Osteoporosis: Hanley DA

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, Hanley DA, Bilezikian JP, Binkley N, Brown JP, Hodsman AB, Josse RG, Kendler DL, Lewiecki EM, Miller PD, Olszynski WP, Petak SM, Syed ZA, Theriault D, Watts NB, Anonymous00369. · Division of Endocrinology, McMaster University, Hamilton, Ontario, Canada, and Hanover General Hospital, PA, USA. · J Clin Densitom. · Pubmed #16731431 No free full text.

Abstract: This document addresses skeletal health assessment in individuals with secondary causes of osteoporosis. Recommendations are based on consensus of the Canadian Panel of the International Society for Clinical Densitometry and invited international experts. Bone mineral density (BMD) testing in these populations is performed in conjunction with careful evaluation of the disease state contributing to bone loss and increased fragility fracture risk, as well as assessment of other contributing risk factors for fracture. The presence of secondary causes of bone loss may further increase the risk of fracture independently of BMD and may necessitate earlier pharmacologic intervention. Dual-energy X-ray absorptiometry is indicated in the initial workup of secondary causes of osteoporosis. The BMD fracture risk relationship is not known for individuals with chronic renal failure (CRF). The BMD testing in this population may be normal in the presence of skeletal fragility, and quantitative bone histomorphometry is better at evaluating skeletal status than BMD in CRF. Dual-energy X-ray absorptiometry is a valuable tool in assessing skeletal health in individuals with secondary causes of osteoporosis.

Khan AA, Bachrach L, Brown JP, Hanley DA, Josse RG, Kendler DL, Leib ES, Lentle BC, Leslie WD, Lewiecki EM, Miller PD, Nicholson RL, O'Brien C, Olszynski WP, Theriault MY, Watts NB, Anonymous00235. · Divisions of Endocrinology and Geriatrics, McMaster University, Hamilton, ON, Canada. · J Clin Densitom. · Pubmed #14742888 No free full text.

Abstract: The Canadian Panel of the International Society for Clinical Densitometry has developed standards in order to establish the minimum level of acceptable performance for the practice of bone densitometry in Canada. Previously, this group addressed the performance of densitometry in postmenopausal women. This report addresses the use of densitometry in men, premenopausal women, and children with a focus on dual-energy X-ray absorptiometry.

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.

Khan AA, Colquhoun A, Hanley DA, Jankowski LG, Josse RG, Kendler DL, Lentle B, Leslie WD, Lewiecki EM, O'neill E, Robertson S, Syed ZA, Tanner SB, Webster D. · Division of Endocrinology, McMaster University, Hamilton, Ontario, Canada. · J Clin Densitom. · Pubmed #17485038 No free full text.

This publication has no abstract.

Sawka AM, Papaioannou A, Adachi JD, Gafni A, Hanley DA, Thabane L. · Department of Medicine, St, Joseph's Healthcare and McMaster University, Hamilton, Ontario, Canada. · BMC Musculoskelet Disord. · Pubmed #16008835 links to  free full text

Abstract: BACKGROUND: Alendronate has been found to reduce the risk of fractures in postmenopausal women as demonstrated in multiple randomized controlled trials enrolling thousands of women. Yet there is a paucity of such randomized controlled trials in osteoporotic men. Our objective was to systematically review the anti-fracture efficacy of alendronate in men with low bone mass or with a history of prevalent fracture(s) and incorporate prior knowledge of alendronate efficacy in women in the analysis. METHODS: We examined randomized controlled trials in men comparing the anti-fracture efficacy of alendronate to placebo or calcium or vitamin D, or any combination of these. Studies of men with secondary causes of osteoporosis other than hypogonadism were excluded. We searched the following electronic databases (without language restrictions) for potentially relevant citations: Medline, Medline in Process (1966-May 24/2004), and Embase (1996-2004). We also contacted the manufacturer of the drug in search of other relevant trials. Two reviewers independently identified two trials (including 375 men), which met all inclusion criteria. Data were abstracted by one reviewer and checked by another. Results of the male trials were pooled using Bayesian random effects models, incorporating prior information of anti-fracture efficacy from meta-analyses of women. RESULTS: The odds ratios of incident fractures in men (with 95% credibility intervals) with alendronate (10 mg daily) were: vertebral fractures, 0.44 (0.23, 0.83) and non-vertebral fractures, 0.60 (0.29, 1.44). CONCLUSION: In conclusion, alendronate decreases the risk of vertebral fractures in men at risk. There is currently insufficient evidence of a statistically significant reduction of non-vertebral fractures, but the paucity of trials in men limit the statistical power to detect such an effect.

Sawka AM, Boulos P, Beattie K, Thabane L, Papaioannou A, Gafni A, Cranney A, Zytaruk N, Hanley DA, Adachi JD. · Division of Endocrinology and Department of Medicine, St. Joseph's Healthcare and McMaster University, Hamilton, Ontario, Canada. · Osteoporos Int. · Pubmed #15990949 No free full text.

Abstract: Hip fractures are an important cause of morbidity and mortality in the elderly. Hip protectors are padded undergarments designed to decrease the impact of a fall on the hip. We systematically reviewed randomized controlled trials of hip protectors to determine if they reduce hip fractures in the elderly. Analyses were pooled according to participant residence--community or institutional (the latter, included nursing homes, residential group homes or seniors' hostels). We included individually randomized and statistically adjusted cluster randomized trials. Seven trials of 12- to 28-month duration were included. The Safehip brand of hip protector was used in most studies. Compliance rates in the treatment groups varied from 31 to 68%. In four trials including a total of 5,696 community-dwelling seniors, the hip fracture rates in control groups ranged from 1.1 to 7.4%, and the pooled risk difference with hip protector allocation was 0% [95% confidence intervals (CI), -1%, +1%), with a relative risk of 1.07 (0.81, 1.42). In three trials including 1,188 institutionalized elderly participants, hip fracture rates in the control groups varied from 8 to 19.4%, and the pooled risk difference for sustaining one or more hip fractures with hip protector allocation was -3.7% (95% CI, -7.4%, 0.1%), with a relative risk of 0.56 (0.31, 1.01) (with statistically significant heterogeneity of treatment effect). In a post-hoc subgroup analysis of two trials comprised of exclusively nursing home residents, the risk difference with hip protector allocation was -4.4% (-8.09, -0.76) with a relative risk of 0.50 (0.28, 0.91) (n=1,014). Thus, there is little evidence to support the use of hip protectors outside the nursing home setting. The potential benefit of hip protectors in reducing hip fractures in nursing home residents requires further confirmation.

Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, Kendler DL, McClung MR, Miller PD, Olszynski WP, Orwoll E, Yuen CK. · University of Western Ontario, St. Joseph's Health Care, Room 2F-15, 268, Grosvenor Street, London, Ontario N6A 4V2, Canada. · Endocr Rev. · Pubmed #15769903 links to  free full text

Abstract: All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.

L'Abbé MR, Whiting SJ, Hanley DA. · Bureau of Nutritional Sciences, Health Canada, Ottawa, Canada. mary_l' · J Am Coll Nutr. · Pubmed #15310733 links to  free full text

Abstract: To provide evidence for or against allowing a health claim for calcium in Canada, we undertook a review of the current U.S. health claim for calcium and osteoporosis, and also reviewed the scientific literature published since that health claim was first proposed and reviewed by the U.S. Food and Drug Administration in 1991 and adopted in 1993. Our objectives were 1) to determine if the science behind the claim was still valid, and if so, 2) to recommend any new wording to the claim, if warranted, prior to implementation in Canada. Based on a review of the evidence (to May 2000) related to the various claim elements, the following health claim for calcium has been established in Canada: A healthy diet with adequate calcium and vitamin D, and regular physical activity, help to achieve strong bones and may reduce the risk of osteoporosis. The compositional criteria for foods bearing this claim are that the food must provide at least 200 mg calcium per serving and that the phosphorus content (excluding that provided by phytate) must be less than the calcium content.

Olszynski WP, Shawn Davison K, Adachi JD, Brown JP, Cummings SR, Hanley DA, Harris SP, Hodsman AB, Kendler D, McClung MR, Miller PD, Yuen CK. · Department of Medicine, University of Saskatchewan, Saskatoon Osteoporosis Centre, Saskatoon, Saskatchewan, Canada. · Clin Ther. · Pubmed #14996514 No free full text.

Abstract: BACKGROUND: Osteoporosis and fragility fractures in men account for substantial health care expenditures and decreased quality of life. OBJECTIVE: This article reviews the most current information about the epidemiology, diagnosis, prevention, and treatment of osteoporosis in men. METHODS: Relevant literature was identified through a search of MEDLINE (1966-June 2003) limited to English-language studies in men. The search terms included fractures, bone density, or osteoporosis plus either epidemiology, diagnosis, prevention, control, or therapy. Additional search terms included specific subtopics (eg, bisphosphonates, calcium, exercise, parathyroid hormone). The authors contributed additional relevant publications. RESULTS: Morbidity after fragility fracture is at least as high in men as in women, and the rate of fracture-related mortality 1 year hip fracture is approximately double in men compared with women. The bioavailable fraction of testosterone slowly declines into the ninth decade in men. There is evidence that the effect of estrogen on bone is greater than that of testosterone in men. Diagnosing osteoporosis in men is complicated by a lack of consensus on how it should be defined. Significant risk factors for osteoporosis or fracture include low bone mineral density, previous fragility fracture, maternal history of fracture, marked hypogonadism, smoking, heavy alcohol intake or alcoholism, low calcium intake, low body mass or body mass index, low physical activity, use of bone-resorbing medication such as glucocorticoids, and the presence of such conditions as hyperthyroidism, hyperparathyroidism, and hypercalciuria. Prevention is paramount and should begin in childhood. During adulthood, calcium (1000-1500 mg/d), vitamin D (400-800 IU/d), and adequate physical activity play crucial preventive roles. When treatment is indicated, the bisphosphonates are the first choice, whereas there is less support for the use of calcitonin or androgen therapy. Parathyroid hormone (1-34) is a promising anabolic therapy. There is also strong evidence for the use of bisphosphonates for the treatment of glucocorticoid-induced osteoporosis.

Hanley DA, Ioannidis G, Adachi JD. · Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. · J Clin Densitom. · Pubmed #10745305 No free full text.

Abstract: Etidronate disodium is an oral bisphosphonate compound known to reduce bone resorption through the inhibition of osteoclastic activity. This article is a review of its efficacy and safety in the treatment and prevention of postmenopausal and corticosteroid-induced osteoporosis. In general, studies of cyclical etidronate therapy (400 mg daily for 2 wk every 3 mo) have found a significant improvement in bone density. These studies have not been powered to study fracture incidence, but a reduced fracture rate has been found in some of the studies reviewed. Studies examining cyclical etidronate in the prevention of osteoporosis indicate it prevents early menopausal bone loss and is free of significant side effects. In both prevention of corticosteroid-induced osteoporosis and treatment of patients who have been on long-term corticosteroid therapy, cyclical etidronate appears to increase bone density and prevent further loss of bone. In summary, a review of available literature pertaining to the use of etidronate in prevention and treatment of primary and secondary osteoporosis has been presented. This review suggests etidronate, used as a cyclical therapy, is a safe and effective therapy. The weight of evidence suggests it is capable of reducing fracture risk in patients with osteoporosis. Increases in bone density at the spine and hip are not as pronounced as with some other bisphosphonates, particularly alendronate, but no direct clinical comparison trials of significant size or duration have been undertaken.

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.

Majumdar SR, Kim N, Colman I, Chahal AM, Raymond G, Jen H, Siminoski KG, Hanley DA, Rowe BH. · Division of General Internal Medicine, Department of Medicine, Room 2E3.07 Walter Mackenzie Health Sciences Centre, Uinversity of Alberta Hospital, 8440 112th St, Edmonton, Alberta, Canada T6G 2B7. · Arch Intern Med. · Pubmed #15851642 links to  free full text

Abstract: BACKGROUND: Vertebral fractures are common and usually an indication for osteoporosis treatment. However, screening is not recommended, and many fractures go undetected. Our objectives were to determine the utility of chest radiographs for detecting previously unrecognized vertebral fractures; document rates of recognition; and evaluate osteoporosis treatments. METHODS: In 2001, we conducted a cohort study in a random sample of 500 patients older than 60 years who presented to our emergency department and underwent chest radiography for any indication. The primary outcome was prevalence of moderate-to-severe vertebral fractures determined by independent radiograph review using validated semiquantitative techniques. Secondary outcomes were rates of fracture recognition according to official radiologists' reports and rates of osteoporosis diagnosis and treatment. We conducted multivariable regression analyses to determine correlates of study-defined and officially reported fractures. RESULTS: We excluded 36 patients with inadequate radiographs and 5 for other reasons. Mean age was 75.2 years; 47% were women; and 80% were white. The prevalence of moderate-to-severe vertebral fractures according to independent review was 72 (16%) of 459; 29 (40%) of these fractures were not recorded in the official radiologists' report (kappa = 0.64; 95% confidence interval [CI], 0.53-0.75). A history of osteoporosis was the only independent correlate of having a vertebral fracture identified by independent review (adjusted odds ratio [OR], 2.18; 95% CI, 1.14-4.17) or by official report (adjusted OR, 4.97; 95% CI, 0.95-25.86). Of the 72 patients with fractures, only 18 (25%) had histories of osteoporosis or received osteoporosis medications. CONCLUSIONS: One in 6 elderly patients who underwent chest radiography in our emergency department had clinically important vertebral fractures. Nevertheless, only 43 (60%) of these fractures were reported, and only 25% of patients with fractures received a diagnosis of or treatment for osteoporosis.

Majumdar SR, Rowe BH, Folk D, Johnson JA, Holroyd BH, Morrish DW, Maksymowych WP, Steiner IP, Harley CH, Wirzba BJ, Hanley DA, Blitz S, Russell AS. · Department of Medicine, University of Alberta, 2E3.07 Walter Mackenzie Health Sciences Centre, University of Alberta Hospital, 8440 112th Street, Edmonton, Alberta T6G 2B7, Canada. · Ann Intern Med. · Pubmed #15353428 links to  free full text

Abstract: BACKGROUND: Despite the high risk for future fractures and the availability of effective treatments, fewer than 10% to 20% of patients who sustain a fragility fracture are tested or treated for osteoporosis. OBJECTIVES: To improve rates of testing and treatment for osteoporosis in patients with wrist fractures who are seen in the emergency department. DESIGN: Nonrandomized, controlled trial with blinded ascertainment of outcomes. SETTING: Emergency departments in Edmonton, Alberta, Canada. PATIENTS: Persons 50 years of age or older who were treated for a wrist fracture and their physicians. Patients admitted to the hospital or treated for osteoporosis were excluded. Overall, 572 consecutive patients with fractures were screened, and 102 patients (55 intervention, 47 control) and 101 physicians were studied. MEASUREMENTS: The primary end point was the prescription of osteoporosis treatment 6 months after fracture. Secondary end points included rates of testing for bone mineral density and patients' knowledge, satisfaction, and quality of life. INTERVENTION: Faxed physician reminders that contained osteoporosis treatment guidelines endorsed by local opinion leaders and patient education. Control patients received usual care and information about falls and home safety. RESULTS: The median patient age was 66 years. Most patients were female (78%) and white (79%); 70% of patients reported a previous fracture, and 22% had a fall with injury in the previous year. The intervention increased the rates of testing for bone mineral density to 62% (vs. 17% for controls; adjusted relative increase, 3.6 [P < 0.001]) and the rates of osteoporosis treatment to 40% (vs. 10% for controls; adjusted relative increase, 3.8 [P = 0.002]) within 6 months of fracture. Intervention patients were more likely to report a diagnosis of osteoporosis, but other patient-reported outcomes did not differ significantly between groups. LIMITATIONS: This was a small, nonrandomized, controlled study with process-based outcomes. CONCLUSIONS: In a multifaceted intervention directed at patients and their physicians, the rates of testing and treatment for osteoporosis after emergency department care for a fragility fracture were more than 3 times those of controls.

Harris ST, Watts NB, Li Z, Chines AA, Hanley DA, Brown JP. · University of California, San Francisco, California 94117, USA. · Curr Med Res Opin. · Pubmed #15140343 No free full text.

Abstract: OBJECTIVE: The efficacy and tolerability of risedronate once-a-week dosing (35 and 50mg) were compared with risedronate daily dosing (5mg) in a 2-year study in women with osteoporosis. DESIGN AND METHODS: This was a randomized, double-blind, active-control study with lumbar spine bone mineral density (BMD) as the primary efficacy endpoint at 1 year. Subjects were women aged 50 years or older, postmenopausal for at least 5 years, and had either a BMD T-score of -2.5 or lower (lumbar spine or total proximal femur) or a T-score lower than -2 and at least one prevalent vertebral fracture. In addition to risedronate treatment, the subjects received 1000 mg daily of elemental calcium supplementation and received vitamin D if the baseline serum 25-hydroxyvitamin D(3) level was low. RESULTS: The results after 1 year of treatment were previously published. Of the 1456 women who were randomized and received study medication, 1127 (77%) completed the 2-year study. Over the 2 years of treatment, the incidence of both new vertebral fractures (2.9, 1.5, and 1.7% for the 5, 35, and 50 mg groups, respectively; for women with postmenopausal osteoporosis who p = 0.298) and osteoporosis-related non-vertebral fractures reported as adverse events (5.0, 4.9, and 4.5% for the 5, 35, and 50 mg groups, respectively; p = 0.918) was similar for all 3 treatment groups. The reduction from baseline at Month 24 in bone turnover markers was similar based on an analysis of variance for the 5 mg daily and the 35 mg once-a-week groups. The mean percentage change in lumbar spine BMD after 24 months was 5.17, 4.74, and 5.47% for the 5, 35, and 50 mg groups, respectively. Both the 35 and 50 mg once-a-week treatment groups met the pre-specified criterion of non-inferiority to the 5 mg daily treatment group. No apparent difference in the pattern or distribution of serious and upper gastrointestinal adverse events was observed. CONCLUSIONS: The 2-year data agree with the 1-year results demonstrating that the risedronate once-a-week doses are comparable in efficacy and safety to the 5 mg daily dose. Risedronate 35 mg once a week is considered the optimal dose want a once-a-week dosing regimen.

Hodsman AB, Hanley DA, Ettinger MP, Bolognese MA, Fox J, Metcalfe AJ, Lindsay R. · Department of Medicine, Lawson Health Research Institute, University of Western Ontario, London, Ontario, Canada N6A 4V2. · J Clin Endocrinol Metab. · Pubmed #14602752 links to  free full text

Abstract: Daily sc injections of N-terminal analogs of PTH increase bone mass and decrease fractures in osteoporotic women. We investigated the efficacy and safety of human PTH-(1-84) (full-length PTH) in the treatment of postmenopausal osteoporosis in a double-blind, placebo-controlled study. The women (n = 50-53/group) self-administered PTH (50, 75, or 100 microg) or placebo by daily sc injection for 12 months. PTH treatment induced time- and dose-related increases in lumbar spine bone mineral density (BMD). The 100-microg dose increased BMD significantly at 3 months (+2.0%) and 12 months (+7.8%). BMD underestimated the anabolic effect of PTH in lumbar spine (bone mineral content, +10.0%) because bone area increased significantly (+2.0%). A nonsignificant decrease (-0.9%) in total hip BMD occurred during the first 6 months with the 100-microg dose, but this trend reversed (+1.6%) during the second 6 months. Bone turnover markers increased during the first half of the study and were maintained at elevated levels during the second 6 months. Protocol compliance was excellent (95-98%), and treatment was generally safe and well tolerated. Dose-related incidences of transient hypercalcemia occurred, but only one patient (100-microg group) was withdrawn because of repeated hypercalcemia. Thus, full-length PTH was efficacious and safe over 12 months.

Brown JP, Olszynski WP, Hodsman A, Bensen WG, Tenenhouse A, Anastassiades TP, Ste-Marie LG, Kendler DL, Hanley DA, Josse R, Hanly JG, Lentle B, Jovaisas A, Ioannidis G, Stephenson GF, Barton I, Pack S, Chines A, Dias R, Adachi JD. · Centre de Recherche du CHUL, Centre Hospitalier Universitaire de Quebec, 2705 boul Laurier #S-784, Ste-Foy, Québec, G1V 4G2 Canada. · J Clin Densitom. · Pubmed #11748341 No free full text.

Abstract: Following a 52-wk randomized controlled trial of intermittent cyclic etidronate therapy in patients using corticosteroids, we performed a 52-wk open-label trial of calcium alone in 114 corticosteroid-treated patients to determine whether the beneficial effect of etidronate is maintained after the drug is discontinued. All patients were given 500 mg/d of elemental calcium. Sixty-one and 53 patients made up the former placebo and etidronate groups, respectively. A total of 89 (98%) of patients in the former placebo and etidronate groups remained on corticosteroids throughout the second year. The mean (SE) percentage change in bone mineral density of the lumbar spine, femoral neck, and trochanter were compared between groups. The difference between groups in mean percentage change from baseline (wk 0, initiation of etidronate or placebo therapy) in the bone density of the lumbar spine, femoral neck, and trochanter, following 104 wk, was 3.8 (0.9), 3.0 (1.1), and 4.3 (1.1), respectively (p < 0.05, all sites), in favor of the former etidronate group. While not significant, the former placebo group demonstrated a slightly larger rate of decline in bone density over the second year than the former etidronate group at all three sites. Following the discontinuation of etidronate therapy, there was no accelerated bone loss and there was evidence of a residual protective effect in both the lumbar spine and femoral neck for up to 1 yr posttreatment.

Rittmaster RS, Bolognese M, Ettinger MP, Hanley DA, Hodsman AB, Kendler DL, Rosen CJ. · Department of Medicine and the Queen Elizabeth II Health Sciences Center, Dalhousie University, Halifax, Nova Scotia, Canada. · J Clin Endocrinol Metab. · Pubmed #10852440 links to  free full text

Abstract: Treatment of osteoporosis with PTH causes a marked increase in vertebral bone mineral density (BMD). However, this effect is rapidly reversed when the treatment is stopped. The purpose of the present study was to determine whether the bisphosphonate alendronate could preserve or enhance bone density in patients previously treated with PTH. Sixty-six postmenopausal osteoporotic women were treated for 1 yr with 50, 75, or 100 microg recombinant human PTH-(1-84) or placebo, and then were given 10 mg alendronate daily for an additional year. BMD was measured in the femoral neck, lumbar spine, and whole body. Markers of bone turnover included skeletal alkaline phosphatase, osteocalcin, and N-telopeptide. During the first year, changes in BMD (mean +/- SD) in women receiving PTH (all doses combined) were 7.1 +/- 5.6% (spine), 0.3 +/- 6.2% (femoral neck), and -2.3 +/- 3.3% (total body). After switching to alendronate for 1 yr in women who previously had received PTH, mean changes in BMD were 13.4 +/- 6.4% (spine), 4.4 +/- 7.2% (femoral neck), and 2.6 +/- 3.1% (whole body). In the subgroup of patients who had received the highest dose of PTH, the mean increase in vertebral BMD was 14.6 +/- 7.9%. All markers of bone turnover increased during treatment with PTH and decreased to below baseline after 1 yr of alendronate. In conclusion, sequential treatment of osteoporosis with PTH and alendronate results in an increase in vertebral bone density that is considerably more than has been reported with alendronate or estrogens alone. This combination of drugs may be a useful approach to maximizing bone density in women with vertebral osteoporosis.

Pols HA, Felsenberg D, Hanley DA, Stepán J, Muñoz-Torres M, Wilkin TJ, Qin-sheng G, Galich AM, Vandormael K, Yates AJ, Stych B. · Erasmus University Medical School, Rotterdam, The Netherlands. · Osteoporos Int. · Pubmed #10550467 No free full text.

Abstract: This randomized, double-masked, placebo-controlled trial evaluated the safety, tolerability and effects on bone mineral density (BMD) of alendronate in a large, multinational population of postmenopausal women with low bone mass. At 153 centers in 34 countries, 1908 otherwise healthy, postmenopausal women with lumbar spine BMD 2 standard deviations or more below the premenopausal adult mean were randomly assigned to receive oral alendronate 10 mg (n = 950) or placebo (n = 958) once daily for 1 year. All patients received 500 mg elemental calcium daily. Baseline characteristics of patients in the two treatment groups were similar. At 12 months, mean increases in BMD were significantly (p</=0.001) greater in the alendronate than the placebo group by 4.9% (95% confidence interval 4.6% to 5.2%) at the lumbar spine, 2.4% (2.0% to 2.8%) at the femoral neck, 3.6% (3.2% to 4.1%) at the trochanter and 3.0% (2.6% to 3.4%) for the total hip. The incidence of nonvertebral fractures was significantly lower in the alendronate than the placebo group (19 vs 37 patients with fractures), representing a 47% risk reduction for nonvertebral fracture for alendronate-treated patients (95% confidence interval 10% to 70%; p = 0.021). Incidences of adverse events, including upper gastrointestinal adverse events, were similar in the two groups. Therefore, for postmenopausal women with low bone mass, alendronate is well tolerated and produces significant, progressive increases in BMD at the lumbar spine and hip in addition to significant reduction in the risk of nonvertebral fracture.

Fenton TR, Eliasziw M, Lyon AW, Tough SC, Brown JP, Hanley DA. · Alberta Health Services, Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada T2N 4N1. · Nutr Res. · Pubmed #19555813 No free full text.

Abstract: Most analyses of urine ion excretion and pH are based on 24-hour urine collections. However, fasting morning urine, collected in the morning after an initial void and a short fast, is easier to collect and may be sensitive to dietary intake. The objective of this study was to determine whether the within-subject dietary acid load is stable by testing the levels of urine pH and ion excretion (ie, calcium, chloride, magnesium, phosphate, potassium, sodium, sulfate) in fasting morning urine specimens collected at a 5-year interval. Stable variables provide the best utility as potential risk factors. The subjects were 200 randomly selected adults (mean age = 61.5 +/- 11.1 years) from the 420 subjects who donated baseline and 5-year urine samples in the Canadian Multicentre Osteoporosis Study. The samples were collected in the morning after an initial void and a wait of 2 hours, while subjects maintained a fast from the evening before. The intraclass correlation coefficient was calculated to characterize the level of agreement between the baseline and 5-year urine samples as an indirect measure of diet stability. The stability of the within-subject urine measures over 5 years ranged from fair to moderate, and none were ranked as substantially stable. This fair-to-moderate stability of fasting morning urine measures of the diet acid load indicates a limited ability of a single sample of fasting morning urine to estimate subjects' actual long-term urine composition.

Brown JP, Albert C, Nassar BA, Adachi JD, Cole D, Davison KS, Dooley KC, Don-Wauchope A, Douville P, Hanley DA, Jamal SA, Josse R, Kaiser S, Krahn J, Krause R, Kremer R, Lepage R, Letendre E, Morin S, Ooi DS, Papaioaonnou A, Ste-Marie LG. · Université Laval, Québec, QC, Canada. · Clin Biochem. · Pubmed #19362543 No free full text.

Abstract: Osteoporosis is the most common cause of fragility fractures. Bone remodelling is essential for repairing damaged areas within bone to preserve bone strength and for assisting in mineral homeostases. In young adults, bone remodelling is usually balanced with approximately as much bone replaced as is removed during each remodelling cycle. However, when remodelling becomes accelerated in combination with an imbalance that favours bone resorption over formation, such as during menopause, precipitous losses in bone mass occur. Bone turnover markers (BTMs) measure the rate of bone remodelling allowing for a dynamic assessment of skeletal status and hold promise in identifying those at highest risk of rapid bone loss and subsequent fracture. Further, the use of BTMs to monitor individuals administered osteoporosis therapy is attractive as monitoring anti-fracture efficacy with bone mineral density has significant limitations. This review details remodelling biology, pre-analytical and analytical sources of variability for BTMs, describes the most commonly used resorption and formation markers, and offers some guidelines for their use and interpretation in the laboratory and the clinic.

Morrish DW, Beaupre LA, Bell NR, Cinats JG, Hanley DA, Harley CH, Juby AG, Lier DA, Maksymowych WP, Majumdar SR. · University of Alberta, Edmonton, Alberta, Canada. · Arthritis Rheum. · Pubmed #19177538 No free full text.

Abstract: OBJECTIVE: We previously demonstrated that a case manager intervention improved osteoporosis (OP) treatment within 6 months of hip fracture compared with usual care. The second phase of the randomized trial compared a less intensive intervention, facilitated bone mineral density (BMD) testing, with usual care and the case manager intervention. METHODS: We initially randomized 220 hip fracture patients to either an OP case manager intervention or usual care. After completing the original trial at 6 months postfracture, usual care patients were reallocated to facilitated BMD testing; BMD tests were arranged and results sent to primary care physicians. Main outcomes (bisphosphonate treatment, BMD tests, receipt of appropriate care) were reascertained 1 year following hip fracture and compared with outcomes achieved by the OP case manager intervention and usual care. RESULTS: Compared with usual care, facilitated BMD testing increased testing from 29% to 68% (P < 0.001), bisphosphonate use from 22% to 38% (P < 0.001), and receipt of appropriate care from 26% to 45% (P < 0.001). The more intensive (70 versus 30 minutes) and expensive ($56 versus $24 Canadian per patient) OP case manager intervention led to significantly higher bisphosphonate use (54% versus 38%; P = 0.03), receipt of appropriate care (71% versus 45%; P < 0.001), and more BMD testing (80% versus 68%; P = 0.06) than usual care followed by facilitated BMD testing. CONCLUSION: Compared with usual care, 2 different inexpensive interventions resulted in significant increases in appropriate management of OP after hip fracture. The magnitude of improvements achieved was directly related to the intensity of the interventions.

Majumdar SR, Lier DA, Beaupre LA, Hanley DA, Maksymowych WP, Juby AG, Bell NR, Morrish DW. · Institute of Health Economics and Department of Medicine, University of Alberta, Edmonton, AB T6G 2B7, Canada. · Arch Intern Med. · Pubmed #19139320 No free full text.

Abstract: BACKGROUND: In a randomized trial of patients with hip fractures, we previously demonstrated that a hospital-based case manager could increase rates of appropriate osteoporosis treatment to 51% compared with 22% for usual care (P < .001). Alongside that trial, we conducted an economic analysis. METHODS: Patients with hip fractures were randomized to usual care (n = 110) or a case manager (n = 110) and followed up for 1 year. Time-motion studies were used to determine intervention costs. From a third-party health care payer perspective and over the patient's remaining lifetime, a Markov decision-analytic model was constructed to determine cost-effectiveness of the intervention compared with usual care. Costs and benefits were discounted at 3% and expressed in 2006 Canadian dollars. RESULTS: The intervention cost CaD $56 per patient. Compared with usual care, the intervention strategy was dominant: for every 100 patients case managed, 6 fractures (4 hip fractures) were prevented, 4 quality-adjusted life-years were gained, and CaD $260 000 was saved by the health care system. Irrespective of the number of patients case managed, the intervention reached a break-even threshold within 2 years. The intervention dominated usual care over the entire spectrum of 1-way sensitivity analyses and was cost-saving in 82% of probabilistic model simulations. CONCLUSIONS: Compared with usual care, we found that using a case manager for patients with hip fractures increased rates of appropriate osteoporosis treatment. The intervention dominated usual care, and the analysis suggests that systems implementing an intervention similar to ours should expect to see a reduction in fractures, gains in life expectancy, and substantial cost savings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00175175.

Berger C, Langsetmo L, Joseph L, Hanley DA, Davison KS, Josse RG, Prior JC, Kreiger N, Tenenhouse A, Goltzman D, Anonymous00201. · CaMos Methods Centre, McGill University, Montreal, Quebec, Canada. · J Bone Miner Res. · Pubmed #18847328 No free full text.

Abstract: Our objective was to estimate the relationship between longitudinal change in BMD and fragility fractures. We studied 3635 women and 1417 men 50-85 yr of age in the Canadian Multicentre Osteoporosis Study who had at least two BMD measurements (lumbar spine, femoral neck, total hip, and trochanter) within the first 5 yr of the study and fragility fractures (any, main, forearm/wrist, ribs, hip) within the first 7 yr. Multiple logistic regression was used to model the relationship between baseline BMD, BMD change, and fragility fractures. We found that, among nonusers of antiresorptives, independent of baseline BMD, a decrease of 0.01 g/cm(2)/yr in total hip BMD was associated with an increased risk of fragility fracture with ORs of 1.15 (95% CI: 1.01; 1.32) in women and 1.34 (95% CI: 1.02; 1.78) in men. The risk of fragility fractures in subgroups such as fast losers and those with osteopenia was better estimated by models that included BMD change than by models that included baseline BMD but excluded BMD change. Although the association between baseline BMD and fragility fractures was similar in users and nonusers of antiresorptives, the association was stronger in nonusers compared with users. These results show that BMD change in both men and women is an independent risk factor for fragility fractures and also predicts fracture risk in those with osteopenia. The results suggest that BMD change should be included with other variables in a comprehensive fracture prediction model to capture its contribution to osteoporotic fracture risk.

Fenton TR, Eliasziw M, Lyon AW, Tough SC, Hanley DA. · Department of Community Health Sciences, University of Calgary, Calgary, AB, Canada. · Am J Clin Nutr. · Pubmed #18842807 No free full text.

Abstract: BACKGROUND: The acid-ash diet hypothesis of osteoporosis suggests that acid from the modern diet causes a demineralization of the skeleton, and mobilized bone calcium is excreted. A systematic approach has not been used to summarize the findings of the numerous studies about the hypothesis. OBJECTIVES: The purpose of this meta-analysis was to estimate the quantity of net acid excretion and calciuria associated with the modern diet, to assess the association between acid excretion and calcium excretion, and to assess the influence of urine preservatives on calcium measurement. DESIGN: We systematically searched for trials of the acid-ash hypothesis and conducted a meta-analysis. RESULTS: Twenty-five of 105 studies met the inclusion criteria. The estimated quantity of net acid excretion from the weighted average of the control diets from 11 studies was 47 mEq/d. The increase in urinary calcium with a change in renal net acid excretion depended on whether the urine was acidic or alkaline (P < 0.001). A significant linear relation was observed between net acid excretion and calcium excretion for both acidic and alkaline urine (P < 0.001). The estimated change in urine calcium associated with a change of 47 mEq of net acid excretion in acidic urine was 1.6 mmol/d (66 mg/d) of calcium. CONCLUSION: Evidence suggests a linear association between changes in calcium excretion in response to experimental changes in net acid excretion. However, this finding is not evidence that the source of the excreted calcium is bone or that this calciuria contributes to the development of osteoporosis.