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Short cycles of human (h) PTH-(1-34) may have an anabolic effect to increase bone mass in patients with osteoporosis. As PTH also stimulates bone resorption, it is theoretically possible to enhance the anabolic effects of PTH by using a sequential antiresorptive agent in the treatment cycle. To test this hypothesis, 30 women with osteoporosis, aged 67 +/- 8 yr, completed a 2-yr protocol that comprised 28-day courses of hPTH-(1-34) (800 U) given by daily sc injections; each course was repeated at 3-month intervals. By random allocation, patients either received sequential calcitonin (CT) immediately following the cycle of hPTH-(1-34) (75 U/day, sc; PTH + CT; n = 16) or placebo CT (PTH alone; n = 14) for 42 days. Baseline bone mineral density (BMD) at the lumbar spine site revealed t scores of -3.7 +/- 1.2 (+/-SD) for the PTH alone group and -3.0 +/- 1.4 for the PTH + CT groups, who had 2.0 +/- 2.3 and 1.8 +/- 2.4 vertebral fractures, respectively, at entry to the study. At the end of the 2 yr, the lumbar spine BMD increased from 0.720 +/- 0.130 to 0.793 +/- 0.177 g/cm2 (10.2%) in the PTH group and from 0.760 +/- 0.168 to 0.820 +/- 0.149 g/cm2 (7.9%) in the PTH + CT group. These changes were significant over time in both groups (P < 0.001). Although the final 2-yr lumbar spine BMD was not significantly different between the two treatment groups, those patients receiving sequential CT injections gained bone mass at a consistently slower rate. Changes in BMD at the femoral neck averaged +2.4% and -1.8% in the PTH and PTH + CT groups, respectively, neither of which was significant. In the group receiving only cyclical hPTH-(1-34), the observed 2-yr vertebral fracture incidence was 4.5 compared to 23.0/100 patient yr in the PTH + CT group (P = 0.078). During the first two cycles, changes in biochemical markers of bone formation (serum total alkaline phosphatase, bone-specific alkaline phosphatase, and osteocalcin) and bone resorption (fasting urinary hydroxyproline and N-telopeptide excretion) were significantly increased over pretreatment values after 28 days of hPTH-(1-34) injections (P < 0.05 to P < 0.01 for both groups). Even end of cycle values remained elevated over the study baseline across time (P < 0.01). There were no significant differences for any outcome parameter between the two treatment groups. We conclude that short cycles (28 days) of daily hPTH-(1-34) injections result in significant increases in lumbar spine BMD, without significant changes in cortical bone mass at the femoral neck. Very low incident vertebral fracture rates were documented over 2 yr. However, there is no evidence that sequential antiresorptive therapy with CT is of any benefit over that conferred by cyclical PTH alone.

The objectives were to determine the efficacy and safety of nasal salmon calcitonin 200 IU daily in the prevention of corticosteroid-induced osteoporosis. A minimized, double-blind, placebo-controlled trial was carried out in corticosteroid-treated patients with polymyalgia rheumatica. The setting was a tertiary care university-affiliated hospital and a total of 31 patients were enrolled. The primary outcome measure was the percentage change in bone mineral density of the lumbar spine in the two treatment groups from baseline to 1 yr of follow-up. The mean +/- S.D. bone mineral density of the lumbar spine in the calcitonin-treated group decreased by 1.29 +/- 6.76% and in the placebo group by 4.95 +/- 3.50% after 12 months. The observed difference of 3.65 +/- 2.10% between groups is statistically significant (P < 0.05). Nasal salmon calcitonin prevented loss of bone in the lumbar spine as measured by dual-energy X-ray absorptiometry.

The pathophysiology of corticosteroid-induced osteoporosis is outlined in this article. Treatment options, based upon our understanding of the pathophysiology, and a review of the available literature are offered.

Objective: To assess the effects of medroxyprogesterone acetate on bone density in women who have had a hysterectomy., Design: Randomised, double-blind, placebo-controlled trial of medroxyprogesterone acetate 10 mg, 20 mg or placebo as an adjunct to oestrogen therapy., Participants: One hundred and twenty-three women, aged 18 to 45 years and currently receiving daily oestrogen, who presented at a university-based rheumatology practice., Interventions: The women were randomly assigned to receive either medroxyprogesterone acetate 10 mg, 20 mg or placebo daily beginning on day 15 of each month for one year. Forty-one women were randomised into each group., Main Outcome Measure: The primary outcome measurement was the percentage of change from baseline in bone mineral density of the lumbar spine (L2-L4). Secondary outcome measures included differences in femoral neck bone density, cholesterol and triglyceride levels between groups., Results: At one year, change in bone mineral density did not differ between either the treatment or placebo groups. Medroxyprogesterone acetate 20 mg and 10 mg led to statistically significant reductions in very low density lipoprotein cholesterol, total triglycerides, and very low density lipoprotein triglycerides when compared with placebo. Medroxyprogesterone acetate 20 mg also led to a statistically significant reduction in high density lipoprotein cholesterol, high density lipoprotein-2 cholesterol, and high density lipoprotein-2 triglycerides., Conclusions: Medroxyprogesterone acetate at either dose as an adjunct to oestrogen did not improve bone mineral density at one year when compared with placebo. Medroxyprogesterone acetate 10 mg may not adversely affect lipids. Medroxyprogesterone acetate 20 mg, however, did reduce high density lipoprotein cholesterol and therefore may increase cardiovascular risk.

The goals of treatment for patients with osteoporosis are to maintain normal bone and to prevent the deterioration of normal bone to osteoporotic bone. Achievement of these goals, combined with a successful approach to prevention of falls, may substantially decrease the incidence and risk of fractures. Strategies for osteoporosis therapy include patient strategies (e.g., administration of calcium, exercise), drug therapy to stimulate bone formation (e.g., fluoride, anabolic steroids), and drugs to inhibit bone resorption (e.g., estrogen replacement therapy, calcitonin, bisphosphonates).

Objective: To determine the efficacy and safety of vitamin D 50,000 units/week and calcium 1,000 mg/day in the prevention of corticosteroid induced osteoporosis., Methods: A minimized double blind, placebo controlled trial in corticosteroid treated subjects in a tertiary care university affiliated hospital. The sample was 62 subjects with polymyalgia rheumatica, temporal arteritis, asthma, vasculitis, or systemic lupus erythematosus. The primary outcome measure was the percentage change in bone mineral density (BMD) of the lumbar spine in the 2 treatment groups from baseline to 36 mo followup., Results: BMD of the lumbar spine in the vitamin D and calcium treated group decreased by a mean (SD) of 2.6% (4.1%) at 12 mo, 3.7% (4.5%) at 24 mo, and 2.2% (5.8%) at 36 mo. In the placebo group there was a decrease of 4.1% (4.1%) at 12 mo, 3.8% (5.6%) at 24 mo, and 1.5% (8.8%) at 36 mo. The observed differences between groups were not statistically significant. The difference at 36 mo was-0.693% (95% CI -5.34, 3.95)., Conclusion: Vitamin D and calcium may help prevent the early loss of bone seen in the lumbar spine as measured by densitometry of the lumbar spine. Longterm vitamin D and calcium in those undergoing extended therapy with corticosteroids does not appear to be beneficial.

A dedicated computed tomography system was used to acquire transaxial images of the distal radius to assess trabecular bone structure in vivo. We segmented trabecular bone from the marrow and soft tissue background by postprocessing the image with a region grow and skeletonization step. From the processed image we assessed the integrity of the bone by examining the continuity of its trabecular network and by determining the area of the holes comprising its marrow space. The continuity of the bone imaged was assessed by a proposed connectivity index (CI) and the size of the marrow spaces was assessed by calculating a mean hole area (H(A)) in the bone cross-section. Repeat measurements revealed that the intra-subject variability in CI and H(A) was small (CV < 6%). Both CI and H(A) were sensitive enough to reflect differences in structure at the head of the radius and at several sites along its shaft. We tested the diagnostic value of assessing bone structure at the distal end of the radius by measuring trabecular bone density, CI and H(A) in a mixed group of 26 subjects, nine of whom had suffered a wrist fracture. We found that a trabecular bone density threshold of 116 mg cm-3, corresponding to two standard deviations below the mean density in the 17 non-fractured subjects, separated fractured from non-fractured subjects with a sensitivity of 22% and a specificity of 100%. A CI threshold of -4.7 doubled the sensitivity (44%) and maintained the 100% specificity. An H(A) threshold of 4.5 mm2 achieved a sensitivity of 89% and a specificity of 94%. This increased sensitivity achieved by our indices suggests that an in vivo assessment of trabecular bone structure can contribute significantly to the identification of persons at risk of fracture.

Bone metabolism may be measured indirectly by determining markers for bone formation and bone resorption. Traditionally, total alkaline phosphatase has served to mark bone formation, whereas urine calcium and hydroxyproline, corrected for creatinine, have marked bone resorption. Although these markers have contributed to our understanding of bone metabolism, by themselves they lack the sensitivity and specificity to be helpful in the day-to-day management of patients with osteoporosis. Newer bone markers have been developed and others are currently under development. These markers may be helpful in determining the type of osteoporosis and the response to therapy. Nonetheless, despite their increased sensitivity and specificity, they have not yet been shown to predict future fractures. Many prospective studies have shown that bone mass measured at any site and by any method is inversely related to fracture risk. Site-specific measurement of the bone density of the proximal femur appears to have a stronger relationship to the risk of hip fracture. In predicting spinal fractures, however, measurement of bone density in the lumbar spine does not appear to be substantially superior to measurements of bone density at other sites. The lifetime risk for hip fracture can be estimated from bone mass measurements made in the perimenopausal period. In the future, the combination of baseline perimenopausal bone density and assessments of biochemical markers may better predict future fracture risk; however, this has yet to be shown.

The purpose of this study was to evaluate the efficacy of intermittent cyclic therapy (ICT) with etidronate in preventing the loss of lumbar vertebral bone mineral density (BMD) in patients taking corticosteroids. The study population was a cohort of patients taking corticosteroids for at least two years for polymyalgia rheumatica, asthma, rheumatoid arthritis, systemic lupus erythematosus or other conditions. A tertiary care university teaching hospital-affiliated rheumatology office practice. Inclusion and exclusion criteria yielded eighty-eight patients taking corticosteroids for at least two years who had not taken estrogen or fluoride and had no causes of secondary osteoporosis. Changes relative to baseline in individual vertebral (L2-L4) BMD measurements after one and two years were compared between patients who had taken ICT with etidronate (n = 42) and those who had not (n = 46). We found that BMD in the lumbar spine increased significantly over baseline in patients who had taken ICT with etidronate, by 3.9% after one year and by 5.6% after two years, whereas it decreased by 3.7-3.8% in patients who had not. We conclude that ICT with etidronate prevents corticosteroid-induced osteoporosis and progressively ameliorates BMD over two years. Double blind trials are underway to evaluate whether this increased BMD is associated with reductions in vertebral fracture rates.

Objective: To learn about the physical, emotional, and social limitations experienced by postmenopausal women who have back pain due to vertebral fractures resulting from osteoporosis., Methods: We conducted a cross-sectional survey of female patients with persistent pain due to vertebral fractures., Results: Respondents had a mean (+/- SD) bone density of 0.87 +/- 0.13 gm/cm2 and a mean (+/- SD) of 2.84 +/- 2.18 fractures. Disability was identified in pain, movement, activities of daily living, and emotion. There was a poor correlation between quality of life and findings on radiography or densitometry., Conclusion: To evaluate the effects of osteoporosis on a patient's functional status, direct questioning is required.

Corticosteroid-induced osteoporosis is a major problem faced by rheumatologists, with up to 50% of patients at increased risk for vertebral fractures. Our current understanding of the pathophysiology of corticosteroid-induced osteoporosis suggests two basic problems: a reduction in bone formation and an increase in bone resorption leading to an overall reduction in bone mass. Adequate calcium and vitamin D intake, calcitonin, hormone-replacement therapy, and thiazide diuretics are of benefit in preventing corticosteroid-induced bone loss. Other therapies such as the bisphosphonates, fluoride, and anabolic steroids should be considered when fractures occur or ongoing bone loss is evident. A review of the literature outlining the pathophysiology, clinical features, assessment, and treatment is presented.

Female patients (n = 20) with osteoporosis, aged 66 +/- 5 yr were studied during a 24-h infusion of parathyroid hormone (PTH [1-34]) at a rate of 0.5 IU equivalents/kg.h, and then during a 28-d period of subcutaneous injections, at a dose of 800 IU equivalents per day. Thereafter half the patients received subcutaneous injections of calcitonin, 75 U/d for 42 d, and all patients were followed to the end of a 90-d cycle. Biochemical markers of bone formation (serum alkaline phosphatase, osteocalcin, and the carboxy-terminal extension peptide of pro-collagen 1) and bone resorption (fasting urine calcium, hydroxyproline, and deoxypyridinoline) were compared during treatment by the intravenous and subcutaneous route of PTH administration, and subsequently during calcitonin therapy. During intravenous PTH infusion there were significant reductions in all three bone formation markers, despite expected rises in urinary calcium and hydroxyproline. By contrast, the circulating markers of bone formation increased rapidly by > 100% of baseline values during daily PTH injections (P < 0.001). Significant increases in bone resorption markers were only seen at the end of the 28 d of injections, but were < 100% over baseline values, (P < 0.05). Quantitative bone histomorphometry from biopsies obtained after 28 d of PTH treatment confirmed that bone formation at both the cellular and tissue levels were two to five times higher than similar indices measured in a control group of biopsies from untreated osteoporotic women. Subsequent treatment of these patients with calcitonin showed no significant changes in the biochemical markers of bone formation and only a modest attenuation of bone resorption. Thus, PTH infusion may inhibit bone formation, as judged by circulating biochemical markers, whereas daily injections confirm the potent anabolic actions of the hormone. Sequential calcitonin therapy does not appear to act synergistically with PTH in cyclical therapeutic protocols.

The purpose of this study was to use a canine model to compare the ability of vascularized and nonvascularized perichondrial grafts to resurface an experimental joint defect. In five adult mongrel dogs, a 3 x 2 cm segment of perichondrium, subtended by the intercostal-internal mammary vessels, was harvested and transplanted to a surgically created defect on the ulnar condyle of the humerus. A similar defect in the opposite elbow was repaired with a 3 x 2 cm standard perichondrial graft. Five untreated dogs acted as normal controls. The dogs were allowed to mobilize freely for a period of 6 months. At that time, angiography demonstrated that all microvascular anastomoses were patent. There was no statistical difference in the range of motion of the two elbows, in the radiographic appearance, or in bone density of the two groups of joints. Histologic assessment demonstrated that the vascularized perichondrium formed an articular cartilage with an average thickness of 21.8 microns as compared with 38.5 microns for the nonvascularized perichondrium (p < 0.05). The cartilage in both grafts was morphologically hyaline in type. There were degenerative changes in the grafts with partial separation of the graft from the underlying bone and formation of surface clefts or pits, villous projections, and synovial proliferation. Degenerative changes also were observed on the articular surface opposite the grafted humeral condyle. In two animals the grafts displaced from the recipient condyle, which instead became resurfaced by greater amounts of hyaline-type cartilage with lesser degrees of degeneration and subarticular fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Lumbar spine and femoral neck bone mineral density (BMD) were measured with a Novo radioisotope based dual photon densitometer and with a Lunar X-ray densitometer in 94 subjects attending a Metabolic Bone Disease Clinic. There was a strong correlation between results obtained from each machine for the same skeletal site. The correlation coefficients for the spine and femoral neck were 0.97 and 0.88, respectively. The differences between results from each machine were normally distributed with a mean bias of 37.5% for the spine and 27.8% for the femur, which arise principally from differences in machine calibration. In each case the BMD was greater when measured by X-ray absorptiometry. The range for the bias was approximately 25-50% for the spine and 10-45% for the femoral neck. The results from these two machines are not interchangeable. When subjects who are participating in long term studies using a radioisotope densitometer are transferred to an X-ray densitometer, an individual conversion factor must be measured at each site for each subject.

Presently, in the process of new drug development, large sample parallel group randomized trials are often begun without the detailed knowledge of optimal dose, most responsive patient group, and optimal outcomes which would be desirable. We propose that randomized trials in individual subjects (N of 1 RCTs) could be used to elucidate these issues at an early stage of drug development. In appropriate conditions N of 1 RCTs can be used to define the rapidity with which a drug begins and ceases its clinical action, the likely range of the optimal drug dose, and the optimal outcomes on which subsequent trials should focus. N of 1 RCTs can also generate initial estimates of the proportion of patients who respond to a new agent and for determining sample size, inclusion criteria, and dosage regimen(s) for subsequent parallel group trials. We provide an example of 14 N of 1 RCTs of amitriptyline in fibrositis that illustrate the ways in which N of 1 RCTs can elucidate these issues. The multiple uses of N of 1 RCTs suggest that the method has immense potential for use in the early phases of drug development programs.

Objective: To review the feasibility and effectiveness of n-of-1 randomized controlled trials (n-of-1 trials) in clinical practice., Design: Individual trials were double-blind, randomized, multiple crossover trials. The impact of n-of-1 trials was determined by eliciting physicians' plans of management and confidence in those plans before and after each trial., Setting: Referral service doing n-of-1 trials at the requests of community and academic physicians. OBJECT of, Analysis: All trials were planned, started, and completed by the n-of-1 service., Measures of Outcome: The proportion of planned n-of-1 trials that were completed and the proportion that provided a definite clinical or statistical answer. A definite clinical answer was achieved if an n-of-1 trial resulted in a high level of physician's confidence in the management plan. Specific criteria were developed for classifying an n-of-1 trial as providing a definite statistical answer., Main Results: Seventy-three n-of-1 trials were planned in various clinical situations. Of 70 n-of-1 trials begun, 57 were completed. The reasons for not completing n-of-1 trials were patients' or physicians' noncompliance or patients' concurrent illness. Of 57 n-of-1 trials completed, 50 provided a definite clinical or statistical answer. In 15 trials (39% of trials in which appropriate data were available), the results prompted physicians to change their "prior to the trial" plan of management (in 11 trials, the physicians stopped the drug therapy that they had planned to continue indefinitely)., Conclusion: We interpret the results as supporting the feasibility and usefulness of n-of-1 trials in clinical practice.

Three patients who developed thrombocytopenia while taking gold therapy are reviewed. Bone marrow examinations at the time of thrombocytopenia revealed adequate numbers of megakaryocytes. Elevated levels of platelet associated IgG (PAIgG) were demonstrated in relationship to the thrombocytopenia. A response to prednisone therapy was seen with a rise in platelet count and a fall in PAIgG. All 3 patients were found to have the following alloantigens of the major histocompatibility complex, HLA-B8, DR3. These findings suggest that gold induced thrombocytopenia is immunologically mediated and possibly related to the genes of the major histocompatibility complex.

With a cDNA probe for the DQ beta gene, two variants of the DR4-linked DQw3 (3.1 and 3.2) allele were analysed in patients with rheumatoid arthritis (RA), healthy individuals, and homozygous cell lines. The DQw3.1 allele, identified by 3.4 kb (HindIII), 2.3 kb (SstI), and 3.7 kb and 6.9 kb (BamHI) restriction fragment lengths, was expressed in 100% (of 18) DR4-positive patients, compared with only 19% (of 16) of DR4-positive controls including one of five homozygous cell lines. This DQ beta variant showed a highly significant association (relative risk = 78; p less than 10(-6) with RA and may therefore play an important part in susceptibility to RA.

The N of 1 service at our institution acts as a full referral service for clinicians who want a definitive answer to a difficult management question, and an instructional environment for clinicians who have more time and want to learn to run their own N of 1 RCT. The trial design is a double blind, randomized pair, multiple crossover. A number of methodologic issues are discussed, such as appropriateness of the patients problem to N of 1 trials, feasibility, types of measurement, such as clinical objective measurement and quality of life measurement, as well as timing of these measurements. The analysis issues include developing a reporting method which is statistically powerful and understandable to clinicians with little research background. Some of these issues have been well investigated and some have not.

Gold induced thrombocytopenia is immune mediated, with the production of platelet associated IgG leading to peripheral platelet destruction. An association with HLA-DR3 has been demonstrated. Corticosteroid therapy is effective in treatment, although other modes of therapy may be as efficacious.