The impact of osteoporosis (as measured by lumbar spine quantitative computed tomography) on disease activity and survival in myeloma patients: A 13‐year prospective study
Authors: Terrence Diamond, Terry Golombick, Arumugam Manoharan, Yiulam Kwan, Carl Bryant
Journal: American Journal of Hematology (2011)

Myeloma is a progressive neoplastic disease characterized by plasma cell dyscrasia, progressive bone loss, and pathological fractures. We conducted a prospective, single center study on myeloma patients to determine the impact of osteoporosis on disease activity and survival. Data collected on 108 patients followed for 13 years included clinical demographics, markers of myeloma activity, skeletal radiography, and bone densitometry. There were 56 men and 52 women with mean age of 69 years. Of these, 78% presented with stage I/II disease, 11% underwent stem cell or bone marrow transplants, 78% received adjuvant intravenous bisphosphonates, and 80% died during the course of the study (median survival of 47.3 months). There were 66% with osteoporosis, 54% with fractures, and 56% with lytic bone lesions. Femoral neck dual energy X-ray absorptiometry (DXA) and lumbar spine quantitative computed tomography (QCT) were major independent predictors of patient survival. Kaplan–Meier survival estimates demonstrated that patients presenting with a lumbar spine QCT T-score ≤ −3.5, died on average 18 months earlier than those with a lumbar spine QCT T-score > −3.5. These data suggest that the severity of osteoporosis, as defined by initial BMD T-score values, significantly impact on patient survival. Multiple myeloma is a malignant disease characterized by a clonal proliferation of plasma cells often resulting in a protracted course that is complicated by lytic bone lesions, osteoporosis, and skeletal fractures [1]. The advent of newer chemotherapeutic regimens and agents such as bisphosphonates, thalidomide, and proteosome inhibitors has significantly reduced the skeletal burden in myeloma [2, 3]. In recent years, there has been a major shift away from using skeletal parameters in the staging of myelomatous disease. The original Durie and Salmon [DS] classification [4] that included the presence of lytic lesions as one of the predictive criteria of survival has been replaced by the most recent International Staging System (ISS) [5] that evaluates changes in serum β2 microglobulin and albumin and largely ignores the bone lesions. In this study, we determine the frequency of bone disease (lytic lesions and osteoporosis) in newly diagnosed myeloma patients and prospectively evaluate their effect on disease activity and patient survival. Our results show that there were 56 men and 52 women with mean age of 69 years. All patients were treated with standard chemotherapeutic regimens (melphalan, prednisone, vincristine adriamycin dexamethasone, prednisolone cyclophosphamide adriamycin bleomycin, interferon, and in recent years with thalidomide). A total of 11% (n = 12) underwent stem cell or bone marrow transplants; 78% (n = 80) received adjuvant intravenous bisphosphonates; 80% (n = 86) died during the course of the study, with a median survival of 47.3 months (range 10–156); 56% (n = 61) had lytic lesions; 66% (n = 71) had osteoporosis defined by either lumbar spine or femoral neck bone density (T-score ≤ −2.5); and 54% (n = 58) suffered skeletal fractures with 42% (n = 45) of these involving the thoracolumbar spine. The mean lumbar spine QCT T-score = −3.3 and femoral neck DXA T-score= −1.4. Patients were subdivided according to the ISS (Table I). A total of 78% (n = 84) presented with stage I/II disease. Patients with stage III disease had significantly more disease burden (higher serum paraprotein, higher serum β2 microglobulin, higher plasma cell percentage, lower serum albumin, and lower hemoglobin concentrations) than patients with stage I/II disease. These patients also had higher serum creatinine and parathyroid hormone (PTH) levels. No significant differences were noted between the three groups with respect to the presence of lytic lesions, fractures, or number of patients with densitometric evidence of osteoporosis. We were unable to find an association between the ISS parameters and patients survival in our multivariate model (Table II). This is in contrast to the findings of Greipp et al. [5] and may have possibly been related to our small sample size with Stage III disease. In the Cox proportional hazard analysis, both lumbar spine QCT T-scores and femoral neck DXA T-scores were predictive of survival in the univariate but not the multivariate model (Tables III and IV). Kaplan–Meier survival estimates (Fig. 1) demonstrated that patients presenting with a lumbar spine QCT T-score ≤ −3.5, died on average 18 months earlier than those with a lumbar spine QCT T-score > −3.5 (hazard ratio [HR] 2.28x, 95% confidence interval [CI], 1.3–4.0; P value 0.005). BMD T-score cut-off value ≤ −3.5 were selected because this T-score is representative of severe osteoporosis commonly seen with secondary causes and revealed the lowest P value. Survival of patients with multiple myeloma classified according to lumbar spine QCT T-scores > or ≤ −3.5. Skeletal related events such as spinal fractures and lytic lesions have been reported to be associated with a poor prognosis in myeloma [2]. In our study, the presence of fractures and lytic lesions commonly occurred in our cohort, but we were unable to demonstrate a significant effect of these variables on survival. Although the diagnosis of spinal fractures and lytic lesions are observer dependent, volumetric and areal BMD can accurately be quantified by bone densitometry. This lack of precision may explain negative findings in this study. In 1975, Durie and Salmon (DS) [4] introduced a clinical staging system for multiple myeloma using commonly available clinical parameters that predicted myeloma cell tumor burden. Factors in the DS classification included the level and type of monoclonal protein, hemoglobin, calcium level, and number of bone lesions. Although number of bone lesions was found to be an independent predictor of survival duration in the DS classification system, the new ISS for multiple myeloma makes the claim that the number of lytic lesions on routine radiographs (skeletal survey) is observer dependent [5]. For the new ISS, clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients. Potential prognostic factors, including number of bone lesions, compression fractures, and pathologic fractures, were evaluated by univariate and multivariate techniques. Using a tree survival assessment approach, a combination of serum β2 microglobulin and serum albumin provided the simplest, most powerful, and reproducible three-stage classification. No previous study has looked at the impact of osteoporosis as measured by BMD on myeloma patient survival. Our study indicates that the skeletal burden of bone disease, as defined by the initial lumbar spine QCT and femoral neck DXA T-score values, has a major impact on the survival in patients presenting with newly diagnosed multiple myeloma. Therefore, BMD should not be discarded as a prognostic indicator in the diagnosis and treatment of this disease. Databases that include larger cohorts of myeloma patients should evaluate the value of BMD and osteoporotic fractures as a variable that may effect patient survival. A total of 108 consecutive patients with newly diagnosed multiple myeloma were evaluated over 13 years (1995–2008). These patients were referred from the Department of Hematology at St. George Hospital for the management of their bone disease and consideration for bisphosphonate therapies. Their data that included clinical demographics, such as patients' age, sex, smoking history, alcohol intake, medications, and duration of disease were collected prospectively. Venous blood and an early morning fast 2-hr urine sample were collected from all patients for serum biochemistry, markers of myeloma activity, and bone turnover. Serum calcium, albumin, and creatinine were measured by standard auto-analyzer methods. Serum 25 hydroxyvitamin D (25-OHD) and PTH were determined by chemiluminescence assays (Diasorin, Stillwater, MI). The Diasorin assays measures total 25-OHD, which is inclusive of both D2 and D3 metabolites. Serum paraprotein and immunoglobulin electrophoresis were performed using agarose gel (Sebia, France), serum B2 microglobulin using Beckman instruments (Beckman Instruments, Fullerton, CA), and urine deoxypyridinolene excretion rates by a chemiluminescence immunometric assay (Diagnostic Products, Los Angeles, CA). Plasma cell dyscrasia was assessed using plasma cell percentage numbers determined on bone marrow and trephine biopsy. The presence of lytic lesions and fractures was assessed by full-body skeletal radiography. Volumetric bone mineral densities (BMD) of the lumbar spine was measured by QCT using GE scanner and areal BMD of the lumbar spine and femoral neck by DXA with a Lunar DPX-L scanner (Lunar, Madison, WI). An oval region of interest centered in the mid vertebral body was used to determine trabecular volumetric BMD. These areas were selected by directing the computerized tomography beam through regions not significantly affected by posterior bony elements such as facet joints and extravertebral calcifications. Vertebrae confounded by spondylarthropathy or spinal fractures were excluded from the BMD measurements. Absolute BMD measurements were expressed in either mg/cm3 (volumetric) or g/cm2 (areal) and as T-score values. Individual BMD T-score values were derived from a normative database comprising of 250 “healthy” Australian men and women aged 20–40 years [6, 7]. All values are expressed as mean ± 1 standard error of mean and where appropriate 95% confidence intervals (95% CI) are cited. Data are compared using analysis of variance and Kruskall Wallis for post hoc analysis. Logarithmic transformations were used for data with skewed distributions. Statistical analysis was assigned as P < 0.05. Overall survival was estimated using the method of Kaplan–Meier, and HR were obtained using Cox proportional hazards modeling. Patients were censored at the time of last follow-up or death. Elapsed times were calculated from the date of initial presentation. Variables considered a priori to be potential predictors of survival were age, vitamin D status (25-OHD), renal function (serum creatinine), markers of myeloma activity (hemoglobin, serum calcium, serum albumin, serum β2 microglobulin, and percentage of plasma cell count), and severity of bone disease (lytic lesions, spinal fractures, and lumbar spine and femoral neck bone mineral density). Multivariate models were assessed using backward stepwise regression analysis commencing with variables with P < 0.25. Data were analyzed using STATA SE v9.2. The relationship between osteoporosis and survival was determined by classifying patients according to their baseline lumbar spine QCT T-score values. Kaplan–Meier survival estimates were determined for patients defined with lumbar spine QCT T-score values either ≤ −2.5 or ≤ −3.5 (defined as severe osteoporosis). T. Diamond*, T. Golombick*, A. Manoharan , Y. Kwan , C. Bryant§, * Department of Endocrinology, St. George Hospital, Kogarah, Sydney, New South Wales, Australia, Southern Sydney Haematology, University of Wollongong, New South Wales, Australia, Haematology, University of New South Wales, Sydney, Australia, § Radiology, University of New South Wales, Sydney, Australia.