Quality of life in multiple myeloma: considerations and recommendations.

Introduction: Advances in the management of multiple myeloma have culminated in the availability of novel agents which have resulted in improvement in patient outcomes. Nevertheless, the disease remains largely incurable and attention to long-term toxicity and quality of life is of importance. Limited data have addressed quality-of-life consideration in myeloma and most studies have assessed a finite time period during the course of the disease. Quality-of-life measures that have been used have largely focused on symptom reporting. In general, quality of life seems to deteriorate with increasing duration of the disease and improvements are limited. Areas covered: This manuscript will review quality-of-life tools used in myeloma as well as the differential effect of various stages of the therapy. Expert opinion: In general, depth of response has been associated with improved quality-of-life and may be an important surrogate provided that therapy is well tolerated. However, this traditional approach of using the most effective therapy does not take into considerations psychologic and socioeconomic factors which can result in significant burden to the patient. A multidisciplinary team approach with a focus on shared decision-making based on the patient's goals must thus be emphasized.

Trabecular Bone Score in Patients With Chronic Glucocorticoid Therapy-Induced Osteoporosis Treated With Alendronate or Teriparatide.

OBJECTIVE: To determine the effect of alendronate (ALN) and teriparatide on trabecular bone score (TBS) in patients with glucocorticoid-induced osteoporosis. METHODS: Patients with chronic glucocorticoid therapy-induced osteoporosis (median 7.5 mg/day prednisone equivalent for ≥90 days) were randomized to receive oral ALN 10 mg/day (n = 214) or subcutaneous teriparatide 20 µg/day (n = 214) for 36 months; 118 patients in the ALN group and 123 patients in the teriparatide group completed treatment. Dual x-ray absorptiometry (DXA) results for 53 patients receiving ALN and 56 patients receiving teriparatide who had DXA scans with adequate resolution to perform TBS analysis and completed 36 months of therapy were blindly analyzed for TBS at baseline and 3, 6, 12, 18, 24, and 36 months. RESULTS: In teriparatide-treated patients, TBS was significantly increased at 18 months compared to baseline, and by 36 months had increased 3.7% (P < 0.05). In ALN-treated patients, there was not a significant change in TBS compared to baseline at any time point. Changes in lumbar spine bone mineral density (BMD) measured by DXA in the subgroup with TBS data were similar to BMD results in the overall study population. At 36 months, increases in lumbar spine BMD were 5.5% and 10.3% in patients treated with ALN and teriparatide, respectively. CONCLUSION: In patients with glucocorticoid-induced osteoporosis, both ALN and teriparatide increased lumbar spine BMD. However, trabecular bone score significantly increased with teriparatide but did not significantly change with ALN. The pathogenesis of glucocorticoid-induced osteoporosis is predominantly reduced bone formation. TBS may represent a sensitive measure to discriminate treatment effects of an anabolic versus an antiresorptive drug in glucocorticoid-induced osteoporosis.

Creation of an age-adjusted, dual-energy x-ray absorptiometry-derived trabecular bone score curve for the lumbar spine in non-Hispanic US White women.

The trabecular bone score (TBS, Med-Imaps, Pessac, France) is an index of bone microarchitecture texture extracted from anteroposterior dual-energy X-ray absorptiometry images of the spine. Previous studies have documented the ability of TBS of the spine to differentiate between women with and without fractures among age- and areal bone mineral density (aBMD)-matched controls, as well as to predict future fractures. In this cross-sectional analysis of data collected from 3 geographically dispersed facilities in the United States, we investigated age-related changes in the microarchitecture of lumbar vertebrae as assessed by TBS in a cohort of non-Hispanic US white American women. All subjects were 30 yr of age and older and had an L1-L4aBMDZ-score within ±2 SD of the population mean. Individuals were excluded if they had fractures, were on any osteoporosis treatment, or had any illness that would be expected to impact bone metabolism. All data were extracted from Prodigy dual-energy X-ray absorptiometry devices (GE-Lunar, Madison, WI). Cross-calibrations between the 3 participating centers were performed for TBS and aBMD. aBMD and TBS were evaluated for spine L1-L4 but also for all other possible vertebral combinations. To validate the cohort, a comparison between the aBMD normative data of our cohort and US non-Hispanic white Lunar data provided by the manufacturer was performed. A database of 619 non-Hispanic US white women, ages 30-90 yr, was created. aBMD normative data obtained from this cohort were not statistically different from the non-Hispanic US white Lunar normative data provided by the manufacturer (p = 0.30). This outcome thereby indirectly validates our cohort. TBS values at L1-L4 were weakly inversely correlated with body mass index (r = -0.17) and weight (r = -0.16) and not correlated with height. TBS values for all lumbar vertebral combinations decreased significantly with age. There was a linear decrease of 16.0% (-2.47 T-score) in TBS at L1-L4 between 45 and 90 yr of age (vs. -2.34 for aBMD). Microarchitectural loss rate increased after age 65 by 50% (-0.004 to -0.006). Similar results were obtained for other combinations of lumbar vertebra. TBS, an index of bone microarchitectural texture, decreases with advancing age in non-Hispanic US white women. Little change in TBS is observed between ages 30 and 45. Thereafter, a progressive decrease is observed with advancing age. The changes we observed in these American women are similar to that previously reported for a French population of white women (r(2) > 0.99). This reference database will facilitate the use of TBS to assess bone microarchitectural deterioration in clinical practice.

Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with autologous stem cell transplant in refractory cancer: pharmacokinetic and pharmacodynamic correlates.

PURPOSE: To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with chemotherapy-refractory malignancies. EXPERIMENTAL DESIGN: Patients were treated with (in mg/m(2)/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days -8 through -6 and etoposide 500 (days -5 through -3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured. RESULTS: The topotecan MTD in this regimen was 64 mg/m(2) (21.3 mg/m(2)/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose. CONCLUSION: Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy.

Do porous tantalum implants help preserve bone?: evaluation of tibial bone density surrounding tantalum tibial implants in TKA.

BACKGROUND: TKA with conventional metal-backed tibial implants subjects the tibial metaphysis to stress shielding, with resultant loss of bone density. QUESTIONS/PURPOSES: We hypothesized tibial bone mineral density in patients with porous tantalum (trabecular metal) tibial baseplates would (1) more closely parallel tibial bone mineral density in the nonoperative control limb and (2) be better maintained than in conventional historical controls. PATIENTS AND METHODS: We prospectively followed 41 patients (35 men, six women) 60 years of age or younger undergoing TKA with uncemented trabecular metal tibial components. Patients underwent dual-energy xray absorptiometry scans of both proximal tibiae preoperatively and at 2 months, 1 year, and 2 years postoperatively. We determined bone mineral density in three selected regions of interest (Zone 1, between the pegs; Zone 2, beneath the pegs; Zone 3, directly below entire baseplate). Precision analysis revealed a precision error of 4% or less for each region of interest, indicating adequate power to detect bone mineral density changes of 8% or greater. RESULTS: Bone mineral density percent change was different between the operative and nonoperative knees only in Zone 3 and only at 2 months. There was no change in bone mineral density in any zone in the nonoperative knee at any time. Only in Zone 3 did the bone mineral density decrease at 2 months in the operative knee. CONCLUSIONS: Trabecular metal implants appear to maintain tibial bone mineral density in a parallel fashion to the nonoperative limb in this population and better than historical controls.

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.

Prior fractures are common in patients with subsequent hip fractures.

Treating osteoporosis in patients with prior fractures potentially results in a 50% reduction of risk of future fractures. We retrospectively reviewed 632 patients with incident hip fractures to evaluate (1) the prevalence of prior fractures in incident hip fractures, (2) whether prior fractures led to an increase in the treatment of osteoporosis, and (3) the cost utility of osteoporosis treatment after a prior fracture. The patients were treated at three hospitals from January 2000 to June 2001 and 514 (80%) were women. A minimal trauma fracture was defined as a fracture resulting from a fall while standing or walking or falling from a height less than 4 feet. Two hundred eighty-two patients (45%) with incident hip fractures described a prior minimal trauma fracture. Osteoporosis was diagnosed in 43 (13%) women and three (5%) men. In 107 cases (17%), the incident hip fracture was the second hip fracture. A prior minimal trauma fracture did not increase treatment for osteoporosis. Presuming a 50% reduction in fracture risk with medications, treating the 282 patients with prior minimal trauma fracture would have resulted in a savings of $3.5 million.

Less frequent dosing of bisphosphonates in osteoporosis: focus on ibandronate.

BACKGROUND: Bisphosphonates form the mainstay of treatment in osteoporosis; however, current adherence with therapy is inadequate. Problems with adherence are thought to be linked to several factors, including frequency of dosing and bisphosphonate-associated intolerability. For non adherent patients, less frequent dosing may be desirable, because the frequency with which strict and inconvenient dosing procedures must be followed is reduced. OBJECTIVES: A new nitrogen-containing bisphosphonate, ibandronate, offers sustained efficacy, with an extended between-dose interval. The molecular characteristics of ibandronate that support extended dosing are described, and trial outcomes for oral and intravenous ibandronate are summarized, in the context of other available bisphosphonates, based on the results of a search of MEDLINE publications (January 1975-December 2005). Relevant safety issues are discussed. CONCLUSION: Awareness of the scientific basis, published trial findings, and clinical implications associated with a once-monthly bisphosphonate can guide treatment decisions and inform communications with patients.

A randomized, placebo-controlled, 6-month study of once-weekly alendronate oral solution for postmenopausal osteoporosis.

OBJECTIVE: This study evaluated the overall safety and tolerability of once-weekly (OW) alendronate 70 mg oral solution (OS) versus OW placebo OS. METHODS: Postmenopausal, osteoporotic women were enrolled at 51 centers in the United States in a 6-month double-blind, randomized trial. Patients were randomized (1:1) to OW alendronate 70 mg OS or placebo OS. The primary end point was the proportion of patients reporting any upper gastrointestinal (UGI) adverse event (AE) at 6 months. Secondary end points included mean percentage change in urinary N-telopeptide of type I human collagen (NTx) and serum bone-specific alkaline phosphatase (BSAP) at 6 months. RESULTS: Initially, 454 women were enrolled; 392 (86.3%) completed the study. The mean (SD) age was 65.2 (10) years, and the mean (SD) time since menopause was 19.1 (12) years. The proportion of patients experiencing any UGI AE was significantly higher with alendronate OS (23.7%) compared with placebo solution (15.3%), with a treatment difference of 8.3% (95% CI, 0.8%-15.8%; P = 0.024). The proportion of patients experiencing any esophageal AE was 4.0% with alendronate and 3.0% with placebo (treatment difference, 1.0% [95% CI, -2.7% to 4.8%]). In addition, 4.5% of alendronate and 8.7% of placebo patients discontinued the study due to any clinical AE, and 3.3% of alendronate and 1.8% of placebo patients discontinued due to a UGI AE (difference, 1.5% [95% CI, -1.5% to 4.4%]). Alendronate OS produced significantly greater reductions in both NTx and BSAP than placebo (differences, -47.5% and -38.7%, respectively [both, P < 0.001]). CONCLUSIONS: In this 6-month study, patients receiving OW alendronate 70 mg OS had a higher rate of UGI AEs than placebo patients. However, rates of serious UGI AEs, discontinuations due to UGI AEs, and esophageal AEs were similar between groups. UGI AEs in the study were generally mild to moderate in severity and did not result in treatment discontinuation. In addition, OW alendronate 70 mg OS significantly reduced biochemical markers of bone turnover.

Prevalence of vitamin D inadequacy in a minimal trauma fracture population.

OBJECTIVE: The purpose of this analysis was to report the prevalence of vitamin D inadequacy in a population of adults with minimal trauma fractures. RESEARCH DESIGN AND METHODS: 82 adults (ages 52-97 with 63% age 80+) consecutively hospitalized with hip and extremity fractures between August 2001 and January 2002 were recruited from two St. Paul, MN hospitals. Patients came from independent living and assisted living facilities. Demographics, medical history and vitamin D supplementation were obtained by the medical record and self-report. Blood specimens were collected during hospitalization within 48 hours of admission. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were assessed using Diasorin 25-hydroxyvitamin D radioimmunoassay kit (RIA) at Mayo Clinic, Rochester, MN. Results were available for 78 patients and are included in the current analysis. RESULTS: Patients were 99% Caucasian, 63% >/=80 years and 78% female. 97% were admitted due to hip fracture. On admission, 50% reported using at least 400 IU per day of vitamin D through supplements (including multivitamins) and 13% of all patients were taking osteoporosis medication (3 estrogen, 5 alendronate, 1 etidronate, 1 raloxifene). The mean 25(OH)D concentration was 14.2 (SD 6.6) with a range of 5-39 ng/mL (8-38 ng/mL wintertime vales in Rochester, MN). All but two of the 78 patients (97.4%) had 25(OH)D concentrations < 30 ng/mL and the majority (81%) of the patients had 25(OH)D concentrations < 20 ng/mL, including 21% < 9 ng/mL. Mean 25(OH)D concentrations were not substantially different by gender, age, or osteoporosis medication use. Patients who reported vitamin D supplementation >/= 400 IU/day had significantly greater mean 25(OH)D concentrations, albeit suboptimal, compared to those who did not (16.4 vs. 13.7 ng/mL; p = 0.002). CONCLUSIONS: Nearly all patients in this study hospitalized for fracture had vitamin D inadequacy. Significant opportunity exists to ensure adequate and persistent vitamin D intake in a high risk fracture patient population.

The role of vitamin D deficiency in osteoporosis and fractures.

Vitamin D deficiency is a major risk factor for accelerated bone loss, which contributes to morbidity in older adults. It is easy to diagnose, and treatment is safe and cost-effective. This article reviews the amount of vitamin D needed by certain populations in order to help prevent osteoporosis and fractures associated with the disease. It also summarizes the results of a study involving 81 hip-fracture patients that found 80% had abnormally low levels of 25-hydroxyvitamin D.

Evaluation and management of osteoporosis following hospitalization for low-impact fracture.

OBJECTIVE: To evaluate the pattern of osteoporosis evaluation and management in postmenopausal women who present with low-impact (minimal trauma) fracture. DESIGN: Retrospective chart review of patients admitted with a fracture in the absence of trauma or bone disease. Telephone follow-up survey was conducted at 12 months after discharge to collect information on physician visits, pharmacological therapies for osteoporosis, functional status, and subsequent fractures. PATIENTS/PARTICIPANTS: Postmenopausal women admitted to a hospital in St. Paul, Minnesota between June 1996 and December 1997 for low-impact fractures were identified. Low-impact fracture was defined as a fracture occurring spontaneously or from a fall no greater than standing height. Retrospective review of 301 patient medical records was conducted to obtain data on pre-admission risk factors for osteoporosis and/or fracture, and osteoporosis-related evaluation and management during the course of hospitalization. Follow-up 1 year after the incident fracture was obtained on 227 patients. MEASUREMENTS AND MAIN RESULTS: Two hundred twenty-seven women were included in the study. Osteoporosis was documented in the medical record in 26% (59/227) of the patients at hospital discharge. Within 12 months of hospital discharge, 9.6% (22/227) had a bone mineral density test, and 26.4% (60/227) were prescribed osteoporosis treatment. Of those who were prescribed osteoporosis treatment, 86.6% (52/60) remained on therapy for 1 year. Nineteen women suffered an additional fracture. Compared to women without a prior fracture, women with at least 1 fracture prior to admission were more likely to have osteoporosis diagnosed and to receive osteoporosis-related medications. CONCLUSION: Despite guidelines that recommend osteoporosis evaluation in adults experiencing a low-trauma fracture, we report that postmenopausal women hospitalized for low-impact fracture were not sufficiently evaluated or treated for osteoporosis during or after their hospital stay. There are substantial opportunities for improvement of care in this high-risk population to prevent subsequent fractures.

Barriers to osteoporosis identification and treatment among primary care physicians and orthopedic surgeons.

OBJECTIVE: To understand better the barriers among orthopedic surgeons and primary care physicians in identifying and treating possible osteoporosis in patients hospitalized with a fragility fracture sustained spontaneously or from a fall no greater than standing height. METHODS: A 1-page, 7-question survey was sent to 35 admitting orthopedic surgeons and 75 primary care physicians at a midwestern managed care organization in March 2001. Returned surveys were collected until 30 days had passed since the mailing. Primary care physicians were board-certified family practitioners and internal medicine physicians. All orthopedists were admitting surgeons in the hospital system. Responders were anonymous, and posted surveys were returned to the Orthopaedic Collaborative Practice office. The surveys were color-coded to separate responses from orthopedic surgeons and primary care physicians. RESULTS: Thirty-one surveys were returned: 23 (31%) from primary care physicians and 8 (23%) from orthopedic surgeons. Survey respondents agreed that the responsibility for postfracture attention to nutritional needs, including calcium and vitamin D, rested with the primary care provider. When asked about barriers to recommending bone mineral density testing with dual energy x-ray absorptiometry, 9 primary care physicians (39%) thought this type of testing was unnecessary for treatment, and 4 primary care physicians (17%) thought a barrier was caused by patient frailty. Primary care physicians indicated that potential adverse effects of medication (n=14 [61%]) and cost of therapy (n=13 [57%]) were the main factors limiting treatment. When asked to identify the single most important barrier in treatment, 14 physicians (61%) indicated cost was the greatest deterrent. Twenty-one primary care physicians (91%) reported they would be more likely to treat a patient with osteoporosis if a safe medication with proven fracture risk reduction were available. Primary care physicians indicated they were more likely to treat independently living adults (n=12 [52%]) and women compared with men (n=15 [65%]). All orthopedic surgeons (n=8) were willing for all patients to be evaluated in consultation with a nurse practitioner. Primary care respondents were less apt to agree with a nurse practitioner referral (n=5 [22%]). Both primary care physicians (n=16 [70%]) and orthopedic surgeons (n=4 [50%]) agreed that there is a need for increased primary care education about managing osteoporosis in patients hospitalized with low-impact fracture. CONCLUSIONS: Orthopedic surgeons were consistent in their opinion that postfracture attention to osteoporosis should rest with the primary care physician. Primary care physicians agree but report that cost and possible adverse effects of medication are major barriers to this care. Despite therapies for high-risk postfracture patients showing relative safety and proven efficacy in reducing future fractures, deterrents to this care are focused on cost and potential adverse effects. Further education is needed to promote a standard of care for the postfracture patient that is directed toward the prevention of a subsequent fracture.