Anti-fracture efficacy of zoledronate in subgroups of osteopenic postmenopausal women: secondary analysis of a randomized controlled trial.

BACKGROUND: We recently reported that the administration of zoledronate every 18 months to osteopenic older women reduces the incidence of fractures. OBJECTIVE: Here, we present a more detailed analysis of that trial to determine whether baseline clinical characteristics impact on the anti-fracture efficacy of this intervention. METHODS: This is a prospective, randomized, placebo-controlled, double-blind trial in osteopenic postmenopausal women aged ≥ 65 years, to determine the anti-fracture efficacy of zoledronate. 2000 women were recruited using electoral rolls and randomized to receive 4 infusions of either zoledronate 5 mg or normal saline, at 18-month intervals. Each participant was followed for 6 years. Calcium supplements were not supplied. RESULTS: Fragility fractures (either vertebral or nonvertebral) occurred in 190 women in the placebo group (227 fractures) and in 122 women in the zoledronate group (131 fractures), odds ratio (OR) 0.59 (95%CI 0.46, 0.76; P < 0.0001). There were no significant interactions between baseline variables (age, anthropometry, BMI, dietary calcium intake, baseline fracture status, recent falls history, bone mineral density, calculated fracture risk) and the treatment effect. In particular, the reduction in fractures appeared to be independent of baseline fracture risk, and numbers needed to treat (NNT) to prevent one woman fracturing were not significantly different across baseline fracture risk tertiles. CONCLUSIONS: The present analyses indicate that the decrease in fracture numbers is broadly consistent across this cohort. The lack of relationship between NNTs and baseline fracture risk calls into question the need for BMD measurement and precise fracture risk assessment before initiating treatment in older postmenopausal women.

Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial.

BACKGROUND: Severe vitamin D deficiency causes osteomalacia, yet trials of vitamin D supplementation in the community have not on average demonstrated benefit to bone mineral density (BMD) or fracture risk in adults. OBJECTIVE: To determine whether monthly high-dose vitamin D supplementation influences BMD in the general population and in those with low 25-hydroxyvitamin D levels. METHODS: Two-year substudy of a trial in older community-resident adults. A total of 452 participants were randomized to receive monthly doses of vitamin D3 100 000 IU, or placebo. The primary end-point was change in lumbar spine BMD. Exploratory analyses to identify thresholds of baseline 25-hydroxyvitamin D for vitamin D effects on BMD were prespecified. RESULTS: Intention-to-treat analyses showed no significant treatment effect in the lumbar spine (between-groups difference 0.0071 g cm-2 , 95%CI: -0.0012, 0.0154) or total body but BMD loss at both hip sites was significantly attenuated by ~1/2% over 2 years. There was a significant interaction between baseline 25-hydroxyvitamin D and treatment effect (P = 0.04). With baseline 25-hydroxyvitamin D ≤ 30 nmol L-1 (n = 46), there were between-groups BMD changes at the spine and femoral sites of ~2%, significant in the spine and femoral neck, but there was no effect on total body BMD. When baseline 25-hydroxyvitamin D was >30 nmol L-1 , differences were ~1/2% and significant only at the total hip. CONCLUSIONS: This substudy finds no clinically important benefit to BMD from untargeted vitamin D supplementation of older, community-dwelling adults. Exploratory analyses suggest meaningful benefit in those with baseline 25-hydroxyvitamin D ≤ 30 nmol L-1 . This represents a significant step towards a trial-based definition of vitamin D deficiency for bone health in older adults.

Acute effects of calcium supplements on blood pressure: randomised, crossover trial in postmenopausal women.

Calcium supplements appear to increase cardiovascular risk, but the mechanism is unknown. We investigated the acute effects of calcium supplements on blood pressure in postmenopausal women. The reduction in systolic blood pressure was smaller after calcium compared with the placebo in the hours following dosing. INTRODUCTION: Calcium supplements appear to be associated with increased cardiovascular risk; however, the mechanism of this is uncertain. We previously reported that blood pressure declined over a day in older women, and that this reduction was smaller following a calcium supplement. To confirm this finding, we investigated the acute effects of calcium supplements on blood pressure. METHODS: This was a randomised controlled crossover trial in 40 healthy postmenopausal women (mean age 71 years and BMI 27.2 kg/m2). Women attended on two occasions, with visits separated by ≥7 days. At each visit, they received either 1 g of calcium as citrate, or placebo. Blood pressure and serum calcium concentrations were measured immediately before, and 2, 4 and 6 h after each intervention. RESULTS: Ionised and total calcium concentrations increased after calcium (p < 0.0001 versus placebo). Systolic blood pressure decreased after both calcium and placebo, but significantly less so after calcium (p = 0.02). The reduction in systolic blood pressure from baseline was smaller after calcium compared with placebo by 6 mmHg at 4 h (p = 0.036) and by 9 mmHg at 6 h (p = 0.002). The reduction in diastolic blood pressure was similar after calcium and placebo. CONCLUSIONS: These findings are consistent with those of our previous trial and indicate that the use of calcium supplements in postmenopausal women attenuates the post-breakfast reduction in systolic blood pressure by around 6-9 mmHg. Whether these changes in blood pressure influence cardiovascular risk requires further study.

Acute and 3-month effects of calcium carbonate on the calcification propensity of serum and regulators of vascular calcification: secondary analysis of a randomized controlled trial.

SUMMARY: Calcium supplements have been associated with increased cardiovascular risk, but the mechanism is unknown. We investigated the effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50). Changes in serum calcium were related to changes in T50. INTRODUCTION: Calcium supplements have been associated with increased cardiovascular risk; however, it is unknown whether this is related to an increase in vascular calcification. METHODS: We investigated the acute and 3-month effects of calcium supplements on the propensity of serum to calcify, based on the transition time of primary to secondary calciprotein particles (T50), and on three possible regulators of calcification: fetuin-A, pyrophosphate and fibroblast growth factor-23 (FGF23). We randomized 41 postmenopausal women to 1 g/day of calcium as carbonate, or to a placebo containing no calcium. Measurements were performed at baseline and then 4 and 8 h after their first dose, and after 3 months of supplementation. Fetuin-A, pyrophosphate and FGF23 were measured in the first 10 participants allocated to calcium carbonate and placebo who completed the study. RESULTS: T50 declined in both groups, the changes tending to be greater in the calcium group. Pyrophosphate declined from baseline in the placebo group at 4 h and was different from the calcium group at this time point (p = 0.04). There were no other significant between-groups differences. The changes in serum total calcium from baseline were significantly related to changes in T50 at 4 h (r = -0.32, p = 0.05) and 8 h (r = -0.39, p = 0.01), to fetuin-A at 3 months (r = 0.57, p = 0.01) and to pyrophosphate at 4 h (r = 0.61, p = 0.02). CONCLUSIONS: These correlative findings suggest that serum calcium concentrations modulate the propensity of serum to calcify (T50), and possibly produce counter-regulatory changes in pyrophosphate and fetuin-A. This provides a possible mechanism by which calcium supplements might influence vascular calcification.

Bone density is normal and does not change over 2 years in sarcoidosis.

SUMMARY: Small studies have previously suggested that sarcoidosis may be associated with low bone mineral density. In this observational study of 64 patients with sarcoidosis, bone mineral density was within the normal range at baseline, and there was no evidence of accelerated bone loss over 1-2 years. INTRODUCTION: Several small studies have suggested that sarcoidosis may be associated with low bone mineral density (BMD). METHODS: We undertook a cross-sectional study of BMD in 64 patients with sarcoidosis. Of these, 27 with 25-hydroxyvitamin D<50 nmol/L entered a 1-year intervention study of vitamin D supplements, and 37 entered a 2-year longitudinal study of BMD, with the primary endpoint of the change in lumbar spine BMD. RESULTS: The mean age of participants was 58 years, 68% were female, and 8% were currently using oral glucocorticoids. At baseline, BMD for the entire cohort was greater than the expected values for the population at the lumbar spine (mean Z-score 0.7, P<0.001) and total body (0.5, P<0.001) and similar to expected values at the femoral neck (0.2, P=0.14) and total hip (0.2, P=0.14). BMD did not change at any of these four sites (P>0.19) over 2 years in the longitudinal study. In the intervention study, vitamin D supplements had no effect on BMD, and therefore we pooled the data from all participants. BMD did not change over 1 year at the spine, total hip, or femoral neck (P>0.3), but decreased by 0.7% (95% confidence interval 0.3-1.1) at the total body (P=0.019). CONCLUSIONS: BMD was normal at baseline, and there was no consistent evidence of accelerated bone loss over 1-2 years, regardless of baseline vitamin D status. Patients with sarcoidosis not using oral glucocorticoids do not need routine monitoring of BMD.

The impact of dietary calcium intake and vitamin D status on the effects of zoledronate.

UNLABELLED: We investigated whether baseline dietary calcium intake or vitamin D status modified the effects of zoledronate. Neither variable influenced the effect of zoledronate on bone mineral density, bone turnover, or risk of acute phase reaction, suggesting that co-administration of calcium and vitamin D supplements with zoledronate may not always be necessary. INTRODUCTION: Calcium and vitamin D supplements are often co-administered with bisphosphonates, but it is unclear whether they are necessary for therapeutic efficacy or minimizing side effects of bisphosphonates. We investigated whether baseline dietary calcium intake or vitamin D status modified the effect of zoledronate on bone mineral density (BMD) or bone turnover at 1 year, or the risk of acute phase reactions (APR). METHODS: Data were pooled from two trials of zoledronate in postmenopausal women without vitamin D deficiency in which calcium and vitamin D were not routinely administered. The cohort (zoledronate n = 154, placebo n = 68) was divided into subgroups by baseline dietary calcium intake (<800 vs. ≥800 mg/day) and vitamin D status [25-hydroxyvitamin D (25OHD) <50 vs. ≥50 nmol/L, and <75 nmol/L vs. ≥75 nmol/L] and treatment × subgroup interactions tested. RESULTS: There were 52, 86, and 36 % of the zoledronate group and 64, 94, and 46 % of the placebo group that had dietary calcium intake ≥800 mg/day, 25OHD ≥50 nmol/L, and 25OHD ≥75 nmol/L, respectively. There were no significant interactions between treatment and either baseline dietary calcium or baseline vitamin D status for lumbar spine BMD, total hip BMD, the bone turnover markers P1NP and ß-CTx, or the risk of an APR. There was also no three-way interaction between baseline dietary calcium intake, baseline vitamin D status, and treatment for any of these variables. CONCLUSIONS: Baseline dietary calcium intake and vitamin D status did not alter the effects of zoledronate, suggesting that co-administration of calcium and vitamin D with zoledronate may not be necessary for individuals not at risk of marked vitamin D deficiency.

High-dose oral vitamin D3 supplementation in the elderly.

SUMMARY: Daily dosing with vitamin D often fails to achieve optimal outcomes, and it is uncertain what the target level of 25-hydroxyvitamin D should be. This study found that large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels, and that monthly dosing is similarly effective after 3-5 months. With baseline 25OHD > 50 nmol/L, vitamin D supplementation does not reduce PTH levels. INTRODUCTION: There is concern that vitamin D supplementation doses are frequently inadequate, and that compliance with daily medication is likely to be suboptimal. METHODS: This randomized double-blind trial compares responses to three high-dose vitamin D(3) regimens and estimates optimal 25-hydroxyvitamin D (25OHD) levels, from changes in parathyroid hormone (PTH), and procollagen type I amino-terminal propeptide (P1NP) in relation to baseline 25OHD. Sixty-three elderly participants were randomized to three regimens of vitamin D supplementation: a 500,000-IU loading dose; the loading dose plus 50,000 IU/month; or 50,000 IU/month. RESULTS: The Loading and Loading + Monthly groups showed increases in 25OHD of 58 +/- 28 nmol/L from baseline to 1 month. Thereafter, levels gradually declined to plateaus of 69 +/- 5 nmol/L and 91 +/- 4 nmol/l, respectively. In the Monthly group, 25OHD reached a plateau of ~80 +/- 20 nmol/L at 3-5 months. There were no changes in serum calcium concentrations. PTH and P1NP were only suppressed by vitamin D treatment in those with baseline 25OHD levels <50 and <30 nmol/L, respectively. CONCLUSIONS: Large loading doses of vitamin D(3) rapidly and safely normalize 25OHD levels in the frail elderly. Monthly dosing is similarly effective and safe, but takes 3-5 months for plateau 25OHD levels to be reached.

Hormone replacement therapy causes a respiratory alkalosis in normal postmenopausal women.

Menopause is associated with an increase in venous bicarbonate concentrations that is reversible with hormone replacement therapy (HRT). However, the mechanism underlying this effect is not known. To address this question, we studied the changes in acid-base indexes in the arterialized venous blood of normal postmenopausal women commencing conjugated equine estrogen (0.625 mg/day), medroxyprogesterone acetate (MPA; 5 mg/day), their combination, or placebo, in a double blind randomized controlled study over 3 months. Serum bicarbonate concentrations decreased significantly in the groups receiving either MPA or estrogen plus MPA (P = 0.008). This trend was apparent as early as 2 days and reached 2.7 and 2.3 mmol/L in the respective groups by 3 months. Similar changes were seen with partial pressure of carbon dioxide (P = 0.04); a change of -0.7 kPa occurred in the estrogen plus MPA group at 3 months. There were no changes in bicarbonate concentrations or partial pressure of carbon dioxide in those receiving estrogen alone or placebo. Accompanying changes in blood pH were apparent in the estrogen plus MPA group, where there was an upward trend at 1 week (P = 0.056) and a significant change from baseline (+0.013) at 3 months (P = 0.03). In the whole group, the changes in pH were inversely correlated with those in urinary excretion of hydroxyproline (r = -0.44; P = 0.01). We conclude that HRT using conjugated estrogens and MPA produces small, but sustained, changes in acid-base status. These may contribute to the effects of HRT and menopause on many tissues and disease processes, including the development of osteoporosis.

Hydrochlorothiazide reduces loss of cortical bone in normal postmenopausal women: a randomized controlled trial.

PURPOSE: Thiazide diuretics reduce urine calcium excretion and might therefore reduce postmenopausal bone loss. In some, but not all, case-control studies, their use has been associated with a reduced incidence of hip fractures. We studied the effects of hydrochlorothiazide on bone loss in normal postmenopausal women. SUBJECTS AND METHODS: We performed a randomized, double-blind, 2-year trial of the effects of hydrochlorothiazide (50 mg per day) and placebo on bone mineral density in normal postmenopausal women. Participants were not required to have either low bone mineral density or hypertension. Bone mineral density was measured using dual-energy x-ray absorptiometry. RESULTS: One hundred eighty-five women entered the study, of whom 138 completed 2 years of follow-up. In an intention-to-treat analysis, hydrochlorothiazide produced significant benefits on bone mineral density of the total body (between-group difference at 2 years of 0.8%, 95% confidence interval [CI]: 0.3% to 1.3%, P <0.0001), legs (0.9%, 95% CI: 0.2% to 1.7%, P <0.0001), mid-forearm (1.2%, 95% CI: 0.2% to 2.2%, P = 0.02), and ultradistal forearm (1.7%, 95% CI: 0.1% to 3.2%, P = 0.04). There was no effect in the lumbar spine (0.5%, 95% CI: -0.5% to 1.6%) or femoral neck (0.2%, 95% CI: 1.3% to 1.7%). The between-group changes tended to be greatest during the first 6 months, except in the mid-forearm where there appeared to be a progressive divergence. An as-treated analysis produced similar results. Urine calcium excretion and indices of bone turnover decreased in the thiazide group, but parathyroid hormone concentrations did not differ between the groups. Treatment was tolerated well. CONCLUSIONS: Hydrochlorothiazide (50 mg per day) slows cortical bone loss in normal postmenopausal women. It may act directly on bone as well as on the renal tubule. The small size of the effect suggests that thiazides may have a role in the prevention of postmenopausal bone loss, but that they are not an appropriate monotherapy for treating osteoporosis.

Aggressive behavior in normal and deviant members of intact versus mother-only families.

Single-parent families have been identified as using more coercion and aggression to elicit compliance than intact families. The present study compared 9 mother-only and 15 intact families from a referred clinical sample to 9 mother-only and 16 intact nonreferred "normal" families using a family behavioral observation code. Clinical families emitted higher rates of aggressive behavior than normals, and mother-only emitted higher rates than intact. However, mother-only normals had lower rates than intact clinical families. The intact versus mother-only factor appears to be less important in understanding aggression than do the specific interactional patterns of family members.

Characteristics of fowl cholera diagnosed in Georgia, 1989-91.

One hundred seventy-six cases of fowl cholera were diagnosed at the Georgia Poultry Laboratory over a 3-year period. The disease occurred throughout the year, with peak incidence during March and April. Fowl cholera was diagnosed in flocks from 4 to 83 weeks of age, with a mean of 33 weeks of age. The Pasteurella multocida isolates were highly susceptible to all antimicrobial agents tested, except sulfonamides. The serotypic distribution of isolates showed that serotype 3,4 predominated (40%), followed by serotype 3 (22%), serotype 1 (18%), untypable (15%), serotype 5 (3%), and serotype 4 (2%). Associations were found between the P. multocida serotypes isolated from birds of different ages and between the age of the bird and the sites of choice for isolating the organism.

Isolation of Salmonella from chickens reacting in the pullorum-typhoid agglutination test.

Over a 3-year period, 134,171 serum samples were screened by the pullorum-typhoid tube agglutination test. Of the 680 (0.5%) reactors, Salmonella organisms were isolated from 226 of the chickens. Thirteen serotypes of Salmonella were isolated. The predominant serotypes were heidelberg, pullorum, kentucky, saintpaul, and enteritidis, and they were isolated from 60%, 18%, 5%, 4%, and 3% of the chickens, respectively. Salmonella were isolated from the ceca of 161 chickens, the cecal tonsils of 148 chickens, the organ pool of 150 chickens, and the ovary-oviduct pool of 110 chickens. Delayed secondary enrichment was required to isolate Salmonella from 36 (15%) of the 226 Salmonella-positive chickens and to detect 20% of the total isolations.

Influence of enrichment incubation time on the isolation of Salmonella.

The optimum incubation times for Salmonella enrichment cultures were determined by inoculation of enrichment broths onto plating media after 24 hours at 37 C, after 48 hours at 37 C, after a 3-day delayed secondary enrichment (DSE), and after a 5-day DSE procedure. The results showed a step-wise increase in Salmonella isolations with the longer incubation times. Inoculation of the enrichment broths onto plating media after 24 hours incubation followed by a 5-day DSE made possible the detection of 96% to 98% of the Salmonella-positive samples and was the best combination of conditions.

Prevalence of Salmonella enteritidis in spent hens.

As part of a USDA/APHIS study on the prevalence of Salmonella enteritidis in spent laying hens, 3700 pooled cecal samples were cultured for Salmonella. Samples were received from a single processing plant and represented 81 commercial egg-type layer flocks from nine southern states. Salmonella were isolated from 2418 of the 3700 (65.4%) cecal pools, but only six isolates were serotype enteritidis. S. enteritidis was isolated from three flocks from two states but was detected in only six of 140 samples from those flocks. Various Salmonella isolation media and procedures were compared. Xylose-lysine-tergitol-4 plates detected 64% of the total Salmonella-positive cecal samples. Brilliant green agar with novobiocin detected 72% of the total Salmonella-positive samples. When used in combination, 82% of the positive samples were detected with these two plates. The remaining 425 Salmonella-positive samples were detected after delayed secondary enrichment.

Use of delayed secondary enrichment for the isolation of Salmonella in poultry and poultry environments.

A conventional method of isolating Salmonella was compared with isolation using novobiocin-supplemented plating media and delayed secondary enrichment (DSE). The DSE greatly increased the ability to isolate Salmonella from poultry and environmental samples. Four hundred sixty-four isolations of Salmonella were made from a total of 4377 cultures (11%). Two hundred sixty-nine (58%) isolations of Salmonella were made following the 24-hour incubation; of these, 43 (9%) isolates were isolated only at this time. In comparison, a total of 421 (91%) Salmonella were isolated by DSE, of which 195 isolates (42%) were isolated only with DSE. The addition of novobiocin to the selective plating medium increased the isolation rate for Salmonella and reduced the level of contaminating bacteria growing on the plate.

Marital satisfaction and social learning family therapy for child conduct problems: generalization of treatment effects.

Successful treatment outcome and maintenance for families with aggressive children by means of social learning family therapy were reported by Sayger, Horne, Walker, and Passmore (1988). The present study examined the generalization of treatment effects to the child's classroom, the parental level of marital satisfaction, the general family relationship environment, and the parental level of depression. Results of this study show that teachers reported improved child behavior following treatment. Parental level of marital satisfaction was increased and sustained for those parents who were experiencing low levels of marital satisfaction prior to treatment. The participating families also became more cohesive and expressive, and less conflictual. Although pretreatment levels of parental depression were moderately low, these levels were alleviated.

Institutional males' perception of three counseling techniques.

The use of advice-giving, Adlerian interpretation, and analytically derived interpretation with regard to whether feelings of approach, attack, or withdrawal were elicited was investigated by having subjects view a videotape of eight-role-played counseling segments. The videotape presented problem-statements by a role-playing adolescent followed by a role-playing counselor who made three separate responses to the statements. Subjects were 20 internally and 20 externally controlled incarcerated youth who indicated how each counselor's response made them feel (approach, attack, or withdrawal). Both internally and externally controlled subjects tended to respond to Adlerian interpretation and analytically derived interpretation with attack - and withdrawal - feelings and to advice-giving with approach-feelings in this quasi-counseling situation.