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Randomized Trial of Once-Weekly PTH(1-84) on Bone Mineral Density and Remodeling
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Journal of Clinical Endocrinology & Metabolism
March 2008
Dennis M. Black PhD*, Mary L. Bouxsein PhD, Lisa Palermo MA, Joan A. McGowan PhD, David Newitt PhD, Eyal Rosen DMD, Sharmila Majumdar PhD, Clifford J. Rosen PhD, and for the PTH Once-Weekly Research (POWR) group
San Francisco Coordinating Center, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Department of Orthopedics, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; The National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; Department of Radiology, University of California, San Francisco, San Francisco, CA, USA; Maine Center for Osteoporosis Research, St. Joseph Hospital, Bangor, ME, USA
Context: Daily parathyroid hormone (PTH) administration increases bone mineral density (BMD) and reduces fracture risk. However, cost and compliance significantly limit clinical use.
Objective: To determine whether less frequent PTH administration increases lumbar spine BMD
Design: Double-blind, randomized placebo-controlled trial
Participants: 50 postmenopausal women ages 45-70 with femoral neck BMD T-score between -1.0 and -2.0
Setting: St. Joseph Hospital, Bangor, Maine
Intervention: Subcutaneous injections of daily PTH(1-84) (100 μg) or placebo for one month, followed by weekly injections (PTH or placebo) for 11 months
Outcomes: Change in lumbar spine DXA areal BMD (aBMD, Primary). Secondary outcomes included volumetric BMD (vBMD) at spine and hip by QCT, trabecular bone microarchitecture by MRI of distal radius, and biochemical bone turnover markers.
Results: At 12 months, lumbar spine aBMD increased 2.1% in PTH-treated women compared to placebo (p=0.03). Vertebral trabecular vBMD increased 3.8% in PTH-treated women compared to placebo group (p=0.08). PTH-treated women also had higher distal radial trabecular bone volume, number, and thickness compared to placebo-treated women (p<0.04). After one month of daily PTH, PINP was markedly increased compared to placebo (p<0.0001) and a difference persisted, although lessened, throughout the study. Bone resorption indices were unchanged in PTH-treated women and were reduced in placebo group.
Conclusion: Once-weekly PTH after one month of daily treatment increases spine BMD, radial trabecular bone and bone formation markers in postmenopausal women. These results suggest that less frequent alternatives to daily PTH dosing for two years could be effective. Further studies are required to define the optimal frequency of PTH administration.
Introduction
Current approved treatments for postmenopausal osteoporosis include two
classes of drugs: 1) anti-resorptives, such as the bisphosphonates, estrogen, calcitonin and the selective estrogen receptor modulators; and 2) anabolics, such as teriparatide (PTH 1-34). In contrast to the former class of drugs that prevent bone loss through inhibition of bone turnover, PTH enhances bone mass through stimulation of bone formation and remodeling. Since its approval in 2002, teriparatide has been used relatively sparingly despite its proven antifracture efficacy and its capacity to markedly increase bone mineral density (BMD).(1)
High cost and the burden of daily injections for as long as two years have been the most significant barriers to widespread use of PTH, particularly among primary care providers.(2) In order to increase clinical acceptability of PTH, various treatment regimens have been proposed which might retain the anabolic effect while reducing the duration of PTH treatment. Using PTH 1-84, we showed that one year of PTH followed by one year of alendronate resulted in larger bone density increases than 2 years of PTH 1-84.(3, 4) Cosman and colleagues (5) found that 3-month on/off cycles of PTH 1-34 in the context of on-going alendronate therapy for 15 months yielded similar BMD increases to 15 months of continuous PTH. In another approach, once-weekly PTH 1-34 was shown to significantly increase BMD over 1 year.(6) In the largest dosage group (200 IU/week), there was an increase in lumbar spine BMD of approximately 8%.
However, since there was no placebo comparison group, it is difficult to separate the effects of the drug from longitudinal increases often seen in lumbar spine BMD due to artifactual changes in the lumbar spine with aging. In order to address the question of whether less frequent PTH administration could positively influence BMD, we performed a 12-month double-blind, randomized placebo-controlled trial in postmenopausal women in a design that used a daily loading dose of PTH 1-84 for four weeks, followed by weekly therapy.
Methods
Subjects
We included women (recruitment goal=50) between the ages of 45 and 70 who were at least five years postmenopausal, had a total hip aBMD T-score -1.0 to -2.0, and no history of osteoporotic fractures or presence of morphometric fractures on x-ray. Exclusion criteria included current use of bisphosphonates, estrogen, raloxifene or calcitonin or previous exposure to PTH. Previous exposure to oral bisphosphonates was limited to no more than 12 months ever and no more than 4 weeks within the previous two years. No previous use of IV
bisphosphonates was allowed. In addition, women with 25(OH)-Vitamin D levels <15 ng/ml, serum calcium >10.3 mg/dl, urine calcium/creatinine ratio >0.3 or with creatinine clearance <40 ml/min were excluded. The patients were recruited from St. Joseph Hospital, Bangor, Maine. The first one was screened in January 2004, and the last patient visit occurred in February 2006. Informed consent was obtained from all subjects prior to screening.
Trial Design and Treatments
This was a double-blind, randomized, placebo-controlled trial of 12 months duration with spine aBMD by DXA as the principal outcome. After a run-in of two weeks during which the women received placebo injections and calcium and vitamin D, women were randomized to PTH or placebo (n=25 each). The PTH group self-administered daily subcutaneous injections of PTH 1-84 (100 ug, PreOS, NPS, Salt Lake, UT) for four weeks, followed by weekly injections (100 ug) for the next 11 months. The placebo group self-administered placebo injections according to the same schedule. Both groups received 500 mg of calcium and 400 IU of vitamin D daily.
Efficacy Outcome Variables
Details of the methods for assessing outcome DXA and QCT measurements have been previously described in detail(7) and will only be summarized here. Areal BMD (aBMD, g/cm2) at the lumbar spine, hip, whole body, and radius was assessed by dual-energy X-ray absorptiometry (Hologic Delphi) at baseline, 1 (spine only), 6 and 12 months. Change in lumbar spine aBMD as assessed by DXA was the primary efficacy parameter. Volumetric bone density (vBMD, g/cm3) at the lumbar spine (L1 and L2, trabecular bone density only) and total hip (trabecular, cortical and integral bone densities) and bone geometry were assessed by quantitative computed tomography (QCT), as previously described.(7, 8) Scans were obtained at 80 KvP using contiguous 3 mm slices.
Trabecular architecture and cortical thickness were assessed in the distal radius using magnetic resonance imaging (MRI), as previously described.(9) Slices were 0.5 mm thick for the first 9 patients and 0.75 mm for the remaining patients.
Trabecular and cortical bone regions were segmented using in-house developed
semi-automatic routines in IDL (RSI, Boulder, CO). Trabecular bone measures that were calculated, using 2D histomorphometry on a slice by slice basis,(10) included apparent bone volume fraction (app. BV/TV), apparent trabecular number (app. Tb.N), apparent trabecular spacing (app. Tb.Sp), and apparent
trabecular thickness (app. Tb.Th). The mean cortical thickness for each segmented slice was calculated using a 3D distance transformation technique previously developed for trabecular bone.(11) 2D trabecular bone calculations and cortical bone thicknesses were then averaged over the entire scanning region and then into 1.5 mm segments starting at 6 mm and ending at 30 mm from the endplate.
After an overnight fast, serum was drawn and stored (-70°C) at baseline, 1, 2, 3, 6 and 12 months. Samples were stored until assayed for markers of bone metabolism (serum C-telopeptide of type I collagen (CTX), bonespecific alkaline phosphatase (BSAP) and Nterminal propeptide of type I collagen (PINP)) in a central laboratory (P. Garnero, Synarc, Lyon, France). Assays for all time points were performed simultaneously.
Results
Approximately 350 women were screened; 50 postmenopausal women between the ages of 45-70 were enrolled and randomly assigned to active treatment, PTH 1-84, or placebo (Figure 1). Forty-nine women completed the trial; one was lost to follow-up (Figure 1). At baseline, the mean age of the women was 58.2 (6.4) years, and the mean BMI was 26.8 (3.6) (Table 1). The mean T-score for aBMD at the lumbar spine was -1.0 (1.1).
Compared to placebo-treated women, spine aBMD increased by 2.1% (p=0.03, Table 2, Figure 2) and vertebral trabecular vBMD by 3.8% (p=0.08, Table 2, Figure 2) in women on once-weekly PTH. Changes in total hip and femoral neck aBMD by DXA and total hip vBMD by QCT did not differ between treatments (Table 2, Figure 2).
As assessed by MRI, in the more proximal regions of the distal radius, trabecular bone separation and number significantly improved (p<.05) in the once weekly PTH group versus placebo (Figure 3). There were similar trends for trabecular bone fraction and thickness in the proximal region (p=.06 and p=.10, respectively). (Figure 3) In the more distal region, there were no differences for any trabecular parameters. No parallel trend from distal to proximal was evident for aBMD at the radius (Table 2).
Changes in bone turnover were different between the treatment groups. Following one month of daily PTH, P1NP increased by 98% versus baseline (p<0.0001; Figure 4). Thereafter, during the period of once-weekly PTH, the decline in P1NP was relatively slow, and values did not return to baseline until the end of the 12-month study period. The modest declines in the placebo group for PINP (and the other markers) are consistent with the mildly antiresorptive effect of calcium and vitamin D seen in placebo controls in previous trials.(12, 13) P1NP levels differed significantly in the PTH and placebo groups at 1, 2, 3 and 6 months of treatment (p<0.001; Figure 4) but not at 12 months. Bone ALP showed a similar pattern to PINP with a significant increase compared to placebo by 2 months (p=0.054 at 1 mon). However, the magnitude of the increase was much less than that of PINP. Serum CTX was initially unchanged in the PTH-treated women (Figure 3), showed a small increase at 3 months, and then subsequently declined modestly. In the placebo group, serum CTX also showed an initial but modest decline. Differences in serum CTX between PTH and placebo were significant at 1, 2, 3, and 6 months but not at 12 months.
Serum calcium elevations were observed in 5 patients (20%) in the PTH group and none in the placebo group. Four of the five were mild (10.5-11.2 mg/dl) while the fifth was above 11.2 mg/dl. Four of the five occurred at one month at the end of the daily PTH period and the fifth occurred at 12 months. All of those women normalized their calcium after the 1st retest within 1 week: PTH was continued and calcium and vitamin D were not discontinued. There were no serious AEs in either group, and compliance with >80% of the injections was more than 90%.
Discussion
In this small trial, we demonstrated that one month of daily PTH followed by 11 months of weekly PTH had a positive effect on vertebral BMD measured by DXA and a similar trend for trabecular BMD measured by QCT. The increment in spine BMD relative to placebo-treated women was modest (+2.1% for aBMD and +3.8% trabecular vBMD) when compared to daily PTH.(1, 7, 14) However, the 2% difference in areal BMD between treatment and placebo groups over 1 year is not trivial in that it is similar to that previously reported for several treatments (e.g. raloxifene, risedronate) which have been shown to reduce fracture risk.(12, 15, 16) Yet, we did not see an increase in hip BMD compared to placebo as would be expected with antiresorptive drugs and seen previously with daily PTH.(1, 4, 7) Interestingly, we observed an increase in bone formation levels which remained significant for at least 6 months with no corresponding increase in serum markers of bone resorption. Whereas the magnitudes of the BMD and biochemical marker changes were much less than those seen with daily PTH,(7) the fact that significant effects could be achieved with a reduced frequency of PTH suggests that alternative regimens and dosing for PTH deserve further study.
It is still not clear whether this regimen or other non-daily dosing of PTH could reduce fracture risk. Both the increase in spine BMD and bone formation without an accompanying increase in resorption would argue for a positive impact on bone strength. On the other hand, the lack of effect on hip BMD is not supportive of an increase in bone strength at this site. Changes in BMD and markers are only weakly related to changes in fracture risk, and therefore the potential impact of this PTH dosing or some variation of intermittent PTH dosing would have to be tested in a randomized fracture trial.
We saw an increase in bone formation without an increase in bone resorption, evidence of a so-called uncoupling of the two processes. It has been suggested that such an improved balance between formation and resorption could signal a much improved ability of a therapy to increase bone strength. Daily PTH therapy yields a temporary uncoupling: formation increases during the first 3 months while resorption increases do not fully occur until about 3 to 6 months.(7, 17) This period has been termed the ganabolic windowh and it has been hypothesized to be important to the bone building effect of anabolic treatments. A similar uncoupling was suggested in a study using the combination of PTH 1-34 and raloxifene, where formation for the combination was similar to that for PTH alone but the resorption increases for the combination were only about half of those seen with PTH alone.(18) A similar qualitative guncouplingh has been claimed for strontium ranelate, but the magnitude of the increase in formation (about 5%) and decrease in resorption (about 8%) are very small compared to much larger effects seen with antiresorptive (40-80%) and anabolic treatments (100 to 200%). Using some combination of cyclic and non-daily anabolic treatment, possibly in combination with a mild antiresorptive, may be possible to maximize and extend the period of increased formation while minimizing resorption increases, and therefore maximizing the increases in bone strength. Specific possibilities for alternative PTH dosing include a longer loading period (perhaps 3 months), a more frequent follow-up dosing (perhaps twice per week), or a second one-month loading period (perhaps after 6 months of weekly PTH). Generally, these findings, along with the recent study of 3-month cyclic PTH(5) provide rationale for further exploration of alternative PTH dosing regimes.
Our MRI results suggested a trend towards an improvement in trabecular architecture, especially in the more proximal regions of the radius. The magnitude of the differences was modest, mirroring modest changes in trabecular BMD in the spine, but suggests that our treatment regimen had a positive effect on trabecular bone. The only other published treatment study that has used MRI to analyze trabecular bone examined the effects of nasal calcitonin on the distal radius(9) and, notably, this study found a similar trend, whereby differences in trabecular architecture between treatment groups were more prominent in the more proximal regions of the distal radius. Whether our findings truly reflect greater trabecular changes with PTH in the more proximal regions or whether MRI simply has a greater ability to detect changes in more proximal regions requires further study. Trials of daily PTH show that radius aBMD decreases relative to placebo(1, 7) and that these losses are greater in the more proximal regions of the radius, presumably reflecting greater cortical loss in these areas. These complex changes in the radius, together with fracture risk reduction
observed for PTH 1-34, confirm that areal BMD does not reflect changes in bone architecture, and that future trials should include measurements that can define specific changes in the cortical and trabecular compartments at various skeletal sites. Such measurements may provide greater insight into the anti-fracture efficacy of osteoporosis treatments.
There were several limitations to this study. First, we used a daily loading dose of PTH for one month. Thus, we cannot be certain that once-weekly PTH for 12 months without a loading dose is more effective than placebo. Rather, we believe the loading dose of PTH is essential to activate lining cells and osteoblasts, and elicit a true anabolic effect. Second, we did not directly compare once weekly with daily PTH; hence, most of our comparisons with daily PTH are based on previously published studies using either the 1,34 or 1,84 preparation.(1, 7, 17) Third, the 100 mcg dose of PTH(1-84) utilized in this study, and administered weekly, is identical to the daily dose approved in Europe. (4) However, the only other study of weekly PTH used PTH(1-34) at a maximum dose of 60 mcg, three times the daily dose of teriparitide, and found a larger effect on spine BMD (+8% at 1 year).(6) Thus, it is possible that a dose higher than 100 mcg of PTH(1-84) used once per week would have a larger impact. It should also be noted that, we studied a group of relatively young women without severe osteoporosis; hence our results may not be generalizable to older patients with more severe disease. Lastly, this study was very small and not powered to see subtle differences in many of the measurements used, particularly MRI and QCT. The trends we noted will have to be examined in larger multicenter trials.
Nonetheless, we have shown that a daily loading dose for 1 month followed by weekly administration of PTH has an anabolic effect on the skeleton. Taken together with other recent results on cyclical use of PTH, these results suggest that it may not be necessary to use PTH daily for an extended period to receive the full anabolic benefit; less frequent or shorter duration use of PTH may be as good as or better than daily PTH for 2 years in strengthening bone and reducing fracture risk. Future trials are warranted to define the optimal frequency and duration of PTH administration that can increase bone strength and ultimately reduce fracture risk.
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