Imre Pavo

Differential Effects of Teriparatide on BMD After Treatment With Raloxifene or Alendronate

We investigated the effects of 18 months of treatment with teriparatide in patients previously treated with long‐term antiresorptive therapy using bone turnover markers and bone densitometry. Previous raloxifene treatment allowed for teriparatide‐induced early bone marker and BMD increases comparable with previously published results for treatment‐naïve patients. Conversely, previous alendronate treatment reduced the bone marker and BMD response.

Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis : a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial

Raloxifene reduces vertebral fracture risk in postmenopausal women with osteoporosis and established osteoporosis, but its efficacy in women with osteopenia has not been studied. The objective of this study was to evaluate the effect of raloxifene hydrochloride on the risk of vertebral fractures in postmenopausal women with osteopenia and to compare this effect with that in women with osteoporosis as defined by the bone mineral density (BMD) T-score at the hip. We studied the 3204 postmenopausal women with osteopenia or osteoporosis without vertebral fractures at baseline in the Multiple Outcomes of Raloxifene Evaluation trial. Compared with placebo, 60 mg/day raloxifene reduced the risk of new vertebral fractures at 3 years independent of baseline total hip BMD. The relative risk for new vertebral fractures for the raloxifene group compared with placebo was 0.53 (95% CI, 0.32-0.88) for those with osteopenia and 0.31 (0.06-0.71) for those with osteoporosis. In raloxifene-treated women the rate of vertebral fracture was similar in women with osteoporosis (2%) to that in women with osteopenia (1.9%). For clinically apparent vertebral fractures, the relative risk of fracture in the osteopenia group for raloxifene was 0.25 (0.04-0.63) compared with placebo. There were no new clinical vertebral fractures in women with osteoporosis receiving raloxifene, whereas four occurred in the placebo group. We conclude that treatment with 60 mg/day raloxifene significantly decreases the risk of new vertebral fractures and new clinical vertebral fractures in postmenopausal women without baseline vertebral fracture who have osteopenia or osteoporosis.

Increases in BMD correlate with improvements in bone microarchitecture with teriparatide treatment in postmenopausal women with osteoporosis

Increases in BMD are correlated with improvements in 2D and 3D trabecular microarchitecture indices with teriparatide treatment. Therefore, improvements in trabecular bone microarchitecture may be one of the mechanisms to explain how BMD increases improve bone strength during teriparatide treatment.

Raloxifene Treatment Is Associated With Increased Serum Estradiol and Decreased Bone Remodeling in Healthy Middle‐Aged Men With Low Sex Hormone Levels

In healthy middle‐aged men, raloxifene treatment was associated with increased serum estradiol and decreased biochemical markers of bone turnover in subjects with estradiol levels below a threshold of 101.8 pM.

Histomorphometric changes by teriparatide in alendronate-pretreated women with osteoporosis

SummaryThe level of increased bone formation after 24xa0months of treatment with teriparatide (rhPTH (1–34), TPTD) is similar in patients who were either treatment-naïve (TN) or had lower bone turnover initially due to previous alendronate (ALN) therapy.IntroductionBone anabolic effects of TPTD in postmenopausal women with osteoporosis may be blunted during the initial phase after switching from ALN to TPTD. To explore the long-term implications, we examined histomorphometric and biochemical markers of bone turnover of patients on TPTD therapy after long-term ALN treatment.MethodsPaired biopsies were obtained after tetracycline double labeling at baseline and after 24xa0months of TPTD treatment from 29 ALN-pretreated (64.5u2009±u200916.4xa0months) and 16 TN patients. Biochemical markers were measured at baseline, during the treatment, or at study end.ResultsCompared with the baseline, after 24-month TPTD, activation frequency (Ac.F.) and osteoid surface (OS) increased in both groups: 0.11–0.34 cycles per year, 3.96–9.8% in the ALN-pretreated group and 0.19–0.33 cycles per year, 6.2–11.3% (pu2009<u20090.05) in the TN group, respectively. Biochemical and histomorphometric markers correlated positively both at baseline and endpoint. Serum amino terminal propeptide of type I procollagen (PINP) correlated with Ac.F. (ru2009=u20090.57, pu2009<u20090.001 and ru2009=u20090.48, pu2009<u20090.01) and OS (ru2009=u20090.51, pu2009<u20090.01 and ru2009=u20090.56, pu2009<u20090.01) at baseline and endpoint, respectively. Following 3xa0months of treatment, increases in biochemical markers like PINP predicted the increase in Ac.F. (ru2009=u20090.52, pu2009<u20090.01) and OS (ru2009=u20090.54, pu2009<u20090.01) after 24xa0months.ConclusionsThe increased level of formation is similar in patients who were either TN or had lower bone turnover initially due to previous ALN therapy. Elevated bone formation in postmenopausal women with osteoporosis was sustained over a 24-month period by TPTD. Biochemical markers of bone formation are a good surrogate for the assessment of TPTD effects.

Effect of raloxifene combined with monofluorophosphate as compared with monofluorophosphate alone in postmenopausal women with low bone mass: a randomized, controlled trial

Raloxifene effectively reduces the incidence of vertebral fractures in patients with postmenopausal osteoporosis. Recent data suggest that low-dose monofluorophosphate (MFP) plus calcium reduces the vertebral fracture rate in postmenopausal women with moderate osteoporosis. The objective of this study was to evaluate the combination of raloxifene and MFP in the treatment of postmenopausal women with osteopenia, osteoporosis and severe osteoporosis. A total of 596 postmenopausal women with osteopenia, osteoporosis and severe osteoporosis (mean femoral neck T-score of –2.87xa0SD) were randomized to treatment with 60xa0mg/day raloxifene HCl and 20 mg/day fluoride ions (as MFP) or 20xa0mg/day fluoride and placebo for 18 months. All patients received calcium (1000xa0mg/day) and vitamin D (500xa0IU/day) supplements. Changes in bone mineral density (BMD), as primary endpoint, and the rate of osteoporotic fractures and biochemical markers, as secondary endpoints, were assessed. As compared with MFP, raloxifene plus MFP was associated with significantly greater mean increases in the BMD of the femoral neck (1.37% versus 0.33%; P=0.004), total hip (0.89% versus −0.42%; P<0.001) and lumbar spine (8.80% versus 5.47% P<0.001). In the raloxifene plus MFP group, 16 patients sustained 17 osteoporotic fractures, as compared with 22 patients sustaining 34 incident osteoporotic fractures in the MFP group (P=0.313). One patient in the raloxifene plus MFP group sustained multiple osteoporotic fractures, as compared with eight patients in the MFP group (P=0.020). MFP alone significantly increased the serum bone alkaline phosphatase (bone ALP) and the urinary C-terminal crosslinking telopeptide of type I collagene (U-CTX). The addition of raloxifene in the combination arm blunted the rise in bone ALP, which remained nevertheless significant, and abolished the increase in U-CTX. The combination of raloxifene with MFP was generally well tolerated. This study demonstrates that, in postmenopausal women with osteopenia, osteoporosis and severe osteoporosis, the combination therapy of raloxifene plus MFP favorably influences the BMD and the bone formation and resorption balance, and may reduce the risk of multiple osteoporotic fractures compared to MFP alone.

Teriparatide in patients with osteoporosis and type 2 diabetes

Despite evidence for higher fracture risk, clinical effects of osteoporosis treatments in type 2 diabetes (T2D) are largely unknown. Post hoc analyses of the DANCE observational study compared T2D patients and patients without diabetes to assess the effect of teriparatide, an osteoanabolic therapy on skeletal outcomes and safety. Patients included ambulatory men and women with osteoporosis receiving teriparatide 20μg/day SQ up to 24months followed by observation up to 24months. Main outcome measures included nonvertebral fracture incidence comparing 0-6months with 6+ months of teriparatide, change from baseline in BMD and back pain severity, and serious adverse events. Analyses included 4042 patients; 291 with T2D, 3751 without diabetes. Treatment exposure did not differ by group. For T2D patients, fracture incidence was 3.5 per 100 patient-years during 0-6months treatment, and 1.6 during 6months to treatment end (47% of baseline, 95% CI 12-187%); during similar periods, for patients without diabetes, fracture incidence was 3.2 and 1.8 (57% of baseline, 95% CI 39-83%). As determinants of fracture outcome during teriparatide treatment, diabetes was not a significant factor (P=0.858), treatment duration was significant (P=0.003), and the effect of duration was not significantly different between the groups (interaction P=0.792). Increases in spine and total hip BMD did not differ between groups; increase in femoral neck BMD was greater in T2D patients than in patients without diabetes (+0.34 and +0.004g/cm(2), respectively; P=0.014). Back pain severity decreased in both groups. Teriparatide was well tolerated without new safety findings. In conclusion, during teriparatide treatment, reduction in nonvertebral fracture incidence, increase in BMD, and decrease in back pain were similar in T2D and non-diabetic patients.

Bone quality of the newest bone formed after two years of teriparatide therapy in patients who were previously treatment-naïve or on long-term alendronate therapy

SummaryThe results of the present study, involving analysis of biopsies from patients who received teriparatide for 2xa0years and were previously either treatment-naïve or on long-term alendronate therapy, suggest that prior alendronate use does not blunt the favorable effects of teriparatide on bone quality.IntroductionExamine the effect of 2xa0years of teriparatide (TPTD) treatment on mineral and organic matrix properties of the newest formed bone in patients who were previously treatment-naïve (TN) or on long-term alendronate (ALN) therapy.MethodsRaman and Fourier transform infrared microspectroscopic analyses were used to determine the mineral/matrix (M/M) ratio, the relative proteoglycan (PG) content, and the mineral maturity/crystallinity (MMC; determined by three methods: carbonate content, full width at half height of the v1PO4 band [FWHH], and wavelength at maxima of the v1PO4 band), as well as collagen maturity (ratio of pyridinoline/divalent cross-links), in paired iliac crest biopsies at trabecular, endosteal, and osteonal surfaces of newly formed bone in postmenopausal osteoporotic women who were previously either TN (nu2009=u200916) or receiving long-term ALN treatment (nu2009=u200924).ResultsTrabecular M/M ratio increased and matrix content decreased significantly in the ALN pretreated group. Collagen maturity decreased in both patient groups. Endosteal M/M ratio increased significantly in the TN group. Trabecular M/M ratio was higher at endpoint in the ALN pretreated group than in the TN group. Overall, no changes from baseline were observed in PG content, except that PG content was higher in the ALN pretreated group than in the TN group at endosteal surfaces at endpoint. The ability of TPTD treatment to reduce MMC in both patient groups and at the different bone surfaces depended on the measurement tool (relative carbonate content or wavelength at maxima of the v1PO4 band). None of the changes in MMC were different between the two patient groups.ConclusionsThe results suggest some favorable impact of TPTD on bone mineral and organic matrix properties of in situ forming bone in terms of increased initial mineralization and decreased MMC and collagen maturity. Moreover, prior long-term ALN administration may have only limited influence on these properties in bone newly formed after 2xa0years of TPTD treatment.

Influence of Postprandial Hyperglycemic Conditions on Arterial Stiffness in Patients With Type 2 Diabetes

CONTEXTnPatients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease.nnnOBJECTIVEnThe objective of the study was to determine whether postprandial hyperglycemia affects arterial function in T2D.nnnDESIGNnA single-center, open-label study of three groups of men were studied: 1) T2D patients with albuminuria (n = 22), 2) T2D patients without albuminuria (n = 24), and 3) nondiabetic controls (n = 25). Patients were randomized to a two-period crossover study schedule, ingesting breakfast, with or without insulin lispro (to induce low or high postprandial glycemia).nnnMAIN OUTCOME MEASURESnArterial stiffness was assessed by calculating pulse wave velocity (PWV) and augmentation index using applanation tonometry, and endothelial dysfunction was assessed using peripheral arterial tonometry, 30 minutes before breakfast and up to 240 minutes after breakfast.nnnRESULTSnAt baseline, arterial stiffness was increased in patients. When adjusted for age and body mass index, in a combined group of patients with and without albuminuria, brachial PWV was higher during low (P = .032) and high (P = .038) postprandial glycemia vs controls. These differences were driven by the albuminuria group vs controls during low (P = .014) and high (P = .018) postprandial glycemia. No differences were observed in aortic PWV, augmentation index, or peripheral arterial tonometry ratio between patients and controls. Endothelin-1 and IL-6 were higher, and superoxide dismutase was lower, during postprandial hyperglycemia in T2D patients vs controls.nnnCONCLUSIONSnIn patients with T2D and albuminuria, brachial PWV was higher under postprandial hyperglycemic conditions, relative to controls. These data suggest that hyperglycemia induces an increase in stiffness of intermediate-sized arteries. We found no changes in other parts of the arterial bed.

Effect of once-weekly dulaglutide on glycated haemoglobin (HbA1c) and fasting blood glucose in patient subpopulations by gender, duration of diabetes and baseline HbA1c

To evaluate the efficacy and safety of dulaglutide 1.5 and 0.75u2009mg in patients with type 2 diabetes by subgroups of gender, duration of diabetes and baseline glycated haemoglobin (HbA1c) in the dulaglutide clinical development programme (AWARD‐1 to ‐6 and ‐8 clinical trials).