Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammatory joint disorders: new insights from emerging data. An expert consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

PURPOSE: This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate. METHODS: This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized. RESULTS: The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects. DISCUSSION: Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation. CONCLUSIONS: Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach.

One-year effects of vitamin D and calcium supplementation on chronic periodontitis.

BACKGROUND: A previous study reported by this group found that patients in periodontal maintenance programs taking vitamin D and calcium supplementation had a trend for better periodontal health compared to patients not taking supplementation. The objective of the present study is to determine, for the same cohort of subjects, whether such differences persist over a 1-year period. METHODS: Fifty-one patients enrolled in maintenance programs from two dental clinics were recruited. Of these, 23 were taking vitamin D (≥400 IU/day) and calcium (≥1,000 mg/day) supplementation, and 28 were not. All subjects had at least two interproximal sites with ≥3 mm clinical attachment loss. For mandibular-posterior teeth, gingival index, plaque index, probing depth, attachment loss, bleeding on probing, calculus index, and furcation involvement were evaluated. Photostimulable-phosphor, posterior bitewing radiographs were taken to assess alveolar bone. Daily vitamin D and calcium intakes were estimated by nutritional analysis. Data were collected at baseline, 6 months, and 12 months. RESULTS: Total daily calcium and vitamin D intakes were 1,769 mg (95% confidence interval, 1,606 to 1,933) and 1,049 IU (781 to 1,317) in the taker group, and 642 mg (505 to 779) and 156 IU (117 to 195) in the non-taker group, respectively (P <0.001 for both). Clinical parameters of periodontal health improved with time in both groups (P <0.001). When clinical measures were considered collectively, the differences between supplement takers and non-takers had the following P values: baseline (P = 0.061); 6 months (P = 0.049); and 12 months (P = 0.114). After adjusting for covariates, the P values for the effect of supplementation were as follows: baseline (P = 0.028); 6 months (P = 0.034); and 12 months (P = 0.058). CONCLUSIONS: Calcium and vitamin D supplementation (≤1,000 IU/day) had a modest positive effect on periodontal health, and consistent dental care improved clinical parameters of periodontal disease regardless of such supplements. Our findings support the possibility that vitamin D may positively impact periodontal health and confirm the need for randomized clinical trials on the effects of vitamin D on periodontitis.

Cross-sectional study of vitamin D and calcium supplementation effects on chronic periodontitis.

BACKGROUND: A low dietary intake of vitamin D and calcium hastens bone loss and osteoporosis. Because vitamin D metabolites may also alter the inflammatory response and have antimicrobial effects, we studied whether the use of vitamin D and calcium supplements affects periodontal disease status. METHODS: A cohort of 51 subjects receiving periodontal maintenance therapy was recruited from two dental clinics; 23 were taking vitamin D (>or=400 IU/day) and calcium (>or=1,000 mg/day) supplementation, and 28 were not taking such supplementation. All subjects had at least two interproximal sites with >or=3 mm clinical attachment loss. Daily calcium and vitamin D intake (from food and supplements) were estimated by nutritional analysis. The following clinical parameters of periodontal disease were recorded for the mandibular posterior teeth: gingival index, probing depth, cemento-enamel junction-gingival margin distance (attachment loss), bleeding on probing, and furcation involvement. Posterior photostimulable-phosphor bitewing radiographs were taken to determine cemento-enamel junction-alveolar crest distances (alveolar crest height loss). Data were analyzed with a repeated-measures multivariate analysis of variance. RESULTS: Compared to subjects who did not take vitamin D and calcium supplementation, supplement takers had shallower probing depths, fewer bleeding sites, lower gingival index values, fewer furcation involvements, less attachment loss, and less alveolar crest height loss. The repeated-measures analysis indicated that collectively these differences were borderline significant (P = 0.08). CONCLUSIONS: In these subjects receiving periodontal maintenance therapy, there was a trend for better periodontal health with vitamin D and calcium supplementation. More expanded longitudinal studies are required to determine the potential of this relationship.

Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study.

OBJECTIVE: An effective and well tolerated intravenous (IV) bisphosphonate could provide a new treatment method for patients with osteoporosis. The Dosing IntraVenous Administration (DIVA) study was designed to identify the optimal ibandronate IV injection schedule for the treatment of postmenopausal osteoporosis by comparing the efficacy and tolerability of 2- and 3-monthly injections with the previously evaluated daily oral ibandronate regimen. We report the effects on lumbar spine and proximal femur bone mineral density (BMD) and bone resorption markers over 2 years. METHODS: This randomized, double-blind, double-dummy, noninferiority study recruited 1395 women (aged 55-80 yrs; > or = 5 yrs since menopause) with osteoporosis [mean lumbar spine (L2-L4) BMD T-score < -2.5 and > or = -5.0]. Patients received IV ibandronate (2 mg every 2 mo or 3 mg every 3 mo) plus daily oral placebo, or 2.5 mg daily oral ibandronate plus 2- or 3-monthly IV placebo. Supplemental vitamin D (400 IU) and calcium (500 mg) were provided throughout the 2-year study. RESULTS: At 2 years, the 2- and 3-monthly IV regimens achieved statistically noninferior and also superior increases in lumbar spine BMD compared with the daily regimen (6.4% and 6.3% vs 4.8%, respectively; p < 0.001). Greater increases were also obtained with IV ibandronate versus daily in proximal femur BMD. Serum concentrations of the biochemical marker of bone resorption C-telopeptide of the alpha-chain of type I collagen were reduced to a similar extent in all treatment arms (53.4%-59.9%). The tolerability profile of the IV regimens was similar to that observed with daily oral therapy. CONCLUSION: Ibandronate IV injections are an effective and well tolerated treatment for postmenopausal osteoporosis and provide a useful alternative to oral dosing.

Effects of dietary calcium compared with calcium supplements on estrogen metabolism and bone mineral density.

BACKGROUND: High calcium intake has been associated with both high bone mineral density (BMD) and high urinary estrogen metabolites. However, the role of dietary calcium and calcium supplements on estrogen metabolism and BMD remains unknown. OBJECTIVE: The objective was to investigate the importance of the source of calcium intake on estrogen metabolism and BMD. DESIGN: The average total daily calcium intake from supplements and diet, urinary estrogen metabolites, and spine and proximal femur BMD were studied in 168 healthy postmenopausal white women. RESULTS: Women who obtained calcium primarily from the diet or from both the diet and supplements had significantly (P=0.03) lower ratios of nonestrogenic to estrogenic metabolites (2-hydroxyestrone 1/16 alpha-hydroxyestrone) than did those who obtained calcium primarily from supplements. Adjusted BMD z scores were significantly greater in the subjects who obtained calcium primarily from the diet or from both the diet and supplements than in those who obtained calcium primarily from calcium supplements at the spine (P=0.012), femoral neck (P=0.02), total femur (P=0.003), and intertrochanter (P=0.005). This difference was evident especially in those who obtained calcium primarily from the diet, whose total calcium intake was lower than that in those who obtained calcium primarily from supplements. CONCLUSION: Calcium from dietary sources is associated with a shift in estrogen metabolism toward the active 16 alpha-hydroxyl metabolic pathway and with greater BMD and thus may produce more favorable effects in bone health in postmenopausal women than will calcium from supplements.

Estrogen and/or calcium plus vitamin D increase mandibular bone mass.

BACKGROUND: We have previously reported that estrogen/hormone replacement therapy (E/HRT) has beneficial effects on oral bone density over 3 years and that calcium and vitamin D supplementation has a lesser effect. Here we report on mandibular bone mass for 49 women (of the original cohort of 135) who continued in an additional 2-year, open-label extension. METHODS: Postmenopausal women were randomly assigned to receive calcium and vitamin D plus E/HRT, or calcium and vitamin D only. Regression analysis of mandibular bone mass over time was performed for each woman. RESULTS: Twenty-two of 26 women who took calcium and vitamin D plus E/HRT for 5 years had small mandibular bone mass increases (0.35 +/- 0.38%, P<0.001). Seventeen of 19 women who took only calcium and vitamin D for 3 years had increases in mandibular bone mass (0.74 +/- 0.89%, P<0.002). The largest gains in mandibular bone mass occurred during the first 3 years of the study. CONCLUSIONS: The data of this study indicate that E/HRT and/or calcium and vitamin D may result in increases of mandibular bone mass in postmenopausal women. Because of the long-term risks associated with E/HRT, caution should be exercised in prescribing E/HRT for prevention of chronic menopausal conditions.

Alveolar and postcranial bone density in postmenopausal women receiving hormone/estrogen replacement therapy: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: We conducted a 3-year, double-blind, randomized, placebo-controlled study to determine whether the positive effects of hormone/estrogen replacement therapy (H/ERT) on postcranial bone density are accompanied by similar positive effects on oral bone mass. METHODS: A total of 135 postmenopausal women (aged 41-70 years) with no evidence of moderate or severe periodontal disease were randomized to receive daily oral conjugated estrogen (Premarin; 0.625 mg) alone or in combination with medroxyprogesterone acetate (Prempro; 0.625 and 2.5 mg, respectively) or placebo. All subjects received calcium carbonate (1000 mg/d) and cholecalciferol (400 [corrected] IU/d) supplements. The primary efficacy end points were the changes in alveolar crest height and alveolar bone density. Alveolar crest height was measured on bite-wing radiographs, and changes in alveolar bone mass were assessed by means of digital-subtraction radiography. Postcranial bone density was measured in the lumbar spine and left proximal femur by means of dual-energy x-ray absorptiometry. RESULTS: Hormone/estrogen replacement therapy significantly increased alveolar bone mass compared with placebo (+1.84% vs +0.95% [P =.04]), and tended to improve alveolar crest height (+4.83% vs +3.46% [P =.34]). Bone mineral density of the proximal femur significantly increased in the H/ERT compared with the placebo group (total proximal femur, +3.59% vs +0.22% [P =.001]; neck, +2.05% vs -0.34% [P =.02]; trochanter, +3.49% vs +0.08% [P<.001]), but not the lumbar spine (+1.01% vs +0.17% [P =.39]). Changes in alveolar bone mass correlated with bone density changes in the total femur (r = 0.28 [P =.02]) and femoral trochanter (r = 0.25 [P =.04]) in the H/ERT but not in the placebo group. CONCLUSIONS: Postcranial and oral bone mass were increased in postmenopausal women receiving H/ERT. Improvement in oral bone health constitutes an additional benefit of H/ERT.

Intercellular calcium signaling occurs between human osteoblasts and osteoclasts and requires activation of osteoclast P2X7 receptors.

Signaling between osteoblasts and osteoclasts is important in bone homeostasis. We previously showed that human osteoblasts propagate intercellular calcium signals via two mechanisms: autocrine activation of P2Y receptors, and gap junctional communication. In the current work we identified mechanically induced intercellular calcium signaling between osteoblasts and osteoclasts and among osteoclasts. Intercellular calcium responses in osteoclasts required P2 receptor activation but not gap junctional communication. Pharmacological studies and reverse transcriptase-PCR amplification demonstrated that human osteoclasts expressed functional P2Y1 receptors, but, unexpectedly, desensitization of P2Y1 did not block calcium signaling to osteoclasts. We also found that osteoclasts expressed functional P2X7 receptors and showed that pharmacological inhibition of these receptors blocked calcium signaling to osteoclasts. Thus these studies show that calcium signaling between osteoblasts and osteoclasts occurs via activation of P2 receptors, but that different families of P2 receptors are required for calcium signaling in these two cell types. Intercellular calcium signaling among bone cells is therefore amenable to pharmacological manipulation that will specifically affect only bone-forming or bone-resorbing cells. P2 receptors may be important drug targets for the modulation of bone turnover.