Osteoporosis: Brown J

Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F, Peters E, Hanley DA, Chaudry SR, Dempster DW, Glorieux FH, Neville AJ, Talwar RM, Clokie CM, Al Mardini M, Paul T, Khosla S, Josse RG, Sutherland S, Lam DK, Carmichael RP, Blanas N, Kendler D, Petak S, St-Marie LG, Brown J, Evans AW, Rios L, Compston JE, Anonymous00076. · Divisions of Endocrinology and Geriatrics, McMaster University, Hamilton, Ontario, Canada. · J Rheumatol. · Pubmed #18528958 No free full text.

Abstract: OBJECTIVE: Following publication of the first reports of osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates in 2003, a call for national multidisciplinary guidelines based upon a systematic review of the current evidence was made by the Canadian Association of Oral and Maxillofacial Surgeons (CAOMS) in association with national and international societies concerned with ONJ. The purpose of the guidelines is to provide recommendations regarding diagnosis, identification of at-risk patients, and prevention and management strategies, based on current evidence and consensus. These guidelines were developed for medical and dental practitioners as well as for oral pathologists and related specialists. METHODS: The multidisciplinary task force established by the CAOMS reviewed all relevant areas of research relating to ONJ associated with bisphosphonate use and completed a systematic review of current literature. These evidence-based guidelines were developed utilizing a structured development methodology. A modified Delphi consensus process enabled consensus among the multidisciplinary task force members. These guidelines have since been reviewed by external experts and endorsed by national and international medical, dental, oral surgery, and oral pathology societies. RESULTS: Recommendations regarding diagnosis, prevention, and management of ONJ were made following analysis of all current data pertaining to this condition. ONJ has many etiologic factors including head and neck irradiation, trauma, periodontal disease, local malignancy, chemotherapy, and glucocorticoid therapy. High-dose intravenous bisphosphonates have been identified as a risk factor for ONJ in the oncology patient population. Low-dose bisphosphonate use in patients with osteoporosis or other metabolic bone disease has not been causally linked to the development of ONJ. Prevention, staging, and treatment recommendations are based upon collective expert opinion and current data, which has been limited to case reports, case series, surveys, retrospective studies, and 2 prospective observational studies. Recommendations: In all oncology patients, a thorough dental examination including radiographs should be completed prior to the initiation of intravenous bisphosphonate therapy. In this population, any invasive dental procedure is ideally completed prior to the initiation of high-dose bisphosphonate therapy. Non-urgent procedures are preferably delayed for 3 to 6 months following interruption of bisphosphonate therapy. Osteoporosis patients receiving oral or intravenous bisphosphonates do not require a dental examination prior to initiating therapy in the presence of appropriate dental care and good oral hygiene. Stopping smoking, limiting alcohol intake, and maintaining good oral hygiene should be emphasized for all patients receiving bisphosphonate therapy. Individuals with established ONJ are most appropriately managed with supportive care including pain control, treatment of secondary infection, removal of necrotic debris, and mobile sequestrate. Aggressive debridement is contraindicated. CONCLUSION: Our multidisciplinary guidelines, which provide a rational evidence-based approach to the diagnosis, prevention, and management of bisphosphonate-associated ONJ in Canada, are based on the best available published data and the opinion of national and international experts involved in the prevention and management of ONJ.

Khan AA, Brown J, Faulkner K, Kendler D, Lentle B, Leslie W, Miller PD, Nicholson L, Olszynski WP, Watts NB, Anonymous00159. · McMaster University, Oakville, Ontario, Canada. · J Clin Densitom. · Pubmed #12665644 No free full text.

Abstract: The International Society for Clinical Densitometry (ISCD) is a multidisciplinary nonprofit global organization formed to ensure excellence in densitometry imaging, interpretation, and application. The Canadian panel of the ISCD represents ISCD in Canada and oversees Canadian bone densitometry certification programs. The standards of care from the Canadian panel of the ISCD have been developed in order to establish the minimum level of acceptable performance for the practice of bone densitometry in Canada. A variety of techniques are available for skeletal assessment of bone mineral density, which vary in accuracy, precision, and clinical utility as well as availability. This article focuses on central dual X-ray absorptiometry in adults and does not address densitometry in the pediatric population. Other technologies will be addressed in a subsequent article.

Khan AA, Sándor GK, Dore E, Morrison AD, Alsahli M, Amin F, Peters E, Hanley DA, Chaudry SR, Lentle B, Dempster DW, Glorieux FH, Neville AJ, Talwar RM, Clokie CM, Mardini MA, Paul T, Khosla S, Josse RG, Sutherland S, Lam DK, Carmichael RP, Blanas N, Kendler D, Petak S, Ste-Marie LG, Brown J, Evans AW, Rios L, Compston JE, Anonymous00115. · Divisions of Endocrinology and Geriatrics, McMaster University, Oakville, ON L6J 1X8, Canada. · J Rheumatol. · Pubmed #19286860 No free full text.

Abstract: In 2003, the first reports describing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BP) were published. These cases occurred in patients with cancer receiving high-dose intravenous BP; however, 5% of the cases were in patients with osteoporosis receiving low-dose bisphosphonate therapy. We present the results of a systematic review of the incidence, risk factors, diagnosis, prevention, and treatment of BP associated ONJ. We conducted a comprehensive literature search for relevant studies on BP associated ONJ in oncology and osteoporosis patients published before February 2008.All selected relevant articles were sorted by area of focus. Data for each area were abstracted by 2 independent reviewers. The results showed that the diagnosis is made clinically. Prospective data evaluating the incidence and etiologic factors are very limited. In oncology patients receiving high-dose intravenous BP, ONJ appears to be dependent on the dose and duration of therapy, with an estimated incidence of 1%-12% at 36 months of exposure. In osteoporosis patients, it is rare, with an estimated incidence < 1 case per 100,000 person-years of exposure. The incidence of ONJ in the general population is not known. Currently, there is insufficient evidence to confirm a causal link between low-dose BP use in the osteoporosis patient population and ONJ. We concluded BP associated ONJ is associated with high-dose BP therapy primarily in the oncology patient population. Prevention and treatment strategies are currently based on expert opinion and focus on maintaining good oral hygiene and conservative surgical intervention.

Kanis JA, Oden A, Johnell O, Johansson H, De Laet C, Brown J, Burckhardt P, Cooper C, Christiansen C, Cummings S, Eisman JA, Fujiwara S, Glüer C, Goltzman D, Hans D, Krieg MA, La Croix A, McCloskey E, Mellstrom D, Melton LJ, Pols H, Reeve J, Sanders K, Schott AM, Silman A, Torgerson D, van Staa T, Watts NB, Yoshimura N. · WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK. · Osteoporos Int. · Pubmed #17323110 No free full text.

Abstract: SUMMARY: BMD and clinical risk factors predict hip and other osteoporotic fractures. The combination of clinical risk factors and BMD provide higher specificity and sensitivity than either alone. INTRODUCTION AND HYPOTHESES: To develop a risk assessment tool based on clinical risk factors (CRFs) with and without BMD. METHODS: Nine population-based studies were studied in which BMD and CRFs were documented at baseline. Poisson regression models were developed for hip fracture and other osteoporotic fractures, with and without hip BMD. Fracture risk was expressed as gradient of risk (GR, risk ratio/SD change in risk score). RESULTS: CRFs alone predicted hip fracture with a GR of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR (3.7/SD), and was improved further with the combined use of CRFs and BMD (4.2/SD). For other osteoporotic fractures, the GRs were lower than for hip fracture. The GR with CRFs alone was 1.4/SD at the age of 50 years, similar to that provided by BMD (GR = 1.4/SD) and was not markedly increased by the combination (GR = 1.4/SD). The performance characteristics of clinical risk factors with and without BMD were validated in eleven independent population-based cohorts. CONCLUSIONS: The models developed provide the basis for the integrated use of validated clinical risk factors in men and women to aid in fracture risk prediction.

Adachi JD, Olszynski WP, Hanley DA, Hodsman AB, Kendler DL, Siminoski KG, Brown J, Cowden EA, Goltzman D, Ioannidis G, Josse RG, Ste-Marie LG, Tenenhouse AM, Davison KS, Blocka KL, Pollock AP, Sibley J. · Department of Medicine, St Joseph's Hospital, McMaster University, Hamilton, Ontario, Canada. · Semin Arthritis Rheum. · Pubmed #10707991 No free full text.

Abstract: OBJECTIVES: To educate scientists and health care providers about the effects of corticosteroids on bone, and advise clinicians of the appropriate treatments for patients receiving corticosteroids. METHODS: This review summarizes the pathophysiology of corticosteroid-induced osteoporosis, describes the assessment methods used to evaluate this condition, examines the results of clinical trials of drugs, and explores a practical approach to the management of corticosteroid-induced osteoporosis based on data collected from published articles. RESULTS: Despite our lack of understanding about the biological mechanisms leading to corticosteroid-induced bone loss, effective therapy has been developed. Bisphosphonate therapy is beneficial in both the prevention and treatment of corticosteroid-induced osteoporosis. The data for the bisphosphonates are more compelling than for any other agent. For patients who have been treated but continue to lose bone, hormone replacement therapy, calcitonin, fluoride, or anabolic hormones should be considered. Calcium should be used only as an adjunctive therapy in the treatment or prevention of corticosteroid-induced bone loss and should be administered in combination with other agents. Conclusions: Bisphosphonates have shown significant treatment benefit and are the agents of choice for both the treatment and prevention of corticosteroid-induced osteoporosis.

Watts NB, Lindsay R, Li Z, Kasibhatla C, Brown J. · University of Cincinnati, Cincinnati, Ohio 45219, USA. · Osteoporos Int. · Pubmed #12730756 No free full text.

Abstract: Placebo controls are essential to assess anti-fracture efficacy of new osteoporosis therapies, but inclusion of a placebo arm in a subsequent clinical trial may be limited by practical or ethical considerations; in these cases, use of an historical control may be appropriate. A recent active-controlled study of risedronate 35 mg once a week demonstrated that this regimen produces increases in bone mineral density (BMD) that are comparable to those seen with the risedronate 5 mg daily dose, which has proven anti-fracture efficacy. To assess the anti-fracture efficacy of this new regimen, we have analyzed the fracture data collected in an active controlled study of risedronate dosing regimens (the Once-a-Week study) using matched historical control data from previous placebo-controlled trials. Women in the Once-a-Week study were matched for age, years since menopause, BMD, and prevalent vertebral fracture status, with placebo patients in the Vertebral Efficacy of Risedronate Therapy (VERT) trials forming an historical placebo group. We also constructed an historical active treatment group from the 5 mg daily arm of the VERT trials for comparison with the 5 mg daily and 35 mg once weekly treatment groups in the Once-a-Week study. Data were obtained from the risedronate 5 mg daily group (n=480) and 35 mg once-a-week group (n=485) in the Once-a-Week study and historical control groups representing daily placebo patients (n=114, matched from 993) and risedronate 5 mg daily patients (n=120; matched from 990) in the VERT studies. Patients received calcium supplementation (1000 mg daily); vitamin D was given if baseline serum 25-hydroxyvitamin D levels were low. Over 1 year, new vertebral fracture risk in the 35 mg once-a-week group was reduced by 77% relative to the historical placebo group (1.2% versus 5.0%; RR 0.23; 95% CI, 0.54 to 0.91, P=0.018), similar to the 1-year risk reduction observed in the VERT trials of risedronate 5 mg daily (61-65%). The incidence of new vertebral fractures in the three active treatment groups was similar: 1.7% in the historical risedronate 5 mg group, 1.5% in the risedronate 5 mg daily group from the Once-a-Week study, and 1.2% in the 35 mg once-a-week group. Risedronate 35 mg once a week appears as effective as the 5 mg daily dose in reducing the risk of new vertebral fractures in the first year of treatment. The use of appropriate historical control data provides an approach to the assessment of fracture effects in osteoporosis trials for which placebo-controlled data are not available.

Adachi JD, Saag KG, Delmas PD, Liberman UA, Emkey RD, Seeman E, Lane NE, Kaufman JM, Poubelle PE, Hawkins F, Correa-Rotter R, Menkes CJ, Rodriguez-Portales JA, Schnitzer TJ, Block JA, Wing J, McIlwain HH, Westhovens R, Brown J, Melo-Gomes JA, Gruber BL, Yanover MJ, Leite MO, Siminoski KG, Nevitt MC, Sharp JT, Malice MP, Dumortier T, Czachur M, Carofano W, Daifotis A. · Department of Medicine, McMaster University, Hamilton, Ontario, Canada. · Arthritis Rheum. · Pubmed #11212161 links to  free full text

Abstract: OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids. METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence. RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups. CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

Wallach S, Cohen S, Reid DM, Hughes RA, Hosking DJ, Laan RF, Doherty SM, Maricic M, Rosen C, Brown J, Barton I, Chines AA. · Hospital for Joint Diseases, New York, New York, USA. · Calcif Tissue Int. · Pubmed #11000340 No free full text.

Abstract: Men and women (n = 518) receiving moderate-to-high doses of corticosteroids were enrolled in two studies with similar protocols and randomly assigned to receive either placebo or risedronate (2.5 or 5 mg) for 1 year. All patients received daily calcium supplementation (500-1000 mg), and most also received supplemental vitamin D (400 IU). The primary endpoint was the difference between the placebo and active groups in lumbar spine bone mineral density (BMD) at 1 year; changes in BMD at other sites, biochemical markers of bone turnover, and the incidence of vertebral fractures were also assessed. In the overall population, the mean (SE) lumbar spine BMD increased 1.9 +/- 0.38% from baseline in the risedronate 5 mg group (P < 0.001) and decreased 1.0 +/- 0.4% in the placebo group (P = 0. 005). BMD at the femoral neck, trochanter, and distal radius increased or was maintained with risedronate 5 mg treatment, but decreased in the placebo group. Midshaft radius BMD did not change significantly in either treatment group. The difference in BMD between the risedronate 5 mg and placebo groups was significant at all skeletal sites (P < 0.05) except the midshaft radius at 1 year. The 2.5 mg dose also had a positive effect on BMD, although of a lesser magnitude than that seen with risedronate 5 mg. A significant reduction of 70% in vertebral fracture risk was observed in the risedronate 5 mg group compared with the placebo group (P = 0.01). Risedronate was efficacious in both men and women, irrespective of underlying disease and duration of corticosteroid therapy, and had a favorable safety profile, with a similar incidence of upper gastrointestinal adverse events in the placebo and active treatment groups. Daily treatment with risedronate 5 mg significantly increases BMD and decreases vertebral fracture risk in patients receiving moderate-to-high doses of corticosteroid therapy.

Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, Chesnut CH, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD. · University of California, San Francisco 94117-3608, USA. · JAMA. · Pubmed #10527181 links to  free full text

Abstract: CONTEXT: Risedronate, a potent bisphosphonate, has been shown to be effective in the treatment of Paget disease of bone and other metabolic bone diseases but, to our knowledge, it has not been evaluated in the treatment of established postmenopausal osteoporosis. OBJECTIVE: To test the efficacy and safety of daily treatment with risedronate to reduce the risk of vertebral and other fractures in postmenopausal women with established osteoporosis. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial of 2458 ambulatory postmenopausal women younger than 85 years with at least 1 vertebral fracture at baseline who were enrolled at 1 of 110 centers in North America conducted between December 1993 and January 1998. INTERVENTIONS: Subjects were randomly assigned to receive oral treatment for 3 years with risedronate (2.5 or 5 mg/d) or placebo. All subjects received calcium, 1000 mg/d. Vitamin D (cholecalciferol, up to 500 IU/d) was provided if baseline levels of 25-hydroxyvitamin D were low. MAIN OUTCOME MEASURES: Incidence of new vertebral fractures as detected by quantitative and semiquantitative assessments of radiographs; incidence of radiographically confirmed nonvertebral fractures and change from baseline in bone mineral density as determined by dual x-ray absorptiometry. RESULTS: The 2.5 mg/d of risedronate arm was discontinued after 1 year; in the placebo and 5 mg/d of risedronate arms, 450 and 489 subjects, respectively, completed all 3 years of the trial. Treatment with 5 mg/d of risedronate, compared with placebo, decreased the cumulative incidence of new vertebral fractures by 41 % (95% confidence interval [CI], 18%-58%) over 3 years (11.3 % vs 16.3%; P= .003). A fracture reduction of 65% (95% CI, 38%-81 %) was observed after the first year (2.4% vs 6.4%; P<.001). The cumulative incidence of nonvertebral fractures over 3 years was reduced by 39% (95% CI, 6%-61 %) (5.2 % vs 8.4%; P = .02). Bone mineral density increased significantly compared with placebo at the lumbar spine (5.4% vs 1.1 %), femoral neck (1.6% vs -1.2%), femoral trochanter (3.3% vs -0.7%), and midshaft of the radius (0.2% vs -1.4%). Bone formed during risedronate treatment was histologically normal. The overall safety profile of risedronate, including gastrointestinal safety, was similar to that of placebo. CONCLUSIONS: These data suggest that risedronate therapy is effective and well tolerated in the treatment of women with established postmenopausal osteoporosis.

Papaioannou A, Ioannidis G, Adachi JD, Sebaldt RJ, Ferko N, Puglia M, Brown J, Tenenhouse A, Olszynski WP, Boulos P, Hanley DA, Josse R, Murray TM, Petrie A, Goldsmith CH. · Department of Medicine, McMaster University, Hamilton, Ontario, Canada. · Osteoporos Int. · Pubmed #14523610 No free full text.

Abstract: 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.

Ungar WJ, Josse R, Lee S, Ryan N, Adachi R, Hanley D, Brown J, Breton MC. · Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. · J Clin Densitom. · Pubmed #11090234 No free full text.

Abstract: The Simple Calculated Osteoporosis Risk Estimation (SCORE) questionnaire is a tool to assist physicians to identify women who might require bone densitometry. The purpose of this study was to develop a Canadian SCORE and to assess validity and reliability. Twenty sites enrolled 307 postmenopausal women ages 50-70 yr. SCORE results were compared to hip and lumbar spine bone density assessed by dual X-ray absorptiometry. Sensitivity and specificity of a range of SCORE cut-points were assessed in a receiver operating characteristics analysis to determine the optimal cut-point for SCORE. With low bone density defined as a T-score < or = -2.0, a SCORE cut-point of 6 in women ages 50-59 yr displayed a sensitivity of 0. 96, 95% confidence interval (CI) (0.89, 1.00), a specificity of 0.51, 95% CI (0.43, 0.58). In women ages 60-70 yr, a SCORE cut-point of 8 displayed a sensitivity of 0.90, 95% CI (0.80, 0.97) and a specificity of 0.20, 95% CI (0.11, 0.29). The test-retest reliability (intraclass correlation coefficient) was 0.95. SCORE performed better in women in their fifties than women in ther sixties. Older women require higher SCORE cut-points. The use of SCORE as an initial measure for identifying those at risk for osteoporosis may reduce costs by limiting unnecessary tests.

Adachi JD, Roux C, Pitt PI, Cooper C, Moniz C, Dequeker J, Ioannidis G, Cawley MI, Jenkins EA, Walker-Bone KE, Pack S, Stephenson GF, Laan RF, Brown J, Geusens P. · St. Joseph's Hospital, McMaster University, Hamilton, Ontario, Canada. · J Rheumatol. · Pubmed #11036840 No free full text.

Abstract: OBJECTIVE: To conduct a pooled data analysis in a group of patients defined by sex, menopausal status, and underlying disease in order to examine the effect of intermittent cyclical etidronate in the prevention and treatment of corticosteroid induced osteoporosis. METHODS: We selected 5 randomized, placebo controlled studies that examined the efficacy of intermittent cyclical etidronate therapy in which the raw data were available for analysis. Three were prevention studies and 2 treatment studies. The primary outcome was the difference between treatment groups in the percentage change from baseline in lumbar spine bone density. Secondary outcomes included the difference between treatment groups in the percentage change from baseline in femoral neck and trochanter bone density, and vertebral fracture rates. RESULTS: Results are separately pooled for the prevention and treatment studies. The prevention studies had significant mean differences (95% CI) between groups in mean percentage change from baseline in lumbar spine, femoral neck, and trochanter bone density of 3.7 (2.6 to 4.7), 1.7 (0.4 to 2.9), and 2.8% (1.3 to 4.2) after one year of treatment, in favor of the etidronate group. The treatment studies displayed a mean difference between groups in mean percentage change from baseline in lumbar spine bone density of 4.8 (2.7 to 6.9) and 5.4% (2.5 to 8.4) after one and 2 years of therapy. In the prevention studies, a reduced fracture incidence was observed in the etidronate group compared with the placebo group (relative risk 0.50; CI 0.21 to 1.19). CONCLUSION: Etidronate therapy was effective in preventing bone loss in the prevention studies and in preventing or slightly increasing bone mass in the treatment studies. A fracture benefit was observed in postmenopausal women treated with etidronate in the prevention studies.

Byers RJ, Brown J, Brandwood C, Wood P, Staley W, Hainey L, Freemont AJ, Hoyland JA. · Department of Pathological Sciences, University of Manchester, U.K. · J Pathol. · Pubmed #10398094 No free full text.

Abstract: Investigation of osteoblast dysfunction in osteoporosis has been hampered by a poor understanding of normal early osteoblast differentiation, due to a relative lack of markers for the earliest cells in the lineage. Attempts to identify such markers have used cultures of animal or immortalized human cells, of uncertain relevance to human biology, or heterogeneous cultures in which genetic variability precludes the isolation of stage-specific genotypic markers. Primary in vitro generation of clonal populations of human bone marrow stromal cells was used in order to overcome these problems. Fibroblast-like stromal cells were isolated from human sternal bone marrow. They showed differentiation to an osteoblastic phenotype when stimulated with dexamethasone (10(-7) M) and fluorescence activated cell analysis demonstrated immunopositivity for STRO-1 (an antibody that recognizes osteoprogenitor stem cells of the colony-forming unit-fibroblastic) in from 8 to 40 per cent of the cells, dependent on time post-harvest. Cells positive for STRO-1 were immunoselected using magnetic activated cell sorting and seeded at low density (10 cells/cm2) to produce clones. Each clone was subpassaged, osteoblastic differentiation stimulated with dexamethasone, and mRMA-extracted at time points post-stimulation (0 h and 1-14 days). A novel poly (A) reverse transcriptase-polymerase chain reaction (RT-PCR) was used to amplify cDNA representative of all transcripts expressed at each time point. Differential gene expression within the amplified cDNA was assessed using 3' end cDNA probes to osteocalcin, osteopontin, and collagen type I (positive), demonstrating the acquisition of an osteoblastic phenotype. Time-specific gene products for early osteoblast differentiation have been generated from primary human cultures, utilizing very low density seeding and poly (A) RT-PCR. These products overcome the problems associated with animal, immortalized or heterogeneous culture and can be used to study normal and altered early osteoblast differentiation, indicating the possibility of using the same system to study other disease states.