Randomised controlled trial of melatonin for paediatric functional abdominal pain disorders.

AIM: Melatonin seems to have a positive impact on the brain-gut axis and many direct and indirect effects on the gastrointestinal tract. This trial aimed at assessing the efficacy of melatonin combined with Lactobacillus Rhamnosus GG given in the treatment of paediatric patients with functional abdominal pain disorders. METHODS: Forty-two patients aged 4-18 years old who fulfilled the Rome IV Diagnostic Criteria for functional abdominal pain disorders were enrolled. Melatonin 3 or 5 mg in combination with Lactobacillus Rhamnosus GG (group 1, n = 22) or a placebo in combination with Lactobacillus Rhamnosus GG (control group, n = 20) were taken in the evening for a period of 4 weeks. The study duration was 12 weeks. The primary study endpoint was represented by clinical improvement at week 12 - defined as at least a 50% reduction in mean abdominal pain index (API) from baseline to week 12. RESULTS: The mean API was reduced by more than 50% between T0 and T2 in the group of children treated with melatonin. However, the difference in the distributions of the variations of the scores between the two groups was not significant between T0 and T2 (P = 0.082), while it was significant between T0 and T1 (P = 0.001). Similar results were obtained by analysing the API variables 'weekly frequency of pain' (item 1) and 'perceived intensity of pain' (item 4) individually. CONCLUSIONS: This is the first study to investigate the role of the combination of melatonin and Lactobacillus Rhamnosus GG in the treatment of children with functional abdominal pain disorders. Melatonin combined with Lactobacillus Rhamnosus GG can be considered a therapeutic option for these conditions in children.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

OBJECTIVE: To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. RESULTS: A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. CONCLUSION: Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Fracture risk in diabetic elderly men: the MrOS study.

AIMS/HYPOTHESIS: Diabetes mellitus is associated with increased fracture risk in women but few studies are available in men. To evaluate the relationship between diabetes and prospective non-vertebral fractures in elderly men, we used data from the Osteoporotic Fractures in Men (MrOS) study. METHODS: The MrOS enrolled 5,994 men (aged ≥65 years). Diabetes (ascertained by self-report, the use of medication for diabetes or an elevated fasting glucose level) was reported in 881 individuals, 80 of whom were using insulin. Hip and spine bone mineral density (BMD) was measured using dual x-ray absorptiometry (DXA). After recruitment, the men were followed for incident non-vertebral fractures using a triannual (3 yearly) questionnaire for an average of 9.1 (SD 2.7) years. The Cox proportional hazards model was used to assess the incident risk of fractures. RESULTS: In models adjusted for age, race, clinic site and total hip BMD, the risk of non-vertebral fracture was higher in men with diabetes compared with normoglycaemic men (HR 1.30, 95% CI 1.09, 1.54) and was elevated in men using insulin (HR 2.46, 95% CI 1.69, 3.59). Men with impaired fasting glucose did not have a higher risk of fracture compared with normoglycaemic men (HR 1.04, 95% CI 0.89, 1.21). After multivariable adjustment, the risk of non-vertebral fracture remained higher only among men with diabetes who were using insulin (HR 1.74, 95% CI 1.13, 2.69). CONCLUSIONS/INTERPRETATION: Men with diabetes who are using insulin have an increased risk of non-vertebral fracture for a given age and BMD.

Intensive blood pressure control, falls, and fractures in patients with type 2 diabetes: the ACCORD trial.

BACKGROUND: There are few rigorous studies to confirm or refute the commonly cited concern that control of blood pressure to lower thresholds may result in an increased risk of falls and fractures. OBJECTIVE: To compare falls and fractures in participants with type 2 diabetes in the intensive (targeting a systolic blood pressure of < 120 mmHg) and standard (targeting a systolic blood pressure of < 140 mmHg) blood pressure control arms of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) randomized trial (N = 4,733). PARTICIPANTS: A subset of 3,099 participants self-reported annually on the occurrence of falls and non-spine fractures. Fractures were centrally adjudicated. MAIN MEASURES: The incidence of falls in the two treatment groups was compared using a random-effects negative binomial model, and fracture risk was compared using Cox proportional hazards models. KEY RESULTS: At enrollment in both groups, the mean age was 62 years, 44% were women, 25% were Black, and mean blood pressure was 138/75 mmHg. During follow-up, all classes of medications, particularly thiazide diuretics, were more commonly prescribed in the intensive group. After 1 year of follow-up, the mean systolic blood pressure was 133 ± 15 mmHg in the standard group and 119 ± 14 mmHg in the intensive group. The adjusted rate of falls did not differ in the intensive and standard groups (62.2/100 person-years vs. 74.1/100 person-years, RR = 0.84, 95% CI 0.54-1.29, p = 0.43). The risk of non-spine fractures was nonsignificantly lower in the intensive than in the standard blood pressure group (HR 0.79, 95% CI 0.62-1.01, p = 0.06). CONCLUSIONS: We conclude that intensive antihypertensive treatment that lowered mean systolic blood pressure to below 120 mmHg was not associated with an increased risk of falls or non-spine fractures in patients age 40 to 79 years with type 2 diabetes.

Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur.

BACKGROUND: A number of recent case reports and series have identified a subgroup of atypical fractures of the femoral shaft associated with bisphosphonate use. A population-based study did not support this association. Such a relationship has not been examined in randomized trials. METHODS: We performed secondary analyses using the results of three large, randomized bisphosphonate trials: the Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial, and the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT). We reviewed fracture records and radiographs (when available) from all hip and femur fractures to identify those below the lesser trochanter and above the distal metaphyseal flare (subtrochanteric and diaphyseal femur fractures) and to assess atypical features. We calculated the relative hazards for subtrochanteric and diaphyseal fractures for each study. RESULTS: We reviewed 284 records for hip or femur fractures among 14,195 women in these trials. A total of 12 fractures in 10 patients were classified as occurring in the subtrochanteric or diaphyseal femur, a combined rate of 2.3 per 10,000 patient-years. As compared with placebo, the relative hazard was 1.03 (95% confidence interval [CI], 0.06 to 16.46) for alendronate use in the FIT trial, 1.50 (95% CI, 0.25 to 9.00) for zoledronic acid use in the HORIZON-PFT trial, and 1.33 (95% CI, 0.12 to 14.67) for continued alendronate use in the FLEX trial. Although increases in risk were not significant, confidence intervals were wide. CONCLUSIONS: The occurrence of fracture of the subtrochanteric or diaphyseal femur was very rare, even among women who had been treated with bisphosphonates for as long as 10 years. There was no significant increase in risk associated with bisphosphonate use, but the study was underpowered for definitive conclusions.

Intensive glycemic control and thiazolidinedione use: effects on cortical and trabecular bone at the radius and tibia.

Factors that contribute to bone fragility in type 2 diabetes are not well understood. We assessed the effects of intensive glycemic control, thiazolidinediones (TZDs), and A1C levels on bone geometry and strength at the radius and tibia. In a substudy of the Action to Control Cardiovascular Risk in Diabetes trial, peripheral quantitative computed tomographic (pQCT) scans of the radius and tibia were obtained 2 years after randomization on 73 participants (intensive n = 35, standard n = 38). TZD use and A1C levels were measured every 4 months during the trial. Effects of intervention assignment, TZD use, and A1C on pQCT parameters were assessed in linear regression models. Intensive, compared with standard, glycemic control was associated with 1.3 % lower cortical volumetric BMD at the tibia in men (p = 0.02) but not with other pQCT parameters. In women, but not men, each additional year of TZD use was associated with an 11 % lower polar strength strain index (SSIp) at the radius (p = 0.04) and tibia (p = 0.002) in models adjusted for A1C levels. In women, each additional 1 % increase in A1C was associated with an 18 % lower SSIp at the ultradistal radius (p = 0.04) in models adjusted for TZD use. There was no consistent evidence of an effect of intensive, compared with standard, glycemic control on bone strength at the radius or tibia. In women, TZD use may reduce bone strength at these sites. Higher A1C may also be associated with lower bone strength at the radius, but not tibia, in women.

Consistency of bone turnover marker and calcium responses to parathyroid hormone (1-84) therapy in postmenopausal osteoporosis.

We investigated whether those who experience the greatest increases in bone turnover in response to parathyroid hormone (PTH) therapy are the same as those who experience elevations in calcium levels. Baseline and follow-up procollagen type I N propeptide (PINP), bone-specific alkaline phosphatase (BAP), C-terminal telopeptide (CTX), and serum and urinary calcium levels were analyzed post hoc from the 119 postmenopausal women with osteoporosis randomized to PTH(1-84) in the Parathyroid Hormone and Alendronate trial. Short-term changes in the markers of bone turnover were highly correlated with one another (r=0.57-0.87, p<0.001). In contrast, change in serum calcium correlated only modestly with changes in markers of formation (r=0.22-0.30, p≤0.02) and did not correlate significantly with change in CTX (r=0.13, p=0.18). Participants who experienced hypercalcemia experienced greater 3-mo changes in BAP than those who did not (78% vs. 42% increase in BAP, p=0.04), with similar trends for PINP and CTX. In conclusion, the use of 1 marker of bone turnover, rather than multiple markers, may be sufficient to assess biochemical response to PTH(1-84). The relationship between bone turnover marker and calcium responses to PTH(1-84) is modest and does not suggest a profound, broadly heightened responsiveness of certain individuals to therapy.

Association of BMD and FRAX score with risk of fracture in older adults with type 2 diabetes.

CONTEXT: Type 2 diabetes mellitus (DM) is associated with higher bone mineral density (BMD) and paradoxically with increased fracture risk. It is not known if low BMD, central to fracture prediction in older adults, identifies fracture risk in patients with DM. OBJECTIVE: To determine if femoral neck BMD T score and the World Health Organization Fracture Risk Algorithm (FRAX) score are associated with hip and nonspine fracture risk in older adults with type 2 DM. DESIGN, SETTING, AND PARTICIPANTS: Data from 3 prospective observational studies with adjudicated fracture outcomes (Study of Osteoporotic Fractures [December 1998-July 2008]; Osteoporotic Fractures in Men Study [March 2000-March 2009]; and Health, Aging, and Body Composition study [April 1997-June 2007]) were analyzed in older community-dwelling adults (9449 women and 7436 men) in the United States. MAIN OUTCOME MEASURE: Self-reported incident fractures, which were verified by radiology reports. RESULTS: Of 770 women with DM, 84 experienced a hip fracture and 262 a nonspine fracture during a mean (SD) follow-up of 12.6 (5.3) years. Of 1199 men with DM, 32 experienced a hip fracture and 133 a nonspine fracture during a mean (SD) follow-up of 7.5 (2.0) years. Age-adjusted hazard ratios (HRs) for 1-unit decrease in femoral neck BMD T score in women with DM were 1.88 (95% confidence interval [CI], 1.43-2.48) for hip fracture and 1.52 (95% CI, 1.31-1.75) for nonspine fracture, and in men with DM were 5.71 (95% CI, 3.42-9.53) for hip fracture and 2.17 (95% CI, 1.75-2.69) for nonspine fracture. The FRAX score was also associated with fracture risk in participants with DM (HRs for 1-unit increase in FRAX hip fracture score, 1.05; 95% CI, 1.03-1.07, for women with DM and 1.16; 95% CI, 1.07-1.27, for men with DM; HRs for 1-unit increase in FRAX osteoporotic fracture score, 1.04; 95% CI, 1.02-1.05, for women with DM and 1.09; 95% CI, 1.04-1.14, for men with DM). However, for a given T score and age or for a given FRAX score, participants with DM had a higher fracture risk than those without DM. For a similar fracture risk, participants with DM had a higher T score than participants without DM. For hip fracture, the estimated mean difference in T score for women was 0.59 (95% CI, 0.31-0.87) and for men was 0.38 (95% CI, 0.09-0.66). CONCLUSIONS: Among older adults with type 2 DM, femoral neck BMD T score and FRAX score were associated with hip and nonspine fracture risk; however, in these patients compared with participants without DM, the fracture risk was higher for a given T score and age or for a given FRAX score.

Accounting for multiple births in neonatal and perinatal trials: systematic review and case study.

OBJECTIVES: To determine the prevalence in the neonatal literature of statistical approaches accounting for the unique clustering patterns of multiple births and to explore the sensitivity of an actual trial to several analytic approaches to multiples. STUDY DESIGN: A systematic review of recent perinatal trials assessed the prevalence of studies accounting for clustering of multiples. The Nitric Oxide to Prevent Chronic Lung Disease (NO CLD) trial served as a case study of the sensitivity of the outcome to several statistical strategies. We calculated odds ratios using nonclustered (logistic regression) and clustered (generalized estimating equations, multiple outputation) analyses. RESULTS: In the systematic review, most studies did not describe the random assignment of twins and did not account for clustering. Of those studies that did, exclusion of multiples and generalized estimating equations were the most common strategies. The NO CLD study included 84 infants with a sibling enrolled in the study. Multiples were more likely than singletons to be white and were born to older mothers (P < .01). Analyses that accounted for clustering were statistically significant; analyses assuming independence were not. CONCLUSIONS: The statistical approach to multiples can influence the odds ratio and width of confidence intervals, thereby affecting the interpretation of a study outcome. A minority of perinatal studies address this issue.

Randomized trial of once-weekly parathyroid hormone (1-84) on bone mineral density and remodeling.

CONTEXT: Daily PTH administration increases bone mineral density (BMD) and reduces fracture risk. However, cost and compliance significantly limit clinical use. OBJECTIVE: Our objective was to determine whether less frequent PTH administration increases lumbar spine BMD. PARTICIPANTS, DESIGN, AND SETTING: Fifty postmenopausal women ages 45-70 yr with femoral neck BMD T-score between -1.0 and -2.0 participated in a double-blind, randomized, placebo-controlled trial at St. Joseph Hospital, Bangor, ME. INTERVENTION: Subjects received sc injections of daily PTH(1-84) (100 mug) or placebo for 1 month, followed by weekly injections (PTH or placebo) for 11 months. OUTCOMES: Change in lumbar spine dual-energy x-ray absorptiometry areal BMD (primary) was assessed. Secondary outcomes included volumetric BMD at spine and hip by quantitative computed tomography, trabecular bone microarchitecture by magnetic resonance imaging of distal radius, and biochemical bone turnover markers. RESULTS: At 12 months, lumbar spine areal BMD increased 2.1% in PTH-treated women compared with placebo (P = 0.03). Vertebral trabecular volumetric BMD increased 3.8% in PTH-treated women compared with placebo group (P = 0.08). PTH-treated women also had higher distal radial trabecular bone volume, number, and thickness compared with placebo-treated women (P < 0.04). After 1 month of daily PTH, N-terminal propeptide of type I collagen (P1NP) was markedly increased compared with placebo (P < 0 .0001), and a difference persisted, although lessened, throughout the study. Bone resorption indices were unchanged in PTH-treated women and were reduced in the placebo group. CONCLUSION: Once-weekly PTH after 1 month of daily treatment increases spine BMD, radial trabecular bone, and bone formation markers in postmenopausal women. These results suggest that less frequent alternatives to daily PTH dosing for 2 yr could be effective. Additional studies are required to define the optimal frequency of PTH administration.

One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis.

BACKGROUND: Since the use of parathyroid hormone as a treatment for osteoporosis is limited to two years or less, the question of whether antiresorptive therapy should follow parathyroid hormone therapy is important. We previously reported results after the first year of this randomized trial comparing the use of full-length parathyroid hormone (1-84) alone, alendronate alone, or both combined. In the continuation of this trial, we asked whether antiresorptive therapy is required to maintain gains in bone mineral density after one year of therapy with parathyroid hormone (1-84). METHODS: In the data reported here, women who had received parathyroid hormone (1-84) monotherapy (100 microg daily) in year 1 were randomly reassigned to one additional year with either placebo (60 subjects) or alendronate (59 subjects). Subjects who had received combination therapy in year 1 received alendronate in year 2; those who had received alendronate monotherapy in year 1 continued with alendronate in year 2. Bone mineral density at the spine and hip was assessed with the use of dual-energy x-ray absorptiometry and quantitative computed tomography (CT). RESULTS: Over two years, alendronate therapy after parathyroid hormone therapy led to significant increases in bone mineral density in comparison with the results for placebo after parathyroid hormone therapy, a difference particularly evident for bone mineral density in trabecular bone at the spine on quantitative CT (an increase of 31 percent in the parathyroid hormone-alendronate group as compared with 14 percent in the parathyroid hormone-placebo group). During year 2, subjects receiving placebo lost substantial bone mineral density. CONCLUSIONS: After one year of parathyroid hormone (1-84), densitometric gains appear to be maintained or increased with alendronate but lost if parathyroid hormone is not followed by an antiresorptive agent. These results have clinical implications for therapeutic choices after the discontinuation of parathyroid hormone.

One-year respiratory outcomes of preterm infants enrolled in the Nitric Oxide (to prevent) Chronic Lung Disease trial.

OBJECTIVE: To identify whether inhaled nitric oxide treatment decreased indicators of long-term pulmonary morbidities after discharge from the neonatal intensive care unit. STUDY DESIGN: The Nitric Oxide (to Prevent) Chronic Lung Disease trial enrolled preterm infants (<1250 g) between 7 to 21 days of age who were ventilated and at high risk for bronchopulmonary dysplasia. Follow-up occurred at 12 +/- 3 months of age adjusted for prematurity; long-term pulmonary morbidity and other outcomes were reported by parents during structured blinded interviews. RESULTS: A total of 456 infants (85%) were seen at 1 year. Compared with control infants, infants randomized to inhaled nitric oxide received significantly less bronchodilators (odds ratio [OR] 0.53 [95% confidence interval 0.36-0.78]), inhaled steroids (OR 0.50 [0.32-0.77]), systemic steroids (OR 0.56 [0.32-0.97]), diuretics (OR 0.54 [0.34-0.85]), and supplemental oxygen (OR 0.65 [0.44-0.95]) after discharge from the neonatal intensive care unit. There were no significant differences between parental report of rehospitalizations (OR 0.83 [0.57-1.21]) or wheezing or whistling in the chest (OR 0.70 [0.48-1.03]). CONCLUSIONS: Infants treated with inhaled nitric oxide received fewer outpatient respiratory medications than the control group. However, any decision to institute routine use of this dosing regimen should also take into account the results of the 24-month neurodevelopmental assessment.

Does a history of non-vertebral fracture identify women without osteoporosis for treatment?

BACKGROUND: Postmenopausal women with a prior fracture have an increased risk for future fracture. Whether a history of non-vertebral fracture defines a group of women with low bone mass but without osteoporosis for whom alendronate would prevent new non-vertebral fracture is not known. SUBJECTS AND METHODS: Secondary analysis of data from the Fracture Intervention Trial (FIT). Of 2,785 postmenopausal women with a T-score at the femoral neck between -1 and -2.5 and without prevalent radiographic vertebral deformity, 880 (31.6%) reported experiencing a fracture after 45 years of age. Women were randomized to placebo or alendronate (5 mg/day years for the first 2 years and 10 mg/day thereafter) and were followed for an average of 4.2 +/- 0.5 years. Incident non-vertebral fractures were confirmed by x-rays and radiology reports. RESULTS: In the placebo arm, a self-report of prior fracture identified women with a 1.5-fold (hazard ratio [RH] 1.46, 95% C.I. 1.04-2.04) increased risk for incident non-vertebral fracture. However, there was no evidence that the effect of alendronate differed across subgroups of women with (RH 1.26 for alendronate vs placebo, 95% C.I. 0.89-1.79) and without prior fracture (RH 1.02 for alendronate vs placebo, 95% C.I. 0.76-1.38; P = 0.37 for interaction). CONCLUSION: Assessing a clinical risk factor, prior non-vertebral fracture, did not identify women with low bone mass for whom alendronate reduced future non-vertebral fracture risk.

Elevations in serum and urinary calcium with parathyroid hormone (1-84) with and without alendronate for osteoporosis.

CONTEXT: The effect of PTH therapy on serum and urinary calcium levels and the risk of hypercalcemia or hypercalciuria has not been formally evaluated. OBJECTIVE: The objective was to examine changes in serum and urinary calcium associated with PTH(1-84) therapy in the PaTH trial and the extent to which a defined algorithm resolved the elevated values. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: A total of 178 postmenopausal women were randomized to PTH(1-84) either alone or in combination with alendronate during the first year of the PaTH study. MAIN OUTCOME MEASURE(S): The main outcome measures were fasting serum calcium at baseline and 1, 3, and 12 months and 24-h urinary calcium at baseline and 3 months. RESULTS: In 14% of participants, serum calcium more than 10.5 mg/dl (>2.6 mmol/liter) developed. Following the defined algorithm, 58% of elevated measurements were normal on repeat testing; 38% required discontinuation of calcium and vitamin D supplementation, and one necessitated a decrease in PTH injection frequency to normalize serum calcium. One participant developed transient hypercalcemia between study visits and required hospitalization; the episode resolved with iv hydration and PTH discontinuation. Baseline characteristics associated with the development of hypercalcemia were serum calcium [relative hazards = 1.9 per 0.5 mg/dl (0.12 mmol/liter); 95% confidence interval = 1.1-3.2] and serum 1,25-dihydroxyvitamin D [relative hazard = 1.9 per 10 pg/ml (26 pmol/liter); 95% confidence interval = 1.2-3.1]. Fifteen women (8%) developed hypercalciuria [urinary calcium > 400 mg (100 mmol)/24 h or calcium/creatinine ratio > 0.4]; 80% of cases resolved after discontinuing calcium and vitamin D, 13% without intervention, and one after PTH injection frequency was decreased. Higher baseline urinary calcium excretion was associated with development of hypercalciuria [relative hazard = 1.5 per 50 mg/d (12.5 mmol/d); 95% confidence interval = 1.2-4.0]. Proportions of patients with elevated serum and urinary calcium were similar on single and combination therapy. CONCLUSIONS: The frequency of episodic hypercalcemia or hypercalciuria in the PaTH trial was 21%. Episodes were generally mild, and nearly all cases resolved spontaneously or with discontinuation of calcium and vitamin D. The algorithms used to address hypercalcemia and hypercalciuria in the PaTH trial proved effective in safely resolving clinical episodes of increased urinary or serum calcium and might therefore be helpful to clinicians caring for patients on PTH.

The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis.

BACKGROUND: Parathyroid hormone increases bone strength primarily by stimulating bone formation, whereas antiresorptive drugs reduce bone resorption. We conducted a randomized, double-blind clinical study of parathyroid hormone and alendronate to test the hypothesis that the concurrent administration of the two agents would increase bone density more than the use of either one alone. METHODS: A total of 238 postmenopausal women (who were not using bisphosphonates) with low bone mineral density at the hip or spine (a T score of less than -2.5, or a T score of less than -2.0 with an additional risk factor for osteoporosis) were randomly assigned to daily treatment with parathyroid hormone (1-84) (100 microg; 119 women), alendronate (10 mg; 60 women), or both (59 women) and were followed for 12 months. Bone mineral density at the spine and hip was assessed by dual-energy x-ray absorptiometry and quantitative computed tomography. Markers of bone turnover were measured in fasting blood samples. RESULTS: The bone mineral density at the spine increased in all the treatment groups, and there was no significant difference in the increase between the parathyroid hormone group and the combination-therapy group. The volumetric density of the trabecular bone at the spine increased substantially in all groups, but the increase in the parathyroid hormone group was about twice that found in either of the other groups. Bone formation increased markedly in the parathyroid hormone group but not in the combination-therapy group. Bone resorption decreased in the combination-therapy group and the alendronate group. CONCLUSIONS: There was no evidence of synergy between parathyroid hormone and alendronate. Changes in the volumetric density of trabecular bone, the cortical volume at the hip, and levels of markers of bone turnover suggest that the concurrent use of alendronate may reduce the anabolic effects of parathyroid hormone. Longer-term studies of fractures are needed to determine whether and how antiresorptive drugs can be optimally used in conjunction with parathyroid hormone therapy.

Long-term risk of incident vertebral fractures.

CONTEXT: Vertebral fractures are the most common osteoporotic fracture. Women with low bone mineral density (BMD) and prevalent vertebral fractures have a greater risk of incident vertebral fractures over the short-term, but their absolute risk of vertebral fracture over the long-term is uncertain. OBJECTIVE: To examine the absolute risk of incident vertebral fracture by BMD and prevalent vertebral fracture status over 15 years. DESIGN, SETTING, AND PARTICIPANTS: A total of 9704 white women were recruited at 4 US clinical centers and enrolled in the Study of Osteoporotic Fractures, a longitudinal cohort study. Of these, 2680 attended a clinic visit an average of 14.9 years after baseline; mean age of 68.8 years at entry and 83.8 years at follow-up. Mean Outcome Measure Incident vertebral fractures identified from lateral spinal radiographs defined as a decrease of at least 20% and 4 mm at any vertebral level. Prevalent vertebral fractures were identified on the baseline radiographs using vertebral morphometry. Bone mineral density was measured at the total hip and lumbar spine using dual-energy x-ray absorptiometry. RESULTS: Of the 2680 women, 487 (18.2%) had an incident vertebral fracture including 163 of the 394 (41.4%) with a prevalent vertebral fracture at baseline and 324 of the 2286 (14.2%) without a prevalent vertebral fracture at baseline (odds ratio, 4.21; 95% confidence interval, 3.33-5.34). Low BMD was associated with an increased risk of incident vertebral fracture (odds ratio per 1 SD decrease in total hip BMD, 1.78 [95% confidence interval, 1.58-2.00]). The absolute risk of vertebral fracture ranged from 56% among women with total hip BMD T score of -2.5 or less and a prevalent vertebral fracture to 9% in women with normal BMD and no prevalent vertebral fracture. CONCLUSIONS: Low BMD and prevalent vertebral fractures are independently related to new vertebral fractures over 15 years of follow-up. Women with a prevalent vertebral fracture have a substantially increased absolute risk of an incident fracture, especially if they have osteoporosis diagnosed by BMD.

Thiazolidinedione use and bone loss in older diabetic adults.

CONTEXT: Activation of peroxisome proliferator-activated receptor-gamma by thiazolidinediones (TZDs) results in lower bone mass in mice. OBJECTIVE: The objective of the study was to determine whether TZD use is associated with changes in bone mineral density (BMD) in older adults with type 2 diabetes. DESIGN: We analyzed 4-yr follow-up data from the Health, Aging, and Body Composition observational study. SETTING: The study was conducted in a general community. PATIENTS: White and black, physically able men and women, aged 70-79 yr at baseline with diabetes defined by self-report, use of hypoglycemic medication, elevated fasting glucose (>/=126 mg/dl), or elevated 2-h glucose tolerance test (>/=200 mg/dl) participated in the study. MAIN OUTCOME MEASURES: Whole-body, lumbar spine (derived from whole body), and hip BMD were measured by dual-energy x-ray absorptiometry at 2-yr intervals. RESULTS: Of 666 diabetic participants, 69 reported TZD use at an annual visit, including troglitazone (n = 22), pioglitazone (n = 30), and/or rosiglitazone (n = 31). Those with TZD use had higher baseline hemoglobin A(1c) and less weight loss over 4 yr but similar baseline BMD and weight than others with diabetes. In repeated-measures models adjusted for potential confounders associated with TZD use and BMD, each year of TZD use was associated with greater bone loss at the whole body [additional loss of -0.61% per year; 95% confidence interval (CI) -1.02, -0.21% per year], lumbar spine (-1.23% per year; 95% CI -2.06, -0.40% per year), and trochanter (-0.65% per year; 95% CI -1.18, -0.12% per year) in women, but not men, with diabetes. CONCLUSION: These observational results suggest that TZDs may cause bone loss in older women. These results need to be tested in a randomized trial.

Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.

CONTEXT: The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. OBJECTIVE: To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. DESIGN AND SETTING: Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT). PARTICIPANTS: One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. INTERVENTION: Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). MAIN OUTCOME MEASURES: The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. RESULTS: Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. CONCLUSIONS: Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT 00398931.

What proportion of incident radiographic vertebral deformities is clinically diagnosed and vice versa?

UNLABELLED: We prospectively examined, in a large cohort of older women, the proportion of incident radiographic vertebral deformities diagnosed as incident clinical vertebral fractures in the same women at the same vertebral level. The proportion of deformities clinically diagnosed ranged from <15% for milder deformities to nearly 30% for more severe deformities. INTRODUCTION: The relationship between radiographic and clinical vertebral fractures is incompletely understood. No previous study has prospectively compared the agreement between incident radiographic vertebral deformities and incident community-recognized, radiographically confirmed vertebral fractures in the same women at the same vertebral level(s). MATERIALS AND METHODS: This analysis of data from the Fracture Intervention Trial included all participants who completed both baseline and at least one scheduled follow-up lateral spinal radiograph (n = 6084). Incident vertebral deformities were defined at a given vertebral level as a reduction between baseline and closeout radiographs of > or = 20% and 4 mm in any vertebral height and subdivided into two severity categories. Incident clinical vertebral fractures were those reported to clinical centers by participants and confirmed by the study radiologist, who compared the community spinal radiograph with the participant's baseline study radiograph using semiquantitative methods. RESULTS: A total of 446 incident radiographic vertebral deformities were identified in 330 women, whereas 121 women experienced one or more confirmed incident clinical vertebral fracture. Of incident radiograpic vertebral deformities, 22.6% were also clinically diagnosed as incident vertebral fractures, with clinical diagnoses made for 28.4% of the deformities that exceeded 30% and 4 mm height loss (severe deformity) compared with 14.3% for deformities that involved > or = 20% and 4 mm but < 30% height loss (milder deformity). Of incident clinical vertebral fractures, 72.7% were morphometrically identified as incident deformities, most of them as severe deformities. More than 20% of incident clinical fractures were not identified as incident deformities by even the most liberal morphometric criterion used in this study. CONCLUSIONS: Approximately one-fourth of incident radiographic vertebral deformities were clinically diagnosed as new vertebral fractures, although the proportion clinically diagnosed was increased for more severe deformities. Whereas most incident clinical vertebral fractures were identified as severe morphometric deformities, approximately one-fourth did not meet even the most liberal study criterion for morphometric deformity. Further study of factors that may explain the discordance between incident vertebral deformities and incident clinical vertebral fractures is important.