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Original article

A randomized, multicenter controlled trial to compare the efficacy of recombinant human parathyroid hormone (1-34) with elcatonin in postmenopausal women with osteoporosis in China

ZHANG, Xiu-zhen; WANG, Bo; YANG, Jun; XUAN, Miao; SONG, Li-ge; LI, Hong; GUO, Xiao-hui; Xiao-feng, LÜ; XUE, Qing-yun; YANG, Gang-yi; JI, Qiu-he; SHEN, Jie; LIU, Zhi-min; LI, Cheng-jiang; WU, Tian-feng; TONG, Xiao-cui; JIA, Yuan

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doi: 10.3760/cma.j.issn.0366-6999.2009.24.003
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Abstract

Osteoporosis is a disease characterized by low bone mass and microarchitectural deterioration leading to bone fragility and an increased risk of fracture.1 The fractures associated with osteoporosis have been shown to cause considerable disability, loss of quality of life, and increased mortality rates.2 Treatments for postmenopausal women with osteoporosis include estrogens, selective estrogen-receptor modulators, bisphosphonates, calcitonin, vitamin D, and calcitriol. These treatments mainly reduce bone resorption (and formation), and moderately increase bone density. Some agents reduce the risk of fracture, but none routinely restore normal bone mass or strength.3 Treatments that stimulate bone formation may overcome these limitations.

Recombinant human parathyroid hormone (1-34) (rhPTH (1-34)) comprises the first 34 amino acids of the hormone and produces its principal biologic effects. It prevents or partially reverses bone loss in animals and humans.4 rhPTH (1-34) stimulates bone formation, increases bone mineral density (BMD), and improves bone architecture and integrity. Several mechanisms have been proposed for the anabolic actions of human parathyroid hormone (PTH). These include proliferation and differentiation of osteoblasts,5 inhibition of osteoblast apoptosis, changes in growth factors such as insulin-like growth factor (IGF)-1,6 and alterations in transcriptional mediators in bone, such as c-Fos7 and Runx2.8 These changes are associated with the known effects of rhPTH (1-34) on increasing the rate of new bone formation.1,9,10

Elcatonin is a potent agent which increases bone density and has been used in the treatment of postmenopausal osteoporosis for many years. In addition to its hypocalcemic effect, elcatonin also inhibits bone resorption by a direct action on osteoporosis.11,12In vitro and in vivo studies have shown that this drug stimulates the growth of bone tissue.13 Compared with the other agents currently used for osteoporosis, elcatonin offers an additional benefit of providing analgesic effects.14 Its mechanism of bone pain relief is still unknown but it may be a central effect.14 Possible explanations for this effect include increases in circulating beta endorphins, inhibition of prostaglandin synthesis, interference with calcium flux, involvement of the cholinergic or serotoninergic systems, a direct action by the drug on central nervous system receptors, or a neuromodulatory effect.14,15

This study was designed to compare the effects of rhPTH (1-34) and elcatonin on the BMD of lumbar spine, femoral neck and the biochemical markers of bone turnover in Chinese postmenopausal women with osteoporosis. Clinical adverse experiences were also assessed.

METHODS

Study subjects

This multicenter, randomized, open-label, active-controlled study was conducted at 11 urban medical centers in Beijing, Shanghai, Zhejiang, Guangdong and Chongqing. The study was carried out between October 2006 and April 2008. All participants were given their written informed consent before enrolment into the study according to the “Declaration of Helsinki”. Subjects were deemed eligible to participate in the study if they were free of chronic, disabling conditions other than osteoporosis, had a lumbar spine or femoral neck BMD at least 2.5 standard deviation (SD) below the mean in normal young women or a BMD at least 1 SD below the mean in normal young women, and at least one radiographically documented, prevalent, osteoporotic, vertebral or nonvertebral fragility fracture. Patients deemed ineligible for the study were those who had secondary osteoporosis, other diseases which could affect bone metabolism, those with a risk of osteosarcoma, active nephrolithiasis or urolithiasis, those with significant hepatic or renal diseases, those with malignant neoplasm, or those with a recent use of drugs known to affect bone metabolism in the preceding 2-24 months of the study (e.g. androgens, anabolic steroids, bisphosphonates, glucocorticoids, estrogens, fluoride). In addition, diabetic patients who had HbA1c>7.0% and patients allergic to elcatonin or PTH, or PTH analogs were excluded from the study.

The study was composed of an induction, or screening period of up to 3 months, followed by a treatment phase of 6 months. The patients were randomized to receive either rhPTH (1-34) (n=100), or elcatonin (n=105). Spine BMD (L1-4) and femoral neck BMD were measured at baseline, 3 months and 6 months of the study. Physical examinations of the patients were performed during each visit to the trial centre. Adverse events were documented and assessed, and laboratory tests were performed to evaluate the safety of the trial drug and its comparator.

Conduct of the trial

A total of 219 ambulatory postmenopausal Chinese women were recruited for the trial. Of these 205 met the eligibility criteria and were enrolled in the trial. The demographic and baseline characteristics of the patients were similar in the two groups (Table 1).

Table 1
Table 1:
Baseline characteristics

The patients were randomly assigned to two groups. The first group received 20 μg (200 U) rhPTH (1-34) (Shanghai United Cell Biotechnology Corp., China. lot: 20060921; exp: 2008.9) by subcutaneous injection each day. The second group received 20 U elcatonin (Asahi Kasei Corp., Japan. lot: ELB11MM; exp: 2008.7) by intramuscular injection every week.

All patients were given additional supplemental caltrate D (Caltrate D is 600 mg elemental calcium and 125 U vitamin D; Wyeth Corp., USA. lot: 0608124; exp: 2008.8). The supplements were given daily throughout the 6-month trial period.

The patients in the first group, injected themselves with subcutaneous rhPTH (1-34). The injection sites were the lower abdomen or outer thigh. The injections were given on a daily basis throughout the study period by insulin syringe. The patients in the second group were given elcatonin by injection, on a weekly basis, by a trained nurse.

Compliance with the trial protocol was assessed by counting the number of unused doses of the drug held by each patient at study visits. Trial subjects were questioned about adverse events at each follow-up visit and asked to rate the severity of each unwanted drug related adverse event as “mild”, “moderate” or “severe”.

BMD, markers of bone turnover and laboratory measurements

During therapy, lumbar spine BMD (L1-4) and femoral BMD were measured at baseline and at 3 months and 6 months. BMD was measured by dual energy X-ray absorptiometry using densitometers from GE Lunar Corp. (DPX-MD, USA). The stability of the measurements recorded by the dual energy X-ray absorptiometry (DXA) instruments was evaluated by the use of serial measurements of a local spine “phantom”. The variability of DXA measurements across the different clinical sites was also assessed by utilising the same spine phantom technique. Using this technique, the long-term coefficient of variation of each instrument in the study was estimated as less than 1%. These phantom measurements were used to adjust for any “drift” in measurements of bone densitometry during the study.

Biochemical markers of bone formation (BSAP) and bone resorption (NTX/Cr) were collected in the fasting condition and measured at baseline, at 3 months and 6 months of the study period. BSAP was measured by enzyme immunoassay (EIA) (ELX800, Immunodiagnostic System Ltd, USA). NTX/Cr was measured by enzyme linked immunosorbent assay (ELISA) (ELX800, Wampole Laboraties, USA). Clinical hematology, chemistry and urinalysis were assessed at baseline, 3 months and 6 months. Serum concentrations of calcium, phosphorus and urinary calcium were also measured by automated techniques (Unicel DXC800, Beckman Coulter, USA) at baseline, 3 months and 6 months.

Statistical analysis

Baseline characteristics of the study subjects were summarized with means and SD for continuous variables, and by percentages for categorical items. The normality of the distribution of the study sample was assessed by “Kolmogorov-Smirnov” test. The presence of group differences at baseline was assessed by “Student's t test” or “Pearson's χ2 test” for continuous and categorical items, respectively. The changes in BMD and biochemical markers from baseline to endpoint were compared between the two treatment groups using “independent-sample t test”. The “paired t test” was used to test the changes from baseline to endpoint within each treatment group. The adverse events experienced by subjects in the study, were analyzed using “Pearson's χ2 test”. All statistical tests were two sided, with an α level of 0.05.

RESULTS

The subjects were all postmenopausal for at least three years. Their overall average age was 65.25 years (rhPTH (1-34): 64.70±7.67, elcatonin: 65.78±7.62). The average body mass index (BMI) was 23.49 (rhPTH (1-34): 23.38±3.17, elcatonin: 23.60±3.29). Of the 205 study subjects, the average baseline L1-4, femoral neck BMD were 0.736 (rhPTH (1-34): 0.731±0.114, elcatonin: 0.741±0.109), and 0.641 g/cm2 (rhPTH (1-34): 0.629±0.111, elcatonin: 0.653±0.111).

BMD

Both rhPTH (1-34) and elcatonin increased lumbar spine BMD at the study endpoint, but the femoral neck BMD did not change significantly. From baseline to endpoint, rhPTH (1-34) increased L1-4 and femoral neck BMD by 5.51% (P <0.01) and 0.65% (P >0.05). In comparison, elcatonin increased L1-4 and femoral neck BMD by 1.55% (P <0.05) and 0.11% (P >0.05). Thus the percentage increase in L1-4 BMD for the rhPTH (1-34) group was 1.79% greater than that in the elcatonin group (P <0.05) at 3 months, and this difference increased to 3.96% at 6 months (P <0.01) (Figure 1). It was noted that the femoral neck BMD showed no significant difference throughout the study period in either group (Figure 1).

Figure 1.
Figure 1.:
Percent change from baseline to endpoint in L1-4 (A) and femoral neck (B) BMD. * P <0.05, P <0.01, within-group comparisons between at baseline, at 3 months and 6 months; P <0.05, § P <0.01, between-group comparisons of rhPTH (1-34) vs elcatonin at 3 months and 6 months.

Markers of bone turnover and mineral metabolism

In the elcatonin group, BSAP increased by 0.31% at 3 months, and fell by 0.17% at 6 months. However, NTX/Cr fell by −5.32% at 3 months, and −10.86% at 6 months. In contrast, in the rhPTH (1-34) group BSAP increased by 36.79% at 3 months (P <0.01) and 92.42% at 6 months (P <0.01). The NTX/Cr also increased by 48.91% at 3 months (P <0.01) and 68.82% at 6 months (P <0.01), respectively, compared with baseline data. Thus the increases in BSAP and NTX/Cr levels of the rhPTH (1-34) group were significantly greater than those of the elcatonin group at 3 and 6 months (P <0.01) (Figure 2 A-2B).

Figure 2.
Figure 2.:
Mean percent change from baseline to endpoint for observed cases at 3 and 6 months. * P <0.01, within-group comparisons between at baseline, 3 months and 6 months; P <0.01, between-group comparisons of rhPTH (1-34) vs elcatonin at 3 months and 6 months.

Mean serum calcium concentration increased at 3 and 6 months in the rhPTH (1-34) group compared with baseline. The serum calcium reached its maximum of 2.43 mmol/L at 3 months, which was 2.75% higher than baseline (P <0.01). Following this, there was a decrease in measured serum calcium at 6 months as compared with the level at 3 months (P <0.05), but this level was higher than baseline (P=0.06). The elevations in serum calcium caused no symptoms and were not associated with any clinically significant adverse outcomes. In the elcatonin group, serum calcium decreased by 0.82% at the 6-month visit, but there was no significant difference from baseline (Figure 3A).

Figure 3.
Figure 3.:
Mean percent change from baseline to endpoint for observed cases at 3 months and 6 months. * P <0.05, P <0.01, within-group comparisons between at baseline, 3 months and 6 months; P <0.05, between-group comparisons at 3 months and 6 months.

The application of the two trial drugs increased the 24-hour urinary calcium excretion in both groups of subjects. In the elcatonin group, the 24-hour urinary calcium excretion increased by 10.32% at 3 months (P=0.132), and 17.56% at 6 months (P <0.01) of the trial. In the rhPTH (1-34) group there was an increase in the 24-hour urinary calcium excretion by 21.90% at 3 months (P <0.01), and 20.75% at 6 months (P <0.01). There was no significant difference between two groups (Figure 3B).

Adverse events

Only 3 patients withdrew from the study because of an adverse event, 2 (2.0%) in the rhPTH (1-34) group, and 1 (1.0%) in the elcatonin group. The reason for withdrawal was different for each participant. There were neither significant differences in the numbers of clinical adverse events in the two groups (67.0% in the rhPTH (1-34) group vs 62.0% in the elcatonin group) nor in the numbers of serious adverse events (0 in the rhPTH (1-34) group vs 0 in the elcatonin group) (Table 2). The drug-related adverse events were similar in the two groups (45.0% vs 32.4%, P >0.05). The predominant drug-related adverse events were dizziness (20.0% in the rhPTH (1-34) group vs 13.3% in the elcatonin group), muscular spasm (21.0% in the rhPTH (1-34) group vs 11.4% in the elcatonin group), nausea/vomiting (6.0% in the rhPTH (1-34) group vs 4.8% in the elcatonin group) and pruritis (9.0% in the rhPTH (1-34) group vs 4.8% in the elcatonin group). The occurrence of hypercalcemia in the rhPTH (1-34) group was 5.0% and 1.0% in the elcatonin group (P=0.112). Blood pressure and heart rate, measured at each visit, were unaffected by treatment with both rhPTH (1-34) and elcatonin.

Table 2
Table 2:
Clinical adverse events (AE) (n (%))

DISCUSSION

rhPTH (1-34) is a bone formation agent, and elcatonin is an antiresorptive agent, both have previously been shown to have a significant effect on BMD and reduction of fracture risk.1,3,10,16-21 This study was a randomized, multicenter, controlled trial to compare the effects of rhPTH (1-34) and elcatonin on certain parameters of bone metabolism in a selected group of Chinese postmenopausal women with osteoporosis.

The results of the study demonstrated that daily injections of rhPTH (1-34) at a dose of 20 μg (200 U), compared with weekly injections of elcatonin 20 U, increased spinal BMD in the rhPTH (1-34) group by 1.79% at 3 months and 3.96% at 6 months, but not femoral neck BMD in either group, in postmenopausal women with osteoporosis.

The explanation for the difference may be that rhPTH (1-34) requires a longer duration of treatment (more than 12 months) to achieve optimum benefit at this site.3,19,22 Because newly formed bone tissue is less mineralized in the periosteal region, the response of cortical bone to the drug is not as marked as that of a trabecular bone.16

Therapy with rhPTH (1-34) was associated with increases in markers of bone formation and bone resorption. This provides further evidence for this site, as the primary site of action of this agent, to increase bone turnover. BSAP was significantly increased at 3, 6 months in the rhPTH (1-34) group from baseline, and this was significantly higher than that of the elcatonin group. NTX/Cr was higher in the rhPTH (1-34) group at 3 months and 6 months. As compared to this, the elcatonin group showed minimal and nonsignificant changes in BSAP and NTX/Cr.

rhPTH (1-34) may directly mediate bone growth through the regulation of osteoblast proliferation and differentiation,5,23 through preexisting bone-lining cells24 as well as inhibiting osteoblast apoptosis.25 It may also exert its anabolic effect on bone indirectly, although this also requires an increase of osteoclastic bone resorption. This is the mechanism by which alendronate is thought to reduce the ability of parathyroid hormone to increase BSAP, and thereby affect BMD at the spine and femoral neck,19 ie. the mechanism by which rhPTH (1-34) exerts its effect on bone depends on its ability to induce bone resorption.

Many of the adverse events reported in this study were mild, in both arms of the study. No serious adverse events were observed in any of the study population. The unwanted clinical adverse events and drug-related adverse events were similar in the two groups. Patients treated with rhPTH (1-34) did experience changes in serum calcium and urinary calcium (the serum calcium increased at 3 months, but it decreased at 6 months). Urinary calcium output was noted to increase in both groups after caltrate D supplementation, implying that calcium and vitamin D supplementation exerts a major effect on calcium excretion. This is consistent with previous publications.26

This multicentre trial has several limitations. The sample size was relatively small, and the duration of the study relatively short (the study lasted only 6 months). No subject experienced a fracture during the study; thus evaluation of the effects of the trial drugs on fractures could not be carried out. The study gave no information about the effects of the trial drugs on femoral neck bone density.

We conclude that once daily administration of rhPTH (1-34) increased BMD at the lumbar spine, and showed significant anabolic effects on bone. The results of the present study tentatively indicate that rhPTH (1-34) is an effective, safe agent in treating postmenopausal osteoporosis.

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Keywords:

recombinant human parathyroid hormone; elcatonin; osteoporosis; bone mineral density

© 2009 Chinese Medical Association