Stephen P. Heyse

Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States

OBJECTIVE To provide a single source for the best available estimates of the national prevalence of arthritis in general and of selected musculoskeletal disorders (osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, the spondylarthropathies, systemic lupus erythematosus, scleroderma, polymyalgia rheumatica/giant cell arteritis, gout, fibromyalgia, and low back pain). METHODS The National Arthritis Data Workgroup reviewed data from available surveys, such as the National Health and Nutrition Examination Survey series. For overall national estimates, we used surveys based on representative samples. Because data based on national population samples are unavailable for most specific musculoskeletal conditions, we derived data from various smaller survey samples from defined populations. Prevalence estimates from these surveys were linked to 1990 US Bureau of the Census population data to calculate national estimates. We also estimated the expected frequency of arthritis in the year 2020. RESULTS Current national estimates are provided, with important caveats regarding their interpretation, for self-reported arthritis and selected conditions. An estimated 15% (40 million) of Americans had some form of arthritis in 1995. By the year 2020, an estimated 18.2% (59.4 million) will be affected. CONCLUSION Given the limitations of the data on which they are based, this report provides the best available prevalence estimates for arthritis and other rheumatic conditions overall, and for selected musculoskeletal disorders, in the US population.

Prevalence of Low Femoral Bone Density in Older U.S. Adults from NHANES III

Most estimates of osteoporosis in older U.S. adults have been based on its occurrence in white women, even though it is known to affect men and minority women. In the present study, we used dual‐energy X‐ray absorptiometry measurements of femoral bone mineral density (BMD) from the third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) to estimate the overall scope of the disease in the older U.S. population. Specifically, we estimate prevalences of low femoral BMD in women 50 years and older and explore different approaches for defining low BMD in older men in that age range. Low BMD levels were defined in accordance with an approach proposed by an expert panel of the World Health Organization and used BMD data from 382 non‐Hispanic white (NHW) men or 409 NHW women ages 20–29 years from the NHANES III dataset. For women, estimates indicate 13–18%, or 4–6 million, have osteoporosis (i.e., BMD >2.5 standard deviations [SD] below the mean of young NHW women) and 37–50%, or 13–17 million, have osteopenia (BMD between 1 and 2.5 SD below the mean of young NHW women). For men, these numbers depend on the gender of the reference group used to define cutoff values. When based on male cutoffs, 3–6% (1–2 million) of men have osteoporosis and 28–47% (8–13 million) have osteopenia; when based on female cutoffs, 1–4% (280,000–1 million) have osteoporosis and 15–33% (4–9 million) have osteopenia. Most of the older U.S. adults with low femur BMD are women, but, regardless of which cutoffs are used, the number of men is substantial.

Updated Data on Proximal Femur Bone Mineral Levels of US Adults

Abstract: This paper describes data on bone mineral levels in the proximal femur of US adults based on the nationally representative sample examined during both phases of the third National Health and Nutrition Examination Survey (NHANES III, 1988–94), and updates data previously presented from phase 1 only. The data were collected from 14646 men and women aged 20 years and older using dual-energy X-ray absorptiometry, and included bone mineral density (BMD), bone mineral content (BMC) and area of bone scanned in four selected regions of interest (ROI) in the proximal femur: femur neck, trochanter, intertrochanter and total. These variables are provided separately by age and sex for non-Hispanic whites (NHW), non-Hispanic blacks (NHB) and Mexican Americans (MA). NHW in the southern United States had slightly lower BMD levels than NHW in other US regions, but these differences were not sufficiently large to prevent pooling of the data. The updated data provide valuable reference data on femur bone mineral levels of noninstitutionalized adults. The updated data on BMD for the total femur ROI of NHW have been selected as the reference database for femur standardization efforts by the International Committee on Standards in Bone Measurements.

Proximal femur bone mineral levels of US adults.

This paper describes bone mineral levels in the proximal femur of US adults based on a nationally representative sample of 7116 men and women aged 20 years and older. The data were collected in phase 1 of the third National Health and Nutrition Examination Survey (NHANES III, 1988–1991) using dual-energy X-ray absorptiometry, and included bone mineral density (BMD), bone mineral content (BMC) and area of bone scanned in five selected regions of interest (ROI) in the proximal femur: femur neck, trochanter, intertrochanter, Wards triangle and total. These variables are provided separately by age and sex for non-Hispanic whites (NHW), non-Hispanic blacks (NHB) and Mexican Americans (MA). BMD and BMC in the five ROI tended to decline with age, whereas area did not. BMD and BMC were highest in NHB, intermediate in MA and lowest in NHW, but areas were highest in NHW, intermediate in NHB and lowest in MA. Men had greater BMD, BMC and area than women in all three race/ethnic groups. Differences by age, sex or race/ethnicity tended to be the largest in Wards triangle, followed by the femur neck; patterns in the trochanter, intertrochanter and total ROI were reasonably similar to each other. This report provides extensive data on femur bone mineral levels of adults from one of the largest samples available to date and should be valuable as reference data for other studies which examine this skeletal site in adults.

Minocycline in Rheumatoid Arthritis: A 48-Week, Double-Blind, Placebo-Controlled Trial

Rheumatoid arthritis is a chronic, sometimes incapacitating systemic disease of unknown cause that affects at least two million Americans [1, 2]. Various pharmacologic agents are used to manage rheumatoid arthritis, but none is completely effective. On the basis of the theory that persistent Mycoplasma infection may cause rheumatoid arthritis, some physicians have prescribed and reported benefit from lengthy courses of tetracyclines [3, 4]. A small 1-year clinical trial comparing tetracycline, 250 mg/d, with placebo could not show significant benefit in patients with rheumatoid arthritis [5]. Because of these contradictory outcomes, the treatment of rheumatoid arthritis with antibiotics has remained controversial. Tetracyclines have several nonantibiotic effects that may be beneficial for patients with rheumatoid arthritis. Minocycline, a semi-synthetic tetracycline that is rapidly absorbed and has a prolonged half-life, inhibits collagenase activity of gingival fibroblasts from diabetic rats, even in a germ-free environment [6, 7]. Oral minocycline at a dose of 100 mg twice a day for 10 days reduced collagenase activity in the synovial tissue of patients with rheumatoid arthritis [8]. Moreover, the addition of minocycline to synovial tissue cultures from patients with rheumatoid arthritis also resulted in the inhibition of this enzyme. Other properties of tetracycline analogs include inhibition of protein synthesis by rapidly dividing cells [9], perturbation of leukocyte functions [10, 11], interference with lymphocyte proliferation [12-14], and anti-inflammatory effects [15] that are probably related to its antioxidant activity [16, 17]. Minocycline can also suppress the induction of experimental arthritis in rats [18]. Recently, favorable results from uncontrolled clinical studies of minocycline in rheumatoid arthritis were reported [19, 20]. In addition, Kloppenburg and colleagues [21, 22] observed improvement when minocycline was added to baseline nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs or corticosteroid therapy in a 26-week randomized, placebo-controlled trial. We conducted a 48-week, randomized, double-blind, multicenter trial to determine the efficacy and safety of minocycline in treating rheumatoid arthritis when it is added to background NSAIDs or low-dose prednisone therapy in patients not receiving concomitant disease-modifying antirheumatic drugs. Methods Protocol Development The protocol for the Minocycline in Rheumatoid Arthritis (MIRA) Trial was developed by the investigators from the clinical centers, the coordinating center, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases on the basis of protocols for clinical trials of therapies for rheumatoid arthritis that were previously done by the Cooperative Systematic Studies of Rheumatic Diseases (CSSRD) program [23, 24]. Inclusion criteria for those CSSRD trials were two of the following: nine or more tender joints capable of response, an erythrocyte sedimentation rate of 28 mm/h or greater, and morning stiffness lasting 45 minutes or longer. To simplify recruitment of patients, we modified these criteria to require the presence of nine or more tender joints capable of response with no minimum specified for either the erythrocyte sedimentation rate or for morning stiffness. The study protocol was reviewed and approved by institutional review boards at each participating clinical center. Patients To be eligible for the minocycline trial, patients had to meet the 1987 American Rheumatism Association (now the American College of Rheumatology) classification criteria for rheumatoid arthritis [25]. Patients were required to have active disease, defined as nine or more tender joints and six or more swollen joints capable of assessable improvement. Patients had to be 18 years of age or older and to have experienced onset of rheumatoid arthritis at 16 years of age or older. Patients receiving NSAIDs or low-dose corticosteroids (prednisone equivalent of a daily dose of 10 mg or less) were required to be receiving stable concurrent medication for 4 weeks before entering the study; these medications were to be kept stable throughout the study. One change from equivalent doses of one NSAID to another was permitted during the trial. Phenylbutazone, oxyphenbutazone, or parenteral steroids (including intra-articular corticosteroids) and disease-modifying antirheumatic drugs were not allowed for 4 weeks before the study; the use of these drugs during the trial was a protocol violation. Women were required to be postmenopausal, surgically sterile, or practicing a reliable method of contraception and to have a negative pregnancy test result. Before randomization, eligible patients for the minocycline trial could have received therapeutic trials of hydroxychloroquine and, at most, one other disease-modifying antirheumatic drug (oral or parenteral gold salts, d-penicillamine, azathioprine, methotrexate, or sulfasalazine) unless therapy was discontinued for toxicity. Patients could have tried any number of disease-modifying antirheumatic drugs if discontinued for toxicity, provided that no drug was administered for more than 3 months or, for parenteral gold salts, was not given in a cumulative dose of more than 500 mg. These exclusion criteria were designed to avoid recruiting patients with a history of repeated failures of therapeutic trials of disease-modifying antirheumatic drugs but did allow entry of those who had discontinued therapy with these drugs because of toxicity before prespecified dosages or durations were reached. Patients were not eligible at screening if they had known hypersensitivity to tetracycline; required long-term tetracycline therapy for another disorder; required ongoing therapy with antacids containing aluminum, calcium, or magnesium; or had received anticoagulant therapy. We excluded patients with chronic illnesses that would limit successful participation in the trial and patients classified as American Rheumatism Association-Steinbrocker functional class IV [26]. Three patients who met eligibility criteria at their screening visit were found to have too few affected joints at their baseline (randomization) visit and were inadvertently randomized. We included these patients in the analysis. All three patients were in the placebo group and were not considered responders to treatment. Removing these patients did not change the results of the trial. Study Design The MIRA trial was a six-center, double-blind, randomized, placebo-controlled trial comparing minocycline and placebo in treating rheumatoid arthritis. Patients were randomly assigned within the clinical center (that is, the clinical center was a stratifying factor), and randomization was blocked using randomly chosen block sizes between 4 and 6 to minimize the possibility that staff would guess the next treatment assignment. For 48 weeks, patients received two 50-mg capsules of minocycline hydrochloride or a visually similar placebo taken with water twice daily on an empty stomach. To minimize interference with the absorption of minocycline, patients were instructed not to ingest food or iron within 2 hours of receiving study medication. Investigators were allowed to adjust the dosage (without breaking the treatment code) if patients experienced side effects. Measurements The following measurements were obtained at the baseline and randomization visits and every 12 weeks thereafter. Evaluator Assessments Sixty diarthrodial joints were examined for the presence or absence of tenderness, and 58 were examined for swelling (hips excluded). Joint counts for tenderness and for swelling were the sum of the number of affected joints [27]. These joints were also evaluated for the severity of both tenderness and swelling on a 4-point scale. For tenderness, 0 = none, 1 = mild (positive response on questioning), 2 = moderate (spontaneous response elicited on examination), and 3 = severe (withdrawal by patient on examination); for swelling, 0 = none, 1 = mild (detectable synovial thickening without loss of bony contours), 2 = moderate (loss of distinctness of bony contours), and 3 = severe (bulging synovial proliferation with cystic characteristics). The sum of these determinations for all joints constituted a collective scores for either swelling or tenderness [23]. To foster agreement, evaluators attended a training session at the coordinating center before the trial. During the trial, all joint assessments for each patient were done by the same evaluator if possible. (During the trial, 94% of patients receiving minocycline and 92% of those receiving placebo had their joints evaluated by the same examiner at every visit.) Grip strength was measured bilaterally using a mercury strain sphygmomanometer [28]. An evaluator assessed disease activity on the day of the examination using a scale of 1 to 5: absent, mild, moderate, severe, or very severe activity [29]. For functional class, patients were assessed according to the American Rheumatism Association-Steinbrocker classification [26] (at baseline and 48 weeks only). Patient Assessments Patients were asked about the duration of morning stiffness they experienced on the day before each study visit [23]. Function was assessed on eight activities of daily living with the Modified Health Assessment Questionnaire (MHAQ) [30]. Patients used a scale of 0 to 3: activity without any difficulty, with some difficulty, with much difficulty, and unable to do; thus, the higher the score, the greater the incapacitation. Patients were also asked to give an overall assessment of their disease activity for the preceding day on a scale of 1 to 5: absent, mild, moderate, severe, and very severe [29]. Ancillary Assessments Laboratory determinations included urinalysis, complete blood count with differential, and a chemistry profile at the screening visit and every 4 weeks through week 12 an

Incidence of hip fractures in the elderly: A cross-national analysis

This paper reviews international data on incidence rates of hip fracture in persons 50 years of age and older, based on a bibliographic search of articles published since 1960. Incidence rates are higher in white populations than in black, Asian, and Hispanic populations. In both sexes and in all ethnic groups and geographic areas, incidence rates increase markedly with age. The steep increase with age, however, occurs later in black, Asiatic and Hispanic populations than in whites. The ratio of female to male incidence rates is higher than 1.0 in whites, while in blacks and Asians it has often been the reverse, with higher rates among men. In recent years in Hong Kong incidence rates in females have increased more rapidly than incidence rates in males, so that now the incidence rates in females are higher than those in males. In addition to the study in Hong Kong, most studies in Northern Europe and North America show an increase in age-adjusted hip fracture incidence rates over time over the past few decades.Methodological differences among the various studies (including differences in the definition of hip fracture, in case ascertainment, and in the selection and sample size of the study population) necessitate cautious interpretation of the findings of this report.

International variation in the incidence of hip fractures: cross-national project on osteoporosis for the World Health Organization Program for Research on Aging

Abstract: A cross-national study of hip fracture incidence was carried out in five geographic areas – Beijing, China; Budapest, Hungary; Hong Kong; Porto Alegre, Brazil; and Reykjavik, Iceland – during the years 1990–1992. Cases of hip fracture among women and men of age 20 years and older were identified using hospital discharge data in conjunction with medical records, operating room logs, and radiology logs. Estimated incidence rates varied widely, with Beijing reporting the lowest rates (age-adjusted rate per 100 000 population for men 20 years and older = 45.4; women = 39.6) and Reykjavik the highest rates (men = 141.3; women = 274.1). Rates were higher for women than for men in every area except Beijing. In every area except Budapest, review of the operating room or radiology logs identified additional cases that were not reported in the discharge list, increasing the estimated number of hip fractures by 11% to 62%, depending on the area. Review of medical records identified miscoding of hip fractures (ICD9 820) as ‘shaft of femur and other femur fractures’ (ICD9 821) in the discharge lists of every area except Budapest, increasing the estimated number of hip fractures by 1% to 30%. The final estimates of hip fracture incidence taking into account all investigated sources of undercount and overcount ranged from 15% lower to 89% higher than an estimate based on the discharge diagnoses alone. Although these results indicate substantial limitations in relying on hospital discharge data alone to estimate hip fracture incidence rates, the extent of errors found in the discharge lists is smaller than the large international variation found here and previously reported in incidence rates. The findings support the conclusion that the differences reported among countries mainly reflect genuine variation in the hip fracture incidence rates.

Epidemiology of osteoporosis: A study of fracture mortality in Italy

Little is known about the epidemiology of osteoporosis in Italy. From epidemiologic studies in other countries, we know that fractures of the distal radius, proximal humerus, proximal femur, and the vertebral bodies are associated with osteoporosis. To the best of our knowledge, there has been no population-based Italian survey of osteoporosis or its associated fractures. The current study of mortality associated with fractures has been undertaken to provide some sense of the magnitude of the problem in Italy and to lay the groundwork for such a population-based national survey. Melton [1] presents a table of age-adjusted incidence rates from studies around the world for femoral, radial, and humeral fractures. The annual hip fracture rates range from a high of 421/100,000 in Norwegian women to a low of 14/100,000 in Bantu women in South Africa. In most of the countries listed, the hip fracture rates in women are approximately twice that of men. No rates are provided for any Italian populations. There have been publications from Italian researchers on some epidemiologic aspects of osteoporosis. For example, Borgonovi and Dellamano [2] have reported on the economic and social costs of osteoporosis based on hospital admission data from three regions of Italy: Piemonte, Lombardia, and Veneto. Palummeri et al. [3] have reported on a cross-sectional study of 281 clinically healthy women between the ages of 20 and 80 years who

Epidemiology of hip fractures in the elderly: a cross-national analysis of mortality rates for femoral neck fractures

Femoral neck fractures (hip fractures) represent a major public health problem in the United States and other developed countries with significant populations of older people. In 1986 the US Medicare Program paid for 187 739 hospitalization for femoral neck fractures, which represents a hospitalization rate of 7.03 per 1000 enrollees. There were 63.5 deaths per 1000 discharges within 30 days of admission to the hospital in this population [1]. A recent review of the literature on hip fracture incidence rates in persons over the age of 50 years found that there were wide variations in the ageand sex-specific rates between ethnic groups and geographic regions. The rates are highest among white, intermediate in Asian and lowest in black and Hispanic populations. The ratio of females to males was found to be greater than 1 in white and Hispanic populations, but often less than 1 in black and Asian populations. A temporal trend toward higher rates in recent years was observed [2].

The Cynomolgus Macaque Natural History Model of Pneumonic Tularemia for Predicting Clinical Efficacy Under the Animal Rule

Francisella tularensis is a highly infectious Gram-negative bacterium that is the etiologic agent of tularemia in animals and humans and a Tier 1 select agent. The natural incidence of pneumonic tularemia worldwide is very low; therefore, it is not feasible to conduct clinical efficacy testing of tularemia medical countermeasures (MCM) in human populations. Development and licensure of tularemia therapeutics and vaccines need to occur under the Food and Drug Administrations (FDAs) Animal Rule under which efficacy studies are conducted in well-characterized animal models that reflect the pathophysiology of human disease. The Tularemia Animal Model Qualification (AMQ) Working Group is seeking qualification of the cynomolgus macaque (Macaca fascicularis) model of pneumonic tularemia under Drug Development Tools Qualification Programs with the FDA based upon the results of studies described in this manuscript. Analysis of data on survival, average time to death, average time to fever onset, average interval between fever and death, and bacteremia; together with summaries of clinical signs, necropsy findings, and histopathology from the animals exposed to aerosolized F. tularensis Schu S4 in five natural history studies and one antibiotic efficacy study form the basis for the proposed cynomolgus macaque model. Results support the conclusion that signs of pneumonic tularemia in cynomolgus macaques exposed to 300–3,000 colony forming units (cfu) aerosolized F. tularensis Schu S4, under the conditions described herein, and human pneumonic tularemia cases are highly similar. Animal age, weight, and sex of animals challenged with 300–3,000 cfu Schu S4 did not impact fever onset in studies described herein. This study summarizes critical parameters and endpoints of a well-characterized cynomolgus macaque model of pneumonic tularemia and demonstrates this model is appropriate for qualification, and for testing efficacy of tularemia therapeutics under Animal Rule.