Among patients with osteoporosis who were at high risk for fracture, bone mineral density increased more in patients receiving teriparatide than in those receiving alendronate. (ClinicalTrials.gov number, NCT00051558 [ClinicalTrials.gov].).

OBJECTIVE -To determine the safety and efficacy of the long-acting analog insulin glargine compared with NPH insulin in patients with type 2 diabetes who were previously treated with insulin alone. RESEARCH DESIGN AND METHODS-A total of 518 subjects with type 2 diabetes who were receiving NPH insulin with or without regular insulin for postprandial control were randomized to receive insulin glargine (HOE 901) once daily (n ϭ 259) or NPH insulin once or twice daily (n ϭ 259) for 28 weeks in an open-label, multicenter trial. Doses were adjusted to obtain target fasting glucose Ͻ6.7 mmol/l. At study end point, the median total daily insulin dose in both treatment groups was 0.75 IU/kg. RESULTS -The treatment groups showed similar improvements in HbA 1c from baseline to end point on intent-to-treat analysis. The mean change (means Ϯ SD) in HbA 1c from baseline to end point was similar in the insulin glargine group (Ϫ0.41 Ϯ 0.1%) and the NPH group (Ϫ0.59 Ϯ 0.1%) after patients began with an average baseline HbA 1c of ϳ8.5%. The treatments were associated with similar reductions in fasting glucose levels. Overall, mild symptomatic hypoglycemia was similar in insulin glargine subjects (61.4%) and NPH insulin subjects (66.8%). However, nocturnal hypoglycemia in the insulin glargine group was reduced by 25% during the treatment period after the dose-titration phase (26.5 vs. 35.5%, P ϭ 0.0136). Subjects in the insulin glargine group experienced less weight gain than those in the NPH group (0.4 vs. 1.4 kg, P Ͻ 0.0007).CONCLUSIONS -In patients with type 2 diabetes, once-daily bedtime insulin glargine is as effective as once-or twice-daily NPH in improving and maintaining glycemic control. In addition, insulin glargine demonstrates a lower risk of nocturnal hypoglycemia and less weight gain compared with NPH insulin. Diabetes Care 24:631-636, 2001I nsulin treatment can improve and maintain glycemic control, preventing long-term complications in type 2 diabetes (1-3). Over time, most patients with type 2 diabetes experience progressive ␤-cell dysfunction and will require insulin therapy, either alone or in combination with oral agents, for satisfactory glycemic control (4). Attempts to mimic physiologic patterns of basal insulin secretion have been difficult because most currently available insulins have disadvantages, including variable absorption, pronounced peaks after injection, and abbreviated durations of action (5-8).The novel recombinant insulin analog insulin glargine (HOE 901; 21b-L-Arg-human insulin) is a modification of human insulin in which two arginines are added to the B-chain and glycine is substituted for asparagine at the A21 position of the insulin molecule. These changes cause a shift of the isoelectric point to a neutral pH (9 -11), precipitation at physiologic tissue pH, and increased hexamer stability, resulting in delayed absorption and a flat profile after injection, compared with the shorter duration of action and early peak of NPH insulin (9 -12). Short-term clinical trials in patients with type 1...

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Two distinct options for the management of osteoporosis lead to increases in BMD by opposite mechanisms of action on bone remodeling.

Transiliac bone biopsies were obtained from 55 women treated with teriparatide or placebo for 12-24 months. We report direct evidence that modeling bone formation at quiescent surfaces was present only in teriparatide-treated patients and bone formation at remodeling sites was higher with teriparatide than placebo.Introduction: Recombinant teriparatide [human PTH(1-34)], a bone formation agent for the treatment of osteoporosis when given once daily subcutaneously, increases biochemical markers of bone turnover and activation frequency in histomorphometry studies. Materials and Methods:We studied the mechanisms underlying this bone-forming action of teriparatide at the basic multicellular unit by the appearance of cement lines, a method used to directly classify surfaces as modeling or remodeling osteons, and by the immunolocalization of IGF-I and IGF-II. Transiliac bone biopsies were obtained from 55 postmenopausal women treated with teriparatide 20 or 40 g or placebo for 12-24 months (median, 19.8 months) in the Fracture Prevention Trial. Results: A dose-dependent relationship was observed in modeling and mixed remodeling/modeling trabecular hemiosteons. Trabecular and endosteal hemiosteon mean wall thicknesses were significantly higher in both teriparatide groups than in placebo. There was a dose-dependent relationship in IGF-II immunoreactive staining at all bone envelopes studied. The greater local IGF-II presence after treatment with teriparatide may play a key role in stimulating bone formation. Conclusions: Direct evidence is presented that 12-24 months of teriparatide treatment induced modeling bone formation at quiescent surfaces and resulted in greater bone formation at remodeling sites, relative to placebo.

FE modeling was used to estimate the biomechanical effects of teriparatide and alendronate on lumbar vertebrae. Both treatments enhanced predicted vertebral strength by increasing average density. This effect was more pronounced for teriparatide, which further increased predicted vertebral strength by altering the distribution of density within the vertebra, preferentially increasing the strength of the trabecular compartment.Introduction: Teriparatide 20 g/day (TPTD) and alendronate 10 mg/day (ALN) increase areal, measured by DXA, and volumetric, measured by QCT, lumbar spine BMD through opposite effects on bone remodeling. Using finite element (FE) modeling of QCT scans, we sought to compare the vertebral strength characteristics in TPTD-and ALN-treated patients. Materials and Methods: A subset of patients (N ‫ס‬ 28 TPTD; N ‫ס‬ 25 ALN) from the Forteo Alendronate Comparator Trial who had QCT scans of the spine at baseline and postbaseline were analyzed. The QCT scans were analyzed for compressive strength of the L 3 vertebra using FE modeling. In addition, using controlled parameter studies of the FE models, the effects of changes in density, density distribution, and geometry on strength were calculated, a strength:density ratio was determined, and a response to bending was also quantified. Results: Both treatments had positive effects on predicted vertebral strength characteristics. At least 75% of the patients in each treatment group had increased strength of the vertebra at 6 months compared with baseline. Patients in both treatment groups had increased average volumetric density and increased strength in the trabecular bone, but the median percentage increases for these parameters were 5-to 12-fold greater for TPTD. Larger increases in the strength:density ratio were also observed for TPTD, and these were primarily attributed to preferential increases in trabecular strength. Conclusions: These results provide new insight into the effects of these treatments on estimated biomechanical properties of the vertebra. Both treatments positively affected predicted vertebral strength through their effects on average BMD, but the magnitudes of the effects were quite different. Teriparatide also affected vertebral strength by altering the distribution of density within the vertebra, so that overall, teriparatide had a 5-fold greater percentage increase in the strength:density ratio.

RESEARCH DESIGN AND METHODS -Patients with type 1 diabetes receiving basalbolus insulin treatment with NPH human insulin and insulin lispro were randomized to receive insulin glargine (HOE 901), a long-acting basal insulin analog, once a day (n = 310) or NPH human insulin (n = 309) as basal treatment with continued bolus insulin lispro for 16 weeks in an open-label study. NPH insulin patients maintained their prior schedule of administration once or twice a day, whereas insulin glargine patients received basal insulin once a day at bedtime.RESULTS -Compared with all NPH insulin patients, insulin glargine patients had significant decreases in fasting blood glucose measured at home (means ± SEM, Ϫ42.0 ± 4.7 vs. Ϫ12.4 ± 4.7 mg/dl [-2.33 ± 0.26 vs. Ϫ0.69 ± 0.26 mmol/l]; P = 0.0001). These differences were evident early and persisted throughout the study. More patients in the insulin glargine group (29.6%) than in the NPH group (16.8%) reached a target fasting blood glucose of 119 mg/dl (Ͻ6.6 mmol/l). However, there were no differences between the groups with respect to change in GHb. Insulin glargine treatment was also associated with a significant decrease in the variability of fasting blood glucose values (P = 0.0124). No differences in the occurrence of symptomatic hypoglycemia, including nocturnal hypoglycemia, were observed. Overall, adverse events were similar in the two treatment groups with the exception of injection site pain, which was more common in the insulin glargine group (6.1%) than in the NPH group (0.3%). Weight gain was 0.12 kg in insulin glargine patients and 0.54 kg in NPH insulin patients (P = 0.034).CONCLUSIONS -Basal insulin therapy with insulin glargine once a day appears to be as safe and at least as effective as using NPH insulin once or twice a day in maintaining glycemic control in patients with type 1 diabetes receiving basal-bolus insulin treatment with insulin lispro.

An 18-month randomized double-blind study was conducted in postmenopausal women with osteoporosis to compare the effects of once-daily teriparatide 20 µg with alendronate 10 mg on bone histomorphometry. Biopsies were obtained from 42 patients. Indices of bone formation were significantly higher after 6 or 18 months of teriparatide compared with alendronate treatment.Introduction: Alendronate and teriparatide increased BMD, assessed by DXA, by different mechanisms of action, supported by changes in biochemical markers of bone turnover. The purpose of this cross-sectional study was to explore the differential effects of these two osteoporosis treatments at the bone tissue level by examining bone histomorphometric parameters of bone turnover after either 6 or 18 months of treatment. Materials and Methods:Patients were a cohort from a randomized parallel double-blind study conducted to compare the effects of once-daily teriparatide 20 g and alendronate 10 mg in postmenopausal women with osteoporosis. Transiliac crest bone biopsies were obtained after tetracycline double labeling from 42 patients treated for 6 months (n ‫ס‬ 23) or 18 months (n ‫ס‬ 14); 5 additional patients were biopsied from contralateral sides at 6 and 18 months. Biopsy specimens adequate for quantitative analysis were analyzed by 2D histomorphometry from 17 patients at 6 months (teriparatide, n ‫ס‬ 8; alendronate, n ‫ס‬ 9) and 15 patients at 18 months (teriparatide, n ‫ס‬ 8; alendronate, n ‫ס‬ 7). Data were analyzed by two-sample tests. Results: Histomorphometric indices of bone formation were significantly and markedly greater in the teriparatide group than in the alendronate group at 6 and 18 months, whereas indices of bone resorption were only significantly greater in the teriparatide group than in the alendronate group at 6 months. Bone formation and activation frequency were significantly lower at 18 months compared with 6 months in the teriparatide group, returning to levels comparable with untreated postmenopausal women. In the teriparatide group, the peak in histomorphometric bone formation indices coincided with peak levels for N-terminal propeptide of type I collagen, a biochemical marker of bone formation. The degree of mineralization was lower at 18 months than at 6 months with treatment in both groups but was not different between groups. Conclusions: These results confirm the opposite mechanisms of action of teriparatide and alendronate on bone remodeling and confirm the bone formation effect of teriparatide.