Sophie A. Jamal

2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary

See related commentary by Kanis, page [1829][1] Since the publication of the Osteoporosis Canada guidelines in 2002, there has been a paradigm shift in the prevention and treatment of osteoporosis and fractures. [1][2],[2][3] The focus now is on preventing fragility fractures and their negative

The Association of Radiographically Detected Vertebral Fractures with Back Pain and Function: A Prospective Study

Radiographically detected vertebral fractures (hereafter referred to as vertebral fractures) are a hallmark of postmenopausal osteoporosis and an important end point in clinical trials of osteoporosis treatment. Women with vertebral fractures have low bone mass compared with women without these fractures and, independently of bone mass, have an increased risk for additional vertebral and other fractures [1-4]. Vertebral fractures are common: Five percent of 50-year-old white women and 25% of 80-year-old women have had at least one vertebral fracture [5]. Surprisingly, however, the manner in which vertebral fractures affect health remains uncertain. Cross-sectional studies in community-derived samples of older women have demonstrated only a modest association [6-8] or no association [9-11] between prevalent vertebral fractures and back pain or disability. Cross-sectional studies do not distinguish more recent fractures from older vertebral fractures and may fail to capture transient increases in pain or disability [12], a limitation that may underestimate the clinical effect of these fractures [13]. Back pain is common among elderly women [14], and frequent causes of back pain, such as degenerative disc disease, facet joint osteoarthritis, spinal stenosis, and scoliosis, may obscure the impact of vertebral fracture. Only about one third of new vertebral fractures come to medical attention [15, 16], suggesting that most vertebral fractures are asymptomatic. However, attitudes toward back pain in older women and access to health care may also play a role in determining whether vertebral fractures come to medical attention. We examined the effect of incident vertebral fractures on back pain and back-related functional limitations in a large community-based sample of elderly women who underwent serial spinal radiography and annual assessments of back pain and disability over the same period. Methods Participants Study patients were participants in the Study of Osteoporotic Fractures, a cohort recruited from population-based listings in four U.S. metropolitan areas. Details of the design of this study are published elsewhere [17]. Lateral spine radiographs were obtained for 9677 white women between the ages of 65 and 99 years (median age, 70 years) who underwent baseline examination between 1986 and 1988. Repeated spinal radiographs suitable for morphometry were obtained for 7223 women (75% of the original cohort) at a follow-up clinic visit held an average of 3.7 years (range, 1.3 to 5.1 years) later. All participants gave informed consent. Vertebral Morphometry Lateral radiographs of the thoracic and lumbar spine were obtained in accordance with current guidelines [18]. Quantitative vertebral morphometry was performed using six-point digitization as described elsewhere [3, 19] to calculate the anterior (Ha), mid- (Hm), and posterior (Hp) height for each vertebral body from T4 to L4. A system of triage of radiographs, described elsewhere [3, 20], was used to reduce the number of radiographs requiring morphometric measurements. Briefly, trained technicians separated sets of radiographs into normal, uncertain, or probably fractured groups on the basis of a limited semiquantitative grading scheme that categorized women by the most abnormal vertebral level [20]. Uncertain grades were further categorized by the study radiologist as normal or probably fractured. Morphometry was done on the radiograph pairs that were categorized as probably fractured (42%). In a random sample of 503 women whose radiographs were triaged and then digitized, triage missed no incident fractures according to the study definition. Definition of Vertebral Fracture A vertebra was classified as having a prevalent fracture on the baseline radiograph if any of the following ratios were more than 3 SDs (>4 SDs for severe fractures) below the normal mean for that vertebral level: (Ha/Hp), (Hm/Hp), or a combination of (H/H [] 1) and (Hai/Hai 1) [3, 21]. A new (incident) fracture was identified if any of the three vertebral heights (Ha, Hm, or Hp) on follow-up radiographs decreased by 20% or more and by at least 4 mm compared with the baseline height. Incident fractures identified by morphometry were reviewed by a radiologist to exclude imaging artifacts or such conditions as osteophytosis and Scheuermann disease; 7% of vertebrae meeting the morphometric criteria for incident fracture were reclassified as not fractured. Incident Clinical Fractures We used previously described methods [22] to assess the occurrence of clinical fractures of any bone during follow-up. Women were considered to have a clinical vertebral fracture if they reported a new diagnosis of spinal fracture and a clinical radiology report confirmed that a vertebral fracture was present. Measurements of Pain, Disability, and Limited Activity We evaluated outcome measures by using a previously described questionnaire [7, 23] that asked about back pain and back-related disability in the past 12 months and the number of days of limited activity due to back pain. The questionnaire was administered at baseline and at three annual follow-up contacts held before assessment of vertebral fractures. The third follow-up contact coincided with follow-up radiography. Back pain was assessed on scales of frequency (0, never or rarely; 1, some of the time; 2, most of the time; or 3, all of the time) and severity (0, no pain; 1, mild pain; 2, moderate pain; or 3, severe pain). The two pain questions had high internal consistency (Cronbach = 0.81) and were summed for a total score that could range from 0 to 6. We defined clinically significant back pain as pain that was experienced most or all of the time or pain that was moderate or severe. Women without significant back pain at baseline were considered to have increased back pain if clinically significant pain had developed between any follow-up contacts. For women with clinically significant back pain at baseline, increased back pain was defined as an increase in total pain score of at least two points. Both types of increase had a similar association with incident fractures and thus were combined for a single outcome. Back-related disability was assessed with questions about the degree of difficulty (0, no difficulty; 1, some difficulty; 2, much difficulty; or 3, unable to perform activity) in six activities of daily living that involved the back (bending down to pick up light-weight objects, lifting a 10-pound object from the floor, reaching for objects just above the head, putting on socks or stockings, getting in and out of an automobile, and standing for 2 hours). These measures were combined in a back-related disability score ranging from 0 to 18. As reported elsewhere [7], this scale has high internal consistency (Cronbach = 0.82) and is highly correlated (Spearman r = 0.73) with a more extensive instrument used to assess disability caused by low back pain [24]. We defined clinically significant disability as much difficulty or unable in one or more of the six activities. Women without significant disability at baseline were considered to have increased disability if clinically significant disability had developed between any follow-up contacts. For women with clinically significant disability at baseline, increased disability was defined as an increase in disability score of at least three points. Both types of increase had a similar association with incident fractures and thus were combined for a single outcome. We also asked participants if they had limited their activities because of back pain since the last contact; if the answer was yes, we asked for the number of days they had stayed in bed and the number of days on which activity was limited (not including days in bed) because of back pain. Questions were adapted from previous surveys [25, 26]. For all follow-up contacts, we summed the number of days of bed rest and, in a separate measure, the number of days of limited activity; we then divided these numbers by the total years of follow-up to estimate the average number of affected days per year. Other Measurements The baseline questionnaire assessed potential confounding factors that may be associated with the risk for incident vertebral fracture and with back pain or disability, including smoking (current or past smoker); inactivity, defined as walking less than one block daily (yes or no); a previous physician diagnosis of osteoporosis or spinal fracture (yes or no); current use of estrogen (yes or no); hip pain in the past 12 months (yes or no); and height at 25 years of age. At the baseline examination, we assessed height and weight and calculated body mass index (kg/m2). We assessed grip strength by using an isometric dynamometer (Jamar Hydraulic Hand Dynamometer, JA Preston, Jackson, Mississippi) at baseline and at the follow-up examination and calculated change in grip strength between the two measurements. A random sample of 16% of baseline spine radiographs was assessed for spinal disc degeneration by using previously published methods [27]. Statistical Analysis Unless otherwise indicated, analyses were done separately in groups stratified by the presence of one or more baseline prevalent vertebral fractures. Descriptive and bivariate associations were assessed by using the t-test for continuous variables and the chi-square test for dichotomous variables. The association between incident vertebral fractures and dichotomous outcomes (increased back pain and increased back disability) was analyzed with logistic regression techniques. We analyzed the association of incident vertebral fracture with days of bed rest and days of limited activity per year by using Poisson regression. The distribution of days of bed rest (mean SD, 0.44 5.15) and limited-activity days (16.3 53.7) indicate that considerable overdispersion is present. Poisson regression allowing for this overdispersion provides a good estimation and inferential scheme [2

Endogenous Hormones and the Risk of Hip and Vertebral Fractures among Older Women

BACKGROUND AND METHODS In postmenopausal women, the serum concentrations of endogenous sex hormones and vitamin D might influence the risk of hip and vertebral fractures. In a study of a cohort of women 65 years of age or older, we compared the serum hormone concentrations at base line in 133 women who subsequently had hip fractures and 138 women who subsequently had vertebral fractures with those in randomly selected control women from the same cohort. Women who were taking estrogen were excluded. The results were adjusted for age and weight. RESULTS The women with undetectable serum estradiol concentrations (<5 pg per milliliter [18 pmol per liter]) had a relative risk of 2.5 for subsequent hip fracture (95 percent confidence interval, 1.4 to 4.6) and subsequent vertebral fracture (95 percent confidence interval, 1.4 to 4.2), as compared with the women with detectable serum estradiol concentrations. Serum concentrations of sex hormone-binding globulin that were 1.0 microg per deciliter (34.7 nmol per liter) or higher were associated with a relative risk of 2.0 for hip fracture (95 percent confidence interval, 1.1 to 3.9) and 2.3 for vertebral fracture (95 percent confidence interval, 1.2 to 4.4). Women with both undetectable serum estradiol concentrations and serum sex hormone-binding globulin concentrations of 1 microg per deciliter or more had a relative risk of 6.9 for hip fracture (95 percent confidence interval, 1.5 to 32.0) and 7.9 for vertebral fracture (95 percent confidence interval, 2.2 to 28.0). For those with low serum 1,25-dihydroxyvitamin D concentrations (< or =23 pg per milliliter [55 pmol per liter]), the risk of hip fracture increased by a factor of 2.1 (95 percent confidence interval, 1.2 to 3.5). CONCLUSIONS Postmenopausal women with undetectable serum estradiol concentrations and high serum concentrations of sex hormone-binding globulin have an increased risk of hip and vertebral fracture.

Practice patterns in the diagnosis and treatment of osteoporosis after a fragility fracture: a systematic review

Fragility fractures are a strong indicator of underlying osteoporosis (OP). With the risk of future fracture being increased 1.5- to 9.5-fold following a fragility fracture, the diagnosis and treatment of OP in men and women with fragility fractures provides the opportunity to prevent future fragility fractures. This review describes the current status of practice in investigation and diagnosis of OP in men and women with fragility fractures, the rates and types of postfracture treatment in patients with fragility fractures and OP, interventions undertaken in this population, and the barriers to OP identification and treatment. A literature search performed in Medline, Healthstar, CINAHL, EMBASE, PreMedline, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews identified 37 studies on OP diagnosis, treatment, and interventions. The studies varied in design methodology, study facilities, types of fractures, and pharmacological treatments. Some studies revealed that no patients with fragility fractures received investigation or treatment for underlying OP. Investigation of OP by bone mineral density was low: 14 of 16 studies reported investigation of less than 32% of patients. Investigation by bone mineral density resulted in high rates of OP diagnosis (35–100%), but only moderate use of calcium and vitamin D (8–62%, median 18%) and bisphosphoates (0.5–38%) in patients investigated postfracture. Studies on barriers to OP identification and treatment focused on various groups of health practitioners. Barriers included the cost of therapies, time and cost of resources for diagnosis, concerns about medications, and the lack of clarity regarding the responsibility to undertake this care.

Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis.

BACKGROUND Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease. METHODS We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model. FINDINGS Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0·78, 95% CI 0·61-0·98). INTERPRETATION Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder. FUNDING None.

Low bone mineral density and fracture burden in postmenopausal women

Background: The study objectives were to determine fracture rates in relation to bone mineral density at various central skeletal sites, using the World Health Organization definition for osteoporosis (T-score –2.5 or less), and to contrast fracture patterns among women 50 to 64 years of age with those among women 65 years of age and older. Methods: Historical cohort study with a mean observation period of 3.2 (standard deviation [SD] 1.5) years. The study group (16 505 women 50 years of age or older) was drawn from the Manitoba Bone Density Program database, which includes all bone mineral density results for Manitoba. Baseline density measurements for the lumbar spine and hip were performed with dual-energy x-ray absorptiometry. Outcomes included the percentage of osteoporotic fractures and the rates of fracture and excess fracture (per 1000 person-years) among postmenopausal women with osteopenia and osteoporosis relative to those with normal bone mineral density (according to the classification of the World Health Organization). Results: The mean age was 65 (SD 9) years, and the mean T-scores for all sites fell within the osteopenic category. There were 765 incident fractures (fracture rate 14.5 [95% confidence interval, CI, 13.5–15.6 [per 1000 person-years). Fracture rates were significantly higher among women 65 years of age or older than among women 50–64 years of age (21.6 [95% CI 19.7–23.4] v. 8.6 [95% CI 7.5–9.7] per 1000 person-years, p < 0.001). Although fracture rates were significantly higher among women with osteoporotic T-scores, most fractures occurred in women with nonosteoporotic values (min–max: 59.7%–67.8%). Interpretation: In this study, most of the postmenopausal women with osteoporotic fractures had nonosteoporotic bone mineral density values. This finding highlights the importance of considering key clinical risk factors that operate independently of bone mineral density (such as age) when assessing fracture risk.

Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial.

To determine if alendronate had differential effects on BMD and fracture by renal function, we performed a secondary data analysis of women participating in the FIT. Alendronate increased BMD and decreased fractures to a similar degree among women with and without reduced renal function. There was no increase in adverse events among women with impaired renal function treated with alendronate. Alendronate is safe and effective among this group of women with reduced renal function.

Effects of denosumab on fracture and bone mineral density by level of kidney function.

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft‐Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow‐up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.

Effective initiation of osteoporosis diagnosis and treatment for patients with a fragility fracture in an orthopaedic environment

BACKGROUND 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 enrolled in a program for osteoporosis education, investigation, and treatment and receive appropriate osteoporosis care within the program. METHODS An Osteoporosis Exemplary Care Program was implemented to identify, educate, evaluate, refer, and treat patients considered to be at risk for osteoporosis because of a typical fragility fracture. System modifications included coordination among the orthopaedic unit, Metabolic Bone Disease Clinic, and nuclear medicine unit to provide a continuum of care for these patients. Barriers were addressed through ongoing education of physicians, staff, and patients to increase knowledge and awareness of osteoporosis. The percentages of patients previously diagnosed and treated for osteoporosis, referred for investigation of osteoporosis, treated by the orthopaedic team, and receiving appropriate attention for osteoporosis were calculated. Risk factors for osteoporosis were also assessed. RESULTS Three hundred and forty-nine patients with a fragility fracture (221 outpatients and 128 inpatients) who met the inclusion criteria and an additional eighty-one patients with a fracture (fifty-five outpatients and twenty-six inpatients) who did not meet the inclusion criteria but were suspected by their orthopaedic surgeons of having underlying osteoporosis were enrolled in the Osteoporosis Exemplary Care Program. More than 96% (414) of these 430 patients received appropriate attention for osteoporosis. Approximately one-third (146) of the 430 patients had been diagnosed and treated for osteoporosis before the time of recruitment. Two hundred and twenty-two of the remaining patients were referred to the Metabolic Bone Disease Clinic or to their family physician for further investigation and treatment for osteoporosis. Treatment was initiated by the orthopaedic team for another twenty-three patients. Many patients had risk factors for osteoporosis in addition to the fragility fracture; these included a previous fracture (forty-nine of 187; 26%), a mother who had had a fragility fracture (forty-two of 188; 22%), or a history of smoking (105 of 188; 56%). CONCLUSIONS In a coordinated post-fracture osteoporosis education and treatment program directed at patients with a fragility fracture and their caregivers, >95% of patients were appropriately diagnosed, treated, or referred for osteoporosis care. To accomplish this, a dedicated coordinator and the full cooperation of orthopaedic surgeons and residents, orthopaedic technologists, allied health-care professionals (nurses, physical and occupational therapists, and social workers), and administrative staff were required.

Vitamin K Supplementation in Postmenopausal Women with Osteopenia (ECKO Trial): A Randomized Controlled Trial

Background Vitamin K has been widely promoted as a supplement for decreasing bone loss in postmenopausal women, but the long-term benefits and potential harms are unknown. This study was conducted to determine whether daily high-dose vitamin K1 supplementation safely reduces bone loss, bone turnover, and fractures. Methods and Findings This single-center study was designed as a 2-y randomized, placebo-controlled, double-blind trial, extended for earlier participants for up to an additional 2 y because of interest in long-term safety and fractures. A total of 440 postmenopausal women with osteopenia were randomized to either 5 mg of vitamin K1 or placebo daily. Primary outcomes were changes in BMD at the lumbar spine and total hip at 2 y. Secondary outcomes included changes in BMD at other sites and other time points, bone turnover markers, height, fractures, adverse effects, and health-related quality of life. This study has a power of 90% to detect 3% differences in BMD between the two groups. The women in this study were vitamin D replete, with a mean serum 25-hydroxyvitamin D level of 77 nmol/l at baseline. Over 2 y, BMD decreased by −1.28% and −1.22% (p = 0.84) (difference of −0.06%; 95% confidence interval [CI] −0.67% to 0.54%) at the lumbar spine and −0.69% and −0.88% (p = 0.51) (difference of 0.19%; 95% CI −0.37% to 0.75%) at the total hip in the vitamin K and placebo groups, respectively. There were no significant differences in changes in BMD at any site between the two groups over the 2- to 4-y period. Daily vitamin K1 supplementation increased serum vitamin K1 levels by 10-fold, and decreased the percentage of undercarboxylated osteocalcin and total osteocalcin levels (bone formation marker). However, C-telopeptide levels (bone resorption marker) were not significantly different between the two groups. Fewer women in the vitamin K group had clinical fractures (nine versus 20, p = 0.04) and fewer had cancers (three versus 12, p = 0.02). Vitamin K supplements were well-tolerated over the 4-y period. There were no significant differences in adverse effects or health-related quality of life between the two groups. The study was not powered to examine fractures or cancers, and their numbers were small. Conclusions Daily 5 mg of vitamin K1 supplementation for 2 to 4 y does not protect against age-related decline in BMD, but may protect against fractures and cancers in postmenopausal women with osteopenia. More studies are needed to further examine the effect of vitamin K on fractures and cancers. Trial registration: ClinicalTrials.gov (#NCT00150969) and Current Controlled Trials (#ISRCTN61708241)