Differential effects of abaloparatide and teriparatide on hip cortical volumetric BMD by DXA-based 3D modeling

Abaloparatide (ABL) is a human parathyroid hormone–related peptide (PTHrP)(1-34) analog that stimulates bone formation, resulting in significant increases in areal bone mineral density (aBMD) and reductions in fracture incidence after 18 months of daily subcutaneous administration in postmenopausal women with osteoporosis [1‐3]. Teriparatide (TPTD), or PTH(1-34) which binds the same PTH type 1 receptor (PTH1R), also stimulates bone formation, but results in significantly smaller increases in BMD at the total hip, femur neck, and distal radius than ABL at the US Food and Drug Administration (FDA)–approved clinical doses [1, 2, 4, 5]. These differences may be related to their relative affinities to the RG and R0 conformations of the PTH1R [1], resulting in differential activation of pathways that regulate bone formation and bone resorption [6]. Lesser stimulation of serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) with ABL relative to TPTD in the ACTIVE trial suggested that bone resorption may mediate these BMD differences, which were greater at sites with more cortical bone, such as the femoral neck and radius [2, 4].

PTH is an important regulator of calcium homeostasis, and pathologic elevations in PTH due to renal disease result in bone loss and hypercalcemia, associated with increased bone resorption [7]. Although daily TPTD provides a positive balance between bone formation and resorption and increases BMD at most skeletal sites, BMD has been shown to decrease at purely cortical sites [8]. Unlike its effects on trabecular or endocortical surfaces, where TPTD-stimulated “over-filling” of each bone multicellular unit is part of its anabolic effect, the increased rate of remodeling within the cortex has been associated with increased cortical porosity and decreased cortical volumetric BMD (vBMD) in both monkeys [9, 10] and humans [11]. The intracortical effects of ABL have not been thoroughly examined in humans; however, cortical vBMD and cortical porosity did not change with ABL treatment for up to 16 months in ovariectomized primates [12]. In addition, unlike TPTD, ABL did not lead to significant decreases in aBMD versus placebo at the purely cortical 1/3 distal radius in humans [4], suggesting a fundamental difference in the cortical effects of ABL.

Further clinical examination of the specific effects of ABL on cortical versus trabecular bone have been limited, as quantitative computed tomography (QCT) was not performed at the hip in the ACTIVE trial. Recently, three-dimensional (3D) modeling methods were developed to estimate cortical and trabecular measurements from two-dimensional (2D) dual-energy X-ray absorptiometry (DXA) scans. At the proximal femur, these 3D-DXA measurements were shown to correlate well with QCT results [13], and provided insights into the compartmental effects of various osteoporosis therapeutics including TPTD [14]. Therefore, to better understand and compare the effects of ABL and TPTD on the cortical and trabecular compartments of the proximal femur over 18 months, hip DXA images were subjected to 3D modeling in a subset of randomly selected patients from the ACTIVE trial.

The 3D-DXA cohort was well balanced across groups for age, DXA BMD, and prior fracture history (Table 1). The baseline demographics in the cohort were consistent with the intent-to-treat (ITT) population reported in the overall ACTIVE study [2].

3D modeling methods using DXA images provide a unique opportunity to revisit the 2D-DXA data collected in osteoporosis therapeutic studies, to predict whether DXA aBMD changes were driven by effects in the trabecular or cortical compartments. Although both ABL and TPTD stimulate bone formation through the same receptor, in the ACTIVE trial, ABL increased aBMD at the total hip, femur neck, and distal radius to a significantly greater extent at 18 months [2, 4]. The current results indicate that this difference corresponded to significant increases in 3D-DXA-based cortical vBMD and sBMD with ABL relative to TPTD, while trabecular vBMD and cortical thickness were both increased to a similar extent. Furthermore, the differential effect of TPTD on cortical vBMD may be related to its inverse relationship with serum biomarkers of bone turnover, a relationship that was not present with ABL.

The current data are consistent with a previous 3D-DXA study that examined the effects of alendronate, denosumab, and TPTD over a 24-month period [14]. In that study, the antiresorptive agents consistently increased cortical bone indices in the proximal femur, while TPTD simultaneously increased cortical thickness and decreased cortical vBMD. Decreased cortical vBMD with TPTD has been reported in both animal [9] and human [16] studies, an effect attributed to increased intracortical remodeling. In humans, the decrease in cortical vBMD with TPTD has been associated with both increased porosity [11] and decreased cortical tissue mineralization observed in iliac biopsies [17, 18]. Cortical porosity increases with TPTD have been hypothesized to be transient and this parameter is often not significantly increased in iliac crest biopsies after up to 2 years of treatment [19], despite continued elevations in the intracortical remodeling rate [20]. However, cortical porosity has been shown to expand with TPTD over time at clinically relevant cortical sites by HRpQCT (high-resolution peripheral QCT), with increases at the radius of 19% and 32% at 6 and 18 months, respectively, corresponding to declines in cortical vBMD of − 2.0% and − 2.4% [11]. Similar observations were found after 12 and 24 months of TPTD [21]. Decreases in cortical vBMD with TPTD have also been reported at the femur neck by QCT both in treatment-naïve patients [22] and, to a greater extent, in alendronate-pretreated patients [23, 24].

In the current study in treatment-naïve patients, TPTD had a neutral effect on cortical vBMD, while ABL resulted in a significant increase from baseline. The positive effect of ABL on cortical vBMD may reflect a reversal of age-related [25] and menopause-related [26] trabecularization of the cortex through bone apposition. As both ABL and TPTD resulted in similar increases in cortical thickness reflecting appositional growth, much of the difference in cortical vBMD may be due to increased cortical porosity rather than to lower tissue mineralization of newly formed bone. Nevertheless, conclusions cannot be made regarding the relative impact of ABL and TPTD on cortical porosity from the results in this study, and it is likely that the differences in serum CTX levels at the end of the study between ABL and TPTD may reflect some differential effects on tissue mineralization.

Cortical porosity (as estimated from hip QCT scans) has been identified as a risk factor for nonvertebral fragility fractures in postmenopausal women, independent of both FRAX (Fracture Risk Assessment Tool) score and hip BMD [27]. Thus, changes in porosity and vBMD should be considered in the context of their impact on bone strength. Previous studies using finite element modeling have demonstrated that TPTD-mediated reductions in femur neck cortical vBMD prevented significant improvements in proximal femur strength in patients treated for up to 18 months [23, 28]. No data on estimated strength indices have been generated in ABL clinical studies to date. Further analysis to estimate changes in strength in the current study may provide additional insights into the mechanisms by which ABL and TPTD affect bone fragility.

3D-DXA demonstrated the degree to which cortical and trabecular regions may be affected by anabolic therapy and how these changes are reflected in DXA BMD. Both ABL and TPTD increased vBMD in the trabecular compartment to a similar degree, with increases that were twice those for total hip aBMD over an 18-month period. These results are consistent with the greater trabecular vBMD increases reported previously for TPTD by QCT of the proximal femur [22, 29], and reflect the robust anabolism that can occur in trabecular bone with PTH1R agonism. Cortical thickness was increased to a similar though lesser degree in both the ABL and TPTD groups, and only ABL significantly increased cortical vBMD from baseline.

Correlation analyses demonstrated that trabecular vBMD was a better surrogate for DXA total hip aBMD than cortical endpoints suggesting that, despite the importance of cortical bone to proximal femur strength [30], DXA BMD may underestimate the changes that occur in this compartment with anabolic therapy.

Differences in the degree to which ABL and TPTD stimulate bone resorption, and thus bone remodeling, are fundamental to the initial selection of ABL as a PTHrP analog with lower calcium-mobilizing potential [31]. These differences were reflected in lesser peaks and greater temporal declines in serum CTX with ABL versus TPTD, with similar gradual declines in serum PINP with continued ABL reflecting the decreasing remodeling rate. In the current study, the changes in serum biomarkers with TPTD were inversely correlated with cortical vBMD and cortical sBMD, further supporting that higher levels of bone resulted in lower cortical bone density and thus lower bone mass. These results suggest that persistent elevations in bone turnover may be a limiting factor in cortical bone mass accrual with TPTD. That no such relationship existed for ABL suggests that intracortical remodeling was less of a factor in determining cortical vBMD, particularly at month 18 when serum CTX was not elevated above baseline compared to a 40% increase above baseline for TPTD (by geometric means) [2]. In contrast, changes in serum biomarkers at month 3 were positively correlated with month 18 trabecular vBMD and cortical thickness in the ABL group, but not in the TPTD group. Similar observations were reported for lumbar aBMD changes in ACTIVE [32], suggesting that early serum biomarker responses are a better predictor of the later bone mass increases with ABL compared to TPTD.

Limitations in this study include the use of a subset of patients instead of the entire cohort from ACTIVE. However, at 250 patients per group, this subset represents the largest treatment study reported to date for 3D-DXA, and the baseline characteristics and hip BMD response in this subset were consistent with the overall patient population in ACTIVE. The 3D modeling approach itself is a relatively new technique and has several limitations as described elsewhere [14]. The software was originally developed to mimic QCT endpoints from DXA images in a treatment-naïve population and measurements correlate well between the two methods. However, the effects of therapeutics on this relationship are unknown. QCT-based delineation of cortical thickness and cortical vBMD can vary by imaging technique, making these endpoints less consistent across studies. However, their product, cortical sBMD, may be more precise and continues to reflect the differences in cortical effects between ABL and TPTD. A final limitation of the study is that data are provided across the entire proximal femur, which contains subregions that are both predominantly trabecular (intertrochanteric) and cortical (femur shaft). Region-specific analysis of treatment-related changes in the trabecular and cortical parameters remain to be determined.

In summary, 18 months of ABL administration was associated with significant improvements in 3D-DXA-based vBMD in both cortical and cancellous compartments of the proximal femur. Although TPTD increased cortical thickness and trabecular vBMD to a similar extent as ABL, cortical vBMD remained at baseline levels. These results suggest that the greater increase in hip areal BMD and lesser serum CTX response with ABL may reflect a lower stimulation of intracortical remodeling than TPTD.