Robert A. Adler

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients with no exposure to these drugs. In this report, we review studies on the epidemiology, pathogenesis, and medical management of AFFs, published since 2010. This newer evidence suggests that AFFs are stress or insufficiency fractures. The original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution. The periosteal stress reaction at the fracture site was changed from a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features, because it was considered that these associations should be sought rather than be included in the case definition. Studies with radiographic review consistently report significant associations between AFFs and BP use, although the strength of associations and magnitude of effect vary. Although the relative risk of patients with AFFs taking BPs is high, the absolute risk of AFFs in patients on BPs is low, ranging from 3.2 to 50 cases per 100,000 person‐years. However, long‐term use may be associated with higher risk (∼100 per 100,000 person‐years). BPs localize in areas that are developing stress fractures; suppression of targeted intracortical remodeling at the site of an AFF could impair the processes by which stress fractures normally heal. When BPs are stopped, risk of an AFF may decline. Lower limb geometry and Asian ethnicity may contribute to the risk of AFFs. There is inconsistent evidence that teriparatide may advance healing of AFFs.

Effects of Teriparatide Versus Alendronate for Treating Glucocorticoid-Induced Osteoporosis Thirty-Six-Month Results of a Randomized, Double-Blind, Controlled Trial

OBJECTIVE To compare the bone anabolic drug teriparatide (20 microg/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid-induced osteoporosis (OP). METHODS This was a 36-month, randomized, double-blind, controlled trial in 428 subjects with OP (ages 22-89 years) who had received > or =5 mg/day of prednisone equivalent for > or =3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety. RESULTS Increases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N-terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C-terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001). CONCLUSION Our findings indicate that subjects with glucocorticoid-induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate.

Osteoporosis in Men: An Endocrine Society Clinical Practice Guideline

OBJECTIVE The aim was to formulate practice guidelines for management of osteoporosis in men. EVIDENCE We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and evidence quality. CONSENSUS PROCESS Consensus was guided by systematic evidence reviews, one in-person meeting, and multiple conference calls and e-mails. Task Force drafts were reviewed successively by The Endocrine Societys Clinical Guidelines Subcommittee and Clinical Affairs Core Committee; representatives of ASBMR, ECTS, ESE, ISCD; and members at large. At each stage, the Task Force received written comments and incorporated needed changes. The reviewed document was approved by The Endocrine Society Council before submission for peer review. CONCLUSIONS Osteoporosis in men causes significant morbidity and mortality. We recommend testing higher risk men [aged ≥70 and men aged 50-69 who have risk factors (e.g. low body weight, prior fracture as an adult, smoking, etc.)] using central dual-energy x-ray absorptiometry. Laboratory testing should be done to detect contributing causes. Adequate calcium and vitamin D and weight-bearing exercise should be encouraged; smoking and excessive alcohol should be avoided. Pharmacological treatment is recommended for men aged 50 or older who have had spine or hip fractures, those with T-scores of -2.5 or below, and men at high risk of fracture based on low bone mineral density and/or clinical risk factors. Treatment should be monitored with serial dual-energy x-ray absorptiometry testing.

Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations.

Quantitative ultrasound of the heel and fracture risk assessment: an updated meta-analysis

SummaryMeta-analysis of prospective studies shows that quantitative ultrasound of the heel using validated devices predicts risk of different types of fracture with similar performance across different devices and in elderly men and women. These predictions are independent of the risk estimates from hip DXA measures.IntroductionClinical utilisation of heel quantitative ultrasound (QUS) depends on its power to predict clinical fractures. This is particularly important in settings that have no access to DXA-derived bone density measurements. We aimed to assess the predictive power of heel QUS for fractures using a meta-analysis approach.MethodsWe conducted an inverse variance random effects meta-analysis of prospective studies with heel QUS measures at baseline and fracture outcomes in their follow-up. Relative risks (RR) per standard deviation (SD) of different QUS parameters (broadband ultrasound attenuation [BUA], speed of sound [SOS], stiffness index [SI], and quantitative ultrasound index [QUI]) for various fracture outcomes (hip, vertebral, any clinical, any osteoporotic and major osteoporotic fractures) were reported based on study questions.ResultsTwenty-one studies including 55,164 women and 13,742 men were included in the meta-analysis with a total follow-up of 279,124 person-years. All four QUS parameters were associated with risk of different fracture. For instance, RR of hip fracture for 1 SD decrease of BUA was 1.69 (95% CI 1.43–2.00), SOS was 1.96 (95% CI 1.64–2.34), SI was 2.26 (95%CI 1.71–2.99) and QUI was 1.99 (95% CI 1.49–2.67). There was marked heterogeneity among studies on hip and any clinical fractures but no evidence of publication bias amongst them. Validated devices from different manufacturers predicted fracture risks with similar performance (meta-regression p values > 0.05 for difference of devices). QUS measures predicted fracture with a similar performance in men and women. Meta-analysis of studies with QUS measures adjusted for hip BMD showed a significant and independent association with fracture risk (RR/SD for BUA = 1.34 [95%CI 1.22–1.49]).ConclusionsThis study confirms that heel QUS, using validated devices, predicts risk of different fracture outcomes in elderly men and women. Further research is needed for more widespread utilisation of the heel QUS in clinical settings across the world.

Efficacy and safety of a once-yearly i.v. Infusion of zoledronic acid 5 mg versus a once-weekly 70-mg oral alendronate in the treatment of male osteoporosis: A randomized, multicenter, double-blind, active-controlled study

Zoledronic acid (ZOL) has shown beneficial effects on bone turnover and bone mineral density (BMD) in postmenopausal osteoporosis. This study compared the efficacy and safety of a once‐yearly i.v. infusion of ZOL with weekly oral alendronate (ALN) in men with osteoporosis. In this multicenter, double‐blind, active‐controlled, parallel‐group study, participants (n = 302) were randomized to receive either once‐yearly ZOL 5 mg i.v. or weekly oral ALN 70 mg for 24 months. Changes in BMD and bone marker levels were assessed. ZOL increased BMD at the lumbar spine, total hip, femoral neck, and trochanter and was not inferior to ALN at 24 months [least squares mean estimates of the percentage increases in lumbar spine BMD of 6.1% and 6.2%; difference approximately 0.13; 95% confidence interval (CI) 1.12–0.85 in the ZOL and ALN groups, respectively]. At month 12, the median change from baseline of markers for bone resorption [serum β‐C‐terminal telopeptide of type I collagen (β‐CTx) and urine N‐terminal telopeptide of type I collagen (NTx)] and formation [serum N‐terminal propeptide of type I collagen (P1NP) and serum bone‐specific alkaline phosphatase (BSAP)] were comparable between ZOL and ALN groups. Most men preferred i.v. ZOL over oral ALN. The incidence of adverse events and serious adverse events was similar in the treatment groups. It is concluded that a once‐yearly i.v. infusion of ZOL 5 mg increased bone density and decreased bone turnover markers similarly to once‐weekly oral ALN 70 mg in men with low bone density.

Performance of the Osteoporosis Self-assessment Screening Tool for Osteoporosis in American Men

OBJECTIVE To determine whether the Osteoporosis Self-assessment Tool (OST) can predict central bone mineral density in men, as defined by dual energy x-ray absorptiometry (DXA). PATIENTS AND METHODS We applied the OST index to men in pulmonary (evaluated January-May 2001) and rheumatology (evaluated November 2001-March 2002) clinics at a veterans hospital. The calculated OST risk index is based on weight and age. RESULTS In 181 men, we arbitrarily defined osteoporosis as a DXA T score of -25 or less in the spine, total hip, or femoral neck. The mean age and weight of the men were 64.3 years and 91.2 kg; 15.6% had osteoporosis by DXA. The OST index ranged from -5 to 19, from which we categorized risk as follows: low, 4 or greater; moderate,-1 to 3; and high, -2 or less. Only 2.0% of men with a low-risk OST index had osteoporosis, whereas 27.0% with a moderate risk and 72.7% with a high risk had osteoporosis. Using an OST cutoff score of 3, we predicted osteoporosis with a sensitivity of 93% and a specificity of 66%. When patients were studied by age in decades, race, or current glucocorticoid use, the predictive value of the OST was maintained. CONCLUSION The OST is an easy method to predict osteoporosis by DXA.

Skeletal health in long-duration astronauts: Nature, assessment, and management recommendations from the NASA Bone Summit

Concern about the risk of bone loss in astronauts as a result of prolonged exposure to microgravity prompted the National Aeronautics and Space Administration to convene a Bone Summit with a panel of experts at the Johnson Space Center to review the medical data and research evidence from astronauts who have had prolonged exposure to spaceflight. Data were reviewed from 35 astronauts who had served on spaceflight missions lasting between 120 and 180 days with attention focused on astronauts who (1) were repeat fliers on long‐duration missions, (2) were users of an advanced resistive exercise device (ARED), (3) were scanned by quantitative computed tomography (QCT) at the hip, (4) had hip bone strength estimated by finite element modeling, or (5) had lost >10% of areal bone mineral density (aBMD) at the hip or lumbar spine as measured by dual‐energy X‐ray absorptiometry (DXA). Because of the limitations of DXA in describing the effects of spaceflight on bone strength, the panel recommended that the U.S. space program use QCT and finite element modeling to further study the unique effects of spaceflight (and recovery) on bone health in order to better inform clinical decisions.

Low dose radioiodide thyroid ablation in postsurgical patients with thyroid cancer

Sixty-four patients with well-differentiated carcinoma of the thyroid were treated with initial high (80 to 100 mCi) or low (less than 30 mCi) doses of I131 after bilateral subtotal thyroidectomy. A total of 36 patients in the various histologic categories were initially treated with the low dose of I131 (group 1), and a total of 28 patients were treated with the higher dose (group 2). Disease-free criteria were no visible tissue in the neck or body, a protein-bound radioactive iodine (PBI131) of less than 0.005 per cent per liter at seven days and/or whole body retention of less than 3 per cent at seven days. Of the patients receiving less than 30 mCi (group 1), 56 per cent with papillary carcinoma, 67 per cent with follicular carcinoma and 56 per cent with mixed carcinoma of the thyroid were rendered disease-free after this initial dose. Of the patients receiving the higher dose of I131 (group 2), 67 per cent with papillary carcinoma, 50 per cent with follicular carcinoma and 67 per cent with mixed carcinoma of the thyroid were rendered disease-free after this initial dose. Disease-free mean follow-up time was 5.17 years (group 1) and 5.82 years (group 2). There was no statistical difference in these mean follow-up times, nor was there a statistical difference in the net (total minus initial) dose of I131 needed to render the patient disease-free. These data demonstrate that low dose I131 therapy is as effective as the larger more routine doses of I131 given in this disease.

Mild Vitamin D Deficiency and Secondary Hyperparathyroidism in Nursing Home Patients Receiving Adequate Dietary Vitamin D

To compare the vitamin D metabolite and nutritional status of institutionalized elderly males with a non‐institutionalized control group.