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Background and Objective: Abaloparatide, an anabolic osteoporosis treatment administered by subcutaneous (SC) injection, increases bone mineral density (BMD) and reduces fracture risk in postmenopausal women with osteoporosis. The abaloparatide-solid Microstructured Transdermal System [abaloparatide-sMTS (Kindeva, St Paul, MN, USA)], which delivers abaloparatide intradermally, is in development to provide an alternative method for abaloparatide delivery. The objective of this study was to evaluate the ability of subjects to self-administer abaloparatide-sMTS, based on pharmacokinetic and pharmacodynamic markers., Methods: In this single-arm, open-label, Phase 1b study, 22 healthy postmenopausal women aged 50-85 years with low BMD were trained to self-administer abaloparatide-sMTS 300 μg once daily to the thigh for 5 min for 29 days. The primary endpoint was systemic exposure to abaloparatide. Secondary endpoints included percent change from baseline in serum procollagen type I N-terminal propeptide (s-PINP), patient experience, and safety., Results: All 22 subjects completed the study. At baseline, mean age was 65.2 years, mean total hip T-score was - 1.32, and mean lumbar spine T-score was - 1.98. On Day 1, the median time to reach maximum concentration (T max ) for abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration (C max ) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC 0-t ) were 447 (38.0) pg/mL and 678 (45.3) pg·h/mL, respectively; the pharmacokinetic profile was similar on Days 15 and 29. Median percentage change in s-PINP was 45.4% and 64.4% at Days 15 and 29, respectively. The most common adverse events (AEs) were application site erythema, pain, and swelling, which were mostly of mild or moderate severity. No AEs led to study drug withdrawal and no serious AEs were reported. The success rate for self-administration at first application was 99.7%, and subject acceptability was high (~ 4.5 on a 5-point Likert Scale)., Conclusions: Subjects successfully self-administered abaloparatide-sMTS, which provided a consistent pharmacokinetic profile over 29 days and produced s-PINP increases from baseline similar to that observed in the pivotal trial with abaloparatide-SC. Observed patient experience along with the clinical data support continued clinical development of abaloparatide-sMTS., Trial Registration Number: NCT04366726, Date of registration 04/29/2020, retrospectively registered.

Context: The effects of long-term exposure to denosumab in individuals with renal insufficiency are unknown., Objective: This post hoc analysis evaluates the long-term safety and efficacy of denosumab in individuals with mild-to-moderate chronic kidney disease (CKD) (stages 2 and 3) using data from the pivotal phase 3, double-blind, 3-year FREEDOM (NCT00089791) and open-label, 7-year extension (NCT00523341) studies., Participants and Methods: Women age 60 to 90 years with a bone mineral density (BMD) T-score of less than -2.5 to greater than -4.0 at the total hip or lumbar spine were randomly assigned 1:1 to receive denosumab 60 mg subcutaneously every 6 months (long-term arm) or placebo (cross-over arm) in FREEDOM; eligible participants could enroll in the extension to receive denosumab 60 mg subcutaneously every 6 months. Change in estimated glomerular filtration rate (eGFR) from study baseline and annualized rates of fracture and adverse events (AEs) were the main outcome measures., Results: Most participants (1259/1969 [64%] long-term arm; 1173/1781 [66%] crossover arm) with baseline CKD stage 2 or 3 remained within the same CKD subgroup at study completion; less than 3% progressed to CKD stage 4. Participants in all eGFR subgroups showed similar, persistent BMD gains over time and a low incidence of fractures. The percentage of participants reporting serious AEs was similar among renal subgroups (normal, CKD stage 2, CKD stage 3a, CKD stage 3b) both for the long-term (54% vs 52% vs 57% vs 58%) and crossover (43% vs 42% vs 43% vs 68%) arms, except CKD stage 3b subgroup, crossover arm., Conclusion: The safety and efficacy of denosumab did not differ among participants with mild to moderate CKD., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Advanced age is an important risk factor for fracture. The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) trial showed that subcutaneous abaloparatide increased bone mineral density (BMD) and reduced the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis. This study describes the effects of abaloparatide in the subgroup of women aged 80 or more years in ACTIVE., Methods: Post hoc analyses of BMD and fracture incidence in this subgroup of women who received abaloparatide or placebo in the 18-month, phase 3, double-blind, randomized controlled ACTIVE trial., Results: The mean ages of the women ≥80 years were 81.9 and 81.7 years in the placebo (n = 43) and abaloparatide (n = 51) groups, respectively. The increases in BMD from baseline to 18 months with abaloparatide treatment were 3.9% at the total hip (P < 0.001), 3.6% at the femoral neck (P < 0.01), and 12.1% at the lumbar spine (P < 0.001), and were similar to those observed in the overall population. Abaloparatide therapy was associated with numerical, but not statistically significant, reductions in the risk of vertebral and nonvertebral fractures in this subpopulation, compared with placebo. The proportion of participants reporting adverse events was similar between treatment groups and between the older subgroup and the overall population., Conclusion: Abaloparatide was effective in increasing BMD in the very elderly subgroup of ACTIVE, with a safety profile similar to that of the overall study population.

If oversuppression of bone turnover explained the association between bisphosphonate use and atypical subtrochanteric femur fractures (AFF), this could be reversed with anabolic treatment such as teriparatide. We conducted a prospective, open-label study in patients previously treated with bisphosphonates who sustained AFF, examining the response to 24-month treatment with teriparatide on bone mineral density (BMD), trabecular bone score (TBS), bone turnover markers (BTM), and fracture healing as well as quantitative histomorphometry. We studied 14 patients. Baseline BMD, BTM, and TBS varied widely. On initial bone biopsies, 12 of 14 patients showed tetracycline labels, but mineralizing surface/bone surface was below published normal values in all but 2. Lumbar spine BMD increased significantly at month 24 (6.1% ± 4.3%, p < 0.05 versus baseline), whereas total hip BMD and TBS did not change significantly. Changes in BTM occurred as reported previously for patients without AFF treated with teriparatide after prior bisphosphonate treatment. At month 24, fractures were healed in 6 patients, showed partial healing in 3, were unchanged in 2, and showed nonunion in 1. In a patient with two fractures, the fracture that occurred before teriparatide treatment was reported as healed, but the fracture that occurred while on treatment showed only partial healing. Bisphosphonate-treated patients who sustain AFF show heterogeneity of bone turnover. Treatment with teriparatide resulted in increases in BTM and lumbar spine BMD, as has been reported for patients without AFF. There was no significant effect of teriparatide on hip BMD, mineralizing surface to bone surface (MS/BS), or TBS and no consistent effect on fracture healing. In the context of a patient who has experienced an AFF after receiving bisphosphonate treatment, therapy with teriparatide for 24 months would be expected to increase BMD and BTM (and probably reduce the risk of fractures resulting from osteoporosis) but should not be relied on to aid in healing of the AFF. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Objective: To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis)., Patients and Methods: ACTIVExtend, an extension of ACTIVE, enrolled patients who completed 18 months of ABL-SC or PBO in ACTIVE to receive up to 24 additional months of open-label ALN; there was 1 month between the studies to re-consent patients., Results: Of 1243 eligible ACTIVE patients, 1139 (92%) were enrolled in ACTIVExtend beginning November 20, 2012. These results are from a prespecified 6-month interim analysis (cutoff date, June 2, 2015); the study is ongoing. Findings indicated percentages of patients with new morphometric vertebral fractures: PBO/ALN, 4.4% vs ABL-SC/ALN, 0.55%; relative risk reduction, 87% (relative risk, 0.13; 95% CI, 0.04-0.41; P<.001). Kaplan-Meier estimated rates of nonvertebral fractures were PBO/ALN, 5.6% vs ABL-SC/ALN, 2.7%; risk reduction, 52% (hazard ratio [HR], 0.48; 95% CI, 0.26-0.89; log-rank P=.02). There was also a 58% risk reduction of major osteoporotic fractures (HR, 0.42; 95% CI, 0.21-0.85; log-rank P=.01) and a 45% risk reduction of clinical fractures (HR, 0.55; 95% CI, 0.33-0.92; log-rank P=.02) in the ABL-SC/ALN group vs the PBO/ALN group. At 25 months, bone mineral density percentage change from ACTIVE baseline for ABL-SC/ALN vs PBO/ALN was as follows: lumbar spine, 12.8%; total hip, 5.5%; femoral neck, 4.5% vs 3.5%, 1.4%, 0.5%, respectively (group differences at all sites P<.001)., Conclusion: Use of ABL-SC for 18 months followed by ALN for 6 months improved bone mineral density and reduced fracture risk throughout the skeleton and may be an effective treatment option for postmenopausal women with osteoporosis., Trial Registration: clinicaltrials.gov Identifier: NCT01657162., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Objectives: Bisphosphonate-associated atypical sub-trochanteric femur fractures (ASFF) may be seen with long-term bisphosphonate use, though these fractures are also seen in patients never exposed to bisphosphonates. One theory for the mechanism of action whereby bisphosphonates may induce these ASFF is over-suppression of bone turnover. Bisphosphonates suppress bone turnover, but in bisphosphonate clinical trials, over-suppression defined whether by maintaining the biochemical markers of bone turnover below the defined reference range or by quantitative bone histomorphometry, has not been observed., Methods: We studied 15 clinic patients referred to The Colorado Center for Bone Research (CCBR) after they had a bisphosphonate-associated ASFF and performed quantitative bone histomorphometry both before and after 12 months of teriparatide (20µg SQ/day). All patients had been on long-term alendronate (mean = 7 years, range: 6-11 years) and had already had intramedullary rods placed when first seen (6 weeks to 7 months after rod placement). Alendronate had been discontinued in all patients at the time of their first clinic visit to CCBR. All of the fractures fulfilled The American Society for Bone and Mineral Research major radiological criteria for ASFF., Results: Three key dynamic histomorphometric features show that 7 of the 15 patients had unmeasurable bone formation, mineralizing surface, and mineral apposition, while the other 8 patients had measurable dynamic parameters; although for all 15 patients, the mean values for all 3 dynamic parameters was far below the average for the published normal population. Administration of teriparatide was associated with an increase in all 3 dynamic histomorphometric parameters. Baseline bone turnover markers did not correlate with the baseline histomorphometry. While there is heterogeneity in the bone turnover in patients with bisphosphonate ASFF, there is a large portion in this uncontrolled series that had absent bone turnover at the standard biopsy site (iliac crest). Discontinuation of the bisphosphonate and administration of the anabolic agent, teriparatide was associated with improvement in bone turnover., Conclusions: While our study does not establish causality or address the ability of teriparatide to prevent progression of early stress fracture to displaced fractures, it does suggest that teriparatide may improve bone formation in these patients. Our study should stimulate other investigations using larger sample sizes and early stress fractures to see if anabolic agents can reverse these fractures from becoming displaced., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: To gain insight into how teriparatide affects various bone health parameters, we assessed the effects of teriparatide treatment with use of standard DXA (dual x-ray absorptiometry) technology and two newer technologies, high-resolution MRI (magnetic resonance imaging) and finite element analysis of quantitative CT (computed tomography) scans., Methods: In this phase-4, open-label study, postmenopausal women with severe osteoporosis received 20 μg/day of teriparatide. Assessments included (1) changes in areal BMD (bone mineral density) (in g/cm 2 ) at the radius, spine, and hip on DXA, (2) changes in volumetric BMD (in mg/cm 3 ) at the spine and hip on quantitative CT scans, (3) changes in bone microarchitecture at the radius on high-resolution MRI, (4) estimated changes in spine and hip strength according to finite element analysis of quantitative CT scans, (5) changes in bone turnover markers in serum, and (6) safety., Results: Thirty-five subjects were enrolled; thirty completed eighteen months and twenty-five completed an optional six-month extension. No significant changes were observed for the primary outcome, high-resolution MRI at the distal aspect of the radius. At month eighteen, the least-squares mean percentage change from baseline in total volumetric BMD at the spine was 10.05% (95% confidence interval [CI], 6.83% to 13.26%; p < 0.001), and estimated spine strength increased 17.43% (95% CI, 12.09% to 22.76%; p < 0.001). Total volumetric BMD at the hip increased 2.22% (95% CI, 0.37% to 4.06%; p = 0.021), and estimated hip strength increased 2.54% (95% CI, 0.06% to 5.01%; p = 0.045). Areal BMD increased at the lumbar spine and femoral neck, was unchanged for the total hip and at the distalmost aspect of the radius, and decreased at a point one-third of the distance between the wrist and elbow. Bone turnover markers increased at months three, six, and twenty-four (all p < 0.05). No unexpected adverse events were observed., Conclusions: High-resolution MRI failed to identify changes in bone microarchitecture at the distal aspect of the radius, a non-weight-bearing site that may not be suitable for assessing effects of an osteoanabolic agent. Teriparatide increased areal BMD at the spine and femoral neck and volumetric BMD at the spine and hip. Estimated vertebral and femoral strength also increased. These findings and increases in bone turnover markers through month twenty-four are consistent with the known osteoanabolic effect of teriparatide., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., (Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.)

Dual-energy X-ray absorptiometry (DXA) is an inexpensive, noninvasive, widely available method for diagnosing osteoporosis, assessing fracture risk, and monitoring the effects of therapy. By diagnosing high-risk patients before a fracture occurs, clinicians can intervene early to reduce fracture risk. Appropriate use of DXA results in money saving for healthcare systems that might otherwise be spent for fracture-related care. Recent reports of studies evaluating DXA screening criteria and intervals for retesting have received considerable media coverage, sometimes suggesting that DXA is expensive, over-utilized, and unnecessary. This may lead to more patients who might benefit from early detection of osteoporosis remaining undiagnosed. We advocate for the use of current clinical practice guidelines with individualization of patient care factors to determine the optimal intervals for DXA testing.

The core of the 2012 Santa Fe Bone Symposium consisted of plenary presentations on new developments in the fields of osteoporosis and metabolic bone disease, with a focus on current and future implications for patient care. These were complemented by oral abstracts, interactive discussions of challenging cases, a debate on benefits and risks of long-term bisphosphonate therapy, and a panel discussion of controversial issues in the management of osteoporosis. Other topics included a review of the most important scientific publications in the past year, new and emerging therapy for osteoporosis, the benefits and limitations of clinical practice guidelines in the care of individual patients, the effects of metallic elements on skeletal health, clinical applications of bone turnover markers, an engineering perspective of skeletal health and disease, and an update on the role of the International Society for Clinical Densitometry in education, certification, accreditation, and advocacy for high-quality bone density testing. The symposium was highlighted by an inaugural presentation of "2 Million 2 Many," a national campaign of the National Bone Health Alliance to increase awareness of osteoporosis., (Copyright © 2013 The International Society for Clinical Densitometry. All rights reserved.)

Context: Men with low bone mineral density (BMD) were treated with denosumab., Objective: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment., Design, Subjects, and Intervention: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD., Main Outcome Measure: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12., Results: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P ≤ 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups., Conclusions: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed.

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function., (Copyright © 2011 American Society for Bone and Mineral Research.)

FRAX(®) is a fracture risk assessment algorithm developed by the World Health Organization in cooperation with other medical organizations and societies. Using easily available clinical information and femoral neck bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA), when available, FRAX(®) is used to predict the 10-year probability of hip fracture and major osteoporotic fracture. These values may be included in country specific guidelines to aid clinicians in determining when fracture risk is sufficiently high that the patient is likely to benefit from pharmacological therapy to reduce that risk. Since the introduction of FRAX(®) into clinical practice, many practical clinical questions have arisen regarding its use. To address such questions, the International Society for Clinical Densitometry (ISCD) and International Osteoporosis Foundations (IOF) assigned task forces to review the best available medical evidence and make recommendations for optimal use of FRAX(®) in clinical practice. Questions were identified and divided into three general categories. A task force was assigned to investigating the medical evidence in each category and developing clinically useful recommendations. The BMD Task Force addressed issues that included the potential use of skeletal sites other than the femoral neck, the use of technologies other than DXA, and the deletion or addition of clinical data for FRAX(®) input. The evidence and recommendations were presented to a panel of experts at the ISCD-IOF FRAX(®) Position Development Conference, resulting in the development of ISCD-IOF Official Positions addressing FRAX(®)-related issues., (Copyright © 2011 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Tools to predict fracture risk are useful for selecting patients for pharmacological therapy in order to reduce fracture risk and redirect limited healthcare resources to those who are most likely to benefit. FRAX® is a World Health Organization fracture risk assessment algorithm for estimating the 10-year probability of hip fracture and major osteoporotic fracture. Effective application of FRAX® in clinical practice requires a thorough understanding of its limitations as well as its utility. For some patients, FRAX® may underestimate or overestimate fracture risk. In order to address some of the common issues encountered with the use of FRAX® for individual patients, the International Society for Clinical Densitometry (ISCD) and International Osteoporosis Foundation (IOF) assigned task forces to review the medical evidence and make recommendations for optimal use of FRAX® in clinical practice. Among the issues addressed were the use of bone mineral density (BMD) measurements at skeletal sites other than the femoral neck, the use of technologies other than dual-energy X-ray absorptiometry, the use of FRAX® without BMD input, the use of FRAX® to monitor treatment, and the addition of the rate of bone loss as a clinical risk factor for FRAX®. The evidence and recommendations were presented to a panel of experts at the Joint ISCD-IOF FRAX® Position Development Conference, resulting in the development of Joint ISCD-IOF Official Positions addressing FRAX®-related issues., (Copyright © 2011 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.)

Context: Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women., Objective: The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation., Design: We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study., Participants: A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of -1.61 at randomization participated in the study., Interventions: Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment., Main Outcome Measures: We measured the percentage changes in BMD and BTM, and evaluated safety., Results: Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P ≤ 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups., Conclusions: In postmenopausal women with low BMD, the effects of 60 mg denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo.

Context: This is a study extension to evaluate the efficacy and safety of long-term treatment with denosumab in postmenopausal women with low bone mass., Objective: Our objective was to describe changes in bone mineral density (BMD) and bone turnover markers as well as safety with 6 yr of denosumab treatment., Design: We conducted an ongoing 4-yr, open-label, single-arm, extension study of a dose-ranging phase 2 trial. This paper reports a 2-yr interim analysis representing up to 6 yr of continuous denosumab treatment., Setting: This multicenter study was conducted at 23 U.S. centers., Patients: Of the 262 subjects who completed the parent study, 200 enrolled in the study extension and 178 (89%) completed the first 2 yr., Intervention: All subjects received denosumab 60 mg sc every 6 months., Main Outcome Measures: We evaluated BMD at the lumbar spine, total hip, femoral neck, and one third radius; biochemical markers of bone turnover; and safety, reported as adverse events., Results: Over a period of 6 yr, continuous treatment with denosumab resulted in progressive gains in BMD in postmenopausal women with low bone mass. Reduction in bone resorption was sustained over the course of continuous treatment. Independent of past treatment and discontinuation period, subjects demonstrated responsiveness to denosumab therapy as measured by BMD and bone turnover markers. The safety profile of denosumab did not change over time., Conclusions: In this study, denosumab was well tolerated and effective through 6 yr of continuous treatment in postmenopausal women with low bone mass.

The relationship between bisphosphonate-induced bone mineral density (BMD) gains and antifracture efficacy remains to be fully elucidated. Data from two antifracture studies were analyzed. Postmenopausal osteoporotic women received oral (2.5 mg daily, 20 mg intermittent) or intravenous (0.5 mg, 1 mg quarterly) ibandronate. Outcome measures included moving averages plots and logistic regression analyses of the relationship between BMD change and vertebral fracture rate. In moving averages plots, ibandronate-induced BMD gains were consistently associated with decreased fracture rates. In the oral study, total-hip BMD increases at years 2 and 3 and lumbar spine BMD increases at year 3 were associated with 3-year vertebral fracture rate (relative risk reduction [RRR] at year 3 for 1% change from baseline: hip, 7.9% [95% CI 2.1-13.5%, P = 0.0084]; lumbar spine, 4.7% [-0.1% to 9.3%, P = 0.0565]). In the intravenous study, total-hip BMD increases at years 1, 2, and 3 and lumbar spine BMD increases at years 2 and 3 were significantly associated with vertebral fracture rate (RRR at year 3 for 1% change from baseline: hip, 11.6% [7.0-16.0%, P < 0.0001]; lumbar spine, 6.9% [2.9-10.6%, P = 0.0008]). In a pooled analysis, changes in total-hip and lumbar spine BMD were associated with 3-year vertebral fracture risk reduction and explained a substantial proportion of the antifracture effect (23-37% at 2 and 3 years). This analysis suggests that ibandronate-induced BMD gain in postmenopausal osteoporotic women is associated with vertebral fracture risk reduction.

Response to osteoporosis therapy is often assessed by serial BMD testing. Patients who lose BMD without secondary causes of bone loss may be considered to be "nonresponders" to treatment. We examined vertebral fracture (VF) risk, change in lumbar spine (LS) BMD, and change in amino-terminal extension peptide of procollagen type I (PINP) in postmenopausal women whose femoral neck (FN) BMD decreased, increased, or was unchanged after receiving teriparatide (TPTD) or placebo (PL) in the Fracture Prevention Trial. FN and LS BMD were measured at baseline and 12 mo. VFs were assessed by lateral spine radiographs at baseline and study endpoint. A BMD change from baseline of >4% was considered to be clinically significant. Decreases of >4% FN BMD were less common in women receiving TPTD (10%) versus PL (16%, p < 0.05), yet women on TPTD who lost FN BMD still had significant reductions in VF risk compared with PL (RR = 0.11; 95% CI = 0.03-0.45). VF risk reduction with TPTD compared with PL was similar across categories of FN BMD change from baseline at 12 mo (loss >4%, loss 0-4%, gain 0-4%, or gain >4%; interaction p = 0.40). Irrespective of FN BMD loss or gain, TPTD-treated women had statistically significant increases in LS BMD and PINP compared with PL. In both groups, losses or gains in FN BMD at 12 mo corresponded to losses or gains in BMC rather than changes in bone area. In conclusion, loss of FN BMD at 12 mo in postmenopausal women with osteoporosis treated with TPTD is nevertheless consistent with a good treatment response in terms of VF risk reduction.

Introduction: Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL), an essential mediator of osteoclast formation, function, and survival that has been shown to decrease bone turnover and increase bone mineral density (BMD) in treated patients. We assessed the long-term efficacy and safety of denosumab, and the effects of discontinuing and restarting denosumab treatment in postmenopausal women with low bone mass., Methods: Postmenopausal women with a lumbar spine T-score of -1.8 to -4.0 or proximal femur T-score of -1.8 to -3.5 were randomized to denosumab every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral alendronate weekly. After 24 months, patients receiving denosumab either continued treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued treatment for 12 months then re-initiated denosumab (60 mg Q6M) for 12 months. The placebo cohort was maintained. Alendronate-treated patients discontinued alendronate and were followed. Changes in BMD and bone turnover markers (BTM) as well as safety outcomes were evaluated., Results: Overall, 262/412 (64%) patients completed 48 months of study. Continuous, long-term denosumab treatment increased BMD at the lumbar spine (9.4% to 11.8%) and total hip (4.0% to 6.1%). BTM were consistently suppressed over 48 months. Discontinuation of denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months of treatment discontinuation. Retreatment with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Levels of BTM increased upon discontinuation and decreased with retreatment. Adverse event rates were similar among treatment groups., Conclusions: In postmenopausal women with low BMD, long-term denosumab treatment led to gains in BMD and reduction of BTM throughout the course of the study. The effects on bone turnover were fully reversible with discontinuation and restored with subsequent retreatment.

Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, an essential mediator of osteoclast activity and survival. In postmenopausal women with low bone mineral density (BMD), subcutaneous denosumab decreases bone resorption and increases BMD. This post hoc analysis reports on subjects treated for up to 24 months with denosumab 60mg 6 monthly (N=39), placebo (N=39), or open-label alendronate 70mg once weekly (N=38) in a phase 2 study. Hip scans were done by dual-energy X-ray absorptiometry at baseline, 12, and 24 months; these were analyzed with hip structural analysis software to evaluate BMD and cross-sectional geometry parameters at the narrowest segment of the femoral neck, the intertrochanter, and the proximal shaft. Geometric parameters and derived strength indices included bone cross-sectional area, section modulus, and buckling ratio. At 12 and 24 months denosumab and alendronate improved these parameters compared with placebo. Denosumab effects were greater than alendronate at the intertrochanteric and shaft sites. The magnitude and direction of the changes in structural geometry parameters observed in this study suggest that denosumab treatment may lead to improved bone mechanical properties. Ongoing phase 3 studies will determine whether denosumab reduces fracture risk.

Unlabelled: Osteoporosis is an increasingly common health concern in postmenopausal women. In a 2-yr phase III study, bazedoxifene prevented bone loss, reduced bone turnover, and was well tolerated in early postmenopausal women with normal or low BMD., Introduction: Bazedoxifene is a novel selective estrogen receptor modulator that has increased BMD and bone strength in experimental models, without stimulating breast or uterus. This 24-mo, randomized, double-blind study assessed the efficacy and safety of three doses of bazedoxifene compared with placebo and raloxifene in the prevention of postmenopausal osteoporosis., Materials and Methods: Healthy postmenopausal women with a BMD T-score at the lumbar spine or femoral neck between -1.0 and -2.5 or clinical risk factors for osteoporosis were randomly assigned to one of five groups: bazedoxifene 10, 20, or 40 mg/d, placebo, or raloxifene 60 mg/d. All women received elemental calcium. Efficacy outcomes included changes from baseline through 24 mo in BMD of the lumbar spine, hip, femoral neck, and femoral trochanter and biomarkers of bone metabolism., Results: The intent-to-treat population included 1434 women (mean age, 58 yr; mean time from last menstrual period, 11 yr). All doses of bazedoxifene and raloxifene prevented bone loss, whereas in the placebo group, there was significant loss of BMD at all skeletal sites. Mean differences in percent change in lumbar spine BMD from baseline to 24 mo relative to placebo were 1.08 +/- 0.28%, 1.41 +/- 0.28%, 1.49 +/- 0.28%, and 1.49 +/- 0.28% for 10, 20, and 40 mg bazedoxifene and 60 mg raloxifene, respectively (p < 0.001 for all comparisons). Comparable BMD responses were observed at other body sites. Significant and comparable decreases in serum osteocalcin and C-telopeptide levels from baseline and relative to placebo with active treatment were observed as early as 3 mo and were sustained through study conclusion (p < 0.001). Overall incidences of adverse events, serious adverse events, and discontinuations caused by adverse events were similar between groups. The most common adverse events included headache, infection, arthralgia, pain, hot flush, and back pain., Conclusions: Treatment with bazedoxifene prevented bone loss and reduced bone turnover equally as well as raloxifene and was generally well tolerated in postmenopausal women with normal/low BMD.

Unlabelled: Denosumab is a monoclonal antibody to RANKL. In this randomized, placebo-controlled study of 412 postmenopausal women with low BMD, subcutaneous denosumab given every 3 or 6 mo was well tolerated, increased BMD, and decreased bone resorption markers for up to 24 mo. Continued study of denosumab is warranted in the treatment of low BMD in postmenopausal women., Introduction: Denosumab is a fully human monoclonal antibody that inhibits RANKL, a key mediator of osteoclastogenesis and bone remodeling. This prespecified exploratory analysis evaluated the efficacy and safety of denosumab through 24 mo in the treatment of postmenopausal women with low BMD., Materials and Methods: Four hundred twelve postmenopausal women with lumbar spine BMD T-scores of -1.8 to -4.0 or femoral neck/total hip T-scores of -1.8 to -3.5 were randomly assigned to receive double-blind, subcutaneous injections of placebo; denosumab 6, 14, or 30 mg every 3 mo; denosumab 14, 60, 100, or 210 mg every 6 mo; or open-label oral alendronate 70 mg once weekly. Outcome measures included BMD at the lumbar spine, total hip, distal one-third radius, and total body; bone turnover markers; and safety., Results: Denosumab increased BMD at all measured skeletal sites and decreased concentrations of bone turnover markers compared with placebo at 24 mo. At the lumbar spine, BMD increases with denosumab ranged from 4.13% to 8.89%. BMD changes with denosumab 30 mg every 3 mo and > or =60 mg every 6 mo were similar to, or in some cases greater than, with alendronate. The incidence of adverse events was similar in the placebo, denosumab, and alendronate treatment groups. Exposure-adjusted adverse events over 2 yr of treatment were similar to those reported during the first year of treatment., Conclusions: In these postmenopausal women with low BMD, treatment with denosumab for 2 yr was associated with sustained increases in BMD and reductions in bone resorption markers compared with placebo.

Unlabelled: Increases in BMD are correlated with improvements in 2D and 3D trabecular microarchitecture indices with teriparatide treatment. Therefore, improvements in trabecular bone microarchitecture may be one of the mechanisms to explain how BMD increases improve bone strength during teriparatide treatment., Introduction: Bone strength is determined by BMD and other elements of bone quality, including bone microarchitecture. Teriparatide treatment increases BMD and improves both cortical and trabecular bone microarchitecture. Increases in lumbar spine (LS) BMD account for approximately 30-41% of the vertebral fracture risk reduction with teriparatide treatment. The relationship between increases in BMD and improvements in cortical and trabecular microarchitecture has not yet been studied., Materials and Methods: The relationship between increases in BMD and improvements in cortical and trabecular microarchitecture after teriparatide treatment was assessed using data from a subset of patients who had areal BMD measurements and structural parameters from transiliac bone biopsies in the Fracture Prevention Trial. 2D histomorphometric and 3D microCT parameters were measured at baseline and 12 (n = 21) or 22 (n = 36) mo. LS BMD was assessed at baseline and 12 and 18 mo, and femoral neck (FN) BMD was measured at baseline and 12 mo. Pearson correlation was performed to assess the relationship between actual changes in BMD and actual changes in microarchitectural parameters., Results: Changes in LS BMD at 12 mo were significantly correlated with improvements in trabecular bone structure at 22 mo: 2D bone volume (r = 0.45, p = 0.02), 2D mean wall thickness (r = 0.41, p = 0.03), 3D bone volume (r = 0.48, p = 0.006), 3D trabecular thickness (r = 0.44, p = 0.01), 3D trabecular separation (r = -0.37, p = 0.04), 3D structural model index (r = -0.54, p = 0.001), and 3D connectivity density (r = 0.41, p = 0.02). Changes in LS BMD at 18 mo had similar correlations with improvements in bone structure at 22 mo. Changes in FN BMD at 12 mo were significantly correlated with changes in 2D mean wall thickness (r = 0.56, p = 0.002), 3D bone volume (r = 0.51, p = 0.004), 3D trabecular thickness (r = 0.44, p = 0.01), 3D trabecular separation (r = -0.46, p = 0.01), and 3D structural model index (r = -0.55, p = 0.001)., Conclusions: Increases in BMD are correlated with improvements in trabecular microarchitecture in iliac crest of patients with teriparatide treatment. Therefore, improvements in trabecular bone microarchitecture may be one of the mechanisms to explain how BMD increases improve bone strength during teriparatide treatment.

In 1997, the National Health and Nutrition Examination Survey III (NHANES III) total hip reference database was adopted for T-score derivation in an effort to optimize diagnostic agreement among densitometers from different manufacturers. Our study was undertaken to evaluate the effectiveness of the NHANES III standardized database at achieving agreement in diagnostic classification (normal, osteopenia, or osteoporosis) based on total hip T-scores comparing 2 different dual-energy X-ray absorptiometry (DXA) systems. This was a retrospective analysis of standard bilateral hip and lumbar spine scans done in duplicate for 60 women scanned on both a GE Lunar Prodigy and Hologic Delphi DXA system. Classification based on lumbar spine T-scores using manufacturer-specific databases was also compared as no standardized lumbar spine reference database exists. Subject's mean age was 62 yr (range: 47-83 yr). There was no statistically significant difference in diagnostic classification between DXA systems (Prodigy vs Delphi), with agreement (same women classified same way) of 92% at the left total hip. Agreement was 100% when T-scores were greater than or equal to -0.8 and less than or equal to -1.2. There was 90% agreement between DXA systems at the lumbar spine. For both hip and spine, all diagnostic discrepancies occurred when the T-scores were at or near transition thresholds between normal and osteopenia or osteopenia and osteoporosis. The difference in mean T-scores between DXA systems at left total hip was 0.11 vs 0.32 for lumbar spine (p less than 0.001). Use of the NHANES III standardized database results in good diagnostic agreement at total hip between Prodigy and Delphi.

Introduction: This 7-year, prospective, matched-cohort, clinical study evaluated the effects of intramuscular depot medroxyprogesterone acetate (DMPA) (150 mg/mL) on bone mineral density (BMD) in women aged 25-35 years., Methods: Bone mineral density changes in new DMPA-IM users (n=248) were compared with those in women using nonhormonal contraception (n=360) for up to 240 weeks of treatment and 96 weeks of posttreatment follow-up (in subjects receiving >or=1 dose)., Results: At week 240 of treatment, mean percentage changes from baseline in DMPA-IM vs. nonhormonal subjects were: -5.16% (n=21) vs. +0.19% (n=65), total hip (p<.001); -5.38% (n=33) vs. +0.43% (n=105), lumbar spine (p<.001). At week 96 posttreatment, these values were: -0.20% (n=25) vs. +0.84% (n=43), total hip (p=.047); -1.19% (n=41) vs. +0.47% (n=66), lumbar spine (p=.017)., Conclusions: These results show BMD declines during DMPA-IM use; following discontinuation, significant increases in BMD occur through 96 weeks posttreatment.

Background: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action., Methods: The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur). Subjects were randomly assigned to receive denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in bone mineral density at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase., Results: Denosumab treatment for 12 months resulted in an increase in bone mineral density at the lumbar spine of 3.0 to 6.7 percent (as compared with an increase of 4.6 percent with alendronate and a loss of 0.8 percent with placebo), at the total hip of 1.9 to 3.6 percent (as compared with an increase of 2.1 percent with alendronate and a loss of 0.6 percent with placebo), and at the distal third of the radius of 0.4 to 1.3 percent (as compared with decreases of 0.5 percent with alendronate and 2.0 percent with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident three days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent., Conclusions: In postmenopausal women with low bone mass, denosumab increased bone mineral density and decreased bone resorption. These preliminary data suggest that denosumab might be an effective treatment for osteoporosis. (ClinicalTrials.gov number, NCT00043186.)., (Copyright 2006 Massachusetts Medical Society.)

In 2003, the International Society for Clinical Densitometry (ISCD) developed Official Positions regarding the applicability of the World Health Organization (WHO) classification of bone mineral density to populations other than postmenopausal women. However, these prior Official Positions do not fully address bone mineral density reporting in females prior to menopause, men, and non-whites. During the 2005 ISCD Position Development Conference, members of the ISCD Expert Panel in conjunction with the ISCD Scientific Advisory Committee re-addressed these topics and, based upon stringent reviews of best available data, developed ISCD Official Positions that provide greater specificity and clarification with respect to the following: (1) the utility of the term 'osteopenia'; (2) utilization of T- and Z-scores for bone mineral density reporting; (3) when to apply the WHO densitometric classification; and (4) which normative database(s) should be used for non-white individuals. Briefly, the term "osteopenia" is retained, but 'low bone mass' or 'low bone density' is preferred. Z-scores, not T-scores, are preferred in females prior to menopause and males under age 50. In these individuals, a Z-score of -2.0 or lower is defined as "below the expected range for age" and a Z-score above -2.0 is "within the expected range for age." T-scores are preferred and the WHO classification is applicable for postmenopausal women and men age 50 and older. These Official Positions, rationale and evidence are discussed in the following report.

Surrogate markers in clinical medicine provide a useful means to assess therapeutic response to pharmacologic therapy in a wide range of chronic disease states. In the area of osteoporosis, the surrogate markers of change in bone mineral density (BMD) and bone turnover markers (BTM) provide the clinician with a means of assessing the biologic response to osteoporosis-specific pharmacologic agents. Increases in BMD and/or reductions in BTM can independently be correlated to reductions in vertebral and nonvertebral fracture risk. In managing osteoporosis patients, the BTM change at an earlier point of time after initiation of therapy and a change in BTM can provide earlier feed-back to the patient and clinician regarding issues such as compliance and a bone biologic response. An increase in BMD at 12 or 24 months after initiation of therapy is also evidence of an improvement in bone strength though with antiresorptive agents no change in BMD may also be associated with risk reduction within clinical trial sets. In this regard, changes in BMD and BTM are complimentary in their application to patient management.

Measurements of bone mineral density (BMD) and biochemical markers of bone turnover are useful in the diagnosis and management of osteoporosis, as well as in research relating to the pathogenesis and treatment of the disease. Recent challenges to the utility of these measures have resulted in some confusion among both researchers and clinicians. BMD accounts for the great majority of bone strength and is the current gold standard for the diagnosis of osteoporosis, as well as for prediction of fracture risk. Although bone turnover increases sharply after menopause, biochemical markers of bone turnover have limited usefulness in fracture risk prediction. Persistently elevated bone turnover throughout the menopause is associated with structural decrements, cannot be measured routinely and non-invasively. In research applications, both BMD and markers of bone turnover are used to identify candidate agents in preclinical and clinical studies. In addition, head-to-head comparisons of treatments utilize these measures, because fracture endpoint trials would need to be extraordinarily large and complex. Analyses that have suggested that change in BMD or bone turnover 'explains' little of change in fracture risk with treatment appear to be flawed. Although neither can perfectly predict fracture, they are our current best alternatives.

Unlabelled: The relationship of low bone mass and fracture in younger postmenopausal women has not been extensively studied. In a large cohort of postmenopausal women > or =50 years of age, we found the relationship of BMD measured at peripheral sites and subsequent 1-year fracture risk to be similar between women <65 and those > or =65 years of age., Introduction: Low bone mass and fractures are prevalent in older postmenopausal women. However, the frequency of low bone mass and fracture in younger postmenopausal women has not been studied extensively. There are very limited data regarding the association between BMD measurements and fractures in postmenopausal women who are between the ages of 50 and 64., Materials and Methods: In the National Osteoporosis Risk Assessment (NORA) we studied the frequency of low bone mass and its association with fracture in women 50-64 years of age in comparison with women > or =65 of age. NORA enrolled 200,160 postmenopausal women > or =50 years of age who had no prior diagnosis of osteoporosis. Baseline BMD was measured at the heel, forearm, or finger. A 1-year follow-up survey requesting incident fractures since baseline was completed by 163,935 women, 87,594 (53%) of whom were 50-64 years of age. The association between BMD and fracture was assessed using logistic regression, adjusted for important covariates., Results: Thirty-one percent of women 50-64 years of age had low bone mass (T scores < or = -1.0) compared to 62% of women > or =65 years of age. During the first year of follow-up, 2440 women reported fractures of wrist/forearm, rib, spine, or hip, including 440 hip fractures. Nine hundred four women 50-64 years of age reported fractures, including 86 hip fractures, accounting for 37% of fractures and 20% of hip fractures reported in the entire NORA cohort. Relative risk for osteoporotic fracture was 1.5 for each SD decrease in BMD for both the younger and older groups of women., Conclusion: Low BMD in younger postmenopausal women 50-64 years of age showed a 1-year relative risk of fracture similar to that found in women > or =65 years of age.

Bone mineral density (BMD) measurements have been the single greatest advancement for osteoporosis. BMD measurements have helped define a prefracture diagnosis of osteoporosis, predict fracture risk in postmenopausal women and elderly men, and monitor the course of disease processes that negatively affect bone or therapeutic agents that can improve bone strength. Despite the large amount of clinical, epidemiologic, and basic science data that has advanced our understanding of BMD performance and interpretation, many pitfalls in BMD performance and interpretation pervade the practice of bone densitometry. However, all of these pitfalls can be overcome. Proper quality control and clinical interpretation of BMD computer printout reports are paramount for correct diagnosis, risk assessment, and serial BMD measurements. Though BMD application(s) are a clinical tool that can and should be used by many different primary care and specialty physicians, the performances and interpretations are not simple processes. Proper education and training in the use of BMD technologies provides the means of achieving the great intent that BMD measurements are capable of providing.

Background: Identification and management of women to reduce fractures is often limited to T scores less than -2.5, although many fractures occur with higher T scores. We developed a classification algorithm that identifies women with osteopenia (T scores of -2.5 to -1.0) who are at increased risk of fracture within 12 months of peripheral bone density testing., Methods: A total of 57 421 postmenopausal white women with baseline peripheral T scores of -2.5 to -1.0 and 1-year information on new fractures were included. Thirty-two risk factors for fracture were entered into a classification and regression tree analysis to build an algorithm that best predicted future fracture events., Results: A total of 1130 women had new fractures in 1 year. Previous fracture, T score at a peripheral site of -1.8 or less, self-rated poor health status, and poor mobility were identified as the most important determinants of short-term fracture. Fifty-five percent of the women were identified as being at increased fracture risk. Women with previous fracture, regardless of T score, had a risk of 4.1%, followed by 2.2% in women with T scores of -1.8 or less or with poor health status, and 1.9% for women with poor mobility. The algorithm correctly classified 74% of the women who experienced a fracture., Conclusions: This classification tool accurately identified postmenopausal women with peripheral T scores of -2.5 to -1.0 who are at increased risk of fracture within 12 months. It can be used in clinical practice to guide assessment and treatment decisions.

Background: Treatment intervention thresholds for prevention of osteoporotic fractures can be derived from reports from the World Health Organization (diagnostic criteria) and National Osteoporosis Foundation (treatment criteria). It is not known how well these thresholds work to identify women who will fracture and are therefore candidates for treatment interventions. We used data from the National Osteoporosis Risk Assessment (NORA) to examine the effect of different treatment thresholds on fracture incidence and numbers of women with fractures within the year following bone mineral density measurement., Methods: The study comprised 149 524 white postmenopausal women aged 50 to 104 years (mean age, 64.5 years). At baseline, bone mineral density was assessed by peripheral bone densitometry at the heel, finger, or forearm. New fractures during the next 12 months were self-reported., Results: New fractures were reported by 2259 women, including 393 hip fractures; only 6.4% had baseline T scores of -2.5 or less (World Health Organization definition for osteoporosis). Although fracture rates were highest in these women, they experienced only 18% of the osteoporotic fractures and 26% of the hip fractures. By National Osteoporosis Foundation treatment guidelines, 22.6% of the women had T scores of 2.0 or less, or -1.5 or less with 1 or more clinical risk factors. Fracture rates were lower, but 45% of osteoporotic fractures and 53% of hip fractures occurred in these women., Conclusions: Using peripheral measurement devices, 82% of postmenopausal women with fractures had T scores better than -2.5. A strategy to reduce overall fracture incidence will likely require lifestyle changes and a targeted effort to identify and develop treatment protocols for women with less severe low bone mass who are nonetheless at increased risk for future fractures.

The Canadian Panel of the International Society for Clinical Densitometry has developed standards in order to establish the minimum level of acceptable performance for the practice of bone densitometry in Canada. Previously, this group addressed the performance of densitometry in postmenopausal women. This report addresses the use of densitometry in men, premenopausal women, and children with a focus on dual-energy X-ray absorptiometry.

Objectives: Results from the Women's Health Initiative showed that postmenopausal hormone replacement therapy (HRT) prevents fractures but has an overall unfavorable risk:benefit ratio, leading to the recommendation that HRT be used only for women with troublesome menopause symptoms, and for as short a time as possible. This recommendation has important implications for the timing and duration of HRT and the prevention of osteoporosis. The large number of women participating in the National Osteoporosis Risk Assessment (NORA) program provided the opportunity to evaluate bone mineral density (BMD) and 1-year fracture risk in analyses stratified by duration and recency of HRT., Design: Participants were 170,852 postmenopausal women aged 50 to 104, without known osteoporosis, who were recruited from primary physicians offices across the US. BMD was measured at one of four peripheral sites, and the 1-year risk of osteoporotic fracture was assessed by questionnaire., Results: At baseline, current HRT users had the highest T-scores at every age. Among current hormone users, women who had used HRT longest had the highest BMD levels. Women who had stopped HRT more than 5 years previously, regardless of duration of use, had T-scores similar to never-users. Current but not past hormone use at baseline was associated with a 25% to 29% lower risk of osteoporotic fracture (P < 0.0001) in 1 year, compared with nonusers. These findings were independent of age, ethnicity, body mass index, lifestyle, years postmenopausal, and site of BMD measurement., Conclusions: We conclude that postmenopausal BMD and fracture are closely associated with current, but not prior, HRT use. Use of HRT for 5 years or less, as proposed for treatment of symptomatic women during menopause transition, is unlikely to preserve bone or significantly reduce fracture risk in later years.

In a series of three published articles, the International Society for Clinical Densitometry has recorded the findings reached by an expert panel at the ISCD Position Development Conference held in July 2001. The key elements of those papers have been reviewed in this executive summary. It should be emphasized that the ISCD recommendations are not meant to serve as rigid guidelines or to replace clinical judgment. The recommendations will be reviewed and updated periodically as more data become available. A second Position Development Conference will be held in July 2003 in Cincinnati, OH. For information, visit the ISCD web site: http://www.iscd.org/.

The clinical application of bone densitometry is one of the advances in the field of osteoporosis that has led to the increased patient awareness of this increasingly prevalent disease. Bone densitometry has made it possible for clinicians to diagnose osteoporosis before the first fracture has occurred; predict risk for fracture in postmenopausal women, men, and in patients who are receiving glucocorticoids; and can be used as a surrogate marker to follow the efficacy of therapies and to examine those patients that might be osteoporosis-specific therapeutic nonresponders.

Clinical application of bone densitometry has led to increased patient awareness of this increasingly prevalent disease. With bone densitometry, it is possible for clinicians to diagnose osteoporosis before the first fracture has occurred; predict risk for fracture in men, postmenopausal women, and in patients receiving glucocorticoids; and can be used as a surrogate marker to follow the efficacy of therapies and to examine those patients who might be osteoporosis-specific therapeutic non-responders.

Low bone mineral density (BMD) is a risk factor for fracture. Although the current "gold standard" test is DXA of the hip and spine, this method is not universally available. No large studies have evaluated the ability of new, less expensive peripheral technologies to predict fracture. We studied the association between BMD measurements at peripheral sites and subsequent fracture risk at the hip, wrist/forearm, spine, and rib in 149,524 postmenopausal white women, without prior diagnosis of osteoporosis. At enrollment, each participant completed a risk assessment questionnaire and had BMD testing at the heel, forearm, or finger. Main outcomes were new fractures of the hip, wrist/forearm, spine, or rib within the first 12 months after testing. After 1 year, 2259 women reported 2340 new fractures. Based on manufacturers' normative data and multivariable adjusted analyses, women who had T scores < or = -2.5 SD were 2.15 (finger) to 3.94 (heel ultrasound [US]) times more likely to fracture than women with normal BMD. All measurement sites/devices predicted fracture equally well, and risk prediction was similar whether calculated from the manufacturers' young normal values (T scores) or using SDs from the mean age of the National Osteoporosis Risk Assessment (NORA) population. The areas under receiver operating characteristic (ROC) curves for hip fracture were comparable with those published using measurements at hip sites. We conclude that low BMD found by peripheral technologies, regardless of the site measured, is associated with at least a twofold increased risk of fracture within 1 year, even at skeletal sites other than the one measured.

Background: Many elderly female residents of long-term care facilities have osteoporosis and could benefit from intervention to increase bone density., Objective: To examine the efficacy and safety of alendronate for treatment of osteoporosis in elderly female residents of long-term care facilities., Design: Multicenter, randomized, double-blind, placebo-controlled 2-year study., Setting: 25 long-term care facilities., Patients: 327 elderly women with osteoporosis., Intervention: Patients were randomly assigned to receive alendronate, 10 mg/d, or placebo. All patients also received vitamin D, 400 IU/d, and some patients received supplemental calcium (total intake, approximately 1500 mg/d)., Measurements: Bone mineral density (BMD) of the spine and hip and biochemical markers of bone turnover., Results: Alendronate produced significantly greater increases in BMD than did placebo (24-month differences: spine, 4.4% [95% CI, 3.3% to 5.5%]; femoral neck, 3.4% [CI, 2.3% to 4.4%]). Alendronate produced greater decreases from baseline in biochemical markers of bone turnover than did placebo (P < 0.001)., Conclusion: Alendronate increased BMD at both the spine and hip in elderly female residents of long-term care facilities.

Some, but not all, antiresorptive agents have been shown to reduce the risk of nonvertebral fractures. Agents that significantly reduced nonvertebral fracture risk also appear to produce larger mean increases in bone mineral density (BMD) and reductions in biochemical markers (BCM) of bone turnover, compared with other agents. To examine the extent to which increases in BMD and reductions in BCM during antiresorptive therapy are associated with reductions in risk of nonvertebral fractures, we performed a meta-analysis of all randomized, placebo-controlled trials of antiresorptive agents conducted in postmenopausal women with osteoporosis (i.e. prior vertebral fracture or low BMD) with available relevant data. A total of 18 such trials with usable data were identified, including a total of 2,415 women with incident nonvertebral fractures over 69,369 women-years of follow-up. Poisson regression was used to estimate the association between changes in BMD or BCM during the first year and overall reductions in risk of nonvertebral fractures (vs. the placebo group) across all trials. Larger increases in BMD and larger reductions in BCM were significantly associated with greater reductions in nonvertebral fracture risk. For example, each 1% increase in spine BMD at 1 yr was associated with an 8% reduction in nonvertebral fracture risk (P = 0.02). Mean BMD changes at the hip were smaller than at the spine, but the predicted net effect on fracture risk was the same; an agent that increases spine BMD by 6% at 1 yr reduces nonvertebral fracture risk by about 39%, and an agent that increases hip BMD by 3% at 1 yr reduces nonvertebral fracture risk by about 46%. The results also predict that a 70% reduction in resorption BCM would reduce risk by 40%, and a 50% reduction in formation BCM would reduce risk by 44%. It appears that either BMD or BCM changes are able to explain the effect of treatment, because a separate variable for treatment was not independently significant in any models. These data demonstrate that larger increases in BMD at both the spine and hip and larger reductions in both formation and resorption BCM are associated with greater reductions in the risk of nonvertebral fractures. Antiresorptive agents that do not produce large increases in BMD or large reductions in BCM do not appear to and would not be expected to decrease the risk of nonvertebral fractures.