Effect of oral zoledronate administration on bone turnover in older women.

AIM: The aim of this work is to assess the safety and efficacy of two oral zoledronate preparations by determining their effects on bone resorption in healthy postmenopausal women. METHODS: The preparations studied were zoledronic acid in enteric-coated capsules or a microparticle preparation of zoledronic acid in these capsules. Bone resorption was measured as ß-C-telopeptideof type I collagen (CTX) in fasting serum. Separate cohorts, each of five women, were recruited and allocated in sequence to single doses of 20 mg, 40 mg, or 60 mg of oral zoledronate. RESULTS: Zoledronate 20 mg enteric capsules were well tolerated, reduced serum CTX by a median 51% at 1 week, but by only 17% at 1 month. Doses of 40 or 60 mg of this preparation produced APR and/or gastrointestinal symptoms in more than half of participants. With these doses, median CTX reduction at 1 week was >80%, ~70% at 1 month, but only ~30% at 6 months. Enteric capsules containing microparticles of zoledronate 20 mg reduced CTX by a median 53% at 1 week, with offset over 3 months. Two or three of these capsules dosed weekly reduced CTX by ~50% at 1 month, and by ~30% at 3 and 6 months. CONCLUSIONS: Oral zoledronate 20 mg circumvents the problem of APR symptoms but, even with multiple doses, the anti-resorptive effect is smaller and less sustained than with intravenous zoledronate. Probably a viable oral regimen of zoledronate dosing at intervals of weeks to months could be developed, but the advantage of infrequent dosing would be lost.

Fracture Prevention with Zoledronate in Older Women with Osteopenia.

BACKGROUND: Bisphosphonates prevent fractures in patients with osteoporosis, but their efficacy in women with osteopenia is unknown. Most fractures in postmenopausal women occur in those with osteopenia, so therapies that are effective in women with osteopenia are needed. METHODS: We conducted a 6-year, double-blind trial involving 2000 women with osteopenia (defined by a T score of -1.0 to -2.5 at either the total hip or the femoral neck on either side) who were 65 years of age or older. Participants were randomly assigned to receive four infusions of either zoledronate at a dose of 5 mg (zoledronate group) or normal saline (placebo group) at 18-month intervals. A dietary calcium intake of 1 g per day was advised, but calcium supplements were not provided. Participants who were not already taking vitamin D supplements received cholecalciferol before the trial began (a single dose of 2.5 mg) and during the trial (1.25 mg per month). The primary end point was the time to first occurrence of a nonvertebral or vertebral fragility fracture. RESULTS: At baseline, the mean (±SD) age was 71±5 years, the T score at the femoral neck was -1.6±0.5, and the median 10-year risk of hip fracture was 2.3%. A fragility fracture occurred in 190 women in the placebo group and in 122 women in the zoledronate group (hazard ratio with zoledronate, 0.63; 95% confidence interval, 0.50 to 0.79; P<0.001). The number of women that would need to be treated to prevent the occurrence of a fracture in 1 woman was 15. As compared with the placebo group, women who received zoledronate had a lower risk of nonvertebral fragility fractures (hazard ratio, 0.66; P=0.001), symptomatic fractures (hazard ratio, 0.73; P=0.003), vertebral fractures (odds ratio, 0.45; P=0.002), and height loss (P<0.001). CONCLUSIONS: The risk of nonvertebral or vertebral fragility fractures was significantly lower in women with osteopenia who received zoledronate than in women who received placebo. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12609000593235 .).

Effect of Zoledronate on Lower Respiratory Infections in Older Women: Secondary Analysis of a Randomized Controlled Trial.

A recent observational study of the incidence of pneumonia in patients with previous hip fractures found that bisphosphonate use reduced pneumonia risk by about one-quarter, in comparisons with those either not receiving osteoporosis treatment or receiving treatment with non-bisphosphonate drugs. Mortality from pneumonia was similarly reduced. It was hypothesized that effects of these drugs on immune or inflammatory function might mediate this effect. We have used the adverse event database from our recent 6-year randomized controlled trial of zoledronate in 2000 women over the age of 65 years, to determine whether a similar effect is observed using this more rigorous study design. Seventy-five women had at least one episode of pneumonia (32 [3.2%] zoledronate, 43 [4.3%] placebo) and 119 women had at least one episode of either pneumonia or a lower respiratory tract infection (57 [5.7%] zoledronate, 62 [6.2%] placebo). There were 93 pneumonia events and 167 pneumonia/lower respiratory infection events. For pneumonia, the hazard ratio associated with randomization to zoledronate was 0.73 (95% confidence interval, 0.46-1.16; P = 0.18) and the rate ratio was 0.69 (0.45, 1.04; P = 0.073). For the composite endpoint of pneumonia or lower respiratory infection, the hazard ratio was 0.90 (0.61, 1.30; P = 0.58) and the rate ratio 0.74 (0.54, 0.997; P = 0.048). The proportion of people with events changed approximately linearly over time in both groups, suggesting a progressive divergence in cumulative incidence during the study. In conclusion, these findings lend support to the hypothesis that bisphosphonate use reduces the number of lower respiratory tract infections in older women, though the present study is under-powered for this endpoint and the findings are of borderline statistical significance. Further analysis of other trials of bisphosphonates is necessary to test this possibility further, and exploration of the possible underlying mechanisms is needed.

Zoledronate Slows Weight Loss and Maintains Fat Mass in Osteopenic Older Women: Secondary Analysis of a Randomized Controlled Trial.

Studies in mice have suggested that osteocalcin plays an important role in glucose and fat metabolism. Since anti-resorptive drugs reduce circulating levels of osteocalcin they might be associated with increased fat mass and an increased risk of diabetes. Positive changes in body weight have been found in trials of alendronate and denosumab, but no significant effect in a previous trial of zoledronate. Whether those weight differences were in fat or lean mass is unknown. There were no effects of anti-resorptive treatments on fasting glucose concentrations or incidence of diabetes in those three studies. We have used our recent trial comparing zoledronate and placebo over 6 years in 2000 older osteopenic women to re-examine these questions. Both treatment groups lost body weight during the study (placebo 1.65 kg, zoledronate 1.05 kg), and this was significantly greater in the placebo group (P = 0.01). Both groups lost lean mass, and this loss was marginally (0.17 kg) but significantly (P = 0.02) greater in those receiving zoledronate. The placebo group had a mean loss of fat mass of 0.63 kg but there was no change in fat mass in the zoledronate group (between-groups comparison, P = 0.007). In the placebo group, there were 20 new diagnoses of diabetes, and in the zoledronate group, 19 (P = 0.87). Zoledronate prevented age-related loss of fat mass in these late postmenopausal women. The present study is the first to document a significant effect of zoledronate treatment on body weight, confirming results previously found with alendronate and denosumab. It also demonstrates that this is principally an effect to maintain fat mass rather than influencing lean mass, raising an important physiological question as to how anti-resorptive drugs have this effect on intermediary metabolism. It is possible that this anti-catabolic action contributes to the beneficial effects of anti-resorptive drugs on bone and longevity.

Long-Term Stable Bone Mineral Density in HIV-Infected Men Without Risk Factors for Osteoporosis Treated with Antiretroviral Therapy.

INTRODUCTION: Most prospective studies of bone mineral density (BMD) in HIV-infected cohorts taking antiretroviral therapy (ART) have been of short duration, typically < 3 years. Such studies have reported short-term stable or increasing BMD. We assessed whether this BMD stability persists for > 10 years in middle-aged and older men established on ART. METHODS: A 12-year, prospective, longitudinal study in 44 HIV-infected men treated with ART who had measurements of BMD at the lumbar spine, proximal femur and total body at baseline, 2, 6 and 12 years. RESULTS: At baseline, the mean age of participants was 49 years, the mean duration of HIV infection was 8 years, and the mean duration of ART was 50 months. After 12 years, BMD increased by 6.9% (95% CI 3.4 to 10.3) at the lumbar spine, and remained stable (range of BMD change: - 0.6% to 0.0%) at the total hip, femoral neck and total body. Only two individuals had a decrease of > 10% in BMD at any site during follow-up and both decreases in BMD were explained by co-morbid illnesses. CONCLUSIONS: BMD remained stable over 12 years in middle-aged and older HIV-infected men treated with ART. Monitoring BMD in men established on ART who do not have risk factors for BMD loss is not necessary.

Bone Loss After Romosozumab/Denosumab: Effects of Bisphosphonates.

Romosozumab and denosumab are monoclonal antibodies for the treatment of osteoporosis. Both have a rapid offset of effect resulting in loss of bone density (BMD) gained on-treatment and, in some cases, multiple vertebral fractures following treatment cessation. We recently reported disappointing results from transitioning patients from denosumab to intravenous zoledronate at the time the next denosumab injection is due. The present report re-assesses the role of bisphosphonates following the use of denosumab. In the FRAME trial, osteoporotic women were randomized to romosozumab or placebo for 1 year, then both groups were provided with open-label denosumab for the subsequent 2 years. In women completing this study at our center, we offered treatment with either oral or intravenous bisphosphonates. In the eleven women opting for intravenous treatment, zoledronate was given after a median delay of 65 days from trial-end, in the hope that this might increase skeletal uptake of the drug and, thereby, its efficacy to maintain bone density. In these women, spine BMD was 17.3% above baseline at trial-end, and still 12.3% above baseline a year later, a 73% (CI: 61%, 85%) retention of the treatment benefit. The comparable BMD figures for the total hip were 10.7 and 9.2% above baseline, a 87% (CI: 77%, 98%) retention of treatment effect. In contrast, those not receiving treatment after the conclusion of the FRAME trial lost 80-90% of the BMD gained on-trial in the following 12 months. Women treated with risedronate showed an intermediate response. In the zoledronate group, mean PINP 6 months post-FRAME was 23 ± 4 µg/L and at 12 months it was 47 ± 8 µg/L, suggesting that repeat zoledronate dosing is needed at 1 year to maintain the BMD gains. In conclusion, delaying administration of intravenous bisphosphonate when transitioning from short-term denosumab appears to increase the extent to which the gains in BMD are maintained.

Bone Loss After Denosumab: Only Partial Protection with Zoledronate.

A case series of six women with postmenopausal osteoporosis who had received continuous denosumab for 7 years and were then given a single infusion of zoledronate (5 mg) is reported. During denosumab treatment, bone mineral density (BMD) in the spine increased 18.5% (P = 0.006), and total hip BMD by 6.9% (P = 0.03). Post-zoledronate BMDs were measured 18-23 months after treatment, and there were significant declines at each site (P spine = 0.043, P hip = 0.005). Spine BMD remained significantly above the pre-denosumab baseline (+9.3%, P = 0.003), but hip BMD was not significantly different from baseline (-2.9%). At the time of post-zoledronate BMD measurements, serum PINP levels were between 39 and 60 µg/L (mean 52 µg/L), suggesting that the zoledronate treatment had not adequately inhibited bone turnover. It is concluded that this regimen of zoledronate administration is not adequate to preserve the BMD gains that result from long-term denosumab treatment.

Dietary calcium intake and rate of bone loss in men.

A high Ca intake has been recommended for osteoporosis prevention; however, little research has examined the relationship between dietary Ca and bone health in men. We examined associations between dietary Ca intake, bone mineral density (BMD) and change in BMD at the total body, hip and spine over 2 years in a cohort of men (mean age 57 years, BMI 26 kg/m2) from a trial. Data from the total cohort (n 323) were used in the analysis of Ca intake and BMD at baseline, and data from the placebo group (n 99) were used in the longitudinal analysis of Ca intake and change in BMD. Parathyroid hormone (PTH) and the markers of bone turnover serum total alkaline phosphatase activity, serum C-telopeptide and serum procollagen type-1 N-terminal propeptide were measured in a subset of participants at baseline (n 150), and associations with dietary Ca at baseline were examined. Mean Ca intake was 870 mg/d. Baseline BMD was not related to dietary Ca intake at any site, before or after adjustment for covariables. Similarly, bone loss over 2 years was not related to Ca intake at any site, before or after adjustment. Dietary Ca intake was inversely correlated with PTH at baseline (r -0·19, P=0·02), but was not associated with the markers of bone turnover. BMD and rates of bone loss were unrelated to Ca intake in these men. This suggests that strategies to increase Ca intake are unlikely to impact on the prevalence of and morbidity from male osteoporosis.

Acute effects of calcium supplements on blood pressure and blood coagulation: secondary analysis of a randomised controlled trial in post-menopausal women.

Recent evidence suggests that Ca supplements increase the risk of cardiovascular events, but the mechanism(s) by which this occurs is uncertain. In a study primarily assessing the effects of various Ca supplements on blood Ca levels, we also investigated the effects of Ca supplements on blood pressure and their acute effects on blood coagulation. We randomised 100 post-menopausal women to 1 g/d of Ca or a placebo containing no Ca. Blood pressure was measured at baseline and every 2 h up to 8 h after their first dose and after 3 months of supplementation. Blood coagulation was measured by thromboelastography (TEG) in a subgroup of participants (n 40) up to 8 h only. Blood pressure declined over 8 h in both the groups, consistent with its normal diurnal rhythm. The reduction in systolic blood pressure was smaller in the Ca group compared with the control group by >5 mmHg between 2 and 6 h (P≤0·02), and the reduction in diastolic blood pressure was smaller at 2 h (between-groups difference 4·5 mmHg, P=0·004). Blood coagulability, assessed by TEG, increased from baseline over 8 h in the calcium citrate and control groups. At 4 h, the increase in the coagulation index was greater in the calcium citrate group compared with the control group (P=0·03), which appeared to be due to a greater reduction in the time to clot initiation. These data suggest that Ca supplements may acutely influence blood pressure and blood coagulation. Further investigation of this possibility is required.

Acute effects of calcium citrate with or without a meal, calcium-fortified juice and a dairy product meal on serum calcium and phosphate: a randomised cross-over trial.

Ca supplements, but not dietary Ca, have been associated with increased cardiovascular risk. This difference could be related to differences in their acute effects on serum Ca. We therefore examined the effects of Ca from different sources on serum Ca and phosphate in a randomised, cross-over trial of ten women (mean age of 69 years). Fasting participants received a single dose of 500 mg of Ca as citrate, citrate with a meal, fortified juice or a dairy product meal, with at least 6 d between each intervention. Blood was sampled before and 1, 2, 4 and 6 h after each intervention was ingested. Serum ionised and total Ca increased significantly from baseline over 6 h. Using calcium citrate fasting as a comparator, the elevations in ionised and total Ca were similar after fortified juice, delayed after calcium citrate with a meal and smaller after a dairy product meal. Serum phosphate and calcium-phosphate product increased from baseline after calcium citrate with a meal and after a dairy product meal, and they declined after calcium citrate fasting and after fortified juice. The elevations in serum Ca in the present study were only slightly different from those observed after the administration of 1000 mg of Ca in a previous study. These data indicate that different sources of Ca have different acute effects on serum Ca and support recommendations that dietary Ca might be safer than supplements. Whether these differences contribute to differences in cardiovascular risk requires further study.

Acute and 3-month effects of microcrystalline hydroxyapatite, calcium citrate and calcium carbonate on serum calcium and markers of bone turnover: a randomised controlled trial in postmenopausal women.

Ca supplements are used for bone health; however, they have been associated with increased cardiovascular risk, which may relate to their acute effects on serum Ca concentrations. Microcrystalline hydroxyapatite (MCH) could affect serum Ca concentrations less than conventional Ca supplements, but its effects on bone turnover are unclear. In the present study, we compared the acute and 3-month effects of MCH with conventional Ca supplements on concentrations of serum Ca, phosphate, parathyroid hormone and bone turnover markers. We randomised 100 women (mean age 71 years) to 1 g/d of Ca as citrate or carbonate (citrate-carbonate), one of two MCH preparations, or a placebo. Blood was sampled for 8 h after the first dose, and after 3 months of daily supplementation. To determine whether the acute effects changed over time, eight participants assigned to the citrate dose repeated 8 h of blood sampling at 3 months. There were no differences between the citrate and carbonate groups, or between the two MCH groups, so their results were pooled. The citrate-carbonate dose increased ionised and total Ca concentrations for up to 8 h, and this was not diminished after 3 months. MCH increased ionised Ca concentrations less than the citrate-carbonate dose; however, it raised the concentrations of phosphate and the Ca-phosphate product. The citrate-carbonate and MCH doses produced comparable decreases in bone resorption (measured as serum C-telopeptide (CTX)) over 8 h and bone turnover (CTX and procollagen type-I N-terminal propeptide) at 3 months. These findings suggest that Ca preparations, in general, produce repeated sustained increases in serum Ca concentrations after ingestion of each dose and that Ca supplements with smaller effects on serum Ca concentrations may have equivalent efficacy in suppressing bone turnover.

Duration of fracture prevention after zoledronate treatment in women with osteopenia: observational follow-up of a 6-year randomised controlled trial to 10 years.

BACKGROUND: We previously identified that zoledronate administered at 18-month intervals reduced fragility fractures by a third in a 6-year trial of women older than 65 years with osteopenia. This extension aims to identify the persistence of these effects. METHODS: Of the 2000 ambulant, community dwelling, postmenopausal women older than 65 years recruited in Auckland, New Zealand, with T-scores at the total hip or femoral neck in the range -1·0 to -2·5, we invited participants who received four doses of intravenous zoledronate, completed follow-up to year 6 of the core trial, did not have metabolic bone disease (other than osteoporosis), and were not using bone-active drugs into this 4-year observational study extension, during which further treatment was at the discretion of their own doctors. Participants were asked to notify study staff of any new fractures and were telephoned at 7·5 years and 9·0 years to update their health status. Participants were then invited to an onsite visit at 10·0 years. Fractures and other health events were documented at each contact and analysed in all women who entered the extension, and bone mineral density (BMD; analysed in participants without notable use of bone-active medications who attended an onsite visit at 10 years) and turnover markers (measured from fasting morning blood in a random subset of 50 participants) were measured at year 10. FINDINGS: Of the 1000 women randomly assigned to receive zoledronate in the core trial, 796 participants were eligible for the extension, of whom 762 (96%) entered the extension between Sept 24, 2015, and Dec 13, 2017. Mean follow-up duration was 4·24 years (SD 0·57, range 0·61-6·55; final follow-up on May 25, 2022). 727 (91%) of participants were assessed at 10 years. 25 women died during the extension, six withdrew for medical reasons, and four were lost to follow-up. 92 women suffered 114 non-vertebral fractures during the extension. Non-vertebral fracture rates increased from a nadir of 15 fractures per 1000 woman-years (95% CI 10-21) in the last 2 years of the core trial to 24 fractures (17-33) in years 6-8 and 42 fractures (32-53) in years 8-10, similar to that in the placebo group in the last 2 years of the core trial. Total hip BMD (relative risk per 0·1 g/cm2 0·73, 95% CI 0·57-0·93; p=0·011) and a previous history of non-vertebral fracture (1·74, 1·12-2·69; p=0·013) at year 6 predicted incident fractures but change in total hip BMD did not. Total hip BMD decreased from 4·2% above study baseline to 0·8% above baseline (p<0·0001) during the extension. Turnover markers were not useful for predicting BMD loss in individuals. Osteonecrosis of the jaw or atypical femoral fractures did not occur in any participants. INTERPRETATION: The reduced fracture rates following zoledronate in the core trial were substantially maintained for 1·5-3·5 years after the last zoledronate infusion, but not thereafter. FUNDING: Health Research Council of New Zealand.

Testosterone levels following decreases in serum osteocalcin.

Recent preclinical studies suggest that osteoblasts are able to induce testosterone production by the testis, a process mediated by osteocalcin. Bisphosphonates substantially reduce osteocalcin levels. If osteocalcin is an important regulator of testosterone levels in adult men, it would be expected that the substantial reductions in osteocalcin induced by zoledronate would impact negatively on testosterone levels. Previously, we carried out a 2-year randomized, controlled trial of annual 4 mg zoledronate in 43 HIV-infected men. To explore the relationship between osteocalcin and testosterone further, we measured serum testosterone at baseline, 3 months, and 2 years; luteinizing hormone at 3 months and 2 years; and total osteocalcin at 2 years in 28 trial participants with available blood samples. At 2 years, total osteocalcin was 39 % lower in the zoledronate group than the placebo group (zoledronate mean 10.1 [SD 3.0] µg/L, placebo 16.5 [SD 4.9] µg/L, P = 0.003). Despite these substantial differences in osteocalcin levels, testosterone levels did not change over time in either group and there were no between-group differences over time, P = 0.4 (mean change at 2 years [adjusted for baseline levels] in zoledronate group -0.4 nmol/L, 95 % CI -2.5 to 1.6; placebo group 0.4 nmol/L, 95 % CI -1.6 to 2.5). Luteinizing hormone was within the normal range and did not differ between the groups at either 3 months or 2 years. Thus, the absence of a change in testosterone despite a substantial reduction in osteocalcin following zoledronate treatment argues against a biologically significant role for osteocalcin in the regulation of testosterone in adult men. This provides reassurance that men receiving potent antiresorptive drugs are not at risk of iatrogenic hypogonadism.

Impact of Television Depictions of Gout on Perceptions of Illness: A Randomized Controlled Trial.

OBJECTIVE: Gout is a chronic disease that can be effectively managed with long-term urate-lowering therapy. However, it is frequently portrayed on screen as an acute disease caused by a poor diet that should be managed with lifestyle changes. This study was undertaken to investigate the impact of a fictional television depiction of gout on perceptions of the disease and its management. METHODS: In a randomized controlled single-blind study, 200 members of the public watched either a 19-minute commercial television comedy episode that depicted gout as an acute disease caused by poor diet and managed with lifestyle changes, or a control episode from the same television series that did not mention gout or other diseases. Participants completed a survey regarding their perceptions of gout, its likely causes, and management strategies. RESULTS: Participants randomized to watch the gout-related episode believed gout had greater consequences (mean score of 7.1 versus 6.2 on an 11-point Likert scale; P < 0.001) and were more likely to rank the most important cause as poor eating habits compared to the control group (70% versus 38%; P < 0.001). They were also less likely to believe it is caused by genetic factors or chance. Participants watching the gout-related episode believed a change in diet would be a more effective management strategy (9.0 versus 8.4; P = 0.004) and long-term medication use would be less effective (6.9 versus 7.6; P = 0.007) compared to participants in the control group. CONCLUSION: Television depictions of gout can perpetuate inaccurate beliefs regarding causes of the disease and underemphasize effective medical strategies required in chronic disease management.

No Effect of NSAID Use on Efficacy of Zoledronate: A Post Hoc Analysis of a Randomized Trial in Osteopenic Older Women.

Bisphosphonates are widely used for the prevention and treatment of osteoporosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are also widely used among the older population group at high risk of fractures. NSAIDs have been shown to impact on bone turnover, and a recent reanalysis of a clinical trial of clodronate found that NSAID use at baseline abrogated any effect of clodronate on either bone density (BMD) or fracture risk. To determine whether NSAIDs influence the efficacy of other bisphosphonates, we have reanalyzed our 6-year randomized controlled trial of zoledronate in 2000 osteopenic postmenopausal women. NSAID use was reported at baseline in 38% of the cohort and anytime use was reported by 65%. The evolution of the zoledronate effects on BMD were almost identical whether or not women were using NSAIDs at baseline and were significant in both subgroups at all BMD sites (p < 0.0001). The significant reduction in the risk of fracture in those allocated to zoledronate (p < 0.0001) showed no interaction with baseline use of NSAIDs (p = 0.33) nor with NSAID use at any time during the study (p = 0.28). The odds of fracture were significantly reduced in both NSAID users and nonusers. We conclude that the present analysis provides no support for the suggestion that NSAIDs interfere with the efficacy of potent bisphosphonates in terms of their effects on bone density or fracture. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Effect of a Three-Day Course of Dexamethasone on Acute Phase Response Following Treatment With Zoledronate: A Randomized Controlled Trial.

Zoledronate is a potent intravenous bisphosphonate effective in the management of osteoporosis, Paget's disease and skeletal-related events in malignancy. Its most frequent adverse effect is the acute phase response (APR), an inflammatory reaction characterized by fever, musculoskeletal pain, headache, and nausea. This randomized, placebo-controlled, double-blind study investigated the efficacy of a three-day course of dexamethasone 4 mg daily in reducing incidence of APR. Participants (n = 60) were randomized to receive either 4 mg of oral dexamethasone 1.5 hours before zoledronate and once a day for the following 2 days, or placebo. Oral temperature was measured at baseline and three times a day for the following 3 days, and questionnaires assessing symptoms of the APR were completed at baseline and for 3 days following zoledronate. Use of anti-inflammatory medication in the 3 days following zoledronate was recorded. The primary outcome was the temperature change from baseline. There was a significant difference in the primary outcome between the dexamethasone and placebo groups (p < 0.0001), with a mean decrease in temperature of 0.10°C (95% confidence interval [CI], -0.34 to 0.14) in the dexamethasone group compared with a mean increase in temperature of 0.84°C (95% CI, 0.53-1.16) in the placebo group on the evening following zoledronate. There was also a difference in APR-related symptom score over time between the two groups (p = 0.0005), with a median change in symptom score in the dexamethasone group 1 day after zoledronate of 0 (95% CI, 0-1) compared with 3 (95% CI, 0-5) in the placebo group. An increase in temperature of ≥1°C to a temperature of >37.5°C occurred in two of 30 (6.7%) participants in the dexamethasone group compared with 14 of 30 participants (46.7%) in the placebo group (p = 0.0005). This study demonstrates that a 3-day course of dexamethasone substantially reduces the APR following zoledronate infusion. © 2023 American Society for Bone and Mineral Research (ASBMR).

Stable bone mineral density over 6 years in HIV-infected men treated with highly active antiretroviral therapy (HAART).

OBJECTIVE: Most longitudinal studies of bone mineral density (BMD) in HIV-infected cohorts have been of short duration, typically 1-2 years. Some studies, especially of cohorts treated with highly active antiretroviral therapy (HAART), report short-term stable or increasing BMD, but other studies, often in cohorts initiating HAART, report short-term losses in BMD. We assessed BMD changes over the medium term in HIV-infected men already established on HAART at baseline. DESIGN: Six-year, prospective, longitudinal study. SUBJECTS: Forty-four HIV-infected men treated with HAART and 37 uninfected, healthy controls. MEASUREMENTS: Participants had measurements of BMD at baseline, 2 and 6 years. RESULTS: In the HIV-infected men at baseline, the mean age was 49 years, the mean duration of infection was 8 years, and the mean duration of HAART was 50 months. Over 6 years of follow-up, there was a greater increase in lumbar spine BMD (5·3%, 95% CI 3·8-6·5%) in the HIV-infected men compared with controls (0·3%, 95% CI -1·0 to 1·6%), P < 0·001. There was no difference between the groups in the change in BMD over time at the total hip (HIV group: -0·6%, 95% CI -1·7 to 0·4%, controls -1·0%, 95% CI -2·2 to 0%, P = 0·8) or at the total body (HIV group, 0·3%, 95% CI -0·3 to 1·0%; controls, 0·5%, 95% CI -0·2 to 1·1%, P = 0·15). Lean mass increased in the HIV group, but not in the controls. CONCLUSIONS: There was no evidence of accelerated bone loss over 6 years in middle-aged, HIV-infected men treated with HAART. For such patients, routine monitoring of BMD is not necessary over the short/medium term.

Zoledronate Reduces Height Loss Independently of Vertebral Fracture Occurrence in a Randomized Trial in Osteopenic Older Women.

Vertebral fractures are associated with height loss, reduced quality of life, and increased mortality and are an important endpoint for osteoporosis trials. However, height loss is associated with quality of life and mortality independent of associations with fracture. We have used data from a recent 6-year trial of zoledronate in 2000 osteopenic women aged >65 years to assess the impact of the semiquantitative and quantitative components of the definition of vertebral fracture on the outcome of that trial, to determine what factors impacted on height loss and to test whether height loss can be used as a surrogate for vertebral fracture incidence. In the trial protocol, an incident vertebral fracture was defined as a change in Genant grade plus both a 20% and 4 mm decrease in a vertebral height. The addition of the quantitative criteria reduced the number of fractures detected but did not change the size of the anti-fracture effect (odds ratios of 0.49 versus 0.45) nor the width of the confidence intervals for the odds ratios. Multivariate analysis of baseline predictors of height change showed that age accelerated height loss (p < 0.0001) and zoledronate reduced it (p = 0.0001). Incident vertebral fracture increased height loss (p = 0.0005) but accounted for only 0.7% of the variance in height change, so fracture could not be reliably inferred from height loss. In women without incident vertebral fractures, height loss was still reduced by zoledronate (height change: zoledronate, -1.23; placebo -1.51 mm/yr, p < 0.0001). This likely indicates that zoledronate prevents a subtle but widespread loss of vertebral body heights not detected by vertebral morphometry. Because height loss is associated with quality of life and mortality independent of associations with fracture, it is possible that zoledronate impacts on these endpoints via its effects on vertebral body integrity. © 2022 American Society for Bone and Mineral Research (ASBMR).