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UnlabelledThe purpose of this study is to examine the effect of PTH(1-84) treatment over 24 months followed by 12 months discontinuation on BMD, bone turnover markers, fractures and the impact of adherence on efficacy.IntroductionThere is limited information about the effect of PTH(1-84) after 18 months and limited data about the impact of compliance on response to anabolic therapy.MethodsSeven hundred and eighty-one subjects who received active PTH(1-84) in the Treatment of Osteoporosis with Parathyroid hormone trial for approximately 18 months were entered into a 6-month open-label extension. Thereafter, they were followed for 12 additional months after discontinuation of treatment. Endpoints examined included changes in BMD and biochemical markers.ResultsPTH(1-84) treatment over 24 months increased BMD at the lumbar spine by 6.8% above baseline (p

Abstract Background The identification of new methods of evaluating patients with osteoporotic fracture should focus on their usefulness in clinical situations such that they are easily measured and applicable to all patients. Thus, the purpose of this study was to examine the association between iliocostal distance and vertebral and non-vertebral fractures in patients seen in a clinical setting. Methods Patient data were obtained from the Canadian Database of Osteoporosis and Osteopenia (CANDOO). A total of 549 patients including 508 women and 41 men participated in this cross-sectional study. There were 142 women and 18 men with prevalent vertebral fractures, and 185 women and 21 men with prevalent non-vertebral fractures. Results In women multivariable regression analysis showed that iliocostal distance was negatively associated with the number of vertebral fractures (-0.18, CI: -0.27, -0.09; adjusted for bone mineral density at the Ward's triangle, epilepsy, cerebrovascular disease, inflammatory bowel disease, etidronate use, and calcium supplement use) and for the number of non-vertebral fractures (-0.09, CI: -0.15, -0.03; adjusted for bone mineral density at the trochanter, cerebrovascular disease, inflammatory bowel disease, and etidronate use). However, in men, multivariable regression analysis did not demonstrate a significant association between iliocostal distance and the number of vertebral and non-vertebral fractures. Conclusions The examination of iliocostal distance may be a useful clinical tool for assessment of the possibility of vertebral fractures. The identification of high-risk patients is important to effectively use the growing number of available osteoporosis therapies.

Aims: To describe the mechanisms of action of denosumab, a novel antiresorptive agent, contrasting it with other antiresorptive and anabolic osteoporosis treatments.Methods: Published papers related to the mechanism of action of approved osteoporosis treatments were sought through MEDLINE searches.Findings: Osteoporotic fractures carry a substantial burden of morbidity and mortality, but pharmacotherapy can prevent such fractures in high-risk individuals. Antiresorptive drugs (e.g. bisphosphonates, oestrogen, denosumab) reduce bone turnover by distinct mechanisms. Denosumab, a recently approved therapy, is a fully human monoclonal antibody that binds the cytokine RANKL (receptor activator of NFκB ligand), an essential factor initiating bone turnover. RANKL inhibition blocks osteoclast maturation, function and survival, thus reducing bone resorption. In contrast, bisphosphonates bind bone mineral, where they are absorbed by mature osteoclasts, inducing osteoclast apoptosis and suppressing resorption. These differences in mechanism influence both the onset and reversibility of treatment.Discussion: Effective pharmacotherapy is necessary for patients at high risk of fracture. Among the treatment options for postmenopausal osteoporosis, there are significant differences in mechanism and dosing. Denosumab acts by a novel mechanism and is administered twice yearly by subcutaneous injection. Identified by Osteoporosis Canada Clinical Practice Guidelines as a first-line agent for treatment of postmenopausal osteoporosis, denosumab represents an important addition to our treatment options. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous research has shown that dietary patterns are related to the risk of several adverse health outcomes, but the relation of these patterns to skeletal fragility is not well understood. OBJECTIVE: Our objective was to determine the relation between dietary patterns and incident fracture and possible mediation of this relation by body mass index, bone mineral density, or falls. DESIGN: We performed a retrospective cohort study based on the Canadian Multicentre Osteoporosis Study-a randomly selected population-based cohort. We assessed dietary patterns by using self-administered food-frequency questionnaires in year 2 of the study (1997-1999). Our primary outcome was low-trauma fracture occurring before the 10th annual follow-up (2005-2007). RESULTS: We identified 2 dietary patterns by using factor analysis. The first factor (nutrient dense) was strongly associated with intake of fruit, vegetables, and whole grains. The second factor (energy dense) was strongly associated with intake of soft drinks, potato chips, French fries, meats, and desserts. The nutrient-dense factor was associated with a reduced risk of fracture per 1 SD in men overall [hazard ratio (HR): 0.83; 95% CI: 0.64, 1.08] and in women overall (HR: 0.86; 95% CI: 0.76, 0.98). An age trend (P = 0.03) was observed, which yielded an HR of 0.97 in younger women (age < 70 y) compared with an HR of 0.82 in older women (age greater than or equal to 70 y). The associations were independent of body mass index, bone mineral density, falls, and demographic variables. The energy-dense pattern was not related to fracture. CONCLUSION: A diet high in vegetables, fruit, and whole grains may reduce the risk of low-trauma fracture, particularly in older women. [ABSTRACT FROM AUTHOR]

Background: The relationship between kidney function and bone loss is unclear.Study Design: A prospective observational study.Setting& Participants: 191 men and 444 women aged > or = 50 years participating in a population-based observational study designed to determine risk factors for bone loss and fractures.Predictors: The primary predictor of change in bone mineral density (BMD) was estimated creatinine clearance (using the Cockcroft-Gault formula) measured at baseline and stratified by quartiles. Our secondary predictor was estimated glomerular filtration rate using the Modification of Diet in Renal Disease Study equation, also stratified by quartiles.Outcomes& Measurements: Changes in BMD at the lumbar spine, total hip, and femoral neck during 5 years.Results: Compared with participants in the first quartile of estimated creatinine clearance (>101.2 mL/min), those in remaining quartiles were older (quartile 1, 50.0 years; quartile 2 [101.2-83.4 mL/min], 54.7 years; quartile 3 [83.4-68.3 mL/min], 60.5 years; and quartile 4 [<68.3 mL/min], 68.3 years); weighed less; reported more sedentary hours; were less likely to report excellent, very good, or good self-reported health; consumed less caffeine; and had lower serum calcium and phosphate and higher serum parathyroid hormone levels. After adjusting for age, weight, sex, baseline BMD, and these differences, compared with those in the first quartile, those in the fourth quartile had decreases in BMD of 0.08 g/cm(2) (95% CI, 0.04-0.1) at the lumbar spine, 0.08 g/cm(2) (95% CI, 0.06-0.1) at the femoral neck, and 0.09 g/cm(2) (95% CI, 0.07-0.1) at the total hip. Bone loss did not increase with worsening kidney function (P for trend > 0.05). Results were not substantially different using estimated glomerular filtration rate.Limitations: Observational study design and indirect measures of kidney function.Conclusions: Men and women with impaired kidney function are at increased risk of bone loss, even with minimal reduction in kidney function. [ABSTRACT FROM AUTHOR]

BACKGROUND: Teriparatide (parathyroid hormone [1-34] [ribosomal DNA origin]) stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. It has been found to significantly reduce vertebral fractures by 65%, and nonvertebral fragility fractures by 53% in treatment-naive postmenopausal women who have previously suffered a vertebral fracture. OBJECTIVE: This study examined the compliance, acceptance, and adherance of SC teriparatide 20 pg QD. METHODS: In this 18-month, multicenter, openlabel, prospective study, women with postmenopausal osteoporosis, and men >30 years of age with either idiopathic or hypogonadal osteoporosis (with low bone mass [T-score of -1 or worse] and > or =1 fragility fracture), who had experienced a treatment-related adverse event (AE) or an inadequate response while receiving antiresorptive treatment, and who were willing to receive open-label teriparatide for > or =18 months were eligible. Compliance was defined as self-reported use of > or =80% of study medication. Acceptance of the injection pen was determined by scores obtained from questionnaires and rating scales measuring patients' perception. Patients self-reported on injection discomfort, ease of use, and the overall injection administration. Acceptance was assessed at baseline, and 3, 6, and 18 months. AEs were recorded at each clinical visit from the patients' self-reports. At the 3-month visit, a serum calcium level was drawn > or =16 hours after the previous teriparatide dose. RESULTS: In this study, 116 patients-102 women with postmenopausal osteoporosis and 14 men (12 with idiopathic osteoporosis and 2 with hypogonadal osteoporosis)-were assessed for inclusion in the study. The mean (SD) age was 68.8 (11.1) years (range, 40-89 years) and the mean (SD) weight was 60.5 (11.7) kg (range, 37-87 kg). Seventy-three percent of the patients in this study had baseline spinal T-scores < or =-2.5, and 72% had fractured during treatment with an osteoporosis medication. Reported compliance was 89% at 6 months and 82% at 18 months. At baseline, 42% of patients were concerned about injection discomfort, and 43% were somewhat concerned with daily injections, while 7% were quite concerned. At 6 months, most patients reported much less concern (49%) or no concern (42%). Patient perceptions associated with learning how to use the pen injection, attaching the needle, holding the pen, and injecting the dose, improved during the first 6 months of the study. The most commonly reported AEs were dizziness, 12 (10.3%); nausea, 12 (10.3%); back pain, 9 (7.8%); and muscle cramps, 9 (7.8%). No AEs were believed to be associated with the use of the pen injection or teriparatide. Five patients had mildly elevated serum calcium concentrations (maximum value 2.8 mmol/L) at 3 months. However, all were normal on repeat testing approximately 4 weeks thereafter. CONCLUSIONS: This study found that teriparatide pen injection was well accepted in these patients, and acceptance rates improved during the first 6 months of treatment and, thereafter, improved slightly for approximately 18 months. Reported compliance remained high throughout the study (82%-89%). Teriparatide pen injection was a viable treatment in these osteopenic or osteoporotic patients with fragility fractures. [ABSTRACT FROM AUTHOR]

Background: Recombinant human parathyroid hormone (1-84) (PTH) increases bone mass and strength and improves bone quality by stimulating new bone formation.Objective: To determine the safety of PTH and its effect on the incidence of vertebral fractures in postmenopausal women with osteoporosis.Design: 18-month, randomized, double-blind, placebo-controlled, parallel-group study.Setting: 168 centers in 9 countries.Patients: 2532 postmenopausal women with low bone mineral density at the hip or lumbar spine.Interventions: Women received 100 mug of recombinant human PTH or placebo daily by subcutaneous injection. All received calcium, 700 mg/d, and vitamin D3, 400 U/d.Measurements: New or worsened vertebral fractures (primary outcome) and changes in bone mineral density and safety (secondary outcomes).Results: 67.2% of patients who received at least 1 dose of the study drug completed the study. Parathyroid hormone reduced the risk for new or worsened vertebral fractures, but in sensitivity analyses, the magnitude of the reduction was changed with assumptions about fracture incidence in patients who did not complete the study (relative risk assuming no fractures, 0.42 [95% CI, 0.24 to 0.72] [P = 0.001]; relative risk assuming fracture incidence observed in all patients who completed the trial, 0.60 [CI, 0.36 to 1.00] [P = 0.05]; relative risk assuming fracture incidence observed in the placebo group, 0.62 [CI, 0.37 to 1.04] [P = 0.07]). Compared with placebo, mean bone mineral density increased at the spine by 6.9% (CI, 6.4% to 7.4%) and at the hip by 2.1% (CI, 1.7% to 2.5%) but decreased at the forearm in the PTH-treated group. Parathyroid hormone treatment increased the percentage of participants with hypercalciuria, hypercalcemia, and nausea by 24% (CI, 20% to 27%), 23% (CI, 21% to 26%), and 14% (CI, 11% to 16%), respectively, compared with placebo.Limitations: Baseline serum PTH and vitamin D levels were not measured. Many patients discontinued the trial prematurely.Conclusions: Parathyroid hormone (1-84) reduced the overall risk for new or worsened vertebral fracture in postmenopausal women with osteoporosis. Hypercalciuria, hypercalcemia, and nausea were more common in women who took the drug. Although the magnitude of the reduction was sensitive to assumptions about fracture incidence in patients who did not complete the study, the findings suggest that PTH provides an alternative therapeutic option for fracture prevention. [ABSTRACT FROM AUTHOR]

PURPOSE: To devise, validate, and test a software model that improves how clinicians calculate individual risk for osteoporotic fracture and expected treatment benefit. METHODS: We developed a simple model of seven easily ascertained items plus bone mineral density (BMD) that calculates absolute fracture risk and expected absolute risk reduction after treatment. Baseline clinical variables and longitudinal fracture data from two large osteoporosis cohort studies validated the model's accuracy in predicting fracture risk. We then surveyed 298 clinicians to evaluate the likelihood they would prescribe alendronate in three hypothetical cases, first given the clinical data alone and then with model-derived data on fracture risk and expected treatment benefit. RESULTS: We found a strong linear relationship with the model's predicted fracture risk and observed fracture rates in two large observational cohorts but the model overestimated risk 2-3 fold. The model predicted a 1:200 5-year risk for spinal fracture and a 1:40 risk for nonspinal fracture in an index case of a younger, thin, osteopenic woman. Given this hypothetical history with BMD t-scores, 26% of clinicians were likely to prescribe alendronate; when also given model-calculated 5-year fracture risks with or without treatment, only 13% were likely to prescribe alendronate (p < 0.001). For 2 other osteoporosis patients in whom risk was much higher, further information on fracture risk and expected treatment benefit did not alter prescribing. CONCLUSIONS: Reporting absolute fracture risk with and without treatment promises to be most useful in women with osteopenia, a common clinical dilemma in younger postmenopausal women. [ABSTRACT FROM AUTHOR]

Background: The SF-36 is widely used to assess health-related quality of life (HRQOL), but with few longitudinal studies in healthy populations, it is difficult to quantify its natural history. This is important because any measure of change following an intervention may be confounded by natural changes in HRQOL. This paper assesses mean changes in SF-36 scores over a 3-year period in men and women between the ages of 40 and 59 years at baseline.Methods: Subjects were randomly selected from nine Canadian cities. Mean SF-36 changes over a 3-year period (1996/1997-1999/2000) were calculated for each gender within 5-year age categories. Multiple imputation was used to correct for potential bias due to missing data.Results: The baseline cohort included 1,974 women and 975 men between 40 and 59 years. Mean changes in HRQOL tended to be small. Women demonstrated small average declines in 22 of the 32 age and domain groupings (4 age groups, 8 SF-36 domains) while men showed declines in 14/32. Most participants stayed within 10 points of their original baseline score.Interpretation: Mean SF-36 scores change only slightly over three years in middle-aged Canadians, although there is much individual variation. It may be necessary to adjust for the natural evolution of SF-36 scores when interpreting results from longitudinal studies. [ABSTRACT FROM AUTHOR]

Background: Most vertebral compression fractures are not recognized or treated. We conducted a controlled trial in older patients with vertebral fractures incidentally reported on chest radiographs, comparing usual care with osteoporosis interventions directed at physicians (opinion-leader-endorsed evidence summaries and reminders) or physicians+patients (adding activation with leaflets and telephone counseling). Methods: Patients aged >60 years who were discharged home from emergency departments and who had vertebral fractures reported but were not treated for osteoporosis were allocated to usual care (control) or physician intervention using alternate-week time series. After 3 months, untreated controls were re-allocated to physician+patient intervention. Allocation was concealed, outcomes ascertainment blinded, and analyses intent-to-treat. Primary outcome was starting osteoporosis treatment within 3 months. Results: There were 1315 consecutive patients screened, and 240 allocated to control (n=123) or physician intervention (n=117). Groups were similar at baseline (average age 74 years, 45% female, 58% previous fractures). Compared with controls, physician interventions significantly (all P <.001) increased osteoporosis treatment (20 [17%] vs 2 [2%]), bone mineral density testing (51 [44%] vs 5 [4%]), and bone mineral density testing or treatment (57 [49%] vs 7 [6%]). Three months after controls were re-allocated to physician+patient interventions, 22% had started treatment and 65% had bone mineral density testing or treatment (P <.001 vs controls). Physician+patient interventions increased bone mineral density testing or treatment an additional 16% compared with physician interventions (P=.01). Conclusions: An opinion-leader-based intervention targeting physicians substantially improved rates of bone mineral density testing and osteoporosis treatment in patients with incidental vertebral fractures, compared with usual care. Even better osteoporosis management was achieved by adding patient activation to physician interventions [NCT00388908]. [ABSTRACT FROM AUTHOR]

BACKGROUND: Osteoporosis and fragility fractures in men account for substantial health care expenditures and decreased quality of life. OBJECTIVE: This article reviews the most current information about the epidemiology, diagnosis, prevention, and treatment of osteoporosis in men. METHODS: Relevant literature was identified through a search of MEDLINE (1966-June 2003) limited to English-language studies in men. The search terms included fractures, bone density, or osteoporosis plus either epidemiology, diagnosis, prevention, control, or therapy. Additional search terms included specific subtopics (eg, bisphosphonates, calcium, exercise, parathyroid hormone). The authors contributed additional relevant publications. RESULTS: Morbidity after fragility fracture is at least as high in men as in women, and the rate of fracture-related mortality 1 year hip fracture is approximately double in men compared with women. The bioavailable fraction of testosterone slowly declines into the ninth decade in men. There is evidence that the effect of estrogen on bone is greater than that of testosterone in men. Diagnosing osteoporosis in men is complicated by a lack of consensus on how it should be defined. Significant risk factors for osteoporosis or fracture include low bone mineral density, previous fragility fracture, maternal history of fracture, marked hypogonadism, smoking, heavy alcohol intake or alcoholism, low calcium intake, low body mass or body mass index, low physical activity, use of bone-resorbing medication such as glucocorticoids, and the presence of such conditions as hyperthyroidism, hyperparathyroidism, and hypercalciuria. Prevention is paramount and should begin in childhood. During adulthood, calcium (1000-1500 mg/d), vitamin D (400-800 IU/d), and adequate physical activity play crucial preventive roles. When treatment is indicated, the bisphosphonates are the first choice, whereas there is less support for the use of calcitonin or androgen therapy. Parathyroid hormone (1-34) is a promising anabolic therapy. There is also strong evidence for the use of bisphosphonates for the treatment of glucocorticoid-induced osteoporosis. [ABSTRACT FROM AUTHOR]

Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height, and weight, and then additionally adjusted for FN aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ -2.5, whereas 53% had T-scores between -1.0 and -2.5 and 37% had T-scores ≥-1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load (FL) was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, FL and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

DXA-derived reference data for visceral adipose tissue (VAT) and advanced hip analysis (AHA) parameters spanning the entire adult lifespan are limited. The purpose of this study was to develop age-, site- and sex-specific reference data for dual X-ray absorptiometry (DXA) -derived body composition, trabecular bone score (TBS) and advanced hip analysis (AHA) parameters across the adult lifespan. Adults (N = 908; female: 561 and male: 347) from Calgary and the surrounding area over the age of 20 years participated in this study. Participants received DXA scans of their hip (total hip [TH] and femoral neck [FN]), lumbar spine [LS], forearm [33 % site] and total body (iDXA, GE Lunar, GE Healthcare). Areal bone mineral density (aBMD, g/cm 2 ) was captured at all sites, and body composition variables, including lean mass, fat mass and percent fat, were analyzed from the total body scan. VAT mass was assessed from total body DXA scans. Advanced hip analysis (AHA) was performed on hip scans and trabecular bone score (TBS) on the LS scans to assess bone quality. Site- and sex-specific centile curves and tables were generated using the Generalized Additive Models for Location, Scale, and Shape (GAMLSS) method. Clinicians and researchers can use these Canadian reference data as a tool to assess body composition, TBS and AHA parameters across the adult lifespan., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fracture risk increases with lower areal bone mineral density (aBMD); however, aBMD-related estimate of risk may decrease with age. This may depend on technical limitations of 2-dimensional (2D) dual energy X-ray absorptiometry (DXA) which are reduced with 3D high-resolution peripheral quantitative computed tomography (HR-pQCT). Our aim was to examine whether the predictive utility of HR-pQCT measures with fracture varies with age. We analyzed associations of HR-pQCT measures at the distal radius and distal tibia with two outcomes: incident fractures and major osteoporotic fractures. We censored follow-up time at first fracture, death, last contact or 8 years after baseline. We estimated hazard ratios (HR) and 95%CI for the association between bone traits and fracture incidence across age quintiles. Among 6835 men and women (ages 40-96) with at least one valid baseline HR-pQCT scan who were followed prospectively for a median of 48.3 months, 681 sustained fractures. After adjustment for confounders, bone parameters at both the radius and tibia were associated with higher fracture risk. The estimated HRs for fracture did not vary significantly across age quintiles for any HR-pQCT parameter measured at either the radius or tibia. In this large cohort, the homogeneity of the associations between the HR-pQCT measures and fracture risk across age groups persisted for all fractures and for major osteoporotic fractures. The patterns were similar regardless of the HR-pQCT measure, the type of fracture, or the statistical models. The stability of the associations between HR-pQCT measures and fracture over a broad age range shows that bone deficits or low volumetric density remain major determinants of fracture risk regardless of age group. The lower risk for fractures across measures of aBMD in older adults in other studies may be related to factors which interfere with DXA but not with HR-pQCT measures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Most fracture risk assessment tools use clinical risk factors combined with bone mineral density (BMD) to improve assessment of osteoporosis; however, stratifying fracture risk remains challenging. This study developed a fracture risk assessment tool that uses information about volumetric bone density and three-dimensional structure, obtained using high-resolution peripheral quantitative compute tomography (HR-pQCT), to provide an alternative approach for patient-specific assessment of fracture risk. Using an international prospective cohort of older adults (n = 6802) we developed a tool to predict osteoporotic fracture risk, called μFRAC. The model was constructed using random survival forests, and input predictors included HR-pQCT parameters summarizing BMD and microarchitecture alongside clinical risk factors (sex, age, height, weight, and prior adulthood fracture) and femoral neck areal BMD (FN aBMD). The performance of μFRAC was compared to the Fracture Risk Assessment Tool (FRAX) and a reference model built using FN aBMD and clinical covariates. μFRAC was predictive of osteoporotic fracture (c-index = 0.673, p < 0.001), modestly outperforming FRAX and FN aBMD models (c-index = 0.617 and 0.636, respectively). Removal of FN aBMD and all clinical risk factors, except age, from μFRAC did not significantly impact its performance when estimating 5-year and 10-year fracture risk. The performance of μFRAC improved when only major osteoporotic fractures were considered (c-index = 0.733, p < 0.001). We developed a personalized fracture risk assessment tool based on HR-pQCT that may provide an alternative approach to current clinical methods by leveraging direct measures of bone density and structure. © 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)., (© 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).)

In a 36-month randomized controlled trial examining the effect of high-dose vitamin D 3 on radial and tibial total bone mineral density (TtBMD), measured by high-resolution peripheral quantitative tomography (HR-pQCT), participants (311 healthy males and females aged 55-70 years with dual-energy X-ray absorptiometry T-scores > -2.5 without vitamin D deficiency) were randomized to receive 400 IU (N = 109), 4000 IU (N = 100), or 10,000 IU (N = 102) daily. Participants had HR-pQCT radius and tibia scans and blood sampling at baseline, 6, 12, 24, and 36 months. This secondary analysis examined the effect of vitamin D dose on plasma measurements of the vitamin D metabolome by liquid chromatography-tandem mass spectrometry (LC-MS/MS), exploring whether the observed decline in TtBMD was associated with changes in four key metabolites [25-(OH)D 3 ; 24,25-(OH) 2 D 3 ; 1,25-(OH) 2 D 3 ; and 1,24,25-(OH) 3 D 3 ]. The relationship between peak values in vitamin D metabolites and changes in TtBMD over 36 months was assessed using linear regression, controlling for sex. Increasing vitamin D dose was associated with a marked increase in 25-(OH)D 3 , 24,25-(OH) 2 D 3 and 1,24,25-(OH) 3 D 3 , but no dose-related change in plasma 1,25-(OH) 2 D 3 was observed. There was a significant negative slope for radius TtBMD and 1,24,25-(OH) 3 D 3 (-0.05, 95% confidence interval [CI] -0.08, -0.03, p < 0.001) after controlling for sex. A significant interaction between TtBMD and sex was seen for 25-(OH)D 3 (female: -0.01, 95% CI -0.12, -0.07; male: -0.04, 95% CI -0.06, -0.01, p = 0.001) and 24,25-(OH) 2 D 3 (female: -0.75, 95% CI -0.98, -0.52; male: -0.35, 95% CI -0.59, -0.11, p < 0.001). For the tibia there was a significant negative slope for 25-(OH)D 3 (-0.03, 95% CI -0.05, -0.01, p < 0.001), 24,25-(OH) 2 D 3 (-0.30, 95% CI -0.44, -0.16, p < 0.001), and 1,24,25-(OH) 3 D 3 (-0.03, 95% CI -0.05, -0.01, p = 0.01) after controlling for sex. These results suggest vitamin D metabolites other than 1,25-(OH) 2 D 3 may be responsible for the bone loss seen in the Calgary Vitamin D Study. Although plasma 1,25-(OH) 2 D 3 did not change with vitamin D dose, it is possible rapid catabolism to 1,24,25-(OH) 3 D 3 prevented the detection of a dose-related rise in plasma 1,25-(OH) 2 D 3 . © 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)., (© 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).)

Femoral neck areal bone mineral density (FN aBMD) is a key determinant of fracture risk in older adults; however, the majority of individuals who have a hip fracture are not considered osteoporotic according to their FN aBMD. This study uses novel tools to investigate the characteristics of bone microarchitecture that underpin bone fragility. Recent hip fracture patients (n = 108, 77% female) were compared with sex- and age-matched controls (n = 216) using high-resolution peripheral quantitative computed tomography (HR-pQCT) imaging of the distal radius and tibia. Standard morphological analysis of bone microarchitecture, micro-finite element analysis, and recently developed techniques to identify void spaces in bone microarchitecture were performed to evaluate differences between hip fracture patients and controls. In addition, a new approach for phenotyping bone microarchitecture was implemented to evaluate whether hip fractures in males and females occur more often in certain bone phenotypes. Overall, hip fracture patients had notable deterioration of bone microarchitecture and reduced bone mineral density compared with controls, especially at weight-bearing sites (tibia and femoral neck). Hip fracture patients were more likely to have void spaces present at either site and had void spaces that were two to four times larger on average when compared with non-fractured controls (p < 0.01). Finally, bone phenotyping revealed that hip fractures were significantly associated with the low density phenotype (p < 0.01), with the majority of patients classified in this phenotype (69%). However, female and male hip fracture populations were distributed differently across the bone phenotype continuum. These findings highlight how HR-pQCT can provide insight into the underlying mechanisms of bone fragility by using information about bone phenotypes and identification of microarchitectural defects (void spaces). The added information suggests that HR-pQCT can have a beneficial role in assessing the severity of structural deterioration in bone that is associated with osteoporotic hip fractures. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Reducing fracture risk is the objective of osteoporosis treatment. Bone-forming osteoporosis drugs increase bone mass, restore bone microarchitecture, and reduce fracture risk more effectively than oral bisphosphonates, providing strong justification for the use of these agents as the initial therapy or after anti-remodeling agents in patients at very high risk of fracture. At the end of a 12-to-24-month course of osteoanabolic therapy, transitioning to a potent anti-remodeling agent maintains and enhances the treatment benefit. This review describes the clinical applications of osteoanabolic therapy for osteoporosis.