
Timothy M MurrayUniversity of Toronto | U of T · Department of Medicine
Timothy M Murray
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Introduction
Publications
Publications (137)
Fluoride has been proposed as a therapy for the vertebral crush fracture syndrome for many years; such proposals have been based largely on the well-characterized syndrome of fluoride intoxication (fluorosis), which is marked by increased skeletal mass and sometimes exuberant bony overgrowths. For various reasons, including the inability to develop...
Twenty-two patients with steroid-induced osteoporosis were studied retrospectively to assess the effects on bone mass of fluoride therapy over 4 years. Thirteen of 19 patients with miscellaneous disorders and 2 with Cushing's syndrome received 1 g calcium/day, 50,000 IU vitamin D (D) weekly, and 40-60 mg/day sodium fluoride (F). Six patients with m...
The possible effects of fluoride in inducing fractures were studied in 61 patients treated with sodium fluoride (NaF), 40-60 mg daily in combination with calcium and vitamin D. Nine patients developed the fluoride-(F) related lower extremity pain syndrome. Four other patients had stress fractures associated with trauma. Seven of the 61 patients had...
We report on 61 women with postmenopausal osteoporosis who were treated with either plain sodium fluoride (NaF) capsules or enteric-coated NaF tablets for 4 years, in whom possible therapeutic and toxic effects were monitored. In these patients there was a mean increase in axial bone mineral mass, assessed by neutron activation analysis, of 26.2% +...
Pseudohypoparathyroidism (PHP) is characterized by a lack of response to parathyroid hormone (PTH); however, normal skeletal responsiveness to PTH in some patients with PHP type Ia was previously suggested on the basis of clinical observations. To test this hypothesis, we measured cyclic adenosine monophosphate (cAMP) production in response to vari...
A young girl had tibial osteotomies at age 14 for genu valgum and then had recurrent tibial cysts over a number of years. Hypocalcemia and hyperphosphatemia were first noted at age 21. The diagnosis of pseudohypoparathyroidism was made at age 28, when elevated plasma PTH was detected. Clinical and biochemical features, including a PTH response test...
Bone cells derived from human trabecular explants display osteoblastic features. We examined the modulation of alkaline phosphatase activity and cAMP production as the result of exposing trabecular explants to physiologic concentrations of dexamethasone for 4 weeks during cellular outgrowth and subculture. Cells treated with dexamethasone were obse...
Previous findings in our laboratory have shown that hPTH-(53-84) stimulates alkaline phosphatase activity in dexamethasone-treated ROS 17/2.8 cells. In the present study, we examined the effects of hPTH-(53-84) and hPTH-(1-34) on the expressions of alkaline phosphatase, osteocalcin, and collagen type I mRNA levels in the human osteosarcoma cell lin...
Forty-one women with idiopathic postmenopausal osteoporosis have been followed for 2 years after initiation of sodium fluoride at 40-50 mg/day, given together with a daily calcium supplement of 1 gram and vitamin D2, at 50,000 IU weekly. Histological and histomorphometric analyses were done on bone biopsies taken prior to and after 1 year of treatm...
Oxidative stress induced by reactive oxygen species (ROS) is associated with the risk of osteoporosis, and can be reduced by certain dietary antioxidants. Lycopene is an antioxidant known to decrease the risk of age-related chronic diseases, such as cancer. However, the role of lycopene in osteoporosis has not yet been investigated.
In a cross-sect...
Routine bone mineral densitometry (BMD) screening has been recommended for women aged >or=65 yr (Osteoporosis Canada [OC], International Society for Clinical Densitometry [ISCD], Canadian and United States Task Forces on Preventative Healthcare, and National Osteoporosis Foundation) and for men >or=65 yr (OC) or >or=70 yr (ISCD). We estimated the n...
Human parathyroid hormone (hPTH)(1-34) was approved in 2004 for the treatment of severe osteoporosis. Members of the Osteoporosis Canada clinical guidelines committee conducted a systematic review of randomized controlled trials (RCTs) to assess the efficacy and safety of hPTH for fracture prevention in postmenopausal women and men with osteoporosi...
The prevalence of osteoporosis in men is higher than previously assumed; consequently, numerous therapies are being investigated to treat these patients. The Canadian Database of Osteoporosis and Osteopenia patients (CANDOO) was analyzed to examine changes in bone mineral density (BMD) in consecutively seen osteoporotic men administered alendronate...
Health-related quality of life (HRQL) is an important consideration in the management of patients with vertebral fractures. The purpose of this study was to examine patient-related factors that contribute to HRQL after vertebral fractures, including co-morbidities, medications, fracture history, family disease history, demographics, exercise, educa...
Fragility fractures resulting from osteoporosis are common injuries. However, the identification and treatment of osteoporosis in these high-risk patients are widely reported to be inadequate. The goals of this study were to determine how many patients receiving inpatient or outpatient treatment for a fragility fracture could be identified and enro...
We have shown that osteoblastic cells derived from trabecular bone explants of osteoporotic subjects (OP cells) exhibited an altered alkaline phosphatase (ALP) response to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] compared to control (CON) cells. Our hypothesis that OP cells have other intrinsic abnormalities was investigated using our cell models rep...
Utilizing data from the Canadian Multicentre Osteoporosis Study (CaMos), we examined the association between potential risk factors and incident vertebral and nonvertebral fractures. A total of 5,143 postmenopausal women were enrolled. Information collected during the study included data from the CaMos baseline and annually mailed fracture question...
PTH is a major systemic regulator of the concentrations of calcium, phosphate, and active vitamin D metabolites in blood and of cellular activity in bone. Intermittently administered PTH and amino-terminal PTH peptide fragments or analogs also augment bone mass and currently are being introduced into clinical practice as therapies for osteoporosis....
Fracture 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.
Of 3426 postmenopausal women in CANDOO, 40, 158, 99, and 64...
Background: The SF-36 is widely used to assess health-related quality of life (HRQOL), but with few longitudinal studies in healthy populations, it is difficult to quantify its natural history. This is important because any measure of change following an intervention may be confounded by natural changes in HRQOL. This paper assesses mean changes in...
The SF-36 is widely used to assess health-related quality of life (HRQOL), but with few longitudinal studies in healthy populations, it is difficult to quantify its natural history. This is important because any measure of change following an intervention may be confounded by natural changes in HRQOL. This paper assesses mean changes in SF-36 score...
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 traum...
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 observa...
Although it is well established that estrogen inhibits bone resorption, its effects on bone formation remain controversial. We studied the effects of intermittent and continuous treatment with estrogen on bone formation in vitro using long term cultures of SaOS-2 cells under conditions that permit mineralization. SaOS-2 cells cultured in dexamethas...
This cross-sectional cohort study of 5566 women and 2187 men 50 years of age and older in the population-based Canadian Multicentre Osteoporosis Study was conducted to determine whether reported past diseases are associated with bone mineral density or prevalent vertebral deformities. We examined 12 self-reported disease conditions including diabet...
The identification of new methods of evaluating patients with osteoporotic fracture should focus on their usefulness in clinical situations such that they are easily measured and applicable to all patients. Thus, the purpose of this study was to examine the association between iliocostal distance and vertebral and non-vertebral fractures in patient...
Canadian normative data for the Medical Outcomes Study 36-item short form (SF-36) have recently been published. However, there is evidence from other countries to suggest that regional variation in health-related quality of life (HRQOL) may exist. We therefore examined the SF-36 data from nine Canadian centres for evidence of systematic differences...
Background: Canadian normative data for the Medical Outcomes Study 36-item short form (SF-36) have recently been published. However, there is evidence from other countries to suggest that regional variation in health-related quality of life (HRQOL) may exist. We therefore examined the SF-36 data from nine Canadian centres for evidence of systematic...
Bisphosphonates are effective agents for the management of osteoporosis. Their low bioavailability and low potency necessitate frequent administration on an empty stomach, which may reduce compliance. Gastrointestinal intolerance limits maximal dosing. Although intermittent intravenous treatments have been used, the optimal doses and dosing interva...
Positive and negative effects on bone mineral density (BMD) have been described as a result of the premenopausal use of oral contraceptives (OCs); increased fracture rates have also been reported. This study assessed the relation between OC use and BMD in a population-based, 9-centre, national sample of women aged 25-45 years.
Premenopausal women w...
Identification of women with low bone mineral density (BMD) is an important strategy in reducing the incidence of osteoporotic fractures. However, screening all women is not recommended.
To assess the diagnostic properties of 4 decision rules--Simple Calculated Osteoporosis Risk Estimation (SCORE), Osteoporosis Risk Assessment Instrument (ORAI), Ag...
We compared the effects of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] and its analog, 1alpha,25-dihydroxy-16-ene-vitamin D3 [1alpha,25(OH)2-16-ene-D3], as well as their interactions with 17-beta estradiol (E2) on osteoblastic function in our human normal (HOB) and osteosarcoma SaOS-2 cell models representing two different stages of differenti...
Health-related quality of life (HRQL) was examined in relation to prevalent fractures in 4816 community-dwelling Canadian men and women 50 years and older participating in the Canadian Multicentre Osteoporosis Study (CaMos). Fractures were of three categories: clinically recognized main fractures, subclinical vertebral fractures and fractures at ot...
It is now well established that estrogen inhibits bone resorption. However, its effect on bone formation remains controversial. We studied the effect of 17beta-estradiol (E2) on mineralized bone nodule formation in long-term cultures of osteosarcoma SaOS-2 cells. We showed that SaOS-2 cells formed mineralized nodules which under electron microscopy...
We compared the effects of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] and its analog, 1α,25-dihydroxy-16-ene-vitamin D3 [1α,25(OH)2-16-ene-D3], as well as their interactions with 17-β estradiol (E2) on osteoblastic function in our human normal (HOB) and osteosarcoma SaOS-2 cell models representing two different stages of differentiation, the more dif...
The Medical Outcomes Study 36-item Short Form (SF-36) is a widely used measure of health-related quality of life. Normative data are the key to determining whether a group or an individual scores above or below the average for their country, age or sex. Published norms for the SF-36 exist for other countries but have not been previously published f...
Background: The Medical Outcomes Study 36-item Short Form (SF-36) is a widely used measure of health-related quality of life. Normative data are the key to de- termining whether a group or an individual scores above or below the average for their country, age or sex. Published norms for the SF-36 exist for other coun- tries but have not been previo...
The role of estrogen deficiency in the pathogenesis of postmenopausal osteoporosis is well established. Despite this, the cellular mechanisms of action of estrogen in bone are complex and far from clear. In vitro studies of cellular and molecular biology have concentrated on rodent cells. However, species differences have been noted, and an analysi...
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 > or = 25 years recruited in approximately equal numbers in nine centers across Canada. In this pape...
Bone densitometry using dual energy X-ray absorptiometry (DXA) is the 'gold standard' for osteoporosis diagnosis. However, mass screening for osteoporosis has not been recommended, and no consensus has been reached regarding specific targeted screening programs. Recently, the Simple Calculated Osteoporosis Risk Estimation (SCORE) was developed to i...
To determine the prevalence and seasonal variation of vitamin D deficiency among older residents of long-term care facilities.
Cross-sectional survey with 6-month follow-up.
Three long-term care facilities in Toronto.
Persons more than 65 years old, medically stable, who had resided in the facility for at least 6 months and had no conditions known...
We compared the separate effects of 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) and its analog, 1alpha,25-dihydroxy-16ene,23yne-vitamin D3 (1alpha25(OH)2-16ene,23yne-D3), as well as their interactions with 17-beta estradiol (E2) in our human osteosarcoma SaOS-2 cell models representing two stages of differentiation, the SaOS+DEX and SaOS-DEX c...
To recommend appropriate levels of calcium intake in light of the most recent studies.
Dietary calcium intake, calcium supplementation, calcium and vitamin D supplementation; ovarian hormone therapy in postmenopausal women.
Fracture and loss of bone mineral density in osteoporosis; increased bone mass, prevention of fractures and improved quality o...
To present the latest findings on the use of fluoride in the treatment of osteoporosis.
Plain sodium fluoride (NaF), enteric-coated sodium fluoride (EC-NaF), sodium monofluorophosphate (Na2FPO4), slow-release sodium fluoride (SR-NaF); fluoride with a calcium supplement.
Fracture and loss of bone mineral density in osteoporosis; increased bone mass,...
We have seen rapid and important advances in the understanding of bone resorption processes at the cellular and molecular levels. Indeed, the field of molecular and cellular biology of bone is proliferating at a virtually exponential rate. Osteoclastic bone resorption, the major process involved in Type 1 osteoporosis, is the target of several phar...
We have previously shown that the combination of estrogen (E2) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] enhanced alkaline phosphatase (ALP) activity in human osteosarcoma SaOS-2 cells which had been grown in the presence of 10 nmol/L dexamethasone (SaOS + DEX cells). To determine whether this increase in ALP activity was associated with changes i...
We previously developed two models of human osteoblasts with distinct differentiation stages using cells derived from iliac crest trabecular bone explants cultured long term in the presence (HOB + DEX) and absence (HOB - DEX) of 10 nM dexamethasone (DEX) (Wong et al., J Bone Miner Res 1990;5:803). Using these models from 36 subjects aged 41-80 year...
We tested the effect of osteoblastic differentiation on the interactive effects of 17β-oestradiol (E 2 ) and 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) on alkaline phosphatase activity. As cell models we utilized the more differentiated human osteosarcoma (SaOS) cells that had been cultured for 6 days in medium containing 10 n m dexamethasone (Dex...
We have previously shown that osteoblasts derived from trabecular bone explants and cultured long term in 10 nM dexamethasone ((HOB + DEX) cells) exhibited properties consistent with a more differentiated phenotype compared with those grown in the absence of dexamethasone ((HOB-DEX) cells). To characterize these two cell models further, we measured...
We have examined bone cells derived from iliac crest trabecular explants of 30 patients with idiopathic osteoporosis and 45 control subjects in order to determine whether intrinsic abnormalities in osteoblast function may contribute to the decreased bone formation observed in this disease. Bone cells isolated from all subjects expressed several in...
We studied the effects of 17 beta-estradiol (E2) and PTH on alkaline phosphatase activity in SaOS-2 cells that had been passaged and grown continually in the presence (SaOS + Dex) or absence (SaOS - Dex) of 10(-8) M dexamethasone (Dex). We showed that the more differentiated SaOS + Dex cells had higher alkaline phosphatase activity and PTH-responsi...
We studied the effects of 17 beta-estradiol (E2) and PTH on alkaline phosphatase activity in SaOS-2 cells that had been passaged and grown continually in the presence (SaOS + Dex) or absence (SaOS - Dex) of 10(-8) M dexamethasone (Dex). We showed that the more differentiated SaOS + Dex cells had higher alkaline phosphatase activity and PTH-responsi...
Inbred mice of strains A/J, DBA/1J, and SJL/J were housed and aged in our animal colony, and parameters of carbohydrate metabolism were assessed at various ages. The patterns of age-related change were both organ- and strain-specific. Age-related changes in two of the strains were associated with relative carbohydrate intolerance. Common to all thr...
We tested the effects of various parathyroid hormone (PTH) peptides on alkaline phosphatase (ALP) activity in the osteoblastic cell line ROS 17/2.8. In dexamethasone-treated ROS 17/2.8 cells there was a dose-related increase in ALP activity due to treatment with hPTH (53-84). ALP activity was stimulated by 10 nM hPTH (53-84) by a mean of 1.51 +/- 0...
Vertebral morphometry on thoracic and lumbar spine radiographs and bone mass measurements were carried out on 215 patients investigated for postmenopausal osteoporosis. Bone mineral mass was measured on the central third of the skeleton by neutron activation analysis and the result, normalized for body size, expressed as a calcium bone index (CaBI)...
Osteoporosis is, by definition, a reduction in bone mass with remaining bone of normal composition. The related loss in bone strength results in fractures with little or no abnormal force. Since a valid measurement of low bone mass or osteopenia was not widely available until recently, the diagnosis of osteoporosis was based on evidence of vertebra...
Both parathyroid hormone (PTH)- and forskolin-stimulated adenylate cyclase activities in ROS 17/2.8 cells are enhanced by increasing the medium concentrations of CaCl2 from 10(-5) M to 3 x 10(-3) M. The ED50 for CaCl2 for both PTH- and forskolin-stimulated activities are similar. The tumor-promoting phorbol ester phorbol 12-myristate 13-acetate (PM...
The calcium modulation of the cyclic 3',5'-adenosine monophosphate (cAMP) response to parathyroid hormone (PTH) was studied in a clonal osteosarcoma cell line ROS 17/2.8. CaCl2 was found to stimulate the PTH-sensitive cAMP response of intact cells. At the maximal concentration of 1 mM CaCl2, the maximum response to PTH was increased, but the ED50 f...
Previous studies in our laboratory have demonstrated relatively large numbers of cell surface binding sites for the carboxylterminal (53-84) region of PTH on ROS 17/2.8 rat osteosarcoma cells, a clonal osteoblast-like cell line. In order to gain insight into the significance of these carboxylterminal binding sites, we studied the effect of intact b...
The study was conducted in order to determine the effect of exercise on osteoporotic patients with a mean age of 65 years. The majority of these patients had been on sodium fluoride for at least 2 years. Thirty-eight patients were assigned to either the hospital or home group. Nineteen were in the former group, which performed the 1 hour exercise t...
Twenty-one patients with postmenopausal osteoporosis were studied for 4 years after initiation with sodium fluoride (NaF), 20-25 mg b.i.d., elemental calcium, 1.0 g/day, and vitamin D2, 50,000-100,000 I.U. weekly. Histomorphometry was carried out on bone biopsies taken prior to and while on NaF treatment. The total bone mineral mass of the central...
The linear rate of bone mineral apposition (BMAR) was measured in vitamin D-deficient and vitamin D-sufficient adult rats before and during treatment with either 25-hydroxyvitamin D3 (25OHD3), 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], or 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3]. Dietary vitamin D restriction caused a fall in BMAR which began after...
This is the first known attempt to quantitate periosteal resorption (PR) and perisoteal neostosis (PN) by a semi-automatic image analysis system (Zeiss MOP-3). The normal ranges and errors for PR were found to be similar to those of a previous study using a measuring magnifier. The findings in chronic renal failure patients showed that MOP-3 measur...
Regional migratory osteoporosis is a disorder of unknown etiology, characterized by successive episodes of joint pain, accompanied by localized osteoporosis. The disorder affects the lower limbs, usually the region of the foot, knee, or hip, and each episode usually lasts several months and is followed by spontaneous recovery. This disorder has not...
To determine the structural requirements for parathyroid hormone (PTH) activity in mature bone, we perfused the surgically isolated hindquarters of adult male rats with either native bovine PTH-(1-84) [bPTH-(1-84)] or the synthetic amino-terminal fragment, bovine PTH-(1-34) [bPTH-(1-34)]. Changes in the release of cyclic AMP (cAMP) and bone Gla pro...
We studied the binding of bovine PTH (bPTH) to chicken renal plasma membranes using an intact hormone radioligand, [125I]bPTH-(1-84). In contrast to previous studies using amino-terminal radioligands, our experiments revealed the presence of two distinct binding sites for intact bPTH. Scatchard analysis of competition curves consistently gave a bip...
Most studies of PTH receptor binding have been carried out with amino-terminal radioligands which only detect binding within that region of the hormone molecule. We studied the binding of electrolytically labeled intact bovine PTH [bPTH-(1-84)], and its amino-terminal fragment, bPTH-(1-34) to intact cloned rat osteosarcoma cells (ROS 17/2.8). We al...
The calcium content of the central one third of the skeleton was measured using neutron activation analysis in 109 patients with idiopathic calcium nephrolithiasis. The bone mineral content (calcium bone index or CaBI, corrected for body size) was significantly decreased by 5.2% in 20- to 60-year-old patients with calcium nephrolithiasis (p less th...
We have investigated the binding of biologically active radioiodinated bovine PTH-(1-84) to cloned osteoblast-like rat osteosarcoma cells (ROS 17/2.8) and correlated binding with biological response assessed as cAMP production. The hormone was labeled with 125I on tyrosine-43 using a constant current microelectrolytic method which allows full reten...
Cross-reactivity to some component of rat erythrocytes with an antiserum to parathyroid hormone (anti-PTH) was detected in fixed demineralized sections of bone using the peroxidase-antiperoxidase method. The cross-reactivity was eliminated by the preabsorption of anti-PTH with fixed, washed rat erythrocytes. This technique provides an easy and rapi...
Deparaffinized sections of fixed decalcified neonatal rat radii were incubated in bovine PTH (bPTH; 1-10 MRC units/ml) or in PTH-solvent. They were then stained for PTH by the peroxidase-antiperoxidase method using guinea pig antiserum to bPTH and the substrate 3,3'-diaminobenzidine-H2O2. Staining caused by nonspecific binding of PTH to the bone ma...
Binding of PTH to purified canine renal cortical membranes was investigated using biologically active radioiodinated bovine PTH-(1-84) [bPTH-(1-84)] as radioligand. PTH-(1-84) is thought to be the major circulating form of bioactive PTH, but oxidative inactivation upon iodination has prevented its use as a radioligand probe of PTH receptors. We hav...
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 membrane...
Bone biopsies of 23 subjects suffering from primary hyperparathyroidism, which was proven by the demonstration of parathyroid pathology during neck surgery, were studied by morphometric analysis and short interval sequential tetracycline labelling and compared with those of 13 patients without metabolic bone disease. In 19 of these patients, abnorm...