Surgically treated osteonecrosis and osteomyelitis of the jaw and oral cavity in patients highly adherent to alendronate treatment: a nationwide user-only cohort study including over 60,000 alendronate users.

Osteonecrosis of the jaw (ONJ) is rare (2.53/10,000 person-years) among alendronate users, but long-term and compliant use are associated with an increased risk of surgically treated ONJ. Risk of surgically treated ONJ is higher in patients with rheumatoid diseases and use of proton pump inhibitors. INTRODUCTION: ONJ is a rare event in users of oral bisphosphonates. Our aims were to evaluate if the risk of surgically treated ONJ increases with longer or more compliant treatment with alendronate for osteoporosis and to identify risk factors for surgically treated ONJ. METHODS: Open nationwide register-based cohort study containing one nested case-control study. Patients were treatment-naïve incident users of alendronate 1996-2007 in Denmark, both genders, aged 50-94 at the time of beginning treatment (N = 61,990). Participants were followed to 31 December 2013. RESULTS: Over a mean of 6.8 years, 107 patients received surgery for ONJ or related conditions corresponding to an incidence rate of 2.53 (95% confidence interval (CI) 2.08 to 3.05) per 10,000 patient years. Recent use was associated with an adjusted odds ratio (OR) 4.13 (95% CI 1.94 to 8.79) compared to past use. Similarly, adherent users (medication possession ratio (MPR) >50%) were at two to threefold increased risk of ONJ compared to low adherence (MPR <50%), and long-term (>5 years) use was related with higher risk (adjusted OR 2.31 (95% CI (1.14 to 4.67)) than shorter-term use. History of rheumatoid disorders and use of proton pump inhibitors were independently associated with surgically treated ONJ. CONCLUSIONS: Our data suggest that recent, long-term, and compliant uses of alendronate are associated with an increased risk of surgically treated ONJ. Nevertheless, the rates remain low, even in long-term adherent users. ONJ risk appears higher in patients with conditions likely to indirectly affect the oral mucosa.

Subsequent fracture rates in a nationwide population-based cohort study with a 10-year perspective.

SUMMARY: Fractures after the age of 50 are frequently observed in Denmark, and many of these may be osteoporotic. This study examined the incidence of all and subsequent fractures in a 10-year period from 2001 to 2011. The incidence of subsequent fractures was high, especially following hip fracture. INTRODUCTION: The purpose of this study is to examine patterns of subsequent fractures and mortality rates over a 10-year period in patients already suffering from fracture. METHODS: The study was designed as a nationwide, register-based follow-up study. Patients were included if diagnosed with an index fracture (ICD-10 codes: S22.x, S32.x, S42.x, S52.x, S62.x, S72.x, S82.x, S92.x, T02.x, T08.x, T10.x and T12.x) between January 1st, 2001 and December 31st, 2001 and if older than 50 years at time of fracture. The patients were investigated for future subsequent fractures from January 1st, 2002 to December 31st, 2011. RESULTS: In this study, we demonstrated that patients with fractures (especially hip fractures) have a high risk of subsequent fractures, especially hip fracture. Other fractures, which are not commonly considered as osteoporotic fractures, such as lower leg, were frequently observed in the 10 years following index fracture. The cumulative incidence proportion (CIP) of subsequent fractures during the 10-year follow-up period was high for all recurrent fractures (9-46 %). Subsequent hip fracture, regardless of index fracture, had the highest CIP across the study period, ranging from 9 to 40 %. Appendicular fractures were often followed by a recurrent fracture, or subsequent fractures at a more proximal location in the same limb, i.e. forearm fractures were followed by humerus fractures. These results have not been previously demonstrated to this extent, and according to our knowledge, no previous studies have estimated cumulative 10-year subsequent fracture incidences for any non-hip fractures. CONCLUSION: Patients suffering a fracture (and especially a hip fracture) have a high incidence of subsequent fracture. Fractures after the age of 50 may be considered an early warning of increased risk for future fractures in many patients.

Characteristics of patients who suffer major osteoporotic fractures despite adhering to alendronate treatment: a National Prescription registry study.

UNLABELLED: Antiresorptive treatment reduces the risk of fractures, but most patients remain at elevated risk. We used health registers to identify predictors of new major osteoporotic fractures in patients adhering to alendronate. Risk factors showed a different pattern than in the general population and included dementia, ulcer disease, and Parkinson's disease. INTRODUCTION: Antiresorptives reduce the excess risk of fractures in patients with osteoporosis, but most patients remain at elevated risk. In some countries, patients must sustain fractures while on bisphosphonate (BP) treatment to qualify for more expensive treatment. It is unclear if patients who fracture on BP can be viewed as a distinct subgroup. METHODS: The National Prescription registry was used to identify 38,088 new alendronate users. The outcome was major osteoporotic fractures 6+ months after filling the first prescription in patients with a medication possession ratio > 80 %. RESULTS: One thousand and seventy-two (5.5 %) patients sustained major osteoporotic fractures. The risk increased with age and was lower in men. The most important risk factor was the number of comedications (hazard ratio (HR) 1.04, 95 % CI 1.03-1.06, for each drug). Dementia (HR 1.81, 95 % CI 1.18-2.78), prior fracture (one: HR 1.17, 95 % CI 1.02-1.34; multiple: HR 1.34, 95 % CI 1.08-1.67), and ulcer disease (HR 1.45, 95 % CI 1.04-2.03) also increased the risk. Diabetes did not influence fracture risk, nor did rheumatic disorders. The risk was lower in glucocorticoid users (HR 0.78, 95 % CI 0.65-0.93). CONCLUSION: Risk factors while adhering to BP show a somewhat different pattern than that of the general population and FRAX. Ulcer disease and dementia may impair the ability to use the medications correctly. Though this is an observational study and associations may not be causal, it may be prudent to include dementia, ulcer disease, and Parkinson's disease to capture the risk of fractures on treatment. Lower risk in patients treated with glucocorticoids and in men probably reflects a lower treatment threshold related to guidelines.

Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate--Danish National Register Based Cohort Study.

UNLABELLED: In this Danish national register-based cohort study, we examined the effects of alendronate on the development of colon cancers and survival. The incidence of colon cancer and mortality rate, once colon cancer had been diagnosed, were lower in patients treated with alendronate, posing the question whether alendronate acts as chemopreventive. INTRODUCTION: When bisphosphonates are given by mouth, around 99% remains non-absorbed in the intestine. Based on their biochemical actions, we predicted that oral bisphosphonates might prevent colon cancers. METHODS: This is a Danish national register-based cohort study. We identified 30,606 women aged 50+, mean age 71.9 years, who had not previously taken treatments for osteoporosis, who began to take alendronate in 1996-2005, and assigned 124,424 individually age- and gender-matched control subjects. The main outcome measure was colorectal cancers incidence and post-diagnosis survival in patients taking oral alendronate for osteoporosis. RESULTS: Cox proportional hazards analysis of death due to colon cancer showed lower risk in alendronate users, crude hazard ratio (HR) 0.69 (95% CI 0.59-0.81) with an adjusted HR of 0.62 (95% CI 0.52-0.72). The reduction in risk comprised both a lower incidence of colon cancer-adjusted HR 0.69 (95% CI 0.60-0.79) and a lower mortality once colon cancer had been diagnosed, adjusted HR 0.82 (95% CI 0.70-0.97). Weekly alendronate was associated with a greater risk reduction than daily alendronate. The main findings were unaffected by excluding patients from the analysis who had pulmonary disease, a major co-morbid condition in users of alendronate and an important cause of death. CONCLUSIONS: The risk of overall deaths from cancer and in particular death caused by colon cancer was significantly and substantially decreased (40%) in patients treated with alendronate, with survival curves deviating progressively after 2 years. Also, the incidence of colon cancer was lower in those patients.

[SERM--selective estrogen receptor modulators]. / SERM--selektive østrogenreceptormodulatorer.

SERM describes a category of drugs that exert their influence on estrogen-sensitive tissue and are known especially in the treatment of estrogen receptor-positive breast cancer. The development and clinical trials of new SERM in recent years seem to establish more fields of diseases, where treatment with SERM may be indicated.

[Hormone replacement therapy reduces the risk of forearm fracture in postmenopausal women. Results of the Danish Osteoporosis Prevention Study]. / Behandling med hormonsubstitutionsterapi nedsaetter risikoen for underarmsbrud hos postmenopausale kvinder. Resultater fra Danish Osteoporosis Prevention Study.

In a prospective, controlled, comprehensive cohort trial of 2,016 healthy early postmenopausal women aged 45-58 years we studied fracture prevention through the use of oestrogen. There were two main study arms: a randomised arm (randomised to HRT [n = 502] or not [n = 504]) and a non-randomised arm (on HRT [n = 221] or not [n = 789] by own choice). After five years, an intention-to-treat analysis (n = 2,016) showed a reduction in the overall fracture risk (RR = 0.73, 95% CI: 0.50-1.05) and in the forearm fracture risk (RR = 0.45, 95% CI: 0.22-0.90) with oestrogen. Restriction of the analysis to women who had adhered to their initial allocation of either oestrogen (n = 395) or no oestrogen (n = 977) showed a significant reduction in both the overall fracture risk (RR = 0.61, 95% CI: 0.39-0.97) and the risk of forearm fractures (RR = 0.24, 95% CI: 0.09-0.69). We conclude that it is possible to reduce the number of forearm fractures in early postmenopausal women by the use of oestrogen as primary prevention.

[The effect of hormone replacement therapy on bone mineral content and on fractures]. / Virkningen af hormonal substitutionsterapi på knoglemineralindholdet og på frakturer.

A review of five case-control- and eight prospective studies provides evidence of a decreased risk of fractures among postmenopausal women, who currently use or ever have used hormone replacement therapy. Twenty-three randomized clinically controlled studies provide evidence that hormone replacement therapy could increase bone mass or at least give a significantly higher bone mineral content than placebo or calcium in both the axial and peripheral skeleton. This is true for 1) healthy early postmenopausal 2) normal elderly women, 3) osteoporotic women, and 4) oophorectomized women. Moreover, one of these studies of osteoporotic women showed a significant decrease in the number of compression fractures of the spine after hormone replacement therapy.

[Osteoporosis: assessment, prevention and treatment in Danish departments of orthopedic surgery]. / Osteoporose: udredning, profylakse og behandling på danske ortopaedkirurgiske afdelinger.

Questionnaires were sent to all departments of orthopaedic surgery in Denmark and all departments of general surgery that treat patients with fractures in order to examine: A) whether patients with osteoporosis are identified, B) whether such patients are treated for osteoporosis, and C) whether doctors need more information about osteoporosis. Fifty-six departments (97%) returned the questionnaires. Eighty-eight percent of the departments do not refer the patients with low-energy fractures to bone mineral densitometry. Only 18% of the departments make further evaluations of patients with possible osteoporosis. Eleven percent of the departments treat patients with a low-energy fracture for osteoporosis. The medication used was typically vitamin tablets combined with calcium. One department used oestrogens and none used bisphosphonates. About half of the departments advised the patients about changes in their lifestyle, and half of the departments wanted more information about osteoporosis. In conclusion, few Danish departments with orthopaedic surgery functions evaluate and treat the cause of the fractures.

[Physical activity and bone mineral content in postmenopausal women]. / Fysisk aktivitet og knoglemineralindholdet hos postmenopausale kvinder.

A review of 18 cross-sectional and 29 prospective studies provides evidence that physical exercise causes an increase in bone mineral content or at least preserves the bone mass of both younger and older postmenopausal women. This is true both for women with normal and with reduced bone mineral content. Regular weight-bearing exercises seem to be especially effective. There are no randomized studies which have been able to prove that physical exercise reduces the incidence and prevalence of low-energy fractures, but this reduction seems probable.

[Theophylline treatment of irreversible, chronic obstructive pulmonary disease]. / Teofyllinbehandling ved irreversibel, kronisk obstruktiv lungesygdom.

Even though the clinical efficacy is not well established, theophylline is commonly prescribed as a second or third line drug after inhaled beta 2-agonists and corticosteroids for patients with chronic obstructive pulmonary disease (COPD). The therapeutic index is narrow, and therefore theophylline is often given in a "safe standard dose", e.g. 300 mg b.i.d. We studied the long-term effect of sustained-release theophylline 300 mg b.i.d. over four weeks in 48 patients with severe irreversible COPD (FEV1: 0.99 +/- 0.45 l, FVC: 2.21 +/- 0.68 l) in a randomized, double-blind crossover study. During theophylline treatment there was significant improvements in dyspnoea score (p < 0.001) and morning peak-flow (p < 0.05). In spite of this, there was no significant change in the patients' "sense of well-being" or their daily use of inhaled beta-agonist. Spirometric tests or arterial blood gas values did not change significantly either. It is concluded that addition of theophylline in a "safe standard dose" (i.e. 300 mg b.i.d.) has only limited value in these patients.

[Diagnosis of allergy in bee-keepers. A 1-year prospective study]. / Allergidiagnostik hos biavlere. En etårs prospektiv undersøgelse.

Thirty-six Danish bee-keepers were clinically investigated by means of a questionnaire before and after the bee season 1990. Their serum was assayed for IgE and IgG antibody reacting with bee venom, and skin prick tests were performed prior to the season. Thirty-six percent had previously reacted abnormally, either with a systemic reaction (SR) (25%) or a large local reaction (LLR) (11%). Retrospectively, eight of the nine bee-keepers with SR had upon re-exposure developed a normal reaction, in spite of the fact that seven of them had specific IgE and/or a positive prick test at subsequent examination. At follow up 38% of the persons who had previously had a SR reacted with a SR or a LLR on the first sting in the season. Two of eight with previous SR reacted with SR during the observation period in spite of a negative prick test and no specific IgE. Of the bee-keepers who had previously only reacted normally there were no systemic of large localised reactions during the observed period, although six showed signs of IgE-sensitization. The results confirm the problems of identifying patients where immunotherapy is superfluous in the group with previous SR and IgE sensitization.

[Early discharge after acute myocardial infarction. Cost-effectiveness of early echocardiographic risk evaluation]. / Tidlig udskrivelse efter akut myokardieinfarkt. Cost-effectiveness af tidlig ekkokardiografisk risikobedømmelse.

A total of 195 consecutive patients with acute myocardial infarction were examined and risk classified (low or middle/high risk) on the fifth day by two physicians. These two physicians employed two different sets of criteria: conventional clinical examination compared with 2-D echocardiographic assessment of the wall motion of the left ventricle (wall motion index, WMI). Both physicians concluded their examination by determination of a theoretical time for discharge. By design this was on the 5th-7th days for low risk patients by echocardiography, while low risk patients by clinical criteria are normally discharged on the 7th to 8th days. The most sensitive method of identifying the low risk patients was achieved by combining the clinical examination with echocardiographic WMI determination. In this manner, a total of 104 (53%) low risk patients could be identified. A potential saving of 18% of the total duration of hospitalization could be calculated from the two theoretical times of discharge for the total population. All of the patients in this study could be assessed by echocardiography which provided valuable information and thus may be implemented in the routine treatment of acute myocardial infarction.

[Obstructive sleep apnoea syndrome. Assessment of the costs of examination and treatment in a department for pulmonary medicine]. / Obstruktivt søvnapnøsyndrom. En vurdering af omkostningerne ved undersøgelse og behandling i lungemedicinsk regi.

Twenty-five patients suspected of having obstructive sleep apnoea syndrome (OSA) were examined in the medical department. Sixteen patients had OSA. The difference between the two groups are described. The socio-economical consequences of the disease are discussed. Five of the patients remitted because of weight loss. Seven patients were successfully treated with nasal airway positive pressure. This treatment is of great benefit for the patients as well as for the society, and is inexpensive.