Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover

INTRODUCTION: Teriparatide is a bone formation agent that increases bone turnover and mass, resulting in an increase in bone strength and a decrease in fracture risk. METHODS: The primary purpose of this analysis was to evaluate the association between pretreatment bone turnover marker (BTM) concentrations and the absolute and relative fracture risks after adjusting for baseline femoral neck BMD, number of prevalent vertebral fractures, and age. Because femoral neck BMD is commonly attained in the assessment of patients at risk for osteoporosis, we examined the ability of a multivariate assessment including pretreatment BTM concentration and femoral neck BMD to predict future fracture risk after adjusting for the number of prevalent vertebral fractures. We examined data from the Fracture Prevention Trial, a study designed to determine the effect of teriparatide 20 mcg/day and teriparatide 40 mcg/day on vertebral and nonvertebral fracture risk in postmenopausal women with osteoporosis. BTM were analyzed in two subsets of women within the Fracture Prevention Trial, and included serum bone-specific alkaline phosphatase (BSAP), serum carboxy-terminal extension peptide of procollagen type I (PICP), serum amino-terminal extension peptide of procollagen type I (PINP), urinary free deoxypyridinoline (DPD), and urinary N-terminal telopeptide (NTX). RESULTS: Teriparatide significantly reduced the risk of fracture [four BTM subset (n = 520), placebo = 14.3%, teriparatide = 5.8%, P < 0.05; PINP subset (n = 771), placebo = 17.7%, teriparatide = 5.5%, P < 0.05]. Subjects with the highest pretreatment BTM concentrations had the greatest fracture risk. Teriparatide-mediated absolute risk reduction was greatest for women with high pretreatment bone turnover; however, the relative fracture risk reduction was independent of pretreatment bone turnover. After adjusting for pretreatment BTM and number of prevalent vertebral fractures, baseline femoral neck BMD was not a significant predictor of fracture risk. CONCLUSION: Teriparatide-mediated relative fracture risk reduction was independent of pretreatment bone turnover, demonstrating that this therapy offers clinical benefit to patients across a range of disease severity.     

Change in Trabecular Bone Score (TBS) With Antiresorptive Therapy Does Not Predict Fracture in Women: The Manitoba BMD Cohort

Bone mineral density (BMD) and trabecular bone score (TBS), along with additional clinical risk factors, can be used to identify individuals at high fracture risk. Whether change in TBS in untreated or treated women independently affects fracture risk is unclear. Using the Manitoba (Canada) DXA Registry containing all BMD results for the population we identified 9044 women age ≥40 years with two consecutive DXA scans and who were not receiving osteoporosis treatment at baseline (baseline mean age 62 ± 10 years). We examined BMD and TBS change, osteoporosis treatment, and incident major osteoporotic fractures (MOFs) for each individual. Over a mean of 7.7 years follow‐up, 770 women developed an incident MOF. During the interval between the two DXA scans (mean, 4.1 years), 5083 women initiated osteoporosis treatment (bisphosphonate use 80%) whereas 3961 women did not receive any osteoporosis treatment. Larger gains in both BMD and TBS were seen in women with greater adherence to osteoporosis medication (p for trend <0.001), and the magnitude of the increase was consistently greater for BMD than for TBS. Among treated women there was greater antifracture effect for each SD increase in total hip BMD change (fracture decrease 20%; 95% CI, 13% to 26%; p < 0.001), femoral neck BMD change (19%; 95% CI, 12% to 26%; p < 0.001), and lumbar spine BMD change (9%; 95% CI, 0% to 17%; p = 0.049). In contrast, change in TBS did not predict fractures in women who initiated osteoporosis treatment (p = 0.10). Among untreated women neither change in BMD or TBS predicted fractures. We conclude that, unlike antiresorptive treatment–related changes in BMD, change in lumbar spine TBS is not a useful indicator of fracture risk irrespective of osteoporosis treatment. © 2016 American Society for Bone and Mineral Research.     

Assessing the effect of baseline status of serum bone turnover markers and vitamin D levels on efficacy of teriparatide 20 μg/day administered subcutaneously in Japanese patients with osteoporosis

In this previously reported multicenter study, teriparatide 20 μg/day was administered to elderly Japanese subjects (93 % female; median age 70 years) with osteoporosis and at high risk of fracture during a 12-month, randomized, double-blind, placebo-controlled period, which was followed by a 12 month treatment period in which all subjects received open-label teriparatide. Subjects were randomized 2:1 to teriparatide versus placebo (teriparatide n = 137, placebo-teriparatide n = 70). This was an exploratory analysis to determine whether the baseline status of serum bone turnover markers (BTMs) and vitamin D levels affect the efficacy of teriparatide at 20 μg/day. The BTMs included were type I procollagen N-terminal pro-peptide (P1NP) and type I collagen cross-linked C-telopeptide (CTX). Changes in BMD were analyzed by subgroups: (1) tertile subgroups of BTM; (2) BTM determined by the upper limit of normal; and (3) level of vitamin D. Teriparatide increased lumbar spine BMD in all subgroups by 10 % or more through 24 months. Subgroups with higher baseline BTM levels had greater mean percent changes of lumbar spine BMD through 24 months. The baseline status of vitamin D sufficiency did not impact the mean percent change of lumbar spine BMD through 24 months. Results of this study suggest that clinically significant increases in BMD can be achieved in patients receiving teriparatide regardless of baseline BTM or vitamin D levels. Additionally, when vitamin D is coadministered, vitamin D insufficiency would not be expected to affect the overall efficacy of teriparatide.     

Teriparatide Reduces Bone Microdamage Accumulation in Postmenopausal Women Previously Treated With Alendronate

Suppression of bone turnover by bisphosphonates is associated with increased bone microdamage accumulation in animal models. Our objective was to study the effects of teriparatide treatment on changes in microdamage accumulation at the iliac crest in previously treatment‐naïve patients or in those switched from alendronate to teriparatide. Sixty‐six postmenopausal women with osteoporosis (mean age, 68.0 yr; and mean BMD T‐score of ?2.8 at lumbar spine and ?1.7 at total hip; 62% with prevalent fractures) entered this prospective, nonrandomized study and started with 24‐mo 20 μg/d subcutaneous teriparatide treatment in monotherapy: 38 patients stopped previous alendronate treatment (10 mg/d or 70 mg/wk for a mean duration of 63.6 mo) and switched to teriparatide, whereas 28 were previously treatment naïve. Thirty‐one paired biopsies with two intact cortices were collected and analyzed for microstructure and microdamage accumulation at baseline and after 24 mo of teriparatide administration. After 24 mo of teriparatide treatment, crack density (Cr.Dn), crack surface density (Cr.S.Dn), and crack length (Cr.Le) were decreased in previously alendronate‐treated patients, whereas only Cr.Le was reduced in former treatment‐naïve patients. Patients with lower initial femoral neck BMD also showed a higher reduction of microdamage accumulation. Better bone microarchitecture correlated positively, whereas bone turnover markers and age did not correlate with reduced microdamage accumulation on teriparatide. In conclusion, teriparatide reduces microdamage accumulation in the iliac crest of patients previously treated with alendronate. There is insufficient evidence to suggest that age or bone turnover would be associated with this change.     

Assessment of Bone Microarchitecture in Postmenopausal Women on Long‐Term Bisphosphonate Therapy With Atypical Fractures of the Femur

Reports of atypical femoral fractures (AFFs) in patients receiving long‐ term bisphosphonate therapy have raised concerns regarding the genesis of this rare event. Using high‐resolution peripheral quantitative computed tomography (HR‐pQCT), we conducted a study to evaluate bone microarchitecture in patients who had suffered an AFF during long‐term bisphosphonate treatment. The aim of our study was to evaluate if bone microarchitecture assessment could help explain the pathophysiology of these fractures. We compared bone volumetric density and microarchitectural parameters measured by HR‐pQCT in the radius and tibia in 20 patients with AFFs with 35 postmenopausal women who had also received long‐term bisphosphonate treatment but had not experienced AFFs, and with 54 treatment‐naive postmenopausal women. Control groups were similar in age, body mass index (BMI), and bone mineral density (BMD). Mean age of the 20 patients with AFFs was 71 years, mean lumbar spine T‐score was ?2.2, and mean femoral neck T‐score was ?2. Mean time on bisphosphonate treatment was 10.9 years (range, 5–20 years). None of the patients had other conditions associated with AFFs such as rheumatoid arthritis, diabetes or glucocorticoid use. There were no statistically significant differences in any of the parameters measured by HR‐pQCT between postmenopausal women with or without treatment history and with or without history of atypical fractures. We could not find any distinctive microarchitecture features in the peripheral skeleton of women who had suffered an atypical fracture of the femur while receiving bisphosphonate treatment. This suggests that risk of developing an atypical fracture is not related to bone microarchitecture deterioration. Our results indicate that there may be other individual factors predisposing to atypical fractures in patients treated with bisphosphonates, and that those are independent of bone microarchitecture. In the future, identification of those factors could help prevent and understand the complex physiopathology of these rare events. © 2014 American Society for Bone and Mineral Research.     

Bone biopsy findings and correlation with clinical,radiological, and biochemical parameters in children with fractures

In children the diagnosis of osteoporosis is based on fracture history and DXA‐derived BMD. Bone biopsy is an invasive but accurate method for studying bone characteristics. In this study we evaluated bone biopsy findings and their correlation with noninvasive measures of bone health. Transiliac bone biopsy was performed on 24 consecutive children (17 boys, median age 12 years, range 6 to 16 years) evaluated for suspected primary osteoporosis. Biopsy findings were compared with normative data and correlated with clinical, radiological, biochemical, and densitometric findings. The patients had sustained altogether 64 nonvertebral fractures (median 2.5) from low‐ or moderate‐energy traumas, and 14 patients (58%) had vertebral fractures. The median lumbar spine BMD Z‐score was ?1.2 (range ?3.1 to +1.0). Hypovitaminosis D was present in 58%. Histomorphometry showed low bone volume in 7 patients and normal bone volume in 17. Bone turnover was high in 7, low in 7, and normal in 10 patients. Histomorphometric findings correlated poorly with fracture history, serum bone turnover markers, and DXA findings. Vitamin D deficiency and low lumbar BMD were associated with high bone turnover in the biopsy. These findings underscore the difficulties in diagnosing pediatric osteoporosis. Bone histomorphometry gives additional information and may be useful when considering bisphosphonate treatment in children with suspected primary osteoporosis. © 2011 American Society for Bone and Mineral Research     

Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density

Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 μg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a −0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (−4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Teriparatide increases bone mineral density in a man with osteoporosis pseudoglioma

Osteoporosis Pseudoglioma (OPPG) is characterized by severe juvenile-onset osteoporosis and ocular abnormalities. It is caused by one of several inactivating mutations in LRP5, a gene importantly involved in bone formation. The objective of this study was to evaluate the efficacy of teriparatide in a young man with OPPG. The subject of this case report is a 19-year-old man with congenital blindness and low trauma fractures because of OPPG. A 2-year course of teriparatide, 20 μg/day, was initiated after a 6-year course of intravenous pamidronate infusions, the latter 3 years of which had minimal effects on bone mineral density (BMD). Measurements in serum were made of C-terminal telopeptide of type I collagen (CTX), N-terminal propeptide of type I collagen (P1NP), total and ionized calcium, phosphate, uric acid, complete blood count, and renal and liver function tests. Urinary calcium/creatinine ratio was determined. BMD was measured by DXA yearly. BMD increased by 9.7% in lumbar spine and 10.2% in right femur hip. CTX rose early, peaking in month 3, followed by an increase in P1NP, peaking in month 9. Both indices returned to baseline by month 24. The increase in CTX followed by P1NP is an unusual time course when teriparatide is used to treat osteoporosis but may be typical of low bone turnover states. There were no adverse events. In a patient with OPPG, teriparatide markedly increased BMD in the lumbar spine and femur hip.     

Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: A three‐year study

The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual‐energy X‐ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean ± SD) were similar between groups in terms of age, 76.8 ± 5.0 years; body mass index (BMI), 24.5 ± 3.6 kg/m²; TBS, 1.178 ± 0.1 but for LS T‐score (ZOL–2.9 ± 1.5 versus PLB–2.1 ± 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus–0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once‐yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years. © 2013 American Society for Bone and Mineral Research.     

Efficacy of Zoledronic Acid in Maintaining Areal and Volumetric Bone Density After Combined Denosumab and Teriparatide Administration: DATA-HD Study Extension

Combined teriparatide and denosumab rapidly and substantially increases bone mineral density (BMD) at all anatomic sites. Discontinuation of denosumab however, results in high-turnover bone loss and increased fracture risk. The optimal way to prevent this bone loss remains undefined. This study is a preplanned extension of the DATA-HD study, where postmenopausal women with osteoporosis were randomized to receive 9 months of either 20 μg or 40 μg of teriparatide daily overlapping with denosumab (60 mg administered at months 3 and 9). At the completion of this 15-month study, women were invited to enroll in the DATA-HD Extension where they received a single dose of zoledronic acid (5 mg) 24 to 35 weeks after the last denosumab dose. Areal BMD and bone turnover markers were measured at month 27 and 42 (12 and 27 months after zoledronic acid, respectively) and spine and hip volumetric bone density by quantitative CT was measured at month 42. Fifty-three women enrolled in the DATA-HD Extension. At the femoral neck and total hip, the mean 5.6% and 5.1% gains in BMD achieved from month 0 to 15 were maintained both 12 and 27 months after zoledronic acid administration. At the spine, the mean 13.6% gain in BMD achieved from month 0 to 15 was maintained for the first 12 months but modestly decreased thereafter, resulting in a 3.0% reduction (95% CI, −4.0% to −2.0%, p < .0001) 27 months after zoledronic acid. The pattern of BMD changes between months 15 and 42 were qualitatively similar in the 20-μg and 40-μg groups. A single dose of zoledronic acid effectively maintains the large and rapid total hip and femoral neck BMD increases achieved with combination teriparatide/denosumab therapy for at least 27 months following the transition. Spine BMD was also largely, though not fully, maintained during this period. These data suggest that the DATA-HD Extension regimen may be an effective strategy in the long-term management of patients at high risk of fragility fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Trabecular Bone Score and Hip Structural Analysis in Patients With Atypical Femur Fractures

Bisphosphonate use has declined dramatically in recent years, partly because of fear of rare side effects like atypical femur fractures (AFFs). It is therefore desirable to have a diagnostic method to identify those at risk of AFF to prevent this serious complication. We compared trabecular microarchitecture and hip geometry between 30 patients with AFF and 141 controls of similar age and sex, using bisphosphonates. Trabecular bone score (TBS) and hip structural analysis (HSA) were used to assess trabecular microarchitecture and macroscopic hip geometry from dual-energy X-ray absorptiometry images of the lumbar spine and hip, respectively. General characteristics, TBS, and HSA were compared between patients with AFF and controls using Student's t tests and chi-square statistics. Associations between AFF and TBS and femur geometric characteristics by HSA were adjusted for sex, age, height, weight, ethnicity, duration of bisphosphonate use, and glucocorticoid use. Additionally, the analysis of TBS was adjusted for lumbar spine bone mineral density and the time difference between dual-energy X-ray absorptiometry scanning and the diagnosis of AFF. Patients with AFF had significantly higher body mass index than controls, had used bisphosphonates longer, and glucocorticoids and proton pump inhibitors more frequently. Sex-specific T-score was significantly higher in patients with AFF at the lumbar spine (p?=?0.004), but not at the femoral neck (p?=?0.190) after adjustment for age, height, and weight. TBS did not differ significantly between patients with AFF and controls. Neither neck shaft angle nor any geometric variables at the femoral shaft measured by HSA differed between patients with AFF and controls. At the narrow neck, patients with AFF had lower buckling ratio and higher centroid position, consistent with a lower risk of classical fragility hip fractures. The findings at narrow neck and higher bone mineral density might be explained by the fact that the majority of patients with AFF used bisphosphonates to prevent glucocorticoid-induced osteoporosis. Based on our results, TBS and HSA do not appear to have value in detecting patients at risk of AFF.     

Post-fracture Risk Assessment: Target the Centrally Sited Fractures First! A Substudy of NoFRACT

The location of osteoporotic fragility fractures adds crucial information to post-fracture risk estimation. Triaging patients according to fracture site for secondary fracture prevention can therefore be of interest to prioritize patients considering the high imminent fracture risk. The objectives of this cross-sectional study were therefore to explore potential differences between central (vertebral, hip, proximal humerus, pelvis) and peripheral (forearm, ankle, other) fractures. This substudy of the Norwegian Capture the Fracture Initiative (NoFRACT) included 495 women and 119 men ≥50 years with fragility fractures. They had bone mineral density (BMD) of the femoral neck, total hip, and lumbar spine assessed using dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS) calculated, concomitantly vertebral fracture assessment (VFA) with semiquantitative grading of vertebral fractures (SQ1–SQ3), and a questionnaire concerning risk factors for fractures was answered. Patients with central fractures exhibited lower BMD of the femoral neck (765 versus 827 mg/cm²), total hip (800 versus 876 mg/cm²), and lumbar spine (1024 versus 1062 mg/cm²); lower mean TBS (1.24 versus 1.28); and a higher proportion of SQ1-SQ3 fractures (52.0% versus 27.7%), SQ2–SQ3 fractures (36.8% versus 13.4%), and SQ3 fractures (21.5% versus 2.2%) than patients with peripheral fractures (all p < 0.05). All analyses were adjusted for sex, age, and body mass index (BMI); and the analyses of TBS and SQ1–SQ3 fracture prevalence was additionally adjusted for BMD). In conclusion, patients with central fragility fractures revealed lower femoral neck BMD, lower TBS, and higher prevalence of vertebral fractures on VFA than the patients with peripheral fractures. This suggests that patients with central fragility fractures exhibit more severe deterioration of bone structure, translating into a higher risk of subsequent fragility fractures and therefore they should get the highest priority in secondary fracture prevention, although attention to peripheral fractures should still not be diminished. © 2019 American Society for Bone and Mineral Research. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.     

Comparative effects of teriparatide and risedronate in glucocorticoid‐induced osteoporosis in men: 18‐month results of the EuroGIOPs trial

Data on treatment of glucocorticoid‐induced osteoporosis (GIO) in men are scarce. We performed a randomized, open‐label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T‐score ≤ –1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L₁–L₃) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high‐resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X‐ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18‐month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE‐derived strength than risedronate.     

Postmenopausal osteoporosis treatment with antiresorptives: effects of discontinuation or long-term continuation on bone turnover and fracture risk--a perspective

Osteoporosis may be a lifelong condition. Robust data regarding the efficacy and safety of both long-term osteoporosis therapy and therapy discontinuation are therefore important. A paucity of clinical trial data regarding the long-term antifracture efficacy of osteoporosis therapies necessitates the use of surrogate endpoints in discussions surrounding long-term use and/or discontinuation. Long-term treatment (beyond 3-4 years) may produce further increases in bone mineral density (BMD) or BMD stability, depending on the specific treatment and the skeletal site. Bisphosphonates, when discontinued, are associated with a prolonged reduction in bone turnover markers (BTMs), with a very gradual increase to pretreatment levels within 3 to 60 months of treatment cessation, depending on the bisphosphonate used and the prior duration of therapy. In contrast, with nonbisphosphonate antiresorptive agents, such as estrogen and denosumab, BTMs rebound to above pretreatment values within months of discontinuation. The pattern of BTM change is generally mirrored by a more or less rapid decrease in BMD. Although the prolonged effect of some bisphosphonates on BTMs and BMD may contribute to residual benefit on bone strength, it may also raise safety concerns. Adequately powered postdiscontinuation fracture studies and conclusive evidence on maintenance or loss of fracture benefit is lacking for bisphosphonates. Similarly, the effects of rapid reversal of bone turnover upon discontinuation of denosumab on fracture risk remain unknown. Ideally, studies evaluating the effects of long-term treatment and treatment discontinuation should be designed to provide head-to-head "offset" data between bisphosphonates and nonbisphosphonate antiresorptive agents. In the absence of this, a clinical recommendation for physicians may be to periodically assess the benefits/risks of continuation versus discontinuation versus alternative management strategies.     

Comparative effects of teriparatide and ibandronate on spine bone mineral density (BMD) and microarchitecture (TBS) in postmenopausal women with osteoporosis: a 2-year open-label study

Summary

Treatment effects over 2 years of teriparatide vs. ibandronate in postmenopausal women with osteoporosis were compared using lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). Teriparatide induced larger increases in BMD and TBS compared to ibandronate, suggesting a more pronounced effect on bone microarchitecture of the bone anabolic drug.

Introduction

The trabecular bone score (TBS) is an index of bone microarchitecture, independent of bone mineral density (BMD), calculated from anteroposterior spine dual X-ray absorptiometry (DXA) scans. The potential role of TBS for monitoring treatment response with bone-active substances is not established. The aim of this study was to compare the effects of recombinant human 1–34 parathyroid hormone (teriparatide) and the bisphosphonate ibandronate (IBN), on lumbar spine (LS) BMD and TBS in postmenopausal women with osteoporosis.

Methods

Two patient groups with matched age, body mass index (BMI), and baseline LS BMD, treated with either daily subcutaneous teriparatide (N?=?65) or quarterly intravenous IBN (N?=?122) during 2 years and with available LS BMD measurements at baseline and 2 years after treatment initiation were compared.

Results

Baseline characteristics (overall mean ± SD) were similar between groups in terms of age 67.9?±?7.4 years, body mass index 23.8?±?3.8 kg/m², BMD L1–L4 0.741?±?0.100 g/cm², and TBS 1.208?±?0.100. Over 24 months, teriparatide induced a significantly larger increase in LS BMD and TBS than IBN (+7.6 %?±?6.3 vs. +2.9 %?±?3.3 and +4.3 %?±?6.6 vs. +0.3 %?±?4.1, respectively; P?<?0.0001 for both). LS BMD and TBS were only weakly correlated at baseline (r ²?=?0.04) with no correlation between the changes in BMD and TBS over 24 months.

Conclusions

In postmenopausal women with osteoporosis, a 2-year treatment with teriparatide led to a significantly larger increase in LS BMD and TBS than IBN, suggesting that teriparatide had more pronounced effects on bone microarchitecture than IBN.     

Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism

Patients with adrenal incidentalomas (AIs) and subclinical hypercortisolism (SH) have increased risk of fracture independent of bone mineral density (BMD) and possibly due to reduced bone quality. The trabecular bone score (TBS) has been proposed as a index of bone microarchitecture. The aim of the study was to investigate TBS in AI. In 102 AI patients, SH was diagnosed in the presence of at least two of the following: (1) urinary free cortisol >70 µg/24 h (193.1 nmol/L); (2) cortisol after 1‐mg dexamethasone suppression test (1‐mg DST) >3.0 µg/dL (82.8 nmol/L); or (3) adrenocorticotropic hormone (ACTH) <10 pg/mL (<2.2 pmol/L). In patients and in 70 matched controls, BMD was measured at lumbar spine (LS) and femur (neck [FN] and total [FT]) by dual X‐ray absorptiometry and TBS was assessed in the region of LS‐BMD; BMD and TBS data were reported as Z‐scores. In patients, vertebral deformities were assessed by radiograph. Patients with SH (n = 34) had lower LS‐BMD (?0.31 ± 1.17), FT‐BMD (?0.29 ± 0.91), and TBS (?3.18 ± 1.21) than patients without SH (n = 68, 0.31 ± 1.42, p = 0.03; 0.19 ± 0.97, p = 0.01; ?1.70 ± 1.54, p < 0.0001, respectively) and controls (0.42 ± 1.52, p = 0.02; 0.14 ± 0.76, p = 0.02; ?1.19 ± 0.99, p < 0.0001, respectively). TBS was inversely correlated with 1‐mg DST (β = ?0.26, t = ?2.79, p = 0.006) regardless of age, LS‐BMD, body mass index (BMI), and gender. The presence of fracture was associated with low TBS alone (odds ratio [OR], 4.8; 95% confidence interval [CI], 1.85–12.42, p = 0.001) and with the cluster low TBS plus low LS‐BMD (OR, 4.37; 95% CI, 1.71–11.4, p = 0.002), after adjustment for age, BMI, and gender. Low TBS plus low LS‐BMD showed a good specificity (79%) for predicting fractures, whereas normal TBS (ie, > ?1.5) plus normal LS‐BMD high specificity (88.1%) for excluding fractures. Finally, TBS predicted the occurrence of a new fracture in 40 patients followed for 24 months (OR, 11.2; 95%CI, 1.71–71.41, p = 0.012) regardless of LS‐BMD, BMI, and age. In SH, bone quality, as measured by TBS, is altered. TBS is useful in detecting AI patients at risk of fractures. © 2012 American Society for Bone and Mineral Research.     

Efficacy of Antiosteoporotic Medications in Patients With Rebound-Associated Fractures After Denosumab Discontinuation

Denosumab discontinuation results in rapid bone loss and increased risk of multiple rebound-associated vertebral fractures (RAVFs). The optimal treatment for patients who have sustained such fractures is currently unknown. We aimed to investigate the bone mineral density (BMD) changes achieved with various regimens in postmenopausal women who had sustained RAVFs after denosumab discontinuation in everyday clinical practice. In this multicenter, retrospective observational study, 39 Greek postmenopausal women from six regional bone centers throughout Greece with RAVFs after denosumab discontinuation were included. We collected BMD and fracture data before and 1 year after treatment with denosumab (n = 20), teriparatide (n = 8), zoledronate (n = 8) or teriparatide/denosumab combination (n = 3). Both lumbar spine (LS)-- and femoral neck (FN)-BMD were preserved with all regimens used. With the exception of zoledronate, a trend towards increase was observed with all regimens in LS-BMD. Three patients sustained additional fractures despite treatment reinstitution (2 with zoledronate and 1 with teriparatide). Among patients with RAVFs following denosumab discontinuation both antiresorptive (zoledronate and denosumab) and anabolic (teriparatide) treatment as well as the combination of denosumab with teriparatide seem to be effective in terms of BMD response.     

Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls

Atypical femoral fractures (AFF) associated with long‐term bisphosphonates (LTB) are a growing concern. Their etiology is unknown, but bone material properties might be deteriorated. In an AFF series, we analyzed the bone material properties by microindentation. Four groups of patients were included: 6 AFF, 38 typical osteoporotic fractures, 6 LTB, and 20 controls without fracture. Neither typical osteoporotic fractures nor controls have received any antiosteoporotic medication. A general laboratory workup, bone densitometry by dual‐energy X‐ray absorptiometry (DXA), and microindentation testing at the tibia were done in all patients. Total indentation distance (Total ID), indentation distance increase (IDI), and creep indentation distance (Creep ID) were measured (microns). Age‐adjusted analysis of covariance (ANCOVA) was used for comparisons. Controls were significantly younger than fracture groups. Bisphosphonate exposure was on average 5.5 years (range 5 to 12 years) for the AFF and 5.4 years (range 5 to 8 years) for the LTB groups. Total ID (microns) showed better material properties (lower Total ID) for controls 36 (± 6; mean ± SD) than for AFF 46 (± 4) and for typical femoral fractures 47 (± 13), respectively. Patients on LTB showed values between controls and fractures, 38 (± 4), although not significantly different from any of the other three groups. IDI values showed a similar pattern 13 (± 2), 16 (± 6), 19 (± 3), and 18 (± 5). After adjusting by age, significant differences were seen between controls and typical (p < 0.001) and atypical fractures (p = 0.03) for Total ID and for IDI (p < 0.001 and p < 0.05, respectively). There were no differences in Creep ID between groups. Our data suggest that patients with AFF have a deep deterioration in bone material properties at a tissue level similar to that for the osteoporotic fracture group. The LTB group shows levels that are in between controls and both type of fractures, although not statistically different. These results suggest that bisphosphonate therapy probably does not put the majority of patients at risk for AFF. © 2013 American Society for Bone and Mineral Research     

Impact of bisphosphonate wash-out prior to teriparatide therapy in clinical practice

Concurrent use of bisphosphonate therapy reduces the anabolic effect of teriparatide. Consequently, in clinical practice bisphosphonates are discontinued and teriparatide therapy held for a few months to allow bone turnover to increase. We aimed to evaluate the effect of prior bisphosphonate exposure and the effect of bisphosphonate wash-out on the treatment response to teriparatide. Thirty-nine patients with primary osteoporosis (mean age 63.6 ± 14.0 years), including 26 patients previously treated with oral bisphosphonates (median duration 53 months) and 13 bisphosphonate-naïve patients were started on teriparatide (20 μg daily) and followed prospectively over 12 months. The primary study outcome was change in bone formation markers (PINP, bone ALP, osteocalcin). Secondary outcomes included changes in bone resorption (βCTX) and 12-month changes in BMD. Markers of bone formation increased early during teriparatide therapy and were followed by an increase in βCTX (p < 0.001). The magnitude of the increase in bone markers was comparable in both patient groups irrespective of prior bisphosphonate exposure; similarly, increases in BMD after 12 months were not significantly different between bisphosphonate-pretreated and bisphosphonate-naïve patients (lumbar spine 7.1 vs. 8.9%, p = 0.58; total hip 4.1 vs. 1.1%, p = 0.48). The response of teriparatide was not related to the duration of bisphosphonate wash-out (median duration 4.2 months). This study confirms that beneficial effects of teriparatide on intermediate bone endpoints can be translated into clinical practice with less constringent methodological circumstances than in RCTs. Furthermore, as bisphosphonate wash-out does not appear to influence the treatment effect, teriparatide therapy can be started immediately after ceasing bisphosphonate therapy and wash-out.     

Denosumab and changes in bone turnover markers during androgen deprivation therapy for prostate cancer

Androgen deprivation therapy (ADT) for prostate cancer increases fracture risk, decreases bone mineral density, and increases bone turnover markers (BTMs) including serum type 1 C‐telopeptide (sCTX), tartrate‐resistant alkaline phosphatase 5b (TRAP‐5b), and procollagen‐1 N‐terminal telopeptide (P1NP). In a prespecified exploratory analysis of a phase 3, multicenter, double‐blind study, we evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1468 patients, 734 in each group) on BTM values. BTMs were measured at baseline, month 1, and predose at months 6, 12, 24, and 36 in the overall population. BTMs at month 1 are also reported for subgroups based on age (< 70 years versus ≥ 70 years), prior duration of ADT (≤ 6 months versus >6 months), and baseline BTM (≤ median versus > median BTM values). Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in sCTX levels at month 1 was ?90% in the denosumab group and ?3% in the placebo group (p < 0.0001). The median change in TRAP‐5b levels at month 1 was ?55% in the denosumab group and ?3% in the placebo group (p < 0.0001). The maximal median change in P1NP was ?64% in the denosumab group and ?11% in the placebo group, (p < 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously. © 2011 American Society for Bone and Mineral Research