Ghrelin is an Osteoblast Mitogen and Increases Osteoclastic Bone Resorption In Vitro.

Ghrelin is released in response to fasting, such that circulating levels are highest immediately prior to meals. Bone turnover is acutely responsive to the fed state, with increased bone resorption during fasting and suppression during feeding. The current study investigated the hypothesis that ghrelin regulates the activity of bone cells. Ghrelin increased the bone-resorbing activity of rat osteoclasts, but did not alter osteoclast differentiation in a murine bone marrow assay nor bone resorption in ex vivo calvarial cultures. Ghrelin showed mitogenic activity in osteoblasts, with a strong effect in human cells and a weaker effect in rat osteoblasts. The expression of the human ghrelin receptor, GHSR, varied among individuals and was detectable in 25-30% of bone marrow and osteoblast samples. However, the rodent Ghsr expression was undetectable in bone cells and cell lines from rat and mouse. These data suggest that elevated levels of ghrelin may contribute to the higher levels of bone turnover that occurs in the fasted state.

Molecular mechanisms involved in the mitogenic effect of lactoferrin in osteoblasts.

Lactoferrin, an iron-binding glycoprotein present in milk and other exocrine secretions in mammals, is anabolic to bone at physiological concentrations. Lactoferrin stimulates the proliferation, differentiation and survival of osteoblasts, as well as potently inhibiting osteoclastogenesis in bone marrow cultures. In the current study we further investigated the mechanism of action of lactoferrin in osteoblasts. We used low-density arrays to measure the level of expression of 45 genes in MC3T3-E1 osteoblast-like cells treated with lactoferrin, and identified transient, dose-dependent increases in the transcription levels of interleukin-6, of the pro-inflammatory factor prostaglandin-endoperoxide synthase 2 (Ptgs2), and of the transcription factor nuclear factor of activated T cells (Nfatc1). We demonstrated similar changes in primary osteoblast cultures from human and rat. Levels of prostaglandin E2 were increased in conditioned media collected from osteoblasts treated with lactoferrin, indicating that the activity of the enzyme cyclooxygenase 2 (COX2), which is encoded by Ptgs2, was also up-regulated. Using a luciferase reporter construct we showed that lactoferrin induced transcription from the NFAT consensus sequence. We found that inhibiting either COX2 or NFATc1 activity blocked the mitogenic effect of lactoferrin in osteoblasts and that inhibition of NFATc1 activity partially blocked the transcriptional activation of Ptgs2. Our study has provided the first evidence that COX2 and NFATc1 activities are increased by lactoferrin, and demonstrated a role for each of these molecules as mediators of the mitogenic effects of lactoferrin in osteoblasts.

Evaluation of the FRAX and Garvan fracture risk calculators in older women.

Fracture risk calculators estimate the absolute risk of osteoporotic fractures. We investigated the performance of the FRAX and Garvan Institute fracture risk calculators in healthy, older, New Zealand, postmenopausal women with normal bone mineral density (BMD) for their age. Fractures were ascertained in women initially enrolled in a 5-year trial of calcium supplements and followed on average for 8.8 years. Baseline data (1422 women, mean age 74 years, mean femoral neck BMD T-score -1.3) were used to estimate fracture risk during follow-up using the FRAX and Garvan calculators. The FRAX-New Zealand tool was used both with and without baseline BMD. The discrimination of the calculators was assessed using the area under the curve (AUC) of receiver operating characteristic curves. The calibration was assessed by comparing estimated risk of fracture with fracture incidence across a range of estimated fracture risks and clinical factors. For each fracture subtype, the calculators had comparable moderate predictive discriminative ability (AUC range: hip fracture 0.67-0.70; osteoporotic fracture 0.62-0.64; any fracture 0.60-0.63) that was similar to that of models using only age and BMD. The Garvan calculator was well calibrated for osteoporotic fractures but overestimated hip fractures. FRAX with BMD underestimated osteoporotic and hip fractures. FRAX without BMD underestimated osteoporotic and overestimated hip fractures. In summary, none of the calculators provided better discrimination than models based on age and BMD, and their discriminative ability was only moderate, which may limit their clinical utility. The calibration varied, suggesting that the calculators should be validated in local cohorts before clinical use.

Relationships between vascular calcification, calcium metabolism, bone density, and fractures.

Factors involved with calcium metabolism, such as serum calcium and phosphate and calcium intake, have been associated with vascular disease in different populations. We investigated whether this association is mediated via increased vascular calcification by assessing relationships between these factors and abdominal aortic calcification (AAC) and coronary artery calcification (CAC). A total of 1471 healthy postmenopausal women participated in a 5-year randomized, placebo-controlled trial of calcium 1 g/day, and 323 healthy middle-aged and older men participated in a 2-year randomized, placebo-controlled trial of calcium 600 or 1200 mg/day. AAC was assessed on vertebral morphometric images at baseline and follow-up. Based on computed tomography, 163 men had CAC assessed, on average, 1.5 years after study completion. In elderly women, AAC was positively related to serum calcium (p < .001), phosphate (p = .04), and the calcium-phosphate product (p = .003), but changes in AAC over time and incidence of cardiovascular events were not related to these variables. In middle-aged men, AAC and CAC were not consistently related to these variables. Neither dietary calcium intake nor calcium supplementation was associated with changes in the prevalence of AAC over time, and calcium supplementation also was not related to CAC scores in men. After adjusting for age, AAC was not associated with low bone mineral density (BMD) at baseline, changes in BMD over time, or fracture incidence. CAC also was not related to baseline BMD. In summary, serum calcium and phosphate are associated with AAC in older women, but dietary calcium intake and calcium supplementation were not associated with changes in AAC over 2 to 5 years.

Effect of osteoporosis treatment on mortality: a meta-analysis.

CONTEXT: Fragility fractures cause significant morbidity and mortality. Effective osteoporosis treatment can reduce fracture incidence, but it is not known whether it reduces mortality. OBJECTIVE: The aim of the study was to determine whether effective osteoporosis treatment reduces mortality. DATA SOURCES: We searched Medline and the Cochrane Central Register of Trials prior to September 2008, as well as 2000-2008 American Society for Bone and Mineral Research conference abstracts. STUDY SELECTION: Eligible studies were randomized placebo-controlled trials of approved doses of medications with proven efficacy in preventing both vertebral and nonvertebral fractures, in which the study duration was longer than 12 months and there were more than 10 deaths. Trials of estrogen and selective estrogen receptor modulators were specifically excluded. DATA EXTRACTION: Data were extracted from the text of the retrieved articles, published meta-analyses, or the Food and Drug Administration web site. DATA SYNTHESIS: Eight eligible studies of four agents (risedronate, strontium ranelate, zoledronic acid, and denosumab) were included in the primary analysis. During two alendronate studies, the treatment dose changed, and those studies were only included in secondary analyses. In the primary analysis, treatment was associated with an 11% reduction in mortality (relative risk, 0.89; 95% confidence interval, 0.80-0.99; P = 0.036). In the secondary analysis, the results were similar (relative risk, 0.90; 95% confidence interval, 0.81-1.0; P = 0.044). Mortality reduction was not related to age or incidence of hip or nonvertebral fracture, but was greatest in trials conducted in populations with higher mortality rates. CONCLUSIONS: Treatments for osteoporosis with established vertebral and nonvertebral fracture efficacy reduce mortality in older, frailer individuals with osteoporosis who are at high risk of fracture.

Vitamin D insufficiency and health outcomes over 5 y in older women.

BACKGROUND: Vitamin D insufficiency was shown to be associated with adverse musculoskeletal and nonskeletal outcomes in numerous observational studies. However, some studies did not control for confounding factors such as age or seasonal variation of 25-hydroxyvitamin D [25(OH)D]. OBJECTIVE: We sought to determine the effect of vitamin D status on health outcomes. DESIGN: Healthy community-dwelling women (n = 1471) with a mean age of 74 y were followed in a 5-y trial of calcium supplementation. 25(OH)D was measured at baseline in all women. Skeletal and nonskeletal outcomes were evaluated according to seasonally adjusted vitamin D status at baseline. RESULTS: Fifty percent of women had a seasonally adjusted 25(OH)D concentration <50 nmol/L. These women were significantly older, heavier, and less physically active and had more comorbidities than women with a seasonally adjusted 25(OH)D concentration > or =50 nmol/L. Women with a seasonally adjusted 25(OH)D concentration <50 nmol/L had an increased incidence of stroke and cardiovascular events that did not persist after adjustment for between-group differences in age or comorbidities. Women with a seasonally adjusted 25(OH)D concentration <50 nmol/L were not at increased risk of adverse consequences for any musculoskeletal outcome, including fracture, falls, bone density, or grip strength or any nonskeletal outcomes, including death, myocardial infarction, cancer, heart failure, diabetes, or adverse changes in blood pressure, weight, body composition, cholesterol, or glucose. CONCLUSIONS: Vitamin D insufficiency is more common in older, frailer women. Community-dwelling older women with a seasonally adjusted 25(OH)D concentration <50 nmol/L were not at risk of adverse outcomes over 5 y after control for comorbidities. Randomized placebo-controlled trials are needed to determine whether vitamin D supplementation in individuals with vitamin D insufficiency influences health outcomes. This trial was registered at www.anzctr.org.au as ACTRN 012605000242628.

Abdominal aortic calcification on vertebral morphometry images predicts incident myocardial infarction.

Abdominal aortic calcification (AAC) measured on spine X-rays is an established risk factor for cardiovascular disease. We investigated whether AAC assessed using vertebral morphometry and a recently developed scoring system (AAC-8) is reliable and associated with cardiovascular risk factors or events. A total of 1471 healthy postmenopausal women and 323 healthy middle-aged and older men participated in 5 and 2 year trials of calcium supplements, respectively. AAC-8 was assessed on vertebral morphometry images at baseline and follow-up. In addition, 163 men also had coronary artery calcification measured using computed tomography. Cardiovascular events during the trials were independently adjudicated. We found strong inter- and intrameasurer agreement for AAC-8 (kappa > 0.87). The prevalence of AAC increased with age (p < .01) in women and in men. AAC was associated with many established cardiovascular risk factors, with serum calcium in women (p = .002) and with higher coronary calcium scores in men (p = .03). Estimated 5 year cardiovascular risk increased with increasing AAC-8 score (p < .001) in women and in men. The presence of AAC independently predicted myocardial infarction (MI) in women [hazards ratio (HR) = 2.30, p = .007] and men (HR = 5.32, p = .04), even after adjustment for estimated cardiovascular risk in women. In women, AAC independently predicted cardiovascular events (MI, stroke, or sudden death) (HR = 1.74, p = .007), and changes in AAC-8 score over time were associated with MI and cardiovascular events, even after adjustment for estimated cardiovascular risk. In summary, scoring AAC on vertebral morphometric scans is a reproducible method of assessing cardiovascular risk that independently predicts incident MI and cardiovascular events, even after taking into account traditional cardiovascular risk factors.

Does degree of baldness influence vitamin D status?

OBJECTIVE: To determine the association, if any, between male-pattern hair loss (baldness) and serum 25-hydroxyvitamin D (25-OHD) levels. DESIGN AND PARTICIPANTS: A cross-sectional study of 296 healthy middle-aged and older men. MAIN OUTCOME MEASURES: Degree of baldness was independently assessed by two researchers using the Hamilton-Norwood scale and serum 25-OHD was measured in all men. RESULTS: Classification of the degree of baldness by the two researchers showed a high level of agreement (kappa = 0.93). Forty-eight per cent of men had no hair loss or mild frontotemporal recession, 15% had predominant vertex loss, and 37% had significant scalp and vertex loss. After data were adjusted for potential confounding factors - including age, month of 25-OHD measurement, exercise levels, use of sunscreen, skin type and frequency of outdoor hat wearing - no significant differences in 25-OHD levels between these groups was detected (P = 0.60). CONCLUSIONS: The degree of baldness does not appear to influence serum 25-OHD levels. The high prevalence of baldness in older men does not explain sex differences in 25-OHD levels. Other novel hypotheses are required to help determine whether baldness serves any physiological purpose.

Prospective 10-year study of postmenopausal women with asymptomatic primary hyperparathyroidism.

AIM: There are few prospective studies of people with asymptomatic primary hyperparathyroidism (PHPT) who have not had parathyroidectomy. We followed a group of postmenopausal women with asymptomatic PHPT for up to 10 years to determine whether they could be managed conservatively without parathyroidectomy. METHODS: A 10-year, prospective, longitudinal study of 23 postmenopausal women with asymptomatic PHPT initially enrolled into a 4-year randomised controlled trial of hormone replacement therapy. Serum total and ionised calcium, biochemistry, urine calcium, and bone mineral density were measured every 6-12 months. RESULTS: Serum ionised calcium, creatinine, and urine calcium:creatinine remained stable throughout follow-up. In contrast, there was a steady increase in the total and adjusted serum calcium and a small rise in serum PTH. Only one woman had an adjusted serum calcium >3.0 mmol/L during follow-up. There were few other clinical events possibly related to PHPT (1 possible episode of nephrolithiasis, 4 fractures, 1 severe osteoporosis). Three women underwent parathyroidectomy, although 19/23 women met the updated criteria for parathyroidectomy from the 2002 NIH-sponsored workshop during follow-up. CONCLUSIONS: Many postmenopausal women with asymptomatic PHPT do not develop symptoms or complications of PHPT, and their biochemical parameters remains stable. Therefore, such asymptomatic women with PHPT can often be managed conservatively without parathyroidectomy.

Modulation of osteoclastogenesis by fatty acids.

Clinical studies have shown that total body fat mass is related to both bone density and fracture risk and that fat ingestion reduces bone turnover. These effects are at least partially mediated by endocrine mechanisms, but it is possible that lipids might act directly on bone. We assessed the effects of broad fractions of milk lipids in osteoblasts, bone marrow, and neonatal mouse calvariae. Several milk fractions and their hydrolysates inhibited osteoclastogenesis in bone marrow cultures, so we assessed the effects of free fatty acids in this model. Saturated fatty acids (0.1-10 microg/ml) inhibited osteoclastogenesis in bone marrow cultures and RAW264.7 cells. This effect was maximal for C14:0 to C18:0 fatty acids. The introduction of greater than 1 double bond abrogated this effect; omega3 and omega6 fatty acids had comparable low activity. Osteoblast proliferation was modestly increased by the antiosteoclastogenic compounds, ruling out a nonspecific toxic effect. Active fatty acids did not consistently change expression of receptor activator of nuclear factor-kappaB ligand or osteoprotegerin in osteoblastic cells nor did they affect the activity of key enzymes in the mevalonate pathway. However, receptors known to bind fatty acids were found to be expressed in osteoblastic (GPR120) and osteoclastic (GPR40, 41, 43, 120) cells. A synthetic GPR 40/120 agonist mimicked the inhibitory effects of fatty acids on osteoclastogenesis. These findings provide a novel link between lipid and bone metabolism, which might contribute to the positive relationship between adiposity and bone density as well as provide novel targets for pharmaceutical and nutriceutical development.

Effects of intravenous zoledronate on bone turnover and BMD persist for at least 24 months.

The duration of the antiresorptive effects of the intravenous bisphosphonate, zoledronate, is not known. Recently, we reported that two annual 4-mg doses of zoledronate suppressed bone turnover and increased BMD in HIV-infected men over 24 mo. We set out to determine the persistence of these effects after two doses of zoledronate. Thirty-three HIV-infected men who completed a randomized trial of 4 mg annual zoledronate (n = 17) or placebo (n = 16) were studied for a further 12 mo, during which time no skeletal therapy was administered. Participants received calcium (400 mg/d) and vitamin D supplements (50,000 IU/mo) for the first 24 mo of the study only. Biochemical markers of bone turnover and BMD were measured every 6 mo. Bone turnover markers were stably suppressed at 24 and 36 mo (12 and 24 mo after the second annual dose of zoledronate, respectively). There were no significant within-group changes in urine N-telopeptide, serum C-telopeptide, and osteocalcin between 24 and 36 mo (p > 0.07), and at each time point, each of the turnover markers was significantly lower in the zoledronate group. There were also no significant between-group differences in the changes in BMD at each site between 24 and 36 mo (p > 0.5), and at each time point, BMD at each site was significantly higher in the zoledronate group. These results suggest that the antiresorptive effects of zoledronate last >12 mo and raise the possibility that zoledronate could be administered less frequently than annually. Randomized trials that address this issue should be performed.

The effects of seasonal variation of 25-hydroxyvitamin D and fat mass on a diagnosis of vitamin D sufficiency.

BACKGROUND: The effect of season on vitamin D status is often overlooked in studies of optimal vitamin D concentrations and in clinical practice. OBJECTIVES: We aimed to determine the effects of seasonal variation of 25-hydroxyvitamin D [25(OH)D] on a previously selected minimum concentration for vitamin D sufficiency (50 nmol/L) and to determine whether fat mass modifies these effects. DESIGN: A cross-sectional study evaluated 1606 healthy postmenopausal women and 378 older men from Auckland, New Zealand, who were undergoing single measurements of 25(OH)D. RESULTS: Concentrations of <50 nmol 25(OH)D/L were seen in 49% (range: 23%-74%) of women and 9% (range: 0%-26%) of men when measured, but 73% of women and 39% of men were predicted to have trough 25(OH)D concentrations < 50 nmol/L, according to the demonstrated seasonal variation. The predicted duration of 25(OH)D concentrations < 50 nmol/L was 250 d/y in women and 165 d/y in men. CONCLUSION: Seasonal variation significantly affects the diagnosis of vitamin D sufficiency, which requires seasonally adjusted thresholds individualized for different locations. Clinicians should consider the month of sampling and the amount of body fat when interpreting 25(OH)D measurements.

CLINICAL Review # : low body weight mediates the relationship between HIV infection and low bone mineral density: a meta-analysis.

CONTEXT: HIV infection has been associated with low bone mineral density (BMD) in many cross-sectional studies, although longitudinal studies have not demonstrated accelerated bone loss. The cross-sectional studies may have been confounded by the failure to control for low body weight in HIV-infected patients. OBJECTIVE: Our objective was to determine whether low body weight might explain the association of HIV infection with low BMD. DATA SOURCES: MEDLINE and EMBASE were searched for English language studies published from 1966 to March 2007, and conference abstracts prior to 2007 were hand-searched. STUDY SELECTION: All studies reporting BMD and weight or body mass index in adult patients with HIV and a healthy age- and sex-comparable control group were included. Nine of 40 identified studies and one of 68 identified abstracts were eligible. DATA SYNTHESIS: We adjusted for the between-groups weight differences using regression coefficients from published cohorts of healthy men and women. On average, HIV-infected patients were 5.1 kg [95% confidence interval (CI), -6.8, -3.4; P < 0.001] lighter than controls. At all skeletal sites, unadjusted BMD was lower by 4.4-7.0% in the HIV-infected groups than the controls (P < 0.01). After adjustment for body weight, residual between-groups differences in BMD were small (2.2-4.7%) [lumbar spine, -0.02 (95% CI, -0.05, 0.01) g/cm2; P = 0.12; total hip, -0.02 (95% CI, -0.04, 0.00) g/cm2; P = 0.031; femoral neck, -0.04 (95% CI, -0.07, -0.01) g/cm2; P = 0.013; and total body, -0.03 (95% CI, -0.07, 0.01) g/cm2, P = 0.11]. CONCLUSION: HIV-infected patients are lighter than controls and low body weight may largely account for the high prevalence of low BMD reported in HIV-infected patients. However, in the setting of current treatment practice, HIV infection per se is not a risk factor for low BMD.

Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity?

Osteonecrosis of the jaw (ONJ) is a complication of high-dose bisphosphonate use, characterized by the finding of exposed bone in the oral cavity. It has been assumed that the primary lesion lies in bone and is related to over-suppression of bone turnover, but it is unclear why such a lesion should present with loss of the soft tissue covering of the mandible or maxilla as the primary clinical feature. A possible explanation of this paradox is that bisphosphonate is accumulated in bone in concentrations sufficient to be directly toxic to the oral epithelium. This would result in the failure of healing of soft tissue lesions (such as those caused by invasive dental procedures or by subclinical trauma from dentures) leading to secondary infection of the underlying bone. This model would explain why bone resection is unhelpful in managing this problem, suggests that low bone turnover caused by non-bisphosphonate drugs should not cause the same problem, and raises the possibility that agents which reverse bisphosphonate effects in vitro might have a role in the management of ONJ.

Bone mineral density remains stable in HAART-treated HIV-infected men over 2 years.

OBJECTIVE: Recently we reported that human immunodeficiency virus (HIV)-infected Caucasian men treated with highly active antiretroviral therapy (HAART) have normal weight-adjusted bone mineral density (BMD), in contrast to most other cross-sectional analyses, which have reported low BMD in HIV-infected patients. We have now addressed the question of whether there is accelerated BMD loss over time in HIV-infected men. DESIGN: A 2-year, prospective, longitudinal study. SUBJECTS: Twenty-three HAART-treated, HIV-infected men and 26 healthy controls. MEASUREMENTS: All participants had measurements of BMD and bone-related laboratory parameters at baseline, and a repeat measurement of BMD at 2 years. RESULTS: In the HIV-infected men the mean age was 47 years, the mean duration of infection was 8.2 years, and the mean duration of HAART was 54 months. Over 2 years of follow-up, BMD increased from baseline in the HIV-infected men by 2.6% at the lumbar spine (P = 0.05 vs. baseline), and remained stable at the total hip (mean change 0.1%, P > 0.99) and total body (mean change 0.6%, P = 0.39). Mean changes in BMD in the control group were 1.4% at the lumbar spine, -0.1% at the total hip, and -0.8% at the total body. The HIV-infected men lost less total body BMD than the control group (P = 0.01). In the HIV-infected men, body weight remained stable over 2 years while fat mass decreased and lean mass tended to increase, whereas in the controls, body weight and fat mass increased while lean mass remained stable. CONCLUSIONS: Accelerated bone loss does not occur in HIV-infected men treated with HAART. Monitoring of BMD in HIV-infected men may not be necessary.

Age-, gender-, and weight-related effects on levels of 25-hydroxyvitamin D are not mediated by vitamin D binding protein.

OBJECTIVE: 25-hydroxyvitamin D (25OHD) levels are inversely related to body weight, and have been reported to decline with age and be lower in women than men. We hypothesized that these findings might be explained by effects of these variables on vitamin D binding protein (DBP) levels. We set out to determine the relationships between DBP and gender, 25OHD, body weight and body composition. DESIGN: Cross-sectional analysis. PATIENTS: One hundred healthy, middle-aged and older, community-dwelling men and women. MEASUREMENTS: All participants were measured for 25OHD, DBP, body weight, bone mineral density and body composition. RESULTS: Women had higher mean DBP levels than men but lower total 25OHD levels [DBP: women, mean (SD) 339 (36) mg/l, men 307 (71) mg/l, P = 0.005; 25OHD: women 67 (23) nmol/l, men 91 (39) nmol/l, P < 0.001]. In women, there were significant positive relationships between DBP and albumin (r = 0.33) and 25OHD (r = 0.34) whereas in men there were no significant relationships between DBP and any measured variables. There was no significant relationship between DBP and age, body weight, body mass index, fat mass or percentage fat in men or women. CONCLUSION: We found no evidence to support the hypothesis that DBP levels are related to age, or adiposity. The changes in 25OHD levels with age, gender, or fat mass are not due to underlying relationships between DBP and these variables. This suggests that the relationships consistently observed between 25OHD and body composition and gender are of biological origin and not due to adaptation to changes in transport proteins.

Addition of monofluorophosphate to estrogen therapy in postmenopausal osteoporosis: a randomized controlled trial.

INTRODUCTION: Treatment of osteoporosis with high-dose fluoride alone does not reduce fracture risk. We hypothesized that the antifracture efficacy of fluoride could be optimized by its use in low doses combined with an antiresorptive agent. EXPERIMENTAL SUBJECTS: Subjects included 80 women with postmenopausal osteoporosis who had been taking estrogen for at least 1 yr. METHODS: Subjects were randomized to receive monofluorophosphate (MFP) (fluoride content of 20 mg/d) or placebo over 4 yr in a double-blind trial. RESULTS AND DISCUSSION: There were progressive increases in lumbar spine bone density over the duration of the study (MFP, 22%; placebo, 6%; P < 0.0001). In the trabecular bone of L3, these increases were even greater (MFP, 49%; placebo, 2.5%; P < 0.0001). In the proximal femur, there were smaller but significant treatment effects (P = 0.015). Total body scans and their subregions also showed significantly greater increases in the MFP group. Bone formation markers increased significantly in the MFP group at yr 1. Hyperosteoidosis was present in biopsies from five of seven MFP subjects, with osteomalacia in two of seven. The hazards ratio for vertebral fractures was 0.20 (95% confidence interval, 0.05-1.30), and the incidence rate ratio was 0.12 (95% confidence interval, 0.06-0.23; P < 0.01). The hazards ratio for nonvertebral fractures was 3.3 (95% confidence interval, 0.8-12.0). CONCLUSIONS: We conclude that fluoride at 20 mg/d produces substantial increases in bone mineral density but still interferes with bone mineralization. This indicates that most previous studies with this ion have used toxic doses and that much lower doses should be assessed to find a safe dose window for the use of this powerful anabolic agent.

Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trial.

CONTEXT: Recent studies have reported low bone mineral density (BMD) in HIV-infected patients. Annual iv administration of 4 mg zoledronate has been shown to increase BMD and suppress bone turnover in postmenopausal women. OBJECTIVE: The objective of the study was to determine whether annual administration of 4 mg zoledronate will increase BMD in HIV-infected men receiving highly active antiretroviral therapy. DESIGN AND SETTING: A 2-yr randomized placebo-controlled trial was conducted in a clinical research center. PARTICIPANTS: A total of 43 HIV-infected men were treated with highly active antiretroviral therapy for at least 3 months, with BMD T score less than -0.5. INTERVENTION: Participants received annual iv administration of 4 mg zoledronate or placebo. All participants took 400 mg/d calcium and 1.25 mg/month vitamin D. MEASUREMENTS: BMD at the lumbar spine, total hip and total body, and bone turnover markers were measured. RESULTS: At the lumbar spine, BMD increased by 8.9% over 2 yr in the zoledronate group compared with an increase of 2.6% in the control group (P<0.001). At the total hip, BMD increased by 3.8% over 2 yr in the zoledronate group compared with a decrease of 0.8% in the control group (P<0.001). At the total body, BMD increased by 2.3% over 2 yr compared with a decrease of 0.5% in the control group (P<0.001). Urine N-telopeptide decreased by 60% at 3 months in the zoledronate group and thereafter remained stable. CONCLUSIONS: Annual administration of zoledronate is a potent and effective therapy for the prevention or treatment of bone loss in HIV-infected men. The current data provide the first trial evidence of the BMD effects of annual zoledronate beyond 1 yr in any population, as well as being the first reported trial in men.