J.P.B.) and the Irving Center for Clinical Research (D.J.M.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Maine Center for Osteoporosis Research, St. Joseph Hospital (C.J.R.), Bangor, Maine 04401; and Regional Bone Center, Helen Hayes Hospital (F.C., R.L.), West Haverstraw, New York 10993
Address all correspondence and requests for reprints to: Etah S. Kurland, M.D., Department of Medicine, Columbia University College of Physicians Surgeons, 630 West 168th Street; New York, New York 10032. E-mail: esk11{at}columbia.edu
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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We conducted an 18-month randomized, double blind, placebo-controlled trial of 23 men with idiopathic osteoporosis, 30–68 yr old (mean age ± SEM, 50 ± 1.9 yr). All patients received 1500 mg calcium and 400 IU vitamin D daily. Ten patients were randomized to receive 400 IU PTH-(1–34), and 13 patients received vehicle, administered by daily sc injection. Serum and urinary biochemistries, including markers of bone turnover were measured every 3 months. Bone densitometry of the lumbar spine, hip, and radius was performed every 6 months.
PTH-(1–34) was associated with a marked 13.5% increase in bone mass at the lumbar spine, whereas that in the control group did not change (P < 0.001). The mean lumbar spine T-score improved from -3.5 ± 0.2 to -2.4 ± 0.4. Femoral neck bone mineral density in the PTH-treated group increased 2.9% (P < 0.05). The 1/3 site of the distal radius showed no change from baseline in the PTH-treated group. There were no significant changes in serum calcium concentration, 24-h urinary calcium excretion, or 1,25-dihydroxyvitamin D in either group. All markers of bone turnover increased in the PTH-treated patients, with the greatest changes in serum osteocalcin and urinary N-telopeptide (230% and 375% above baseline by 12 months, respectively; P < 0.001). Free pyridinoline and markers of bone formation that showed little correlation with each other at baseline, became highly correlated in the PTH-treated group (r = 0.1; P = 0.29 at baseline; to r = 0.7; P < 0.0001 at 18 months), a pattern absent in the control patients. The best predictor of the lumbar spine response to PTH at 18 months was the combination of pyridinoline at baseline and osteocalcin at 3 months (70% of the variance).
PTH is a potent stimulator of skeletal dynamics in men with idiopathic, low turnover osteoporosis; is associated with substantial increases in lumbar spine and hip bone density; and may prove to be an efficacious anabolic agent in men with this disorder.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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When osteoporosis in men is secondary to a defined etiology such as hypogonadism or glucocorticoid excess, therapy is aimed specifically at the underlying pathophysiology. In hypogonadal men, testosterone replacement increases bone density (14, 15). In men exposed to glucocorticoids, bisphosphonates have been effective in preventing bone loss or increasing bone density (16, 17). In idiopathic osteoporosis, however, effective therapy is a challenge. The few studies that have addressed this problem have generally been uncontrolled and often of brief duration (18, 19, 20, 21, 22). Treatment options have included cyclical etidronate, intermittent low dose fluoride, testosterone, and intermittent sc PTH (18, 20, 21, 22).
Among the therapeutic options that have been considered, anabolic agents that stimulate bone formation would seem to be an ideal approach for men with idiopathic osteoporosis. Intermittent, low dose administration of PTH or its fragment [PTH-(1–34)] is particularly attractive (23, 24, 25). Clinical trials using PTH have shown that it is well tolerated and associated with impressive gains of cancellous bone (18, 26, 27, 28, 29, 30, 31), the site most severely affected in these patients. In two small uncontrolled pilot trials conducted in men increases in cancellous bone volume and bone content were demonstrated (18, 26). We now report the results of a randomized, double-blind, placebo-controlled trial of PTH-(1–34) in young and middle-aged men with idiopathic osteoporosis.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 23 men were enrolled, 30–68 yr of age (mean, 50 ± 1.9 yr), 17 at Columbia-Presbyterian Medical Center (CPMC) and 6 at Helen Hayes Hospital (HHH). Inclusion criteria for this study were a z-score of less than -2.0 or a T-score of less than -2.5 at the lumbar spine or femoral neck, using a male reference database. Twenty-two patients met both criteria. This symptomatic group was comprised of men who had sustained fractures (78% had sustained fractures of the spine, hip, or appendicular skeleton) or had presented with back pain (22%). Patients were thoroughly evaluated to exclude any known secondary causes of osteoporosis; this group of men with idiopathic osteoporosis has been previously well described (5, 32). Their characteristics include low bone turnover with markedly reduced indexes of bone formation on histomorphometry (mineralizing surface and bone formation rate reduced by 58% and 54%, respectively) (5). In addition, serum and urinary markers of bone turnover were in the lower range of normal.
Although hypogonadism was an exclusion criterion, we did allow men who had been on a stable regimen of testosterone for at least 2 yr and who still met our T- or Z-score criteria to enroll. Two men, both of whom were randomized to placebo, were receiving stable doses of androgen replacement (testosterone enanthate, by injection) with stable testosterone levels (as assessed by peak and trough levels measured quarterly) for at least 2 yr. All other men were eugonadal. Patients were permitted to have been taking other medications for osteoporosis, but not within 6 months of randomization. Two patients in the control group had been previously treated with etidronate, and one man had been treated with calcitonin and sodium fluoride (NaF). In the PTH arm, three men had received etidronate (and one of these had used NaF as well), and one man had been treated with calcitonin. The duration of therapy and the time elapsed before beginning the protocol did not differ significantly between groups.
This study was conducted with the approval of the institutional review boards of CPMC and HHH. All subjects gave written informed consent.
Protocol
After enrollment, patients were observed (before randomization) for an average of 12–15 months, during which time they were instructed to achieve a total daily calcium intake of 1500 mg. In most cases, calcium supplementation was required. Patients were also instructed to take 400 IU vitamin D. Concealed randomization was accomplished by computer-generated randomly permuted blocks of 4; patients were randomized to receive either the 34-amino acid fragment of human PTH-(1–34) (Bachem, San Diego, CA) at a dose of 400 IU (n = 10) or a visually identical vehicle consisting of mannitol and citric acid (n = 13). PTH or vehicle was reconstituted from powder with 0.8 cc sterile water diluent, and patients used 0.5 cc of this solution for sc injection. PTH potency was ascertained by using the International Chick Assay Standard (33). The drug was stable with refrigeration for up to 2 yr. After randomization, all patients continued calcium and vitamin supplementation.
Serum and urinary calcium were measured within 1 month of beginning treatment. Blood samples were obtained in the fasting state in the morning, close to 24 h after the last daily injection. Subsequent visits were conducted every 3 months. One patient, randomized to treatment, withdrew after 6 months, but was still included in the intention to treat analysis. Reasons offered for withdrawal were inconvenience of injections as well as arthralgias. All other patients completed 18 months. Compliance was assessed by medication diaries as well as by vial counts. One patient in the treatment group was found to be poorly compliant in his first year, missing the equivalent of 4 months of therapy, although compliance improved in the final 6 months of the protocol.
Bone mineral density (BMD)
BMD of the lumbar spine, right hip, and nondominant radius was measured by dual energy x-ray absorptiometry using a QDR-1000 bone densitometer (Hologic, Inc., Waltham MA) at CPMC and a QDR-1500 bone densitometer at HHH. At CPMC the in vitro precision of the QDR-1000 is 0.28%, and at HHH it is 0.51%. Short-term in vivo precision at CPMC in a group of postmenopausal osteoporotic women is 1.2% at the lumbar spine and 1.4% at the femoral neck; at HHH short term in vivo precision is 0.8% at the lumbar spine and 1.5% at the femoral neck. Bone density was expressed as grams per cm2 and as T- and Z-scores, which compare, by SD, individual bone density determinations to those of younger and age-matched, normal populations of the same gender, respectively. The NHANES III database (34) was used to calculate T- scores of the hip.
Bone densitometry was performed at least twice during the 90 days preceding randomization, and these values were averaged for each patient to obtain a mean baseline measurement (35). Densitometry was performed every 6 months after initiation of treatment. Patients had two separate densitometric measurements performed (on the same day) at the 12 and 18 month visits, and the two studies were averaged at each of these time points (35).
Radiographs
Radiographs of the thoracolumbar spine were performed at baseline and after treatment for 1 yr. All patients had 2 sets of films performed, but because of film quality and retrieval problems, only 18 sets of films could be properly evaluated for comparative purposes (6 PTH-treated and 12 control patients). The radiographs were assessed quantitatively by a radiologist without knowledge of treatment assignment. Vertebral heights (anterior, central, and posterior) were estimated by micrometer, after criteria for the vertebral borders were established. Vertebral measurements were made from T4 to L5. Baseline fractures were defined by a reduction of 20–25% in any of the vertebral heights compared with the adjacent craniad vertebra or closest intact craniad vertebra. Fractures that occurred during the study were identified by reduction in vertebral height of 20–25% (36) at the 1 yr point.
We used available radiological data to estimate between-subject variability in compression and to determine that in order to have 80% power with a P value of 0.05 to detect a 20–25% reduction in vertebral height, we would have needed 50 subjects/group. This study was thus not powered to detect a difference in incidence of vertebral compression between groups.
Serum and urinary measurements
Serum concentrations of total calcium, phosphorus, alkaline phosphatase activity, albumin, blood urea nitrogen, and creatinine were measured by automated techniques (Technicon Instruments, Tarrytown, NY) on at least two separate visits during the enrollment period, at the 1 month visit, and every 3 months thereafter.
The PTH concentration was determined by an immunoradiometric assay for intact PTH (37), the 25-hydroxyvitamin D concentration was determined by RIA (38), and the 1,25-dihydroxyvitamin D concentration was determined by RRA (39). A 24-h urine collection was analyzed for calcium by atomic absorption spectrophotometry and for creatinine by standard autoanalyzer techniques. These tests were performed twice during enrollment and every 6 months thereafter. The 24-h urinary calcium was also checked 1 month postrandomization.
Two markers of bone resorption, urinary excretion of free pyridinoline (PYD) and N-telopeptide (NTX), were measured by enzyme-linked immunosorbent assay (40, 41). Three markers of bone formation were measured: serum osteocalcin (OC) and bone-specific alkaline phosphatase activity (BSAP) by immunoradiometric assay (42, 43), and carboxy-terminal propeptide of type 1 procollagen (PICP) by RIA (44). These markers of bone turnover were measured on two separate visits during the enrollment period, at 1 month, and every 3 months after randomization. As a 24-h urine collection was available only at the 1,6, 12, and 18 month samples, measurements of bone resorption markers PYD and NTX at months 3, 9, and 15 were performed on urine obtained from the second morning specimen.
Samples for a given visit were batched and assayed at the same time. Intraassay coefficients of variability were less than 10%, and interassay coefficients of variability were less than 10.4% for 24-h urinary calcium and creatinine, PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and OC. Intraassay coefficients of variability were less than 8%, and interassay coefficients of variability less than 13.4% for PICP, BSAP, PYD, and NTX.
Statistical analysis
Baseline characteristics are summarized with means and SD for continuous variables or by percentages for categorical items. The presence of group differences at baseline was assessed with t tests or Fisher’s exact test for continuous and categorical items, respectively. A multivariate omnibus F test for the three bone sites was first calculated, and the null hypothesis of equal outcomes of treatment groups was rejected with a two-tailed 5% type I error rate. The primary outcome analysis of the between-group differences in the longitudinal effects of treatment at each site are analyzed under intent to treat, with the last available value carried forward, with repeated measures ANOVA of two treatment groups (PTH-treated and control) and four sample times (baseline and 6, 12, and 18 months). Exploratory analyses of the associations among markers of bone resorption and bone formation at baseline and at 18 months used Pearson correlations, whereas exploratory analyses seeking the best predictors of 18-month treatment response from among measures available at baseline and 3 months used multiple regression methods. All statistical analyses were conducted with SAS/STAT (version 6.12) software from SAS Institute, Inc. (Cary, NC).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Patients in the randomized groups were well matched for clinical
characteristics, including age, body mass index, smoking history,
physical activity level, and use of prior medications for the treatment
of osteoporosis (Table 1
). Although
patients randomized to the PTH group had significantly higher calcium
intake at enrollment (Table 1), all patients were counseled equally on
calcium intake upon entry to the study, the enrollment period lasted
12–15 months before randomization, and compliance with calcium and
vitamin D intake was reinforced at each visit. Patients were well
matched with regard to baseline bone density at all sites, baseline
serum and urinary biochemistries, and markers of bone turnover (Table 2).
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In men treated with PTH there was a linear increase in lumbar
spine (LS) bone density with a mean gain of 4.8 ± 2.0% at 6
months, 9.6 ± 2.4% at 1 yr, and 13.5 ± 3.0% at 18 months
(range, 3.0–30.4%) compared with control patients, in whom bone
density was unchanged (P < 0.001; Fig. 1A). At the femoral neck (FN) there was a
gradual increase in the PTH-treated patients, reaching 2.9 ±
1.5% at 18 months (P < 0.05; Fig. 1B). Total hip
density did not change significantly. In the treatment group, a small
1.2 ± 0.6% decline in cortical bone density at the 1/3 site of
the radius was not significantly different from baseline. It differed
significantly, however, from the control group, which increased
0.5 ± 0.4% (P < 0.05; Fig. 1C). In men treated
with PTH, T- and Z-scores improved by approximately 1 T- or Z-score
unit at the LS (-3.3 ± 0.3 to -2.4 ± 0.4
(P < 0.10) and -2.8 ± 0.3 to -1.9 ± 0.5
(P < 0.005), respectively], but T- or Z-scores did
not change significantly at the FN or the 1/3 radius.
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Of the 6 pairs of thoracolumbar films available for comparison in PTH-treated patients, 1 man experienced a new vertebral compression fracture, with reduction in vertebral height of 20–25%. Of the 12 pairs of spine films evaluated for control patients, 2 patients met criteria for new vertebral compression fracture, with 1 of these men experiencing 3 new fractures. These numbers were too small to establish significance (see Materials and Methods).
Biochemical values
As expected, the endogenous serum PTH level fell in the
PTH-(1–34)-treated patients by more than 50% at 6 months and was
still 40% lower than the baseline value at 18 months
(P = 0.05). In the control group there was no change
(Table 3). Serum calcium, 24-h
urinary calcium, serum 25-hydroxyvitamin D, and
1,25-dihydroxyvitamin D levels did not differ significantly between the
groups or compared to baseline values throughout the trial (Table 3).
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All markers of bone turnover increased in the PTH-treated men.
Markers of bone formation are shown in Fig. 2. PICP peaked in the treated patients at
6 months to a mean increase of 67 ± 22% above baseline
(P = NS) with a decline to baseline thereafter (Fig. 2A). BSAP peaked to 168 ± 272% above baseline at 9 months
(P = 0.053) and was still 43 ± 45% greater than
baseline at 18 months (Fig. 2B). OC changed most markedly in response
to PTH administration, with a 230 ± 48% increase at 1 yr
(P < 0.001). It was sustained at 150 ± 24%
greater than baseline at 18 months (Fig. 2C).
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. PYD peaked to 131 ± 37% above
baseline by 9 months (P = 0.057) and remained at
64 ± 11% above baseline at 18 months (Fig. 3A). NTX showed a
steady increase over time with values already 209 ± 102% greater
than baseline as early as 3 months after therapy. NTX peaked at 1 yr,
to 375 ± 97% greater than baseline (P < 0.001),
and values were sustained at 261 ± 56% at 18 months (Fig. 3B).
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). In contrast, although there appeared
to be no relationship between markers of bone formation and PYD
throughout the 18 months in the control patients (r = -0.1, 0.02,
and 0.1 for PYD to BSAP, PICP, and OC, respectively; P
= NS; Fig. 4B), a marked shift in this relationship occurred in the
PTH-treated patients (r = 0.7, 0.6, and 0.6 for BSAP, PICP, and OC
to PYD, respectively; P < 0.0001; Fig. 4B).
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17 nmol bone collagen equivalents/mmol
creatinine in our assay) had the poorest response to PTH. These markers
were then combined in pairs, with 1 formation and 1 resorption marker
per pair for a total of 16 combinations. The change in OC at 3 months
together with baseline PYD contributed 70% to the variance in 18 month
lumbar spine bone density, superior to any other combination or any
marker alone. Adverse events
Hypercalcemia, with values greater than 10.5 mg/dL, was noted in 2 of the 10 patients in the PTH group at the 1 month or 3 month visit; the dose of medication was titrated to normalize serum calcium (new doses, 320 and 200 IU, respectively). Despite dose reductions, both patients had significant increases in LS bone density (26.4% and 9.9% increase at 18 months, respectively).
Five men treated with PTH noted redness at the injection site compared with one patient in the control group, and there was a trend to significance when analyzed by Fisher’s exact test (P = 0.073). There were no significant differences between the groups with respect to generalized systemic, musculoskeletal, or neurological reactions or any specific organ system.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The magnitude of the increase in bone density at the lumbar spine is noteworthy. With the exception of fluoride, most therapeutic agents for osteoporosis are not associated with such marked increases in bone mass (10, 12, 20, 49). Other studies using PTH, however, have shown impressive increases in BMD (18, 30, 31). Because of the limited numbers of patients enrolled in our study, a reduction in fracture incidence could not be assessed. Nevertheless, as suggested by Lindsay et al. (30), such impressive increases in BMD produced by PTH may well be associated with a reduction in vertebral fracture incidence. Larger numbers of patients will need to be studied to confirm this point.
There is limited experience with other anabolic agents in men with idiopathic osteoporosis. Using low dose, intermittent fluoride, Ringe et al. (22) showed a mean 8.9% increase in lumbar spine bone density and a more modest 1.9% increase in FN density after 3 yr. There also appeared to be a reduction in vertebral fracture incidence. When administered in this way or as a slow release formulation (50), chronic concerns about this agent with respect to its narrow therapeutic window and the quality of bone resulting from its presence might be alleviated. Additional anabolic agents for which data are still quite limited include androgens (21), GH, and insulin-like growth factor I (19).
Therapy with PTH-(1–34) was associated with increases in markers of bone formation and bone resorption, providing further evidence for a primary action of this agent to increase bone turnover. The combination of bone markers observed to account best for the change in bone density was the baseline urinary PYD concentration combined with the serum OC concentration after 3 months of therapy. Together, these two indexes accounted for 70% of the variance in lumbar spine bone density at 18 months. It would seem, therefore, that some residual elements of bone resorption (e.g. urinary PYD) (51) as well as a substantial increase in osteoblast activity, as seen at the 3 month OC determination, are needed for optimal responsiveness to therapy.
The increase in bone markers, reflecting stimulation by PTH of bone turnover, contrasts with the reduction in bone markers that typifies antiresorptive therapies. In fact, just as a reduction in markers of bone turnover is correlated with responsiveness to antiresorptive therapy (52), it would appear that an increase in bone turnover markers is predictive of the response to PTH. The conventional view is that increased bone turnover in the adult is associated with inefficient coupling between bone formation and bone resorption and consequent loss of bone mass. This point is certainly valid when bone turnover is accelerated by aging, estrogen deficiency, or the initial effects of glucocorticoid therapy (53, 54, 55). In these situations, more bone is resorbed than formed, even though both processes are enhanced. With PTH, on the other hand, stimulation of bone turnover appears to be accompanied by improved skeletal coupling dynamics, with the implication that PTH stimulates bone formation more than bone resorption at sites of cancellous bone.
We conclude that PTH-(1–34) shows great potential as an effective anabolic agent for the treatment of idiopathic osteoporosis in men and may serve as a valuable addition to the limited array of drugs currently available to treat this disorder.
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Acknowledgments |
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Footnotes |
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Received April 13, 2000.
Revised June 12, 2000.
Accepted June 13, 2000.
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). The data are shown as percent changes from
baseline ± SEM for lumbar spine, FN, and 1/3 radius.
*, P < 0.05 for repeated measures analysis of
between-group comparisons. **, P < 0.005 for
repeated measures analysis of between-group comparisons. +,
P < 0.05 for repeated measures analysis of
within-group comparisons between baseline and 6, 12, or 18 months. ++,
P < 0.005 for repeated measures analysis of
within-group comparisons between baseline and 6, 12, or 18 months.
) and
treated patients (•) throughout the 18-month period. A, r = 0.6
for both control and treated patients, with similar slopes. B, r =
-0.1; P = 0.29 for control (dotted
line) and r = 0.7; P < 0.0001 for
treated patients.