David A. Hanley

Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline

OBJECTIVE The objective was to provide guidelines to clinicians for the evaluation, treatment, and prevention of vitamin D deficiency with an emphasis on the care of patients who are at risk for deficiency. PARTICIPANTS The Task Force was composed of a Chair, six additional experts, and a methodologist. The Task Force received no corporate funding or remuneration. CONSENSUS PROCESS Consensus was guided by systematic reviews of evidence and discussions during several conference calls and e-mail communications. The draft prepared by the Task Force was reviewed successively by The Endocrine Societys Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and cosponsoring associations, and it was posted on The Endocrine Society web site for member review. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS Considering that vitamin D deficiency is very common in all age groups and that few foods contain vitamin D, the Task Force recommended supplementation at suggested daily intake and tolerable upper limit levels, depending on age and clinical circumstances. The Task Force also suggested the measurement of serum 25-hydroxyvitamin D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D(2) or vitamin D(3) was recommended for deficient patients. At the present time, there is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the noncalcemic benefit for cardiovascular protection.

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

INTERMITTENT ETIDRONATE THERAPY TO PREVENT CORTICOSTEROID- INDUCED OSTEOPOROSIS

BACKGROUND AND METHODS Osteoporosis is a recognized complication of corticosteroid therapy. Whether it can be prevented is not known. We conducted a 12-month, randomized, placebo-controlled study of intermittent etidronate (400 mg per day for 14 days) followed by calcium (500 mg per day for 76 days), given for four cycles, in 141 men and women (age, 19 to 87 years) who had recently begun high-dose corticosteroid therapy. The primary outcome measure was the difference in the change in the bone density of the lumbar spine between the groups from base line to week 52. Secondary measures included changes in the bone density of the femoral neck, trochanter, and radius and the rate of new vertebral fractures. RESULTS The mean (+/-SE) bone density of the lumbar spine and trochanter in the etidronate group increased 0.61 +/- 0.54 and 1.46 +/- 0.67 percent, respectively, as compared with decreases of 3.23 +/- 0.60 and 2.74 +/- 0.66 percent, respectively, in the placebo group. The mean differences between the groups after one year were 3.72 +/- 0.88 percentage points for the lumbar spine (P = 0.02) and 4.14 +/- 0.94 percentage points for the trochanter (P = 0.02). The changes in the femoral neck and the radius were not significantly different between the groups. There was an 85 percent reduction in the proportion of postmenopausal woman with new vertebral fractures in the etidronate group as compared with the placebo group (1 of 31 patients vs. 7 of 32 patients, P = 0.05), and the etidronate-treated postmenopausal women also had significantly fewer vertebral fractures per patient (P = 0.04). CONCLUSIONS Intermittent etidronate therapy prevents the loss of vertebral and trochanteric bone in corticosteroid-treated patients.

Multinational placebo controlled, randomized trial of the effects of alendronate on bone density and fracture risk in postmenopausal women with low bone mass: results of the FOSIT-study.

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.

Diagnosis of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop

BACKGROUND At the Third International Workshop on Asymptomatic Primary Hyperparathyroidism (PHPT) in May 2008, recent data on the disease were reviewed. We present the results of a literature review on issues arising from the clinical presentation and natural history of PHPT. METHODS Questions were developed by the International Task Force on PHPT. A comprehensive literature search for relevant studies was reviewed, and the questions of the International Task Force were addressed by the Consensus Panel. CONCLUSIONS 1) Data on the extent and nature of cardiovascular involvement in those with mild disease are too limited to provide a complete picture. 2) Patients with mild PHPT have neuropsychological complaints. Although some symptoms may improve with surgery, available data remain inconsistent on their precise nature and reversibility. 3) Surgery leads to long-term gains in spine, hip, and radius bone mineral density (BMD). Because some patients have early disease progression and others lose BMD after 8-10 yr, regular monitoring (serum calcium and three-site BMD) is essential in those followed without surgery. Patients may present with normocalcemic PHPT (normal serum calcium with elevated PTH concentrations; no secondary cause for hyperparathyroidism). Data on the incidence and natural history of this phenotype are limited. 4) In the absence of kidney stones, data do not support the use of marked hypercalciuria (>10 mmol/d or 400 mg/d) as an indication for surgery for patients. 5) Patients with bone density T-score -2.5 or less at the lumbar spine, hip, or distal one third radius should have surgery.

Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Randomized Trial

Context Researchers have not previously reported the efficacy and safety of parathyroid hormone (1-84) (PTH) for the primary prevention of osteoporotic fractures. Contributions Among 2532 postmenopausal women with osteoporosis randomly assigned to receive PTH or placebo, PTH decreased new vertebral fractures. The magnitude of the effect depended on assumptions about fractures in the one third of patients who withdrew from the trial prematurely. Adverse effects included hypercalciuria, hypercalcemia, and nausea. Caution Endogenous PTH and vitamin D levels could affect patients response to the drug but were not assessed in the study. Implications Parathyroid hormone (1-84) effectively prevented new vertebral fractures but also increased hypercalciuria, hypercalcemia, and nausea. The Editors Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing patients to an increased risk for fracture (1). Optimal treatment for osteoporosis should improve the amount, density, and quality of bone, thereby reducing skeletal fragility and fractures. Antiresorptive agents, such as bisphosphonates, are commonly used for treating postmenopausal osteoporosis. Although these agents preserve bone architecture, they do not stimulate new bone formation or improve bone architecture. Anabolic or bone-forming agents are an alternative approach to the treatment of osteoporosis. Researchers have shown that parathyroid hormone (PTH) and certain peptide fragments of PTH increase bone mass and improve bone quality (2, 3). Teriparatide, a fragment of human PTH composed of its N-terminal 34 amino acids, has been approved for the treatment of postmenopausal women with osteoporosis who are at high risk for bone fracture. However, researchers have studied this agent only in women with prevalent vertebral fractures (4), and data demonstrating prevention of the first vertebral fracture are lacking. We conducted the Treatment of Osteoporosis with Parathyroid Hormone (TOP) Study to examine the efficacy and safety of PTH (1-84) versus placebo for treating postmenopausal women with osteoporosis. We designed the study to examine the change in incidence of all vertebral fractures between the treatment groups. We also designed the study to examine the efficacy of this new bone-forming agent in preventing a first vertebral fracture in women without a vertebral fracture. Methods Study Participants We included postmenopausal women 45 to 54 years of age if bone mineral density (BMD) was 3.0 SDs or more (T-score 3.0) below the mean peak bone mass of young adult women at the lumbar spine, femoral neck, or total hip with no prevalent vertebral fracture or if BMD T-score was2.5 and they had 1 to 4 vertebral fractures before enrollment. We included postmenopausal women 55 years of age or older if BMD T-score was2.5 and they had no vertebral fractures or if BMD T-score was2.0 and they had 1 to 4 vertebral fractures. We excluded women if baseline serum calcium level was greater than 2.66 mmol/L (>10.7 mg/dL) or if urinary calciumcreatinine ratio was 1.0 or more. We included women with mild hypercalcemia (serum calcium, 2.55 to 2.66 mmol/L [10.2 to 10.7 mg/dL]) and mild hypercalciuria (24-hour urine calcium7.6 mmol [302 mg]) at baseline. We did not measure baseline levels of serum PTH and vitamin D. We excluded women if they had taken bisphosphonates for a total of more than 12 months or for more than 90 days in the 12 months before enrollment. We allowed previous estrogen therapy if it had been discontinued for at least 4 weeks before the screening visit. We excluded women who had received PTH (or a peptide fragment or analogue), PTH-related protein, fluoride, or strontium and those who had a history of metabolic bone disease (other than osteoporosis), nephrolithiasis, or clinically significant hepatic or renal disorders. We also excluded women who were taking medications known to affect bone mineral metabolism. The ethics review committee for each center approved the study. All women provided written informed consent. An independent data and safety monitoring board reviewed the progress and safety of the study. Study Design We conducted a randomized, double-blind, placebo-controlled, parallel-group study in 168 centers in 9 countries. We randomly assigned the study drug to blocks of 4 patients by using a computer-generated algorithm and shipped it in blocks of 4 to each study site. Women at each site were sequentially assigned the uniquely numbered, randomly assigned study drug treatment kits by telephone. Women were stabilized for at least 2 weeks with supplemental calcium, 700 mg/d citrate salt, and vitamin D3, 400 U/d, and then received 100 g of recombinant human PTH or placebo daily by subcutaneous injection for 18 months with continued calcium and vitamin D3 supplementation. Patients were instructed to administer the injection in the morning in the thigh or abdomen by using an injector pen. Study Conduct and Outcome Measures The primary end point was the occurrence of new or worsened vertebral fractures (in all women and in women with and without a prevalent fracture) identified by radiography at baseline, month 18, or the final study visit. Radiologists assessed vertebral fractures in a blinded manner at a central reading organization by using a semiquantitative 4-point grading scale (5). An incident vertebral fracture (new or worsened) was identified by a change in grade of 1 or more from baseline. Secondary outcomes included changes in BMD at lumbar spine, hip, whole body, and forearm (distal one-third radius) that we measured by using dual-energy x-ray absorptiometry with Hologic (Hologic Inc., Bedford, Massachusetts) or Lunar (GE Medical Systems, Madison, Wisconsin) densitometers (reported as percentage change from baseline to standardize instrumental differences in determining absolute BMD) and stadiometric measurements of height. We measured whole body and forearm BMD only in a subset of approximately 300 women from selected sites with appropriate software. We reported nonvertebral clinical fractures and bone loss (>7% at lumbar spine or >9% at total hip or femoral neck) as adverse events. We did not distinguish between traumatic and fragility nonvertebral fractures. We used quantitative computed tomography (6, 7) to evaluate the effects of PTH treatment at month 18 on volumetric cortical and trabecular BMD at lumbar vertebra (L3) and the hip in 122 consenting women from a single center at which the technique was available. We assessed bone turnover markers (serum bone-specific alkaline phosphatase and urinary N-telopeptides of type I collagen) in the first 600 randomly assigned women in the study. We measured bone-specific alkaline phosphatase by using the Tandem R-Ostase immunoradiometric assay (interassay coefficient of variation, 8%) (Hybritech, San Diego, California). We measured N-telopeptides of type I collagen by using Osteomark enzyme-linked immunoabsorbent assay kits (interassay coefficient of variation, 4.0%) (Wampole Laboratories, Princeton, New Jersey) normalized to urine creatinine concentrations. We made safety assessments at months 1, 3, 6, 9, 12, 15, and 18 that included physical examinations, vital signs, electrocardiography (months 1, 12, and 18), adverse-event monitoring and central clinical laboratory assessments consisting of chemistry (including serum total calcium and creatinine), hematology, and urinalysis (including 24-hour urine collections and fasting, morning urinary calciumcreatinine ratios). Adverse events were reported spontaneously by patients, captured in a patients diary, or reported by a patient in response to an open-ended question from clinical study personnel. We used a central laboratory normal range for serum total calcium level of 2.15 to 2.55 mmol/L (8.6 to 10.2 mg/dL). We performed an analysis for antibodies to PTH with a validated electrochemiluminescent immunoassay by using biotinylated recombinant human PTH (range, 26.3 to 2632.5 pmol/L; intra-assay coefficient of variation, 8% to 16%) (Igen International, Inc., Gaithersburg, Maryland). We obtained iliac crest bone biopsy specimens at month 12 or 18 from a subset of 40 consenting women after tetracycline double-labeling (8) that we examined for abnormal bone structure. We anticipated that women might need to discontinue calcium supplementation and reduce the dosing frequency of the study drug to prevent excessive increases in serum calcium level, urinary calcium level, or both. We conservatively predefined hypercalcemia as a single, unconfirmed, predose serum total calcium value greater than 2.66 mmol/L (>10.7 mg/dL) and hypercalciuria as a 24-hour urinary calcium value of 7.6 mmol or more (302 mg) (increased to >9.0 mmol [>360 mg] during the study) or a fasting urinary calciumcreatinine ratio of 1.0 or more. If a woman developed hypercalcemia or hypercalciuria, we discontinued the daily calcium supplementation; if either condition continued, we reduced the dosing frequency of the study drug. Statistical Analysis We estimated the sample size for our study by assuming that 67% of the patients would not have a prevalent fracture; that the 18-month vertebral fracture incidence for patients with and without a prevalent fracture who received placebo would be 10% and 2.5%, respectively; and that 20% of the patients in each group would discontinue the study early without a new or worsened fracture. We expected a sample of 2600 patients (1300 per treatment group) to provide at least 90% power to detect a significant 60% or greater reduction in vertebral fracture incidence in the PTH treatment group compared with the placebo group (2-sided level of 0.05). We analyzed data by using SAS software, version 8.0 (SAS Institute, Inc., Cary, North Carolina). We used descriptive statistics to summarize demographic and other baseline variables. We assessed comparability of the treatment groups at baseline by using t-tests for continuous varia

Guidelines for Preventing and Treating Vitamin D Deficiency and Insufficiency Revisited

Boston University School of Medicine (M.F.H.), Boston, Massachusetts 02118-2526; Osteoporosis Research Program (N.C.B.), University of Wisconsin, Madison, Wisconsin 53706; Department of Rheumatology and Institute for Physical Medicine (H.A.B.-F.), University Hospital Zurich, 8091 Zurich, Switzerland; Divisions of Adolescent Medicine and Endocrinology (C.M.G.), Childrens Hospital, Boston, Massachusetts 02115; Division of Endocrinology and Metabolism (D.A.H.), Health Science Centre, University of Calgary Faculty of Medicine (R.P.H.), Calgary, Canada AB T2N 4N1; Creighton University (R.P.H.), Omaha, Nebraska 68131; Division of Preventative, Occupational, and Aerospace Medicine Mayo Clinic (M.H.M.), Rochester, Minnesota 55905; and Department of Foods and Nutrition (C.M.W.), Purdue University, West Lafayette, Indiana 47907

Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study

Background: Fractures have largely been assessed by their impact on quality of life or health care costs. We conducted this study to evaluate the relation between fractures and mortality. Methods: A total of 7753 randomly selected people (2187 men and 5566 women) aged 50 years and older from across Canada participated in a 5-year observational cohort study. Incident fractures were identified on the basis of validated self-report and were classified by type (vertebral, pelvic, forearm or wrist, rib, hip and “other”). We subdivided fracture groups by the year in which the fracture occurred during follow-up; those occurring in the fourth and fifth years were grouped together. We examined the relation between the time of the incident fracture and death. Results: Compared with participants who had no fracture during follow-up, those who had a vertebral fracture in the second year were at increased risk of death (adjusted hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1–6.6); also at risk were those who had a hip fracture during the first year (adjusted HR 3.2, 95% CI 1.4–7.4). Among women, the risk of death was increased for those with a vertebral fracture during the first year (adjusted HR 3.7, 95% CI 1.1–12.8) or the second year of follow-up (adjusted HR 3.2, 95% CI 1.2–8.1). The risk of death was also increased among women with hip fracture during the first year of follow-up (adjusted HR 3.0, 95% CI 1.0–8.7). Interpretation: Vertebral and hip fractures are associated with an increased risk of death. Interventions that reduce the incidence of these fractures need to be implemented to improve survival.

Trends in Hip Fracture Rates in Canada

CONTEXT Hip fractures are a public health concern because they are associated with significant morbidity, excess mortality, and the majority of the costs directly attributable to osteoporosis. OBJECTIVE To examine trends in hip fracture rates in Canada. DESIGN, SETTING, AND PATIENTS Ecologic trend study using nationwide hospitalization data for 1985 to 2005 from a database at the Canadian Institute for Health Information. Data for all patients with a hospitalization for which the primary reason was a hip fracture (570,872 hospitalizations) were analyzed. MAIN OUTCOME MEASURES Age-specific and age-standardized hip fracture rates. RESULTS There was a decrease in age-specific hip fracture rates (all P for trend <.001). Over the 21-year period of the study, age-adjusted hip fracture rates decreased by 31.8% in females (from 118.6 to 80.9 fractures per 100,000 person-years) and by 25.0% in males (from 68.2 to 51.1 fractures per 100,000 person-years). Joinpoint regression analysis identified a change in the linear slope around 1996. For the overall population, the average age-adjusted annual percentage decrease in hip fracture rates was 1.2% (95% confidence interval, 1.0%-1.3%) per year from 1985 to 1996 and 2.4% (95% confidence interval, 2.1%-2.6%) per year from 1996 to 2005 (P < .001 for difference in slopes). Similar changes were seen in both females and males with greater slope reductions after 1996 (P < .001 for difference in slopes for each sex). CONCLUSIONS Age-standardized rates of hip fracture have steadily declined in Canada since 1985 and more rapidly during the later study period. The factors primarily responsible for the earlier reduction in hip fractures are unknown.

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

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