O. Di Munno

Determinants of adherence to osteoporosis treatment in clinical practice

IntroductionPoor adherence to prescribed treatments is widespread in clinical practice and this can lead to potentially life-threatening events. This problem is apparently very common for osteoporosis treatment but the causes of discontinuation and low compliance are complex and poorly defined.MethodsGlobal adherence to osteoporosis treatment was specifically addressed in a nation-wide survey carried out in 9851 postmenopausal women referred to 141 Italian centres for osteoporosis management for a follow-up assessment, at least one year after having been prescribed a treatment with one of the following drugs: calcium±vitamin D supplements alone (CaVitD), hormone replacement therapy (HRT), raloxifene 60 mg (RLX), intramuscular clodronate 100 mg/7-14 days (CLOD), risedronate 5 mg/day (RIS) and alendronate 10mg/daily (ALN10) or 70 mg once weekly (ALN OW).ResultsOverall 19.1% of the patients discontinued the prescribed drug before attending the bone mass re-evaluations, more than half of them within the first 6 months. The discontinuation rate was significantly different between the treatments. The medications most frequently interrupted within one year were CLOD (28.7%; p<0.01 versus any other treatment), while by far the least interrupted was ALN-OW (6.9%; p<0.001 versus any other treatment). The most frequent reasons for discontinuation were drug related side effects, insufficient motivation to treatment and fear of side effects. The prevalence of the reasons for discontinuation were different among treatments: safety concerns were very common for HRT, lack of motivation was the most common cause for CaVitD and CLOD, and drug related side effects for RIS, ALN and RLX. Persistence to treatment was significantly higher in patients with previous vertebral fractures, densitometric osteoporosis, on corticosteroid or anti-inflammatory treatments. A significantly increased risk of treatment interruption was found among patients on benzodiazepine or gastro-protective agents and in patients in whom a bone measurement was not readily available. The highest compliance to recommended dosing was observed with ALN OW and HRT (p<0.001 versus any other) and the lowest for CaVitD (p<0.01 versus any other). Poor treatment compliance (<50% drug taken) was significantly related to benzodiazepine and gastroprotective use, while a significantly better compliance was associated with recognized risk factors for osteoporosis: early menopause, low bone mass values values, previous vertebral fractures. The poorest adherence was observed when treatments were prescribed by General practitioners (GPs), and orthopaedic surgeons (p<0.01 versus global mean).ConclusionsThe results of this large survey of Italian osteoporotic women indicates that the most important determinant of both persistence and compliance to treatment is the type of drug prescribed with a definite advantage of ALN-OW. Treatment compliance is particularly poor for CaVitD and this emphasizes the need for new ways to supplement at least vitamin D. The main reasons for discontinuation are side effects and lack of motivation while the best treatment adherence was observed in patients with severe and well documented osteoporosis.

THE SYNOVIAL PROSTAGLANDIN SYSTEM IN CHRONIC INFLAMMATORY ARTHRITIS: DIFFERENTIAL EFFECTS OF STEROIDAL AND NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

1 The present study was undertaken to characterize the spectrum of arachidonic acid metabolites present in synovial effusions of patients with rheumatoid or psoriatic arthritis, and to compare changes in their concentration following a short‐term treatment with 6α‐methyl‐prednisolone (6‐MeP: 4–8mg/day) or indoprofen (1.2g/day), a nonsteroidal anti‐inflammatory agent with proven synovial prostaglandin inhibitory effect. 2 Measurements of prostaglandin E2 (PGE2), thromboxane (TX) B2, 6‐keto‐PGF1α and PGF2α were performed by radioimmunoassay techniques in synovial effusions obtained from 23 patients, and validated by thin‐layer chromatographic analysis of the extracted immunoreactivity. 3 PGE2 and TXB2 accounted for more than 60% of the total immunoreactivity in untreated patients. The absence of any constant ratio between the different arachidonic acid metabolites detected in synovial fluid is consistent with a heterogeneous cellular origin of these compounds. 4 Indoprofen treatment was associated with a consistent reduction of synovial prostaglandin and thromboxane concentrations, ranging from 36% in the case of 6‐keto‐PGF1α to 90% in the case of PGE2. 5 In contrast, 6‐MeP caused opposite changes on different metabolites originating via the cyclo‐oxygenase pathway. Thus, 6‐keto‐PGF1α concentrations were reduced by 35%, PGF2α concentrations were increased by 30%, while PGE2 and TXB2 were unchanged following 6‐MeP. 6 Although the mechanism(s) underlying the failure of 6‐MeP to reduce synovial PGE2 and TXB2 levels are uncertain, the results of the present study clearly indicate that therapeutic doses of steroidal and nonsteroidal anti‐inflammatory drugs cause quite distinct changes in arachidonic acid metabolism, which might be relevant to their specific therapeutic actions and side‐effects.

Ipriflavone prevents radial bone loss in postmenopausal women with low bone mass over 2 years

Two hundred and fifty-five postmenopausal women with distal forearm bone mineral density (BMD) 1 SD below the mean value for normal age-matched postmenopausal subjects were randomly allocated to a 2-year treatment with oral ipriflavone (200 mg t.i.d.) or a matched placebo, according to a double-masked, parallel-group design. All patients also received a 1 g/day calcium supplement. Distal radius BMD and bone metabolism markers were measured at baseline, and every 6 months. Blood haematology and chemistry and physical parameters were monitored at the same time. One hundred and ninety-six patients completed 2 years of treatment. BMD changes from baseline were analysed according to valid completers (VC) and intention to treat (ITT) analyses. In both cases radial BMD was maintained in patients treated with ipriflavone while it decreased in those receiving the placebo, the between-treatment difference being significant at year 1 and year 2. Urinary hydroxyproline/creatinine levels were decreased in the ipriflavone-treated group and increased in the placebo group, with a significant between-treatment difference. Adverse reactions, mainly gastrointestinal, occurred to a similar extent in the two treatment groups.

Effect of chronic treatment with ipriflavone in postmenopausal women with low bone mass

We present the results of two multicenter, double-blind, placebo-controlled, 2-year studies to evaluate the efficacy and tolerability of ipriflavone in postmenopausal women (PMW) with low bone mass. 453 PMW (aged 50–65 years) with a vertebral (VMD) or radial (RMD) mineral density value 1 SD lower compared with age-matched controls, were randomly selected to receive oral ipriflavone (200 mg T.I.D. at meals) or matching placebo, plus 1 g oral calcium daily. Vertebral (study A, by dual X-ray absorptiometry-DXA) and radial (study B, by dual photon absorptiometry-DPA) bone density, serum bone Gla-protein (BGP), and urinary hydroxyproline/creatinine (HOP/Cr) were measured every 6 months. In both studies, the Valid Completers (VC) analysis showed a maintenance of bone mass in ipriflavone-treated women, whereas in the placebo group, bone mineral density (BMD) was significantly decreased. The final outcome was a bone-sparing effect of 1.6% in study A, and of 3.5% in study B after 2 years. The Intention to Treat (ITT) analysis confirmed the decrease in the placebo group, with no changes in iprifla-vone-treated women. A significant (P < 0.05) between-treatment difference was found in both studies. Biochemical markers of bone turnover decreased in patients treated with ipriflavone, thus suggesting a reduction of bone turnover rate. Twenty-six women treated with ipriflavone and 28 receiving the placebo dropped out because of side effects, mainly gastrointestinal. The compliance to the oral longterm treatment was good. The results of these studies show that ipriflavone is able to prevent both axial and peripheral bone loss in PMW with low bone mass, and is well tolerated.

Prevention of glucocorticoid-induced osteopenia: Effect of oral 25-hydroxyvitamin D and calcium

SummaryTwenty-four patients (9 M and 15 F, age range 51–82) with polymyalgia rheumatica receiving 6-methylprednisolone for a period of 9 months (16 mg/daily/two weeks, 14 mg/daily/two weeks, 12 mg/daily/1 month, 10 mg/daily/1 month, 8 mg/daily/1 month, 6 mg/daily/1 month and 4 mg/daily for the last four months) were randomly assigned to receive either 250HD3 (35 mcg/day for 25 days/month) (Group A) or placebo (Group B) in a double-blind study. All patients also received 500 mg elemental calcium daily. Before and at 3,6 and 9 months ESR, tenderness on palpation and subjective pain were evaluated. At the same times, mineral metabolism parameters (serum calcium, phosphorus, alkaline phosphatase, 24-h urinary calcium, phosphate and 24-h hydroxyproline excretion) and radial bone mineral content (BMC) were evaluated. Activity indexes (ESR and clinical parameters) improved in both groups. Furthermore, serum alkaline phosphatase and 24-h hydroxyproline excretion decreased significantly only in Group A, and BMC decreased significantly in Group B but rose slightly in Group A. No side effects were observed in any of the patients.

Risk factors for osteoporosis in female patients with systemic lupus erythematosus

In the last years it has been recognized that patients with systemic lupus erythematosus (SLE) are at high risk of osteoporosis (OP) and fractures, both occurring through disease-specific (chronic arthritis, reduced physical activity, induction of cytokines promoting bone resorption, renal impairment, endocrine factors) and nondisease-specific mechanisms (sunshine avoidance with consequent vitamin D deficiency, glucocorticoids, immunosuppressants and chronic anticoagulants). Regarding anticoagulants, subcutaneous heparin is crucial against the risk of recurrent thromboembolism or pregnancy loss, specifically in patients with SLE and anti-phospholipid syndrome (APS). Thus heparin-induced OP represents one of the hazards of this treatment, first because heparin must be used long-term and secondly because pregnancy and lactation themselves may predispose to OP and fractures. Current data suggest the use of prophylaxis with calcium and vitamin D in all patients treated with heparin during pregnancy. Nevertheless glucocorticoid-induced OP (GIOP) is considered the most serious risk factor for OP and fractures in SLE patients. All guidelines recommend general measures and supplementation with calcium and vitamin D in all patients. However when considering premenopausal patients, there is no generally recommended treatment. Bisphosphonates, which are considered the first choice therapy for the prevention and treatment of GIOP, should be used ‘cautiously’ in these patients. Therefore the potential risks and lack of efficacy data on fracture risk reduction in premenopausal patients must be weighed against their proven efficacy in postmenopausal patients.

Reduced bone mass and normal calcium metabolism in systemic sclerosis with and without calcinosis

SummaryForty-three female patients with systemic sclerosis divided into subgroups based on the extent of skin involvement and the presence of calcinosis, and 50 sex and age-matched healthy controls were investigated for bone mineral density (BMD) on the basis of radial (dual photon absorptiometry, Osteograph, NIM), lumbar, and total body measurements (dual energy X-ray absorptiometry, Lunar DPX, Lunar Corp.), and for parameters of calcium metabolism. The patients showed a lower BMD (mean±SD; mg/cm2) than the controls at the radial (313±69 vs 347±73; p<0.005), lumbar (974±143 vs 1081±154; p<0.005), and total body (997±82 vs 1075±109; p<0.05) determinations. The patients with the diffuse form of skin involvement had lower values than those with the limited form. There was a negative correlation between BMD and the duration of the disease. The presence of calcinosis was not found to have any effect on BMD. Calcium metabolism was found to be normal in each subgroup.It may be concluded that generalized osteoporosis is a feature of systemic sclerosis, with and without calcinosis. The extent and duration of the disease may play a role in determining bone loss.

Lung function in essential mixed cryoglobulinemia: A short-term follow-up

SummaryLung involvement in essential mixed cryoglobulinemia (EMC) has been recently described. In order to assess whether patients with EMC experience an accelerated deterioration of lung function, nineteen patients (17 females, 2 males;49.6±6.6 years) underwent a short-term follow-up of lung function, chest X-ray and serologic investigations. Reduction of forced expiratory flows and presence of roentgenologic signs of interstitial involvement were confirmed in the baseline evaluation. In addition, a decrease of diffusing capacity was shown. After a mean interval of 15 months, no significant change in lung function was found, with the exception of decrease in maximal expiratory flow at 50% of forced vital capacity, total lung capacity, functional residual capacity, coefficient of transfer of CO. A slight decrease of hemolitic complement (CH50) and of complement fraction (C3) was also observed. This study suggests that patients with EMC tend to have an involvement of pulmonary interstitial space, possibly related to immune complex deposition, but they do not show a severe decline of lung function. Periodical assessment of lung function and chest X-ray is, however, worthwhile.

Risk factors for osteoporosis and fragility fractures in patients with systemic lupus erythematosus

Osteoporosis (OP) and fragility fractures (FFx) are a known comorbidity in patients with systemic lupus erythematosus (SLE). This work aimed at evaluating (1) the prevalence of OP and FFx in a cohort of SLE and (2) the risk factors associated with both OP and FFx. The following data were collected from clinical charts: age, sex, menopausal status (MP), body mass index, smoking habits, disease duration, daily dose and cumulative glucocorticoids (GCs), type of organ involvement, comorbidities and medications. Data on bone metabolism, calcium and vitamin D supplementation and treatment with bisphosphonates, teriparatide or denosumab were collected, together with bone mineral density (BMD) values (measured by dual-energy X-ray absorptiometry (DXA)) and history of FFx (occurred after the onset of SLE and unrelated to trauma). OP and reduced BMD were defined according to the WHO. 186 patients were included (women 175, men 11; mean age 46.4±13 years, mean disease duration 14.9±9 years). At their last visit, 97 patients (52.2%) had a reduced BMD and 52 (27.9%) had OP. 22 patients (11.8%), all women, had at least one FFx; six patients (27.3%) were pre-menopausal. On univariate analysis, age, cumulative dose of GC, MP, therapy with antiepileptics and chronic renal failure (CRF) were correlated with OP (p<0.03); age, total amount of GC, MP, CRF, anticoagulants (AC) and antiepileptic therapy were correlated with FFx (p<0.05). The multivariate logistic model confirmed a direct association of OP and age, MP and antiepileptic therapy (p≤0.01) and of FFx and age, chronic therapy with AC and antiepileptics (p<0.03). In conclusion, low BMD is frequently observed in SLE, and FFx are observed also in premenopausal patients. Together with traditional risk factors (age, MP and GC), CRF and chronic treatments with AC or antiepileptics seem to be associated with a higher risk profile for OP and FFx occurrence.

Multicentric Castleman's disease in a patient with primary Sjögren's syndrome.

SummaryA 38-year-old woman suffering from primary Sjögrens syndrome for 2 years developed angiofollicular hyperplasia (multicentric Castelmans disease). In Sjögrens syndrome (SS) a number of findings indicate the presence of a B-cell hyperactivity that may evolve to a lymphoproliferative disorder. This report adds another pathological event to the complex spectrum of lymphoproliferative diseases in SS.