Use of DXA-based technology for detection and assessment of risk of vertebral fracture in rheumatology practice.

Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) is the recommended method for diagnosis of osteoporosis and assessment of future fracture risk. However, most patients who will suffer fractures do not have osteoporosis by DXA (T-score of -2.5 or less). Bone strength, which is most closely associated with resistance to fracture, is a composite of both bone density and bone quality, and the latter is not measured by DXA. Thus, other technology is needed for non-invasive and inexpensive assessment of bone strength and fracture risk. Vertebral fractures, the most common clinical fracture in the general population, are of even greater importance in rheumatoid arthritis and other rheumatic disorders. Vertebral fracture assessment (VFA) and trabecular bone scores (TBS), two techniques which can aid prediction of future fracture risk, can be used with currently available DXA machines. Description of these techniques and their potential application to clinical rheumatology practice will be the focus of this paper.

Oral calcitonin.

Both injectable and nasal spray calcitonins have been utilized in the treatment of postmenopausal osteoporosis for over 25 years. More widespread use of calcitonin in the treatment of osteoporosis has been hampered in part due to poor patient acceptability and compliance and the inability of patients to take this medication as an oral pill. In recent years, an oral preparation of calcitonin has been developed that combines the active peptide hormone with a caprylic acid derivative to enhance bioavailability. Clinical trials with oral calcitonin in patients with osteoarthritis are currently being conducted. A recent phase 3 study failed to demonstrate significant vertebral fracture reduction, and as a result the clinical program for oral calcitonin in osteoporosis is under review for further consideration.

Osteoporosis update from the 2010 santa fe bone symposium.

The 11th Santa Fe Bone Symposium was held in Santa Fe, NM, USA, on August 6-7, 2010. This annual event addresses clinically relevant advances in the fields of osteoporosis and metabolic bone disease. The venue includes plenary presentations by internationally recognized experts, oral presentations of abstracts, and interactive panel discussions of challenging cases and controversial issues. Attendees are active participants throughout the symposium program. Topics for the 2010 symposium included potential applications of novel technologies for the assessment of skeletal health for research and clinical practice; new and emerging treatments for osteoporosis; appropriate use of pharmacological agents to prevent osteoporosis; controversies with bisphosphonate therapy; practical applications of the World Health Organization fracture risk assessment tool (FRAX; World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK); insights into the use of osteoanabolic agents to enhance fracture healing; and challenges in laboratory testing in the assessment of factors contributing to skeletal fragility. Concurrent sessions focused on critical thinking for technologists in the acquisition and analysis of data with dual-energy X-ray absorptiometry. The key messages from each presentation, including the best available medical evidence and potential current and future clinical applications, are provided here.

Intravenous zoledronic acid: what are the indications for male osteoporosis?

Osteoporosis and fractures are under-recognized and undertreated, both in men and women worldwide. Male osteoporosis is not the epidemic problem that female osteoporosis is; however, the National Osteoporosis Foundation estimates that over 14 million American men have osteoporosis or low bone mass, and approximately 25% to 30% of all hip fractures occur in male individuals who incur greater morbidity and mortality than their female counterparts. Until recently, alendronate, risedronate, and teriparatide were the only pharmacologic agents approved by the US Food and Drug Administration for treating male osteoporosis. In December 2008, zoledronic acid was approved for "treatment to increase bone mass in men with osteoporosis." In 2009, zoledronic acid was also approved for "treatment and prevention of glucocorticoid-induced osteoporosis in patients (both men and women) expected to be on glucocorticoids for at least 12 months."

Osteomalacia.

The finding of low bone mineral density with a T-score of -2.5 or below on dual energy x-ray absorptiometry is usually reported as indicating that the patient has "osteoporosis" according to the World Health Organization classification, and, in postmenopausal women, it is often assumed that this is due to estrogen deficiency. However, up to one third of postmenopausal women have a secondary cause of low density, including osteomalacia. Osteomalacia is defined as a mineralization defect caused by disorders that lead to decreased mineralization of bone. Clues from the history, physical examination, laboratory tests, and radiographs may indicate that the patient suffers from a form of osteomalacia rather than postmenopausal estrogen deficiency alone. Establishing a diagnosis of osteomalacia when present is critical to proper management of the patient.

Proceedings of the Eighth Annual Santa Fe Bone Symposium, August 3-4, 2007.

The Eighth Annual Santa Fe Bone Symposium convened August 3-4, 2007, in Santa Fe, New Mexico, USA, immediately preceded by the Research Symposium in Metabolic Bone Disease and Osteoporosis Update for Endocrine Fellows, and followed by the International Society for Clinical Densitometry (ISCD) Bone Densitometry Course. The symposium faculty consists of internationally recognized experts in osteoporosis and metabolic bone disease who presented state-of-the-art research data and late-breaking developments in the fields of osteoporosis, metabolic bone disease, and assessment of skeletal health. The presentations and numerous interactive discussions that followed focused on applying what is known from clinical trials, knowledge of bone pathophysiology, and the mechanisms of action of therapeutic interventions, to making real-world patient management decisions. Topics included an update on reimbursement issues for bone density testing in the United States, a report on the 2007 ISCD Pediatric and Adult Position Development Conferences, present and future therapeutic concepts, new paradigms for fracture risk assessment and intervention thresholds, evaluation for secondary causes of osteoporosis, nonvertebral fracture risk reduction-medical evidence and clinical practice, epidemiological insights into the prevention of osteoporotic fractures, osteonecrosis of the jaw facts and fictions, and osteomalacia. Presented here are short essays based on the key clinical presentations of the 2007 Santa Fe Bone Symposium.

Dual-Energy X-Ray Absorptiometry Technical issues: the 2007 ISCD Official Positions.

At the 2007 Position Development Conference, the Dual-Energy X-ray Absorptiometry Technical Task Force investigated three major areas of bone density testing. Although bone mineral density (BMD) testing in men had previously been reviewed at the 2005 Position Development Conference, we reviewed the most recent data in men to develop appropriate indications for bone density testing in men. We continue to recommend screening at age 70 and discuss the clinical risk factors that may be an appropriate indication for earlier BMD testing. Menopausal transition (perimenopause) was considered an important time to consider BMD evaluation because bone loss may be significant prior to menopause. However, because fracture risk is inherently low in women of this age without other risk factors, screening BMD testing is not appropriate. We discuss the risk factors that are strong indicators of fracture risk that may be increased during the menopause transition. The presence of these risk factors are appropriate indications for BMD testing with applicability of WHO diagnostic categorization. The issue of establishing a high threshold for BMD was investigated thoroughly and the current literature was reviewed. Despite the fact there is agreement that all BMD values greater than T-score -1.0 are not normal, it was felt that because of the paucity of sensitivity data and confounding factors such as high body mass index, an upper threshold could not be established or recommended at this time. This was felt to be an important area for further research.

Recent developments in bisphosphonate therapy.

OBJECTIVE: To provide a review of current developments in bisphosphonates indicated for the treatment of several rheumatologic conditions, including postmenopausal and glucocorticoid-induced osteoporosis. METHODS: This review summarizes the pathology, diagnosis, and treatment of both postmenopausal and glucocorticoid-induced osteoporosis and examines the results of current clinical trials of the newest oral and intravenous formulations of nitrogen-containing bisphosphonates. We discuss important adverse events, including upper gastrointestinal symptoms and osteonecrosis of the jaw. Additionally, we explore methods that may improve patient adherence to bisphosphonate therapy, which is currently suboptimal. RESULTS: Clinical studies have shown that oral bisphosphonates are efficacious in increasing bone mineral density and reducing risk of fracture. Despite concerns of upper gastrointestinal irritation, most of the newer oral bisphosphonates display a safety profile similar to placebo. Many of the newest formulations offer patients a choice in both dosing frequency and method of administration (either oral or intravenous). CONCLUSIONS: Nitrogen-containing bisphosphonates are important therapeutic options for the prevention and treatment of osteoporosis.

Fracture risk among breast cancer survivors: results from the Women's Health Initiative Observational Study.

BACKGROUND: Breast cancer and its treatment may compromise bone health. We tested the hypothesis in the Women's Health Initiative Observational Study that postmenopausal survivors of breast cancer have a higher risk for fractures compared with women who have no cancer history. METHODS: A prospective cohort (5.1 years' follow-up) study design was used. Breast cancer survivors were women who reported a history of breast cancer (n = 5298). A reference group included women who had no cancer history at baseline (n = 80 848). Fracture occurrence was ascertained from annual self-reports. Hip fractures were confirmed by reviewing medical records. RESULTS: After adjustment for age, weight, ethnicity, and geographic region of enrollment, the hazard ratios (HRs) of breast cancer survivors to women in the reference group were 0.93 (95% confidence interval [CI], 0.64-1.33) for hip; 1.36 (95% CI, 1.16-1.59) for forearm or wrist; 1.31 (95% CI, 1.19-1.43) for eligible fractures other than hip, vertebral, and forearm or wrist; and 1.31 (95% CI, 1.21-1.41) for these fractures combined. The increased risk for clinical vertebral fracture was statistically significant only among survivors who had a breast cancer diagnosis before age 55 years (HR, 1.78; 95% CI, 1.28-2.46). After adjusting for factors related to hormone levels, risk of fall, fracture history, medication use, comorbidity, and lifestyle, the increased risk for all fractures studied among survivors was reduced to 15% (HR, 1.15; 95% CI, 1.05-1.25). CONCLUSIONS: Postmenopausal survivors of breast cancer are at increased risk for clinical fractures. Preventions and therapeutic interventions are needed to reduce fracture risk in this large and growing population.

Clinical use of serum and urine bone markers in the management of osteoporosis.

Osteoporosis is a common disease characterized by decreased bone mass, increased bone turnover, and increased susceptibility to fracture. Almost 44 million Americans are estimated to have low bone mass, which puts them at increased risk of developing osteoporosis and fractures. Osteoporosis is diagnosed by a low bone density (BMD) measurement, because a low BMD is known to contribute to increased fracture risk, which is the main source of morbidity and mortality for osteoporosis. However, changes in bone mass and density in response to anti-resorptive therapy account for only a small portion of the predicted fracture risk reduction. Whereas dynamic changes in bone turnover, estimated by measurement of bone biochemical markers, such as breakdown products of type-I collagen and proteins secreted by osteoblasts and osteoclasts in blood and urine, can account for a major portion of anti-fracture efficacy of anti-resorptive agents. Most anti-resorptive agents act by rapidly reducing bone markers. This has led to advocacy for use of bone turnover markers, in complement to BMD measurement, in the management of osteoporosis. In general, higher bone turnover is associated with accelerated bone loss and potential deterioration in bone quality. Several clinical trials have established the potential utility of markers to identify patients with rapid bone loss, to aid in therapeutic decision-making, and to monitor therapeutic efficacy of various treatments. Elevated marker levels have been shown to be associated with increased risk of fracture in elderly women, but their utility in predicting fracture is not yet established. In this article, we provide a brief summary to primary practitioners about the role bone markers can play in the management of osteoporosis.

Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis.

BACKGROUND: Raloxifene hydrochloride therapy reduces the risk for vertebral fractures at 3 years, but the effects on clinical vertebral fractures in the first year are not known. METHODS: The Multiple Outcomes of Raloxifene Evaluation (MORE) Trial enrolled 7705 women with osteoporosis, defined by prevalent vertebral fractures and/or a bone mineral density (BMD) T score at or below -2.5, who were treated with placebo or raloxifene at a dosage of 60 or 120 mg/d for 3 years. New clinical vertebral fractures were defined as incident vertebral fractures associated with signs and symptoms suggestive of vertebral fractures, such as back pain, and were diagnosed by means of postbaseline adjudicated spinal radiographs. Scheduled spinal radiographs were obtained at baseline and at 2 and 3 years. In addition, unscheduled spinal radiographs were obtained in women who reported signs or symptoms suggestive of vertebral fracture, and these radiographs subsequently underwent adjudication. If an adjudicated fracture was identified, this was also considered a clinical fracture. RESULTS: At 1 year, raloxifene, 60 mg/d, decreased the risk for new clinical vertebral fractures by 68% (95% confidence interval [CI], 20%-87%) compared with placebo in the overall study population, and by 66% (95% CI, 23%-89%) in women with prevalent vertebral fractures, who are at greater risk for subsequent fracture. The risk for clinical vertebral fractures in the raloxifene, 60 mg/d, group was decreased by 46% (95% CI, 14%-66%) at 2 years and by 41% (95% CI, 17%-59%) at 3 years. The cumulative incidence of new clinical vertebral fractures was lower in the group receiving raloxifene, 60 mg/d, compared with placebo (P<.001). We found no significant differences in the risk reductions for clinical vertebral fractures between the raloxifene groups at 1, 2, or 3 years. CONCLUSION: The early risk reduction for new clinical vertebral fractures with 1 year of raloxifene treatment was similar to that reported with other antiresorptive agents.

Review of raloxifene and its clinical applications in osteoporosis.

Raloxifene, a selective oestrogen receptor modulator, is currently utilised for both the prevention and treatment of postmenopausal osteoporosis. Prevention studies with raloxifene have demonstrated preservation of bone density, suppression of markers of bone turnover and maintenance of normal bone histology for up to 4 years in young postmenopausal women. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial, the pivotal treatment trial of raloxifene, demonstrated significant reductions in the risk of vertebral fractures after 1 and 3 years, which is comparable to other currently available agents. Significant reductions in non-vertebral fractures with raloxifene have not been demonstrated yet. In addition to the effects of raloxifene on bone, a number of beneficial non-skeletal effects have been reported on the breast, uterus and cardiovascular system. These latter findings are mainly derived from secondary end points and analyses of the large osteoporosis studies with raloxifene. Two large, prospective, randomised, double-blind studies examining the effects of raloxifene on breast cancer prevention and cardiovascular protection are now underway. Recent information on the effects of raloxifene in postmenopausal osteoporosis, breast cancer prevention and cardiovascular disease in high-risk women and those with uterine disorders is reviewed in this article.

Densitometry in glucocorticoid-induced osteoporosis.

Bone density measurement is a critical tool in the management of glucocorticoid-induced osteoporosis (GIOP). This review addresses the utility of various measurement devices (dual-energy X-ray absorptiometry [DXA], quantitative ultrasound [QUS], quantitative CAT scanning [QCT]), their role in monitoring changes in bone mineral density (BMD), and the relationship of BMD and fracture risk in GIOP. A higher BMD threshold should be utilized for estimating fracture risk in patients on glucocorticoids.

Position statements of the International Society for Clinical Densitometry: methodology.

Given the need for authoritative positions in areas of controversy in the field of bone densitometry, the International Society for Clinical Densitometry (ISCD) convened a Position Development Conference in Denver, CO, USA, in July 2001. Four general areas were selected on the basis of clinical importance and likelihood of reaching agreement. These areas were discussed at length prior to the conference by the Scientific Advisory Committee of the ISCD and presented to a panel of experts at the conference. The four areas included discussions of (1). the regions of interest of central dual X-ray densitometry (DXA), (2). the criteria by which a densitometric diagnosis of osteoporosis can be made in men and non-Caucasian women, (3). the role of serial BMD measurements in patient management, and (4). the standards by which bone mass measurements at peripheral sites should be used in the diagnosis of osteoporosis. Details of the methodology used at the conference are discussed. The following papers explain the results of the discussions and describe the official ISCD positions.

Twice daily versus once nightly dosing of pregabalin for fibromyalgia: a double-blind randomized clinical trial of efficacy and safety.

OBJECTIVE: To compare the efficacy, discontinuation rates, and safety of once nightly versus twice daily dosing of pregabalin in a community-based trial. METHODS: This multicenter, double-blind, 8-week randomized clinical trial compared the effects of 300-mg daily doses of pregabalin given either twice daily or once nightly for the treatment of fibromyalgia in 177 patients. The primary outcome was the comparison of end point mean pain scores derived from a daily diary. RESULTS: Both twice daily (88 patients randomized) and once nightly (89 patients) pregabalin significantly reduced the average severity of pain experienced by patients (P < 0.001 for both). Treatment-emergent adverse events were reported by significantly more patients in the twice daily group than those in the once nightly group (P = 0.023). There were no significant differences between the groups for the frequencies of individual adverse events (P > 0.05 for all). There was no significant difference in adverse events or efficacy in patients taking both pregabalin and a selective serotonin and norepinephrine reuptake inhibitor or selective serotonin uptake inhibitor. CONCLUSION: While a nightly dosing schedule of pregabalin has been used by clinicians hoping to improve treatment, this study showed no significant difference (either beneficial or detrimental) between either treatment option. While there was a decrease in total patient-reported adverse events in the once nightly arm, the lack of specificity in relation to a particular adverse event suggested no real difference in adverse events.

Assessing the Effects of Teriparatide Treatment on Bone Mineral Density, Bone Microarchitecture, and Bone Strength.

BACKGROUND: To gain insight into how teriparatide affects various bone health parameters, we assessed the effects of teriparatide treatment with use of standard DXA (dual x-ray absorptiometry) technology and two newer technologies, high-resolution MRI (magnetic resonance imaging) and finite element analysis of quantitative CT (computed tomography) scans. METHODS: In this phase-4, open-label study, postmenopausal women with severe osteoporosis received 20 µg/day of teriparatide. Assessments included (1) changes in areal BMD (bone mineral density) (in g/cm2) at the radius, spine, and hip on DXA, (2) changes in volumetric BMD (in mg/cm3) at the spine and hip on quantitative CT scans, (3) changes in bone microarchitecture at the radius on high-resolution MRI, (4) estimated changes in spine and hip strength according to finite element analysis of quantitative CT scans, (5) changes in bone turnover markers in serum, and (6) safety. RESULTS: Thirty-five subjects were enrolled; thirty completed eighteen months and twenty-five completed an optional six-month extension. No significant changes were observed for the primary outcome, high-resolution MRI at the distal aspect of the radius. At month eighteen, the least-squares mean percentage change from baseline in total volumetric BMD at the spine was 10.05% (95% confidence interval [CI], 6.83% to 13.26%; p < 0.001), and estimated spine strength increased 17.43% (95% CI, 12.09% to 22.76%; p < 0.001). Total volumetric BMD at the hip increased 2.22% (95% CI, 0.37% to 4.06%; p = 0.021), and estimated hip strength increased 2.54% (95% CI, 0.06% to 5.01%; p = 0.045). Areal BMD increased at the lumbar spine and femoral neck, was unchanged for the total hip and at the distalmost aspect of the radius, and decreased at a point one-third of the distance between the wrist and elbow. Bone turnover markers increased at months three, six, and twenty-four (all p < 0.05). No unexpected adverse events were observed. CONCLUSIONS: High-resolution MRI failed to identify changes in bone microarchitecture at the distal aspect of the radius, a non-weight-bearing site that may not be suitable for assessing effects of an osteoanabolic agent. Teriparatide increased areal BMD at the spine and femoral neck and volumetric BMD at the spine and hip. Estimated vertebral and femoral strength also increased. These findings and increases in bone turnover markers through month twenty-four are consistent with the known osteoanabolic effect of teriparatide. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Update on glucocorticoid-induced osteoporosis.

Glucocorticoid-induced osteoporosis (GIOP) is the most common form of secondary osteoporosis, and fractures are the most frequent adverse effects of this medication. Glucocorticoids have several direct and indirect adverse effects on bone, primarily through reduction in osteoblasts and osteocyte activity, and life span. Recent advances in the pathophysiology and prevention of this complication of therapy provide hope for its amelioration in patients being treated with glucocorticoids. Several effective pharmacologic agents are now available, and guidelines for the prevention and treatment of GIOP have been published. Despite these advances, many patients still do not receive proper prevention or therapy.