Comparative effects of teriparatide, denosumab, and combination therapy on peripheral compartmental bone density, microarchitecture, and estimated strength: the DATA-HRpQCT Study.
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ABSTRACT:
SUBMITTER: Tsai JN
PROVIDER: S-EPMC4396184 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
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Comparative effects of teriparatide, denosumab, and combination therapy on peripheral compartmental bone density, microarchitecture, and estimated strength: the DATA-HRpQCT Study.
Tsai Joy N JN Uihlein Alexander V AV Burnett-Bowie Sherri-Ann M SA Neer Robert M RM Zhu Yuli Y Derrico Nicholas N Lee Hang H Bouxsein Mary L ML Leder Benjamin Z BZ
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 20150101 1
Combined teriparatide and denosumab increases spine and hip bone mineral density more than either drug alone. The effect of this combination on skeletal microstructure and microarchitecture, however, is unknown. Because skeletal microstructure and microarchitecture are important components of skeletal integrity, we performed high-resolution peripheral quantitative computed tomography (HR-pQCT) assessments at the distal tibia and radius in postmenopausal osteoporotic women randomized to receive t ...[more]
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Project description:In postmenopausal osteoporosis, combining denosumab and teriparatide increases hip and spine bone mineral density more than either monotherapy.The objective of the study was to determine the effects of 2 years of combination therapy on bone microarchitecture and estimated strength.This was an open-label, randomized controlled trial.We performed high-resolution peripheral quantitative computed tomography at the distal tibia and radius in 94 postmenopausal osteoporotic women randomized to 2 years of teriparatide 20 ?g sc daily, denosumab 60 mg sc every 6 months, or both.Total volumetric bone mineral density (vBMD) at the radius and tibia, trabecular vBMD at the radius, and cortical vBMD at the tibia all increased more in the combination group than both monotherapy groups (P < .002 for all comparisons with combination). Cortical thickness at the tibia also increased more in the combination group (8.1% ± 4.3%) than both other groups (P < .001). Cortical porosity at both the radius and tibia increased progressively over the 24-month treatment period in the teriparatide group but was stable in both other groups (P < .001 teriparatide vs both other groups). Trabecular vBMD at the tibia increased similarly in all groups, whereas radius trabecular vBMD increased more in the combination group than the other groups (P < .01 for both comparisons). Finite element analysis-estimated strength improved or was maintained by all treatments at both the radius and tibia.Two years of combined teriparatide and denosumab improves bone microarchitecture and estimated strength more than the individual treatments, particularly in cortical bone. These findings suggest that this regimen may be beneficial in postmenopausal osteoporosis.
| S-EPMC4870854 | biostudies-literature
Project description:BackgroundTo gain insight into how teriparatide affects various bone health parameters, we assessed the effects of teriparatide treatment with use of standard DXA (dual x-ray absorptiometry) technology and two newer technologies, high-resolution MRI (magnetic resonance imaging) and finite element analysis of quantitative CT (computed tomography) scans.MethodsIn this phase-4, open-label study, postmenopausal women with severe osteoporosis received 20 μg/day of teriparatide. Assessments included (1) changes in areal BMD (bone mineral density) (in g/cm2) at the radius, spine, and hip on DXA, (2) changes in volumetric BMD (in mg/cm3) at the spine and hip on quantitative CT scans, (3) changes in bone microarchitecture at the radius on high-resolution MRI, (4) estimated changes in spine and hip strength according to finite element analysis of quantitative CT scans, (5) changes in bone turnover markers in serum, and (6) safety.ResultsThirty-five subjects were enrolled; thirty completed eighteen months and twenty-five completed an optional six-month extension. No significant changes were observed for the primary outcome, high-resolution MRI at the distal aspect of the radius. At month eighteen, the least-squares mean percentage change from baseline in total volumetric BMD at the spine was 10.05% (95% confidence interval [CI], 6.83% to 13.26%; p < 0.001), and estimated spine strength increased 17.43% (95% CI, 12.09% to 22.76%; p < 0.001). Total volumetric BMD at the hip increased 2.22% (95% CI, 0.37% to 4.06%; p = 0.021), and estimated hip strength increased 2.54% (95% CI, 0.06% to 5.01%; p = 0.045). Areal BMD increased at the lumbar spine and femoral neck, was unchanged for the total hip and at the distalmost aspect of the radius, and decreased at a point one-third of the distance between the wrist and elbow. Bone turnover markers increased at months three, six, and twenty-four (all p < 0.05). No unexpected adverse events were observed.ConclusionsHigh-resolution MRI failed to identify changes in bone microarchitecture at the distal aspect of the radius, a non-weight-bearing site that may not be suitable for assessing effects of an osteoanabolic agent. Teriparatide increased areal BMD at the spine and femoral neck and volumetric BMD at the spine and hip. Estimated vertebral and femoral strength also increased. These findings and increases in bone turnover markers through month twenty-four are consistent with the known osteoanabolic effect of teriparatide.Level of evidenceTherapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
| S-EPMC6948798 | biostudies-literature
Project description:CONTEXT:In the Denosumab and High-Dose Teriparatide Administration (DATA-HD) study, we reported that 15 months of combined high-dose (HD) teriparatide and denosumab increased mean areal bone mineral density (aBMD) at the hip and spine more than combined denosumab and standard-dose (SD) teriparatide. OBJECTIVE:In the current analysis, we compare the individual rates of aBMD response between the treatment groups. DESIGN:Single-site, open-label, randomized controlled trial in which postmenopausal women received either teriparatide 20-?g daily (SD) or 40-?g daily (HD) given months 0 through 9, overlapped with denosumab 60 mg, given months 3 through 15 (15 months' total duration). The proportion of participants in the SD and HD groups experiencing total hip, femoral neck, and lumbar spine aBMD gains of >3%, >6%, and >9% were compared. PARTICIPANTS:Postmenopausal women with osteoporosis completing all study visits (n = 60). MAIN OUTCOME MEASURE(S):aBMD (dual x-ray absorptiometry). RESULTS:At the end of the 15-month treatment period, a higher proportion of women in the HD group had aBMD increases >3% (83% vs. 58%, P = .037) and >6% (45% vs. 19%, P = .034) at the total hip, and >3% at the femoral neck (86% vs. 63%, P = .044). At the lumbar spine, >3% response rates were similar, whereas the >6% and >9% response rates were greater in the HD group (100% vs. 79%, P = .012 and 93% vs. 59%, P = .003, respectively). CONCLUSION:Compared with the SD regimen, more women treated with the HD regimen achieved clinically meaningful and rapid gains in hip and spine aBMD. These results suggest that this approach may provide unique benefits in the treatment of postmenopausal osteoporosis.
| S-EPMC7112977 | biostudies-literature
Project description:In postmenopausal women, 2?yr of combined teriparatide and denosumab increases bone mineral density more than either drug alone, and switching from either combination or teriparatide to denosumab for an additional 2?yr further increases bone mineral density. Conversely, switching from denosumab to teriparatide results in transient bone loss. The effects of these interventions on spine microarchitecture are unknown. In the DATA and DATA-Switch studies, 94 postmenopausal osteoporotic women were randomized to receive 24?mo of teriparatide (20?µg daily), denosumab (60?mg every 6?mo), or both. Then, women originally assigned to 24?mo of teriparatide received 24?mo of denosumab, whereas subjects originally randomized to 24?mo of denosumab received 24?mo of teriparatide. Subjects who received both drugs received an additional 24?mo of denosumab alone. Spine trabecular bone score (TBS, a gray-level textural assessment of bone microarchitecture) was measured blinded from treatment groups using images from 2-dimensional dual-energy X-ray absorptiometry spine scans at 0, 12, 24, 30, 36, and 48?mo in 65 women who had posterior-anterior spine dual-energy X-ray absorptiometry images suitable for TBS analysis. After 24?mo, TBS increased by 2.7?±?4.7% in the teriparatide group (p?=?0.009 vs baseline), by 1.8?±?5.0% in the denosumab group (p?=?0.118 vs baseline), and by 4.5?±?6.7% in the combination group (p?=?0.017 vs baseline), with no significant between-group differences. In the 6?mo after the treatments were switched (months 24-30), TBS continued to increase in the combination-to-denosumab and teriparatide-to-denosumab groups but decreased by -1.1?±?4.0% in the denosumab-to-teriparatide group (p?<?0.05 vs other groups). After 48?mo, compared to month 0, TBS increased by 5.1?±?5.8% in the teriparatide-to-denosumab group, by 3.6?±?4.2% in the denosumab-to-teriparatide group, and by 6.1?±?4.7% in the combination-to-denosumab group (p?<?0.001 vs baseline for all groups, p?=?not significant for between-group differences). Switching from teriparatide to denosumab also increased spine TBS. Conversely, switching from denosumab to teriparatide transiently degraded spine trabecular microarchitecture, the clinical consequences of which require further study.
| S-EPMC5673584 | biostudies-literature
Project description:BackgroundPatients with rheumatoid arthritis (RA) are at increased risk of fractures. Although their decline in bone mineral density (BMD) is well-established, data regarding the alterations in bone microarchitecture are limited. In this study, we aimed to evaluate bone microarchitecture, geometry, and volumetric BMD among patients with RA in mainland China using high-resolution peripheral quantitative computed tomography (HRpQCT).MethodsIn this cross-sectional study, patients with RA were recruited from the Peking Union Medical College Hospital site of the Chinese Registry of rhEumatoiD arthrITis (CREDIT). Each participant underwent HRpQCT scanning (Scanco XtremeCT II), thoracolumbar X-ray and dual-energy X-ray absorptiometry. The primary outcomes were HRpQCT-related measures at distal radius and tibia. Data regarding demographic features, RA-related characteristics, and history of fragility fractures were collected. Correlation between HRpQCT parameters and potentially related factors were analyzed using linear regression analysis. A group of age- and sex-matched healthy controls was included for comparison.ResultsA total of 81 patients with RA [69 women, aged 57.9 ± 8.7 years, disease duration 5.7 (IQR 1.4-11.2) years] and 81 matched healthy controls were included. Compared with controls, patients with RA had significantly larger bone area and lower total and trabecular vBMD at both the distal radius and tibia. Lower cortical bone thickness was also shown at the distal tibia. Among patients with RA, advanced age, low BMI, female sex, disease duration, and activity were associated with decreased vBMD and impaired bone microstructure. Female reproductive factors including menopause, late menarche, breast feeding, and early childbirth also showed negative correlation with these parameters. Compared to patients with RA without fractures, patients with fragility fractures (n = 11) showed lower trabecular and cortical vBMD, thinner cortical bone, impaired trabecular microstructure, and a trend of declined bone strength. Current glucocorticoid intake was related to decreased vBMD, trabecular number, increased trabecular separation, and inhomogeneity.ConclusionsIn this study, we observed alterations in bone mineral density, geometry, and microarchitecture among patients with RA compared to healthy individuals, which may impair bone strength and lead to increased risk of fractures. Both traditional risk factors for osteoporosis and RA-associated factors need to be considered in the assessment of the bone quality.
| S-EPMC8067377 | biostudies-literature
Project description:Daily and weekly administration of teriparatide (PTH1-34) reduces the risk of osteoporotic bone fractures. However, their effects on markers of bone formation and bone resorption differ. These results indicate that the dosing frequency of teriparatide may affect bone metabolism and bone structure, with different effects on bone strength. In the present study, to evaluate the dose-related effects of a low administration frequency of teriparatide on bone status, we investigated the effects of three-times-weekly administration of teriparatide (1.1, 5.6, or 28.2 µg/kg) for 12 months on bone parameters, including bone metabolism markers, bone mineral density (BMD), micro-computed tomography, and bone strength, using 6-month-old ovariectomized (OVX) rats. Three-times-weekly administration of teriparatide dose-dependently increased the BMD of the lumbar vertebra and femur in OVX rats, and increased serum osteocalcin (a marker of bone formation), but not type I collagen C-telopeptide (a marker of bone resorption). The trabecular number and thickness increased in the vertebrae and femur, as in prior reports of daily teriparatide administration in OVX rats. Cortical thickness increased only toward the endocortical side of the femur, unlike with daily administration. Bone strength of the vertebrae and proximal and shaft of the femur was correlated with the changes in BMD and bone structure. These results demonstrate the effects of low frequency, intermittent administration of teriparatide on the biomechanical, and microstructural properties of bone in OVX rats.
| S-EPMC4491365 | biostudies-literature
Project description:BackgroundWhile changes in biochemical markers of bone turnover (BTM) have been reported to predict changes in bone mineral density (BMD), the relationship between changes in BMD and BTMs with combined antiresorptive/anabolic therapy is unknown.MethodsIn the DATA study, 94 postmenopausal osteoporotic women (ages 51-91) received either teriparatide 20-mcg SC daily, denosumab 60-mg SC every 6months, or both for 2years. Pearson's correlation coefficients (R) were calculated to determine the relationship between baseline and early changes in BTMs (as well as serum sclerostin) and 2-year changes in BMD.ResultsIn women receiving teriparatide, baseline BTMs did not correlate with 2-year BMD changes though 12-month increases in osteocalcin and P1NP were associated with 2-year increases in spine BMD. In women receiving denosumab, spine and hip BMD gains correlated with both baseline and changes in P1NP and C-telopeptide. In women receiving combined teriparatide/denosumab, while both baseline and decreases in P1NP were associated with spine BMD gains, distal radius increases were associated with less CTX suppression. Neither baseline nor changes in serum sclerostin correlated with BMD in any treatment group.Summary and conclusionsIn women treated with teriparatide or denosumab, early BTM changes (increases and decreases, respectively) predict 2-year BMD gains, especially at the spine. In women treated with combined teriparatide/denosumab therapy, BMD increases at the distal radius were associated with less suppression of bone turnover. These results suggest that efficacy of combination therapy at cortical sites such as the radius may depend on residual bone remodeling despite RANKL inhibition.
| S-EPMC6941193 | biostudies-literature
Project description:BackgroundIn the Denosumab and Teriparatide Administration (DATA) study, we showed that denosumab fully inhibits teriparatide-induced bone resorption while allowing for continued teriparatide-induced bone formation, resulting in larger increases in hip and spine bone mineral density (BMD) than with either drug alone. We aimed to assess whether administration of denosumab with high dose teriparatide would stimulate larger increases in bone mass than those observed in the DATA study.MethodsDATA-HD was an open-label, randomised, controlled phase 4 trial done at Massachusetts General Hospital. Eligible women were postmenopausal women (at least 36 months since last menses or since hysterectomy with a follicle-stimulating hormone concentration of ≥40 U/L) with osteoporosis. Participants were randomly assigned (1:1) to receive teriparatide 20 μg (standard dose) or 40 μg (high dose) daily via subcutaneous injection for 9 months. At 3 months, both groups were started on denosumab 60 mg every 6 months via subcutaneous injection for 12 months. Areal BMD (aBMD) was measured at 0, 3, 9, and 15 months. Treatment was given open label, but outcome assessors were masked. The primary endpoint was percentage change from baseline in spine areal BMD (aBMD) at 15 months. Women who completed at least one study visit after baseline were included in the modified intention-to-treat analysis. Safety was assessed in all randomly assigned participants. This study is registered with ClinicalTrials.gov, number NCT02176382.FindingsBetween Oct 15, 2014, and June 10, 2016, 269 women were assessed for eligibility. 76 participants were randomly assigned to 20 μg teriparatide (n=39) or 40 μg teriparatide (n=37), of whom 69 completed at least one post-baseline visit. At 15 months, mean spine aBMD had increased to a significantly greater extent in the 40 μg group (17·5% [SD 6·0] increase) than the 20 μg group (9·5% [3·2]; difference 8·1%, 95% CI 5·5 to 10·6, p<0·0001). Mean femoral neck aBMD had also increased to a greater extent in the 40 μg group (6·8% [SD 4·1] increase) than the 20 μg group (4·3% [3·7]; difference 2·5%, 0·5 to 4·5, p=0·04), as did mean total hip aBMD (40 μg group, 6·1% [3·4] increase; 20 μg group, 3·9% [2·9] increase; difference 2·2%, 0·6 to 3·8, p<0·0001). 30 (77%) of 39 participants in the 20 μg group and 29 (78%) of 37 participants in the 40 μg group had an adverse event, and seven (18%) and two (5%) patients had serious adverse events. The most frequent adverse events were joint pain (15 [38%]), muscle cramp (15 [38%]), and fatigue (12 [31%]) in the 20 μg group group and fatigue (14 [38%]), nausea (16 [43%]), and joint pain (17 [46%]) in the 40 μg group. No deaths were reported.InterpretationCombined treatment with teriparatide 40 μg and denosumab increases spine and hip BMD more than standard combination therapy. This large and rapid increase in bone mass suggest that this high dose regimen might provide a method of restoring skeletal integrity in patients with osteoporosis.FundingNational Institutes of Health and the Dart Foundation.
| S-EPMC6980341 | biostudies-literature
Project description:To investigate the link between bone alteration and micro- and macro-vascular disease in patients with systemic sclerosis (SSc).33 SSc patients were included. In univariate analysis, low values of cortical vBMD were significantly associated with a low DBI at the 2nd finger (p = 0.004) and at the 4th (p = 0.002) and with severe capillaroscopic score (p = 0.008). In multivariate analyses, low cortical vBMD was associated with a low DBI at the 4th finger, age and severe capillaroscopic score (adjusted R2 = 0.58; p = < 0.001). Low cortical thickness was associated with a low DBI at the 4th finger, severe capillaroscopic score and age (adjusted R2 = 0.49, p = < 0.001).Our study findings showed an association between micro- and macro-vessel damage and altered microarchitectural indices at the radius in SSc.We performed a pilot study in female patients with SSc. Microvascular disease was assessed by the capillaroscopic score of Cutolo. Macrovascular involvement was measured by digito-brachial pressure index (DBI) on laser-Doppler at the 2nd and 4th finger. Volumetric bone mineral density (vBMD) and bone microarchitecture involvement were analysed by High-Resolution peripheral Quantitative Computed Tomography (HRpQCT) at the distal radius.
| S-EPMC6047669 | biostudies-other
Project description:BackgroundAfrican Americans (AA) have more favorable bone density and microarchitecture compared to Whites (W), which may explain their observed lower fracture rates. Obesity has deleterious effects on bone microarchitecture and strength estimates and is associated with an increase in fracture risk. Adolescence and young adulthood are periods of active bone accrual and also periods characterized by an increasing prevalence of obesity. The effect of obesity on the relationship between race and bone parameters remains unclear, particularly in youth.ObjectiveTo assess differences in BMD, bone microarchitecture and strength estimates in AA and W adolescents and young adults with moderate to severe obesity. We hypothesized that racial differences in bone endpoints in lean youth would also be noted in youth with moderate to severe obesity.MethodsWe evaluated 24 AA and 48 W adolescent and young adults with a mean age of 18.2 ± 2.4 years and a median body mass index (BMI) of 44.8 (40.5-49.4) kg/m2 who underwent dual energy X-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HRpQCT), extended cortical analysis (ECA) and micro-finite element analysis (FEA) to obtain measures of volumetric bone mineral density (vBMD), bone geometry, microarchitecture, and strength estimates at the distal radius and tibia.ResultsWe found no differences between AA and W for total fat and lean mass, and areal BMD Z-scores (p > 0.05 for all). At the distal radius, no significant differences were detected in vBMD, bone geometry or microarchitecture (p > 0.05 for all); however, stiffness and failure load were higher in the AA group (p = 0.031 and 0.047 respectively). At the distal tibia, cortical vBMD was higher in AA vs. W (p = 0.012), while trabecular number was higher and trabecular separation lower in W vs. AA (p ≤ 0.028). Stiffness and failure load trended higher in AA vs. W (p = 0.052 and p = 0.048, respectively). Groups did not differ for any other bone parameter (p > 0.05).ConclusionRacial differences in bone endpoints appear to be less marked in those with moderate to severe obesity, suggesting that effects of obesity may blunt the effect of race on bone endpoints.
| S-EPMC7423738 | biostudies-literature