CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE QUALITY OF DXA SCANS AND REPORTS.

OBJECTIVE: High-quality dual-energy X-ray absorptiometry (DXA) scans are necessary for accurate diagnosis of osteoporosis and monitoring of therapy; however, DXA scan reports may contain errors that cause confusion about diagnosis and treatment. This American Association of Clinical Endocrinologists/American College of Endocrinology consensus statement was generated to draw attention to many common technical problems affecting DXA report conclusions and provide guidance on how to address them to ensure that patients receive appropriate osteoporosis care. METHODS: The DXA Writing Committee developed a consensus based on discussion and evaluation of available literature related to osteoporosis and osteodensitometry. RESULTS: Technical errors may include errors in scan acquisition and/or analysis, leading to incorrect diagnosis and reporting of change over time. Although the International Society for Clinical Densitometry advocates training for technologists and medical interpreters to help eliminate these problems, many lack skill in this technology. Suspicion that reports are wrong arises when clinical history is not compatible with scan interpretation (e.g., dramatic increase/decrease in a short period of time; declines in previously stable bone density after years of treatment), when different scanners are used, or when inconsistent anatomic sites are used for monitoring the response to therapy. Understanding the concept of least significant change will minimize erroneous conclusions about changes in bone density. CONCLUSION: Clinicians must develop the skills to differentiate technical problems, which confound reports, from real biological changes. We recommend that clinicians review actual scan images and data, instead of relying solely on the impression of the report, to pinpoint errors and accurately interpret DXA scan images. ABBREVIATIONS: AACE = American Association of Clinical Endocrinologists; BMC = bone mineral content; BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; ISCD = International Society for Clinical Densitometry; LSC = least significant change; TBS = trabecular bone score; WHO = World Health Organization.

Corrigendum to "Low Body Mass Index Can Identify Majority of Osteoporotic Inflammatory Bowel Disease Patients Missed by Current Guidelines".

[This corrects the article DOI: 10.1100/2012/807438.].

Bone density, bone quality, and FRAX: changing concepts in osteoporosis management.

Bone densitometry was originally developed to diagnose a high risk for fragility fractures in older postmenopausal women who may have primary osteoporosis. Its widespread availability, however, has led to its use in healthy peri- and premenopausal patients and the unexpected findings of low bone density in this group of patients. Their low bone density caused much uncertainty about the likelihood of fracture risk and what treatment might be needed. Conceptually, bone density reflected bone strength, and so a low density reflected increased fracture risk. Clinical experience and the results of pivotal studies of therapy for osteoporosis suggested that bone density was only partly responsible for skeletal strength. Many structural and material properties of bone, not measured by bone density, made it resist fracturing. Clinical risk factors helped determine these characteristics, albeit imperfectly, and aided clinicians decide whether and what treatment was needed. But now, new fracture risk assessment protocols (namely, FRAX, the WHO risk assessment tool) are available to help resolve this dilemma. This paper reviews some of the clinical observations that led to rethinking the concept bone density and bone strength and how it changes the clinical approach to therapy for the healthy young patient.

A novel lunar bed rest analogue.

INTRODUCTION: Humans will eventually return to the Moon and thus there is a need for a ground-based analogue to enable the study of physiological adaptations to lunar gravity. An important unanswered question is whether or not living on the lunar surface will provide adequate loading of the musculoskeletal system to prevent or attenuate the bone loss that is seen in microgravity. Previous simulations have involved tilting subjects to an approximately 9.5 degrees angle to achieve a lunar gravity component parallel to the long-axis of the body. However, subjects in these earlier simulations were not weight-bearing, and thus these protocols did not provide an analogue for load on the musculoskeletal system. METHODS: We present a novel analogue which includes the capability to simulate standing and sitting in a lunar loading environment. A bed oriented at a 9.5 degrees angle was mounted on six linear bearings and was free to travel with one degree of freedom along rails. This allowed approximately 1/6 body weight loading of the feet during standing. "Lunar" sitting was also successfully simulated. RESULTS: A feasibility study demonstrated that the analogue was tolerated by subjects for 6 d of continuous bed rest and that the reaction forces at the feet during periods of standing were a reasonable simulation of lunar standing. During the 6 d, mean change in the volume of the quadriceps muscles was -1.6% +/- 1.7%. DISCUSSION: The proposed analogue would appear to be an acceptable simulation of lunar gravity and deserves further exploration in studies of longer duration.

Low body mass index can identify majority of osteoporotic inflammatory bowel disease patients missed by current guidelines.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at high risk of developing osteoporosis. Our objective was to determine the usefulness of IBD guidelines in identifying patients at risk for developing osteoporosis. METHODS: We utilized institutional repository to identify patients seen in IBD center and extracted data on demographics, disease history, conventional, and nonconventional risk factors for osteoporosis and Dual Energy X-ray Absorptiometry (DXA) findings. RESULTS: 59% of patients (1004/1703) in our IBD cohort had at least one risk factor for osteoporosis screening. DXA was documented in 263 patients with indication of screening (provider adherence, 26.2%), and of these, 196 patients had DXA completed ("at-risk" group). Ninety-five patients not meeting guidelines-based risk factors also had DXA completed ("not at-risk" group). 139 (70.9%) patients in "at-risk" group had low BMD, while 51 (53.7%) of "not-at-risk" patients had low BMD. Majority of the patients with osteoporosis (83.3%) missed by the current guidelines had low BMI. Multivariate logistic regression analysis showed that low BMI was the strongest risk factor for osteoporosis (OR 3.07; 95% CI, 1.47-6.42; P = 0.003). CONCLUSIONS: Provider adherence to current guidelines is suboptimal. Low BMI can identify majority of the patients with osteoporosis that are missed by current guidelines.

DXA and clinical challenges of fracture risk assessment in primary care.

Dual-energy x-ray absorptiometry (DXA) can detect bone mineral density loss before it can be identified on usual skeletal radiography, making it possible to diagnose osteoporosis in postmenopausal women and older men before clinical fractures arise. However, when DXA is used outside these populations or if the clinical picture does not match the reported T-scores, mistakes can arise in interpreting results and determining the need for pharmaceutical therapy.

History of etidronate.

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.

Dual-energy X-ray absorptiometry diagnostic discordance between Z-scores and T-scores in young adults.

Diagnostic criteria for postmenopausal osteoporosis using central dual-energy X-ray absorptiometry (DXA) T-scores have been widely accepted. The validity of these criteria for other populations, including premenopausal women and young men, has not been established. The International Society for Clinical Densitometry (ISCD) recommends using DXA Z-scores, not T-scores, for diagnosis in premenopausal women and men aged 20-49 yr, though studies supporting this position have not been published. We examined diagnostic agreement between DXA-generated T-scores and Z-scores in a cohort of men and women aged 20-49 yr, using 1994 World Health Organization and 2005 ISCD DXA criteria. Four thousand two hundred and seventy-five unique subjects were available for analysis. The agreement between DXA T-scores and Z-scores was moderate (Cohen's kappa: 0.53-0.75). The use of Z-scores resulted in significantly fewer (McNemar's p<0.001) subjects diagnosed with "osteopenia," "low bone mass for age," or "osteoporosis." Thirty-nine percent of Hologic (Hologic, Inc., Bedford, MA) subjects and 30% of Lunar (GE Lunar, GE Madison, WI) subjects diagnosed with "osteoporosis" by T-score were reclassified as either "normal" or "osteopenia" when their Z-score was used. Substitution of DXA Z-scores for T-scores results in significant diagnostic disagreement and significantly fewer persons being diagnosed with low bone mineral density.

Teriparatide treatment in adult hypophosphatasia in a patient exposed to bisphosphonate: a case report.

We describe the case of a woman with hypophosphatasia previously exposed to bisphosphonate and subsequently treated with teriparatide (recombinant human PTH 1-34).A Caucasian woman sustained bilateral femur stress fractures when she was fifty years old, which widened despite use of calcium, vitamin D and risedronate for 2.5 years and required intramedullary rods for stabilization. Hypophosphatasia was diagnosed in the interim due to low serum alkaline phosphatase (ALP) (ALP 20 IU/L; normal (N), 40-150 IU/L) and high pyridoxal 5' phosphate (3400 nmol/L; N 18-175 nmol/L). She was referred for further management. On presentation, she had significant fracture site pain and generalized bone pain (weight bearing and non-weight bearing) - making her walker dependent at home and wheel chair dependent outside home.She could not sleep at night due to discomfort when she moved. Daily teriparatide injections, 20 mcg subcutaneously were prescribed.At 8-weeks follow-up, fracture site pain, weight-bearing and non weight-bearing pain improved significantly allowing ambulation for prolonged periods without assistance. She slept at night without discomfort. Improvement persisted during her entire treatment period. Radiographs taken at 4 and 16 months of treatment demonstrated healing of femur fractures.Biochemically, mean urine cross-link-N-telopeptide increased 11% as compared to her base-line, while bone specific alkaline phosphatase did not increase as expected.In conclusion, we observed an uncoupling of bone formation and resorption markers during her treatment period in the face of notable clinical and radiological improvement. Off-label use of teriparatide may help patients with hypophosphatasia.

Clinical perspectives on bone quality in osteoporosis: effects of drug therapy.

Treatment of primary osteoporosis has advanced dramatically during the past decade, with more therapeutic options being available now than at any other time. Anti-resorptive (anti-catabolic) drugs have been prominent in the treatment of osteoporosis for decades. However, over time, several clinical observations made during use of these agents have challenged the prevailing dogma about mechanisms of drug action, changes in bone density and fracture reduction during treatment. It has become clear that changes in bone density are only a small part of the explanation for the dramatic reduction of fractures with treatment. From this paradox developed the notion of 'bone quality'- an operational term describing a number of characteristics that enable bone to resist fracturing. This article reviews this concept from a clinical perspective. It discusses the historical paradoxes found in clinical practice that have led to this notion, identifies the major areas of bone physiology circumscribed by the concept and focuses on present therapies and their effects on bone quality.

DXA-generated Z-scores and T-scores may differ substantially and significantly in young adults.

Central dual-energy X-ray absorptiometry (DXA) is the gold standard for non-invasive measurement of bone mineral density (BMD). Using this value and subject demographics, DXA software calculates T-scores and Z-scores. Professional society guidelines for the management of osteoporosis are based on T-scores and Z-scores, rather than on the actual BMD value. Although one expects T-scores and Z-scores to be very similar in young men and women for any given BMD measurement, little literature exists on this issue. Our clinical experience shows that some younger adult individuals (premenopausal women and men younger than 50 yr) have larger than expected difference between their DXA T-score and Z-score. This cross-sectional study evaluates the extent of this discordance between Z-scores and T-scores in a sample of 4275 men and women aged 20-49 yr. All subjects were scanned by central DXA using equipment manufactured by GE Lunar, GE, Madison, WI, or Hologic, Inc., Bedford, MA. Significant differences between Z-scores and T-scores were seen within individuals at the lumbar spine, total hip, femoral neck, and trochanter (p value<0.001) for both DXA systems. Although these differences were less than half a standard deviation (SD) in most instances, the magnitude of difference was substantial at times, being 1 or more SD in up to 11% of cases (range: -1.95 to +1.54 SD). The smallest differences were seen at the total hip and the largest differences were seen at the femoral neck for both technologies. This is in part because there is no single standard Z-score definition, resulting in different methods of calculation across, and even within, DXA manufacturers. Standardization of Z-score definition and method of calculation is indicated. DXA Z-scores should be interpreted with caution in men and women aged 20-50 yr.

Update on therapy for osteoporosis.

Recent advances in understanding skeletal metabolism has expanded the pharmacological options for treating osteoporosis in women. The antiresorptive or anticatabolic drugs are the oldest class known for their positive benefits in therapy. A better appreciation of their mode of action reveals much broader effects than formerly realized. It provides an entrée into understanding the actions of drugs on the qualitative elements of bone in addition to the quantitative ones on density. New bisphosphonates make for better patient adherence to therapy, a continuing problem in long-term care. A new class of drugs called anabolic agents, typified by teriparatide usher, has the potential to reconstitute destroyed bone and bring it to its pristine state. This article briefly focuses on where we were in this arena a mere decade ago and then highlights the new elements in therapy and physiology of the skeleton. A brief exposé on osteoporosis in men is also provided.

Secondary osteoporosis: are we recognizing it?

BACKGROUND: As a growing percentage of Americans will be reaching their elderly years in the next decade, the prevalence of osteoporosis and its effects will have an even greater impact on the healthcare system. Advancements in bone research and development of newer treatments have allowed for the establishment of more refined guidelines and a growing awareness of the need to prevent, screen, and diagnose osteoporosis. Thus, more women are now being screened with dual x-ray absorptiometry scans (DXA) than ever before. The importance of a true understanding of the test results obtained from such screening is paramount. In our institution, recommendations to consider a secondary evaluation are made by the DXA interpreters when the Z-score is low. Few, if any, studies have evaluated the rates of physician and patient adherence with specific recommendations provided on the bone density report. METHODS: To assess compliance with such recommendations provided in DXA interpretations, we investigated the number of ordering providers who actually pursued these advisements. RESULTS: We found that among providers ordering DXAs, primary care providers did not pursue recommendations to pursue a secondary workup as often as their subspecialty counterparts. We also found a significant amount of vitamin D deficiency/insufficiency and primary hyperparathyroidism in the population evaluated. CONCLUSIONS: Primary care providers should be further educated on treatable secondary causes of osteoporosis as opposed to an often reflexive response of prescribing a pharmacological antiresportive agent without other consideration.

Diagnosing primary osteoporosis: it's more than a T score.

Although densitometry has contributed immensely to detecting primary osteoporosis, it is only a tool that generates some useful numbers to guide diagnosis. The T score, a leading diagnostic marker for primary osteoporosis, must be put in its proper context. It is but one measurement that is quite useful in one cohort of patients, namely, postmenopausal women older than 60, but it can be misleading in others. The z score is a more descriptive measurement of bone loss in younger patients. However, both the T score and z score are limited in their diagnostic potential and must be incorporated with other diagnostic aspects, such as family history, laboratory results, and genetic influences. In the end, physicians diagnose osteoporosis, not densitometry.

Replacement of daily load attenuates but does not prevent changes to the musculoskeletal system during bed rest.

The dose-response effects of exercise in reduced gravity on musculoskeletal health have not been well documented. It is not known whether or not individualized exercise prescriptions can be effective in preventing the substantial loss in bone mineral density and muscle function that have been observed in space flight and in bed rest. In this study, typical daily loads to the lower extremities were quantified in free-living subjects who were then randomly assigned to control or exercise groups. Subjects were confined to 6-degree head-down bed rest for 84 days. The exercise group performed individually prescribed 1 g loaded locomotor exercise to replace their free-living daily load. Eleven subjects (5 exercise, 6 control) completed the protocol. Volumetric bone mineral density results from quantitative computed tomography demonstrated that control subjects lost significant amounts of bone in the intertrochanteric and total hip regions (p < 0.0125), whereas the exercise group showed no significant change from baseline in any region (p > 0.0125). Pre-and post-bed rest muscle volumes were calculated from analysis of magnetic resonance imaging data. The exercise group retained a larger percentage of their total quadriceps and gastrocnemius muscle volume (- 7.2% ± 5.9, - 13.8% ± 6.1, respectively) than their control counterparts (- 23.3% ± 5.9, - 33.0 ± 8.2, respectively; p < 0.01). Both groups significantly lost strength in several measured activities (p < 0.05). The declines in peak torque during repeated exertions of knee flexion and knee extension were significantly less in the exercise group than in the control group (p < 0.05) but work done was not significantly different between groups (p > 0.05). The decline in VO2max was 17% ± 18 in exercising subjects (p < 0.05) and 31% ± 13 in control subjects (p = 0.003; difference between groups was not significant p = 0.26). Changes in blood and urine measures showed trends but no significant differences between groups (p > 0.05). In summary, the decline in a number of important measures of musculoskeletal and cardiovascular health was attenuated but not eliminated by a subject-specific program of locomotor exercise designed to replace daily load accumulated during free living. We conclude that single daily bouts of exposure to locomotor exercise can play a role in a countermeasures program during bed rest, and perhaps space flight, but are not sufficient in their own right to ensure musculoskeletal or cardiovascular health.

Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis.

UNLABELLED: The relationship between early changes in biochemical markers of bone turnover and the subsequent BMD response to daily teriparatide therapy in women with postmenopausal osteoporosis was studied. Changes in five biochemical markers, obtained from a subset of women enrolled in the Fracture Prevention Trial, were examined. Early increases in the PICP and the PINP were the best predictors of BMD response to teriparatide in this analysis. INTRODUCTION: Early reductions in biochemical markers of bone turnover with antiresorptive therapy negatively correlate with subsequent increases in BMD. We undertook this analysis to determine if early changes in biochemical markers with teriparatide therapy predict subsequent increases in BMD. MATERIALS AND METHODS: In the Fracture Prevention Trial, 1637 postmenopausal women with osteoporosis were randomized to receive daily, self-administered, subcutaneous injections of placebo, teriparatide 20 microg/day, or teriparatide 40 microg/day. Serum concentrations of two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and the carboxy-terminal extension peptide of procollagen type 1 [PICP]) and urinary concentrations of two bone resorption markers (free deoxypyridinoline [DPD] and N-terminal telopeptide [NTX]) were assessed in a trial population subset (n = 520) at baseline and at 1, 3, 6, and 12 months. We also assessed serum concentrations of another bone formation marker, the amino-terminal extension peptide of procollagen type 1 (PINP), in a subset of 771 women at baseline and 3 months. Lumbar spine (LS) BMD was measured by DXA at baseline and 18 months. Femoral neck BMD was measured at baseline and 12 months. RESULTS AND CONCLUSION: Baseline bone turnover status correlated positively and significantly with BMD response. The highest correlations occurred for the LS BMD response to teriparatide 20 microg/day. Among all studied biochemical markers, increases in PICP at 1 month and PINP at 3 months correlated best with increases in LS BMD at 18 months (0.65 and 0.61, respectively; p < 0.05). The relationships between these two biochemical markers and the LS BMD response were stronger than the corresponding relationships for the femoral neck BMD response. Using receiver operator curve analysis, we determined that the increases in PICP at 1 month and PINP at 3 months were the most sensitive and accurate predictors of the LS BMD response.

Systemic effects of fluticasone nasal spray: report of 2 cases.

OBJECTIVE: To describe two clinical cases of systemic side effects from use of fluticasone nasal spray. METHODS: A retrospective review of medical records of two patients using this drug was undertaken, and their clinical presentations and laboratory data are summarized. RESULTS: Despite many clinical reports about the potential side effects from inhaled corticosteroids, no previously published clinical reports or studies have addressed such problems with the use of potent glucocorticoid nasal sprays. Two patients are described in whom different clinical problems developed after overuse of fluticasone nasal spray, a commonly advertised and prescribed drug. One patient was admitted to the hospital with symptoms of adrenal insufficiency. In the other patient, bone mineral density decreased substantially in 1 to 2 years despite preventive estrogen therapy. These patients had suppressed plasma or urinary cortisol, a low plasma adrenocorticotropic hormone (corticotropin) level, or an abnormal response to a cosyntropin stimulation test. CONCLUSION: Patients should be clearly warned that the prescribed dosing for fluticasone nasal spray should be carefully followed because overuse may cause serious side effects.

Exercise and pharmacological countermeasures for bone loss during long-duration space flight.

Bone loss in the lower extremities and lumbar spine is an established consequence of long-duration human space flight. Astronauts typically lose as much bone mass in the proximal femur in 1 month as postmenopausal women on Earth lose in 1 year. Pharmacological interventions have not been routinely used in space, and countermeasure programs have depended solely upon exercise. However, it is clear that the osteogenic stimulus from exercise has been inadequate to maintain bone mass, due to insufficient load or duration. Attention has therefore been focused on several pharmacological interventions that have been successful in preventing or attenuating osteoporosis on Earth. Anti-resorptives are the class of drugs most commonly used to treat osteoporosis in postmenopausal women, notably alendronate sodium, risedronate sodium, zoledronic acid, and selective estrogen receptor modulators, such as raloxifene. There has also been considerable recent interest in anabolic agents such as parathyroid hormone (PTH) and teriparatide (rhPTH [1-34]). Vitamin D and calcium supplementation have also been used. Recent studies of kindreds with abnormally high bone mineral density have provided insight into the genetic regulation of bone mass. This has led to potential therapeutic interventions based on the LRP5, Wnt and BMP2 pathways. Another target is the RANK-L/osteoprotegerin signaling pathway, which influences bone turnover by regulating osteoclast formation and maturation. Trials using such therapies in space are being planned. Among the factors to be considered are dose-response relationships, bone quality, post-use recovery, and combination therapies--all of which may have unique characteristics when the drugs are used in space.

Challenges of Estimating Fracture Risk with DXA: Changing Concepts About Bone Strength and Bone Density.

INTRODUCTION: Bone loss due to weightlessness is a significant concern for astronauts' mission safety and health upon return to Earth. This problem is monitored with bone densitometry (DXA), the clinical tool used to assess skeletal strength. DXA has served clinicians well in assessing fracture risk and has been particularly useful in diagnosing osteoporosis in the elderly postmenopausal population for which it was originally developed. Over the past 1-2 decades, however, paradoxical and contradictory findings have emerged when this technology was widely employed in caring for diverse populations unlike those for which it was developed. Although DXA was originally considered the surrogate marker for bone strength, it is now considered one part of a constellation of factors-described collectively as bone quality-that makes bone strong and resists fracturing, independent of bone density. These characteristics are beyond the capability of routine DXA to identify, and as a result, DXA can be a poor prognosticator of bone health in many clinical scenarios. New clinical tools are emerging to make measurement of bone strength more accurate. This article reviews the historical timeline of bone density measurement (dual X-ray absorptiometry), expands upon the clinical observations that modified the relationship of DXA and bone strength, discusses some of the new clinical tools to predict fracture risk, and highlights the challenges DXA poses in the assessment of fracture risk in astronauts.