Timothy M. Murray

Estimation of the prevalence of low bone density in Canadian women and men using a population-specific DXA reference standard : The Canadian Multicentre Osteoporosis Study (CAMOS)

Abstract: The Canadian Multicentre Osteoporosis Study (CaMos) is a prospective cohort study which will measure the incidence and prevalence of osteoporosis and fractures, and the effect of putative risk factors, in a random sample of 10 061 women and men aged ≥25 years recruited in approximately equal numbers in nine centers across Canada. In this paper we report the results of studies to establish peak bone mass (PBM) which would be appropriate reference data for use in Canada. These reference data are used to estimate the prevalence of osteoporosis and osteopenia in Canadian women and men aged ≥50 years. Participants were recruited via randomly selected household telephone listings. Bone mineral density (BMD) of the lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry using Hologic QDR 1000 or 2000 or Lunar DPX densitometers. BMD results for lumbar spine and femoral neck were converted to a Hologic base. BMD of the lumbar spine in 578 women and 467 men was constant to age 39 years giving a PBM of 1.042 ± 0.121 g/cm2 for women and 1.058 ± 0.127 g/cm2 for men. BMD at the femoral neck declined from age 29 years. The mean femoral neck BMD between 25 and 29 years was taken as PBM and was found to be 0.857 ± 0.125 g/cm2 for women and 0.910 ± 0.125 g/cm2 for men. Prevalence of osteoporosis, as defined by WHO criteria, in Canadian women aged ≥50 years was 12.1% at the lumbar spine and 7.9% at the femoral neck with a combined prevalence of 15.8%. In men it was 2.9% at the lumbar spine and 4.8% at the femoral neck with a combined prevalence of 6.6%.

Metabolic Bone Disease in Patients Receiving Long-Term Total Parenteral Nutrition

We have prospectively investigated calcium and bone metabolism in 16 patients receiving total parenteral nutrition for periods ranging from 7 to 89 months. In 12 patients, bone biopsies at 6 to 73 months after the start of parenteral nutrition showed osteomalacia. Plasma 25-hydroxyvitamin D levels were normal in all patients. Seven persons developed hypercalcemia, and 10 had hypercalciuria with a negative calcium balance. Serum phosphorus was normal and plasma parathyroid hormone level, normal or decreased. Three patients with the severest form of the disease had vitamin D withdrawn from their solutions. Subsequently, urinary calcium decreased, and serum calcium became normal; two persons reverted to a positive calcium balance. Thus, patients receiving total parenteral nutrition may develop metabolic bone disease characterized by osteomalacia, hypercalcemia, hypercalciuria, and a negative calcium balance. This may be caused by both defective mineralization and increased bone resorption induced by vitamin D, its metabolites, or another unrecognized factor.

The association between osteoporotic fractures and health-related quality of life as measured by the Health Utilities Index in the Canadian Multicentre Osteoporosis Study (CaMos)

Osteoporotic fractures can be a major cause of morbidity. It is important to determine the impact of fractures on health-related quality of life (HRQL). A total of 3,394 women and 1,122 men 50 years of age and older, who were recruited for the Canadian Multicentre Osteoporosis Study (CaMos), participated in this cross-sectional study. Minimal trauma fractures of the hip, pelvis, spine, lower body (included upper and lower leg, knee, ankle, and foot), upper body (included arm, elbow, sternum, shoulder, and clavicle), wrist and hand (included forearm, hand, and finger), and ribs were studied. Participants with subclinical vertebral deformities were also examined. The Health Utilities Index Mark II and III Systems were used to assess HRQL. Past osteoporotic fractures varied in prevalence from 1.2% (pelvis) to 27.8% (lower body) in women and 0.3% (pelvis) to 29.3% (wrist) in men. Multivariate linear regression analyses [parameter estimates and corresponding 95% confidence intervals (CI)] indicated that minimal trauma fractures were negatively associated with HRQL and that this relationship depends on fracture type and gender. The multi-attribute scores for the Mark II system were negatively related to hip (−0.05; 95% CI: −0.09, −0.01), lower body (−0.02; 95% CI: −0.03, −0.000), and subclinical vertebral fractures (−0.02; 95% CI: −0.03, −0.00) for women. The multi-attribute scores for the Mark III system were negatively related to hip (−0.09; 95% CI: −0.14, −0.03) and rib fractures (−0.06; 95% CI: −0.11, −0.00) for women, and rib fractures (−0.06; 95% CI: −0.12, −0.00) for men. In conclusion, this study demonstrates a negative association between osteoporotic fractures and quality of life in both women and men.

Adherence to bisphosphonates and hormone replacement therapy in a tertiary care setting of patients in the CANDOO database

Therapies for osteoporosis must be taken for at least 1 year to be effective. The purpose of this study was to determine the difference in adherence to etidronate, alendronate and hormone replacement therapy in a group of patients seen at our tertiary care centres. The Canadian Database of Osteoporosis and Osteopenia (CANDOO), a prospective observational database designed to capture clinical data, was searched for patients who started therapy following entry into CANDOO. There were 1196 initiating etidronate, 477 alendronate and 294 hormone replacement therapy women and men aged (mean, SD) 65.8 (8.7) years in the study. A Cox proportional hazards regression model was used to assess differences between treatment groups in the time to discontinuation of therapy. Several potential covariates such as anthropometry, medications, illnesses, fractures and lifestyle factors were entered into the model. A forward selection technique was used to generate the final model. Hazard ratios and 95% confidence intervals (CI) were calculated. Adjusted results indicated that alendronate-treated patients were more likely to discontinue therapy as compared with etidronate-treated patients (1.404; 95% CI: 1.150, 1.714). After 1 year, 90.3% of patients were still taking etidronate compared with 77.6% for alendronate. No statistically significant differences were found between hormone replacement therapy and etidronate users (0.971; 95% CI: 0.862, 1.093) and hormone replacement therapy and alendronate users (0.824; 95% CI: 0.624, 1.088) after controlling for potential covariates. After 1 year, 80.1% of patients were still taking hormone replacement therapy, which decreased to 44.5% after 6 years. Increasing age and presence of incident non-vertebral fractures were found to be independent predictors of adherence. In conclusion, alendronate users were more likely to discontinue therapy than etidronate users over the follow-up period. Potential barriers to long-term patient adherence to osteoporosis therapies need to be evaluated.

A Possible Role of Vitamin D in the Genesis of Parenteral-Nutrition-Induced Metabolic Bone Disease

Patients receiving long term parenteral nutrition may develop metabolic bone disease. In all 11 patients studied, histologic studies of bone showed excessive unmineralized bone tissue despite normal plasma 25-hydroxyvitamin D levels. Three patients also had bone pain and fractures and severe urinary loss of calcium and phosphate. Withdrawal of vitamin D from parenteral nutrition solutions was associated with improved histologic findings of bone in all patients, shown by a decrease in osteoid tissue and an increase in tetracycline uptake. In the three patients with symptoms, bone pain subsided, fractures healed, and urinary loss of calcium and phosphate decreased. Thus, vitamin D may be a factor in the genesis of parenteral nutrition-induced metabolic bone disease.

Evaluation of easily measured risk factors in the prediction of osteoporotic fractures

BackgroundFracture represents the single most important clinical event in patients with osteoporosis, yet remains under-predicted. As few premonitory symptoms for fracture exist, it is of critical importance that physicians effectively and efficiently identify individuals at increased fracture risk.MethodsOf 3426 postmenopausal women in CANDOO, 40, 158, 99, and 64 women developed a new hip, vertebral, wrist or rib fracture, respectively. Seven easily measured risk factors predictive of fracture in research trials were examined in clinical practice including: age (<65, 65–69, 70–74, 75–79, 80+ years), rising from a chair with arms (yes, no), weight (< 57, ≥ 57 kg), maternal history of hip facture (yes, no), prior fracture after age 50 (yes, no), hip T-score (>-1, -1 to >-2.5, ≤-2.5), and current smoking status (yes, no). Multivariable logistic regression analysis was conducted.ResultsThe inability to rise from a chair without the use of arms (3.58; 95% CI: 1.17, 10.93) was the most significant risk factor for new hip fracture. Notable risk factors for predicting new vertebral fractures were: low body weight (1.57; 95% CI: 1.04, 2.37), current smoking (1.95; 95% CI: 1.20, 3.18) and age between 75–79 years (1.96; 95% CI: 1.10, 3.51). New wrist fractures were significantly identified by low body weight (1.71, 95% CI: 1.01, 2.90) and prior fracture after 50 years (1.96; 95% CI: 1.19, 3.22). Predictors of new rib fractures include a maternal history of a hip facture (2.89; 95% CI: 1.04, 8.08) and a prior fracture after 50 years (2.16; 95% CI: 1.20, 3.87).ConclusionThis study has shown that there exists a variety of predictors of future fracture, besides BMD, that can be easily assessed by a physician. The significance of each variable depends on the site of incident fracture. Of greatest interest is that an inability to rise from a chair is perhaps the most readily identifiable significant risk factor for hip fracture and can be easily incorporated into routine clinical practice.

Observations on the Mechanism of Bone Resorption Induced by Multiple Myeloma Marrow Culture Fluids and Partially Purified Osteoclast-activating Factor

Supernatant fluids from the cultures of bone marrow cells from 10 of 12 patients with multiple myeloma (MM) caused bone resorption in organ cultures of fetal rat calvaria. In four patients, the marrow cells were cultured with and without indomethacin (1 muM). The supernatant fluids from indomethacintreated marrow cultures caused significantly less bone resorption than supernatant fluids of cell cultures without indomethacin. This inhibition of release of bone resorbing factor(s) by myeloma cultures is similar to the previously observed indomethacin-induced inhibition of osteoclast-activating factor (OAF) production by activated human leukocytes. None of the MM supernatants had any effect on cyclic (c)AMP accumulation in resorbing bone in vitro. Four separate preparations of partially purified OAF obtained from phytohemagglutinin-stimulated peripheral human leukocytes were tested for their ability (a) to cause bone resorption in organ cultures of fetal rat and neonatal mouse calvaria and (b) to cause accumulation of cAMP in rat and mouse skeletal tissue in vitro. Those dilutions of OAF that caused bone resorption had no effect on accumulation of cAMP in rat or mouse calvaria incubated in vitro. In addition, no stimulation of adenylate cyclase activity in membranes prepared from fetal rat calvaria could be found. Bone cell populations isolated by sequential collagenase digestion of fetal rat calvaria also showed no cAMP response to these dilutions of OAF. Parathyroid hormone caused a clear response in all three systems. Furthermore, no cAMP response to OAF was observed in calvaria in the presence of cholera toxin (1 mug/ml) and isobutyl-methylxanthine (0.3 mM). These observations demonstrate that (a) supernatant fluids from MM marrow cultures stimulate bone resorption but do not increase cAMP accumulation in vitro; (b) indomethacin interferes with the release of bone resorbing factors by MM bone marrow cultures suggesting that this process requires prostaglandins; and (c) Sephadex G100 or G75 purified OAF does not stimulate adenylate cyclase or increase cAMP accumulation at equivalent bone resorbing concentrations in rat and mouse skeletal tissue. The resorptive action of MM culture fluids is similar to that of partially purified OAF from activated cultured leukocytes, but different from those of other bone resorbing factors, parathyroid hormone and prostaglandin E(2), which stimulate cAMP production in skeletal tissue.

What Predicts Early Fracture or Bone Loss on Bisphosphonate Therapy

Factors predicting early fracture or bone loss on bisphosphonate therapy are not well defined. We studied 1588 patients over the age of 50 yr who were started on cyclic etidronate (1119) or alendronate (469) in the CANDOO (Canadian Database for Osteoporosis and Osteopenia Patients) Study. Incident fracture within 2 yr of starting therapy occurred in 31 patients and was independently predicted by a previous history of nonvertebral fracture (odds ratio [OR], 2.98, 95% confidence interval [CI], 1.30, 6.83, p = 0.010). Two hundred and fifty-seven patients lost >/=3% bone mass at the hip or spine (early bone loss) while on bisphosphonate therapy. Protection from early bone loss was most strongly independently predicted by treatment with alendronate with no previous history of etidronate use (OR, 0.29, CI, 0.13, 0.62, p = 0.002). In conclusion, early fracture on bisphosphonate therapy is most strongly predicted by a previous history of fracture and early bone loss is most strongly predicted by the potency of the prescribed bisphosphonate.

A radioimmunoassay for a porcine intestinal calcium-binding protein

Abstract A radioimmunoassay for porcine intestinal calcium-binding protein (CaBP) has been developed. 125 I-labeled CaBP was prepared using chloramine-T. Antisera to porcine CaBP were raised in guinea pigs and rabbits. Antibody-bound CaBP was separated from free CaBP using talc. The immunoassay was highly sensitive, measuring concentrations of CaBP in duodenal extracts as low as 1 ng/ml with good reproducibility. This is sufficiently sensitive to measure CaBP in small amounts of duodenal tissue obtained by peroral capsule biopsy. The method was specific for CaBP, showing no reactivity toward other duodenal proteins or several peptide hormones. Measurements of CaBP by immunoassay showed a good correlation with measurements of CaBP-specific calcium-binding. The immunodilution curves obtained when assaying pig renal cortical extracts against pure duodenal CaBP were parallel when tested with six different antisera, demonstrating a high degree of immunochemical similarity between kidney and duodenal CaBP. Clearly, the radioimmunoassay possesses distinct advantages for the study of the biologic role of CaBP.

Preparation and properties of biologically active radioiodinated parathyroid hormone

A constant-current microelectrolytic radioiodination method was used to label bovine parathyroid hormone (BPTH) with 125I to an overall iodination ratio of 1:1 iodide atoms per PTH molecule. Such iodinated preparations were shown to be fully active in several bioassay systems: in vitro adenylate cyclase activation in rat renal and skeletal membranes, in vitro calcium release from rat calvaria, and the in vivo hypercalcemic response in chickens. Analysis by Sephadex G-15 chromatography after enzymatic digestion showed the radioiodine to be incorporated predominantly as monoiodotyrosine. Bioassay of iodinated preparations from which uniodinated hormone had been removed by isoelectric focusing showed essentially full hormonal activity. Such methods can be used to consistently produce radioiodinated biologically active preparations of BPTH 1-84 with high specific activity (2000 Ci/mmol).