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Departments of Pharmacology/Pathology (P.J.K., C.C., S.M., S.A., D.L.L.), Process Development (G.S.), and Development (C.R.D.), Amgen, Inc., Thousand Oaks, California 91320; and Skeletech (V.S.), Bothell, Washington 98021
Address all correspondence and requests for reprints to: Dr. Paul J. Kostenuik, Department of Pathology/Pharmacology, One Amgen Center Drive, Thousand Oaks, California 91320. E-mail: paulk{at}amgen.com
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Numerous studies have demonstrated that the anabolic effects of PTH can be realized in animals cotreated with antiresorptives, including bisphosphonates (3, 6, 7, 9, 10, 11, 12, 13), calcitonin (5, 7, 10, 12, 13), E (3, 5, 6, 7, 9, 11, 12, 13, 14, 15), and selective E receptor modulators (16). Recent clinical trials have also indicated that PTH can exert positive effects on the skeleton of patients who were pre- or cotreated with antiresorptives (17, 18, 19, 20). These studies strongly suggest that bone resorption per se is not a requirement for the anabolic response to PTH. However, nearly all of these studies failed to demonstrate a statistically significant benefit of combination therapy over PTH therapy alone. In the vast majority of preclinical combination therapy studies, antiresorptives failed to significantly increase the anabolic effect of PTH on bone mass or BMD (3, 4, 5, 6, 7, 10, 11, 12, 13, 16, 21, 22, 23, 24, 25). In some animal studies antiresorptives appeared to blunt the anabolic response of osteoblasts to PTH (3, 5, 7, 11, 14, 22, 23, 24, 26). In a clinical trial calcitonin slowed the rate at which PTH increased bone mass (27). It is possible that different dosing regimens from those used previously are necessary to reveal an additive effect of antiresorptives on bone mass in the PTH-treated skeleton. To date, however, the therapeutic benefit of adding an antiresorptive to intermittent PTH therapy has not been demonstrated by direct comparison in clinical trials or in a suitable preclinical model of osteoporosis such as the aged ovariectomized (OVX) rat.
Recently, a potent and naturally occurring bone resorption inhibitor was discovered that has a unique mechanism of action. OPG is a member of the TNF receptor family that acts by preventing the association of OPG ligand [OPGL (28, 29, 30), also known as RANKL (31), TRANCE (32), or ODF (33)] with the RANK receptor on osteoclasts and osteoclast precursors (34). By blocking OPGL/RANKL-induced RANK activation, OPG inhibits osteoclast differentiation, activation, and survival (35). We recently demonstrated that OPG causes the rapid disappearance of osteoclasts in mice treated with intermittent PTHrP (36). The ability of OPG to eliminate PTHrP-induced osteoclasts was also associated with significant inhibition of PTHrP-related hypercalcemia. Interestingly, intermittent PTHrP treatment caused a dramatic increase in osteoblast surface that was not inhibited by OPG cotreatment (36). It is well established that PTHrP and PTH act on the same receptor (37, 38) to initiate increases in osteoclast and osteoblast surfaces, and that both factors increase bone mass when administered intermittently (39, 40). The ability of OPG to completely reverse PTHrP-induced osteoclasts and control hypercalcemia while preserving PTHrP-induced osteoblasts suggested a unique therapeutic opportunity for osteoporosis. We therefore tested in aged OVX rats whether the combination of OPG plus PTH would cause greater increases in bone mass, density, and strength compared with PTH alone.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BMD by DEXA
BMD was measured monthly in anesthetized rats (87 mg/kg ketamine
and 13 mg/kg xylazine) starting at the beginning of the treatment
period. BMD was determined using DEXA (QDR 4500a, Hologic, Inc.). Small animal software (Hologic, Inc.) was
used to obtain BMD in the lumbar vertebrae (L1–L5) and in the
femur/tibia. The femur/tibia site consisted of the proximal half of the
tibia and the entire femur.
Histomorphometry
The tibia and the lumbar vertebrae were decalcified in formic
acid, embedded in paraffin, and longitudinally sectioned.
Histomorphometric analyses were made by tracing the section image onto
a digitizing platen with the aid of a camera lucida attachment on the
microscope and Osteomeasure (Osteometrics, Inc., Decatur, GA) bone
analysis software. For each section, 10–15 fields of cancellous bone
were measured at x10–20 magnification. The tibial analysis was
performed in the proximal metaphysis starting adjacent to the
epiphyseal growth plate, an area that encompassed 1.32
mm2 of the section. In the second lumbar
vertebra, a 1.54-mm2 area was analyzed in the
center of the bone from growth plate to growth plate. To reveal
osteoclasts, sections were stained for immunoreactivity to cathepsin K,
an osteoclast marker (42). Cathepsin K staining was
accomplished with a biotinylated rabbit polyclonal antibody to
cathepsin K, and sections were counterstained with hematoxylin.
Cancellous bone volume was assessed as a percentage of the total bone
tissue volume (BV/TV), and the length of the perimeter of cancellous
bone surfaces was measured. Osteoblast perimeter was determined by
scoring osteoblasts in direct contact with cancellous bone surfaces.
Osteoclast perimeter was determined as the perimeter of multinucleated
cathepsin K-stained osteoclasts in direct contact with cancellous bone
surfaces.
Mechanical testing
A Material Testing System (model 5501R, Instron Corp., Canton,
MA) was used to perform mechanical testing in the femur and the third
lumbar vertebral body (L3). The load and extension (deformation) curves
were collected with the accompanied software (Merlin II, Instron
Corp.). All tests were conducted using a 5-kN load cell at a constant
loading rate of 6 mm/min, and data were collected every 6 msec. A
compression test was used to determine the mechanical properties of L3,
as previously described (5). Briefly, the L3 body was
separated from the ephiphyseal ends, the posterior pedicle, and the
spinous process using a low speed saw. An electronic caliper was used
to determine the dimensions of the L3 body. The L3 body was then
compressed to failure. A three-point bending test was used to determine
the mechanical properties of the femoral midshaft. The moment of
inertia along the load axis was determined using a pQCT scan of the
femur and accompanying software (XCT-RM, Stratech, Norland Corp., Fort
Atkinson, WI). The diameter of the loading axis was measured with an
electronic caliper. The midshaft of the femur was then subjected to
three-point bending to failure with a support span of 14 mm at the
bottom and load applied at the midpoint of the posterior aspect of the
femur. A cantilever compression test was used to determine the
mechanical properties of the femoral neck, as previously described
(4). The proximal end of the femur was anchored in a hole
made in an aluminum block with a notch that holds the greater
trochanter in place. The femoral neck was compressed to failure,
perpendicular to the shaft. For each skeletal site measured, the
maximal load and stiffness were obtained directly from the load and
extension (deformation) curve. Ultimate strength and elastic modulus
were calculated using the deformation curve and caliper measurements of
cross-sectional area (CSA). CSA was calculated based on the formula
CSA = 
x a x b, where
a is the average dorsal to ventral diameter, and
b is the side to side diameter.
Statistical analysis
All statistical analyses were performed by one-way ANOVA using
an 
value of 0.05. For DEXA data, groups were compared at each time
point. Where significant overall differences were observed by one-way
ANOVA, the Tukey Kramer test was applied for the comparison of multiple
pairs. The comparisons reported include each group vs. the
vehicle-treated OVX groups, as well as the PTH-treated OVX group
vs. the PTH- plus OPG-treated OVX group. Analyses were
performed using SAS software version 6.0 (SAS Institute, Inc., Cary, NC). All data are expressed as the mean ±
SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). The effectiveness of ovariectomy was
indicated by uterine atrophy and a lack of ovarian tissue compared with
shams (data not shown). Combining all treatment groups, OVX rats had a
final mean body weight of 409 ± 6 vs. 317 ±
17 g for shams (P < 0.05). There was no
significant effect of any of the treatments on body weight in the OVX
rats (Table 1). Serum calcium levels were not significantly different
between groups at the end of the study (Table 2). At baseline, PTH-treated OVX rats had
slightly lower calcium levels compared with vehicle-treated OVX rats,
which may be attributed to chance randomization. OPG alone had no
significant effect on serum calcium after 1, 2, 4, or 5 months of
treatment, but a transient increase in serum calcium was observed at 3
months compared with vehicle-treated OVX rats (P <
0.05). Treatment with PTH alone caused significant hypercalcemia after
1, 3, and 4 months of treatment (P < 0.05), and
cotreatment with OPG significantly inhibited PTH-induced hypercalcemia
at 3 and 4 months (P < 0.05). Serum creatinine levels
were essentially similar in all groups throughout the study, although
creatinine was significantly elevated in shams at 2 months and in
PTH-treated OVX rats at 4 months compared with vehicle-treated OVX rats
(data not shown).
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). PTH alone caused significant
increases in serum osteocalcin at all time points compared with
vehicle-treated OVX rats (P < 0.05). The maximum
induction of osteocalcin, which occurred after 2 months of PTH
treatment, was 78% greater than that in vehicle-treated OVX rats. OPG
alone caused small, but significant, decreases in serum osteocalcin
(9%–17%) at 3, 4, and 5.5 months of treatment (P <
0.05). OPG also partially attenuated the PTH-associated increases in
osteocalcin observed after 2, 3, 4, and 5.5 months of treatment. In
rats treated with OPG plus PTH, osteocalcin levels were significantly
greater than in vehicle-treated OVX rats after 1 and 2 months of
treatment (P < 0.05), after which time osteocalcin
returned to levels similar to those in vehicle-treated OVX rats (Table 3).
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). OPG alone caused a gradual
increase in lumbar vertebral BMD compared with vehicle-treated OVX
controls that became significant after 4 months of treatment. PTH
treatment, alone or in combination with OPG, rapidly increased lumbar
vertebral BMD, with a significant increase evident after 1 month. After
3 months of treatment with OPG plus PTH, the gain in lumbar vertebral
BMD was significantly greater than that in all other groups, including
PTH alone (Fig. 1A). The raw BMD
data for the lumbar vertebra revealed that by the end of the treatment
period, PTH and PTH plus OPG had restored BMD to levels found in shams
(Table 1). OPG alone caused a significant increase in raw BMD in OVX
rats and restored 32% of the BMD relative to that in shams (Table 1).
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). The
effects of combination therapy on BMD in both the lumbar vertebrae and
the femur/tibia appeared to be a purely additive effect of each agent.
The raw BMD data for the femur/tibia indicated that at the end of
the study, both PTH and PTH plus OPG increased BMD to levels
significantly greater than those in shams, whereas OPG alone restored
about 50% of the BMD relative to that in shams (Table 1).
These changes in BMD were concordant with histomorphometric analysis of
cancellous bone volume (BV/TV). At the end of the study, BV/TV in the
lumbar vertebrae of PBS-treated OVX rats was 45% reduced compared with
that in shams (P < 0.05). PTH alone, but not OPG
alone, significantly increased BV/TV in the lumbar vertebrae of OVX
rats. OPG plus PTH caused a slightly greater increase in BV/TV compared
with PTH alone, and this combination treatment restored BV/TV to levels
similar to those in shams (Fig. 2A). In
the proximal tibial metaphysis, OVX caused an 80% decrease in BV/TV
compared with shams (P < 0.05). OPG treatment of OVX
rats caused a nonsignificant 75% increase in tibial BV/TV,
whereas PTH cause a significant 200% increase in BV/TV
(P < 0.05). The combination of OPG plus PTH caused a
significantly greater increase in tibial BV/TV compared with PTH
treatment alone (P < 0.05; Fig. 2D).
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). Osteoblast surface in the lumbar
vertebrae was not affected by OVX or any treatment (Fig. 2C). A
different cellular response was observed in the proximal tibial
metaphysis. Ovariectomy did not have a significant effect on osteoclast
surface in the tibia at the time of death. OPG alone reduced osteoclast
surface in OVX rats by 65% (P < 0.05), whereas PTH
alone had no effect on osteoclast surface. Treatment with OPG plus PTH
caused a nonsignificant 41% reduction in tibial osteoclast surface
compared with PTH alone (Fig. 2E). PTH treatment caused a 3-fold
increase in osteoblast surface compared with that in vehicle-treated
OVX rats (P < 0.05), and the addition of OPG had no
significant effect on osteoblast surface (Fig. 2F).
Mechanical compression testing of the third lumbar vertebra (L3)
indicated that OVX alone caused significant reductions in stiffness,
maximum load, ultimate strength, and elastic modulus compared with
those in shams (P < 0.05; Fig. 3). OPG alone had no significant effect
on these parameters. PTH treatment alone significantly increased
maximum load and ultimate strength compared with PBS/OVX rats
(P < 0.05). OPG plus PTH also increased maximum load
and ultimate strength significantly compared with vehicle-treated OVX
rats (P < 0.05). OPG plus PTH also significantly
increased stiffness and elastic modulus, and these increases were
significantly greater than those observed with PTH alone
(P < 0.05; Fig. 3).
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).
OPG alone caused a significant increase in maximum load compared with
that in vehicle-treated OVX rats (P < 0.05; Fig. 4).
PTH alone caused significant increases in stiffness, maximum load, and
ultimate strength (P < 0.05; Fig. 4). OPG plus PTH was
the only treatment that significantly increased elastic modulus in the
femur (P < 0.05; Fig. 4). Cantilever compression
testing of the femoral neck did not show any OVX-induced decreases in
maximum load or stiffness (Fig. 5). OPG
alone had no significant effect on these end points. PTH treatment,
alone or in combination with OPG, caused significant increases in
maximum load and stiffness compared with vehicle-treated OVX rats
(P < 0.05; Fig. 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study adds to the growing body of literature indicating that the addition of PTH to antiresorptive therapy is clearly superior to antiresorptive therapy alone (3, 4, 6, 13, 13, 19). However, it has been much more difficult to demonstrate that antiresorptives can add significantly to the robust anabolic actions of PTH. Indirect evidence supporting a benefit of antiresorptive cotherapy was provided by a recent clinical trial of intermittent PTH therapy. Daily PTH-(1–34) treatment of postmenopausal patients receiving hormone replacement therapy (HRT) caused a 20.6% increase in lumbar BMD at 1 yr compared with placebo (20). The lack of a PTH monotherapy group in that study prevents any conclusions regarding the benefit of adding the antiresorptive HRT regimen. However, it may be noteworthy that in separate clinical trials, PTH-(1–84) monotherapy caused a 6.9% increase in lumbar BMD after 1 yr (45), whereas PTH-(1–34) monotherapy increased lumbar BMD by up to 13.7% after 17 months (8). The larger gain in BMD observed with PTH and HRT (20) compared with PTH monotherapy suggests an advantage of combination therapy. However, variations in the study designs and the use of different PTH fragments hinder conclusions on the benefits of added HRT. Clearly, randomized placebo-controlled studies will be required to directly compare the effects of PTH alone vs. those of PTH and antiresorptives.
The present preclinical study is among the first to directly demonstrate a significant additive effect of PTH and antiresorptive therapy on bone volume, BMD, and parameters of mechanical strength compared with PTH alone. The beneficial effects of combination therapy in this study might be attributed to the novel antiresorptive employed or to the nature of the study design. The current study design allowed for 15 months of OVX-induced bone loss, followed by 5.5 months of therapy, which are among the longest durations reported. However, the additive effects of OPG plus PTH observed here do not appear to be a direct function of animal age or the severity of osteopenia, as other long-term aged OVX rat studies have failed to show a benefit of combination therapy over PTH treatment alone. For example, 12 months of OVX-induced bone loss resulted in similarly large deficits in bone density, but there was no apparent benefit of adding IGF-I to intermittent PTH therapy (46). Other rat studies compared the effects of PTH treatment, with and without antiresorptives, on bone mass and mechanical strength starting 12 months after OVX. The combination therapies, which added E, risedronate, or calcitonin to PTH, were no more effective than PTH alone (7, 12, 13).
The rationale for using severely osteopenic aged OVX rats in the current study was based in part on the assumption that in the clinic, the severely osteoporotic elderly patient has the greatest clinical need for effective anabolic therapy to rapidly restore bone mass. Also, acute OVX models, particularly in young rats, may show therapeutic effects that are not realized in more clinically relevant, long-term, aged OVX rat models. For example, a TNF-binding protein was demonstrated to block OVX-induced bone loss in young rats, but not in old rats (47, 48). In another acute OVX study, E plus PTH increased bone mass better than did PTH alone, but only when combination therapy was initiated within 1 wk after OVX (15). There was no benefit of adding E to PTH when treatment was initiated 3 or 5 wk after OVX. In the clinical setting it is not clear that anabolic agents, alone or in combination with antiresorptives, are appropriate or necessary for the modest osteopenia that is typically associated with the early postmenopausal period. In addition to their clinical relevance, aged OVX rats are suitable for combination therapy studies because of their very slow skeletal growth rate. Treatment of young rapidly growing rats with antiresorptives produces growth-related increases in bone mass (35) that cannot be realized in skeletally mature humans. Severely osteopenic aged OVX rats are clearly responsive to the anabolic effects of PTH (Refs. 7, 12, 46 , and 49 and current study), and the effects of combination therapy in these animals can be interpreted with minimal confounding growth effects from the antiresorptive. This idea is highlighted in the current study, where OPG treatment was associated with a near-total lack of osteoclasts, and yet the BMD increases associated with OPG treatment alone were a modest 5%. Adding PTH to OPG led to 20–25% increases in BMD compared with vehicle-treated OVX rats. These observations highlight the challenge of reversing severe osteopenia in aged OVX rats with antiresorptives alone; even a 98% reduction in osteoclast number does not reverse osteopenia in these animals unless accompanied by an anabolic stimulus such as PTH.
Another possible explanation for the beneficial effects of combination therapy in the present study is the nature of the antiresorptive, OPG. Like E, OPG appears to play an important physiological role in the regulation of bone remodeling in mice (35). It was recently demonstrated that E treatment of human osteoblasts increased OPG mRNA and protein (50), suggesting that the bone-protective effects of E may be mediated at least in part through increased OPG production. Providing recombinant OPG to the E-depleted skeleton may directly increase the ratio of OPG to OPGL/RANKL, thereby decreasing bone resorption. OPG also has several properties that appear to complement the effects of PTH. Intermittent PTH therapy, while having a net anabolic effect on bone, stimulates both bone formation and bone resorption (43). Recent data indicate that PTH stimulates bone resorption indirectly by increasing osteoblast production of OPGL/RANKL and by decreasing OPG (reviewed in Ref. 44). PTH inhibits OPG mRNA expression in cultured osteoblasts (51, 52, 53, 54, 55) and increases OPGL/RANKL mRNA (33). A single injection of PTH-(1–38) into rats was recently shown to rapidly decrease skeletal levels of OPG mRNA (54). These changes could decrease the ratio of OPG to OPGL/RANKL and thereby promote bone resorption. The administration of recombinant OPG might directly reverse this ratio and thereby prevent PTH-induced bone resorption. In support of this idea, recombinant OPG completely blocks PTH-induced resorption in bone organ cultures (56) and also blocks the calcemic response of mice to PTH (57). The vertebral histomorphometry data from the present study also suggest that OPG can block the PTH-induced bone resorption. In the vertebrae, PTH alone caused a significant increase in osteoclast surface, and cotreatment with OPG reduced osteoclast surface by 95%. OPG cotreatment had no effect on osteoblast surface in the vertebrae, suggesting a relatively selective inhibition of osteoclasts with OPG.
Despite the profound reduction in osteoclast surface observed at the end of the study, serum calcium was statistically elevated in OPG-treated rats at the 3 month point compared with that in vehicle-treated OVX rats. The significance and mechanism of this apparent calcemic response are currently unknown. Calcemic responses to OPG have not been previously reported in mice or rats, and in the current study serum calcium was normal in OPG-treated rats at all other time points. Furthermore, OPG cotherapy significantly inhibited the hypercalcemic responses associated with PTH treatment, so the paradoxical rise in serum calcium at a single time point is difficult to reconcile with the pharmacology of OPG.
In the tibia, after 5.5 months of treatment, combination therapy was associated with a more modest OPG-induced suppression of osteoclast surface combined with a PTH-induced increase in osteoblast surface that was unaffected by OPG cotreatment. Serum osteocalcin, a marker of osteoblast differentiation, was significantly elevated at all time points in PTH-treated rats. OPG cotherapy partially inhibited the osteocalcin response to PTH during the latter half of the treatment phase, presumably due to a coupled response of osteoblasts to the OPG-related decrease in osteoclast numbers. These responses predict that virtually all of the PTH-mediated osteoclast activity was eradicated by OPG, whereas OPG permitted some, but not all, of the PTH-mediated osteoblast activity. Validating this hypothesis would require assessment of bone formation and apposition rates at multiple skeletal sites throughout the treatment period. Regardless of the mechanism(s) involved, the net effect of these histological and biochemical changes was a significantly greater increase in vertebral and femoral BMD, tibial cancellous bone volume, and elastic modulus with OPG plus PTH compared with all other treatments. The histomorphometric data must be interpreted with caution, as the analysis was conducted at a single time point at the end of the study on 2-yr-old rats, 20.5 months after OVX. We have not assessed the temporal changes in bone histomorphometry, and it is likely that the osteoclast and osteoblast responses to OVX and treatments varied according to time and skeletal site.
OPG plus PTH was statistically superior to all other treatments at
increasing lumbar vertebral stiffness, maximum load, ultimate strength,
and elastic modulus as well as the elastic modulus of the femoral
midshaft. For the remaining comparisons, OPG plus PTH was at least as
effective as any other treatment, including PTH alone. It is difficult
to compare these results to other combination therapy studies, all of
which employed shorter periods of OVX-induced bone loss (<15 months)
and/or shorter durations of treatment (
5.5 months). In an OVX rat
study of comparable treatment duration (24 wk), the addition of E or
calcitonin to PTH treatment failed to improve the mechanical properties
of the lumbar vertebrae compared with PTH alone (5). In
studies with shorter treatment periods (5–15 wk), the combination of
PTH with E or with risedronate did not increase vertebral strength
(6) or femoral neck strength (4) compared
with the increases observed with PTH alone. In a related study,
risedronate (after 5 wk) and E (after 15 wk) actually blocked the
beneficial effects of PTH on the strength of the femoral shaft
(21). In an OVX rat study with a comparable duration of
OVX-induced bone loss (12 months), the addition of E, risedronate, or
calcitonin to PTH therapy provided no improvement in vertebral strength
compared with PTH treatment alone (13). It remains to be
determined whether other antiresorptive agents besides OPG could have
additive effects on bone strength in PTH-treated animals under the same
conditions as those in the present study. It is possible that dosing
regimens different from those used previously would reveal additive
effects of other antiresorptives with PTH.
In conclusion, we have demonstrated that PTH and OPG can each increase bone mass, BMD, and parameters mechanical strength in aged OVX rats. PTH as a monotherapy was clearly superior to OPG in these severely osteopenic rats. The combination of OPG plus PTH caused greater increases in BMD, cancellous bone volume, and parameters of mechanical strength compared with PTH alone. OPG also blocked much of the hypercalcemic effects of PTH, which suggests that OPG combination therapy may improve the therapeutic index of PTH by allowing more aggressive dosing of PTH with better control of hypercalcemia. These data provide an important proof of concept that combination therapies using appropriate antiresorptives and anabolic agents may represent a powerful approach to treating or reversing severe osteoporosis in humans.
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Acknowledgments |
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Footnotes |
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Received March 13, 2001.
Accepted for publication June 26, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, Sham-operated PBS-treated controls; •, vehicle-treated
OVX; 
, OPG-treated OVX; 
, PTH-treated OVX; 
, OPG- plus
PTH-treated OVX. *, Significant difference from vehicle-treated OVX
rats; #, significant difference from PTH-treated OVX rats (by
Tukey-Kramer test, P < 0.05).
