RESUMO
The overarching goal of osteoporosis management is to prevent fractures. A goal-directed approach to long-term management of fracture risk helps ensure that the most appropriate initial treatment and treatment sequence is selected for individual patients. Goal-directed treatment decisions require assessment of clinical fracture history, vertebral fracture identification (using vertebral imaging as appropriate), measurement of bone mineral density (BMD) and consideration of other major clinical risk factors. Treatment targets should be tailored to each patient's individual risk profile and based on the specific indication for beginning treatment, including recency, site, number and severity of prior fractures, and BMD levels at the total hip, femoral neck, and lumbar spine. Instead of first-line bisphosphonate treatment for all patients, selection of initial treatment should focus on reducing fracture risk rapidly for patients at very high and imminent risk, such as in those with recent fractures. Initial treatment selection should also consider the probability that a BMD treatment target can be attained within a reasonable period of time and the differential magnitude of fracture risk reduction and BMD impact with osteoanabolic versus antiresorptive therapy. This position statement of the ASBMR/BHOF Task Force on Goal-Directed Osteoporosis Treatment provides an overall summary of the major clinical recommendations about treatment targets and strategies to achieve those targets based on the best evidence available, derived primarily from studies in older postmenopausal women of European ancestry.
Goal-directed treatment can help healthcare providers recommend the best treatments for individual patients to prevent fractures. The goal-directed strategy considers the site, number and recency of prior fractures. This may require imaging for spine fractures, which may not have caused pain. Treatment decisions also require bone mineral density (BMD) measurement and consideration of other major risk factors. In contrast to the standard approach, same first treatment for all, treatment selection is tailored to an individual's risk. In patients with recent fractures of the spine, hip or pelvis, fracture risk is very high and treatment should rapidly reduce that risk. For others, the target is a specific BMD level and should consider the likelihood that the treatment target can be attained within a reasonable period of time, which differs for osteoporosis medications. After initial therapy, BMD should be assessed to determine if the target has been achieved. If so, strategies should focus on maintaining BMD. If the target is not yet achieved, treatment should be intensified, or continued if it is already the most potent option. This position statement represents a consensus of expert recommendations about treatment targets and strategies to achieve those targets based on the best available evidence.
RESUMO
Osteoanabolic-first treatment sequences are superior to oral bisphosphonates for fracture reduction and bone mineral density (BMD) gain. However, data comparing osteoanabolic medications, with the more potent antiresorptive, denosumab (DMAb), are limited. We analyzed FRAME and FRAME Extension data to assess BMD and fracture incidence in patients treated with romosozumab (Romo) followed by DMAb (Romo/DMAb) versus DMAb (DMAb/DMAb) for 24 months. In FRAME, women aged ≥55 years (total hip [TH] or femoral neck [FN] T-score: -2.5 to -3.5) were randomized to Romo or placebo for 12 months followed by DMAb for 12 months. In FRAME Extension, both cohorts received DMAb for another 12 months. This post hoc analysis compared BMD change and fracture incidence in patients on Romo/DMAb (months 0-24) versus DMAb/DMAb (months 12-36). Patient characteristics were balanced by propensity score weighting (PSW) and sensitivity analyses were conducted using PSW with multiple imputation (PSW-MI) and propensity score matching (PSM). Unmeasured confounding was addressed using E-values. After PSW, over 24 months, compared with DMAb/DMAb, treatment with Romo/DMAb produced significantly greater BMD increases at the lumbar spine [LS], TH, and FN (mean differences: 9.3%, 4.4%, and 4.1%, respectively; all p<0.001). At month 24, in women with a baseline T-score of -3.0, the probability of achieving a T-score > -2.5 was higher with Romo/DMAb versus DMAb/DMAb (LS: 92% versus 47%; TH: 50% versus 5%). In the Romo/DMAb versus DMAb/DMAb cohorts, new vertebral fractures were significantly reduced (0.62% versus 1.26% [odds ratio = 0.45; p=0.003]) and rates of clinical, nonvertebral, and hip fractures were lower (differences not significant). Similar BMD and fracture outcomes were observed with PSW-MI and PSM sensitivity analyses. The sequence of Romo/DMAb resulted in greater BMD gains and higher probability of achieving T-scores > -2.5, significantly reduced new vertebral fracture incidence, and numerically lowered the incidence (not significant) of clinical, nonvertebral, and hip fractures versus DMAb only through 24 months.
In patients with very high fracture risk, a treatment sequence with a bone-forming agent, followed by a bisphosphonate (one type of antiresorptive that reduces bone loss) is more effective in increasing bone mineral density (BMD) and reducing fracture risk compared to treatment with bisphosphonates alone. Here, we utilized patient data from the FRAME and FRAME Extension clinical trials to compare changes in BMD and fracture incidence in postmenopausal women with osteoporosis treated with the bone-forming agent, romosozumab (Romo), for 12 months followed by the most potent antiresorptive, denosumab (DMAb), for 12 months (Romo/DMAb) versus patients treated with DMAb alone for 24 months. Propensity score weighting was used to balance the patient characteristics between the two groups. We found that BMD gains were significantly higher in patients treated with the Romo/DMAb sequence versus DMAb alone; these patients also had a higher probability of achieving a T-score above the osteoporosis range (>2.5). In addition, new vertebral fractures were significantly lower and rates of clinical, nonvertebral, and hip fractures trended lower in patients treated with the Romo/DMAb sequence versus DMAb alone. Thus, a 24-months treatment sequence of Romo/DMAb compared with DMAb alone, resulted in higher BMD gains and lower fracture risk.
Assuntos
Densidade Óssea , Denosumab , Humanos , Denosumab/uso terapêutico , Denosumab/farmacologia , Feminino , Densidade Óssea/efeitos dos fármacos , Idoso , Pessoa de Meia-Idade , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Fraturas Ósseas/epidemiologia , Conservadores da Densidade Óssea/uso terapêutico , Conservadores da Densidade Óssea/farmacologiaRESUMO
Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered PTH tablet on serum markers of bone formation (PINP and osteocalcin), bone resorption (crosslinked C-telopeptide [CTX]), BMD, and safety in postmenopausal women with low BMD or osteoporosis. In this 6-mo, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3, and 6 mo and BMD of LS, TH, and FN was measured at 6 mo. Biochemical marker changes were dose dependent with minimal or no effect at the 2 lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 mo after oral PTH initiation (P < .0001), remained elevated through 3 mo, and were back to baseline at 6 mo. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 mo, respectively (both P ≤ .02). At 6 mo, 2.5 mg tablets increased mean BMD vs placebo of the LS by 2.7%, TH by 1.8%, and FN by 2.8% (all P ≤ .01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.
Despite the superior benefits of bone-building (anabolic) agents and guidelines supporting their use, these medications are used in a minority of patients for whom they are appropriate, in part because they require daily or monthly injections, which limit patient acceptance. An oral anabolic tablet has potential to address this substantial treatment gap. In this double-blind, placebo controlled, dose-finding randomized study, 161 postmenopausal women with low BMD or osteoporosis were treated with varying doses of the active part of PTH(1-34) or placebo given in daily oral tablets for 6 mo. The highest oral PTH tablet dose (2.5 mg) produced an increase in markers of bone formation while simultaneously decreasing the markers of bone breakdown. Significant gains in BMD of the spine and hip were observed at the end of the 6-mo study and there were no significant safety concerns. The 2.5 mg oral PTH tablet dose was well tolerated when patients were instructed to titrate up to the full dose. We conclude that this PTH tablet might be the first effective orally administered bone building medication and should be studied further in treatment of women with osteoporosis.
Assuntos
Densidade Óssea , Humanos , Feminino , Administração Oral , Pessoa de Meia-Idade , Idoso , Densidade Óssea/efeitos dos fármacos , Biomarcadores/sangue , Comprimidos , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/sangue , Método Duplo-Cego , Hormônio Paratireóideo/sangue , Placebos , Teriparatida/administração & dosagem , Teriparatida/farmacologia , Fragmentos de Peptídeos/sangueRESUMO
BACKGROUND: Osteoporosis is a chronic progressive disease that requires lifelong monitoring and treatment. Sequencing from one treatment to another at different ages and stages of disease is an approach that can maximize benefits and avoid potential risks from long-term treatment with a single agent. OBJECTIVE: This article reviews clinical trial data in postmenopausal women that evaluate the effects of antiresorptive agents followed by other antiresorptives, osteoanabolic agents followed by antiresorptives, and antiresorptives followed by osteoanabolic medications. METHODS: Literature review and discussion. RESULTS: When medications are discontinued, in the absence of sequential therapy, bone turnover rates return to baseline or above baseline, and bone loss occurs. The rate of bone loss differs for different treatments, with a very slow decline after stopping bisphosphonates and a particularly rapid decline after stopping denosumab. Careful attention to osteoporosis medication transitions can mitigate bone density loss and its consequences. For women who remain at high risk, switching from bisphosphonates to the more potent antiresorptive, denosumab, will result in further improvement in bone mineral density (BMD). When indicated, stopping denosumab can be accomplished safely by transition to an adequate bisphosphonate regimen. For high- and very-high-risk patients, treating with osteoanabolic agents first, followed by antiresorptive agents, produces substantially larger BMD gains than the reverse treatment sequence, with the biggest differences seen for BMD of the hip. CONCLUSION: Awareness of the importance of treatment sequences can help improve osteoporosis care across the postmenopausal lifespan.
Assuntos
Conservadores da Densidade Óssea , Difosfonatos , Humanos , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Difosfonatos/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Denosumab/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose/tratamento farmacológicoRESUMO
OBJECTIVE: We evaluated the efficacy of romosozumab in women from FRAME who had no prior fracture but met other criteria for very high fracture risk (VHFR). METHODS: In FRAME, postmenopausal women received romosozumab or placebo for 12 months (year 1) followed by denosumab for 12 months (year 2). In this post hoc analysis, we applied the following criteria from the American Association of Clinical Endocrinology to define VHFR: lumbar spine or total hip T-score <-3.0 and/or Fracture Risk Assessment Tool probability of major osteoporotic fracture >30% or hip fracture >4.5% to women with no fracture history at baseline (no fracture-VHFR [NF-VHFR]). Incidence of new vertebral, clinical, and nonvertebral fractures and mean bone mineral density (BMD) percentage change from baseline were assessed at years 1 and 2. RESULTS: Of the 7180 women in FRAME, 2825 were included in the NF-VHFR subgroup analysis. At year 1, romosozumab versus placebo reduced the incidence of new vertebral fracture (relative risk reduction [RRR]: 76%), clinical fracture (RRR: 60%), and nonvertebral fracture (RRR: 54%) (all P <.05). This fracture reduction was maintained through year 2 in women receiving the romosozumab-to-denosumab sequence versus the placebo-to-denosumab sequence for new vertebral, clinical, and nonvertebral fractures (RRR: 77%, 54%, and 46%, respectively; all P <.05). The mean BMD changes in both treatment groups were similar to those in the overall FRAME population at years 1 and 2. CONCLUSION: Romosozumab significantly reduced vertebral, clinical, and nonvertebral fracture risk and increased the BMD more than placebo in women at VHFR.
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Fraturas por Osteoporose , Feminino , Humanos , Anticorpos Monoclonais/uso terapêutico , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Fraturas por Osteoporose/etiologia , Pós-MenopausaRESUMO
Although bone mineral density (BMD) is a predictor of fracture, many fractures occur in women with T-scores > -2.5. Bone microarchitecture, assessed by trabecular bone score (TBS), predicts fracture risk independent of BMD. We evaluated whether abaloparatide improves TBS and whether TBS trends were associated with vertebral fracture risk reduction. Women with osteoporosis randomized to abaloparatide or placebo for 18 months (ACTIVE), followed by alendronate for 24 months (ACTIVExtend), with evaluable TBS, were included in this post hoc analysis (N = 911). TBS was calculated from spine BMD scans using an algorithm adjusted for tissue thickness (TBSth ) at baseline, 6, 18, and 43 months. Mean increments in TBSth from baseline within and between treatment groups, proportion of women with TBSth increments above least significant change (LSC) and proportion with degraded TBSth (<1.027) were calculated. Risk estimates for vertebral fracture were compared using binary logistic regressions adjusted for baseline age and spine BMD. At baseline, 42% had degraded TBSth . Mean TBSth increased 4% after 18 months abaloparatide (p < 0.001) and was unchanged with placebo. After 2 subsequent years of alendronate, the total cumulative TBSth increase was 4.4% with abaloparatide/alendronate and 1.7% with placebo/alendronate (group difference, p < 0.001). At 43 months, the proportion of women with degraded TBSth had declined to 21% with abaloparatide/alendronate and 37% with placebo/alendronate (p < 0.05). An increase in TBSth ≥ LSC was observed in 50% of abaloparatide-treated women at 18 months and was associated with decreased odds (odds ratio [OR]; 95% confidence interval [CI]) of vertebral fracture (0.19; 95% CI, 0.04-0.80, 6 months; 0.30; 95% CI, 0.11-0.79, 43 months). In conclusion, abaloparatide increased TBSth rapidly and progressively over 18 months and increments were maintained over 2 years with alendronate. TBSth increase was associated with vertebral fracture risk reduction. Microarchitectural improvement may be one mechanism by which abaloparatide strengthens vertebral bone. © 2023 Radius Health, Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Feminino , Humanos , Alendronato/farmacologia , Alendronato/uso terapêutico , Osso Esponjoso/diagnóstico por imagem , Fraturas por Osteoporose/tratamento farmacológico , Fraturas da Coluna Vertebral/tratamento farmacológico , Osteoporose/tratamento farmacológico , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Vértebras Lombares , Osteoporose Pós-Menopausa/tratamento farmacológicoRESUMO
PURPOSE: To evaluate the effects of cyclic vs daily teriparatide treatment (TPTD) on volumetric bone mineral density (vBMD) and bone strength at the hip and spine in women who were previously untreated. METHODS: A total of 86 women were randomized to a 24-month open label treatment of either daily TPTD (20 µg daily) or cyclic TPTD (20 µg daily for 3 months followed by 3 months off). During a 2-year extension, women in the daily TPTD group were switched to alendronate (ALN) and those in the cyclic TPTD group continued on cyclic TPTD (without any ALN). QCT images were acquired at baseline, 2-years (n = 54) and 4-years (n = 35) and analyzed for volumetric integral, cortical and trabecular bone mineral density (vBMD) and bone strength (by finite element analysis) at the hip and spine. The primary analysis presented here compared the responses across equal total TPTD doses (2 years daily vs 4 years cyclic). RESULTS: In the spine, integral vBMD and strength increased substantially after 2 years daily and 4 years cyclic TPTD, with no significant differences (vBMD +12 % vs +11 %, respectively, p = 0.70; spine strength +21 % vs +16 %, respectively, p = 0.35). At the hip, the gains were smaller, but again no significant differences were detected between the groups for the increases in either vBMD (+2 % in both groups, p = 0.97) or hip strength (3 % vs 3 %, p = 0.91). In the spine, the vBMD increment was about twice as large in the trabecular vs peripheral compartment; in the hip, significant vBMD gain was seen only in the trabecular compartment. CONCLUSIONS: The gains in volumetric BMD and bone strength for an equivalent dose of TPTD did not depend on whether it was administered every day over two years or cyclically over four years.
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Teriparatida , Feminino , Humanos , Alendronato/uso terapêutico , Densidade Óssea , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Pós-Menopausa , Teriparatida/administração & dosagem , Teriparatida/uso terapêuticoRESUMO
It is uncertain whether the risk of vertebral fracture (VF) and multiple vertebral fractures (MVFs; ≥2 VFs) after denosumab (DMAb) discontinuation is related to treatment duration. A prior analysis of Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) and FREEDOM Extension trials did not find a relationship with DMAb duration and may have underreported MVF incidence because it included women who did not have radiographs. In this post hoc exploratory analysis, the crude incidence and annualized rates of VF and MVF were determined in patients with ≥7 months' follow-up and ≥1 spine radiograph after discontinuing placebo or DMAb. A multivariate analysis was performed to identify predictors of MVF. Clinical characteristics of patients with ≥4 VFs were explored. This analysis included women who discontinued after placebo (n = 327) or DMAb either from FREEDOM or FREEDOM Extension (n = 425). The DMAb discontinuation group was subsequently dichotomized by treatment duration: short-term (≤3 years; n = 262) and long-term (>3 years; n = 213) treatment. For any VF, exposure-adjusted annualized rates per 100 patient-years (95% confidence interval [CI]) were 9.4 (95% CI, 6.4-13.4) for placebo, 6.7 (95% CI, 4.2-10.1) for short-term DMAb, and 10.7 (95% CI, 7.4-15) for long-term DMAb. Annualized rates for MVF were 3.6 (95% CI, 1.9-6.3), 2.9 (95% CI, 1.4-5.4), and 7.5 (95% CI, 4.8-11.1), respectively. Annualized rates for ≥4 VFs were 0.59 (95% CI, 0.1-2.1), 0.57 (95% CI, 0.1-2.1), and 3.34 (95% CI, 1.7-6.0), respectively. In a multivariate regression model, DMAb duration was significantly associated with MVF risk (odds ratio 3.0; 95% CI, 1.4-6.5). Of 15 patients with ≥4 VFs, 13 had DMAb exposure (mean ± standard deviation [SD], 4.9 ± 2.2 years). The risk of MVF after DMAb discontinuation increases with increased duration of DMAb treatment. Patients transitioning off DMAb after 3 years may warrant more frequent administration of zoledronic acid or another bisphosphonate to maintain bone turnover and bone mineral density (BMD) and prevent MVF. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Feminino , Humanos , Densidade Óssea , Denosumab , Fixação de Fratura , Liberdade , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Fraturas da Coluna Vertebral/tratamento farmacológico , Fraturas da Coluna Vertebral/epidemiologiaRESUMO
To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an antiresorptive (alendronate or denosumab). Initial treatment with romosozumab followed by an antiresorptive resulted in larger increases in bone mineral density of both hip and spine compared with the reverse sequence. INTRODUCTION: Teriparatide followed by an antiresorptive increases bone mineral density (BMD) more than using an antiresorptive first. To evaluate whether treatment sequence affects romosozumab response, we reviewed randomized clinical trials where romosozumab was administered before (ARCH, FRAME) or following (STRUCTURE, Phase 2 extension) an antiresorptive (alendronate or denosumab, respectively). METHODS: We evaluated BMD percentage change for total hip (TH) and lumbar spine (LS) and response rates (BMD gains ≥ 3% and ≥ 6%) at years 1 and 2 (except STRUCTURE with only 1-year data available). RESULTS: With 1-year romosozumab initial therapy in ARCH and FRAME, TH BMD increased 6.2% and 6.0%, and LS BMD increased 13.7% and 13.1%, respectively. When romosozumab was administered for 1 year after alendronate (STRUCTURE) or denosumab (Phase 2 extension), TH BMD increased 2.9% and 0.9%, respectively, and LS BMD increased 9.8% and 5.3%, respectively. Over 2 years, TH and LS BMD increased 7.1% and 15.2% with romosozumab/alendronate, 8.5% and 16.6% with romosozumab/denosumab, and 3.8% and 11.5% with denosumab/romosozumab, respectively. A greater proportion of patients achieved BMD gains ≥ 6% when romosozumab was used first, particularly for TH, versus the reverse sequence (69% after romosozumab/denosumab; 15% after denosumab/romosozumab). CONCLUSION: In this study, larger mean BMD increases and greater BMD responder rates were achieved when romosozumab was used before, versus after, an antiresorptive agent. Since BMD on treatment is a strong surrogate for bone strength and fracture risk, this analysis supports the thesis that initial treatment with romosozumab followed by an antiresorptive will result in greater efficacy versus the reverse sequence.
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Alendronato/farmacologia , Alendronato/uso terapêutico , Anticorpos Monoclonais , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Denosumab/farmacologia , Denosumab/uso terapêutico , Feminino , Humanos , Osteoporose Pós-Menopausa/tratamento farmacológico , Teriparatida/farmacologia , Teriparatida/uso terapêuticoRESUMO
PURPOSE: We have previously shown that a brief course of teriparatide (TPTD) stimulates bone formation in the cancellous and endocortical envelopes of the human femoral neck, and the regions of tension and compression respond differently. The purpose of the present study was to determine how much of the new bone was formed by modeling-based formation (MBF) or remodeling-based formation (RBF). METHODS: We performed a double-blind trial of TPTD vs. placebo (PBO) in patients about to undergo a total hip replacement (THR) for osteoarthritis. Participants were randomized to receive daily TPTD 20 µg or PBO for an average of 6.1 weeks (range 4.1-11.8 weeks) prior to THR. After an average of 3 weeks of study drug, double tetracycline labels were administered per standard protocol. During the THR an intact sample of the mid-femoral neck (FN) was procured; this was fixed, embedded, and sectioned transversely. Histomorphometric analysis was performed in the cancellous, endocortical, and periosteal envelopes. Additionally, separate analyses were performed in the tensile and compressive regions of the endocortical and periosteal envelopes. Sites of new bone formation were identified by the presence of tetracycline labels and designated as MBF if the underlying cement line was smooth and as RBF if it was scalloped. New bone formation on smooth cement lines adjacent to scalloped reversal lines was designated as overflow RBF (oRBF). The referent for all indices was bone surface (BS). RESULTS: In the cancellous and endocortical envelopes, the proportion of mineralizing surface engaged in RBF and oRBF was higher in the TPTD-treated than the PBO-treated subjects. There was also a trend toward higher MBF in TPTD vs. PBO in both envelopes. In linear mixed-effects models, TPTD was predicted to increase formation differently on the tensile and compressive surfaces depending on patient-specific anatomy, including body weight, FN angle, offset, and cortical width and porosity. Eroded surface was not different between groups in either envelope and no significant differences were observed in any parameter in the periosteal envelope. CONCLUSION: We conclude that the predominant early effect of TPTD in the human femoral neck is to stimulate RBF and oRBF with a trend toward an increase in MBF in the endocortical and cancellous envelopes.
Assuntos
Conservadores da Densidade Óssea , Teriparatida , Densidade Óssea , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Método Duplo-Cego , Colo do Fêmur , Humanos , Osteogênese , Teriparatida/uso terapêutico , Tetraciclinas/farmacologiaRESUMO
The fully human monoclonal antibody denosumab was approved for treatment of osteoporosis in 2010 on the basis of its potent antiresorptive activity, which produces clinically meaningful increases in bone mineral density (BMD) and reduces fracture risk at key skeletal sites. At that time, questions remained regarding the long-term safety and efficacy of this receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor; and with clinical experience, new questions have arisen regarding its optimal use. Here, we examine these questions through the lens of data from the FREEDOM trial program and other studies to determine where denosumab fits in the osteoporosis treatment landscape. Clinical consensus and evidentiary support have grown for denosumab as a highly effective anti-osteoporosis therapy for patients at high risk of fracture. In the 10-year FREEDOM Extension study, denosumab treatment produced progressive incremental increases in BMD, sustained low rates of vertebral fracture, and further reduction in nonvertebral fracture risk without increased risk of infection, cancer, or immunogenicity. There was no evidence that suppression of bone turnover or mineralization was excessive, and rates of osteonecrosis of the jaw (ONJ) and atypical femoral fracture (AFF) were very low. It is now recognized, however, that transitioning to another anti-osteoporosis therapy after denosumab discontinuation is essential to mitigate a transient rebound of bone turnover causing rapid BMD loss and increased risk of multiple vertebral fractures (MVFs). Taken together, the available data show that denosumab has a favorable benefit/risk profile and is a versatile agent for preventing osteoporotic fractures in the short and long term. Video abstract: Denosumab in the Treatment of Osteoporosis-10 Years Later (MP4 62727 KB).
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Fraturas por Osteoporose , Densidade Óssea , Conservadores da Densidade Óssea/efeitos adversos , Denosumab/efeitos adversos , Feminino , Humanos , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controleRESUMO
Increases in bone mineral density (BMD) with osteoporosis treatment are associated with reduced fracture risk. Increasing BMD is therefore a goal of osteoporosis therapy. Here, we compare the probability of achieving a T-score of > -2.5 over 3 years at the total hip (TH) or lumbar spine (LS) in women with osteoporosis, ≥55 years of age, after the following treatment sequences: 1 year romosozumab followed by 2 years denosumab (FRAME and FRAME extension trials), 1 year romosozumab followed by 2 years alendronate, or alendronate-only for 3 years (ARCH trial). Probabilities of attaining the BMD target within 1 year of treatment were also determined. At both skeletal sites, in women with a baseline Tscore ≥ -2.7, there was >50% probability of achieving the BMD target with any 3-year regimen. The probability of achieving the target BMD in those with a baseline TH Tscore equal to -3.0 was 61% with romosozumab/denosumab, 38% with romosozumab/alendronate, and 9% with alendronate. In those with a baseline LS Tscore equal to -3.0, the probability of achieving a T-score > -2.5 was 93% with romosozumab/denosumab, 81% with romosozumab/alendronate, and 55% with alendronate. With 1 year of treatment, in patients with a baseline TH T-score equal to -2.7, the probability of reaching the target Tscore with romosozumab was 71% to 78% and 38% with alendronate. For patients with an initial LS T-score equal to -3.0, the probability of achieving the target T-score over 1 year was 85% to 86% with romosozumab and 25% for alendronate. Our findings suggest baseline BMD and the probability of achieving BMD T-score goals are factors to consider when selecting initial treatment for patients with osteoporosis. As baseline T-score falls below -2.7 (TH) and -3.0 (LS), alendronate has <50% likelihood of achieving a BMD goal above osteoporosis range, whereas these probabilities remain relatively high for regimens beginning with romosozumab. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
RESUMO
We prospectively assessed, with predefined criteria, the location and rates of all femur fractures (hip, subtrochanteric/femoral shaft [ST/FS], including atypical [AFF] and distal fractures) in women at increased fracture risk during treatment with the cathepsin K inhibitor, odanacatib (ODN), or placebo over 5 years in the Long-Term ODN Fracture Trial (LOFT and LOFT Extension [NCT00529373, EudraCT 2007-002693-66]). ODN was an investigational antiresorptive agent previously in development as an osteoporosis treatment that, unlike bisphosphonates, reduces bone formation only transiently. Women aged ≥65 years with a bone mineral density (BMD) T-score ≤-2.5 at the total hip (TH) or femoral neck (FN) or with a radiographic vertebral fracture and T-scores ≤-1.5 at the TH or FN were randomized (1:1) to receive ODN 50 mg/week or placebo. All patients received vitamin D3 (5600 IU/week) and calcium (total 1200 mg/d); the analysis included 16,071 women. Rates of all adjudicated low-energy femoral fractures were 0.38 versus 0.58/100 patient-years for ODN and placebo, respectively (hazard ratio [HR] = 0.65; 95% confidence interval [CI] 0.51-0.82; nominal p < .001), and for low-energy hip fractures were 0.29 versus 0.56/100 patient-years, respectively (HR = 0.52; 95% CI 0.40-0.67; p < .001). The cumulative incidence of combined hip and ST/FS or hip fractures alone in the ODN group was consistently lower than in the placebo group (1.93% versus 3.11% for combined fractures and 1.53% versus 3.03% for hip fractures at 5 years, respectively). However, low-energy ST/FS fractures were more frequent in ODN-treated women than in placebo-treated women (24 versus 6, respectively). Among these, 12 fractures were adjudicated as AFF in 10 patients treated with ODN (0.03/100 patient-years) compared with none in the 6 placebo-treated women (estimated difference 0.03; 95% CI 0.02-0.06). These results provide insight into possible pathogeneses of AFF, suggesting that the current criteria for diagnosing these fractures may need to be reconsidered. © 2021 American Society for Bone and Mineral Research (ASBMR)..
Assuntos
Conservadores da Densidade Óssea , Fraturas do Quadril , Osteoporose Pós-Menopausa , Osteoporose , Idoso , Compostos de Bifenilo , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Método Duplo-Cego , Feminino , Colo do Fêmur , Fraturas do Quadril/tratamento farmacológico , Fraturas do Quadril/epidemiologia , Humanos , Incidência , Osteoporose Pós-Menopausa/complicações , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoporose Pós-Menopausa/epidemiologia , Pós-MenopausaRESUMO
PURPOSE OF REVIEW: There are now three anabolic agents available for the treatment of postmenopausal women at high risk for fracture. The purpose of this review is to supply a rationale to aid in determining which agent should be used in which clinical settings. RECENT FINDINGS: Studies over the last decade have shown that anabolic agents produce faster and larger effects against fracture than antiresorptive agents. Furthermore, trials evaluating anabolic antiresorptive treatment sequences have shown that anabolic first treatment strategies produce the greatest benefits to bone density, particularly in the hip region. However, there are no head-to-head evaluations of the three anabolic therapies with fracture outcomes or bone density, and these studies are not likely to occur. How to decide which agent to use at which time in a woman's life is unknown. We review the most significant clinical trials of anabolic agents which have assessed fracture, areal or volumetric bone density, microarchitecture, and/or bone strength, as well as information gleaned from histomorphometry studies to provide a rationale for consideration of one agent vs another in various clinical settings. There is no definitive answer to this question; all three agents increase bone strength and reduce fracture risk rapidly. Since the postmenopausal lifespan could be as long as 40-50 years, it is likely that very high-risk women will utilize different anabolic agents at different points in their lives.
Assuntos
Anabolizantes/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Densidade Óssea/efeitos dos fármacos , Feminino , HumanosRESUMO
OBJECTIVE: Fractures due to osteoporosis represent a serious burden on patients and healthcare systems. The objective of this review is to provide an overview of the anabolic agent abaloparatide (ABL) for the treatment of postmenopausal women with osteoporosis at high risk for fracture. METHODS: A literature review was conducted using PubMed to identify articles focused on ABL published prior to February 10, 2020, using the search term "abaloparatide". RESULTS: ABL, a synthetic analog of human parathyroid hormone-related protein, increased bone mineral density (BMD), improved bone microarchitecture, and increased bone strength in preclinical and clinical studies. The pivotal phase 3 trial ACTIVE and its extension (ACTIVExtend) demonstrated the efficacy of initial treatment with ABL for 18 months followed by sequential treatment with alendronate (ALN) for an additional 24 months to reduce the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and to increase BMD in postmenopausal women with osteoporosis. Discontinuations from ACTIVE were slightly more common in ABL-treated patients due to dizziness, palpitations, nausea, and headache. Post hoc analyses of ACTIVE and ACTIVExtend support the efficacy and safety of ABL in relevant subpopulations including postmenopausal women with various baseline risk factors, women ≥80 years, women with type 2 diabetes mellitus, and women with renal impairment. CONCLUSIONS: ABL is an effective and well-tolerated treatment for women with postmenopausal osteoporosis at high risk for fracture. Its therapeutic effects are sustained with subsequent ALN therapy.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Fraturas por Osteoporose/prevenção & controle , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Alendronato/uso terapêutico , Animais , Densidade Óssea/efeitos dos fármacos , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Pós-Menopausa , Fatores de RiscoRESUMO
CONTEXT: Abaloparatide is a US Food and Drug Administration-approved parathyroid hormone-related peptide analog for treatment of osteoporosis in postmenopausal women at high risk of fracture. OBJECTIVES: We assessed the cardiovascular safety profile of abaloparatide. DESIGN: Review of heart rate (HR), blood pressure (BP), and cardiovascular-related adverse events (AEs), including major adverse cardiovascular events (MACEs) and heart failure (HF) from: (a) ACTIVE (NCT01343004), a phase 3 trial that randomized 2463 postmenopausal women with osteoporosis to abaloparatide, teriparatide, or placebo for 18 months; (b) ACTIVExtend (NCT01657162), where participants from the abaloparatide and placebo arms received alendronate for 2 years; and (c) a pharmacology study in 55 healthy adults. RESULTS: Abaloparatide and teriparatide transiently increased HR relative to placebo. Following first dose, mean (standard deviation [SD]) HR change from pretreatment to 1 hour posttreatment was 7.9 (8.5) beats per minute (bpm) for abaloparatide, 5.3 (7.5) for teriparatide, and 1.2 (7.1) for placebo. A similar pattern was observed over subsequent visits. In healthy volunteers, HR increase resolved within 4 hours. The corresponding change in mean supine systolic and diastolic BP 1 hour posttreatment was -2.7/-3.6 mmHg (abaloparatide), -2.0/-3.6 (teriparatide), and -1.5/-2.3 (placebo). The percentage of participants with serious cardiac AEs was similar among groups (0.9%-1.0%). In a post hoc analysis, time to first incidence of MACEâ +â HF was longer with abaloparatide (Pâ =â 0.02 vs placebo) and teriparatide (Pâ =â 0.04 vs placebo). CONCLUSIONS: Abaloparatide was associated with transient increases in HR and small decreases in BP in postmenopausal women with osteoporosis, with no increase in risk of serious cardiac AEs, MACE, or HF.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Conservadores da Densidade Óssea/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Insuficiência Cardíaca/induzido quimicamente , Frequência Cardíaca/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo/efeitos adversos , Idoso , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Proteína Relacionada ao Hormônio Paratireóideo/administração & dosagem , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Pós-Menopausa , Teriparatida/administração & dosagem , Teriparatida/efeitos adversos , Teriparatida/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: Fracture risk increases with age, but few studies focus on persons ≥80 years. In the ACTIVE trial, treatment with abaloparatide for 18 months reduced osteoporotic fracture risk and increased bone mineral density. These effects were maintained with 24 months alendronate treatment in ACTIVExtend. We postulated that similar improvements in bone mineral density and safety would be demonstrated in women ≥80 years. METHODS: Post hoc analyses of bone mineral density and fracture incidence in women with osteoporosis at high risk of fracture ≥80 years from ACTIVExtend. RESULTS: In total, 56 women aged ≥80 years at ACTIVE baseline entered the ACTIVExtend study; 46 of these completed the study. Mean age was 83.3 years; other baseline characteristics were similar. At the end of ACTIVE, bone mineral density increased at all sites for abaloparatide versus placebo. Bone mineral density increased in parallel in both groups during alendronate therapy (19 to 43 months) in ACTIVExtend. At month 43, mean percent change in bone mineral density from baseline was 17.2% abaloparatide/alendronate versus 8.6% placebo/alendronate (Pâ<â0.0001) at the lumbar spine, 5.3% abaloparatide/alendronate versus 3.0% placebo/alendronate (Pâ=â0.024) at the total hip, and 4.6% abaloparatide/alendronate versus 3.1% placebo/alendronate (Pâ=â0.044) at the femoral neck. Fracture incidence was low and did not differ significantly between groups. Sequential treatment with abaloparatide followed by alendronate was well tolerated; the proportion of participants reporting adverse events was similar between groups. CONCLUSIONS: Sequential treatment with abaloparatide followed by alendronate (43 months follow-up) in this small subgroup of ACTIVExtend participants suggests abaloparatide is well tolerated and effective in women aged ≥80 years. : Video Summary:http://links.lww.com/MENO/A618.
Video Summary:http://links.lww.com/MENO/A618.
Assuntos
Conservadores da Densidade Óssea , Osteoporose Pós-Menopausa , Osteoporose , Idoso de 80 Anos ou mais , Alendronato/uso terapêutico , Densidade Óssea , Conservadores da Densidade Óssea/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Osteoporose/tratamento farmacológico , Osteoporose Pós-Menopausa/tratamento farmacológico , Proteína Relacionada ao Hormônio ParatireóideoRESUMO
In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with romosozumab versus 2.9% (T-score change 0.15) with alendronate (p < .001). The proportion of patients with TH T-score > -2.5 increased from 34% at baseline to 55% after 1 year of romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data support the use of T-score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.