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Clinical Studies |
Departments of Medicine (A.B.H., L.J.F., P.H.W.) and Radiology (D.H.T.) and Nuclear Medicine (D.D.), and the Lawson Research Institute (A.B.H., L.J.F., P.H.W.), St. Joseph’s Health Center, and the Department of Epidemiology and Biostatistics, University of Western Ontario (T.O., L.W.S.), London; and St. Joseph’s Hospital (J.D.A.), Hamilton, Ontario, Canada
Address all correspondence and requests for reprints to: Dr. A. B. Hodsman, Department of Medicine, St. Joseph’s Health Center, Room E-231, 268 Grosvenor Street, London, Ontario, Canada N6A 4V2.
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Abstract |
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At the end of the 2 yr, the lumbar spine BMD increased from 0.720 ± 0.130 to 0.793 ± 0.177 g/cm2 (10.2%) in the PTH group and from 0.760 ± 0.168 to 0.820 ± 0.149 g/cm2 (7.9%) in the PTH+CT group. These changes were significant over time in both groups (P < 0.001). Although the final 2-yr lumbar spine BMD was not significantly different between the two treatment groups, those patients receiving sequential CT injections gained bone mass at a consistently slower rate. Changes in BMD at the femoral neck averaged +2.4% and -1.8% in the PTH and PTH+CT groups, respectively, neither of which was significant. In the group receiving only cyclical hPTH-(1–34), the observed 2-yr vertebral fracture incidence was 4.5 compared to 23.0/100 patient yr in the PTH+CT group (P = 0.078). During the first two cycles, changes in biochemical markers of bone formation (serum total alkaline phosphatase, bone-specific alkaline phosphatase, and osteocalcin) and bone resorption (fasting urinary hydroxyproline and N-telopeptide excretion) were significantly increased over pretreatment values after 28 days of hPTH-(1–34) injections (P < 0.05 to P < 0.01 for both groups). Even end of cycle values remained elevated over the study baseline across time (P < 0.01). There were no significant differences for any outcome parameter between the two treatment groups. We conclude that short cycles (28 days) of daily hPTH-(1–34) injections result in significant increases in lumbar spine BMD, without significant changes in cortical bone mass at the femoral neck. Very low incident vertebral fracture rates were documented over 2 yr. However, there is no evidence that sequential antiresorptive therapy with CT is of any benefit over that conferred by cyclical PTH alone.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We have completed a 2-yr protocol involving cyclical PTH therapy, with or without sequential calcitonin (CT) as an adjunctive antiresorptive agent. The therapeutic cycles were repeated every 3 months. Our hypothesis was based on the expectation that sequential CT therapy would limit the bone resorption induced by PTH therapy, but would not interfere with the anabolic actions of PTH. Thus, combined therapy should be more effective than cyclical PTH alone in restoring bone mass to patients with established osteoporosis. The primary outcome was established at the outset to be a change in bone mineral density (BMD) measured at the lumbar spine by dual energy x-ray densitometry (DEXA) with secondary outcomes to include changes in DEXA measurements of the femoral neck, incident vertebral fracture rates, and biochemical markers of bone formation and resorption.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Thirty-nine Caucasian women with established postmenopausal osteoporosis were enrolled. All patients had a clinical diagnosis of osteoporosis based on radiological evidence of at least one vertebral compression fracture. Medical problems associated with secondary osteoporosis, including steroid therapy, and endocrine dysfunction were excluded by appropriate history and biochemical tests. No patients had received therapy that would otherwise modify the progression of bone loss. Although smoking history was cursory, inclusion in the study required the consumption of less than seven alcoholic drinks per week. Patients signed informed consent to the treatment and investigation protocol, which was approved by the institutional review board for research involving human subjects at the University of Western Ontario and McMaster University (Ontario, Canada).
Treatment was assigned randomly to one of two groups: group 1 (PTH alone), all patients received daily sc injections of hPTH-(1–34) (800 IU equivalents; 50 µg; 15,000 U/mg) (11) for 28 days; and group 2 (PTH+CT), all patients received the same 28-day course of PTH injections as well as a sequential dose of salmon CT (75 U, sc) for 42 days. Patients in group 1 received placebo CT.
All injections were given into the anterior abdominal wall, between 0800–1000 h, in the fasting state. When not receiving either PTH or CT injections, all patients were provided with nutritional oral calcium supplements (equivalent to 500 mg elemental calcium/day) for the remainder of the 90-day cycle. No vitamin D supplements were prescribed.
Both hPTH-(1–34) and CT were supplied by Rhône-Poulenc-Rorer (Montreal, Canada).
Methods
The primary study outcome was defined as a measured change in
vertebral BMD (
% from baseline) at 6-month intervals over time.
Secondary outcomes were as follows: 1) changes in DEXA measurements of
the nondominant femoral neck (as maximum change from baseline); 2)
incident vertebral fracture rates over the 2-yr protocol; 3) changes in
biochemical markers of bone formation [total serum alkaline
phosphatase (SAP), bone-specific alkaline phosphatase (BSAP), and
osteocalcin] together with 4) markers of bone resorption [urinary
excretion of hydroxyproline (OH-Pro) and the more specific measurement
of bone resorption, urinary excretion of N-telopeptide collagen
cross-links (NTx)]. Serum and urinary samples for these measurements
were obtained at baseline, day 28, and day 90 of the first two cycles
and at 6-month intervals thereafter (i.e. at the end of the
of therapy cycles). It should be noted that the cyclical nature of this
therapeutic regimen provided for a 20-day interval (during which the
subjects received only nutritional calcium supplements) before
initiating the next cycle; therefore, the data reported in this paper
are end of cycle samples and reflect data on bone turnover at the end
of each cycle of therapy. All serum and urine samples were obtained
while the subjects were fasting between 0800–1000 h in the morning.
During the first two cycles of therapy and at the end of all eight
cycles, serum calcium, creatinine, and immunoreactive intact endogenous
PTH together with spot fasting urinary calcium excretion measurements
were made to monitor the safety of this dose of PTH.
Vertebral and femoral neck BMD were measured in all study patients at baseline, using either a Hologic QDR 1000 dual energy x-ray densitometer in London, Ontario (36 patients; Hologic, Waltham, MA), or the Lunar DPX scanner in Hamilton, Ontario (3 patients; Lunar Corp., Madison, WI); the degree of osteopenia measured by this technique did not constitute an inclusion criterion. The measured precisions of the Hologic and Lunar instruments at the lumbar spine were ±1.3% (coefficient of variation) and ±1.5%, respectively. The calibrations for the Hologic and Lunar dual energy x-ray densitometers differ. In an attempt to minimize the impact of this, all patients within a center were measured by the same instrument, and sequential measurements in each patient across time were expressed as the percent change from the baseline measurement. Data were systematically recorded as the averaged BMD for L2–L4, although 55% of patients in group 1 and 60% of patients in group 2 had at least 1 lumbar vertebral fracture at baseline. No attempt was made to exclude compressed lumbar vertebrae from the BMD analyses.
Vertebral compression fractures were assessed from standardized lateral spinal radiographs as recommended by the National Osteoporosis Foundation Working Group on Vertebral Fractures (12). The posterior, middle, and anterior heights of all consecutive vertebrae from T6–L5 were measured by a single radiologist (D.H.T.). Prevalent fractures at entry into the study were defined as a 20% reduction in the anterior and/or midlateral vertebral body height compared to the posterior vertebral height. This corresponds to 3–4 SD below the normal population vertebral proportions (13, 14) and is regarded as a reasonable method of minimizing falsely positive fracture labels (15). Incident fractures during the 2-yr study interval were identified as a 20% reduction in vertebral heights measured at exit compared to baseline measurements within individual patients. A new fracture was counted when a preexisting fracture was demonstrated to show a 20% reduction in height or when a new fracture was found in a previously undamaged vertebrae.
Daily dietary calcium intakes were estimated for all study patients at entry into the study, using a standardized dietary questionnaire (10). Serum calcium, creatinine, and total alkaline phosphatase were measured by standard automated techniques. Serum BSAP was measured using a two-site immunoradiometric assay (Tandem-R Ostase, Hybritech, San Diego, CA) with a normal range of 5–25 µg/L. Serum osteocalcin was measured by RIA (Incstar Corp., Stillwater, MN) with a normal reference range of 1.80–6.50 µg/L: the within- and between-assay coefficients of variation were ±3% and ±4.5%, respectively. Serum endogenous immunoreactive PTH was measured by a two-site radioimmunometric assay (Incstar) with a normal reference range of 0.5–5.0 pmol/L. There is no cross-reactivity in this assay with the 1–34 amino-terminal hormone fragment. Urinary OH-Pro was measured by a colorimetric assay (16) in fasting 2-h urine samples after a 12-h overnight fast, thus avoiding the influence of exogenous dietary sources on OH-Pro excretion (17) with a normal reference range of 2.6–40.9 µmol/mmol creatinine. NTx were measured in the same urine samples using an enzyme-linked immunosorbant assay (Osteomark, Ostex, Seattle, WA) with a normal range of up to 200 nmol/mmol creatinine.
Potential formation of antibodies to the synthetic hormones was assessed by measuring the specific binding of 125I-labeled human (h) PTH-(1–34) and salmon CT (both from Peninsula Laboratories, Belmont, CA) by plasma samples obtained at the end of cycle 8. The results were compared to titer curves obtained using either a goat anti-hPTH serum or a rabbit antisalmon CT serum. Dilutions of the patient plasma (or authentic antibody) in a 20 mmol/L KH2PO4 buffer at pH 7.0 containing 0.1% BSA were incubated for 24 h at 4 C with 20,000 cpm of the radioligands, and then bound and free fractions were separated using cold charcoal.
Statistical analysis
All data in the text and tables are reported as the mean ± SD, except where specifically indicated in the figures, which show the SEM. Only data for patients completing the full 2-yr protocol were included in the statistical analysis. The treatment groups were compared with respect to baseline demographic characteristics.
For all outcomes, descriptive statistics and plots over time are given for the baseline and 6-month intervals by treatment group. The F Max statistic was used to test for the assumption of equal variances, and where appropriate, the data were transformed before analysis. For each outcome the percent change from baseline was analyzed using a two-factor repeated measures ANOVA to test for differences between groups and over time. The maximum likelihood approach was used to allow for missing values. Fracture incidence between the two groups was compared using Fisher’s exact test.
The F Max statistic was used to test for inequalities of variance, and when found, the data were log transformed before proceeding with the main analysis. If the significance of changes over time was increased by a quadratic transformation of the data rather than a linear analysis, we assumed the possibility that treatment effects might have diminished over time.
For the first two cycles only, biochemical data were available to assess the immediate response to the 28-day course of hPTH-(1–34) injections. The effects of treatment course, cycle, and treatment group were analyzed using a three-factor repeated measures ANOVA. Again, the maximum likelihood approach was used to allow for missing values.
All analyses were performed using the SAS statistical package (SAS Institute, Cary, NC) (18).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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identify the
baseline characteristics of the 30 patients who completed the study;
there were no meaningful between-group differences at baseline in age,
height, weight, dietary calcium intake, vertebral fractures, BMD
(either lumbar spine, L2–L4, or femoral neck), biochemical markers of
bone formation (total SAP, BSAP, and osteocalcin), or biochemical
markers of bone resorption (2-h fasting urinary OH-Pro or NTx,
expressed as analyte excretion/mmol creatinine). Serum and urinary
calcium together with serum PTH levels were comparable between the two
groups.
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Of the 30 patients who completed the 2-yr study protocol, there were 14 patients in the PTH alone group and 16 patients in the PTH+CT group. Reasons for the 9 study drop-outs included 1) inability to learn the self-injection technique; all 3 patients were identified within the first 2 cycles of treatment: 2) a localized indurated erythematous response to the injections of PTH-(1–34) and/or its gelatinized diluent (3 patients), which became apparent in cycles 1, 4, and 7, respectively: 3) recognition of underlying cancer in 3 patients during cycle 2 (cancer of the esophagus), cycle 5 (cancer of the bronchus), and cycle 7 (cancer of the pancreas); in none of these patients did the diagnosis of cancer appear to relate to the treatment protocol. Screening of all patients before they signed the informed consent was limited to that described under patient recruitment, and no systematic effort was made to seek out occult cancer other than a complete history, physical examination, and routine laboratory tests. No other side-effects of therapy were detected in other patients, apart from mild nausea and skin flushing in patients receiving CT (a well described side-effect of this therapy). Analysis of the baseline data relating to those patients who did not complete the regimen did not suggest the introduction of significant bias; it was unfortunately not possible to analyze outcomes on an intention to treat basis.
Means and SDs at baseline, 12 months, and 24 months for BMD
and biochemical markers of bone turnover are shown in Table 2
. The percent changes from baseline measured at 6-month
intervals are shown in Fig. 1 for the lumbar spine and
femoral neck.
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At the end of 2 yr, vertebral BMD increased by 10.2% in the PTH group and by 7.8% in the PTH+CT group. The change from baseline ranged from -2% to 20% in the PTH and from +1 to 21% in the PTH+CT group. Taking an increment of at least 3% (twice the measurement precision of the densitometer instrument), an increment in vertebral BMD could be confidently documented in 86% and 88% of the PTH and PTH+CT patients, respectively.
There was a decrease in femoral neck BMD in the PTH+CT group that remained stable over the remaining 18 months, whereas in the PTH alone group, BMD increased until 18 months and dropped slightly by 24 months. This differential rate of change was not statistically significant (P = 0.126). Neither differences between groups nor across assessments were statistically significant (P = 0.172 and P = 0.099, respectively).
At the end of 2 yr, femoral neck BMD increased by 2.4% in the PTH
alone group, but decreased by 1.8% in the PTH+CT group. The change
from baseline ranged from -4.8% to +19.4% in the PTH alone group and
from -14.8% to +10.5% in the PTH+CT group. Using an arbitrary figure
of ±3% (
1 coefficient of variation for the measurement at this
site), 29% of the PTH alone patients and 19% of the PTH+CT patients
gained bone mass at the femoral neck site.
If the baseline lumbar spine BMD is compared to the increments in BMD for all 30 patients at 24 months, there is a significant negative correlation (r = -0.70; P < 0.0001), indicating that patients with the lowest bone mass stand to gain the most bone during PTH therapy. Statistical significance of these correlations was maintained when each group was tested separately. (group 1, r = -0.56; P = 0.04; group 2, r = -0.79; P < 0.0001). No such correlations existed for the femoral neck.
No patients suffered either a hip fracture or any other appendicular fractures during the 2-yr protocol. For the PTH alone group, 11 of 14 patients had spinal x-rays evaluated before and at the end of 2 yr, of whom only 1 patient had a new vertebral fracture, yielding a vertebral fracture rate of 4.5/100 patient yr. For the PTH+CT group, paired x-rays were available in 13 of 16 patients, in whom 4 new vertebral fractures and 2 incremental fractures in previously damaged vertebrae were detected, yielding an incident fracture rate of 23/100 patient yr (P = 0.078 compared with the PTH alone group) by Fisher’s exact test.
Figure 2 shows the short term changes in the three
markers of bone formation and the two bone resorption markers in
response to the first two courses of hPTH. In each cycle there were
significant (P < 0.01) increments in all markers
during the 28 days of hPTH injection, which fell toward the baseline
during the remaining 62 days of the cycle. With the exception of
fasting NTx excretion, there were no differences between PTH and PTH+CT
patients.
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Fasting urinary OH-Pro showed no incremental differences between cycles (P = 0.646). There were differences between cycles (P = 0.022) and over the course of treatment (P < 0.001). For fasting NTx, the difference between cycles was dependent on the treatment group (P = 0.040). There was no evidence to indicate that the change during the treatment course was dissimilar between cycles for either the PTH group (P = 0.850) or the PTH+CT group (P = 0.634). Within the PTH group there was no difference between cycles (P = 0.421) and no change over the course of treatment (P = 0.253). However, within the PTH+CT group, there was evidence of a difference between cycles (P = 0.018) and of a change over the course of treatment (P < 0.001).
We were unable to study biochemical parameters immediately
post-hPTH-(1–34) therapy from the third cycle onward, but end of cycle
data are shown for the bone formation and resorption data in graphical
form in Fig. 3. Absolute data for biochemistry are shown
in Table 2 at baseline and at the 1 and 2 yr points.
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Fasting spot urinary OH-Pro excretion was increased 41 ± 51% over baseline in the PTH-treated group at 1 yr, but only by 12 ± 31% at 2 yr. Similarly, urinay OH-Pro increments in the PTH+CT group were 48 ± 56% at 1 yr and 27 ± 49% at 2 yr. Although there were no significant differences between the two groups, the increment in urinary OH-Pro excretion from baseline was statistically significant in both groups (P < 0.01); again, the further enhancement of the statistical difference over time using a quadratic transformation (P < 0.001) may indicate a decreasing effect of treatment on bone resorption across time. Fasting urinary NTx assays revealed a pattern similar to that of OH-Pro excretion. There was a significant increase in NTx excretion over time (P < 0.01), with no difference between the two groups. Again, quadratic transformation of the data suggested that this increment was most pronounced during the first year and decreased during the second year. At the conclusion of the study, NTx excretion was not significantly different from baseline in either group.
Although the increments in biochemical markers of bone formation and resorption were consistent with increased bone turnover, they were not predictive of subsequent changes in BMD at either the lumbar spine or femoral neck [e.g. r = -0.13 to -0.29 for the initial increment in bone formation markers during the first cycle of hPTH-(1–34) vs. final lumbar spine BMD, and r = -0.06 to -0.007 for the changes in bone resorption markers vs. final spine BMD].
Safety evaluation was restricted to serum calcium, creatinine, and PTH;
fasting urinary calcium excretion; and measurement of endogenous
antibodies to injected hPTH-(1–34) peptide and salmon CT. These data
are shown in Table 3, combined for both groups; at the
time points selected, all patients were receiving similar treatments.
At the end of the first two treatment cycles (months 1 and 4) with
hPTH-(1–34), both fasting preinjection serum and urinary calcium
levels were significantly increased (P < 0.01), as
expected. However, end-cycle values for these parameters were not
different from baseline over 2 yr. There were no significant
differences in endogenous immunoreactive PTH levels across time or
between the two groups. However, there was a small (10%) increment in
serum creatinine over time, which was first apparent after the second
course of PTH injections (month 4; see Table 3). These changes in
end-cycle serum creatinine levels were statistically significant
(P < 0.01), but no patients developed progressive
renal failure or serum creatinine levels that exceeded clinically
normal ranges.
Specific binding of 125I-labeled PTH was detected in the serum obtained at the end of the last cycle from only 1 of the 30 patients, and in this sample, the binding was equivalent to a dilution of 1:640 of a reference anti-PTH serum. This patient gained 15.5% in lumbar spine BMD during 2 yr of cyclical therapy, which is greater than the mean gain for either treatment group. Therefore, the formation of anti hPTH-(1–34) antibodies appears to be uncommon and has not been shown to impair the biological response to injected PTH therapy. Of the 16 patients who received sequential treatment with CT-specific binding of 125I, salmon CT was detected in the sera of 4 of them, with equivalencies of 1/1000, 1/125, 1/120, and 1/20 with a reference antisalmon CT antibody. When alterations in either BMD or SAP in these patients with antibodies to CT were compared to the group means, there were no differences.
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Discussion |
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Changes in BMD
Over 2 yr, patients receiving cyclical PTH therapy gained an
average of 5% lumbar spine BMD/yr (P < 0.001); over
time, patients receiving sequential CT consistently had a slower rate
of gain, but the final BMD was no different from that of the patients
who did not receive CT. Clearly, there was no advantage to patients in
the sequential CT arm of the study. When considering changes in BMD at
the femoral neck site, neither group experienced significant changes
over baseline, but the group receiving only cyclical PTH consistently
averaged higher increments in femoral neck BMD measurements than those
receiving sequential CT treatment (in keeping with the data observed
for the spine measurements). Had we studied a larger sample of
osteoporotic patients, we may have detected significant differences
between the 2 groups with respect to changes in the femoral neck;
however, sample size calculations (setting 
= 0.05 and ß = 0.20)
predict the need for between 40–60 subjects in each arm of the study
to accomplish this (19). However, the primary study outcome (lumbar
spine BMD) was not powered to detect these changes.
The clinical literature documenting the efficacy of PTH therapy in osteoporosis reveals a heterogeneous group of protocols, with outcomes not easily compared (1, 3, 5, 6, 7, 8). The earliest clinical outcomes used quantitative histological data (1). Several subsequent studies reported quantitative computerized tomography of lumbar spine bone mass, which consistently demonstrated large increments in trabecular bone density when daily PTH injections were combined with concurrent therapy (estrogen, calcitriol, or CT) (3, 5, 7). The primary outcome in this report was the change in measured lumbar spine (L2–L4) BMD assessed by DEXA. Cyclical PTH injections alone given for 1 month of 3 resulted in annual increments of approximately 5%. This compares with reported increments in comparably measured spinal BMD outcomes by DEXA in response to continuous daily PTH injections of 6–7%/yr (6, 8), albeit daily dosing was usually limited to 500 U rather than the higher dose of 800 U reported here. It is also of interest to contrast the spinal BMD increments reported here with the effect of sodium fluoride, another anabolic agent in bone. Published results from controlled trials indicate increased spinal BMD of 5–8%/yr (20, 21, 22). In contrast, changes in spinal BMD in response to bisphosphonates (primarily an antiresorptive class of drugs) range from 1.8–2.9%/yr (23, 24, 25). Thus, this cyclical PTH regimen resulted in comparable increments in spinal BMD compared with alternative anabolic protocols using continuous daily PTH or fluoride treatment and almost twice the improvement reported with an antiresorptive agent (e.g. bisphosphonates).
There is some concern that anabolic agents may increase trabecular bone mass at the expense of reduced cortical bone (4, 6, 26, 27), but these findings are not consistent (3, 5, 7, 21, 22), particularly for PTH. Although this report does not resolve this issue for PTH, it is at least reassuring that femoral neck BMD tended to increase with time in patients treated with cyclical PTH alone, with no significant decrements in this outcome in the combined PTH+CT group.
The hypothesis that sequential CT should augment the beneficial effects of cyclical PTH on bone mass was unequivocally disproven. Biochemical data on bone markers in our preliminary report suggested that CT might be antianabolic (10). None of the biochemical markers of bone turnover in the completed study suggest otherwise. Indeed, the PTH+CT patients gained bone at the lumbar spine site at slower rates and did not appear to derive any protection from bone loss at the femoral neck. CT is a relatively weak antiresorptive agent, at least in terms of its ability to increase spinal bone mass in osteoporotic patients (28), so we may have chosen the wrong antiresorptive agent. However, the case for combined antiresorptive agents in PTH protocols has yet to be made, at least for estrogens in the human syndrome of osteoporosis (7, 8) or for bisphosphonates in animal models of osteoporosis (29). We would conclude at present that the hypothesis of combining antiresorptive therapy with PTH treatment of osteoporosis patients for the purposes of maintaining cortical bone mass awaits confirmation.
Vertebral fractures
No fractures were documented outside of the spinal column. Vertebral fractures were recorded if either new or incremental vertebral deformities occurred, which amounted to at least a 20% reduction in posterior, middle, or anterior vertebral height in lateral spinal x-rays (see Materials and Methods). These are reasonable criteria for fracture definition (12). By these definitions, the PTH-treated patients had fewer fractures (4.5/100 patient yr) than those treated with PTH and sequential CT (23/100 patient yr), although the small sample size within each group resulted in no statistically significant difference between the two groups (P = 0.078).
The fracture data reported here are limited, but we are not aware of any other vertebral fracture data reported in the literature for osteoporotic patients treated with PTH injections. The treated patient cohort in this report were at high risk for incident fractures given an average lumbar spine and femoral neck t score of -3 or less and at least one vertebral fracture on entry to the study. Thus, the incident fracture rates seem very low. Incident vertebral fracture rates reported from this center in a similar osteoporotic group treated successfully with sodium fluoride averaged 53/100 patient yr over 3 yr; we used a scoring system identical to that reported here (30). Published incident vertebral fracture rates in several controlled trials have ranged from 3–45 fractures/100 patient yr in patients treated with either cyclical etidronate or fluoride compared to a range of 6–53 fractures/100 patient yr in placebo-treated groups (20, 22, 23, 24). We cite these studies because patient selection and fracture assessments were comparable to those we used. Given such a wide range, we can make no clear comparisons, except to say that our PTH-treated patients apparently had lower than expected fracture rates. Although the PTH+CT group had more vertebral fractures during the study (23 vs. 4.5/100 patient yr; P = 0.078), this may be consistent with the slower rate of increase in vertebral BMD.
Biochemical markers of bone turnover
In a preliminary report of the responses of biochemical markers of bone turnover in the first 20 patients enrolled in this protocol, we documented significant increments in bone formation and resorption indicators (10). These changes were mirrored in the histomorphometric measurements of bone formation and resorption in bone biopsies obtained from this subgroup after only 28 days of hPTH-(1–34) injections (10). In this study there was no significant difference (either acutely after the first two PTH cycles or chronically at the conclusion of each 3-month cycle) to suggest any modification by CT of the skeletal response to cyclical PTH. However, the data indirectly support the conclusion that bone turnover is consistently increased by cyclical PTH therapy in elderly osteoporotic patients and support our preliminary data evaluating the acute skeletal response to the first cycle of treatment (10). Statistical analysis of end-cycle bone formation markers (serum BSAP and osteocalcin) added no additional information to that obtained from total SAP. The end-cycle fasting urinary NTx marker of bone resorption added nothing further to the urinary OH-Pro data, although this marker pattern closely mirrored the excretory pattern of OH-Pro.
The end of cycle biochemical increases in bone formation and resorption markers suggest that cyclical PTH therapy results in prolonged increments in anabolic bone turnover; however, the statistical analyses suggest that the biochemical changes were progressively less pronounced during the second year. There are several reports suggesting that biochemical markers of bone turnover reflect the underlying status of bone histology (31, 32, 33, 34, 35) or bone mass (36). Neer et al. (6) suggested that increasing vertebral BMD during PTH treatment might plateau during the second year. Thus, our bone turnover data might suggest a diminishing response to PTH across time. However, a skeletal resistance to PTH therapy is not statistically apparent from the bone density data in this study and has not been reported by others (5, 7, 8). This important issue cannot be resolved from our data, but needs to be addressed in prolonged and controlled future clinical studies.
Safety evaluation
Although a small number of patients were recruited to this study, a total of 66.5 patient yr of observation (including study withdrawals) are available for evaluation. Of the study withdrawals, the 3 cases of cancer need to be addressed. Two of these patients had their cancer diagnosed within 3–6 months of entry into the study; we did not perform a detailed cancer screen at entry and assume that their cancers (bronchus and esophagus) existed before their enrollments and were not study related.
Three patients had local inflammatory reactions at the injection sites in the sc tissue of the abdominal wall. All 39 patients originally recruited to this study provided sera at their respective exit points. Antibodies to hPTH-(1–34) could be demonstrated in low titers in only 1 patient, whereas binding of radiolabeled salmon CT could be demonstrated in 4 patients. All patients with demonstrable antibodies to either hormone responded with increased lumbar spine BMD, which suggests that the primary outcome was not influenced by the production of endogenous neutralizing antibodies. The PTH product formulation used for this study was originally designed as a diagnostic reagent and contained significant amounts of gelatin as a preservative; we believe it is more likely that these local inflammatory responses were related to the formulation vehicle rather than the PTH peptide and presume that PTH therapy is unlikely to be associated with significant immunogenic responses in large groups of patients.
Only three patients withdrew because of failure to learn the injection techniques (8%), and the incidence of other side-effects was not discernible. Thus, the treatment was well tolerated over the longer term. Small, but significant, increments in serum calcium levels and urinary calcium excretion were observed at the end of the first two courses of PTH injections, but no detectable increments were seen in the end of cycle values for these two analytes over 2 yr.
For all patients there was a small, but significant (P < 0.01), increment in serum creatinine over the 2 yr. It is difficult to assess the clinical significance of the increasing serum creatinine seen in both treatment groups over 2 yr. Creatinine clearance decreases with age, but the natural decline is less than 2%/yr (37). The increment of serum creatinine in this report (average, 5%/yr) is, therefore, more than expected for age. The obvious factors to explore to account for this apparent decline in renal function include the significant increments in serum and urinary calcium excretion (documented during the first two cycles of PTH treatment). These changes were small and well within ±2 SD of the mean values at baseline. However, preinjection serum calcium levels above the upper limit of normal were documented in six patients (2.7 to 3.0 mmol/L) at the end of either the first or second cycle of PTH injections. Until more data are available from controlled clinical trials, we must caution that this dose of hPTH-(1–34) is probably inadvisable for prolonged cyclical therapy and too high for noncyclical regimens.
In conclusion, this report documents significant increments in spine BMD in response to 28-day courses of hPTH-(1–34) injections, given 3 months apart, with no evidence for significant reductions in BMD measured over the femoral neck. Over the 2-yr study period, incident vertebral fracture rates were lower than might have been expected for patients of this age with diminished BMD and with multiple preexisting vertebral fractures. The fracture data suggest that the improved spine bone mass was associated with some degree of protection from further fracturing. There is no evidence that sequential CT therapy contributes to the therapeutic benefit derived from cyclical hPTH-(1–34) alone. Finally, the increase in bone mass appears to be most pronounced after hPTH-(1–34) therapy in those patients with the lowest bone mass to start with. Thus, the absence of deleterious effects on cortical bone and the enhanced benefits in trabecular bone after hPTH-(1–34) administration suggest that cyclical PTH therapy might be a useful treatment for those patients with severe osteoporosis.
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Acknowledgments |
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Footnotes |
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Received June 4, 1996.
Revised October 25, 1996.
Accepted October 31, 1996.
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E. C. Buxton, W. Yao, and N. E. Lane Changes in Serum Receptor Activator of Nuclear Factor-{kappa}B Ligand, Osteoprotegerin, and Interleukin-6 Levels in Patients with Glucocorticoid-Induced Osteoporosis Treated with Human Parathyroid Hormone (1-34) J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3332 - 3336. [Abstract] [Full Text] [PDF]
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A. B. Hodsman, D. A. Hanley, M. P. Ettinger, M. A. Bolognese, J. Fox, A. J. Metcalfe, and R. Lindsay Efficacy and Safety of Human Parathyroid Hormone-(1-84) in Increasing Bone Mineral Density in Postmenopausal Osteoporosis J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5212 - 5220. [Abstract] [Full Text] [PDF]
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J. P. Brown and R. G. Josse Lignes directrices de pratique clinique 2002 pour le diagnostic et le traitement de l'osteoporose au Canada Can. Med. Assoc. J., March 18, 2003; 168(90060): SF1 - 38. [Abstract] [Full Text] [PDF]
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B. M. Misof, P. Roschger, F. Cosman, E. S. Kurland, W. Tesch, P. Messmer, D. W. Dempster, J. Nieves, E. Shane, P. Fratzl, et al. Effects of Intermittent Parathyroid Hormone Administration on Bone Mineralization Density in Iliac Crest Biopsies from Patients with Osteoporosis: A Paired Study before and after Treatment J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1150 - 1156. [Abstract] [Full Text] [PDF]
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M. J. Horwitz, M. B. Tedesco, C. Gundberg, A. Garcia-Oc |
). ***, P < 0.001 across
time; no difference in final outcome between groups. n.s., No
significant difference at baseline, across time, or between groups.
0.01 (at
the end of either the first or second cycle of PTH injections in both
groups compared with baseline values). Differences between groups were
not significant.