The leading treatments for postmenopausal osteoporosis are the nitrogen-containing bisphosphonates, which are required long term for optimal benefit. Oral bisphosphonates have proven efficacy in postmenopausal osteoporosis in clinical trials, but in practice the therapeutic benefits are often compromised by patients’ low adherence. Nonadherence to bisphosphonate therapy negatively impacts outcomes such as fracture rate; fractures are in turn associated with decreased quality of life. The most common reason cited by patients for their nonadherence is that the strict dosing instructions for bisphosphonates are difficult to follow. One aspect of bisphosphonate administration that can be changed is dosing frequency and several studies have evaluated patient preferences for different dosing schedules. Studies have shown a preference for a weekly bisphosphonate regimen versus daily dosing and it has been demonstrated that this preference for reduced dosing frequency impacts on adherence. Ibandronate is the first nitrogen-containing oral bisphosphonate for osteoporosis that can be administered in a monthly regimen and two robust clinical studies demonstrated a strong patient preference for this monthly regimen versus a weekly regimen. It is important that physicians consider patient preference when prescribing treatment for osteoporosis to ensure that the disease is effectively managed for the long-term benefit of the patient.

Background:

Attribute selection represents an important step in the development of discrete-choice experiments (DCEs), but is often poorly reported. In some situations, the number of attributes identified may exceed what one may find possible to pilot in a DCE. Hence, there is a need to gain insight into methods to select attributes in order to construct the final list of attributes. This study aims to test the feasibility of using the nominal group technique (NGT) to select attributes for DCEs.

Methods:

Patient group discussions (4–8 participants) were convened to prioritize a list of 12 potentially important attributes for osteoporosis drug therapy. The NGT consisted of three steps: an individual ranking of the 12 attributes by importance from 1 to 12, a group discussion on each of the attributes, including a group review of the aggregate score of the initial rankings, and a second ranking task of the same attributes.

Results:

Twenty-six osteoporotic patients participated in five NGT sessions. Most (80%) of the patients changed their ranking after the discussion. However, the average initial and final ranking did not differ markedly. In the final ranking, the most important medication attributes were effectiveness, side effects, and frequency and mode of administration. Some (15%) of the patients did not correctly rank from 1 to 12, and the order of attributes did play a role in the ranking.

Conclusion:

The NGT is feasible for selecting attributes for DCEs. Although in the context of this study, the NGT session had little impact on prioritizing attributes, this approach is rigorous, transparent, and improves the face validity of DCEs. Additional research in other contexts (different decisional problems or different diseases) is needed to determine the added value of the NGT session, to assess the optimal ranking/rating method with control of ordering effects, and to compare the attributes selected with the different approaches.

Over the last 20 years, several studies have investigated the ability of glucosamine sulfate to improve the symptoms (pain and function) and to delay the structural progression of osteoarthritis. There is now a large, convergent body of evidence that glucosamine sulfate, given at a daily oral dose of 1,500 mg, is able to significantly reduce the symptoms of osteoarthritis in the lower limbs. This dose of glucosamine sulfate has also been shown, in two independent studies, to prevent the joint space narrowing observed at the femorotibial compartment in patients with mild-to-moderate knee osteoarthritis. This effect also translated into a 50 % reduction in the incidence of osteoarthritis-related surgery of the lower limbs during a 5-year period following the withdrawal of the treatment. Some discrepancies have been described between the results of studies performed with a patent-protected formulation of glucosamine sulfate distributed as a drug and those having used glucosamine preparations purchased from global suppliers, packaged, and sold over-the-counter as nutritional supplements.

The pharmacological management of disease should involve consideration of the balance between the beneficial effects of treatment on outcome and the probability of adverse effects. The aim of this review is to explore the risk of adverse drug reactions and drug–drug interactions with treatments for postmenopausal osteoporosis. We reviewed evidence for adverse reactions from regulatory documents, randomized controlled trials, pharmacovigilance surveys, and case series. Bisphosphonates are associated with gastrointestinal effects, musculoskeletal pain, and acute-phase reactions, as well as, very rarely, atrial fibrillation, atypical fracture, delayed fracture healing, osteonecrosis of the jaw, hypersensitivity reactions, and renal impairment. Cutaneous effects and osteonecrosis of the jaw are of concern for denosumab (both very rare), though there are no pharmacovigilance data for this agent yet. The selective estrogen receptor modulators are associated with hot flushes, leg cramps, and, very rarely, venous thromboembolism and stroke. Strontium ranelate has been linked to hypersensitivity reactions and venous thromboembolism (both very rare) and teriparatide with headache, nausea, dizziness, and limb pain. The solidity of the evidence base depends on the frequency of the reaction, and causality is not always easy to establish for the very rare adverse reactions. Drug–drug interactions are rare. Osteoporosis treatments are generally safe and well tolerated, though they are associated with a few very rare serious adverse reactions. While these are a cause for concern, the risk should be weighed against the benefits of treatment itself, i.e., the prevention of osteoporotic fracture.

Cutaneous adverse reactions are reported for many therapeutic agents and, in general, are observed in between 0% and 8% of treated patients depending on the drug. Antiosteoporotic agents are considered to be safe in terms of cutaneous effects, however there have been a number of case reports of cutaneous adverse reactions which warrant consideration. This was the subject of a working group meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis in April 2009, which focused on the impact of cutaneous adverse reactions and drug-induced hypersensitivity in the management of postmenopausal osteoporosis. This position paper was drafted following these discussions and includes a flowchart for their recognition. Cutaneous adverse reactions observed with antiosteoporotic agents were reviewed and included information from case reports, regulatory documents and pharmacovigilance. These reactions ranged from benign effects including exanthematous or maculopapular eruption (drug rash), photosensitivity and urticaria, to the severe and potentially life-threatening reactions of angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome and toxic epidermal necrolysis. A review of the available evidence demonstrates that cutaneous adverse reactions occur with all commonly used antiosteoporotic treatments. Notably, there are reports of Stevens Johnson syndrome and toxic epidermal necrolysis for bisphosphonates, and of DRESS and toxic epidermal necrolysis for strontium ranelate. These severe reactions remain very rare (<1 in 10,000 cases). In general, with proper management and early recognition, including immediate and permanent withdrawal of the culprit agent, accompanied by hospitalization, rehydration and systemic corticosteroids if necessary, the prognosis is positive.

Osteoporosis treatments need to combine an unequivocally demonstrated reduction of fractures, at various skeletal sites, long-term safety, and a user-friendly profile, optimizing therapeutic adherence. Strontium ranelate is the first compound to simultaneously decrease bone resorption and stimulate bone formation. Its antifracture efficacy, at various skeletal sites, has been established up to 8 years, through studies of the highest methodological standards. Increases in bone mineral density, observed after 1 year of treatment, are predictive of the long-term fracture efficacy, hence suggesting, for the first time in osteoporosis, that bone densitometry can be used as a monitoring tool for both efficacy and compliance. Owing to a positive benefit/risk ratio, strontium ranelate may now be considered as a first-line treatment in the management of osteoporosis.

Background

Symptomatic slow-acting drugs (SYSADOA) have been largely studied over the last decade. The objective of this study is to prepare a document providing recommendations for the use of SYSADOA in osteoarthritis (OA).

Methods

The following interventions were taken into consideration: avocado/soybean unsaponifiables, chondroitin sulfate, diacereine, glucosamine sulfate, hyaluronic acid, oral calcitonin, risedronate, strontium ranelate. Recommendations were based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The GRADE system is based on a sequential assessment of the quality of evidence, followed by assessment of the balance between benefits versus downsides and subsequent judgment about the strength of recommendations.

Results

Chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid have demonstrated pain reduction and physical function improvement with very low toxicity, with moderate to high quality evidence. Even if pre-clinical data and some preliminary in vivo studies have suggested that oral calcitonin and strontium ranelate could be of potential interest in OA, additional well-designed studies are needed.

Conclusion

In the benefit/risk ratio, the use of chondroitin sulfate, diacereine, glucosamine sulfate, avocado/soybean unsaponifiables and hyaluronic acid could be of potential interest for the symptomatic management of OA.

Background

The efficacy, safety and tolerability of lumiracoxib, a novel selective cyclooxygenase-2 (COX-2) inhibitor, has been demonstrated in previous studies of patients with osteoarthritis (OA). As it is important to establish the long-term safety and efficacy of treatments for a chronic disease such as OA, the present study compared the effects of lumiracoxib at doses of 100 mg once daily (o.d.) and 100 mg twice daily (b.i.d.) with those of celecoxib 200 mg o.d. on retention on treatment over 1 year.

Methods

In this 52-week, multicentre, randomised, double-blind, parallel-group study, male and female patients (aged at least 40 years) with symptomatic primary OA of the hip, knee, hand or spine were randomised (1:2:1) to lumiracoxib 100 mg o.d. (n = 755), lumiracoxib 100 mg b.i.d. (n = 1,519) or celecoxib 200 mg o.d. (n = 758). The primary objective of the study was to demonstrate non-inferiority of lumiracoxib at either dose compared with celecoxib 200 mg o.d. with respect to the 1-year retention on treatment rate. Secondary outcome variables included OA pain in the target joint, patient's and physician's global assessments of disease activity, Short Arthritis assessment Scale (SAS) total score, rescue medication use, and safety and tolerability.

Results

Retention rates at 1 year were similar for the lumiracoxib 100 mg o.d., lumiracoxib 100 mg b.i.d. and celecoxib 200 mg o.d. groups (46.9% vs 47.5% vs 45.3%, respectively). It was demonstrated that retention on treatment with lumiracoxib at either dose was non-inferior to celecoxib 200 mg o.d. Similarly, Kaplan-Meier curves for the probability of premature discontinuation from the study for any reason were similar across the treatment groups. All three treatments generally yielded comparable results for the secondary efficacy variables and all treatments were well tolerated.

Conclusion

Long-term treatment with lumiracoxib 100 mg o.d., the recommended dose for OA, was as effective and well tolerated as celecoxib 200 mg o.d. in patients with OA.

Trial registration

clinicaltrials.gov NCT00145301

Background

Inadequate serum vitamin D [25(OH)D] concentrations are associated with secondary hyperparathyroidism, increased bone turnover and bone loss, which increase fracture risk. The objective of this study is to assess the prevalence of inadequate serum 25(OH)D concentrations in postmenopausal Belgian women. Opinions with regard to the definition of vitamin D deficiency and adequate vitamin D status vary widely and there are no clear international agreements on what constitute adequate concentrations of vitamin D.

Methods

Assessment of 25-hydroxyvitamin D [25(OH)D] and parathyroid hormone was performed in 1195 Belgian postmenopausal women aged over 50 years. Main analysis has been performed in the whole study population and according to the previous use of vitamin D and calcium supplements. Four cut-offs of 25(OH)D inadequacy were fixed : < 80 nmol/L, <75 nmol/L, < 50 nmol/L and < 30 nmol/L.

Results

Mean (SD) age of the patients was 76.9 (7.5) years, body mass index was 25.7 (4.5) kg/m2. Concentrations of 25(OH)D were 52.5 (21.4) nmol/L. In the whole study population, the prevalence of 25(OH)D inadequacy was 91.3 %, 87.5 %, 43.1 % and 15.9% when considering cut-offs of 80, 75, 50 and 30 nmol/L, respectively. Women who used vitamin D supplements, alone or combined with calcium supplements, had higher concentrations of 25(OH)D than non-users. Significant inverse correlations were found between age/serum PTH and serum 25(OH)D (r = -0.23/r = -0.31) and also between age/serum PTH and femoral neck BMD (r = -0.29/r = -0.15). There is a significant positive relation between age and PTH (r = 0.16), serum 25(OH)D and femoral neck BMD (r = 0.07). (P < 0.05)

Vitamin D concentrations varied with the season of sampling but did not reach statistical significance (P = 0.09).

Conclusion

This study points out a high prevalence of vitamin D inadequacy in Belgian postmenopausal osteoporotic women, even among subjects receiving vitamin D supplements.

Osteoarthritis and osteoporosis are the two most common age-related chronic disorders of articular joints and skeleton, representing a major public health problem in most developed countries. Apart from being influenced by environmental factors, both disorders have a strong genetic component, and there is now considerable evidence from large population studies that these two disorders are inversely related. Thus, an accurate analysis of the genetic component of one of these two multifactorial diseases may provide data of interest for the other. However, the existence of confounding factors must always be borne in mind in interpreting the genetic analysis. In addition, each patient must be given an accurate clinical evaluation, including family history, history of drug treatments, lifestyle, and environment, in order to reduce the background bias. Here, we review the impact of recent work in molecular genetics suggesting that powerful molecular biology techniques will soon make possible both a rapid accumulation of data on the genetics of both disorders and the development of novel diagnostic, prognostic, and therapeutic approaches.

The 3-year FREEDOM trial assessed the efficacy and safety of 60 mg denosumab every 6 months for the treatment of postmenopausal women with osteoporosis. Participants who completed the FREEDOM trial were eligible to enter an extension to continue the evaluation of denosumab efficacy and safety for up to 10 years. For the extension results presented here, women from the FREEDOM denosumab group had 2 more years of denosumab treatment (long-term group) and those from the FREEDOM placebo group had 2 years of denosumab exposure (cross-over group). We report results for bone turnover markers (BTMs), bone mineral density (BMD), fracture rates, and safety. A total of 4550 women enrolled in the extension (2343 long-term; 2207 cross-over). Reductions in BTMs were maintained (long-term group) or occurred rapidly (cross-over group) following denosumab administration. In the long-term group, lumbar spine and total hip BMD increased further, resulting in 5-year gains of 13.7% and 7.0%, respectively. In the cross-over group, BMD increased at the lumbar spine (7.7%) and total hip (4.0%) during the 2-year denosumab treatment. Yearly fracture incidences for both groups were below rates observed in the FREEDOM placebo group and below rates projected for a “virtual untreated twin” cohort. Adverse events did not increase with long-term denosumab administration. Two adverse events in the cross-over group were adjudicated as consistent with osteonecrosis of the jaw. Five-year denosumab treatment of women with postmenopausal osteoporosis maintained BTM reduction and increased BMD, and was associated with low fracture rates and a favorable risk/benefit profile. © 2012 American Society for Bone and Mineral Research

Background

Strontium ranelate is currently used for osteoporosis. The international, double-blind, randomised, placebo-controlled Strontium ranelate Efficacy in Knee OsteoarthrItis triAl evaluated its effect on radiological progression of knee osteoarthritis.

Methods

Patients with knee osteoarthritis (Kellgren and Lawrence grade 2 or 3, and joint space width (JSW) 2.5–5 mm) were randomly allocated to strontium ranelate 1 g/day (n=558), 2 g/day (n=566) or placebo (n=559). The primary endpoint was radiographical change in JSW (medial tibiofemoral compartment) over 3 years versus placebo. Secondary endpoints included radiological progression, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and knee pain. The trial is registered (ISRCTN41323372).

Results

The intention-to-treat population included 1371 patients. Treatment with strontium ranelate was associated with smaller degradations in JSW than placebo (1 g/day: −0.23 (SD 0.56) mm; 2 g/day: −0.27 (SD 0.63) mm; placebo: −0.37 (SD 0.59) mm); treatment-placebo differences were 0.14 (SE 0.04), 95% CI 0.05 to 0.23, p<0.001 for 1 g/day and 0.10 (SE 0.04), 95% CI 0.02 to 0.19, p=0.018 for 2 g/day. Fewer radiological progressors were observed with strontium ranelate (p<0.001 and p=0.012 for 1 and 2 g/day). There were greater reductions in total WOMAC score (p=0.045), pain subscore (p=0.028), physical function subscore (p=0.099) and knee pain (p=0.065) with strontium ranelate 2 g/day. Strontium ranelate was well tolerated.

Conclusions

Treatment with strontium ranelate 1 and 2 g/day is associated with a significant effect on structure in patients with knee osteoarthritis, and a beneficial effect on symptoms for strontium ranelate 2 g/day.

Background

Low back pain (LBP) is a major public health problem and the identification of individuals at risk of persistent LBP poses substantial challenges to clinical management. The STarT Back questionnaire is a validated nine-item patient self-report questionnaire that classifies patients with LBP at low, medium or high-risk of poor prognosis for persistent non-specific LBP. The objective of this study was to translate and cross-culturally adapt the English version of the STarT Back questionnaire into French.

Methods

The translation was performed using best practice translation guidelines. The following phases were performed: contact with the STarT Back questionnaire developers, initial translations (English into French), synthesis, back translations, expert committee review, test of the pre-final version on 44 individuals with LBP, final version.

Results

The linguistic translation required minor semantic alterations. The participants interviewed indicated that all items of the questionnaire were globally clear and comprehensible. However, 6 subjects (14%) wondered if two questions were related to back pain or general health. After discussion within the expert committee and with the developer of the STarT Back tool, it was decided to modify the questionnaire and to add a reference to back pain in these two questions.

Conclusions

The French version of the STarT Back questionnaire has been shown to be comprehensible and adapted to the French speaking general population. Investigations are now required to test the psychometric properties (reliability, internal and external validity, responsiveness) of this translated version of the questionnaire.