Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial.

BACKGROUND: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. METHODS: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged ≥55 to ≤90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2·5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 µg once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. FINDINGS: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2·6% (95% CI 2·2 to 3·0) in the romosozumab group and -0·6% (-1·0 to -0·2) in the teriparatide group; difference 3·2% (95% CI 2·7 to 3·8; p<0·0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. INTERPRETATION: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture. FUNDING: Amgen, Astellas, and UCB Pharma.

Persistent organic pollutants, skull size and bone density of polar bears (Ursus maritimus) from East Greenland 1892-2015 and Svalbard 1964-2004.

We investigated skull size (condylobasal length; CBL) and bone mineral density (BMD) in polar bears (Ursus maritimus) from East Greenland (n = 307) and Svalbard (n = 173) sampled during the period 1892-2015 in East Greenland and 1964-2004 at Svalbard. Adult males from East Greenland showed a continuous decrease in BMD from 1892 to 2015 (linear regression: p < 0.01) indicating that adult male skulls collected in the early pre-pollution period had the highest BMD. A similar decrease in BMD over time was not found for the East Greenland adult females. However, there was a non-significant trend that the skull size of adult East Greenland females was negatively correlated with collection year 1892-2015 (linear regression: p = 0.06). No temporal change was found for BMD or skull size in Svalbard polar bears (ANOVA: all p > 0.05) nor was there any significant difference in BMD between Svalbard and East Greenland subpopulations. Skull size was larger in polar bears from Svalbard than from East Greenland (two-way ANOVA: p = 0.003). T-scores reflecting risk of osteoporosis showed that adult males from both East Greenland and Svalbard are at risk of developing osteopenia. Finally, when correcting for age and sex, BMD in East Greenland polar bears increased with increasing concentrations of persistent organic pollutants (POPs) i.e. ΣPCB (polychlorinated biphenyls), ΣHCH (hexachlorohexane), HCB (hexachlorobenzene) and ΣPBDE (polybrominated diphenyl ethers) while skull size increased with ΣHCH concentrations all in the period 1999-2014 (multiple linear regression: all p < 0.05, n = 175). The results suggest that environmental changes over time, including exposure to POPs, may affect bone density and size of polar bears.

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis.

BACKGROUND: There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. OBJECTIVE: To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. METHODS: In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. RESULTS: We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. CONCLUSION: Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS.

Effect of propranolol on survival in patients with decompensated cirrhosis: a nationwide study based Danish patient registers.

BACKGROUND & AIMS: We assessed the impact of propranolol on death, risk of hepatorenal syndrome and peritonitis in patients with cirrhosis. METHODS: This study was a retrospective observational study and data were retrieved from Danish databases. We used our own criteria to stratify the patients into groups of patients with mildly decompensated cirrhosis or severely decompensated cirrhosis. A subgroup of patients with a history of peritonitis was also analyzed. Follow-up time was limited to 2 years from cohort entry. The reported hazard ratios (HR) with 95% confidence interval (CI) were based on a propensity score matched cohort. RESULTS: Among 3719 patients, we found 3075 patients with mildly and 644 with severely decompensated cirrhosis. Propranolol was used by 20% of the patients. Among the patients with mildly decompensated cirrhosis, propranolol use vs. non-propranolol was related with a HR of 0.7 (95% CI 0.6-0.9) and among the patients with severely decompensated cirrhosis, the HR was 0.6 (95% CI 0.4-0.9). Reduced mortality was found for doses of propranolol lower than 160 mg/day only. Among 361 patients with peritonitis, we found reduced mortality in the propranolol group with a HR of 0.5 (95% CI 0.3-0.8). The use of propranolol was associated with a HR of 0.4 (95% CI 0.2-0.9) for developing peritonitis during follow-up among patients with severely decompensated cirrhosis. CONCLUSIONS: In patients with decompensated cirrhosis, we found an association between propranolol use and reduced mortality risk for doses lower than 160 mg/day.

Mortality, cancer, and comorbidities associated with chronic pancreatitis: a Danish nationwide matched-cohort study.

BACKGROUND & AIMS: We aimed to assess the risk of death, cancer, and comorbidities among patients with alcoholic and nonalcoholic chronic pancreatitis (CP). METHODS: We performed a nationwide retrospective cohort study, collecting data from Danish registries from 1995 through 2010. We evaluated the prevalences and incidences of death, cancers, and comorbidities among subjects with CP (cases) compared with age- and sex-matched individuals (controls). In total, 11,972 cases (71,814 person-years) and 119,720 controls (917,436 person-years) were included in the analysis. Hazard ratios (HR) were estimated by Cox proportional hazards regression. RESULTS: Forty-six percent of the cases died during the follow-up period, compared with 13.0% of controls (mean age, 63.7 vs 72.1 y; P < .0001), corresponding to a HR of 5.0 for CP (95% confidence interval [CI], 4.8-5.2). Cancer was a frequent cause of death among cases (10.2%) and controls (3.3%). Cancer (particularly pancreatic cancer) was a frequent cause of death among cases; the HR was 6.9 (95% CI, 7.5-11.8). Alcoholic CP did not produce a higher risk for cancer or death than nonalcoholic CP. Cerebrovascular disease (HR, 1.3; 95% CI, 1.2-1.4), chronic pulmonary disease (HR, 1.9; 95% CI, 1.8-2.1), ulcer disease (HR, 3.6; 95% CI, 3.3-3.9), diabetes (HR, 5.2; 95% CI, 5.0-5.6), and chronic renal disease (HR, 1.7; 95% CI, 1.5-1.9) occurred more frequently among patients with CP, but myocardial infarction did not (HR, 0.9; 95% CI, 0.8-1.0). CONCLUSIONS: Based on a Danish nationwide cohort study, individuals with CP are at higher risk for death from cancer (particularly pancreatic cancer) and have a higher incidence of comorbidities than people without CP.

Penile density and globally used chemicals in Canadian and Greenland polar bears.

Industrially produced chemicals have been a major environmental concern across our entire Globe since the onset of rapid industrial development around the early 1900. Many of the substances being used are known to be endocrine disrupting chemicals (EDCs) and are also known to be long-range dispersed and to biomagnify to very high concentrations in the tissues of Arctic apex predators such as polar bears (Ursus maritimus). A major concern relating to EDCs is their effects on vital organ-tissues such as bone and it is possible that EDCs represent a more serious challenge to the species' survival than the more conventionally proposed prey reductions linked to climate change. We therefore analyzed penile bone mineral density (BMD) as a key phenotype for reproductive success in 279 polar bear samples born 1990-2000 representing eight polar bear subpopulations. Since EDC concentrations were not available from the same specimens, we compared BMD with published literature information on EDC concentrations. Latitudinal and longitudinal BMD and EDC gradients were clearly observed, with Western Hudson bears having the highest BMD and lowest EDCs, and North East Greenland polar bears carrying the lowest BMD and highest EDCs. A BMD vs. polychlorinated biphenyls (PCB) regression analysis showed that BMD decreased as a function of the eight subpopulations' PCB concentrations and this relationship was close to being significant (p=0.10, R(2)=0.39). Risk quotient (RQ) estimation demonstrated that PCBs could be in a range that may lead to disruption of normal reproduction and development. It is therefore likely that EDCs directly affect development and bone density in polar bears. Canadian bears had in general the best health and the North East Greenland subpopulation being at the highest risk of having negative health effects. While reductions in BMD is in general unhealthy, reductions in penile BMD could lead to increased risk of species extinction because of mating and subsequent fertilization failure as a result of weak penile bones and risk of fractures. Based on this, future studies should assess how polar bear subpopulations respond upon EDC exposure since information and understanding about their circumpolar reproductive health is vital for future conservation.

The risk of fractures among patients with cirrhosis or chronic pancreatitis.

BACKGROUND & AIMS: Cirrhosis and chronic pancreatitis (CP) are accompanied by inflammation and malnutrition. Both conditions can have negative effects on bone metabolism and promote fractures. We evaluated the risk of fractures among patients with CP or cirrhosis and determined the effect of fat malabsorption on fracture risk among patients with CP. METHODS: We performed a retrospective cohort study using the Danish National Patient Register to identify patients diagnosed with CP or cirrhosis. We analyzed data collected from January 1, 1995, to December 31, 2010, on 20,769 patients (35.5% women with cirrhosis and 11,972 patients (33.5% women) with CP. Each patient was compared with 10 age- and sex-matched controls. We also assessed the risk of fractures among patients with CP who received pancreatic enzyme substitution (PES) for fat malabsorption. RESULTS: During the study period, bone fractures occurred in 3954 patients with cirrhosis and 2594 patients with CP. The adjusted hazard ratio (HR) for any fracture was 2.4 in patients with cirrhosis (95% confidence interval [CI], 2.2-2.5) and 1.7 in patients with CP (95% CI, 1.6-1.8). The relative risk of low-trauma fractures was highest among individuals younger than 50 years old. Alcohol as an etiology was associated with an increased risk of fracture compared with patients with nonalcoholic cirrhosis (HR, 2.4 vs 1.5; P < .0001) and CP (HR, 2.0 vs 1.5; P < .0001). Patients with CP receiving PES for fat malabsorption had a lower risk of fractures than other CP patients (HR, 0.8; 95% CI, 0.7-0.9). However, increasing the duration of treatment with PES was associated with an increased risk of fracture. CONCLUSIONS: Patients, especially younger patients, with cirrhosis or CP have an increased risk of fractures of all types.

Atypical femoral fracture in an osteogenesis imperfecta patient successfully treated with teriparatide.

OBJECTIVE: We report a case of a successfully healed atypical femoral fracture (AFF) following treatment with teriparatide in a patient with osteogenesis imperfecta (OI). To our knowledge, no successful treatment of AFFs with teriparatide in this subpopulation has ever been described. METHODS: This is a case report of an AFF treated with teriparatide. RESULTS: The patient was treated with hormone replacement therapy for 18 years and bisphosphonates for 9 years before suffering a spontaneous AFF in the form of a dislocated noncomminute transverse fracture of the right femoral shaft, and an open reduction and internal fixation (ORIF) with a T2 Femoral Nail was done. Due to nonunion and another fracture distal to the nail, the patient was reoperated on with exchange ORIF and off-label treatment with teriparatide 20 µg/day was started. An X-ray 1 month later showed early signs of fracture healing. A subsequent X-ray 6 months after the last operation showed a solid healing of both right femoral fractures. CONCLUSION: This is a rare case that highly suggests a potential fracture healing effect of teriparatide treatment and highlights a potential significant practical therapeutic consideration in relation to the management of AFF with delayed healing.

Subtrochanteric fractures in bisphosphonate-naive patients: results from the HORIZON-recurrent fracture trial.

Our purpose was to characterize the risks of osteoporosis-related subtrochanteric fractures in bisphosphonate-naive individuals. Baseline characteristics of patients enrolled in the HORIZON-Recurrent Fracture Trial with a study-qualifying hip fracture were examined, comparing those who sustained incident subtrochanteric fractures with those sustaining other hip fractures. Subjects were bisphosphonate-naive or had a bisphosphonate washout period of 6-24 months and subsequently received an annual infusion of zoledronic acid 5 mg or placebo after low-trauma hip-fracture repair. In total, 2,127 men and women were included. Of the qualifying hip fractures, 5.2% were subtrochanteric, 54.8% femoral neck, 33.0% intertrochanteric, and 7.1% other (generally complex fractures of mixed type). Significant baseline (pre-hip fracture) differences were seen between index hip-fracture types, with the percentage of patients with extreme mobility problems being twofold higher in patients with index subtrochanteric fracture (9.9%) compared to other patients. The distribution of hip-fracture types was similar between the treatment groups at baseline. No patients with index subtrochanteric fractures and six patients with other qualifying hip fractures reported prior bisphosphonate use. Only one further subtrochanteric fracture occurred in each treatment group over an average 2-year patient follow-up. Subtrochanteric fractures are not uncommon in bisphosphonate-naive patients. Extreme difficulties with mobility may be a unique risk factor predisposing to development of incident subtrochanteric fractures rather than other types of hip fracture. In patients with recent hip fracture who received zoledronic acid therapy, the incidence of new subtrochanteric fractures was too small to draw any meaningful conclusions.

Zoledronic acid and clinical fractures and mortality after hip fracture.

BACKGROUND: Mortality is increased after a hip fracture, and strategies that improve outcomes are needed. METHODS: In this randomized, double-blind, placebo-controlled trial, 1065 patients were assigned to receive yearly intravenous zoledronic acid (at a dose of 5 mg), and 1062 patients were assigned to receive placebo. The infusions were first administered within 90 days after surgical repair of a hip fracture. All patients (mean age, 74.5 years) received supplemental vitamin D and calcium. The median follow-up was 1.9 years. The primary end point was a new clinical fracture. RESULTS: The rates of any new clinical fracture were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with zoledronic acid (P=0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8% (P=0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P=0.03). In the safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P=0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia, and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events, including atrial fibrillation and stroke, were similar in the two groups. CONCLUSIONS: An annual infusion of zoledronic acid within 90 days after repair of a low-trauma hip fracture was associated with a reduction in the rate of new clinical fractures and with improved survival. (ClinicalTrials.gov number, NCT00046254 [ClinicalTrials.gov].).

Intensive screening for osteoporosis in patients with hip fracture.

Opportunities to evaluate, treat, and prevent future osteoporotic fractures are often being overlooked, especially in patients with a prior osteoporotic fracture. We find that an intensive outreach osteoporosis investigation strategy can help increase the number of patients investigated and treated for osteoporosis following a hip fracture. PURPOSE: Patients experiencing a hip fracture are subject to an increased risk of subsequent fractures. This suggests an urgent need to develop strategies that will allow a higher number of patients with fragility hip fractures to be investigated and treated for osteoporosis. In accordance, we developed a secondary osteoporosis prevention program and evaluated the results of the program. METHODS: In the study period, 1071 patients with a hip fracture were admitted to Hvidovre University Hospital. Eligible patients were offered an osteoporosis investigation program, which included a DXA-scan with vertebral fracture assessment and a medical consultation. The data retrieved from this program were registered and analyzed. The primary goal of the study was to describe the number of subjects, who completed the program, and to characterize the initiated osteoporosis treatment. Secondary outcomes evaluated were prevalence of DXA-verified osteoporosis, changes in T-score due to treatment, and 1-year mortality rate. RESULTS: In total, 557 patients were offered participation of which 333 patients completed the full program. Among these, 159 patients had DXA-verified osteoporosis and 192 patients were started treatment. This resulted in a significant higher T-score at the lumbar spine and femoral neck compared with subjects not treated. Additionally, we report a 1-year mortality rate of 27.7% among all patients with hip fracture. CONCLUSION: We report that an intensive outreach osteoporosis investigation program can help increase the number of hip fracture patients being tested and treated for osteoporosis. Further, the initiation of treatment can significantly increase the T-score.

Does the nutrition profile of vitamins, fatty acids and microelements counteract the negative impact from organohalogen pollutants on bone mineral density in Greenland sledge dogs (Canis familiaris)?

There is a great need for understanding the impact from dietary OHCs (organohalogen compounds) on bone mineral composition - and thereby osteoporosis - in especially arctic wildlife such as polar bears (Ursus maritimus) as well as humans. For that purpose, we measured BMD (bone mineral density) by DXA scanning (g/cm(-2)) in 15 age and weight normalized sledge dog (Canis familiaris) bitches and their 26 pups divided into a control group (n=26) given 50-200 g/day clean pork (Suis scrofa) fat and a treated group (n=15) given 50-200 g/day OHC polluted minke whale (Balaenoptera acutorostrata) blubber as main lipid sources. The results showed that BMD increased significantly with age (linear regression: p<0.0001, r(2)=0.83, n=41) while no sex difference was found in the F-generation (two-way ANOVA: all p>0.3). No differences in BMD(femur) or BMD(vertebrae) between exposed and control individuals in the bitch generation were found (linear mixed effect model: both p>0.38). Likewise, no difference between exposed and control subadults and juveniles in the F-generation was found (two-way ANOVA: all p>0.33). Correlation analyses between BMD(femur), BMD(vertebrae) and groups of OHCs, respectively, did not show any statistically significant relationships nor a clear or decreasing trend (Pearson's: p: 0.07-0.78; r: -0.2-0.59; n: 10-18). As the groups were similar regarding genetics, age and sex are the only factors that can explain this observation. Either the pollutants did not have an impact on BMD using the present time frame and OHC concentrations (threshold levels not reached), or the difference in food composition (mainly vitamins and n3 fatty acids) conceal the potential OHC impact on BMD. Such information is important when evaluating the positive and negative health consequences from eating polluted marine species.

Fracture risk in women with type II diabetes. Results from a historical cohort with fracture follow-up.

PURPOSE: To examine the independent association between type II diabetes and fracture risk in a population of predominantly postmenopausal women referred to a specialist clinic for osteoporosis evaluation. METHODS: Type II diabetes associated fracture risk were evaluated among to 229 patients with type II diabetes in a cohort of 6285 women followed on average (until major osteoporotic fracture (MOF), death or end of study) for 5.8 years. Information of fracture risk factors was obtained from a clinical database and from national registries. RESULTS: An elevated fracture risk was present. Prevalent fractures (43.7 vs. 33.2%, p = 0.0010) and prevalent MOF (26.2 vs. 20.5% p = 0.038) were more common among patients with type II diabetes. The unadjusted incident fracture risk was increased with a higher relative risk of 42%. An elevated MOF hazard ratio was present (HR = 1.726, p = 0.0006). Adjustment for prevalent osteoporosis and other possible confounders did not change this finding (HR = 1.558, p = 0.0207). CONCLUSIONS: An association between type II diabetes and an increased risk of MOF primarily driven by an increased hip fracture risk was documented. This finding was independent of the presence of osteoporosis. Clinicians need to be aware of and adjust for these findings when evaluating patients with diabetes. Additional research examining pathophysiological mechanisms are needed.

Persistent organic pollutants and penile bone mineral density in East Greenland and Canadian polar bears (Ursus maritimus) during 1996-2015.

Persistent organic pollutants (POPs) are long-range transported to the Arctic via atmospheric and oceanic currents, where they biomagnify to high concentrations in the tissues of apex predators such as polar bears (Ursus maritimus). A major concern of POP exposure is their physiological effects on vital organ-tissues posing a threat to the health and survival of polar bears. Here we examined the relationship between selected POPs and baculum bone mineral density (BMD) in the East Greenland and seven Canadian subpopulations of polar bears. BMD was examined in 471 bacula collected between years 1996-2015 while POP concentrations in adipose tissue were determined in 67-192 of these individuals collected from 1999 to -2015. A geographical comparison showed that baculum BMD was significantly lowest in polar bears from East Greenland (EG) when compared to Gulf of Boothia (GB), Southern Hudson (SH) and Western Hudson (WH) Bay subpopulations (all p < 0.05). The calculation of a T-score osteoporosis index for the EG subpopulation using WH bears as a reference group gave a T-score of -1.44 which indicate risk of osteopenia. Concentrations of ΣPCB74 (polychlorinated biphenyls), ΣDDT3 (dichlorodiphenyltrichloroethanes), p,p'-DDE (dichlorodiphenyldichloroethylene), ΣHCH3 (hexachlorohexane) and α-HCH was significantly highest in EG bears while ΣPBDE (polybrominated diphenyl ethers), BDE-47 and BDE-153 was significantly highest in SH bears (all p < 0.04). Statistical analyses of individual baculum BMD vs. POP concentrations showed that BMD was positively correlated with ΣPCB74, CB-153, HCB (hexachlorobenzene), ΣHCH, ß-HCH, ClBz (chlorobenzene), ΣPBDE and BDE-153 (all p < 0.03). In conclusion, baculum density was significantly lowest in East Greenland polar bears despite the positive statistical correlations of BMD vs. POPs. Other important factors such as nutritional status, body mass and body condition was not available for the statistical modelling. Since on-going environmental changes are known to affect these, future studies need to incorporate nutritional, endocrine and genetic parameters to further understand how POP exposure may disrupt bone homeostasis and affect baculum BMD across polar bear subpopulations.

Low bone mineral density is associated with reduced hip joint space width in women: results from the Copenhagen Osteoarthritis Study.

OBJECTIVE: Since estrogen receptors (ER-alpha/ER-beta) were identified in human chondrocytes, animal and experimental studies have demonstrated the importance of continued estrogen production for the integrity of articular cartilage. However, human epidemiological support of the hypothesis has been inconclusive. The present cross-sectional study investigated the relationship between reduced bone mineral density (BMD), as a surrogate parameter of endogenous estrogen status assessed by digital x-ray radiogrammetry, and reduced minimum hip joint space width (JSW). DESIGN: Standardized hand radiographs of the Copenhagen Osteoarthritis Study cohort of 3,913 adults (1,470 male/2,443 female) with a mean age of 60 years (range, 18-92) were analyzed using X-Posure digital software, version 2.0 (Sectra-Pronosco). The system is operator independent. From 1,200 individual measurements per radiograph, mean BMD was calculated. Minimum hip JSW was assessed on standardized pelvic radiographs. RESULTS: Digital x-ray radiogrammetry BMD decreased in both men and women after the age of 45 years, progressively more so in women. Although minimum hip JSW in men remained relatively unaltered throughout life, a marked decline in female minimum hip JSW after age 45 years was observed. We found moderate but highly significant relationships between reduced BMD and reduced hip JSW in women (P < 0.0001), adjusted for age and dysplastic joint incongruity. CONCLUSION: We believe that the present study supports the hypothetical relationship between reduced estrogen levels and hip JSW reduction in women.

Are organohalogen contaminants a cofactor in the development of renal lesions in east Greenland polar bears (Ursus maritimus)?

Tissues of polar bears (Ursus maritimus) from East Greenland contain the highest concentrations of organohalogen contaminants (OHCs) among subpopulations of any mammalian species in the Arctic. Negative associations also have been found between OHC concentrations and bone mineral density and liver histology parameters for this subpopulation of polar bears. The present study examined the OHC concentrations and adverse effects on renal tissue for 75 polar bears collected during 1999 to 2002. Specific lesions were diffuse glomerular capillary wall thickening, mesangial glomerular deposits, tubular epithelial cell hyperplasia, hyalinization of the tubular basement membrane, tubular dilatation, atrophy and necrosis, tubular medullary hyalin casts, interstitial fibrosis, and mononuclear cell infiltration. With the exception of mononuclear cell infiltrations, all these parameters were correlated with age, whereas none was associated with the sex of the animals. In an age-controlled statistical analysis of covariance, increases in glomerular mesangial deposits and interstitial fibrosis were significantly (p < 0.05) correlated with polybrominated diphenyl ether (sigmaPBDE) concentrations in subadults. In adult males, statistically significant (p < 0.05) positive correlations were found for tubular epithelial cell hyperplasia and dieldrin concentration; diffuse glomerular capillary wall thickening and chlordane (sigmaCHL) concentrations, and tubular medullary hyalin casts and sigmaCHL, sigmaPBDE, polychlorinated biphenyl, and hexachlorocyclohexane concentrations. The lesions were consistent with those reported previously in highly OHC-contaminated Baltic seal populations and exposed laboratory animals. The renal lesions were a result of aging. However, based on the above statistical findings as well as the nature of the findings, we suggest that long-term exposure to OHCs may be a cofactor in renal lesion occurrence, although other cofactors, such as exposure to heavy metals and recurrent infections from microorganisms, cannot be ruled out. This is new and important knowledge in the assessment of health status among wildlife populations and humans relying on food resources that are contaminated with OHCs.

Time trends in osteoporosis risk factor profiles: a comparative analysis of risk factors, comorbidities, and medications over twelve years.

The aim of this article was to identify prevalent osteoporosis risk factors, medications and comorbidities associated with bone mineral density (BMD). Furthermore to evaluate changes in risk factor profiles over 12 years. 6285 women consecutively referred to an osteoporosis specialist clinic were included. Information of potential risk factors was obtained by questionnaire and clinical examination. Additional information on medication use, comorbidities and fractures were obtained from national registries. An association (<0.05) between well-known risk factors negatively influencing bone health was established in a real-life setting. The prevalence of osteoporosis and proportion of patient's having comorbidity's associated with osteoporosis were increasing during the inclusion period (start 23.8 %, end 29.7 %). Increasing age (OR = 1.05), current smoking (OR = 1.18), estrogen deficiency (OR = 1.7), hyperthyroidism (OR = 1.5), previous major osteoporotic fracture (OR = 1.7), former osteoporosis treatment (OR = 3.5), higher BMI (OR = 0.87), use of calcium supplementation (OR = 1.2), high exercise level (OR = 0.7), and use of thiazide diuretics (OR = 0.7) were identified as predictors of osteoporosis by DXA. Rheumatoid arthritis (OR = 2.4) and chronic pulmonary disease (OR = 1.5) was associated with site-specific osteoporosis by DXA at the total hip. Current use of loop diuretics (OR = 1.7) and glucocorticoid use (OR = 1.04-1.06) were associated with both total hip and femoral neck T-score <-2.5. Our data confirms an independent negative association with BMD of many established risk factors, certain comorbidities, and medications. Exercise level, use of loop diuretics, and prevalent chronic pulmonary disease, risk factors not included in fracture risk calculators were associated with osteoporosis by DXA. Time trends indicate risk profile is dynamic, with increasing focus on secondary osteoporosis.

Establishment of age- and sex-adjusted reference data for hand bone mass and investigation of hand bone loss in patients with rheumatoid arthritis treated in clinical practice: an observational study from the DANBIO registry and the Copenhagen Osteoarthritis Study.

BACKGROUND: Rheumatoid arthritis is characterised by progressive joint destruction and loss of periarticular bone mass. Hand bone loss (HBL) has therefore been proposed as an outcome measure for treatment efficacy. A definition of increased HBL adjusted for age- and sex-related bone loss is lacking. In this study, we aimed to: 1) establish reference values for normal hand bone mass (bone mineral density measured by digital x-ray radiogrammetry (DXR-BMD)); and 2) examine whether HBL is normalised in rheumatoid arthritis patients during treatment with tumour necrosis factor alpha inhibitors (TNFI). METHODS: DXR-BMD was measured from hand x-rays in a reference cohort (1485 men/2541 women) without arthritis randomly selected from an urban Danish population. Sex- and age-related HBL/year was estimated. DXR-BMD was measured in rheumatoid arthritis patients (n = 350: at start of TNFI, and ~2 years after TNFI start), of which 135 patients had three x-rays (~2 years prior to TNFI, at start of TNFI, and ~2 years after TNFI start). Individual HBL/year prior to and during TNFI was calculated and compared to reference values. RESULTS: Estimated HBL/year varied strongly with age and sex. Compared to the reference values, 75 % of 135 patients had increased HBL prior to TNFI treatment and 59 % had increased HBL during TNFI treatment (p = 0.17, Chi-squared). In 38 % (38/101) of patients with increased HBL, HBL was normalised during TNFI treatment, whereas 47 % (16/34) of patients with normal HBL prior to TNFI had increased HBL during TNFI treatment. In the 350 patients, increased HBL during TNFI was associated with time-averaged 28-joint disease activity score (odds ratio 1.69 (95 % Confidence Interval 1.34-2.15)/unit increase, p < 0.001), and patients in time-averaged remission had lower HBL than patients without remission (0.0032 vs. 0.0058 g/cm(2)/year; p < 0.001, Mann-Whitney). CONCLUSIONS: We established age- and sex-specific reference values for DXR-BMD in a large cohort without arthritis. HBL was increased in the majority of rheumatoid arthritis patients initiating TNFI in clinical practice, and only normalised in a minority during TNFI.

Do organohalogen contaminants contribute to histopathology in liver from East Greenland polar bears (Ursus maritimus)?

In East Greenland polar bears (Ursus maritimus), anthropogenic organohalogen compounds (OHCs) (e.g., polychlorinated biphenyls, dichlorodiphenyltrichloroethane, and polybrominated diphenyl ethers) contributed to renal lesions and are believed to reduce bone mineral density. Because OHCs are also hepatotoxic, we investigated liver histology of 32 subadult, 24 adult female, and 23 adult male East Greenland polar bears sampled during 1999-2002. Light microscopic changes consisted of nuclear displacement from the normal central cytoplasmic location in parenchymal cells, mononuclear cell infiltrations (mainly portally and as lipid granulomas), mild bile duct proliferation accompanied by fibrosis, and fat accumulation in hepatocytes and pluripotent Ito cells. Lipid accumulation in Ito cells and bile duct hyperplasia accompanied by portal fibrosis were correlated to age, whereas no changes were associated with either sex or season (summer vs. winter). For adult females, hepatocytic intracellular fat increased significantly with concentrations of the sum of hexachlorocyclohexanes, as was the case for lipid granulomas and hexachlorobenzene in adult males. Based on these relationships and the nature of the chronic inflammation, we suggest that these findings were caused by aging and long-term exposure to OHCs. Therefore, these changes may be used as biomarkers for OHC exposure in wildlife and humans. To our knowledge, this is the first time liver histology has been evaluated in relation to OHC concentrations in a mammalian wildlife species, and the information is important to future polar bear conservation strategies and health assessments of humans relying on OHC-contaminated food resources.