Vertebral fractures are a major adverse consequence of osteoporosis. In a large placebo-controlled trial in postmenopausal women with osteoporosis, strontium ranelate reduced vertebral fracture risk by 33% over 4 years, confirming the role of strontium ranelate as an effective long-term treatment in osteoporosis.
Osteoporotic vertebral fractures are associated with increased mortality, morbidity, and loss of quality-of-life (QoL). Strontium ranelate (2 g/day) was shown to prevent bone loss, increase bone strength, and reduce vertebral and peripheral fractures. The preplanned aim of this study was to evaluate long-term efficacy and safety of strontium ranelate.
A total of 1,649 postmenopausal osteoporotic women were randomized to strontium ranelate or placebo for 4 years, followed by a 1-year treatment-switch period for half of the patients. Primary efficacy criterion was incidence of patients with new vertebral fractures over 4 years. Lumbar bone mineral density (BMD) and QoL were also evaluated.
Over 4 years, risk of vertebral fracture was reduced by 33% with strontium ranelate (risk reduction = 0.67, p < 0.001). Among patients with two or more prevalent vertebral fractures, risk reduction was 36% (p < 0.001). QoL, assessed by the QUALIOST®, was significantly better (p = 0.025), and patients without back pain were greater (p = 0.005) with strontium ranelate than placebo over 4 years. Lumbar BMD increased over 5 years in patients who continued with strontium ranelate, while it decreased in patients who switched to placebo. Emergent adverse events were similar between groups.
In this 4- and 5-year study, strontium ranelate is an effective and safe treatment for long-term treatment of osteoporosis in postmenopausal women.
Bone densitometry; Menopause; Osteoporotic fracture; Osteoporosis treatment; Strontium ranelate
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.
antiosteoporosis treatments; cutaneous adverse reactions; hypersensitivity reactions; osteoporosis
Osteoporotic fractures are one of the major causes of increased morbidity and mortality in postmenopausal women and the overall aging population. One of the major issues in the management of postmenopausal osteoporosis is to find a safe and effective treatment in the long term (>3 years) to achieve and maintain a reduction in the risk of fracture. Strontium ranelate (PROTELOS®) is a relatively novel drug, currently approved in Europe for the treatment of postmenopausal osteoporosis. Strontium ranelate is the first agent of a new therapeutic class in osteoporosis, capable of both promoting bone formation and, to a lesser extent, inhibiting bone resorption. This uncoupling in bone turnover results in a net gain in bone mineral density (BMD), bone quality improvement and reduction in risk of vertebral and nonvertebral fractures, as initially demonstrated in the preplanned long-term registrative trials SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment of Peripheral Osteoporosis) at 5 years. Recently, open-label extensions of the SOTI and TROPOS trials up to 8 and, recently, 10 years have confirmed the sustained efficacy of strontium ranelate in increasing BMD, the long-term safety profile and the high compliance to treatment, independently from baseline BMD or other risk factors for osteoporotic fractures. Recent economic impact analyses have proved that long-term treatment with strontium ranelate is highly cost effective, especially in women older than 70 years of age. Histomorphometric analyses in animals and humans participating in the phase III trials have proved that the quality of mineralization is preserved in the long term and bone microarchitecture is ameliorated, with increased bone strength. Thus, strontium ranelate has been confirmed to be an effective compound for the long-term, chronic treatment of postmenopausal osteoporosis.
anabolic; antiresorptive; bone formation; bone mineral density; bone resorption; mineralization; safety; tolerability
Bisphosphonates are the leading drugs for the treatment of osteoporosis. In randomized controlled trials (RCTs), alendronate, risedronate, and zoledronate have shown to reduce the risk of vertebral, nonvertebral, and hip fractures, whereas RCTs with ibandronate show antifracture efficacy at vertebral sites. Bisphosphonates are generally well tolerated and safe. Nevertheless, adverse events have been noted, and it is important to consider the strength of the evidence for causal relationships. Effects on the gastrointestinal tract and kidney function are well recognized, as are transient acute-phase reactions. Atrial fibrillation was first identified as a potential adverse event in a zoledronate trial, but subsequent trials and analyses failed to substantiate an association with bisphosphonates. Case reports have suggested a relationship between oral bisphosphonates and esophageal cancer, but this has not been demonstrated in epidemiologic studies. A possible association between bisphosphonate use and osteonecrosis of the jaw (ONJ) has also been suggested. However, the risk of ONJ in patients with osteoporosis appears to be very low, with no evidence from prospective RCTs of a causal association. There are reports of occasional occurrence of subtrochanteric or diaphyseal fractures in osteoporotic patients, but an association with bisphosphonate therapy is not substantiated by epidemiologic studies or prospective RCTs.
bisphosphonates; osteoporosis; safety
Osteoporosis is a progressive and debilitating disease characterized by a massive bone loss with a deterioration of bone tissues, and a propensity for a fragility fracture. Strontium ranelate is the first antiosteoporotic treatment that has dual mode of action and simultaneously increases bone formation, while decreasing bone resorption, thus rebalancing bone turnover formation. Strontium ranelate rebalances bone turnover in favor of improved bone geometry, cortical thickness, trabecular bone morphology and intrinsic bone tissue quality, which translates into enhanced bone strength. This review describes the mechanism of the strontium ranelate action and its effects on bone mineral density, bone turnover, and osteoporotic fractures. The efficacy of strontium ranelate in postmenopausal osteoporosis treatment to reduce the risk of vertebral and hip fractures has been highlighted in several randomized, controlled trials. Treatment efficacy with strontium ranelate has been documented across a wide range of patient profiles: age, number of prevalent vertebral fractures, body mass index, and a family history of osteoporosis. Because strontium ranelate has a large spectrum of efficacy, it can be used to treat different subgroups of patients with postmenopausal osteoporosis. Strontium ranelate was shown to be relatively well tolerated and the safety aspects were good. Strontium ranelate should be considered as a first-line treatment for postmenopausal osteoporotic patients.
osteoporosis; strontium ranelate; therapy
Oral bisphosphonates are the most commonly prescribed antiresorptive drugs for the treatment of osteoporosis. However, there are several adverse effects associated with oral bisphosphonates including the bisphosphonate related osteonecrosis of the jaw (BRONJ). With a better understanding of this side effect, reported incidences for BRONJ in oral bisphosphonate users have increased in time. The pathogenesis of BRONJ has not been well determined. Several risk factors such as dentoalveolar surgery, therapy duration, and concomitant steroid usage have been linked to BRONJ. Conservative and surgical methods can be preferred in the treatment. Preventative measures are of great importance for the patients at high risk. In this paper, osteonecrosis of the jaw secondary to oral bisphosphonates was reviewed in order to increase awareness as well as to renew the current knowledge.
A genomewide association study was conducted to search for genetic variants that increase the risk for bisphosphonate-related osteonecrosis of the jaw. Findings suggest that genetic susceptibility plays a role in the pathophysiology of bisphosphonate-related osteonecrosis of the jaw, with RBMS3 having a significant effect in the risk.
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Explain the association between bisphosphonates and osteonecrosis of the jaw.Describe the role of RBMS3 in the risk of BRONJ development.
This article is available for continuing medical education credit at CME.TheOncologist.com
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a serious adverse drug reaction. We conducted a genomewide association study to search for genetic variants with a large effect size that increase the risk for BRONJ.
We ascertained BRONJ cases according to the diagnostic criteria of the American Association of Oral and Maxillofacial Surgeons. We genotyped cases and a set of treatment-matched controls using Illumina Human Omni Express 12v1 chip (733,202 markers). To maximize the power of the study, we expanded the initial control set by including population and treatment-tolerant controls from publicly available sources. Imputation at the whole-genome level was performed to increase the number of single nucleotide polymorphisms (SNPs) investigated. Tests of association were carried out by logistic regression, adjusting for population structure. We also examined a list of candidate genes comprising genes potentially involved in the pathogenesis of BRONJ and genes related to drug absorption, distribution, metabolism, and excretion.
Based on principal component analysis, we initially analyzed 30 white cases and 17 treatment-tolerant controls. We subsequently expanded the control set to include 60 genetically matched controls per case. Association testing identified a significant marker in the RBMS3 gene, rs17024608 (p-value < 7 × 10−8); individuals positive for the SNP were 5.8× more likely to develop BRONJ (odds ratio, 5.8; 95% confidence interval, 3.1–11.1). Candidate gene analysis further identified SNPs in IGFBP7 and ABCC4 as potentially implicated in BRONJ risk.
Our findings suggest that genetic susceptibility plays a role in the pathophysiology of BRONJ, with RBMS3 having a significant effect in the risk.
Osteonecrosis; Jaw; Bisphosphonates; Pharmacogenetics; Screening; IGFBP7; ABCC4; RBMS3; Zoledronic acid; Genetic susceptibility; Genomewide association study; ONJ; GWAS
Oral bisphosphonates comprise the most widely prescribed class of antiosteoporotic drugs. Recent reports, however, suggest a link between prolonged bisphosphonate use and atypical low-energy, subtrochanteric fractures. We describe the clinical course of two patient treated for a long term with different bisphosphonates who developed subtrochanteric atypical fractures. They were treated initially with intramedullary rodding without pain disappearance or healing of the fracture. Strontium ranelate, a new orally administered agent for the treatment of osteoporosis, was given to these patients with complete closure of the fracture and pain disappearance after a few months. We conclude that based on the chronology of fracture healing and pain disappearance of our patients and published evidence that strontium ranelate can accelerate fracture healing in a rat model, that strontium ranelate had a positive anabolic effect that contributed to fracture healing that produced the secondary disappearance of pain.
bisphosphonate; atypical fractures; delayed healing; strontium ranelate
Pathologic fractures, spinal compression and pain take a great toll on the healthcare costs and well-being of men with prostate cancer metastatic to the bone. For almost 10 years, the only drug proven to prevent these skeletal-related adverse events was the bisphosphonate zoledronic acid. In a study published by Fizazi et al. in The Lancet, the monoclonal antibody to RANKL, denosumab, is shown to be superior to zoledronic acid in the prevention of these events. The only notable adverse event more frequent in either arm was increased hypocalcemia in the denosumab arm. There was a greater frequency of osteonecrosis of the jaw in the denosumab treatment group that did not reach statistical significance, but is of great concern. While further analysis is needed to determine the value of denosumab in preventing adverse events and improving quality of life, this new therapy is a significant addition to the treatment of men living with metastatic prostate cancer.
bisphosphonates; bone metastasis; denosumab; osteonecrosis of the jaw; prostate cancer
Bisphosphonates are widely used for prevention of fractures in patients at risk, mainly in the presence of osteoporosis and bone metastases. A number of adverse effects of prolonged bisphosphonate treatment have emerged. We would like to highlight the skeletal complications from which a radiologist may be the first healthcare professional to recognise the association with bisphosphonate therapy. We illustrate these complications (namely osteonecrosis of the jaw and less well-known atypical femoral shaft fractures), presenting radiological findings in our patients. Recommendations for safer use of bisphosphonates are included in the conclusion of our review.
Bisphosphonates like alendronic acid, disodium etidronate, and risedronate are effective for preventing postmenopausal and corticosteroid induced osteoporosis. They are also useful in the treatment of Paget's disease, hypercalcaemia of malignancy and in bony metastases. However osteonecrosis of the jaw has been reported following intravenous bisphosphonate use and rarely in those taking them orally.
Increasingly, oroantral fistulae have been shown to occur as sequelae of bisphosphonate-induced osteonecrosis of the jaw and this case report highlights a patient that presented to our ENT department and required sinus surgery in collaboration with maxillofacial surgeons.
This case report aims to raise awareness among ENT surgeons to these patients on bisphosphonates that could present to them with sinus disease from oroantral fistulae. There is an on-going audit in the maxillofacial community on this emerging trend.
Bisphosphonates are a class of agents used to treat osteoporosis and malignant bone metastases. Despite these benefits, osteonecrosis of the jaws has recently emerged as a significant complication in a subset of patients receiving these drugs. Based on a growing number of case reports and institutional reviews, bisphosphonate therapy may cause exposed and necrotic bone that is isolated to the jaw. This complication usually presents following simple dentoalveolar surgery and can cause a significant adverse effect on the quality of life for most patients. The pathogenesis for this complication appears to be related to the profound inhibition of osteoclast function and bone remodeling. This report will review the clinical signs and symptoms and risks associated with this new complication and provide a guideline for establishing a stage-specific diagnosis of BRONJ.
bisphosphonate-related osteonecrosis of the jaw; BRONJ; bisphosphonate associated osteonecrosis of the jaw; bisphosphonate; osteonecrosis of the jaw
Denosumab is a breakthrough biological drug approved by the Food and Drug Administration and European Medicines Agency for the treatment of osteoporosis in 2010. It is a fully human monoclonal antireceptor activator of nuclear factor kappa-B ligand antibody, which inhibits the activity of osteoclasts, resulting in an antiresorptive effect with a significant increase in bone mineral density. The FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months) trial, comparing denosumab with no treatment in 7868 women with postmenopausal osteoporosis, showed an important reduction of fracture risk at hip, vertebral, and nonvertebral sites in the treated group, while no statistically significant difference in the incidence of adverse events was detected between denosumab and placebo groups. The specific action of denosumab directed against a key regulator of osteoclasts makes it a valuable tool in preventing the occurrence of skeletal events caused by bone destruction in patients with advanced malignancies. The drug was approved for postmenopausal osteoporosis in women at increased risk of fracture and for the treatment of bone loss associated with androgen deprivation therapy in men with prostate cancer.
osteoporosis; denosumab; targeted therapy; BMD; antibody; RANK-L
The objective of this article is to evaluate the relationship between the changes in prescriptions of antiosteoporotic drugs (mainly the rapid fall in the use of bisphosphonates [BPs]) and standardized hip fracture (HF) rates over the period 2005–2008 in the Australian Capital Territory (ACT).
Annual sex- and age-specific HF rates (per 100,000 population) were determined and standardized using the Australian 2006 population census. Data on the annual prescriptions of BPs (mainly alendronate and risedronate), strontium ranelate, and hormone replacement therapy were obtained from the Australian Pharmaceutical Benefits Scheme (PBS) and Repatriation Australian Pharmaceutical Benefits Scheme (RPBS) databases.
In the ACT, the peak annual number of prescriptions for BPs was observed in 2006. Following reports linking osteonecrosis of the jaw with BP use, the number of BP prescriptions dropped by 14% in 2007–2008 compared with 2005, when the lowest HF rates were recorded. The reduction in BP prescriptions coincided with increased HF rates in females in 2007 (+22.6%) and in 2008 (+25.2%) compared with 2005; in males, HF incidence declined by 6.6% and 16.7%, respectively. The proportion of filled prescriptions for strontium ranelate, risedronate, and alendronate in 2007–2008 was 1:8.4:15.5, indicating that BPs were the dominant antiosteoporotic drugs. There was an inverse statistically significant relationship between the total annual number of BP prescriptions and standardized HF incidence rates for the 10-year period 1999–2008.
Although currently there is no clear understanding of factors contributing to changing HF epidemiology, the available evidence suggests that much of the decline in HF rates is due to the use of BPs. The fall in the use of BPs is associated with an increase in HF rates in females, indicating that BPs should still be considered the first-line medications for the prevention and treatment of osteoporosis. Our results need to be confirmed in other populations and countries.
bisphosphonate use; hip fracture; epidemiology
Osteonecrosis of the jaw (ONJ) is an adverse effect of drugs that suppress bone turnover – for example, drugs used for the treatment of postmenopausal osteoporosis. The Danish National Registry of Patients (DNRP) is potentially valuable for monitoring ONJ and its prognosis; however, no specific code for ONJ exists in the International Classification of Diseases 10th revision (ICD-10), which is currently used in Denmark. Our aim was to estimate the positive predictive value (PPV) of an algorithm to capture ONJ cases in the DNRP among women with postmenopausal osteoporosis.
We conducted this cross-sectional validation study in the Central and North Denmark Regions, with approximately 1.8 million inhabitants. In total, 54,956 women with postmenopausal osteoporosis were identified from June 1, 2005 through May 31, 2010. To identify women potentially suffering from ONJ, we applied an algorithm based on ICD-10 codes in the DNRP originating from hospital-based departments of oral and maxillofacial surgery (DOMS). ONJ was adjudicated by chart review and defined by the presence of exposed maxillofacial bone for 8 weeks or more, in the absence of recorded history of craniofacial radiation therapy. We estimated the PPV for the overall algorithm and for each separate ICD-10 code used in the algorithm.
Charts were obtained and reviewed for all 60 women with an ICD-10 code potentially representing ONJ. Nineteen potential ONJ cases were confirmed, corresponding to an overall PPV of 32% (95% confidence interval: 20%–45%).
Among women with postmenopausal osteoporosis, only about one-third of the potential ONJ cases identified by our ICD-10 based algorithm were confirmed by medical chart review, despite the restriction to patients treated at DOMS. To capture true ONJ cases among women with postmenopausal osteoporosis, alternative approaches are needed.
bisphosphonate-associated osteonecrosis of the jaw; International Classification of Diseases; osteonecrosis of the jaw; osteoporosis; registries; validity
The availability of a once-a-year zoledronic acid infusion heralds a new era in the management of osteoporosis. It virtually eliminates the problem of poor compliance with orally administered bisphosphonates and, because it bypasses the gastrointestinal tract, it is not associated with gastrointestinal side effects. Zoledronic acid is effective for the treatment and prevention of postmenopausal osteoporosis, and for the treatment of osteoporosis in men, and glucocorticoid-induced osteoporosis. When administered within three months of a hip fracture, it reduces mortality and the risk of subsequent fractures. It is remarkably free of serious adverse effects. After administration of the intravenous infusion, about 18% of bisphosphonate-naïve patients experience an acute-phase reaction, including low-grade temperature, aches, and pains. This is reduced to about 9% in those who have been treated with oral bisphosphonates, and is further reduced by the concomitant and subsequent administration of acetaminophen. The likelihood and magnitude of the acute-phase reaction is less after the second infusion. Other adverse effects are similar to those encountered with other bisphosphonates. Because it is mostly excreted by the kidneys, zoledronic acid should not be administered to patients with a creatinine clearance less than 35 mL/min. It should not be administered to patients with hypocalcemia.
zoledronic acid; zoledronate; osteoporosis; osteopenia; bisphosphonates
Pharmacovigilance is like a sunshade to describe the processes for monitoring and evaluating ADRs and it is a key component of effective drug regulation systems, clinical practice and public health programmes. The number of Adverse Drug Reactions (ADRs) reported resulted in an increase in the volume of data handled, and to understand the pharmacovigilance, a high level of expertise is required to rapidly detect drug risks as well as to defend the product against an inappropriate removal. The current global network of pharmacovigilance centers, coordinated by the Uppsala Monitoring Centre, would be strengthened by an independent system of review. This would consider litigious and important drug safety issues that have the potential to affect public health adversely beyond national boundaries. Recently, pharmacovigilance has been confined, mainly to detect adverse drug events that were previously either unknown or poorly understood. Pharmacovigilance is an important and integral part of clinical research and these days it is growing in many countries. Today many pharmacovigilance centers are working for drug safety monitoring in this global pitch, however, at the turn of the millennium pharmacovigilance faces major challenges in aspect of better safety and monitoring of drugs. In this review we will discuss about drug safety, worldwide pharmacovigilance centers and their role, benefits and challenges of pharmacovigilance and its future consideration in healthcare sectors.
Drug safety; erice declaration; pharmacovigilance
To review the status of pharmacovigilance system among surgeons and in surgical wards with recommendations. Literature search using MEDLINE, cross-reference of published data and review of World Health Organization—Pharmacovigilance transcripts. Pharmacovigilance system is still in its infancy among surgeons and in surgical wards. No major studies have been published addressing this issue, till date. Surgeons are professionals least likely to report adverse drug reactions. Moreover widespread and irrational antibiotic use is contributing towards high incidence of adverse events apart from multidrug resistance. Lack of interest, funding and knowledge pose challenges in effective post marketing drug surveillance in surgery. A three tier proactive pharmacovigilance system in surgical wards is suggested along with specific recommendations. The pros and cons of adverse drug reporting among the surgeons are discussed. With growing awareness of pharmacovigilance in various fields of medicine, surgery can no longer remain an exception. In the transition from medical school to surgery clinic a subtle shift must occur from emphasizing pharmacokinetics to appreciating pharmacodynamics. This change in philosophy will occur at the level of instruction when the surgeons of tomorrow are motivated through regulatory and institutional means at school level to adopt pharmacovigilance in their clinical practices along with the practicing surgeons.
Pharmacovigilance; Pharmacodynamics; Adverse drug reactions; Surgery
Therapy based on androgenic deprivation is one of the standard treatments that many prostate cancer patients receive. Moreover, its use is increasing owing to a clear expansion of the indications for this therapy in patients with localized prostate cancer. Despite classically being considered to be well tolerated, androgenic deprivation has adverse effects. Of these, the loss of mineral bone mass is particularly notable and can lead to osteoporosis, as well as an increased risk of bone fracture. Some fractures, such as hip fractures, may have serious consequences. Useful procedures such as bone densitometry can aid in the diagnosis of these conditions. Once diagnosed, decreases in mineral bone mass can be managed by dietary recommendations, general changes in lifestyle or medication. We review the most important randomized controlled trials evaluating different drugs (bisphosphonates, denosumab and toremifene) in the prevention of bone loss and in the reduction in fracture risk in prostate cancer patients treated with androgen-deprivation therapy. Following the applicable recommendations, urologists must carefully monitor the bone health of prostate cancer patients subjected to androgenic deprivation to obtain an early diagnosis and apply the appropriate general and/or therapeutic measures if necessary.
androgen deprivation therapy; bisphosphonates; bone fracture; bone mass loss; calcium intake; osteoclast; osteoporosis; prostate cancer
The results of this study suggest that, under the assumption of same relative risk reduction of fractures in men as for women, strontium ranelate could be considered a cost-effective strategy compared with no treatment for the treatment of osteoporotic men from a Belgian healthcare payer perspective.
This study was conducted to estimate the cost-effectiveness of strontium ranelate in the treatment of osteoporotic men.
A previously validated Markov microsimulation model was adapted to estimate the cost (€2,010) per quality-adjusted life-year (QALY) gained of strontium ranelate compared with no treatment. Similar efficacy data on lumbar spine and femoral neck bone mineral density (BMD) between men with osteoporosis at high risk of fracture (MALEO Trial) and postmenopausal osteoporotic women (pivotal SOTI, TROPOS trials) supports the assumption, in the base-case analysis, of the same relative risk reduction of fractures in men as for women. Analyses were conducted, from a Belgian healthcare payer perspective, in the population from the MALEO Trial who is a men population with a mean age of 73 years, and BMD T-score ≤−2.5 or prevalent vertebral fracture (PVF).
In the MALEO population, strontium ranelate compared with no treatment was estimated at €49,798 and €25,584 per QALY gained using efficacy data from the intent-to-treat analysis and the per-protocol analysis including only adherent patients, respectively. In men with a BMD T-score ≤−2.5 or with PVF, the cost per QALY gained of strontium ranelate fall below thresholds of €45,000 and €25,000 per QALY gained based on efficacy data from the entire population of the clinical trial and from the per-protocol analyses, respectively.
The results of this study suggest that, under the assumption of same relative risk reduction of fractures in men as for women, strontium ranelate could be considered cost-effective compared with no treatment for male osteoporosis.
Cost-effectiveness; Fractures; Men; Osteoporosis; Strontium ranelate
Several categories of drugs to treat osteoporosis exist in the form of bisphosphonates, strontium, parathyroid hormone, and selective estrogen receptor modulators (SERM). Advantages and disadvantages exist for each category as some patients may, for example, not tolerate bisphosphonates for gastrointestinal side effects, and especially in women in whom osteoporosis is frequent, several options for treatment are needed. The objectives of this review were to critically appraise the effects of bazedoxifene on risk of fractures especially in women at high risk of fractures. A systematic literature search was conducted for studies, especially randomized controlled trials with fractures as end-points. Bazedoxifene is a new member of the SERM group. The literature search identified one randomized controlled trial with fractures as end-point. This was a 3-year randomized double-blind placebo controlled trial in which 7492 postmenopausal women aged 55 to 85 years were randomly allocated to 1) bazedoxifene (20 [n = 1886] or 40 [n = 1872] mg/day); 2) raloxifene (60 mg/day, n = 1849); or 3) placebo (n = 1885). The risk of vertebral fractures decreased with both 20 (HR 0.58, 95% CI 0.38 to 0.89) and 40 (HR 0.63, 95% CI 0.42 to 0.96) mg of bazedoxifene per day compared to placebo. There was no reduction in non-vertebral fractures. A subgroup of women with a priori high risk of fractures was identified post hoc. In this subgroup there was a reduction in the risk of non-vertebral fractures with the 20 mg dose of bazedoxifene compared to placebo (HR 0.50, 95% CI 0.28 to 0.90). In the 40 mg bazedoxifene group no significant reduction in non-vertebral fractures was seen in this subgroup (HR 0.70, 95% CI 0.40 to 1.20). In general post-hoc defined subgroup analyses should be interpreted with caution. However, the results indicate that bazedoxifene may be effective in preventing vertebral fractures in postmenopausal women with osteoporosis.
bazedoxifene; fracture; bone mineral density
Decreased bone mineral density and osteoporosis in postmenopausal women represents a growing source of physical limitations and financial concerns in our aging population. While appropriate medical treatments such as bisphosphonate drugs and hormone replacement therapy exist, they are associated with serious side effects such as osteonecrosis of the jaw or increased cardiovascular risk. In addition to calcium and vitamin D supplementation, previous studies have demonstrated a beneficial effect of dietary silicon on bone health. This study evaluated the absorption of silicon from bottled artesian aquifer water and its effect on markers of bone metabolism.
Seventeen postmenopausal women with low bone mass, but without osteopenia or osteoporosis as determined by dual x-ray absorptiometry (DEXA) were randomized to drink one liter daily of either purified water of low-silicon content (PW) or silicon-rich artesian aquifer water (SW) (86 mg/L silica) for 12 weeks. Urinary silicon and serum markers of bone metabolism were measured at baseline and after 12 weeks and analyzed with two-sided t-tests with p < 0.05 defined as significant.
The urinary silicon level increased significantly from 0.016 ± 0.010 mg/mg creatinine at baseline to 0.037 ± 0.014 mg/mg creatinine at week 12 in the SW group (p = 0.003), but there was no change for the PW group (0.010 ± 0.004 mg/mg creatinine at baseline vs. 0.009 ± 0.006 mg/mg creatinine at week 12, p = 0.679). The urinary silicon for the SW group was significantly higher in the silicon-rich water group compared to the purified water group (p < 0.01). NTx, a urinary marker of bone resorption did not change during the study and was not affected by the silicon water supplementation. No significant change was observed in the serum markers of bone formation compared to baseline measurements for either group.
These findings indicate that bottled water from artesian aquifers is a safe and effective way of providing easily absorbed dietary silicon to the body. Although the silicon did not affect bone turnover markers in the short-term, the mineral's potential as an alternative prevention or treatment to drug therapy for osteoporosis warrants further longer-term investigation in the future.
ClinicalTrials.gov Identifier: NCT01067508
Early osteoporotic fractures have a great impact on disease progression, the first fracture being a major risk factor for further fractures. Strontium ranelate efficacy against vertebral fractures is presently assessed in a subset of women aged 50–65 years.
The Spinal Osteoporosis Therapeutic Intervention (SOTI) was an international, double blind, placebo controlled trial, supporting the efficacy of strontium ranelate 2 g/day in reducing the risk of vertebral fractures in postmenopausal women with osteoporosis and a prevalent vertebral fracture. 353 of these randomly assigned women were included in this analysis.
Over 4 years, strontium ranelate significantly reduced the risk of vertebral fracture by 35% (relative risk 0.65; 95% CI 0.42 to 0.99, p<0.05). In the strontium ranelate group, the bone mineral density increased from baseline by 15.8% at lumbar spine and 7.1% at femoral neck.
These data demonstrate a significant vertebral antifracture efficacy of strontium ranelate in young postmenopausal women aged 50–65 years with severe osteoporosis and confirm the efficacy of this antiosteoporotic treatment to prevent vertebral fractures, whatever the age of the patient.
The introduction of bisphosphonates has increased in the last decade following their indication for metastatic bone diseases, osteoporosis, hypercalcaemia of malignancy and Paget’s disease. Although bisphosphonates have been used clinically for more than three decades there have been no documented long-term complications of their effects on the jaws until recently, where there is now growing evidence of the influence of bisphosphonates on osteonecrosis of the jaws. The aim of this paper is to report a case of this newly described complication, to review this phenomenon, including the clinical implications and to reiterate current clinical guidelines for management of patients in which bisphosphonate therapy is indicated. To the best of our knowledge this is the first reported case of bisphosphonate-induced necrosis of the jaw in South Africa.
Bisphosphonates; Osteonecrosis; Jaws
Strontium ranelate is a new orally administered agent for the treatment of women with postmenopausal osteoporosis that reduces the risk of vertebral and hip fractures. Evidence for the safety and efficacy of strontium ranelate comes from two large multinational trials, the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment Of Postmenopausal Osteoporosis) studies. The SOTI study evaluated vertebral fracture prevention in 1649 postmenopausal women with a mean age of 69 y. The subjects all had at least one previous vertebral fracture and a low spine bone mineral density (BMD) (equivalent to a Hologic spine T-score below −1.9). The strontium ranelate group had a 41% lower risk of a new vertebral fracture than the placebo group over the three-year study period (relative risk [RR]=0.59; 95% confidence interval [CI]: 0.48–0.73; p<0.001). The TROPOS study evaluated non-vertebral fracture prevention in 5091 postmenopausal women with a mean age of 77 y. The subjects were aged 74 y and over (or 70–74 y with one additional risk factor) and a low femoral neck BMD (equivalent to an NHANES III [Third National Health and Nutrition Examination Survey] T-score below −2.2). Over the three-year study period there was a 16% reduction in all non-vertebral fractures (RR=0.84; 95% CI 0.702–0.995; p=0.04) and a 19% reduction at the principal sites for non-vertebral fractures. The TROPOS study was not powered to investigate hip fracture risk. However, in a high risk group of women aged 74 y and over and with an NHANES III femoral neck T-score less than −2.4 there was a 36% reduction in hip fracture risk (RR=0.64; 95% CI: 0.412–0.997; p=0.046). The overall incidence of adverse events did not differ significantly from placebo and were generally mild and transient, the most common being nausea and diarrhea. Strontium ranelate is a useful addition to the range of anti-fracture treatments available for treating postmenopausal women with osteoporosis and is the only treatment proven to be effective at preventing both vertebral and hip fractures in women aged 80 y and over.
Strontium ranelate; osteoporosis treatment; postmenopausal women; vertebral fracture prevention; hip fracture prevention