Dataset Information

Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study.

ABSTRACT: Premenopausal women with idiopathic osteoporosis (IOP) have abnormal cortical and trabecular bone microarchitecture.The purpose of this study was to test the hypotheses that teriparatide increases bone mineral density (BMD) and bone formation and improves trabecular microarchitecture and stiffness in women with IOP.This was an open-label pilot study.The setting was a tertiary care referral center.Participants were 21 premenopausal women with unexplained fragility fractures or low BMD.Teriparatide was administered at 20 ?g daily for 18 to 24 months.The primary endpoint was within-subject percent change in lumbar spine BMD. Secondary endpoints included percent change in hip and forearm BMD, transiliac biopsy parameters (trabecular bone volume, microarchitecture, stiffness, and adipocytes), serum N-terminal propeptide of procollagen type 1 (P1NP), and C-telopeptide.BMD increased at the spine (10.8 ± 8.3% [SD]), total hip (6.2 ± 5.6%), and femoral neck (7.6 ± 3.4%) (all P < .001). Serum P1NP doubled by 1 month, peaked at 6 months, and returned to baseline by 18 to 24 months. Transiliac biopsies demonstrated significant increases in cortical width and porosity and trabecular bone volume and number increased, mirrored by a 71% increase in trabecular bone stiffness (P < .02-.001). Adipocyte area, perimeter, and volume/marrow volume decreased, with no change in adipocyte number. Four women had no increase in BMD and a blunted, delayed increase in serum P1NP. Nonresponders had markedly lower baseline bone formation rate (0.002 ± 0.001 vs 0.011 ± 0.006 mm²/mm/y; P < .001) and higher serum IGF-1 (208 ± 54 vs 157± 44 ng/mL; P = .03).Teriparatide was associated with increased spine and hip BMD and improved trabecular microarchitecture and stiffness at the iliac crest in the majority of women with IOP.

SUBMITTER: Cohen A

PROVIDER: S-EPMC3644608 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study.

Cohen Adi A Stein Emily M EM Recker Robert R RR Lappe Joan M JM Dempster David W DW Zhou Hua H Cremers Serge S McMahon Donald J DJ Nickolas Thomas L TL Müller Ralph R Zwahlen Alexander A Young Polly P Stubby Julie J Shane Elizabeth E

The Journal of clinical endocrinology and metabolism 20130329 5

<h4>Context</h4>Premenopausal women with idiopathic osteoporosis (IOP) have abnormal cortical and trabecular bone microarchitecture.<h4>Objective</h4>The purpose of this study was to test the hypotheses that teriparatide increases bone mineral density (BMD) and bone formation and improves trabecular microarchitecture and stiffness in women with IOP.<h4>Design</h4>This was an open-label pilot study.<h4>Setting</h4>The setting was a tertiary care referral center.<h4>Patients</h4>Participants were ...[more]

PMID: 23543660

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Project description:Without antiresorptive therapy, postmenopausal women lose bone mass after teriparatide (TPTD) discontinuation; estrogen treatment prevents bone loss in this setting. It is not known whether premenopausal women with regular menses lose bone mass after teriparatide discontinuation.This study aimed to test the hypothesis that normally menstruating premenopausal women with idiopathic osteoporosis (IOP) will maintain teriparatide-associated bone mineral density (BMD) gains after medication cessation.Twenty-one premenopausal IOP women previously enrolled in an open-label pilot study of teriparatide (20 mcg for 18-24 mo), had substantial BMD increases at the lumbar spine (LS; 10.8 ± 8.3%), total hip (TH; 6.2 ± 5.6%), and femoral neck (7.6 ± 3.4%). For this study, BMD was remeasured 2.0 ± 0.6 years after teriparatide cessation.Fifteen women, who had gained 11.1 ± 7.2% at LS and 6.1 ± 6.5% at TH and were premenopausal at teriparatide completion, were followed without antiresorptive treatment.Two years after completing teriparatide, BMD declined by 4.8 ± 4.3% (P = .0007) at the LS. In contrast, BMD remained stable at the femoral neck (-1.5 ± 4.2%) and TH (-1.1 ± 3.7%). Those who sustained LS bone loss >3% (-7.3 ± 2.9%; n = 10), did not differ from those with stable LS BMD (0.1 ± 1.1%; n=5) with regard to baseline body mass index, BMD at any site, or duration of followup, but were significantly older at re-evaluation (46 ± 3 vs 38 ± 7; P = .046), had larger increases in LS BMD during teriparatide treatment and higher cancellous bone remodeling on transiliac biopsy at baseline and completion of teriparatide treatment. Serum bone turnover markers did not differ at baseline or teriparatide completion, but tended to be higher at the re-evaluation timepoint in those with post-teriparatide bone loss.These findings lead us to conclude that premenopausal women with IOP, particularly those over 40, may require antiresorptive treatment to prevent bone loss after teriparatide.

Project description:We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum insulin-like growth factor-1 (IGF-1) levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1-related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n = 25) and over 24 months of teriparatide treatment (n = 11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and RUNX2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. Although neither baseline %COP nor increase in %COP after 3 months predicted the bone mineral density (BMD) response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition, and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively and may serve to predict early response to teriparatide and possibly other bone formation-stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP and perhaps in other populations. © 2017 American Society for Bone and Mineral Research.

Project description:Osteoporosis in premenopausal women with intact gonadal function and no known secondary cause of bone loss is termed idiopathic osteoporosis (IOP). Women with IOP diagnosed in adulthood have profound bone structural deficits and often report adult and childhood fractures, and family history of osteoporosis. Some have very low bone formation rates (BFR/BS) suggesting osteoblast dysfunction. These features led us to investigate potential genetic etiologies of bone fragility. In 75 IOP women (aged 20-49) with low trauma fractures and/or very low BMD who had undergone transiliac bone biopsies, we performed Whole Exome Sequencing (WES) using our variant analysis pipeline to select candidate rare and novel variants likely to affect known disease genes. We ran rare-variant burden analyses on all genes individually and on phenotypically-relevant gene sets. For particular genes implicated in osteoporosis, we also assessed the frequency of all (including common) variants in subjects versus 6540 non-comorbid female controls. The variant analysis pipeline identified 4 women with 4 heterozygous variants in LRP5 and PLS3 that were considered to contribute to osteoporosis. All 4 women had adult fractures, and 3 women also had multiple fractures, childhood fractures and a family history of osteoporosis. Two women presented during pregnancy/lactation. In an additional 4 subjects, 4 different relevant Variants of Uncertain Significance (VUS) were detected in the genes FKBP10, SLC34A3, and HGD. Of the subjects with VUS, 2 had multiple adult fractures, childhood fractures, and presented during pregnancy/lactation, and 2 had nephrolithiasis. BFR/BS varied among the 8 subjects with identified variants; BFR/BS was quite low in those with variants that are likely to have adverse effects on bone formation. The analysis pipeline did not discover candidate variants in COL1A1, COL1A2, WNT, or ALPL. Although we found several novel and rare variants in LRP5, cases did not have an increased burden of common LRP5 variants compared to controls. Cohort-wide collapsing analysis did not reveal any novel disease genes with genome-wide significance for qualifying variants between controls and our 75 cases. In summary, WES revealed likely pathogenic variants or relevant VUS in 8 (11%) of 75 women with IOP. Notably, the genetic variants identified were consistent with the affected women's diagnostic evaluations that revealed histological evidence of low BFR/BS or biochemical evidence of increased bone resorption and urinary calcium excretion. These results, and the fact that the majority of the women had no identifiable genetic etiology, also suggest that the pathogenesis of and mechanisms leading to osteoporosis in this cohort are heterogeneous. Future research is necessary to identify both new genetic and non-genetic etiologies of early-onset osteoporosis.

Project description:ObjectiveTo bridge the efficacy and compare the safety of the 24-week teriparatide treatment in a Chinese osteoporosis study (NCT00414973) to a large international trial (FPT, NCT00670501) to determine whether long-term results from the international study were applicable to Chinese patients.MethodsIn this post-hoc analysis, a propensity score matching method was used to select patients with similar baseline characteristics. Patients were female with osteoporosis at high risk of fracture, aged ≥55 years, and had no history of rheumatoid arthritis or corticosteroid use. Outcomes included percentage changes in lumbar-spine bone mineral density (LS-BMD) from baseline to 24 weeks, safety in matched-pair patients, and long-term percentage changes in LS-BMD and fragility fracture incidence in the matched fracture prevention trial (FPT) population. The determination of the acceptability of bridging results was based on the International Conference on Harmonization E5 guidelines.ResultsA total number of 228 patients from each study were matched and paired. Patients were similar at baseline (P-values >0.33) except for ethnicity (98% Caucasian for FPT). For changes in LS-BMD from baseline to week 24, treatment with teriparatide showed significantly greater increases (P-values <0.001; least-squares mean difference: 5.0% in the Chinese study and 5.4% in FPT) than comparator (calcitonin/placebo). The safety profiles over 24 weeks were similar between two studies. For matched-pair FPT patients, long-term changes in LS-BMD were significantly greater (least-squares mean difference: 11.5%, P<0.001) and the fragility fracture rate was marginally lower in the teriparatide group compared with the placebo group (13.1% vs 22.3%, P=0.070).ConclusionAssuming similar pharmacokinetic profiles for teriparatide between populations, comparable increases in LS-BMD and consistent safety profiles within 24 weeks of the treatment suggest long-term LS-BMD results from the FPT may be applicable to Chinese population.

Project description:ContextIn postmenopausal women, bone mineral density (BMD) declines after teriparatide therapy is stopped. The pattern of BMD loss after teriparatide therapy is stopped in men is less clear.ObjectiveThe aim of the study was to determine whether the pattern of teriparatide-induced bone accrual and post-teriparatide bone loss differs between postmenopausal women and eugonadal men.DesignWe conducted a prospective cohort substudy.PatientsThe study included 14 postmenopausal women and 17 eugonadal men, ages 46-85 yr, with lumbar spine or femoral neck BMD T-scores below -2.InterventionTeriparatide (37 microg sc daily) was administered for 24 months, followed by 12 months off therapy.Main outcome measuresWe measured BMD at various anatomic sites by dual-energy x-ray absorptiometry, trabecular spine BMD by quantitative computed tomography, and bone turnover markers during the treatment and observation periods. The response to teriparatide administration and discontinuation was compared between females and males.ResultsBMD of the spine, femoral neck, total hip, and trabecular spine increased similarly during the treatment period in men and women, whereas BMD at the radius was stable in men but decreased by 8.1 +/- 3.3% in women (P < 0.0001). After teriparatide was stopped, BMD at the posterior-anterior spine decreased by 7.1 +/- 3.8% in women and by 4.1 +/- 3.5% in men (P = 0.036). BMD at the total hip and femoral neck decreased by 3.8 +/- 3.9 and 3.1 +/- 4.3%, respectively, in women but remained stable in men (P < 0.05 for both sites). BMD at the distal radius remained stable in men but increased in women by 1.6 +/- 3.1% (P = 0.069).ConclusionsTeriparatide appears to increase BMD similarly in postmenopausal women and eugonadal men with osteoporosis. After teriparatide is stopped, the decline in BMD is greater in women than in men. If confirmed in larger cohorts, these findings would suggest that the indication for immediate antiresorptive therapy after teriparatide may not be as urgent in men as in women.

Dataset Information

Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study.

Publications

Teriparatide for idiopathic osteoporosis in premenopausal women: a pilot study.

Similar Datasets

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