Advances in the evaluation of bone health in kidney transplant patients. / Avances en la valoración de la salud ósea en el trasplantado renal.

Bone disease related to chronic kidney disease and, particularly, to kidney transplant patients is a common cause or morbidity and mortality, especially due to a higher risk of osteoporotic fractures. Despite the fact that this has been known for decades, to date, an appropriate diagnostic strategy has yet to be established. Apart from bone biopsy, which is invasive and scarcely used, no other technique is available to accurately establish the risk of fracture in kidney patients. Techniques applied to the general population, such as bone densitometry, have not been subjected to sufficient external validation and their use is not systematic. This means that the identification of patients at risk of fracture and therefore those who are candidates for preventive strategies is an unmet need. Bone strength, defined as the ability of the bone to resist fracture, is determined by bone mineral density (measured by bone densitometry), trabecular architecture and bone tissue quality. The trabecular bone score estimates bone microarchitecture, and low values have been described as an independent predictor of increased fracture risk. Bone microindentation is a minimally invasive technique that measures resistance of the bone to micro-cracks (microscopic separation of mineralised collagen fibres), and therefore bone tissue biomechanical properties. The superiority over bone densitometry of the correlation between the parameters measured by trabecular bone score and microindentation with the risk of fracture in diverse populations led us to test its feasibility in chronic kidney disease and kidney transplant patients.

Is Prophylactic Intervention More Cost-effective Than the Treatment of Pathologic Fractures in Metastatic Bone Disease?

BACKGROUND: Metastatic bone disease is a substantial burden to patients and the healthcare system as a whole. Metastatic disease can be painful, is associated with decreased survival, and is emotionally traumatic to patients when they discover their disease has progressed. In the United States, more than 250,000 patients have metastatic bone disease, with an estimated annual cost of USD 12 billion. Prior studies suggest that patients who receive prophylactic fixation for impending pathologic fractures, compared with those treated for realized pathologic fractures, have decreased pain levels, faster postoperative rehabilitation, and less in-hospital morbidity. However, to our knowledge, the relative economic utility of these treatment options has not been examined. QUESTIONS/PURPOSES: We asked: (1) Is there a cost difference between a cohort of patients treated surgically for pathologic fractures compared with a cohort of patients treated prophylactically for impending pathologic lesions? (2) Do these cohorts differ in other ways regarding their utilization of healthcare resources? METHODS: We performed a retrospective study of 40 patients treated our institution. Between 2011 and 2014, we treated 46 patients surgically for metastatic lesions of long bones. Of those, 19 (48%) presented with pathologic fractures; the other 21 patients (53%) underwent surgery for impending fractures. Risk of impending fracture was determined by one surgeon based on appearance of the lesion, subjective symptoms of the patient, cortical involvement, and location of the lesion. At 1 year postoperative, four patients in each group had died. Six patients (13%) were treated for metastatic disease but were excluded from the retrospective data because of a change in medical record system and inability to obtain financial records. Variables of interest included total and direct costs per episode of care, days of hospitalization, discharge disposition, 1-year postoperative mortality, and descriptive demographic data. All costs were expressed as a cost ratio between the two cohorts, and total differences between the groups, as required per medical center regulations. All data were collected by one author and the medical center's financial office. RESULTS: Mean total cost was higher in patients with pathologic fractures (cost unit [CU], 642 ± 519) than those treated prophylactically without fractures (CU, 370 ± 171; mean difference, 272; 95% CI, 19-525; p = 0.036). In USD, this translates to a mean of nearly USD 21,000 less for prophylactic surgery. Mean direct cost was 41% higher (nearly USD 12,000) in patients with a pathologic fracture (CU, 382 ± 300 versus 227 ± 93; mean difference, 155; 95% CI, 9-300; p = 0.038). Mean length of stay was longer in patients with pathologic fractures compared with the group treated prophylactically (8 ± 6 versus 4 ± 3 days; mean difference, 4; 95% CI, 1-7; p = 0.01). CONCLUSIONS: These findings show economic and clinical value of prophylactic stabilization of metastatic lesions when performed for patients with painful lesions compromising the structural integrity of long bones. Patients sustaining a pathologic fracture may represent a more severe, sicker demographic than patients treated for impending pathologic lesions. LEVEL OF EVIDENCE: Level IV, economic and decision analysis.

Reducing Skeletal-Related Events in Metastatic Castration-Resistant Prostate Cancer.

Skeletal-related events contribute substantially to morbidity, mortality and cost in men with metastatic castration-resistant prostate cancer (mCRPC). There are five agents available for treatment in mCRPC that reduce skeletal-related events. Here we discuss the efficacy and safety of zoledronic acid, denosumab, enzalutamide, abiraterone, and radium-223. We include data on and a discussion of duration of treatment with zoledronic acid and denosumab, the only two of these agents that do not have a clinically proven anticancer effect. Finally, we review the available data regarding the cost of denosumab compared with that of zoledronic acid.

Burden of skeletal-related events in prostate cancer: unmet need in pain improvement.

PURPOSE: Up to 75% of patients with prostate cancer experience metastatic bone disease, which leads to an increased risk for skeletal-related events (SREs) including pathological bone fracture, spinal cord compression, and hypercalcemia of malignancy. Our objective was to systematically review the literature on the impact of SREs on quality of life (QOL), morbidity, and survival with a primary focus on the impact of SREs on pain in prostate cancer patients. METHODS: We searched PubMed, limiting to peer-reviewed English-language human studies published in 2000-2010. The search was based on the US Food and Drug Administration and European Medicines Agency definition of an SRE, which includes pathologic fracture, spinal cord compression (SCC), hypercalcemia of malignancy, and radiotherapy or surgery to bone resulting from severe bone pain. RESULTS: A total of 209 articles were screened, of which 173 were excluded, and 36 were included in this review. Patients with SREs had more pain and worse survival compared with no SREs. Pathologic bone fractures worsened QOL and were associated with shorter survival. Radiation therapy of SCC alleviated pain and improved morbidity. SCC was associated with decreases in patient survival. Radiation therapy and surgery to bone improved pain. CONCLUSIONS: Specific SREs are associated with worse outcomes, including increased pain, poorer QOL, morbidity, and survival. Treatment of SREs is associated with improved pain, although there remains a need for more effective treatment of SREs in prostate cancer patients.

[Criteria for initiation of pharmacological treatment by Japanese 2011 guidelines for prevention and treatment of osteoporosis].

The goals of osteoporosis treatment are prevention of fracture. If the patients with higher risk of fragility fractures are treated, the larger effect on reduction of the risk of fragility fractures is expected. Criteria for initiating pharmacological treatment in U.S.A or Europe are based on cost-effectiveness. In Japan, the criteria for initiating pharmacological treatment to prevent fragility fracture were established in the revised version of 2011 guidelines for prevention and treatment of osteoporosis. In these criteria, postmenopausal women and men age 50 and older with vertebral fracture are considered for treatment regardless of bone density. FRAX® was newly introduced to consider whether or not to initiate pharmacological treatment in persons without a fragility fracture who have a low bone mass.

Metastatic bone disease in the era of bone-targeted therapy: clinical impact.

Advances in the diagnosis and treatment of tumors by surgery, chemotherapy, biotherapy, radiotherapy and other modalities have increased the survival of cancer patients over the last 20 years. As a consequence, bone now represents the third most common site of metastatic involvement after the lung and liver. Approximately 20-25% of patients with neoplastic disease develop clinically evident bone metastases (BMs) during the natural course of their illness, with a further 50% of such lesions being identified during autopsy. BMs are the major cause of morbidity in cancer patients because of their epidemiological and clinical impact. Pain is the most frequent symptom in about 75% of patients but other serious complications can also occur, such as pathological fractures, spinal cord compression, hypercalcemia and bone marrow suppression. These complications worsen the patient's general condition and reduce patients' mobility, facilitating the development of lung infections, skin ulcers, deep vein thrombosis, etc., and ultimately reducing prognosis and quality of life. The frequency of serious complications depends on the site and type of lesions and the treatment administered. Over the last 10 years, the introduction of bisphosphonates for the treatment of patients with BMs has led to a marked decrease in the frequency of complications, thus improving quality of life and clinical outcome. Furthermore, progress in understanding the pathophysiology of bone metastases has resulted in the development of new bone-targeted molecules such as denosumab. We therefore felt it would be useful to report on the epidemiological, clinical and economic impact of bone disease in a cancer setting.

Duration of treatment for osteoporosis.

Many treatments for postmenopausal osteoporosis with proven efficacy in lowering fracture risk had become available since many years now. In the last few years the issue about treatment duration has become a matter of importance. In this paper the pivotal trials for alendronate, risedronate, zoledronate and other anti reabsorptive drugs such as denosumab are revised with particular attention to the extension studies aimed to verify the effect of drug discontinuation. The results of the review highlight differences among the available drugs and the practical clinical consequences also in terms of cost-effectiveness.

[Assessment of a set of FRAX(®)-based criteria for the indication of bone densitometry in Spanish postmenopausal women]. / Evaluación de una propuesta de criterios de indicación de densitometría ósea en mujeres posmenopáusicas españolas basados en la herramienta FRAX(®)

BACKGROUND AND OBJECTIVE: To assess the effect of the application in routine clinical practice of a proposal of thresholds for the indication of bone densitometry in Spanish postmenopausal women. PATIENTS AND METHODS: We determined the risk of major fracture (RMF) by FRAX(®) of the patients referred to a bone densitometry unit from Primary Care who were untreated. We calculated how many scans would have been avoided if they had been performed only to women ≥ 65 years with a RMF < 10% or women<65 years with a RMF ≥ 3.6%. RESULTS: We included 643 women with a mean age of 61 (9) years. Twenty-three percent had a normal bone mineral density, 56% had osteopenia, and 21% osteoporosis. The RMF was 5.9 (5.5)%. Eighty of 217 (37%) bone scans in women ≥ 65 years and 273 of 426 (64%) in women<65 years would have been avoided. As a whole, 55% of the scans would have been avoided. The sensitivity of the threshold of 3.6% of RMF for the diagnosis of osteoporosis was 51%, specificity 68%, positive predictive value 20%, and negative predictive value 20%. CONCLUSIONS: The application of the proposed thresholds for the indication of bone densitometry in Spanish postmenopausal women, based on age and risk of fracture calculated by FRAX(®) would result in a significant decrease of the activity of the bone densitometry unit.

Comparison of plain vertebral X-ray and dual-energy X-ray absorptiometry for the identification of older women for fracture prevention in primary care.

BACKGROUND: Recently, the dual-energy X-ray absorptiometry (DXA) diagnostic cut-off (T-score) for Australian Pharmaceutical Benefits Scheme (PBS) supported primary fracture prevention therapy with alendronate for older women (>70 years) has been changed from -3.0 to -2.5. AIM: To examine the impact of the expanded criteria for PBS-supported fracture prevention therapy in older women on case finding and cost. METHODS: One thousand, nine hundred and eighty-three women, median age 76 years, not previously known to have low bone mineral density by DXA or a vertebral fracture underwent DXA scanning and a thoracolumbar X-ray. A woman was considered eligible for fracture prevention therapy if she had a T-score ≤-2.5 at the femoral neck and/or the lumbar vertebrae (two to four) or at least one vertebral fracture of ≥20% deformity. RESULTS: Seven hundred and forty-six women (37.6%) met the new criteria as a case for PBS-subsidised fracture prevention therapy. Four hundred and thirty-one (21.7%) had a T-score ≤-2.5 on DXA compared with 10.6% (n = 210) with a T-score ≤-3.0. Four hundred and eighty-three (24.4%) had at least one vertebral fracture. Only 8.5% (n = 168) had both a T-score ≤-2.5 and a prevalent vertebral fracture. The cost per case found by DXA equated to $460 compared with $398 for screening by thoracolumbar X-ray. CONCLUSIONS: The use of either DXA or X-ray will identify approximately two-thirds of women aged 70 years and over who would be eligible for fracture prevention. The use of X-ray would identify a marginally larger number of women and at lower financial cost but involve substantially greater radiation exposure.

What is the role of the orthopaedic surgeon in management of fragility fractures?

Fragility fractures are the most prevalent trauma condition that orthopaedic surgeons face today. Osteoporosis and susceptibility to falls are the key predisposing factors. Despite evidence supporting the impact of treating osteoporosis on reducing the incidence of fragility fractures, it is often left untreated. Orthopaedic surgeons are often the first physicians to assess and treat the patient after a fragility fracture. Their role therefore does not end in the skillful fixation of the fractures, but they have a unique opportunity to ensure that preventive measures are implemented. This includes falls prevention, investigation of possible causes underlying osteoporosis, attention to diet, exercise, calcium, and vitamin D supplementation as well as prescription of anti-resorptive and anabolic medication. The need for a dedicated multidisciplinary team needs to be emphasized and therefore effective communication between the different parties is of paramount importance.

[Assessment of hip fracture risk related to the structure].

Bone strength is determined not only by BMD, but also by many other bone quality relating factors such as bone structure etc.. Hip fractures are the most serious fragile fractures, considering that controlling their risk factors will successfully prevent these fractures. Recently Hip structure (strength) analyses have become available during standard DXA measurements. Bending strength and stability of the bone can be determined by their obtained parameters such as section modulus, cross sectional area and buckling ratio. These parameters shift towards fragile by aging, especially remarkably reduce after 70 years. It has been reported that both anti-resorptive agents and anabolic PTH increase bone strength in different manner. Further progressed 3 dimensional femoral neck strength analysis using CT scanning are now under development.

Overcoming barriers to secondary prevention in hip fracture patients: An electronic referral and management system for osteoporosis.

BACKGROUND: Numerous studies have shown that osteoporosis is both under diagnosed and under treated in patients with fragility fractures. We describe the use of an electronic automated referral system to enable multidisciplinary assessment and treatment of osteoporosis in patients admitted with fragility fracture of the hip. METHODS: An electronic referral system was developed from the hospital's trauma software database. This automatically refers patients admitted with fragility fracture of the hip to osteoporosis services. Data were collected prospectively from May to July 2007, when referral was dependent on members of the orthopaedic team and from August to October 2007, after the implementation of the electronic referral system. Primary outcomes were presence of a referral to osteoporosis services, organisation of bone density scan and follow up appointment in patients less than 75 years, and treatment with osteoporosis medication in patients greater than 75 years of age. RESULTS: There were a total of 90 patients, 47 in the non-intervention group and 43 in the intervention group. In the non-intervention group 8/47 patients (17%) were referred to osteoporosis services whilst 43/43 (100%) were referred in the intervention group. Of patients greater than 75 years, 10/32 (31.3%) were started on a bisphosphonate in the non-intervention group compared to 28/34 (82.4%) in the intervention group. Of patients less than 75 years, 1/15 (7%) in the non-intervention group had a DEXA scan booked and appropriate follow up arranged, compared to 7/9 (78%) in the intervention group. There was significant difference between both groups in all outcomes (p<0.0001). CONCLUSION: We present an electronic system which facilitates delivery of osteoporosis services and significantly improves management of osteoporosis in patients admitted with fragility fracture. We recommend the use of such programmes to facilitate multidisciplinary assessment and treatment of osteoporosis in orthopaedic trauma patients.

Cost-effectiveness model of using zoledronic acid once a year versus current treatment strategies in postmenopausal osteoporosis.

OBJECTIVES: To compare effectiveness, associated cost of outcomes and cost-effectiveness of a single annual infusion of zoledronic acid versus current treatment strategies plans for postmenopausal osteoporosis in France. METHODS: Twelve simulation-based models were built to investigate three types of fractures: vertebral (VF), non-vertebral excluding hip (NVF) and hip (HF), comparing two groups: zoledronic acid and current postmenopausal antiosteoporotic treatment strategies. Two effectiveness comparability assumptions have been tested: specific agent efficacy values, and same standard efficacy values for all active agents. Direct medical costs included drug costs, medical visits, monitoring and fracture management. Adherence levels were integrated into the model under the assumption that non-adherent patients had treatment effects similar to the levels of placebo effectiveness. RESULTS: Using the most conservative assumption (same standard efficacy values for all active agents), zoledronic acid strategy results in less vertebral, non-vertebral and hip fractures than other current antiosteoporotic treatment options over 3 years: 12.04% vs. 14.18%, 10.61% vs. 11.28% and 2.82% vs. 4.64% respectively, (p<0.001). In addition, zoledronic acid is more cost-effective than the current treatment strategies in all types of fractures (p<0.001): 1497 euros vs. 1685 euros per VF avoided, 1337 euros vs. 1404 euros per NVF avoided and 1216 euros vs. 1323 euros per HF avoided. CONCLUSION: Zoledronic acid is a cost-effective treatment strategy regardless of fracture type or effectiveness comparability assumptions.