Essential role of local antibody distribution in mediating bone-resorbing effects.

The link between antibodies and bone mass is debated. Activated IgG, which interacts directly with Fc gamma receptors, stimulates osteoclastogenesis in vitro, and local injection in immune-activated mice leads to bone loss. Multiple myeloma patients with high serum IgG levels have induced osteoclast activation and display bone loss. In addition, bone loss has been linked to serum autoantibodies in autoimmune diseases, including anti-citrullinated protein antibodies (ACPA) in individuals with rheumatoid arthritis (RA). Whether serum IgG or autoantibodies regulate bone mass under healthy conditions is poorly studied. In elderly men, neither serum levels of polyclonal IgG nor autoantibody were associated with areal bone mineral density in the MrOS Sweden study. Repetitive systemic injections of high-dose polyclonal IgG complexes in mice did not exert any discernible impact on bone mineral density. However, repetitive local intra-articular injection of the same IgG complexes led to a localized reduction of trabecular bone density. These results indicate antibodies may only impact bone density when close to the bone, such as within the synovial joint.

Bone Mass Development from Childhood into Young Adulthood in Patients with Childhood-onset Inflammatory Bowel Disease.

BACKGROUND: Children who have inflammatory bowel disease (IBD) have increased risk of low bone mineral density (BMD). There is a scarcity of information on BMD development through puberty and into young adulthood in patients with childhood-onset IBD. METHODS: We conducted a prospective longitudinal study of BMD in patients with childhood-onset IBD. In total, 74 children with IBD were followed into young adulthood, with a mean follow-up of 8.4 years. The BMD was assessed longitudinally using dual-energy X-ray absorptiometry of the lumbar spine, total hip and whole body, and related to anthropometric measures. RESULTS: Young adult male patients with IBD had lower mean BMD Z-scores for the lumbar spine at -0.8 (±1.1 SD) and total hip at -0.5 (±0.9 SD), as compared to standard references. In young female patients, the BMD Z-scores were within the normal range at all 3 measured sites as compared to the standard references. There were no significant differences in the BMD Z-scores between patients with Crohn's disease and patients with ulcerative colitis. The female and male patients showed significantly improved mean lumbar spine BMD Z-scores during follow-up into young adulthood, indicating that bone accumulation in the lumbar spine continues beyond the expected age for achieving peak bone mass. CONCLUSIONS: Male patients with childhood-onset IBD seem to have an increased risk of compromised BMD in young adulthood. Both female and male patients with IBD seem to increase their BMD beyond the age for expected peak bone mass (see Video abstract, Supplemental Digital Content 1, http://links.lww.com/IBD/B648).

Rationale and design of MUSIC OS-EU: an international observational study of the treatment of postmenopausal women for osteoporosis in Europe and Canada.

OBJECTIVES: The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study (MUSIC OS-EU) was designed to better understand the rate and burden of gastrointestinal (GI) events on clinical and health care outcomes among postmenopausal women with osteoporosis. METHODS: MUSIC OS-EU is a prospective, multinational, observational cohort study of postmenopausal women ≥50 years of age diagnosed with osteoporosis and enrolled in physician clinics in six countries: France, Italy, the Netherlands, Sweden, the United Kingdom, and Canada. The MUSIC OS-EU study has three components: (i) a physician survey to describe their management of osteoporotic patients with GI events; (ii) a retrospective chart survey to describe the receipt and type of osteoporosis medication prescribed; and (iii) a prospective cohort study including untreated and treated patients diagnosed with osteoporosis to investigate the rate of GI events and association with osteoporosis medication use patterns, health-related quality of life, treatment satisfaction and resource utilisation among postmenopausal women with osteoporosis. RESULTS: Physicians at 97 sites completed the physician questionnaire and data for 716 patients were abstracted for the retrospective chart review. Enrolment and the baseline data collection for the prospective cohort study were conducted between March 2012 and June 2013 for 292 untreated and 2,959 treated patients, of whom 684 were new users and 2,275 were experienced users of oral osteoporosis medications. CONCLUSIONS: The results of MUSIC OS-EU will illuminate the association of GI events with the management of osteoporosis and with patient-reported outcomes among postmenopausal women with osteoporosis in Europe and Canada.

Holotranscobalamin is not influenced by decreased renal function in elderly men: the MrOS Sweden study.

BACKGROUND: Subclinical cobalamin deficiency is common in the elderly, but the sensitivity and specificity of serum total cobalamin for this diagnosis is poor. Serum holotranscobalamin (holoTC), a measure of biologically available cobalamin, is considered a better marker for early cobalamin depletion than total cobalamin. However, in elderly populations, health-related reference intervals for holoTC and correlations to renal function are not entirely clear. METHODS: HoloTC was determined with an automated microparticle enzyme immunoassay (AxSYM®) in 790 elderly non-vitamin-supplemented Swedish men, median age 75.3 years. Renal function was assessed with creatinine, cystatin C and estimated glomerular filtration rate (eGFR calculated from creatinine). RESULTS: Median holoTC was 51.8 pmol/L, the health-related reference interval 19.6-132.3 pmol/L. There was no significant difference in mean holoTC in probands with normal compared to high creatinine (P = 0.80) and cystatin C (P = 0.82). No significant differences between the quartiles of creatinine or cystatin C in mean of log holoTC were seen. HoloTC correlated strongly with total cobalamin (r = 0.69, P < 0.001), weaker with eGFRcreatinine (r = -0.09, P < 0.05) and creatinine (r = 0.09, P < 0.05), the latter correlation was only seen in subjects with creatinine <100 µmol/L. HoloTC correlated negatively with plasma total homocysteine (r = -0.24, P < 0.001), but not with cystatin C and age. CONCLUSIONS: Serum holoTC in healthy elderly men shows the same distribution as earlier described for a younger reference population. In this group of elderly subjects, holoTC did not correlate to reduced renal function. Thus, holoTC appears to be a promising tool for evaluating cobalamin status also in elderly populations.

Not all elderly people benefit from vitamin D supplementation with respect to physical function: results from the Osteoporotic Fractures in Men Study, Hong Kong.

OBJECTIVES: To examine vitamin D status and its association with physical performance and muscle mass in older Chinese men. DESIGN: Cross-sectional and prospective cohort study design. SETTING: Hong Kong, People's of Republic of China. PARTICIPANTS: Nine hundred thirty-nine community-dwelling men aged 65 and older for cross-sectional analysis and 714 for longitudinal analysis. MEASUREMENTS: Baseline serum 25-hydroxyvitamin D (25OHD) was measured using a competitive radioimmunoassay kit. Baseline and 4-year physical performance measures (grip strength, 6-m walking speed, step length in a 6-m walk, time to complete five chair stands) were measured, and appendicular skeletal muscle mass (ASM) was assessed using dual-energy X-ray absorptiometry. Data were collected for confounding factors: demographic, number of diseases, smoking, alcohol use, body mass index, physical activity, diet, season of blood sampling, and serum parathyroid hormone (PTH) level. Multivariate regression analyses were performed with adjustments for confounding factors. RESULTS: Mean ± standard deviation serum 25OHD level of this sample of Chinese community-dwelling older men who had a high level of baseline physical function was 77.9 ± 20.5 nmol/L; 94.1% of participants had serum 25OHD levels of 50 nmol/L or greater. Median (interquartile range) serum PTH level was 4.1 pmol/L (3.1-5.5 pmol/L). After adjustment for potential confounding factors, serum 25OHD levels were not associated with baseline or 4-year change in physical performance measures and ASM. CONCLUSION: In Chinese older men who are vitamin D replete and have a high level of baseline physical function, vitamin D may not have an important role in physical function and muscle mass.

Associations of estradiol and testosterone with serum phosphorus in older men: the Osteoporotic Fractures in Men study.

Postmenopausal women consistently have higher phosphorus levels than similarly aged men. As it is known that estradiol induces phosphaturia in rodents, we evaluated the cross-sectional association of sex hormones with serum phosphorus in 1346 community-living older men (mean age 76) of which 18% had moderate (stage 3) kidney disease. Using linear regression with serum phosphorus levels as the dependent variable, we found that for each 10 pg/ml higher total estradiol level there was a statistically significant 0.05 mg/dl lower serum phosphorus when adjusted for age, ethnicity, testosterone, sex hormone-binding globulin, calcium, estimated glomerular filtration rate, intact parathyroid hormone, 25(OH) vitamin D, bone mineral density, and alkaline phosphatase. These results were similar in individuals with or without chronic kidney disease. Serum testosterone concentrations were also statistically significantly associated with lower serum phosphorus levels. We confirmed these results in an independent sample of 2555 older men, wherein these associations were not attenuated when adjusted for fibroblast growth factor-23 levels. Hence, our study of community-living older men suggests that estradiol may directly or indirectly induce phosphaturia in humans. The mechanism responsible for the association of testosterone with serum phosphorus remains to be determined.

Fatty acid pattern in serum is associated with bone mineralisation in healthy 8-year-old children.

Animal studies have shown that fatty acids (FA) are important for normal bone development. Human data are scanty and mostly related to diseases. We hypothesised that serum FA pattern might be related to bone mineralisation in healthy children. Serum phospholipid FA pattern was studied in relation to bone parameters in eighty-five healthy Caucasian 8-year-olds. Dual-energy X-ray absorptiometry and blood sampling for analysis of serum phospholipid FA by capillary GLC were performed on the same day. SFA concentrations were associated with bone mineral density (BMD) of the hip, lumbar spine and total body. There was a general trend that linoleic acid (LA; 18 : 2n-6) was negatively associated with BMD, since that was found both for the LA concentration, the total n-6 concentration and the ratio of n-6:n-3 FA. Arachidonic acid (AA; 20 : 4n-6) was positively correlated with bone mineral content (BMC) and BMD of total body, as was the corresponding z-score and the AA:LA ratio. Both saturated and polyunsaturated serum phospholipid FA were associated with BMC and BMD in healthy children. LA and AA were found to inversely influence bone mineralisation and the association with the n-6:n-3 ratio suggested that this balance might also be of importance. The general trend of a negative influence of high n-6 FA concentrations on bone mineralisation might be of concern in relation to the changes in the Western diet. Longitudinal studies are necessary to verify if different bone compartments and different grades of modelling are related to different FA patterns.

UVB therapy increases 25(OH) vitamin D syntheses in postmenopausal women with psoriasis.

BACKGROUND: Vitamin D3 is produced in the epidermis by ultraviolet (UV) radiation (290-315 nm) of 7-dehydrocholesterol. A similar range of 290-320 nm (broadband UVB) has been successfully used for years to treat psoriasis. The aim of this study was to investigate whether UVB therapy was able to influence vitamin D synthesis in psoriasis patients. METHODS: Twenty-four postmenopausal, white Caucasian women, aged 69 +/- 5.9 (mean +/- SD), with active plaque psoriasis, were treated with broadband UVB two to three times per week for 8-12 weeks. The serum concentrations of calcidiol (25(OH)D3), calcitriol (1,25(OH)2D3), intact parathyroid hormone (PTH), thyroid hormones, osteocalcin, calcium and creatinine were measured before the first and after the last dose of radiation. Bone density was measured using Dual-Energy X-ray Absorptiometry (Hologic Delphi A) at the hip and lumbar spine. RESULTS: Serum levels of 25(OH)D3 increased from 36.8 +/- 17 ng/ml (mean +/- SD) to 59.6 +/- 18.7 ng/ml (P<0.001) after the UVB treatment period. Serum PTH decreased from 62.8 +/- 25.7 ng/l to 48.2 +/- 17.4 ng/l (P<0.001). Secondary hyperparathyroidism (PTH>65 ng/l) was revealed in seven patients (29%) in whom PTH values were suppressed by the UVB therapy. The serum levels of calcitriol, calcium, osteocalcin, thyroid hormones and creatinine were unaltered. CONCLUSION: UVB therapy in elderly psoriatic women improved psoriasis, increased serum 25(OH)D3 synthesis and reduced serum PTH concentrations.

Safety and efficacy of teriparatide in elderly women with established osteoporosis: bone anabolic therapy from a geriatric perspective.

OBJECTIVES: To assess the safety and efficacy of teriparatide in patients aged 75 and older and compare these findings with those of women younger than 75 using data from the Fracture Prevention Trial (FPT). DESIGN: The FPT was a randomized, multicenter, double-blind, placebo-controlled study. SETTING: The FPT multicenter international study. PARTICIPANTS: Postmenopausal women aged 42 to 86 were randomized to placebo (N=544) or teriparatide 20 mug (N=541) by daily self-injection for a median of 19 months. Patients received daily oral supplements of 1,000 mg calcium and 400 to 1,200 IU vitamin D. For this analysis, subgroups were defined according to patient age younger than 75 (N=841) and 75 and older (N=244). MEASUREMENTS: The effects of teriparatide on bone mineral density (BMD) of the lumbar spine and femoral neck; the incidence of new vertebral and new nonvertebral fragility fractures; bone turnover markers, including bone-specific alkaline phosphatase; and urinary deoxypyridinoline corrected for creatinine clearance, as well as the safety of teriparatide, were investigated. RESULTS: There were no significant treatment-by-age interactions for the bone turnover markers, femoral neck BMD, vertebral fractures, nonvertebral fragility fractures, height loss, hyperuricemia, or hypercalcemia. A significant treatment-by-age interaction for lumbar spine BMD (P=.08) was due to an increase in BMD observed in the placebo group aged 75 and older. There were no treatment-by-age interactions for important treatment-emergent adverse events (TEAEs), including back pain, nausea, leg cramps, and dizziness. The most important TEAEs in women aged 80 and older (23 patients from the placebo group and 25 patients from the teriparatide group) were also reviewed; no unexpected TEAEs were found in the patients treated with teriparatide. These results indicate that the clinical effects of teriparatide were consistent in the older and younger women. CONCLUSION: Age does not affect the safety and efficacy of teriparatide in postmenopausal women with osteoporosis.

Ultraviolet B radiation improves serum levels of vitamin D in patients with cystic fibrosis.

BACKGROUND: Ultraviolet B (UVB) radiation can be used in the prevention and treatment of vitamin D deficiency. AIM: To investigate, in a controlled study of patients with cystic fibrosis (CF), whether regular UVB radiation would improve serum levels of calcidiol during the dark season (October-April). METHODS: Thirty patients with mild to moderate disease were included (aged 9-40 y). All patients had cholecalciferol supplementation. One group (15 patients) was given UVB one to three times a week for 6 mo and one group (15 sex- and age-matched patients) served as controls. The radiation source consisted of three TL 12/40W UVB fluorescent lamps. Initial treatment duration was 1 min, subsequently increased by 0.5-1 min/treatment to a maximum of 10 min. RESULTS: The mean initial serum calcidiol levels were 21 ng/ml in the controls and 22 ng/ml in the intervention group. Serum calcidiol levels increased to 44 ng/ml after 8 wk and to 50 ng/ml after 24 wk of UVB radiation; the corresponding serum levels in the controls were 19 and 25 ng/ml, respectively. The mean serum calcitriol levels increased in the treated group and were unaltered in the control group. CONCLUSIONS: UVB radiation was effective in increasing vitamin D levels in patients with CF. The study results imply that UVB radiation is valuable in chronic conditions associated with vitamin D deficiency.

Prophylaxis against bone loss in Kock reservoir patients with reduced glomerular filtration rate.

OBJECTIVE: We investigated whether treatment with calcium carbonate and vitamin D3 can improve the bone mineral content of patients with ileal reservoirs for continent urinary diversion and a reduced glomerular filtration rate (GFR). MATERIAL AND METHODS: Twenty-six patients with Kock reservoirs were included in the study. Bone mineralization was determined using dual-energy X-ray absorptiometry. Kidney function was estimated from Cr-EDTA clearance and serum cystatin C concentration. Osteocalcin and parathyroid hormone in serum were also measured. Patients with reduced GFR were treated with calcium carbonate and vitamin D3 perorally. RESULTS: Bone mineral density in the femur neck and hip increased in the treatment group, as reflected by an improved T score. CONCLUSION: Patients with ileal reservoirs for continent urinary diversion and reduced kidney function should be supplemented with calcium carbonate and vitamin D3 in order to reduce the long-term risk of osteoporosis.

Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis.

OBJECTIVE: Hormone replacement therapy (HRT) is known to exert a positive effect in preventing bone loss and a beneficial effect on the disease activity in rheumatoid arthritis (RA). We evaluated the effects of HRT on bone mineral density (BMD) and on the course of established RA. METHODS: Eighty-eight postmenopausal women with RA were randomly allocated to receive HRT, vitamin D3, and calcium supplementation or vitamin D3 and calcium supplementation alone for 2 years. The effects of additional HRT on laboratory and clinical measures of disease activity, quality of life, and BMD and on radiographic joint damage were investigated. RESULTS: Treatment with HRT suppressed signs of inflammation as shown by reduction in erythrocyte sedimentation rate (ESR) (p = 0.025) and an elevation in hemoglobin concentration (p = 0.007), a better clinical outcome assessed by response on the Disease Activity Score 28 (DAS28) (p = 0.036), increased BMD in the forearm, proximal femur and spine (p < 0.01), and retarded (p = 0.026) progression of joint destruction among patients with radiological progressive disease. No significant effect on quality of life was seen. CONCLUSION: Two years of HRT in women with active RA had significant ameliorating effects on inflammation, DAS28 response, and BMD and was associated with slower progression of radiological joint destruction. The mechanisms by which HRT exerts its effects remain to be elucidated. We suggest HRT can be used in addition to conventional therapy in the management of postmenopausal patients with RA.