Zoledronic Acid vs Placebo in Pediatric Glucocorticoid-induced Osteoporosis: A Randomized, Double-blind, Phase 3 Trial.

CONTEXT: Glucocorticoids (GCs) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures. OBJECTIVE: This study aims to determine the efficacy and safety of intravenous (IV) zoledronic acid (ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO). METHODS: Children aged 5 to 17 years with GIO were enrolled in this multinational, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov NCT00799266). Eligible children were randomly assigned 1:1 to 6 monthly IV ZA 0.05 mg/kg or IV placebo. The primary end point was the change in lumbar spine bone mineral density z score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed. RESULTS: Thirty-four children were enrolled (mean age 12.6 ±â€…3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from -2.13 ±â€…0.79 to -1.49 ±â€…1.05 on ZA, compared with -2.38 ±â€…0.90 to -2.27 ±â€…1.03 on placebo (least squares means difference 0.41 [95% CI, 0.02-0.81; P = .04]); when corrected for height z score, the least squares means difference in LBMDZ was 0.75 [95% CI, 0.27-1.22; P = .004]. Two children on placebo had new low-trauma VF vs none on ZA. Adverse events (AEs) were reported in 15 of 18 children (83%) on ZA, and in 12 of 16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths or treatment discontinuations due to treatment-emergent AEs. CONCLUSION: LSBMDZ increased significantly on ZA compared with placebo over 1 year in children with GIO. Most AEs occurred after the first infusion.

The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT).

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits.

Re-treatment of relapsed Paget's disease of bone with zoledronic acid: results from an open-label study.

Six patients from the phase 3 trials of zoledronic acid in Paget's disease, who had received zoledronic acid initially and had subsequently relapsed, were entered into an open re-treatment study. Following re-treatment, each patient reached similar absolute nadirs of serum alkaline phosphatase to those recorded after their first dose. No significant adverse events were reported. It is concluded that, while re-treatment of Paget's disease with zoledronic acid is rarely needed, it is safe and effective, with no evidence of treatment resistance based on this small cohort.

Renal function in type 2 diabetes with rosiglitazone, metformin, and glyburide monotherapy.

BACKGROUND AND OBJECTIVES: In ADOPT (A Diabetes Outcomes Prevention Trial), initial monotherapy with rosiglitazone provided more durable glycemic control than metformin or glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine differences in albumin excretion, renal function (estimated GFR), and BP over 5 years between treatment groups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 4351 recently diagnosed, drug-naïve patients with type 2 diabetes were treated and followed for up to 5 years with rosiglitazone, metformin, or glyburide and were examined with periodic assessments of albumin/creatinine ratio (ACR), modification of diet in renal disease (MDRD)-estimated GFR, and BP. RESULTS: The ACR rose slowly with metformin. It fell with rosiglitazone and less so with glyburide over the first 2 years, and then rose slowly over time. Estimated GFR (eGFR) with all therapies rose into the high normal range over the first 3 to 4 years, more so with rosiglitazone, and then declined, more so with glyburide. Systolic BP was stable over time, values with rosiglitazone being lower, and diastolic BP declined over time, more so with rosiglitazone than with metformin or glyburide. There was no difference among groups in the incidence of emergent albuminuria (ACR ≥30 mg/g), hypertension, or impaired eGFR (<60 ml/min per 1.73 m(2)). CONCLUSIONS: Over a 5-year period, initial monotherapy with rosiglitazone retards the rise of ACR compared with metformin, preserves eGFR compared with glyburide, and lowers BP relative to both comparators.

Effects of rosiglitazone, glyburide, and metformin on ß-cell function and insulin sensitivity in ADOPT.

OBJECTIVE: ADOPT (A Diabetes Outcome Progression Trial) demonstrated that initial monotherapy with rosiglitazone provided superior durability of glycemic control compared with metformin and glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine measures of ß-cell function and insulin sensitivity from an oral glucose tolerance test (OGTT) over a 4-year period among the three treatments. RESEARCH DESIGN AND METHODS: Recently diagnosed, drug-naïve patients with type 2 diabetes (4,360 total) were treated for a median of 4.0 years with rosiglitazone, metformin, or glyburide and were examined with periodic metabolic testing using an OGTT. RESULTS: Measures of ß-cell function and insulin sensitivity from an OGTT showed more favorable changes over time with rosiglitazone versus metformin or glyburide. Persistent improvements were seen in those who completed 4 years of monotherapy and marked deterioration of ß-cell function in those who failed to maintain adequate glucose control with initial monotherapy. CONCLUSIONS: The favorable combined changes in ß-cell function and insulin sensitivity over time with rosiglitazone appear to be responsible for its superior glycemic durability over metformin and glyburide as initial monotherapy in type 2 diabetes.

Effect of rosiglitazone, metformin, and glyburide on bone biomarkers in patients with type 2 diabetes.

CONTEXT: An increase in bone fractures has been observed in women taking thiazolidinediones. OBJECTIVE: The objective of the study was to examine whether changes in circulating bone biomarkers provide insight into the underlying mechanisms responsible for the increase in bone fractures in female participants randomized to rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Paired stored baseline and 12-month serum samples were available from 1605 participants (689 women, 916 men) in ADOPT, a long-term clinical trial comparing the effects of rosiglitazone, glyburide, and metformin on glycemic control in patients with type 2 diabetes. RESULTS: This subset was well matched to the total ADOPT study population. In women a marker of osteoclast activity, C-terminal telopeptide (for type 1 collagen), increased by 6.1% with rosiglitazone compared with reductions of 1.3% (P = 0.03 vs. rosiglitazone) and 3.3% (P = 0.002 vs. rosiglitazone) with metformin and glyburide, respectively. In men, C-terminal telopeptide was unchanged on rosiglitazone (-1.0%) and fell on metformin (-12.7%; P < 0.001) and glyburide (-4.3%, P = NS). Markers of osteoblast activity, procollagen type 1 N-propeptide (P1NP) and bone alkaline phosphatase, were reduced for women and men in almost all treatment groups, with the greatest changes in the metformin group (P1NP in females, -14.4%; P1NP in males, -19.3%), intermediate for rosiglitazone (P1NP in females, -4.4%; P1NP in males, -14.4%), and smallest for glyburide (P1NP in males, +0.2%; bone alkaline phosphatase in females, -11.6%). CONCLUSIONS: Commonly measured bone biomarkers suggest that changes in bone resorption may be partly responsible for the increased risk of fracture in women taking thiazolidinediones.

Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT).

OBJECTIVE: The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS: In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2-19.1) with rosiglitazone, 7.3% (4.4-10.1) with metformin, and 7.7% (3.7-11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS: Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.