Asia-pacific consensus on osteoporotic fracture prevention in postmenopausal women with low bone mass or osteoporosis but no fragility fractures.

Postmenopausal women are at significant risk for osteoporotic fractures due to their rapid bone loss. Half of all postmenopausal women will get an osteoporosis-related fracture over their lifetime, with 25% developing a spine deformity and 15% developing a hip fracture. By 2050, more than half of all osteoporotic fractures will occur in Asia, with postmenopausal women being the most susceptible. Early management can halt or even reverse the progression of osteoporosis. Consequently, on October 31, 2020, the Taiwanese Osteoporosis Association hosted the Asia-Pacific (AP) Postmenopausal Osteoporotic Fracture Prevention (POFP) consensus meeting, which was supported by the Asian Federation of Osteoporosis Societies (AFOS) and the Asia Pacific Osteoporosis Foundation (APOF). International and domestic experts developed ten applicable statements for the prevention of osteoporotic fractures in postmenopausal women with low bone mass or osteoporosis but no fragility fractures in the AP region. The experts advocated, for example, that postmenopausal women with a high fracture risk be reimbursed for pharmaceutical therapy to prevent osteoporotic fractures. More clinical experience and data are required to modify intervention tactics.

Romosozumab and antiresorptive treatment: the importance of treatment sequence.

To evaluate whether treatment sequence affects romosozumab response, this analysis reviewed studies where romosozumab was administered before or following an antiresorptive (alendronate or denosumab). Initial treatment with romosozumab followed by an antiresorptive resulted in larger increases in bone mineral density of both hip and spine compared with the reverse sequence. INTRODUCTION: Teriparatide followed by an antiresorptive increases bone mineral density (BMD) more than using an antiresorptive first. To evaluate whether treatment sequence affects romosozumab response, we reviewed randomized clinical trials where romosozumab was administered before (ARCH, FRAME) or following (STRUCTURE, Phase 2 extension) an antiresorptive (alendronate or denosumab, respectively). METHODS: We evaluated BMD percentage change for total hip (TH) and lumbar spine (LS) and response rates (BMD gains ≥ 3% and ≥ 6%) at years 1 and 2 (except STRUCTURE with only 1-year data available). RESULTS: With 1-year romosozumab initial therapy in ARCH and FRAME, TH BMD increased 6.2% and 6.0%, and LS BMD increased 13.7% and 13.1%, respectively. When romosozumab was administered for 1 year after alendronate (STRUCTURE) or denosumab (Phase 2 extension), TH BMD increased 2.9% and 0.9%, respectively, and LS BMD increased 9.8% and 5.3%, respectively. Over 2 years, TH and LS BMD increased 7.1% and 15.2% with romosozumab/alendronate, 8.5% and 16.6% with romosozumab/denosumab, and 3.8% and 11.5% with denosumab/romosozumab, respectively. A greater proportion of patients achieved BMD gains ≥ 6% when romosozumab was used first, particularly for TH, versus the reverse sequence (69% after romosozumab/denosumab; 15% after denosumab/romosozumab). CONCLUSION: In this study, larger mean BMD increases and greater BMD responder rates were achieved when romosozumab was used before, versus after, an antiresorptive agent. Since BMD on treatment is a strong surrogate for bone strength and fracture risk, this analysis supports the thesis that initial treatment with romosozumab followed by an antiresorptive will result in greater efficacy versus the reverse sequence.

Exploring Fear of Falling and Exercise Self-Efficacy in Older Women With Vertebral Fractures.

Fear of falling is a common issue among older adults, which decreases quality of life and leads to an avoidance of activities they are still able to do. The goal of this secondary data analysis was to explore the relationship between fear of falling and exercise self-efficacy in 141 women with at least one nontraumatic Genant Grade 2 vertebral fracture. Fear of falling, exercise self-efficacy, history of falling, the number of falls, the use of assisting devices, and pain at rest or during movement were obtained using medical history and health status questionnaires. There was a negative association between fear of falling and exercise self-efficacy (pseudo R2 = .253; p = .004), which persisted when the analysis was adjusted for history and number of falls, use of assistive devices, and pain at rest (pseudo R2 = .329; p < .0001) or during movement (pseudo R2 = .321; p < .0001). Fear of falling may be negatively associated with exercise self-efficacy in older women with vertebral fracture.

Distribution of Prevalent and Incident Vertebral Fractures and Their Association with Bone Mineral Density in Postmenopausal Women in the Teriparatide Versus Risedronate VERO Clinical Trial.

Vertebral fractures (VFx) occur most frequently in the mid-thoracic and thoraco-lumbar regions, which experience the highest mechanical loading along the spine. The prevalence and incidence of VFx by their location and severity, and their relationship with bone mineral density (BMD), are seldom reported in randomized clinical trial cohorts. The VERO trial randomized 1360 postmenopausal women with at least two moderate or one severe VFx to receive either teriparatide or risedronate for up to 24 months. In this post hoc analysis, we describe the centrally read distribution and severity of prevalent and incident VFx, and the association of their location with the baseline BMD. At baseline, 21.4% of all evaluable vertebral bodies had a prevalent VFx; most commonly at L1, T12, L2 and T11 (38.5%, 37.4%, 25.3% and 23.5% of patients, respectively). Patients with prevalent VFx only at T12/L1 showed a higher baseline BMD compared to patients with VFx at other levels. At month 24, 100 patients had 126 incident VFx (teriparatide: 35; risedronate: 91). The most frequent incident VFx occurred at T12 (n = 17, 1.6% of patients), followed by L1 and T11 (n = 14, 1.3% both). The frequency of incident VFx was lower at all vertebral levels in patients given teriparatide. These results confirm prior reports that VFx occurs more frequently at mid-thoracic and thoraco-lumbar regions of the spine. Patients with these VFx locations have higher BMD than those who fracture at other sites, suggesting a role for mechanical stress in the etiology of VFx. Teriparatide is superior to risedronate in the prevention of VFx at these common fracture locations.Trial registration ClinicalTrials.gov Identifier: NCT01709110.

Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial.

BACKGROUND: No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe osteoporosis. METHODS: In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to -1·50. Participants were randomly assigned to receive 20 µg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41). FINDINGS: We enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5·4%) of 680 patients in the teriparatide group and 64 (12·0%) of 680 patients in the risedronate group (risk ratio 0·44, 95% CI 0·29-0·68; p<0·0001). Clinical fractures occurred in 30 (4·8%) of 680 patients in the teriparatide group compared with 61 (9·8%) of 680 in the risedronate group (hazard ratio 0·48, 95% CI 0·32-0·74; p=0·0009). Non-vertebral fragility fractures occurred in 25 (4·0%) patients in the teriparatide group and 38 (6·1%) in the risedronate group (hazard ratio 0·66; 95% CI 0·39-1·10; p=0·10). INTERPRETATION: Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate. FUNDING: Lilly.

Repeating Measurement of Bone Mineral Density when Monitoring with Dual-energy X-ray Absorptiometry: 2019 ISCD Official Position.

Bone mineral density (BMD) can be measured at multiple skeletal sites using various technologies to aid clinical decision-making in bone and mineral disorders. BMD by dual-energy X-ray absorptiometry (DXA) has a critical role in predicting risk of fracture, diagnosis of osteoporosis, and monitoring patients. In clinical practice, DXA remains the most available and best validated tool for monitoring patients. A quality baseline DXA scan is essential for comparison with all subsequent scans. Monitoring patients with serial measurements requires technical expertise and knowledge of the least significant change in order to determine when follow-up scans should be repeated. Prior ISCD Official Positions have clarified how and when repeat DXA is useful as well as the interpretation of results. The 2019 ISCD Official Positions considered new evidence and clarifies if and when BMD should be repeated. There is good evidence showing that repeat BMD measurement can identify people who experience bone loss, which is an independent predictor of fracture risk. There is good evidence showing that the reduction in spine and hip fractures with osteoporosis medication is proportional to the change in BMD with treatment. There is evidence that measuring BMD is useful following discontinuation of osteoporosis treatment. There is less documentation addressing the effectiveness of monitoring BMD to improve medication adherence, whether monitoring of BMD reduces the risk of fracture, or effectively discriminates patients who should and should not recommence treatment following an interruption of medication. Further research is needed in all of these areas.

Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial.

BACKGROUND: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. METHODS: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 µg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. FINDINGS: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and -0·6% (-1·0 to -0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. INTERPRETATION: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture. FUNDING: Amgen, Astellas, and UCB Pharma.

Case-Based Review of Osteonecrosis of the Jaw (ONJ) and Application of the International Recommendations for Management From the International Task Force on ONJ.

Osteonecrosis of the jaw (ONJ) has been associated with antiresorptive therapy in both oncology and osteoporosis patients. This debilitating condition is very rare and advances in diagnosis and management may now effectively reduce the risk of its development and offer valuable treatment options for affected patients. This paper provides a case-based review of ONJ and application of the International Task Force on ONJ (referred to as the "Task Force") recommendations for the diagnosis and management of ONJ. The Task Force was supported by 14 international societies and achieved consensus from representatives of these multidisciplinary societies on key issues pertaining to the diagnosis and management of ONJ. The frequency of ONJ in oncology patients receiving oncology doses of bisphosphonate (BP) or denosumab is estimated at 1%-15%, and the frequency in the osteoporosis patient population receiving much lower doses of BP or denosumab is estimated at 0.001%-0.01%. Although the diagnosis of ONJ is primarily clinical, imaging may be helpful in confirming the diagnosis and staging. In those with multiple risk factors for ONJ for whom major invasive oral surgery is being planned, interruption of BP or denosumab therapy (in cancer patients) is advised, if possible, before surgery, until the surgical site heals. Major oral surgery in this context could include multiple extractions if surgical extractions are required, not simple forceps extractions. ONJ development may be reduced by optimizing oral hygiene and postoperatively using topical and systemic antibiotics as appropriate. Periodontal disease should be managed before starting oncology doses of BP or denosumab. Local debridement may be successful in disease unresponsive to conservative therapy. Successful surgical intervention has been reported in those with stage 3 disease; less severe disease is best managed conservatively. Teriparatide may be helpful in healing ONJ lesions and may be considered in osteoporosis patients at a high fracture risk in the absence of contraindications. Resumption of BP or denosumab therapy following healing of ONJ lesions is recommended, and there have not been reports of subsequent local recurrence.

Lamivudine, Entecavir, or Tenofovir Treatment of Hepatitis B Infection: Effects on Calcium, Phosphate, FGF23 and Indicators of Bone Metabolism.

BACKGROUND: Patients with chronic hepatitis B virus (HBV) are often treated with nucleoside/nucleotide antiviral agents and metabolic bone toxicity is a possible concern. OBJECTIVE: To determine the relationships between fibroblast growth factor 23 (FGF23), a phosphaturic hormone, bone mineral density (BMD), and bone biochemical abnormalities in these patients. MATERIAL AND METHODS: This is a cross-sectional observational study comparing HBV-infected subjects treated for at least one year with tenofovir (TDF), lamuvidine (LVD), entacavir (ETV), or not treated (CON). Patients with abnormalities in either calcium (Ca), phosphate (PO4), intact parathyroid hormone (iPTH) or FGF23 were further evaluated with BMD by DXA. RESULTS: No difference in liver enzymes or renal function seen among groups, but hypophosphatemia was seen in all groups with the highest incidence with TDF-treatment (14%). FGF 23 levels were found to be elevated in 11.1% of TDF patients, 2.77% amongst controls. No elevations were found in the LVD or ETV groups. Among a subset of subjects (FGF23, PO4, and/or Ca abnormalities) who underwent further evaluation, 67% had insufficient 25-OH vitamin D, and 30% had elevated 24 h urinary Ca or PO4 excretion. No patients with FGF23 abnormalities had urine abnormalities. 40% had low DXA Z-score (&lt;-2) at spine or hip but there was no difference between control and antiviral treatment groups and the mean FRAX score was 2.33% for major osteoporotic fractures and 0.29% for hip fracture. CONCLUSION: Abnormalities in bone metabolism, particularly involving vitamin D insufficiency, in HBV-treated subjects were observed with a small increased likelihood in TDF treated patients.

Audit of Atypical Femoral Fractures and a Description of Some of Their Features.

PURPOSE: Atypical femoral fractures (AFF) are recently described events related to osteoporosis and, potentially, a rare result of antiresorptive treatment. METHODS: We set out to audit the diagnosis of AFF in an acute hospital. Charts and radiographs were reviewed retrospectively from patients diagnosed with subtrochanteric femoral fractures according to hospital discharge coding at Vancouver General Hospital (VGH), Canada, from January 2005 to March 2013. RESULTS: A total of 3084 patients were discharged from the hospital with a diagnosis of hip fracture between 2005 and 2013. Of these, 204 were coded as having had subtrochanteric fractures; 178 of the patients thus coded had radiographic evidence of other fracture types-usually intertrochanteric fractures. Eleven patients did not have available radiographs. Of the remaining 193 patients whose radiographs were reviewed, 24 (12.4%) fulfilled the published criteria for AFF. OUR OBSERVATIONS WERE: 1) laterality: 13 of 24 AFF (54.2%) were right-sided; 2) there was only one incomplete AFF in this series: a completed fracture was an inclusion criterion, but 1 patient with an AFF had both that fracture and an incomplete fracture and further foci of periosteal or endosteal foci of new bone (PENB) involving the contralateral femur; 3) radiologists had only diagnosed AFF in only 1 of the 24 patients with characteristic radiographic signs of AFF; 4) all but 1 patient had a focus of periosteal and/or endosteal new bone (PENB) through which the fracture line invariably passed, and in the 1 exception the radiography was too poor to be sure of this but there was a symmetrical contralateral focus of PENB; 5) in 19 of 24 patients there was an adequate image of part of the contralateral femur and of these 12 (63%) had a contralateral focus of PENB situated ±2.5 cm from the index lesion site when measured from the upper aspect of the greater trochanter, and in another patient a prior fracture of the contralateral femur had been treated surgically and it was at a symmetrical contralateral location from the index fracture.; 6) in 3 of the 19 patients multiple foci of PENB were detected on the lateral aspect of the contralateral femur even though the examination was of limited extent; and 7) AFFs were associated with bisphosphonate medication in 75% of the patients studied. CONCLUSIONS: Hospital discharge coding misclassified a great majority of femoral fractures as subtrochanteric. As an essential criteria for diagnosing AFF is their subtrochanteric location, this misclassification impaired our ability to retrospectively search for AFF patients. Radiologists tended not to report AFF when typical radiographic characteristics were present. Bilateral and multifocal disease is of interest in pointing to the diagnosis and in suggesting that the mechanism of injury in respect of these unusual fractures is more complex than simple low-energy trauma.

Relationship Between Vertebral Fracture Burden, Height Loss, and Pulmonary Function in Postmenopausal Women With Osteoporosis.

The purpose of this analysis was to assess the association of osteoporosis-related vertebral fracture burden and pulmonary function. This study also examined the relationship between vertebral fracture burden and height loss, estimated by arm span - height. This was a single-site and single-visit study. Patients had a history of at least 1 moderate or severe vertebral fracture. Vertebral fracture burden was quantified using the spinal deformity index (SDI). Pulmonary function during inspiration was determined by spirometry. Forty-one women aged 70-91 completed the study. Vertebral fracture burden negatively correlated with forced inspiratory vital capacity and inspiratory time. For each unit increase in SDI, forced inspiratory vital capacity decreased by 1.62%, and inspiratory time decreased by 2.39%. There was no correlation between SDI and measures of inspiratory flow. For each unit increase in SDI, height decreased by about 0.5 cm. Vertebral fractures were associated with decreased lung volume and height loss.

Fibroblast growth factor 23 is elevated in tenofovir-related hypophosphatemia.

In human immunodeficiency virus (HIV)-infected patients, tenofovir disoproxil fumarate (TDF) may cause hypophosphatemia leading to osteomalacia due to renal phosphate wasting. Fibroblast growth factor 23 (FGF23) may play a role in this setting. We present an HIV-infected patient with TDF-induced profound hypophosphatemia, Fanconi syndrome, osteomalacia, and bilateral hip fracture. Routine serum biochemistry was assessed by standard methods. The plasma FGF23 concentration was measured at Mayo Laboratories (Scottsdale, AZ, USA). Bone mineral density (BMD) was measured using a Hologic Discovery densitometer. At presentation, the patient's plasma C-terminal FGF23 was 2,760 reference units (RU)/mL (15 times upper limit of normal; reference interval [RI] ≤ 180 RU/mL), serum phosphate was 0.58 (RI 0.8-1.6 mmol/L), and TmPO4/GFR was 95%. DXA at the lumbar spine showed a Z score of -4.0. Vitamin D3 and oral phosphate were administered, and TDF was discontinued. After 4 months off TDF, lumbar spine BMD significantly increased by 12% (Z score -3.5); by 6 months the plasma C-terminal FGF23 declined to 1.8 times the upper limit of normal, and both urine and serum phosphate levels normalized. By its marked elevation and subsequent near normalization, FGF23 may be responsible for a component of the phosphate wasting syndrome in these patients. The time course of resolution was 6 months. As expected, with calcium, vitamin D, and phosphate management, BMD significantly improved with resolution of osteomalacia. Clinicians should be aware of this side effect of TDF and the time course of its resolution.

Understanding and communicating the benefits and risks of denosumab, raloxifene, and teriparatide for the treatment of osteoporosis.

The number needed to treat is a valuable metric to determine the benefit of therapy, but it must be viewed against the respective number needed to harm. Denosumab and teriparatide (TPTD) have proven antifracture efficacy at vertebral and nonvertebral sites, whereas raloxifene has proven antifracture efficacy at the spine only. Denosumab use has been associated with a small, yet statistically significant, increased incidence of eczema and serious cellulitis. Raloxifene use has been associated with statistically significant increases in the risk of venous thromboembolism and possibly deadly stroke, although not an increase in total strokes. No significant, nontransient adverse events have been reported with TPTD use. When used for the treatment of postmenopausal osteoporosis, denosumab, raloxifene, and TPTD all generally have favorable risk-to-benefit profiles, but therapy-specific contraindications necessitate thoughtful consideration of all available clinical information and individualization of treatment decisions.

Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays.

OBJECTIVE: To outline the efficacy and risks of bisphosphonate therapy for the management of osteoporosis and describe which patients might be eligible for bisphosphonate "drug holiday." QUALITY OF EVIDENCE: MEDLINE (PubMed, through December 31, 2012) was used to identify relevant publications for inclusion. Most of the evidence cited is level II evidence (non-randomized, cohort, and other comparisons trials). MAIN MESSAGE: The antifracture efficacy of approved first-line bisphosphonates has been proven in randomized controlled clinical trials. However, with more extensive and prolonged clinical use of bisphosphonates, associations have been reported between their administration and the occurrence of rare, but serious, adverse events. Osteonecrosis of the jaw and atypical subtrochanteric and diaphyseal femur fractures might be related to the use of bisphosphonates in osteoporosis, but they are exceedingly rare and they often occur with other comorbidities or concomitant medication use. Drug holidays should only be considered in low-risk patients and in select patients at moderate risk of fracture after 3 to 5 years of therapy. CONCLUSION: When bisphosphonates are prescribed to patients at high risk of fracture, their antifracture benefits considerably outweigh their potential for harm. For patients taking bisphosphonates for 3 to 5 years, reassess the need for ongoing therapy.

Response rates for lumbar spine, total hip, and femoral neck bone mineral density in men treated with abaloparatide: results from the ATOM study.

Osteoporosis in men is an underappreciated public health issue, accounting for approximately 30% of the societal burden of osteoporosis. Although the prevalence of osteoporosis in men is lower, fracture-related morbidity and mortality rates exceed those of women. Abaloparatide is a synthetic, 34-amino acid peptide with homology to human parathyroid hormone-related protein (PTHrP), which favors bone formation by selective activation of PTH receptor type 1. In the Abaloparatide for the Treatment of Men With Osteoporosis (ATOM; NCT03512262) trial, 228 men with primary or hypogonadism-associated osteoporosis were randomized to receive subcutaneous injections of abaloparatide 80 µg or placebo. Abaloparatide significantly improved LS, TH, and FN BMD when compared with placebo. In this prespecified analysis, the proportion of men with a percent change from baseline of >0%, >3%, and > 6% in BMD at the LS, TH, and FN at 3, 6, and 12 mo and/or a shift in T-score category (based on LS and TH T-scores) at 12 mo was compared between the abaloparatide and placebo groups in ATOM. There were significantly more men with a BMD gain of >3% at all 3 anatomical sites in the abaloparatide than placebo group at month 6 (18/122 [14.8%] vs 1/70 [1.4%], P = .002) and at month 12 (38/119 [31.9%] vs 1/66 [1.5%], P < .0001). At month 3, more men treated with abaloparatide than placebo had a > 3% BMD increase at the LS (82/134 [61.2%] vs 21/68 [30.9%], P < .0001). A greater proportion of men treated with abaloparatide had an improvement in T-score category from osteoporosis to low BMD or normal when compared with placebo. In conclusion, use of abaloparatide compared with placebo for 12 mo resulted in significant and rapid improvements in BMD in men with osteoporosis from the ATOM study.

Lasofoxifene in postmenopausal women with osteoporosis.

BACKGROUND: The effects of lasofoxifene on the risk of fractures, breast cancer, and cardiovascular disease are uncertain. METHODS: In this randomized trial, we assigned 8556 women who were between the ages of 59 and 80 years and had a bone mineral density T score of -2.5 or less at the femoral neck or spine to receive once-daily lasofoxifene (at a dose of either 0.25 mg or 0.5 mg) or placebo for 5 years. Primary end points were vertebral fractures, estrogen receptor (ER)-positive breast cancer, and nonvertebral fractures; secondary end points included major coronary heart disease events and stroke. RESULTS: Lasofoxifene at a dose of 0.5 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (13.1 cases vs. 22.4 cases per 1000 person-years; hazard ratio, 0.58; 95% confidence interval [CI], 0.47 to 0.70), nonvertebral fracture (18.7 vs. 24.5 cases per 1000 person-years; hazard ratio, 0.76; 95% CI, 0.64 to 0.91), ER-positive breast cancer (0.3 vs. 1.7 cases per 1000 person-years; hazard ratio, 0.19; 95% CI, 0.07 to 0.56), coronary heart disease events (5.1 vs. 7.5 cases per 1000 person-years; hazard ratio, 0.68; 95% CI, 0.50 to 0.93), and stroke (2.5 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.64; 95% CI, 0.41 to 0.99). Lasofoxifene at a dose of 0.25 mg per day, as compared with placebo, was associated with reduced risks of vertebral fracture (16.0 vs. 22.4 cases per 1000 person-years; hazard ratio, 0.69; 95% CI, 0.57 to 0.83) and stroke (2.4 vs. 3.9 cases per 1000 person-years; hazard ratio, 0.61; 95% CI, 0.39 to 0.96) Both the lower and higher doses, as compared with placebo, were associated with an increase in venous thromboembolic events (3.8 and 2.9 cases vs. 1.4 cases per 1000 person-years; hazard ratios, 2.67 [95% CI, 1.55 to 4.58] and 2.06 [95% CI, 1.17 to 3.60], respectively). Endometrial cancer occurred in three women in the placebo group, two women in the lower-dose lasofoxifene group, and two women in the higher-dose lasofoxifene group. Rates of death per 1000 person-years were 5.1 in the placebo group, 7.0 in the lower-dose lasofoxifene group, and 5.7 in the higher-dose lasofoxifene group. CONCLUSIONS: In postmenopausal women with osteoporosis, lasofoxifene at a dose of 0.5 mg per day was associated with reduced risks of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke but an increased risk of venous thromboembolic events. (ClinicalTrials.gov number, NCT00141323.)

The generalized bone phenotype in children with neurofibromatosis 1: a sibling matched case-control study.

People with neurofibromatosis 1 (NF1) have low bone mineralization, but the natural history and pathogenesis are poorly understood. We performed a sibling-matched case-control study of bone mineral status, morphology, and metabolism. Eighteen children with NF1 without focal bony lesions were compared to unaffected siblings and local population controls. Bone mineral content at the lumbar spine and proximal femur (dual energy X-ray absorptiometry (DXA)) was lower in children with NF1; this difference persisted after adjusting for height and weight. Peripheral quantitative computed tomography (pQCT) of the distal tibia showed that trabecular density was more severely compromised than cortical. Peripheral QCT-derived estimates of bone strength and resistance to bending and stress were poorer among children with NF1 although there was no difference in fracture frequencies. There were no differences in the size or shape of bones after adjusting for height. Differences in markers of bone turnover between cases and controls were in the directions predicted by animal studies, but did not reach statistical significance. Average serum calcium concentration was higher (although within the normal range) in children with NF1; serum 25-OH vitamin D, and PTH levels did not differ significantly between cases and controls. Children with NF1 were less mature (assessed by pubertal stage) than unaffected siblings or population controls. Children with NF1 have a generalized difference of bone metabolism that predominantly affects trabecular bone. Effects of decreased neurofibromin on bone turnover, calcium homeostasis, and pubertal development may contribute to the differences in bone mineral content observed among people with NF1.

High-resolution peripheral quantitative computed tomography for the assessment of bone strength and structure: a review by the Canadian Bone Strength Working Group.

Bone structure is an integral determinant of bone strength. The availability of high resolution peripheral quantitative computed tomography (HR-pQCT) has made it possible to measure three-dimensional bone microarchitecture and volumetric bone mineral density in vivo, with accuracy previously unachievable and with relatively low-dose radiation. Recent studies using this novel imaging tool have increased our understanding of age-related changes and sex differences in bone microarchitecture, as well as the effect of different pharmacological therapies. One advantage of this novel tool is the use of finite element analysis modelling to non-invasively estimate bone strength and predict fractures using reconstructed three-dimensional images. In this paper, we describe the strengths and limitations of HR-pQCT and review the clinical studies using this tool.

The Official Positions of the International Society for Clinical Densitometry: Indications of Use and Reporting of DXA for Body Composition.

The technique of body composition by dual-energy X-ray absorptiometry (DXA) has been used for several years in the research environment. Its ability to accurately and precisely measure lean, fat, and mineral composition in various body compartments has been well validated. Furthermore, the technique is widely available to clinical patients on existing DXA instruments throughout the world through the use of specific software packages and scanning algorithms. There have been few clear statements regarding the clinical indications for body composition measurement in patients outside the research setting. This is in part because of the lack of specific documented interventions that would be affected by body composition test results, beyond usual clinical advice. We have examined a few of the most common, specific scenarios (HIV therapy, sarcopenia, bariatric surgery, obesity) and proposed indications for body composition assessment. We have also discussed contraindications to body composition testing.