Bisphosphonate Use May be Associated With an Increased Risk of Periprosthetic Hip Fracture.

BACKGROUND: Osteoporosis is common among patients undergoing primary total hip arthroplasty (THA). This study aimed to evaluate the effect of bisphosphonate treatment on osteoporotic patients undergoing primary THA. METHODS: Using a national database, 30,137 patients who had osteoporosis before primary elective THA were identified during 2010 to 2020. Patients undergoing nonelective THA and those using corticosteroids or other medications for osteoporosis were excluded. Bisphosphonate users and bisphosphonate naïve patients were matched 1:1 based on age, sex, Elixhauser comorbidity index, and a history of obesity, rheumatoid arthritis, tobacco use, and alcohol abuse. Kaplan-Meier and multivariate analyses were used to compare 2-year outcomes between groups. RESULTS: Among matched cohorts of 9,844 patients undergoing primary THA, bisphosphonate use was associated with a significantly higher 2-year rate of periprosthetic fracture (odds ratio 1.29, 95% confidence interval 1.04 to 1.61, P = .022). There was a trend toward increased risk of any revision with bisphosphonate use (odds ratio 1.19, confidence interval 1.00 to 1.41, P = .056). Rates of infection, aseptic loosening, dislocation, and mortality were not statistically different between bisphosphonate users and bisphosphonate-naïve patients. CONCLUSION: In osteoporotic patients, bisphosphonate use before primary THA is an independent risk factor for periprosthetic fracture. Additional longer-term data are needed to determine the underlying mechanism for this association and identify preventative measures.

Fracture Risk Assessment and Drug Holiday in a Real-Life Setting.

PURPOSE: Describe fracture risk assessment practices among physicians treating osteoporosis in a real-life setting. METHODS: This is a retrospective cohort study in a tertiary academic center. Inclusion criteria involved adults (aged ≥18 years) who received minimum adequate therapy (bisphosphates, raloxifene, or denosumab ≥ 3 years or teriparatide ≥ 18 months). Of 1,814 charts randomly selected and reviewed, 274 patients met the inclusion criteria. Risk stratification tools included fragility fractures, Dual-energy X-ray Absorptiometry (DXA), and fracture risk assessment using the FRAX tool. Fracture risk assessment was performed before therapy initiation (N= 274) and at the time of institution of the drug holiday (N=119). High-risk patients were defined as the presence of a fragility fracture, T-score ≤-2.5, or a high-risk score by FRAX calculation. FRAX scores were independently calculated by the research team for comparison and assessment purposes. RESULTS: Before initiation of therapy (N=274) versus upon starting a drug holiday (DH; N=119), 29.9% versus 3.4% had a history of fragility fractures (P<0.001), 58.8% versus 67.2% had a DXA scan performed (P>0.05), 10.5% versus 10.9% of physicians calculated a FRAX score (P>0.05), and 71.5% versus 66.4% were considered at high risk and eligible for therapy. A DXA scan was performed after DH in 40.2% of these patients and at least once in 95.3% of the entire cohort. CONCLUSION: The reporting of FRAX score in DXA scan reports may significantly increase its utilization in fracture risk assessment. We recommend comprehensive fracture risk assessment utilizing history of prevalent osteoporosis fractures, DXA assessment, and FRAX scoring.

Patterns of Osteoporosis Medications Selection After Drug Holiday or Continued Therapy: A Real-World Experience.

OBJECTIVE: Published literature on physicians' preferences and sequential treatment patterns of osteoporosis therapy is scarce. METHODS: A retrospective cohort study of patients who received bisphosphonates, denosumab, and/or raloxifene for at least 3 consecutive years or teriparatide for at least 18 months for osteoporosis. Data collection spanned 10 years, from October 2007 to September 2016, at a tertiary care center in the United States. RESULTS: In total, 12 885 patients were identified on the basis of receiving at least 1 treatment at any point in time; 1814 patients were randomly reviewed, and 274 patients met the inclusion criteria. The mean age was 68.8 ± 10.7 years, and women represented 90.9% of all the cases. Primary care physicians and rheumatologists constituted 65.7% and 22.6% of the prescribers, respectively. Before instituting a drug holiday, alendronate was the most common initial treatment (percentage, mean duration ± standard deviation in years: 69%, 5.4 ± 2.4 years) followed by ibandronate (9.5%, 4.9 ± 2.1 years) and raloxifene (9.1%, 5.2 ± 1.6 years). Denosumab was the most common second course of treatment, accounting for 29.3% of 82 patients who were subsequently prescribed another therapy, followed by alendronate (24.4%) and zoledronate (20.7%). Among patients who were placed on a drug holiday and eventually restarted on osteoporosis therapy, denosumab was the most common treatment instituted (n = 21), accounting for 40% of the total patients, followed by alendronate (32%) and zoledronate (16%). There was a progressive decline in osteoporosis therapy over the duration of the study. CONCLUSION: Alendronate was the most common initial therapy. Denosumab was the most common second course of treatment prescribed.

Approaches to Fracture Risk Assessment and Prevention.

PURPOSE OF REVIEW: To critically assess recent evidence concerning osteoporosis fracture risk. RECENT FINDINGS: Robust instruments exist for predicting factures incorporating well-documented risk factors especially prior fracture whose magnitude varies with site, occurrence time, and age. Stratifying time-since-prior fracture has resulted in the concept of imminent fracture risk and increased focus on secondary fracture prevention. Secondary fracture prevention recommendations include fracture liaison service, pharmacologic and non-pharmacologic multidisciplinary intervention, and communicating that fractures in older adults are the predictable consequence of underlying osteoporosis rather than unfortunate accidents. Quality improvement in osteoporosis care includes diagnosing osteoporosis on the basis of clinical fractures rather than exclusively relying on bone density testing; applying diagnostic rather than screening approaches to patients with prior fractures; regularly updating fall and fracture histories; performing a physical exam focused on spinal curvature, posture, and musculoskeletal function; reviewing images to identify prevalent fractures that may have been missed; and general use of fracture risk algorithms at all stages of osteoporosis management. Communicating effectively with patients about osteoporosis and fractures, their consequences, and pharmacological and non-pharmacological management is the cornerstone of high-value care.

HYPERCALCEMIA OF MALIGNANCY IN A CASE OF PERIPHERAL NERVE SHEATH TUMOR: ELUCIDATING THE ROLES OF SIMULTANEOUS MECHANISMS.

OBJECTIVE: Hypercalcemia of malignancy (HCM) is caused by 1 of 5 known mechanisms including systemic release of ectopic parathyroid hormone (PTH)-related protein (PTHrP), calcitriol, PTH, cytokines, or destruction of bone by osteolytic metastases. We report the first case of 2 simultaneous mechanisms for HCM in a patient with a peripheral nerve sheath tumor (PNST). METHODS: PubMed and Google Scholar searches were performed using "hypercalcemia of malignancy" as the search term. RESULTS: A 26-year-old woman with neurofibromatosis presented with worsening left hip pain. Magnetic resonance imaging showed a large left paraspinal mass, subtotal resection of which confirmed PNST. Despite chemo-radiation therapy, the tumor progressed over 16 months, requiring tumor debulking and L3-4 lumbar laminectomy. The patient developed progressive bilateral lower extremity weakness due to direct tumor invasion of the lumbosacral vertebrae with concurrent hypercalcemia. Ionized calcium was 1.47 mmol/dL (reference range is 0.95 to 1.32 mmol/dL), PTH was <4.0 pg/mL (reference range is 8 to 85 pg/mL), 25-hydroxyvitamin D was 14 ng/mL, calcitriol was <8.0 pg/mL (reference range is 18 to 78 pg/mL), PTHrP was 40 pg/mL(reference range is 14 to 27 pg/mL), urinary calcium was <2.0 mg/24 hours, serum C-telopeptide was 1,008 pg/mL (reference range is 64 to 640 pg/mL), and bone-specific alkaline phosphatase was 15.7 µg/L (reference range is 4.7 to 17.8 µg/L). Her serum magnesium, phosphorus, and creatinine levels were normal. Intravenous zoledronic acid and hydration resulted in a normal ionized calcium. Additional imaging revealed extensive tumor invasion of L3-S1 vertebrae. Due to her poor response to all cancer therapies, the patient was discharged to home hospice services. CONCLUSION: HCM due to PTHrP and osteolytic metastases has not been independently reported to our knowledge in association with malignant PNST as in our patient. The therapeutic importance of characterizing the mechanism of HCM is further discussed in detail.

The Future of Fracture Risk Assessment in the Management of Osteoporosis.

There have been many advances in the field of osteoporosis that add to a greater understanding of skeletal integrity and the adverse effects menopause and aging have on bone. The World Health Organization, the International Osteoporosis Foundation, and numerous additional governmental and privately sponsored organizations, societies, and their respective task forces have provided guidance for the use of appropriate fracture assessment methodologies and fracture risk assessment tools, and for the prevention and management of osteoporosis. Despite these worldwide efforts, a majority of patients at high risk of fracture have not had bone density testing and are not diagnosed or offered osteoporosis treatment before or even after sustaining a fragility fracture. The future of fracture risk assessment and, in general, osteoporosis management requires health-care systems to develop customizable electronic medical record (EMR) systems that incorporate the tools necessary to identify patients at high fracture risk. As provided in the example of an advanced health-care osteoporosis model, an EMR can be fully customizable to identify fractures and patients at high risk of fracture, to assist clinicians in selecting the most efficacious osteoporosis treatments, and to provide long-term follow-up with or without serial bone density testing. Future fracture risk assessment models will likely be further refined by incorporating advanced fracture predictive technologies for integration into algorithms that have improved discrimination, calibration, risk reclassification capabilities, and clinical utility. These models will include accurate and reproducible bone biomarkers and genomic testing that will be automatically integrated into worldwide EMR systems for screening large numbers of at-risk populations and younger patients for future prediction and prevention of disease. The integration of this type of a fracture prediction model into future electronic medical record systems will result in the prevention of osteoporosis fractures.

Quantitative Ultrasound (QUS) in the Management of Osteoporosis and Assessment of Fracture Risk.

The use of quantitative ultrasound (QUS) for a variety of skeletal sites, associated with the absence of technology-specific guidelines, has created uncertainty with respect to the application of QUS results to the management of individual patients in clinical practice. However, when prospectively validated (this is not the case for all QUS devices and skeletal sites), QUS is a proven, low-cost, and readily accessible alternative to dual-energy X-ray absorptiometry (DXA) measurements of bone mineral density (BMD) for the assessment of fracture risk. Indeed, the clinical use of QUS to identify subjects at low or high risk of osteoporotic fracture should be considered when central DXA is unavailable. Furthermore, the use of QUS in conjunction with clinical risk factors (CRF),allows for the identification of subjects who have a low and high probability of osteoporotic fracture. Device- and parameter-specific thresholds should be developed and cross-validated to confirm the concurrent use of QUS and CRF for the institution of pharmacological therapy and monitoring therapy.

Hypercalcemia of Malignancy in Thymic Carcinoma: Evolving Mechanisms of Hypercalcemia and Targeted Therapies.

Here we describe, to our knowledge, the first case where an evolution of mechanisms responsible for hypercalcemia occurred in undifferentiated thymic carcinoma and discuss specific management strategies for hypercalcemia of malignancy (HCM). Case Description. We report a 26-year-old male with newly diagnosed undifferentiated thymic carcinoma associated with HCM. Osteolytic metastasis-related hypercalcemia was presumed to be the etiology of hypercalcemia that responded to intravenous hydration and bisphosphonate therapy. Subsequently, refractory hypercalcemia persisted despite the administration of bisphosphonates and denosumab indicative of refractory hypercalcemia. Elevated 1,25-dihydroxyvitamin D was noted from the second admission with hypercalcemia responding to glucocorticoid administration. A subsequent PTHrP was also elevated, further supporting multiple mechanistic evolution of HCM. The different mechanisms of HCM are summarized with the role of tailoring therapies based on the particular mechanism underlying hypercalcemia discussed. Conclusion. Our case illustrates the importance of a comprehensive initial evaluation and reevaluation of all identifiable mechanisms of HCM, especially in the setting of recurrent and refractory hypercalcemia. Knowledge of the known and possible evolution of the underlying mechanisms for HCM is important for application of specific therapies that target those mechanisms. Specific targeting therapies to the underlying mechanisms for HCM could positively affect patient outcomes.

Considerations regarding adherence of anti-osteoporosis therapy.

Osteoporosis remains a challenging disease to treat due to a number of barriers including patient adherence to therapies. One of the most recent advances has been the development of the Fracture Risk Assessment Tool, which is helpful in conveying fracture risk to patients and providing treatment guidance to clinicians. The decision to use an anti-osteoporosis therapy must be tailored to the patient's specific clinical scenario. The bisphosphonates are first-line agents in the treatment of osteoporosis and are efficacious in substantially reducing fracture risk between 25% and 70% on average depending on fracture site. Compliance with oral bisphosphonate pills can be poor, resulting in a significant deterrent to the proper management of osteoporosis. Non-pill forms of bisphosphonate and nonbisphosphonate therapy are available for the treatment of osteoporosis and may increase compliance. Among these is Binosto, a new formulation of weekly effervescent alendronate, as well as intravenous bisphosphonates, teriparatide, and subcutaneously administered denosumab, which are all costly medications and are unlikely to become the mainstay of treatment over the oral bisphosphonate pills. Having a detailed conversation between the patient and physician is essential to the development of a tailored treatment plan that will decrease fracture risk.

Ancestral differences in femoral neck axis length: possible implications for forensic anthropological analyses.

In forensic anthropological contexts, very few methods of estimating ancestry from the postcranial skeleton are available. The cranium is widely recognized to show the greatest ancestral variation, and is often regarded by forensic anthropologists as the only reliable bone for estimating ancestry from unidentified skeletal remains. Several studies have demonstrated ancestral variation in aspects of the femur, but none have shown significant predictive power for discriminating multiple groups, and have therefore not gained wide acceptance by forensic anthropologists. Skeletal health experts (particularly bone densitometrists), however, have long recognized a relationship between proximal femur geometry (especially hip axis length) and osteoporosis-related fracture risk. Moreover, fracture risk has been noted to vary between ancestral groups. Here, we investigate whether measurements that are related to fracture risk might also be used to estimate ancestry from unidentified skeletal remains. Specifically, we investigate ancestral differences in femoral neck axis length (FNAL) and find significant differences between European, Asian and African groups in both women and men. FNAL was largest in European groups followed by African and then Asian groups. The greatest discriminating power was found between European and Asian groups, but was also significant between European and African groups. These differences may have utility in estimating ancestry in forensic anthropological contexts.

Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry.

The International Society for Clinical Densitometry (ISCD) convenes a Position Development Conference (PDC) every 2-3 yr to make recommendations for guidelines and standards in the field of musculoskeletal measurement and assessment. The recommendations pertain to clinically relevant issues regarding the acquisition, quality control, interpretation, and reporting of various aspects of musculoskeletal health metrics. Topics for consideration are developed by the ISCD Board of Directors and the Scientific Advisory Committee. For the 2013 PDC, body composition analysis was a central topic area for the first time and considered timely because of the scientific advances in measurement of fat and lean body mass by dual-energy X-ray absorptiometry (DXA). Indications for DXA and vertebral fracture assessment and use of reference data to calculate bone mineral density T-scores were also updated. Task Forces for each of these areas were assigned questions of relevance to a clinical audience and asked to conduct comprehensive literature reviews. Reports with proposed Position Statements were then presented to an international panel of experts. The Expert Panel included representatives of the International Osteoporosis Foundation, the American Society for Bone and Mineral Research, the National Osteoporosis Foundation, Osteoporosis Canada, and the North American Menopause Society. The PDC was held in Tampa, FL, contemporaneously with the Annual Meeting of the ISCD, March 21 through March 23, 2013. This report describes the methodology of the 2013 ISCD PDC and summarizes the results of the 2013 ISCD PDC for vertebral fracture assessment/DXA and National Health and Nutrition Survey (NHANES) Reference Database Task Forces. A separate article in this issue will summarize the results of the Body Composition Analysis Task Forces.

Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on Body Composition.

There have been many scientific advances in measurement of fat and lean body mass as determined by dual-energy X-ray absorptiometry (DXA). The International Society for Clinical Densitometry (ISCD) convened a Position Development Conference (PDC) on the use of DXA for body composition measurement. Previously, no guidelines to the use of DXA for body composition existed. The recommendations pertain to clinically relevant issues regarding DXA indications of use, acquisition, analysis, quality control, interpretation, and reporting were addressed. The topics and questions for consideration were developed by the ISCD Board of Directors and the Scientific Advisory Committee and were designed to address the needs of clinical practitioners. Three Task Forces were created and assigned these questions and asked to conduct comprehensive literature reviews. The Task Forces included participants from 6 countries and a variety of interests including academic institutions, private clinics, and industry. Reports with proposed Position Statements were then presented to an international panel of experts with backgrounds in DXA and bone densitometry and a variety of fields that use body composition measures. The PDC was held in Tampa, FL, contemporaneously with the Annual Meeting of the ISCD, March 21 through March 23, 2013. This report describes the methodology of the 2013 ISCD Body Composition PDC and summarizes the results. Three separate articles in this issue will detail the rationale, discussion, and additional research topics for each question the Task Forces addressed.

Assessment of fracture risk.

Osteoporosis-related fractures (low-trauma, fragility fractures) are associated with significant morbidity, mortality, and health care expenditure worldwide. In the absence of a defining fracture, the diagnosis of osteoporosis is based on the World Health Organization's T-score criteria using central dual-energy x-ray absorptiometry (DXA). Paradoxically, the majority of those patients who will sustain a low-trauma fracture do not meet the T-score definition of osteoporosis. Conversely, younger individuals with bone density in the osteoporotic range but no other risk factors have relatively low fracture rates and yet are frequently considered candidates for osteoporosis therapies. The limited accuracy of bone density testing alone to predict fractures has led to the development of a variety of fracture assessment tools that utilize the combination of bone density and clinical risk factors to improve the prediction of low-trauma fractures. These fracture assessment tools quantitatively predict the 10-year fracture probability of hip and major osteoporosis-related fractures, and can be used to define cost-effective intervention strategies for primary and secondary fracture prevention.

Assessment of fracture risk.

Osteoporosis-related fractures are associated with significant morbidity, mortality, and health care expenditure worldwide. The low sensitivity of bone density testing alone to predict fractures has led to the development of a variety of fracture assessment tools that use the combination of bone density and clinical risk factors to improve the prediction of low-trauma fractures. These fracture assessment tools quantitatively predict the 10-year probability of hip and major osteoporosis-related fractures, and can be used with various intervention strategies to effectively intervene with cost-effective therapies to prevent future fractures.

Joint Official Positions of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX(®). Executive Summary of the 2010 Position Development Conference on Interpretation and use of FRAX® in clinical practice.

The International Society for Clinical Densitometry (ISCD) and the International Osteoporosis Foundation (IOF) convened the FRAX(®) Position Development Conference (PDC) in Bucharest, Romania, on November 14, 2010, following a two-day joint meeting of the ISCD and IOF on the "Interpretation and Use of FRAX(®) in Clinical Practice." These three days of critical discussion and debate, led by a panel of international experts from the ISCD, IOF and dedicated task forces, have clarified a number of important issues pertaining to the interpretation and implementation of FRAX(®) in clinical practice. The Official Positions resulting from the PDC are intended to enhance the quality and clinical utility of fracture risk assessment worldwide. Since the field of skeletal assessment is still evolving rapidly, some clinically important issues addressed at the PDCs are not associated with robust medical evidence. Accordingly, some Official Positions are based largely on expert opinion. Despite limitations inherent in such a process, the ISCD and IOF believe it is important to provide clinicians and technologists with the best distillation of current knowledge in the discipline of bone densitometry and provide an important focus for the scientific community to consider. This report describes the methodology and results of the ISCD-IOF PDC dedicated to FRAX(®).

Algorithm for the management of osteoporosis.

Osteoporosis is a common skeletal disease that weakens bones and increases the risk of fractures. It affects about one half of women over the age of 60, and one third of older men. With appropriate care, osteoporosis can be prevented; and when present, it can be easily diagnosed and managed. Unfortunately, many patients with osteoporosis are not recognized or treated, even after sustaining a low-trauma fracture. Even when treatment is initiated, patients may not take medication correctly, regularly, or for a sufficient amount of time to receive the benefit of fracture risk reduction. Efforts to improve compliance and treatment outcomes include longer dosing intervals and parenteral administration. Clinical practice guidelines for the prevention and treatment of osteoporosis have been developed by the National Osteoporosis Foundation (NOF) but may not be fully utilized by clinicians who must deal with numerous healthcare priorities. We present an algorithm to help streamline the work of busy clinicians so they can efficiently provide state-of-the-art care to patients with osteoporosis.

International Society for Clinical Densitometry official positions: Asia-Pacific Region consensus.

The International Society for Clinical Densitometry (lSCD) is a nonprofit multidisciplinary international professional organization. The ISCD mission is to advance excellence in the assessment of skeletal health. To achieve this mission, the ISCD has conducted a number of Position Development Conferences over the past 10yr, bringing together international experts to review and create evidence-based position statements guiding clinicians involved in the area. The Asia-Pacific (AP) Panel of the ISCD was formed to give regional input to the ISCD from the AP Region and to oversee ISCD education and certification programs in the region. An AP Panel consensus meeting recently reviewed the most current Official Positions of the ISCD in view of the different population characteristics and health standards in the region. The reviewed position statements included those for bone testing by central and peripheral devices but did not include ISCD Official Positions on Vertebral Fracture Assessment or pediatric bone mineral density.

Primary care use of FRAX: absolute fracture risk assessment in postmenopausal women and older men.

Osteoporosis-related fractures (low-trauma or fragility fractures) cause substantial disability, health care costs, and mortality among postmenopausal women and older men. Epidemiologic studies indicate that at least half the population burden of osteoporosis-related fractures affects persons with osteopenia (low bone density), who comprise a larger segment of the population than those with osteoporosis. The public health burden of fractures will fail to decrease unless the subset of patients with low bone density who are at increased risk for fracture are identified and treated. Risk stratification for medically appropriate and cost-effective treatment is facilitated by the World Health Organization (WHO) FRAX algorithm, which uses clinical risk factors, bone mineral density, and country-specific fracture and mortality data to quantify a patient's 10-year probability of a hip or major osteoporotic fracture. Included risk factors comprise femoral neck bone mineral density, prior fractures, parental hip fracture history, age, gender, body mass index, ethnicity, smoking, alcohol use, glucocorticoid use, rheumatoid arthritis, and secondary osteoporosis. FRAX was developed by the WHO to be applicable to both postmenopausal women and men aged 40 to 90 years; the National Osteoporosis Foundation Clinician's Guide focuses on its utility in postmenopausal women and men aged >50 years. It is validated to be used in untreated patients only. The current National Osteoporosis Foundation Guide recommends treating patients with FRAX 10-year risk scores of > or = 3% for hip fracture or > or = 20% for major osteoporotic fracture, to reduce their fracture risk. Additional risk factors such as frequent falls, not represented in FRAX, warrant individual clinical judgment. FRAX has the potential to demystify fracture risk assessment in primary care for patients with low bone density, directing clinical fracture prevention strategies to those who can benefit most.

Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents.

Dual-energy X-ray absorptiometry (DXA) is the most widely used technical instrument for evaluating bone mineral content (BMC) and density (BMD) in patients of all ages. However, its use in pediatric patients, during growth and development, poses a much more complex problem in terms of both the technical aspects and the interpretation of the results. For the adults population, there is a well-defined term of reference: the peak value of BMD attained by young healthy subjects at the end of skeletal growth. During childhood and adolescence, the comparison can be made only with healthy subjects of the same age, sex and ethnicity, but the situation is compounded by the wide individual variation in the process of skeletal growth (pubertal development, hormone action, body size and bone size). The International Society for Clinical Densitometry (ISCD) organized a Pediatric Position Development Conference to discuss the specific problems of bone densitometry in growing subjects (9-19 years of age) and to provide essential recommendations for its clinical use.