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Keywords:

  • RONACALERET;
  • CALCIUM-SENSING RECEPTOR ANTAGONIST;
  • PARATHYROID HORMONE

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Intermittent injections of parathyroid hormone have osteoanabolic effects that increase bone mineral density (BMD). Ronacaleret is an orally administered calcium-sensing receptor antagonist that stimulates endogenous parathyroid hormone release from the parathyroid glands. Our objective was to compare the effects of ronacaleret and teriparatide on volumetric BMD (vBMD) measured by quantitative computed tomography (QCT). We conducted a randomized, placebo-controlled, dose-ranging trial at 45 academic centers with 31 sites participating in the substudy. Patients included 569 postmenopausal women with low bone mineral density; vBMD was assessed at the spine and hip in a subset of 314 women. Patients were treated for up to 12 months with open-label teriparatide 20 µg subcutaneously once daily or randomly assigned in a double-blind manner to ronacaleret 100 mg, 200 mg, 300 mg, or 400 mg once daily, alendronate 70 mg once weekly, or matching placebos. Ronacaleret increased spine integral (0.49% to 3.9%) and trabecular (1.8% to 13.3%) vBMD compared with baseline, although the increments were at least twofold lower than that attained with teriparatide (14.8% and 24.4%, respectively) but similar or superior to that attained with alendronate (5.0% and 4.9%, respectively). There were small non-dose-dependent decreases in integral vBMD of the proximal femur with ronacaleret (−0.1 to −0.8%) compared with increases in the teriparatide (3.9%) and alendronate (2.7%) arms. Parathyroid hormone (PTH) elevations with ronacaleret were prolonged relative to that seen historically with teriparatide. Ronacaleret preferentially increased vBMD of trabecular bone that is counterbalanced by small decreases in BMD at cortical sites. The relative preservation of trabecular bone and loss at cortical sites are consistent with the induction of mild hyperparathyroidism with ronacaleret therapy. © 2012 American Society for Bone and Mineral Research


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Most forms of osteoporosis are the result of bone loss owing to an imbalance in bone remodeling, where bone resorption exceeds bone formation. Many current therapies for osteoporosis aim to reverse excessive bone resorption.1 Bisphosphonates suppress bone resorption, reduce the risk of fracture, and increase BMD, but they have little effect on improving trabecular bone architecture.2, 3 In contrast, once-daily injections of teriparatide and parathyroid hormone (PTH) (1-84) increase bone density by stimulating bone formation.4, 5 Specifically, PTH increases the number and activity of osteoblasts, increases trabecular thickness, improves trabecular connectivity, and increases cortical thickness and bone size.6–8 Teriparatide increases BMD of the lumbar spine, an area that is rich in trabecular bone, and reduces vertebral fractures. Teriparatide has little effect in areal BMD (aBMD) at the distal radius, which consists mainly of cortical bone.

aBMD measured by dual-energy X-ray absorptiometry (DXA) only measures integral (total) BMD. Moreover, at the spine, the posterior processes and parts of the transverse processes contribute to the BMD measurement. In addition, aortic calcifications, disc-space narrowing, and hypertrophic bony changes, which are frequent in elderly subjects, may falsely increase aBMD. Quantitative computed tomography (QCT) is more specific9, 10 and can separately assess vBMD of cortical and trabecular bone compartments plus various aspects of bone structure and strength.11 In the spine, the QCT measurements comprise the vertebral body only and are free of artifacts from aortic calcifications.

Ronacaleret is an orally active, potent, and selective calcium-sensing receptor (CaSR) antagonist (calcilytic) that was under investigation as a possible treatment for postmenopausal osteoporosis. Short-term antagonism of the calcium-sensing receptor in the parathyroid gland results in transient release of endogenous PTH.12 Oral administration of ronacaleret to animal species and humans induces transient increases in PTH.13

The primary purpose of this study was to identify the most suitable dose of ronacaleret for further development as an orally administered treatment for postmenopausal osteoporosis based on indices of BMD and biomarkers of bone turnover. The purpose of the substudy presented here was to assess the efficacy of ronacaleret on changes in spine and hip BMD as measured by QCT.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Study design

The design of the main study has been reported previously.14 A total of 569 women were offered open-label teriparatide or were randomly assigned by a computerized system to one of six treatment regimens (ronacaleret 100 mg, 200 mg, 300 mg, 400 mg, alendronate, or placebo) and followed for 12 months. The open-label teriparatide group was designed to be smaller (n = 20) and subjects qualified if they met the criteria for teriparatide administration as per the country-specific label. These qualified subjects were first offered open-label, injectable teriparatide, so this cohort filled first. If the subject refused teriparatide or if the cohort was filled, then the subject was randomized to one of the doses of ronacaleret. Of these 569 women, 314 participated in the QCT substudy. All women received daily doses of calcium (500 to 660 mg elemental) and vitamin D (at least 400 IU). The study was terminated in a phased manner after the results of a planned interim analysis at 6 months showed that no dose of ronacaleret significantly improved aBMD of the lumbar spine over that attained with placebo. At the time of study termination, all ongoing patients on open-label teriparatide had completed 12 months of treatment, and all ongoing randomized patients (approximately one-quarter) had completed at least 10 months of treatment. At the time of study phaseout, patients completed one additional visit with measurement of BMD by DXA and QCT, which occurred between months 10 and 12. Data from patients at months 10 and 12 are pooled and designated as “months 10 to 12” in this article.

Study participants

The QCT substudy recruited women who had been postmenopausal for at least 5 years at 31 preselected sites in 11 countries. Women who were enrolled in the main study (T-score ≤ −2.5 [if no prevalent vertebral fracture] or ≤ −2.0 [if one prevalent vertebral fracture] and > −4.0 at either the femoral neck, total hip, trochanter, or lumbar spine) were eligible for the substudy provided they did not have any metal implants in either hip that would cause tomographic reconstruction artifacts and consequently distort the BMD quantification. The Institutional Review Board at each center approved the study protocol, and all women provided separate written informed consent before participation in the QCT substudy.

Efficacy outcomes

Areal BMD (in g/cm2) was assessed by DXA (Hologic [Waltham, MA, USA] and GE Lunar [Madison, WI, USA] densitometers). Areal BMD was measured at the posteroanterior lumbar spine (L1–L4) and the hip (femoral neck, trochanter, and total hip regions) at baseline and at months 6 and 10 to 12.

Volumetric BMD (in g/cm3) was measured at the spine (L1 and L2) and the hip at baseline and at months 10 to 12 at preselected centers. Integral, cortical, and trabecular BMD of the total hip and the sub volumes of interest (VOIs) of the femoral neck and trochanter regions were assessed. The spine integral and trabecular BMD were measured for the total vertebral bodies of L1 and L2. In addition, trabecular BMD was determined in the center of the vertebral bodies using the classical 1-cm-thick elliptical15 or the Osteo VOI.16 Cortical bone was only measured in the 1-cm-thick mid-vertebral VOI. Medical Imaging Analysis Framework (MIAF) Femur and MIAF Spine17, 18 developed at the Institute of Medical Physics (IMP; Erlangen, Germany) were used for the analysis, which was performed by a central laboratory (Synarc, Hamburg, Germany, in collaboration with IMP).

Serum was assayed for PTH (Pacific Biometrics, Seattle, WA, USA) in a subset of randomized patients (15 per treatment arm) at predose and at 1, 2, 3, 4, and 8 hours postdose at months 6 and 12. Whole PTH was measured using the Immuno Radiometric assay (Scantibodies Laboratory Inc., Santee, CA, USA), which measures both the C-terminal and N-terminal PTH, resulting in measurement of only PTH(1-84). Intact PTH was measured using the Diagnostic Products Corporation (Los Angeles, CA, USA) Immulite 2000, a solid-phase, two-site chemiluminescent enzyme-labeled immunometric assay that measures 100% intact PTH and 45% 7-84 C-terminal PTH.

Safety assessments

An independent safety review committee consisting of sponsor personnel who were not involved in the conduct of the study provided ongoing unblinded review of the albumin-adjusted serum calcium levels. Patients were questioned at each visit about adverse events, which were classified by system organ class and preferred term.

Statistical analyses

The statistical analyses methods for the primary and secondary endpoints have been reported previously.14 The efficacy comparisons of interest in the substudy were between each dose of ronacaleret and placebo in percentage change from baseline in lumbar spine vBMD at 12 months. This was analyzed by an analysis of covariance (ANCOVA) that adjusted for treatment, baseline BMD, and geographic region. This ANCOVA modeling exercise was also repeated on integrated vBMD at the femoral neck. No adjustments for multiplicity were made. Teriparatide patients were excluded from the models because these patients were not randomized and were disproportionately represented. In Table 2, the placebo contrasts refer to estimates of the difference in treatment effects between ronacaleret and placebo.

Given the exploratory nature of this substudy, all other QCT endpoints were summarized with summary statistics (mean and standard error of the mean). Summary statistics are reported in the tables and have been used to create the graphics.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Disposition and baseline characteristics

The demography and clinical characteristics of the patients who participated in the QCT substudy are presented in Table 1 and are similar to those of the parent study.14 Among the 314 women who consented to participate in the QCT substudy, the ages ranged from 45 to 79 years and 82% were white. The mean age at menopause was 48 years (range 20 to 64 years).

Table 1. Baseline Demographic and Clinical Characteristics of Patients Participating in the QCT Substudy
CharacteristicRONA 100 mgRONA 200 mgRONA 300 mgRONA 400 mgTERIALNPlacebo
(n = 63)(n = 57)(n = 60)(n = 58)(n = 40)(n = 62)(n = 60)
  1. RONA = ronacaleret; TERI = teriparatide; ALN = alendronate; BMD = bone mineral density; 25OHD = 25-hydroxyvitamin D; PTH = intact parathyroid hormone; Ca = albumin-adjusted serum calcium levels.

  2. Data are expressed as means ± SD. The body mass index is the weight in kilograms divided by the square of the height in meters. The T-score is the number of SD above or below the mean plateau value of BMD in young adults.

Age (years)64.5 ± 8.0163.9 ± 7.1964.3 ± 7.0665.2 ± 7.4762.9 ± 5.7865 ± 7.5063.05 ± 6.7
Age at menopause (years)46.2 ± 5.8547.7 ± 6.4647.4 ± 6.4047.3 ± 6.1649.0 ± 3.8947.3 ± 5.5847.9 ± 5.45
Body mass index24.6 ± 3.7324.7 ± 4.1325.3 ± 3.9624.8 ± 3.6524.8 ± 3.3725.0 ± 3.2624.6 ± 3.98
Fractures No. (%)22 (35)19 (33)29 (48)23 (40)20 (50)24 (39)29 (48)
Lumbar spine BMD (T-score)−2.59 ± 0.82−2.64 ± 0.69−2.61 ± 0.77−2.49 ± 0.86−2.83 ± 0.56−2.38 ± 0.74−2.59 ± 0.82
Hip BMD (T-score)−1.53 ± 0.71−1.77 ± 0.69−1.54 ± 0.67−1.85 ± 0.75−1.67 ± 0.72−1.69 ± 0.78−1.58 ± 0.64
Serum 25OHD, (nmol/L)104.59 ± 113.6196.46 ± 76.32120.53 ± 138.76100.953 ± 85.4696.93 ± 96.4294.48 ± 65.08113.66 ± 115.37
PTH (ng/L)35.97 ± 11.7037.05 ± 13.2637.22 ± 11.9538.53 ± 12.5941.79 ± 11.2136.85 ± 14.0138.12 ± 12.35
Albumin adjusted Ca (mmol/L)2.29 ± 0.082.29 ± 0.082.28 ± 0.072.29 ± 0.072.28 ± 0.082.28 ± 0.082.30 ± 0.07

Areal and volumetric bone mineral density

The percentage change from baseline in aBMD at months 10 to 12 for those patients who participated in the QCT substudy were consistent with those reported previously for the parent study (Table 2).14 There were modest increases in aBMD of the lumbar spine as measured by DXA with all doses of ronacaleret compared with larger increases after 10 to 12 months of treatment with teriparatide or alendronate. There were small decreases in hip aBMD with all doses of ronacaleret after 10 to 12 months of therapy compared with increases after teriparatide or alendronate therapy. Similarly, there was a loss in aBMD at the femoral neck and trochanter after 10 to 12 months of treatment with ronacaleret compared with little or no gain in the placebo arm. This contrasts with increases observed in these hip parameters in both the teriparatide and alendronate arms.

Table 2. Volumetric and Areal Bone Mineral Density Percentage Change From Baseline at Months 10 to 12
 RONA 100 mgRONA 200 mgRONA 300 mgRONA 400 mgTERIALNPlacebo
  • RONA = ronacaleret; TERI = teriparatide; ALN = alendronate; vBMD = volumetric bone mineral density; VOI = volumes of interest; aBMD = areal bone mineral density; LS = lumbar spine; TH = total hip; FN = femoral neck; TR = trochanter.

  • a

    Least squares means (SE) for randomized arms, mean (SE) for TERI; p values and confidence intervals are unadjusted.

  • b

    Mean (SE) reported for all arms.

 n = 50n = 43n = 43n = 41n = 36n = 49n = 42
Integral spinal vBMDa0.49 (0.74)2.29 (0.81)2.99 (0.81)3.90 (0.82)14.80 (1.45)4.57 (0.74)−1.50 (0.81)
 Placebo contrast1.99 (0.92)3.78 (0.95)4.48 (0.95)5.40 (0.96)   
 95% CI(0.18, 3.80)(1.91, 5.65)(2.61, 6.35)(3.51, 7.29)   
 p value0.031<0.001<0.001<0.001   
 n = 47n = 40n = 39n = 37n = 26n = 45n = 41
Femur integral vBMDa−0.28 (0.43)−1.07 (0.48)−0.91 (0.48)−0.52 (0.49)3.92 (0.43)2.53 (0.52)−0.15 (0.47)
 Placebo contrast−0.13 (0.53)−0.92 (0.55)−0.76 (0.56)−0.37 (0.57)   
 95% CI(−1.18, 0.92)(−2.01, 0.17)(−1.86, 0.33)(−1.50, 0.75)   
 p value0.8100.0990.1720.512   
Spinal vBMDbn = 50n = 43n = 43n = 41n = 36n = 49n = 42
Total vertebra trabecular VOI BMD (mg/cm3)1.67 (1.02)5.81 (1.27)8.52 (1.37)11.4 (2.00)23.82 (2.44)4.97 (0.92)−2.46 (0.71)
Hip vBMDbn = 47n = 40n = 39n = 37n = 26n = 45n = 41
Femur trabecular VOI BMD (mg/cm3)−0.40 (0.99)−2.16 (1.17)1.16 (0.81)2.81 (1.35)13.19 (1.76)3.05 (0.88)−0.36 (0.86)
Femur cortical VOI BMD (mg/cm3)−0.32 (0.42)−1.46 (0.44)−1.06 (0.41)−1.79 (0.49)0.22 (0.52)2.44 (0.47)1.11 (0.63)
Lumbar spine aBMDbn = 51n = 47n = 46n = 42n = 38n = 55n = 47
Total LS aBMD (g/cm2)0.96 (0.56)2.03 (0.37)1.78 (0.57)1.81 (0.56)9.20 (0.99)4.44 (0.50)0.30 (0.49)
Hip aBMDbn = 50n = 46n = 46n = 42n = 38n = 54n = 47
Total hip aBMD (g/cm2)−0.69 (0.35)−0.47 (0.35)−1.17 (0.34)−1.35 (0.34)2.55 (0.45)3.05 (0.33)0.37 (0.34)
FN aBMD (g/cm2)−0.50 (0.39)−0.96 (0.49)−0.79 (0.49)−0.95 (0.39)2.34 (0.47)2.27 (0.38)−0.51 (0.51)
TR aBMD (g/cm2)−0.39 (0.64)0.01 (0.56)−1.29 (0.48)−1.22 (0.52)3.16 (0.65)4.46 (0.57)0.63 (0.57)

QCT was used to measure vBMD of trabecular and cortical bone at the spine and hip. There was a dose-dependent increase in vertebral integral vBMD of the lumbar spine after 10 to 12 months of therapy with ronacaleret (Fig. 1A). The increase observed with the highest ronacaleret dose (4.8%) was comparable to that observed with alendronate (5.0%) but lower than that attained with teriparatide (14.8%). Vertebral trabecular vBMD increased in a dose-dependent manner with ronacaleret; the increases attained with ronacaleret doses of 200 mg and higher (6.2% to 13.3%) were greater than that achieved with alendronate (4.9%), but the increase with the highest ronacaleret 400 mg dose (13.3%) was almost twofold less than that attained with teriparatide (24.4%) (Fig. 1B). A similar pattern of gains in mid-osteo trabecular and mid-elliptical trabecular vBMD was observed as that of vertebral trabecular bone (Table 2). Both teriparatide and alendronate increased mid-vertebral cortical vBMD compared with more modest non-dose-dependent increments with ronacaleret (Fig. 1C).

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Figure 1. Percentage change from baseline after 10 to 12 months of treatment in vertebral integral spine BMD (A); vertebral spine trabecular vBMD (B); vertebral cortical spine vBMD (C); total hip integral vBMD (D); total hip trabecular vBMD (E); and total hip cortical vBMD (F). Data are presented as mean ± standard error. ALN = alendronate; PBO = placebo; RONA = ronacaleret; TER = teriparatide; vBMD = volumetric bone mineral density. Spine vBMD treatment groups: placebo (n = 42), ronacaleret 100 mg (n = 50), ronacaleret 200 mg (n = 43), ronacaleret 300 mg (n = 43), ronacaleret 400 mg (n = 41), alendronate (n = 49), or teriparatide (n = 36). Total hip vBMD treatment groups: placebo (n = 41), ronacaleret 100 mg (n = 47), ronacaleret 200 mg (n = 40), ronacaleret 300 mg (n = 39), ronacaleret 400 mg (n = 37), alendronate (n = 45), or teriparatide (n = 26).

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There were modest decreases in total hip integral vBMD with all doses of ronacaleret compared with increases in both the teriparatide and alendronate groups (Fig. 1D and Table 1). Total hip trabecular vBMD was increased from baseline with the two highest doses of ronacaleret (300 mg and 400 mg); the increment in total hip trabecular vBMD with the ronacaleret 400 mg dose was comparable to that attained with alendronate but was almost fivefold lower than that measured after teriparatide administration (Fig. 1E). The largest increase in total hip cortical vBMD was observed in the alendronate arm, with a slight increase in the placebo and teriparatide arms and small decreases in the ronacaleret arms (Fig. 1F). A similar pattern of small increments in trabecular vBMD of the femoral neck and trochanter was observed with the two highest doses of ronacaleret (300 mg and 400 mg) that were comparable to that attained with alendronate but four- to fivefold lower than the gains observed in vBMD with teriparatide (Table 1).

Parathyroid hormone

Concentrations of whole PTH at months 10 to 12 increased rapidly with all doses of ronacaleret, reaching maximal concentrations by 1 hour postdose (first assessment) and remaining above the upper limit of normal (reference range 5.0 to 39.0 pg/mL) to 4 hours postdose before declining slowly thereafter (Fig. 2). A similar whole PTH profile was observed after 6 months of therapy with ronacaleret (data not shown). As expected, neither alendronate nor placebo had any effect on whole PTH levels. A similar profile for intact PTH was observed.14

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Figure 2. Median pharmacodynamic (PD) concentrations of whole parathyroid hormone after treatment with placebo, ronacaleret 100 mg, ronacaleret 200 mg, ronacaleret 300 mg, ronacaleret 400 mg, and alendronate at month 12. ALN = alendronate; PBO = placebo; RONA = ronacaleret.

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Safety

The safety of orally administered ronacaleret in postmenopausal women with low BMD has been reported previously.14 Ronacaleret increased trough (predose) levels of albumin-adjusted serum calcium concentrations in a dose-dependent manner, and the mean trough concentrations remained elevated above baseline values throughout the duration of treatment but remained within the upper limit of normal; this compared with more modest predose elevations in the teriparatide arm or slight decreases in the alendronate arm.14 The incidences of adverse events (AEs), withdrawals resulting from AEs, and incidence of patients with any confirmed aBMD loss at the spine and hip within prespecified ranges were similar in the placebo and ronacaleret arms.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

In this study, we compared the effects of ronacaleret with teriparatide, a bone-formation agent, and alendronate, a potent inhibitor of bone resorption, on aBMD and vBMD in postmenopausal women with low BMD. The effects of ronacaleret on aBMD and markers of bone turnover have been reported previously.14 All active treatments increased aBMD and vBMD of the lumbar spine compared with placebo. Ronacaleret increased vertebral integral vBMD of the lumbar spine in a dose-dependent manner after 10 to 12 months of therapy but was associated with small non-dose-dependent decreases in vBMD of the hip similar to that described for aBMD. However, whereas the effects of ronacaleret on aBMD were not as pronounced as that attained with the bisphosphonate alendronate or the osteoanabolic agent teriparatide, the increments obtained in lumbar spine integral vBMD were comparable to that observed with alendronate, although still almost threefold lower than that attained with teriparatide.

All available therapies for osteoporosis increase BMD, but the effects are typically greatest at skeletal sites rich in trabecular bone compared with those sites that are predominantly cortical in nature. Ronacaleret has disparate effects on trabecular and cortical bone. Ronacaleret increased vertebral trabecular, mid-osteo trabecular, and mid-elliptical trabecular vBMD of the lumbar spine in a dose-dependent manner. These increments in trabecular vBMD with the highest dose of ronacaleret were superior to alendronate but twofold lower than the increments observed with teriparatide. The two highest ronacaleret doses also increased trabecular vBMD of the trochanter, femoral neck, and total hip, but the increments were modest compared with that attained with teriparatide, an anabolic agent. In contrast to the effects of ronacaleret on trabecular vBMD at the hip, there were small decreases in hip cortical vBMD at the total hip, trochanter, and femoral neck. Likewise, there were small decreases in femoral neck vBMD with teriparatide and little effect on total hip cortical BMD but slight increments in trochanter cortical BMD. Alendronate increased trabecular and cortical vBMD of all hip parameters. Both teriparatide and ronacaleret led to marked gains in vertebral trabecular vBMD that were greater than that attained with alendronate. The increases in vertebral trabecular vBMD with teriparatide and alendronate were similar to that reported previously, with increases in the order of 19% with teriparatide compared with 3.8% with alendronate. 19, 20 Changes in hip vBMD with all active treatments were smaller in magnitude than at the lumbar spine. Ronacaleret 400 mg, teriparatide, and alendronate all increased trabecular vBMD of the total hip, femoral neck, and trochanter, but the increments observed with teriparatide were substantially greater than that observed with either ronacaleret 400 mg or alendronate. In contrast, cortical vBMD increased more with alendronate than with ronacaleret or teriparatide. Similar trends have been observed in other studies.20 Compared with alendronate, the smaller increases in cortical vBMD of the hip but greater increases in cortical volume with teriparatide is thought to reflect the presence of more endosteal bone formation with PTH that is less mineralized.19 Additional effects on cortical bone after administration of teriparatide include increased periosteal circumference and polar cross-sectional moment of inertia, suggesting an increased mechanical strength in spite of little increase in cortical BMD.21 Without these measurements in the ronacaleret groups, it is difficult to assess the full impact of treatment on bone strength.

This study also shows the superiority of QCT over DXA in elucidating the anatomic mechanisms of treatment actions. The differential effects of ronacaleret, alendronate, and teriparatide on cortical and trabecular BMD are interesting. The integral BMD changes in the hip are similar when measured by DXA and QCT. In contrast, the percentage increases in spine integral BMD are much higher when measured by QCT than those measured by DXA. One reason for this is the inclusion of the substantially cortical BMD of the posterior elements in the aBMD measured by DXA. In addition, degenerative hypertrophic changes and aortic calcification, which are frequent in a population of this age, falsely increase aBMD with the result that percentage changes, which are mainly caused by trabecular BMD, are understated.

Therefore, it is not surprising that aBMD measured by DXA appears to be relatively insensitive for the quantification of the treatment effects of either ronacaleret or teriparatide. However, QCT has modest spatial resolution. Consequently, the so-called cortical VOI in the spine contains significant amounts of subcortical and even trabecular bone. Thus, cortical BMD results in the spine are affected by the high endosteal trabecular BMD change, and one could speculate that the pure cortical changes in the spine are probably much closer to those observed in the hip. With respect to the hip, it must be mentioned that the treatment period was short, and BMD changes in the hip are slower than those in the spine. This effect can perhaps partly explain why, for example, the trabecular BMD changes in the hip were about 50% lower than those in the spine. A longer treatment period would be required to confirm this hypothesis.

The safety of ronacaleret in postmenopausal women with low BMD has been reported previously.14 Ronacaleret increased trough (predose) serum calcium concentrations in a dose-dependent manner throughout the study, and levels returned to pretreatment levels after discontinuation of dosing.14 The transient rise in serum calcium with teriparatide was similar to that reported in other controlled studies with teriparatide.4

In the previous study, we proposed that the changes in bone turnover markers, serum calcium and BMD by DXA, are consistent with the induction of mild primary hyperparathyroidism after administration of ronacaleret.14 The pharmacokinetics also support this hypothesis, as the AUC with ronacaleret for PTH is larger than that seen after administration of teriparatide (Fig. 2).13 Prior work in animal models demonstrated the narrowness of the anabolic window.22 Sprague-Dawley rats were administered continuous teriparatide or intermittent teriparatide for 1 or 2 hours for 6 days. There were striking differences in the cancellous bone architecture between the animals treated for 1 versus 2 hours per day for 6 days compared with continuous administration for the same time period. Bone area/tissue area, trabecular number, and bone-formation rates were lower in the animals treated for longer duration. Osteoclasts were also increased in the 2-hour treatment group compared with the animals who only received 1 hour of treatment, indicating an increase in bone remodeling in the group treated for 2 hours. The narrowness of the anabolic window is confirmed with these data.

Additional support for the hypothesis that ronacaleret induced mild primary hyperparathyroidism comes from the QCT data. The effects of teriparatide on cortical and cancellous bone are well established, and these data are consistent with published literature.4, 6, 7 The actions of PTH as a therapy for osteoporosis as well as in the disorder primary hyperparathyroidism include differential effects at trabecular and cortical sites.4, 19–21 In primary hyperparathyroidism, postmenopausal women are protected against loss of cancellous bone.23–25 In a study that compared postmenopausal normal, osteoporotic, and women with primary hyperparathyroidism, bone histomorphometry was evaluated. Bone-formation rates were higher, cancellous bone volume was normal, and indices of trabecular connectivity were normal or elevated in postmenopausal women with hyperparathyroidism in spite of a higher rate of bone turnover. In this study, cancellous bone was not only preserved but also increased to the same level as that seen in postmenopausal women who were treated with the antiresorptive agent, alendronate.

The preservation of cancellous bone as assessed by QCT and the pharmacokinetics lend additional support and suggest that ronacaleret induced a mild primary hyperparathyroidism.

Disclosures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

LF, CED, GC, and DNG are employees of GlaxoSmithKline. TF has participated in advisory activities for GlaxoSmithKline. KE, an employee of Synarc Inc., served as a consultant and participated in the speakers bureau and in advisory activities for GlaxoSmithKline. HG has participated in speakers bureaus and advisory activities for GlaxoSmithKline, Synarc Inc., Roche, Merck, Amgen, Lilly, Servier, Bristol-Myers Squibb, and Genentech, and owns stock or royalties of Synarc Inc.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Funding for this study was provided by GlaxoSmithKline (Clinicaltrials.gov identifier NCT00471237).

The authors acknowledge the following employees of GlaxoSmithKline for their contributions: Sarah Patricia Brannan, DPhil, for editorial support for the manuscript (development of early drafts, collating author comments, fact-checking, and collating author comments), and Kenneth Pomerantz, PhD, for management of manuscript development. The authors also acknowledge Lee Kempster and Min Zhao of MediTech Media Ltd. (London, UK) for copyediting and graphic services, respectively; these services were funded by GlaxoSmithKline.

Participating substudy centers: Argentina: Zulema Man (Buenos Aires), Carlos Mautalen (Buenos Aires), Jose Zanchetta (Buenos Aires); Australia: Peter Ebeling (Victoria); Geoffrey Nicholson (Victoria), Philip Sambrook (New South Wales); Ego Seeman, (Victoria); Belgium: Gilbert Donders (Tienen); Jean-Marc Kaufman (Gent); Angela Kvasz (Liege); Denmark: Christence Stubbe-Teglbjaerg (Ballerup); Germany: Georg P Dahmen (Hamburg); Dieter Felsenberg (Berlin); Thorsten Hennigs (Frankfurt); Alex Holst (Hamburg); Andreas Kurth (Frankfurt); Reiner Lehmann (Berlin); Gert Foss (Berlin); Andreas Wagenitz (Berlin); Hong Kong: Annie Kung, Chung Ping; Korea: Yoon-Sok Chung (Suwon); Sung Kil Lin (Seoul); Mexico: Lilia Cortez-Perez Barriga-Trevilla (Tlalpan); Norway: Johan Halse (Oslo); Kjetil Høye, (Hamar); Erik Snorre Øfjord (Bergen); Poland: Andrzej Sawicki (Warszawa); Anna Sidoworowicz-Bialynicka (Wroclaw); Cezary Strugala (Grudziadz); Russian Federation: Svetlana Rodionova (Moscow); Ludmila Rozhinskaya (Moscow); South Africa: Tobias de Villiers (Parow); Graham Ellis (Cape Town); Stanley Lipschitz (Johannesburg); Spain: Luis Carreño (Madrid); Juan Antonio García Meijide (Santiago de Composteta); Juan Jesús Gómez Reino Carnota (Santiago de Compostela); Emilio Martín Mola (Madrid); Ingrid Möller (Barcelona); Xavier Nogués i Solan (Barcelona); United States: Michael Bolognese (Bethesda, MD); Chad Deal (Cleveland, OH); Vernon Hershberger (Akron, OH); Alan Kivitz (Duncansville, PA); Michael McClung (Portland, OR); Richard Weinstein (Walnut Creek, CA); Grattan Woodson (Decatur, GA).

Authors' roles: All the authors were fully involved in manuscript development and assume responsibility for the direction and content. All the authors meet the International Committee for Medical Journal Editors criteria for authorship.

References

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  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References
  10. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
jbmr_554_sm_SupplTab1.doc41KSupplementary Table 1
jbmr_554_sm_chinese_translation.pdf781KSupplementary Information: Chinese Translation

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