Relative fracture risk in NICE meta-analysis
\r\n\tThis book will be a self-contained collection of scholarly papers targeting an audience of practicing researchers, academics, PhD students and other scientists. The contents of the book will be written by multiple authors and edited by experts in the field. The area of interest and scope of the project can be described with (but are not limited to) the following keywords: Alcoholism, Depression, Addiction, Blackouts, Relapse, Binge Drinking, Genetic basis, Neurological Aspects, Treatment, Organ Damage.
\r\n\r\n\tAuthors are not limited in terms of topic, but encouraged to present a chapter proposal that best suits their current research efforts. Later, when all chapter proposals are collected, the editor will provide a more specific direction of the book.
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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"47990",title:"Pharmacological Treatment of Osteoporosis",doi:"10.5772/59469",slug:"pharmacological-treatment-of-osteoporosis-",body:'Osteoporosis can be divided into two principle strands, clinical osteoporosis and densitometric osteoporosis. Clinical osteoporosis involves the identification of a fragility fracture and does not need densitometry for treatment to begin. Densitometric osteoporosis is identified via an assessment of bone mineral density. Approaches to treatment depend on the global fracture risk and the outcomes of densitometric tests.
The initial stage of the pharmacological treatment of osteoporosis is to identify the pathology of the primary condition or to determine whether the loss of bone density is a secondary symptom of a separate condition. Where secondary osteoporosis is identified, priority is given to the treatment of the primary condition. The option of pharmacological therapy must only be contemplated if the risk of fracture is too elevated, given that the intention behind pharmacological treatment in osteoporosis is to reduce the fracture risk. Based on World Health Organization figures, less than half of patients presenting a fragility fracture have been diagnosed with densitometric osteoporosis [1]. Once a course of medication has begun, long-term management must address improvements to lifestyle and take aspects of, security, cost, and compliance into account. As such, it is absolutely necessary to assess and make determinations on the basis of cost, assessment of cost-efficiency, and the adaptability of patients to drug security.
Calcitonin binds to osteoclasts and hinders bone resorption. The use of salmon calcitonin has previously been widespread as a result of its extreme potency in humans, a result of its greater affinity for the human calcitonin receptor.
Calcitonin is now no longer a treatment for osteoporosis, having been supplanted by other treatments. Following a European risk-benefit analysis, the scientific committee of the European Medicines Agency (CHMP) advised that treatments using calcitonin should only be deployed in short-term scenarios.. Treatments using injectable calcitonin should be confined to the short-term in Paget\'s disease, the prevention of acute bone loss as a result of sudden immobilization and hypercalcemia resulting from cancer. In addition to this, calcitonin has been proven to be effective in treating pain resulting from fractures of the vertebral column. [2-4]
HRT is a form of treatment which deploys varying doses of estrogen, sometimes on its own, sometimes in combination with progestagens. The calculated risk of fracture, based on principal cohort trials of postmenopausal women treated with HRT over the long term, indicate an appreciable lowering of the likelihood of both vertebral fracture (RR=0.6; CI 95%: 0.36 to 0.99) and wrist fracture (RR=0.39; CI 95%: 0.24 to 0.64), but a non-significant lowering of the likelihood of hip fracture (RR=0.64; CI 95%: 0.32 to 1.04). The WHI trial (Women\'s Health Initiative), a randomised clinical trial (RCT) that assessed postmenopausal women randomly assigned to combined HRT (combined equine estrogen 0.625mg daily plus medroxyprogesterone 2.5mg daily) or a placebo, recorded, following 5.2 years of treatment, a decrease in hip fracture risk of 34% (hazard ratio [HR]=0.66; CI 95%: 0.45 to 0.98), in clinical vertebral fractures of 34% (HR=0.66; CI 95%: 0.44 to 0.98) and in any fracture of 24% (HR=0.76; CI 95%: 0.69 to 0.85) [5,6]. In the same investigation, the cohort taking estrogen on its own demonstrated comparable outcomes, however the treatment was put on hold as a result of an adverse risk-benefit ratio. In two meta-analyses of RCT’s, a decrease of 27% (RR=0.73; CI 95%: 0.56 to 0.94) in non-vertebral fractures and a trend towards a reduction of vertebral fractures (RR=0.66; CI 95%: 0.41 to 1.07) was recorded [7]. Nonetheless, neither the HERS (The Heart and Estrogen + Progestin Replacement Study) RCT nor the subsequent group, the HERS II study (Hulley et al., 1998), were able to register a decrease of the risk of hip fractures or of other locations (RR=1.04; CI 95%: 0.87 to 1.25) in patients with a history of cardiovascular disease [8].
The British National Institute of Health and Clinical Excellence published a meta-analysis of RCTs on HRT efficacy (with estrogen alone or combined) compared with placebo/non-treatment in postmenopausal women or those with surgical menopause [9]. The outcomes were organised according to the location of the fracture and the RCT used as the basis for the calculation of the relative risk was also identified. The outcomes are outlined in table 1.
\n\t\t\t\tFracture Location\n\t\t\t | \n\t\t\t\n\t\t\t\tNr of RCTs\n\t\t\t | \n\t\t\t\n\t\t\t\tn\n\t\t\t | \n\t\t\t\n\t\t\t\tRESULTS\n\t\t\t | \n\t\t\t\n\t\t\t\tReferences\n\t\t\t | \n\t\t
Vertebral fracture | \n\t\t\t4 RCTs | \n\t\t\t11,842 | \n\t\t\tRR=0.55; CI 95%: 0.46 to 0.66 | \n\t\t\t[10-13] | \n\t\t
Non-vertebral fracture | \n\t\t\t3 RCTs | \n\t\t\t11,774 | \n\t\t\tRR=0.73; CI 95%: 0.65 to 0.81 | \n\t\t\t[10, 11,14] | \n\t\t
Hip fracture | \n\t\t\t2 RCTs | \n\t\t\t11,745 | \n\t\t\tRR=0.63; CI 95%: 0.42 to 0.93 | \n\t\t\t[11,14] | \n\t\t
Any type of fracture | \n\t\t\t3 RCTs | \n\t\t\t11,556 | \n\t\t\tRR=0.70; CI 95%: 0.63 to 0.78 | \n\t\t\t[14-16] | \n\t\t
Relative fracture risk in NICE meta-analysis
A thorough and methodical review of five RCTs looking at HRT with estrogen and two looking at combined HRT estrogen plus progesterone, failed to display compelling variance in the occurrence of acute coronary events (including acute myocardial infarction) between the cohort subject to intervention and the control cohort [7]. A combination of the outcomes of three studies contrasting estrogenic therapy to a placebo [11, 17] reported an odds ratio (OR) of 1.34 (IC 95%: 1.07 to 1.68) for cerebral vascular events. The combined outcomes of the studies that contrasted estrogen plus progesterone combined treatment with a placebo [5, 18], indicated an elevated risk of ictus (OR=1.28; CI 95%: 1.05 to 1.57) in the cohort subject to intervention. Out of four thorough and methodical reviews of observational trials looking at women treated with HRT [19-22], three of these indicated a significant decrease in the global mortality risk for acute coronary events. A recently published, thorough and methodical review, that compensated for selection bias of inclusion and analysis, did not reveal any link between the THS and the incidence, and mortality of acute coronary events [22].
The WHI primary prevention trial indicated a distinct elevation of the risk of acute coronary events (41%), starting the second year of treatment (29 instances in the treatment cohort, compared with 21 instances for 10,000 women per year in the general population) [5]. This elevated risk was greater in non-mortal coronary incidents (RR=1.50; CI 95%: 1.08 to 2.08) than in the mortal coronary incidents (RR=1.20; CI 95%: 0.58 to 2.50). The RCTs of HRT with estrogens alone, in both primary and secondary prevention, failed to indicate any positive impact on cerebrovascular illness [23]. In addition, the WHI study cohort with estrogen indicated an elevated risk of cerebrovascular incidents.
In a thorough and methodical review, McLean et al. indicated that estrogen patients treated with estrogen demonstrate an elevated risk of major venous thromboembolic incidents (OR=1.36; CI 95%: 1.01 to 1.86) compared to the placebo cohort [7]. A further thorough and methodical review assessing the impact of HRT (estrogen with or without progestagens) encompassed 12 studies (3 RCTs, 8 case-control studies and 1 cohort study) and indicated an elevated risk of thromboembolism (RR=2.14; CI 95%: 1.64 to 2.81). This risk was elevated in the first two years of the therapy and it varied according to the dose [24].
A thorough and methodical review of 4 RCTs proved that patients treated with estrogens alone have a lower risk of breast cancer (OR=0.79; CI 95%: 0.66 to 0.93) than those treated with the placebo [7]. On the other hand, patients treated with estrogen and progestin have a higher risk of breast cancer (OR=1.28; CI 95%: 1.03 to 1.60) than those treated with the placebo [5, 18, 24].
Nonetheless the combined HRT cohort of the WHI study presented an elevated risk of invasive breast cancer [5]. This elevated risk occurred following the fourth year of treatment (RR=1.26; CI 95 %: 1.0 to 1.59), with a propensity to rise in line with the treatment’s longevity (38 instances compared with 30 for 10,000 women per year).
The treatment of estrogen alone elevates the risk of subsequent endometrial hyperplasia and cancer [25,26]. A meta-analysis including 29 observational studies reported a demonstrable elevation of the risk of endometrial cancer, with or without combined estrogens (RR=2.3; CI 95%: 2.1 to 2.5) [20]. This risk is directly related to the treatment’s longevity and continues to be raised for a maximum of 5 years or more following the termination of treatment.
Recently published thorough and methodical reviews of observational trials indicate an elevated incidence of ovarian cancer amongst women undergoing treatment, particularly long-term therapies (more than 10 years) [28,28]. Two cohort trials of postmenopausal women who underwent treatment for a period of more than 10 years corroborate this elevated risk of ovarian cancer (RR=2.2; CI 95%: 1.53 to 3.17), as well as an elevated mortality risk (RR=1.59; CI 95%: 1.13 to 2.25) [29, 30].
We can conclude that HRT is an effective therapy both for postmenopausal osteoporosis and for the management of fracture risk. Nevertheless, even taking this conclusion into account, the use of combined HRT is not recommeneded for periods greater than 5 years, given the possible risk factors linked with treatments using a daily dose equivalent to 50 pg of estradiol. When HRT treatment is indicated, it should be prescribed at a low dosage (equivalent to estrogen transdermal patches of 25 mcg), only using higher doses if it is absolutely essential to do so. Estrogens and progestagens are only advised for the treatment of women with intact uteri. The level of the progestagen dose should be determined on the basis of the estrogen dose. In instances where a hysterectomy was carried out as a result of endometrial cancer, HRT should not involve combined estrogen and progestagens. Continuous combined HRT treatment should only commence following one whole year of menopause.
Selective estrogen receptor modulators are medications with a selective impact on the estrogen receptor. They can function as estrogen receptor (ER) agonists in some tissues while in other tissues functioning as estrogen receptor antagonists. As a result of their selective estrogen-agonist behaviour within a variety of tissues, SERMs may be indicated as an alternative option for the prevention or treatment of conditions like osteoporosis, which are the result of a deficiency of estrogen, where avoiding the negatives effects of estrogens is a priority.
At present there are two forms of SERM, which are distinguished by their chemical structure: triphenylethylene derivatives, for example tamoxifen and toremifene, and benzothiophene derivatives, for example raloxifene and bazedoxifene. Tamoxifen and toremifene on the one hand are indicated for use in the treatment of breast cancer. Raloxifene on the other hand is used for the prevention and treatment of osteoporosis and in addition the prevention of breast cancer. All SERMs have been linked with an elevated occurrence of pulmonary thromboembolism and with the start of hot flushes, however they also impact in a positive manner on the lipid profile.
The SERMs vary distinctively with regards to tissue specificity. Bazedoxifene appears to have a lower impact on the uterus than estradiol jointly with raloxifene in animal experiments as a result of reduced estrogen receptor alpha agonistic effects.
Raloxifene acts as estrogen agonist in bone and other systems but not in reproductive tissue. Many trials have proved the effectiveness of raloxifene for preserving bone in the early postmenopausal phase. In a meta-analysis of seven studies (four treatment and three prevention studies) which looked at the impact of raloxifene versus a placebo on bone mineral density, raloxifene augmented bone mineral density within the lumbar spine following a two year period of treatment [31]. A trial of 601 women, five years following the menopause, who were given a daily dose of 30, 60 or 150mg of raloxifene over two years, indicated an augmentation of their bone mineral density in spine and hip, whereas those subjected to the placebo presented reduced bone mineral density in the same locations [32]. In contrast with the results from the placebo, the average alteration in BMD with 60mg of raloxifene was 2.4% in the spine and 2.4% at the total hip (p<0.001 versus placebo). Postmenopausal women presenting low bone mass and osteoporosis were monitored over eight years in the study entitled ‘Multiple Outcomes of Raloxifene Evaluation’ (MORE, n=7,705) and its sister trial entitled ‘Continuing Outcomes Relevant to Evista’ (CORE, n=4,011) [33]. In relation to fractures, whilst raloxifene treatment led to a decreased risk of vertebral fracture, it failed to demonstrate a reduced risk of non-vertebral fractures. Nevertheless, in a meta-analysis of RCTs contrasting the effects of raloxifene with those of a placebo, raloxifene typically led to a decreased risk of vertebral fractures in postmenopausal women (OR=0.6; CI 95%: 0.5-0.7).
The results of the MORE trial indicated that, following a raloxifene treatment period of four years, at 60mg per day, the cumulative relative risk of one or more vertebral fractures was 0.64 (IC 95%: 0.53 - 0.76), compared with treatment using a placebo.
Verus placebo, treatment with 60mg of raloxifene was also linked to a decrease of 65% to 78% in occurrences of invasive breast cancer and invasive breast cancer with positive estrogen receptor (both p <0.05).
The MORE and CORE studies reported a link between raloxifene and an elevated incidence (1.7 times) of thromboembolism (TE), versus treatment using a placebo (95% CI: 0.93-3.14; risk difference total of 0.9/1,000 women-years) [34]. In a meta-analysis of nine trials, raloxifene treatment was linked with an elevated incidence of deep venous thrombosis and pulmonary embolism (OR=1.5; CI 95%: 1.1-2.1 and OR=1.9; 95% CI: 1.0-3.5, respectively) [35]. The RUTH trial (‘Raloxifene Use for The Heart’), which studied 10,101 postmenopausal women with an average age of 68 and presenting with coronary heart disease, indicated a link between raloxifene and an elevated incidence of fatal stroke (HR=1.49; 95% CI: 1.00-2.24, a rise in the absolute risk of 0.7/1,000 women-years) as well as an elevated risk of thromboembolism (HR=1.44; 95% CI: 1.06-1.95, a rise in the absolute risk of 1.2/1,000 women-years) in comparison with the placebo results. No elevated risk of myocardial infarction or other coronary events was indicated in the RUTH trial. Nevertheless, in line with the observations regarding thromboembolism and pulmonary embolism, the outcomes of a recent review of a sub-cohort of the trial indicated that age had an impact on the occurrence of coronary events. For women of 60 years or under, the rate of occurrence of coronary events was distinctly reduced with raloxifene (50 cases), compared with the placebo group (84 cases; HR=0.59; 95% CI: 0.41 to 0.83, p=0.003). Raloxifene was also linked with an elevated occurrence of hot flushes, especially amongst women with recent menopause onset [36].
We can conclude that raloxifene provides an alternative option within osteoporosis therapies for specific patients. The drug’s profile relating to heart disease and breast cancer is sound but its links to an elevated risk of venous thrombosis should be taken into account in its use as a treatment.
Bazedoxifene is a third-generation SERM. Some key differences have been demonstrated between the generations regarding their impact on the uterus and on breast tissue in particular [37]. The drug was developed with raloxifene as a template and by replacing the benzothiophene core with an indole ring [38].
In a phase II trial of healthy postmenopausal women, oral doses of bazedoxifene 2.5, 5, 10, 20, 30, or 40mg per day were as a rule well-tolerated and did not aggravate the endometrium. In addition, bazedoxifene 30 and 40 mg resulted in a notably reduced increase in the thickness of the endometrium and distinctly lowered the occurrence of uterine bleeding versus results from the placebo. In a two-year phase III trial of postmenopausal women at risk of osteoporosis, bazedoxifene 10, 20, and 40mg were proven to prevent bone loss and decrease bone turnover and were linked with a positive endometrial, ovarian, and breast security profile [39, 40].
A phase III, multi-centre, double-blind, randomised, controlled trial was formulated with the sole purpose of assessing the effectiveness of bazedoxifene in fracture prevention. The trial looked at 7,492 healthy postmenopausal women presenting with osteoporosis both with or without prevalent vertebral fractures. The women were randomly assigned to 20 or 40mg per day of bazedoxifene, 60mg of raloxifene, or to a placebo plus 1200mg of calcium and 400IU of vitamin D. The primary outcome was the occurrence of new vertebral fractures following a three-year treatment period. Secondary indicators included clinical vertebral fractures, worsening of vertebral fractures, non-vertebral fractures, breast cancer incidence, and variations in height. Both bazedoxifene 20 and 40mg reduced the occurrence of vertebral fractures to a similar extent as raloxifene versus the placebo. The occurrence at 36 months of new vertebral fractures was 2.3%, 2.5%, 2.3%, and 4.1% in the bazedoxifene 20mg, bazedoxifene 40mg, raloxifene 60mg, and placebo cohorts, respectively, with a distinct lowering of the relative incidence for new vertebral fractures of 42%, 37%, and 42%, respectively, versus placebo. There was no overall impact on non-vertebral fractures, with incidence rates of 5.7% and 5.6% for the bazedoxifene 20 and 40mg cohorts, respectively, versus 5.9% for the raloxifene cohort and 6.3% for the placebo cohort. Nevertheless, in a later review of women with elevated fracture risk (poor femoral neck T-score and multiple vertebral fractures, n=1,772), bazedoxifene 20mg reduced the incidence of non-vertebral fracture by 50% and 44% reduction relative to the placebo (HR=0.50; 95% CI: 0.28–0.90; p=0.02) and raloxifene 60mg (HR=0.56; 95% CI: 0.31–1.01; p=0.05), respectively [41].
Miller et al. demonstrated that deep venous thromboembolism was uncommon with bazedoxifene (0% to 0.6% with varying dosage levels after two years) and similar to the placebo (0.3%). The rate of occurrence and the intensity of hot flushes were comparable with raloxifene, but slightly elevated versus placebo [40]. In the trial by Silverman et al., leg cramps (10.9% to 11.7% with varying dosage after three years) and deep venous thromboembolism (0.4% to 0.5% with varying dosage after three years) were decidedly more prevalent with bazedoxifene compared with the placebo (8.2% for leg cramps and 0.2% for deep venous thromboembolism), while fibrocystic breast disease was markedly less frequent. No distinction in risk levels between bazedoxifene and placebo was noted for myocardial infarction, strokes (ischemic or hemorraghic), or retinal vein thrombosis [40-43].
We can conclude that bazedoxifene appears to have improved selectivity in contrast with other SERMs. The impact of bazedoxifene on the skeleton is not dissimilar to raloxifene, and bazedoxifene may be employed in the same way as raloxifene. The usefulness of bazedoxifene possibly lies in its risk profile being distinct to that of raloxifene, particularly with regards to uterine safety, and bazedoxifene may therefore present another option for the prevention and treatment of osteoporosis.
Lasofoxifene is a powerful third-generation SERM. It has a distinct structure compared to first- and second-generation SERMs (raloxifene, tamoxifen and clomiphene or idoxifene). Lasofoxifene displays powerful estrogenic and anti-estrogenic activity in vitro and in vivo, targeting any areas with estrogens receptors, including bone, uterus, breast, blood vessels, and liver. Lasofoxifene has been analysed in postmenopausal women with regards to the prevention and treatment of osteoporosis. Security and tolerance levels of lasofoxifene is similar to that of raloxifene, however nonadherence rates as a result of adverse events are greater with lasofoxifene. Despite these indications, results demonstrate that lasofoxifene treatment may lead to greater endometrial thickness versus the placebo, despite there being no evidence of an elevated incidence of endometrial hyperplasia or cancer.
The PEARL study, a three-year pivotal fracture study, showed that lasofoxifene elevated lumbar spine and femoral neck BMD by approximately 3%. Furthermore, vertebral fractures saw a decrease of 42%, and non-vertebral fractures of 27%, with a decrease in markers of bone turnover. Nevertheless, lasofoxifene did not reduce the risk of hip fractures [43].
Bisphosphonates are a member of a class of antiresorptive agents whose antifracture action is well-documented through randomised controlled studies. There have been no studies to compare different bisphosphonates, a fact which has prevented the identification of a definite order of effectiveness for treatment.
Bisphosphonates lower fracture risk as a result of its inhibitory action of osteoclasts, which enables the osteoblasts to synthesize bone in the resorption spaces and some bone lacunae. This produces an augmentation in bone mass. However, the bisphosphonates also increase bone quality, by conserving the bone architecture, as demonstrated in studies which have analysed the biopsies of treated patients and control subjects.
Bisphosphonates comprise pyrophosphate analogs in which the central oxygen has been replaced by a carbon atom and two side chains (R1 and R2). Two phosphate chains are vital to enable the drug to bind to bone and to have an antiresorptive effect.
Etidronate was the original bisphosphonate used in osteoporosis therapy. It is no longer used in current practice. Its greatest asset is most likely its cost. It augments bone mass in the spine and femur and lowers the risk of vertebral fractures, however it has not demonstrated a reduction in the incidence of femoral fractures [44,45].
Clodronate has been deployed in postmenopausal osteoporosis therapy in oral and intravenous treatments. The trials indicate that it reduces the risk of bone loss in the vertebral spine in comparison to control subjects, and it presents similar results to estrogens after two years. In a six-year long study, it was also demonstrated to lower the incidence rate of vertebral fractures. McCloskey et al. carried out a three-year, double-blind, controlled study to observe the impact of oral clodronate (800mg per day) on fracture rates. In this study, clodronate was linked with a distinct improvement in the mean lumbar spine and hip BMD. Furthermore, it significantly lowered the risk of vertebral fracture (relative risk, 0,54; 95% CI, 0,37-0,80; p<0,0001). Despite these outcomes, subsequent to the introduction of powerful nitrogen bisphosphonates, the first-generation bisphosphonates have been reduced to a therapy of last resort [46].
Alendronate is one of the most commonly deployed bisphosphonates. It augments vertebral bone mass approximately 6-8% and 3-6% at the hip in postmenopausal osteoporotic women after a three-year treatment. It demonstrates a reduction in vertebral and non-vertebral fractures of around 50% in this time period. In male osteoporosis, it has demonstrated improvements in bone mass of 5% after two years of treatment.
Alendronate is given orally, in doses of 70mg/week, fasting with 200 ml of water. The patient is prohibited from consuming solids or liquids for 30 minutes after treatment and must remain standing for this time.
The decisive study of alendronate, the FIT (Fracture Intervention Trial), demonstrated that the incidence of clinical fracture was reduced for the alendronate cohort compared to the control cohort (139 (13.6%) versus 183 (18.2%); relative hazard=0.72 (0.58-0.90)). The corresponding risk of hip and wrist fracture for the alendronate cohort when compared to the placebo cohort were 0.49 (0.23-0.99) and 0.52 (0.31-0.87) [47]. Ensrud et al. provided an assessment of a subset of FIT subjects who were patients with an elevated risk of fracture. The outcomes of this analysis demonstrate a decisive 47% lowering of the risk of new vertebral fractures in the alendronate cohort when set against the control cohort. A number of other papers have been generated from the FIT study, addressing multiple symptomatic fractures, bone mineral density, biochemical markers of formation and resorption, fracture prevention in osteopenic women, impact of alendronate continuation versus discontinuation, and the impact on women who lost bone over the course of treatment [48-51].
We can conclude that alendronate is a well-tolerated, secure and efficacious treatment method for postmenopausal osteoporosis, male osteoporosis, and glucocorticoid induced osteoporosis (GIOP).
This treatment has been proven to improve bone mass in spine and hip and to considerably lower the incidence of fracture in postmenopausal women. Treatment of postmenopausal women with osteoporosis with risedronate over a three-year period has produced a reduction in the risk of vertebral fractures in roughly 50% and non-vertebral fractures in 39% of subjects. At the hip, the fracture reduction rate is between 40 and 60%. After a five-year period, the outcomes are comparable. The treatment has demonstrated its anti-fracture efficacy after a six-month course. In other trials it has been proven that this reduction in risk was still present following a seven-year period of treatment, and was accompanied by a positive security profile. One of the principal studies of risedronate [52] looked at 5,445 women aged 70 to 79 years with osteoporosis (T-score at the femoral neck greater than -4 SD below the mean or lower than -3 plus a non-skeletal risk factor for hip fracture, such as poor gait or a tendency to fall) and 3,886 women aged at least 80 years with a minimum of one non-skeletal risk factor for hip fracture or poor BMD at the femoral neck (T-score below -4 or below -3 plus a hip-axis length of 11.1cm or greater). The subjects were given a treatment at random of either oral risedronate (2.5 or 5.0mg per day) or a placebo, over a three-year period. The outcomes indicated that the risk of hip fracture among subjects given risedronate was 2.8%, versus 3.9% among those given the placebo (relative risk, 0.7; 95% CI, 0.6 to 0.9; p=0.02). In the cohort of women with osteoporosis (70 to 79 years old), the risk of hip fracture among subjects given risedronate was 1.9%, versus 3.2% among subjects given the placebo (relative risk, 0.6; 95% CI, 0.4 to 0.9; p=0.009). In the cohort of subjects chosen principally for non-skeletal risk factors (those at least 80 years old), the risk of hip fracture was 4.2% for subjects given risedronate and 5.1% for those given the placebo (p=0.35) [52].
To assess the impact on vertebral fracture risk, Reginster et al. carried out a randomised, double-blind, controlled trial to evaluate the effectiveness and security of risedronate for reducing the risk of vertebral fractures in postmenopausal women with established osteoporosis. The trial was carried out at 80 locations in Europe and Australia. In total, 1,226 postmenopausal women with two or more prevalent vertebral fractures were given risedronate 2.5mg or 5mg per day or a placebo. Whilst the trial was carried out over three years, the 2.5mg cohort was ended by protocol amendment after two years. Risedronate 5mg lowered the incidence of new vertebral fractures by 49% over three years in comparison with the placebo (p<0.001). A distinct decrease of 61% was witnessed over the initial year alone (p=0.001). The decreased incidence of fracture was comparable in both cohorts after two years. The incidences of non-vertebral fracture saw a decrease of 33% in relation to the placebo figures over three years (p=0.06). Risedronate produced a distinct elevation in BMD at the spine and hip within a six-month period. We can conclude that risedronate 5mg was an efficacious and well-tolerated treatment for severe postmenopausal osteoporosis, decreasing the risk of vertebral fractures and increasing bone density in women with chronic osteoporosis [53].
In trials lasting three years, ibandronate has been proven to decrease the risk of vertebral fractures (52%) and improve vertebral BMD (6.5%) whilst not having a substantial negative impact on bone histology. It has also shown to be very efficacious in reducing bone loss in GIOP (glucocorticoid induced osteoporosis). In women with severe osteoporosis T scores (<-3), it decreases the risk of non-vertebral fractures up to 69% [54].
Randomised clinical studies such as MOPS (Monthly Oral Pilot Study) or MOBILE (Monthly Oral Ibandronate in Ladies) have indicated that the ibandronate monthly dosage is just as efficacious and safe as the daily dosage. Amongst the general population of the pivotal trial (BONE, Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe), the likelihood of adverse incidents of the gastrointestinal tract in both the daily and the intermittent treatment cohorts was similar to the control cohort. Dyspepsia was the only adverse incident with a marginally greater rate in subjects undergoing therapy with ibandronate [55].
Zoledronic acid is a third-generation bisphosphonate. It is roughly as powerful as alendronate, risedronate and ibandronate, however the application of this drug intravenously prevents any negative impact and in fact augments the bioavailability, whilst also improving compliance to 100%.
The HORIZON trial (Health Outcomes and Reduced Incidence with Zoledonic Acid Once Yearly Pivotal Fracture Trial) was a global, multi-centre, double-blind, controlled study of postmenopausal women with osteoporosis, whose goal was to demonstrate the increase efficacy of intravenous zoledronic acid 5mg compared with a control. Subjects presented with densitometric osteoporosis or densitometric osteopenia with a minimum of 2 mild to moderate vertebral fractures [56]. Over 7,700 women were involved in the trial and were monitored over a three-year period; particular scrutiny was made of new fractures, bone remodeling biochemical markers and densitometric developments. On completion of the trial, subjects that had been treated with zoledronic acid presented a decrease in the vertebral fracture risk of 70%. The decrease was comparable for the first two years of the trial, varying from 60% to 71%. In addition, subjects given zoledronate presented a decrease of 41% in hip fracture incidence and 25% in non-vertebral fracture incidence. The outcomes of bone density and biochemical bone remodeling markers were also markedly improved for the cohort given zoledronic acid. Furthermore, bone mineral density was elevated to over 6% in the lumbar spine and total hip, and to over 5% in the femoral neck. The biochemical markers of bone remodeling, after the initial transfusion of zoledronic acid, decreased significantly as anticipated, and stayed stable throughout the remainder of the trial [57].
Many subjects experienced adverse effects over the course of the trial, with a greater occurrence of these in the zoledronate cohort. This variance was explained by post-infusion syndrome, which commonly manifested itself 24-48 hours after the zoledronic acid infusion and dissipated three days after infusion. The syndrome presented with mild fever, myalgias, flu-like symptoms, headache and/or arthralgias and was dissipated with analgesic, non-steroid anti-inflammatory drugs or acetaminophen. A few subjects presented with passing renal function deterioration 9 to 11 days post-infusion, however these instances were of no clinical transcendence [57].
Perhaps the most significant conclusion in relation to zoledronate therapy is the 28% decrease in mortality of any cause, which was demonstrated in a cohort of over 2,000 subjects with femur fracture [56].
We can conclude that zoledronate therapy is extremely efficacious in the reduction of vertebral, non-vertebral and hip fractures. It reduces mortality, independent of the cause, following a femur fracture.Moreover, it is a low-risk therapy that avoids the gastrointestinal adverse events and high nonadherence rates that are commonly encountered with other bisphosphonates, but it should be dispensed and regulated with great caution when treating individuals with severe renal function impairment.
This class of treatments is usually well-tolerated, provided that they are administered carefully and that patients adhere to the instructions for their use. Esophageal ulcerations been encountered in situations where these treatments are given orally and on a daily basis. They must not be given to patients with gastric or esophageal ulcerations, or to patients with pyrosis (heartburn) which requires treatment. They must not be administered to pregnant women, or to individuals with chronic renal impairment. The intravenous bisphosphonates normally give rise to acute phase reactions with fever, arthromyalgia and flu-like symptoms that commonly dissipate before the second dosage and which can be mitigated by giving acetaminophen or ibuprofen concurrently. Hypocalcaemia can present more frequently, so it is advisable to give calcium and vitamin D concurrently. The renal function has to be regulated both prior to and following treatments of intravenous bisphosphonates.
The avascular necrosis of the jaw, also called osteonecrosis of the jaw, is a condition which has concerned many practitioners since Marx identified it for the first time in 2003 and it ought to be outlined more completely in another chapter [58].
Research linking atypical fractures of the femur with longstanding treatments of bisphosphonates caused the American Society for Bone and Mineral Research (ASBMR) to launch an enquiry to consider the important queries raised by the conclusions of this research. The enquiry’s committee identified both major and minor features of incomplete and complete atypical femoral fractures and advised that all significant features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, little or no associated trauma, a medial spike when the fracture is complete, and lack of comminution, be discernible in order to designate a femoral fracture as atypical. Minor features include the fracture’s relationship with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, co-morbid conditions, and concurrent drug usage, including bisphosphonates, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. On the strength of published and unpublished information and the wide application of bisphosphonates, the occurrence of atypical femoral fractures linked with bisphosphonate use for osteoporosis seems to be decidedly uncommon, especially in relation to the extent to which vertebral, hip, and other fractures are in turn prevented. Moreover, a causal link between bisphosphonates and atypical fractures has not been demonstrated. Nevertheless, new investigations infer that the incidence rate increases with longer periods of therapy, and there is a feeling of unease that a lack of understanding and underreporting could be hiding the true extent of the issue.
A 2008 trial of 12,777 Swedish women aged 55 years or more with a fracture of the femur was made public recently. Radiographs of 1,234 of 1,271 women presenting a subtrochanteric or shaft fracture were analysed. Fifty-nine subjects with atypical fractures were isolated. The relative and absolute incidence of atypical fractures linked with bisphosphonate treatment was calculated using a national cohort analysis. The 59 subjects were also subject to a comparison with 263 control subjects who presented typical subtrochanteric or shaft fractures. The cohort analysis indicated an age-adjusted proportional risk of atypical fracture of 47.3. The rise in global risk was 5 instances per 10,000 patient-years. In total, 78% of the fractured patients and 10% of the controls had been given bisphosphonates (multivariable-adjusted odds ratio of 33.3). The incidence level was independent of coexisting ailments. Following cessation of treatment, the incidence level was reduced by 70% per year from the time of last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38) [59].
Conditions that give rise to bone loss, like osteoporosis, are caused by the imbalance in the cycles of bone remodeling favouring bone resorption. The receptor activator of the nuclear factor kB (RANK), and its ligand (RANKL) are critical for the differentiation, activation and survival of osteoclasts and, as a result are the most simple intermediary in the regulating of bone remodeling (Burgess et al.1999). It has been proven that the signaling of the RANKL is inherent to the pathophysiology of many bone loss conditions, such as primary and many secondary forms of osteoporosis.
Denosumab is a fully human monoclonal IgG2 antibody to RANKL that imitates the effects of osteoprotegerine (OPG), endogenous inhibitor of RANKL that blocks bone resorption.
Comercial denosumab is sold as a sterile, uncolored solution administered via subcutaneous injection.
Data is accessible from more than 50 clinical studies in healthy adults and patients with osteoporosis, bone loss linked with hormone-ablation treatments, rheumatoid arthritis, advanced cancer (multiple myeloma and advanced malignancies that involve bone and giant cell tumor of the bone collected since June 2001).
In the Denosumab Fortifies Bone Density (DEFEND) trial, a phase III, randomised, controlled trial of 332 postmenopausal women with osteopenia sorted by the length of menopause (<5 years, >5 years), denosumab showed a distinctive rise in lumbar BMD (6.5%) at the two-year point, in relation to the control (-0.6%). It also raised BMD in other sites including total hip, distal third of the radius, and whole body (p>0.001) in the two cohorts. The rate of side effects was comparable between the control cohort and the denosumab cohort [60].
In a comparative clinical study, the DECIDE (Determining Efficacy: Comparison of Initiating Denosumab vs. Alendronate) trial of 1,189 postmenopausal women with low BMD (T-score: ≤-2 SD), subjects were randomly allocated 1:1 to two groups, one to be given subcutaneous denosumab (60mg per 6 months) plus an oral alendronate placebo weekly or oral alendronate weekly (70mg) plus a subcutaneous denosumab placebo injection every 6 months. Denosumab raised total hip BMD in relation to alendronate (3.5% versus 2.5%, p<0.00001). A more significant increase in BMD could be witnessed with denosumab than with alendronate in other locations, as in the trochanter (4.5% vs. 3.5%), distal radius (1.1% versus 0.6%), lumbar spine (5.3% versus 4.2%) and femoral neck (2.2% versus 1.6%); p<0.0003. The security profile was comparable for the two cohorts. No subject in the trial developed antibodies in reaction to denosumab [61].
Another phase III, multi-centre, double-blind trial, named STAND (Study of transitioning from Alendronate to Denosumab) was carried out to assess the impact of denosumab in subjects who were undergoing alendronate treatment. Five hundred and four postmenopausal women ≥ 55 years old with a BMD T-score of <-2.0 and >-4 SD, who were taking weekly oral alendronate for a minimum of six months, were randomly assigned to the treatment for 44±33 months. Alterations to BMD and bone biochemical markers were assessed. After a year, the cohort taking denosumab (and had been given alendronate before the trial) presented a markedly elevated total hip BMD in comparison with the cohort which continued to take alendronate (1.9% versus 1.05%; p<0.00012). Markedly elevated BMD readings with denosumab in comparison with alendronate were also noted after one year at the lumbar spine, femoral neck, and distal radius (all p<0.0125). The side effects and serious side effects were comparable in both cohorts [62].
Lastly, the principal phase III study, the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months) study, involved 7,868 postmenopausal women with osteoporosis and a BMD T-score between <-2.0 and >-4 SD and assessed the effectiveness in fracture reduction of denosumab. Subjects were given 60mg subcutaneous denosumab or placebo every six months for three years. Approximately 23% of the subjects had experienced a prior vertebral fracture. The trial’s retention rate of subjects was 83%. The decrease in relative risk of fracture was 68% (2.3% versus 7.2%; p<0.0001) for vertebral fractures, 20% (6.5% versus 8.0%) for non-vertebral fractures and 40% (0.7% versus 1.2%) for hip fractures. In comparison to patients in the control cohort, patients in the denosumab cohort saw a proportional elevation of 9.2% in bone mineral density at the lumbar spine and 6.0% at the total hip at three years. No distinctive dissimilarities were apparent between patients who were given denosumab and those who were given a placebo in the overall rate of side effects, serious side effects, or nonadherence to the trial as a result of side effects. No instances of osteonecrosis of the jaw were found in either cohort during this decisive study (Cummings et al. 2009). Lastly, the positive effects of denosumab therapy were generally discernible following the first treatment and remained so over the course of up to eight years of denosumab therapy in an open-ended extension trial [63].
We can conclude that denosumab provides an extremely efficacious substitute for osteoporosis therapy through the reduction of bone resorption and the elevation of bone mineral density via the inhibition of RANKL. A distinct benefit of denosumab is its route of administration and dosage. A subcutaneous injection every 6 months is comparatively free of discomfort and improves the therapy retention levels.
A series of observations were published indicating a low occurrence of fracture in subjects residing in locations with elevated fluoride levels. Fluoride was first employed in osteoporosis therapy in 1961. It was authorised for the prevention of osteoporosis in several European countried, but was never given authorisation by the American Federal Drug Administration (FDA) [64,65].
The outcomes of studies into the impact of fluoride on the reduction of fracture risk are ambiguous. Some trials have shown a reduction in the risk of vertebral fractures under monofluorophosphate, or sodium fluoride treatment, whereas other trials, giving patients the same preparations and dosage, did not. In addition, one meta-analysis extends these investigations and identifies an elevated fracture risk with increasing dosages after four years [66-68]. As a result, fluoride is not employed in the treatment of osteoporosis any longer.
Within the range of treatment options available, teriparatide or recombinant human PTH (1-34), has a significant role to play. It is a member of the group of anabolic bone-forming drugs rather than the anti-resorptive or catabolic group. It is a catalyst for fresh bone formation by accelerating bone turnover in favour of formation. Teriparatide therapy improves trabecular connectivity and cortical bone thickness [69] and augments the mechanical properties of bone causing a marked reduction in vertebral and non-vertebral fractures in postmenopausal women with osteoporosis, male osteoporosis and corticosteroid-induced osteoporosis [70]. For this reason its application is deemed to be suitable mostly for individuals at high risk of fracture and for those for whom other drugs have been unsuccessful [71].
The original indication for teriparatide first made public was the treatment of established osteoporosis in postmenopausal women. Amongst the varying trials which have been carried out on this treatment, the FPT (Fracture Prevention Trial) is the most significant. It assessed teriparatide at dosages of 20 or 40μg/day in controlled conditions in 1,637 postmenopausal women with vertebral fractures. Subjects taking teriparatide presented a marked decrease in the rate of fresh vertebral and non-vertebral fractures. They also experienced elevated lumbar and femoral neck bone density. Whilst the 40μg/day dose had a greater impact on BMD, the risk of fracture did not vary to any marked extent between the two dosage levels, while the higher dosage was less tolerated (11% nonretention due to adverse events with 40μg/day compared with 6% with 20 μg/day or with the placebo). The dosage of 20μg/day presented a decreased risk of vertebral fracture of 65% and a decreased risk of non-hip non-vertebral fracture risk reduction of 35%. This trial was originally supposed to run over a 36-month period, but it was terminated when subjects had undergone on average 21 months of treatment for safety reasons following osteosarcomas witnessed in rats during drug toxicity trials [72]. In other trials it transpired nevertheless that this effect presented only in juvenile rats given with elevated doses of PTH [73]. In addition, no instances of osteosarcomas have been noted in humans.
A subset of subjects were monitored for a maximum of 18 months following the termination of the therapy. This subset, which had been given teriparatide, demonstrated an enduring 40% decrease in vertebral fracture risk at 18 months versus the control sample. These outcomes indicate that the drug’s positive impact on the rate of non-vertebral fractures continues beyond the termination of treatment [74].
Despite bisphosphonates being the current benchmark for the treatment of osteoporosis, several studies exist that have assessed whether the combination of teriparatide and BP can produce a positive impact. The trials indicate that, if both treatments are given at the same time, bisphosphonates reduce rather than increase the anabolic action of teriparatide [75].
Combined teriparatide and denosumab, on the other hand, improves spine and hip BMD to a greater extent than either treatment does when administered in isolation. In the DATA-HRpQCT study, subjects underwent high-resolution peripheral QCT assessments at the distal tibia and radius (postmenopausal osteoporotic women randomly assigned to take teriparatide 20μg daily (n=31), denosumab 60mg every 6 months (n=33), or both (n=30) for 12 months). In the teriparatide cohort, the overall volumetric BMD (vBMD) did not vary at either anatomic location but was improved in both other cohorts at both locations. The elevated vBMD at the tibia showed an increase in the combination cohort (3.1±2.2%) compared with either the denosumab (2.2±1.9%) or teriparatide cohort (-0.3±1.9%) (p<0.02). Cortical vBMD was reduced by 1.6±1.9% at the tibia and by 0.9±2.8% at the radius in the teriparatide cohort whilst it was elevated in both other cohorts at both anatomic locations. Tibia cortical vBMD saw greater increases in the combination cohort (1.5±1.5%) than in the other two cohorts (p<0.04 for both comparisons). Cortical thickness was not affected in the teriparatide cohort, but was elevated in the other cohorts. Elevations in cortical thickness at the tibia was more marked in the combination cohort (5.4±3.9%) than the other cohorts (p<0.01 for both comparisons). In the teriparatide cohort, radial cortical porosity was raised by 20.9±37.6% and by 5.6±9.9% at the tibia but was not affected in the other two cohorts. Bone stiffness and failure load, as calculated through finite element analysis, was not affected in the teriparatide cohort but was elevated in the other two cohorts at both locations. These results suggest that the application of denosumab combined with teriparatide has a positive impact on HR-pQCT indices of bone quality to a greater extent than either treatment in isolation and may be of significant clinical benefit in the management of postmenopausal osteoporosis [76].
The EUROFORS study was a prospective, open-label, randomised study of 865 postmenopausal women with established osteoporosis and aimed to assess a variety of consecutive applications of teriparatide over a two-year period. Subjects were split into several subsets based on their former therapies. The outcomes of the BMD variations and biochemical markers of bone formation indicated that the application of teriparatide has a beneficial impact on bone mass and osteoblast function in postmenopausal women with established osteoporosis whatever the extent or type of former long-term exposure to antiresorptive treatments has been.
The length of the antiresorptive treatment and the length of pause in treatment between the former therapy and the teriparatide had no impact on BMD levels at any anatomic location. The skeletal reaction at the lumbar spine was comparable among former antiresorptive treatment cohorts at every point in time over the course of the trial, however subjects who had previously been given etidronate presented a greater increase, most likely a factor of its poorer anti-remodeling action. At six months, overall hip and femoral neck BMD showed a marked reduction in the former alendronate subset, and total hip BMD showed a marked reduction in the former risedronate subset. Overall hip and femoral neck BMD was statistically reduced from baseline in all other subsets at the six-month point. Nevertheless, this short-term reduction was contradicted over longer-term teriparatide therapy. All subsets demonstrated a numerically distinctive rise in BMD versus baseline after 18 and 24 months of therapy, and without variations between the cohorts at any point in the trial [77].
In a further non-randomised trial, 59 postmenopausal women with osteoporosis formerly given raloxifene or alendronate over an 18-36 month period, were treated with teriparatide over 18 months. Variations in BMD and bone-turnover markers were analysed. Subjects who had formerly been given alendronate saw a delayed rise in bone-turnover markers with results more than a third lower than those of subjects who had formerly been given raloxifene. Over the initial six-month period there were marked variations in the rise in BMD at the lumbar spine and hip. Subjects formerly given raloxifene saw more significant rises in BMD at the two sites. After 18 months of therapy marked variations continued in the lumbar spine, with greater improvement in subjects previously given raloxifene, however the variations in the hip were not as decisive. This proves that this application of teriparatide augments bone turnover in subjects formerly given raloxifene or alendronate, and that this improvement comes sooner and is more significant with the raloxifene pretreatment cohort [78].
Studies have also been published which demonstrate the effectiveness of teriparatide in the management of GIOP. In a randomised, double-blind study, 428 subjects both male and female from 22 to 89 years old, who had been given corticosteroids for a minimum of three months were randomly assigned to be treated with either alendronate 10mg/day or teriparatide 20μg/day over an 18 month period. After a year, the overall femur BMD was greater in the teriparatide cohort and on termination of the trial there were fewer vertebral fractures in the teriparatide cohort [79].
Teriparatide has also been employed as a treatment in men with osteoporosis. The trial analysed results from men with idiopathic or secondary osteoporosis being treated with teriparatide in comparison with a control group. The trial indicated elevated results, independent of gonadal status and other influential elements in the teriparatide cohort [80].
Overall, teriparatide (recombinant human PTH (1-34)) injections are well-tolerated. It disappears from the bloodstream in less than four hours following subcutaneous administration. Injections on a daily basis are required and a passing reddening at the injection site has been observed. Headache and nausea have been noted in under 10% of patients treated with a daily dose of 20µg. Mild, early, short-term hypercalcemia can transpire, but severe hypercalcemia is uncommon. Higher levels of urinary calcium (up 30µg per day) and serum uric acid concentrations (up 13%) are witnessed, however these do not seem to have clinical ramifications.
We can conclude that teriparatide is an appropriate and effective drug for the management of osteoporosis. It is efficacious in addressing a variety of clinical conditions, e.g. male osteoporosis or corticosteroid-induced osteoporosis.
Intact PTH (PTH 1-84) has been reported to have a beneficial impact on bone micro-architecture and to reduce incidence of fresh fractures as a result of its bone-forming mode of action [81].
PTH 1-84 is not procurable any more due to the withdrawal of its marketing licence at the behest of the regulating authority.
The possible clinical applications of strontium were revealed in approximately 1940, when strontium-89 was deployed as an analgesic treatment for bone metastases caused by prostate cancer [82,83].
In-vitro, strontium ranelate augments collagen and non-collagen protein synthesis through mature osteoblasts. The bone-forming action has been demonstrated by the higher levels of replication amongst pre-osteoblastic cells. This catalytic action on the duplication of pre-osteoblastic cells and the higher levels of collagen and non-collagen proteins have caused strontium ranelate to be regarded as a dual effect bone agent, because it does not simply reduce resorption [84]. The principal tool that can determine bone resorption at a molecular level is the RANK/RNAKL/OPG system outlined above. Solutions of 0.1mM to 2nM of strontium ranelate reduce the capacity of human osteoblasts to cause osteoclast differentiation, by reducing expression of mRNA of RANK-L and boosting mRNA expression of OPG, as reported in the trials carried out by Brennan et al. in 2006 [85, 86].
Studies have shown that the chemical properties of strontium ranelate cause the, densitometric values of subjects given the compound to be greater than the true values. Complex mathematical formulas exist to cut out the statistical impact of this from the DMO value, however it is more straightforward and sufficiently accurate to assume instead that half of the DMO achieved in the first year of therapy with strontium ranelate is a result of elevations in BMD and the remainder is a result of the basis caused by the heavier strontium measured by the DXA [87].
Information from the SOTI (Spinal Osteoporosis Therapeutic Intervention) study and the TROPOS (Treatment of Peripheral Osteoporosis) study looked at 1,649 postmenopausal subjects (SOTI trial) and 5,091 subjects (TROPOS trial) [88,89]. The initial three-year outcomes demonstrated a decrease in vertebral fractures of 41% with a NNT of 9. Moreover, an improvement in BMD of 12.7% was recorded. The decrease in vertebral fractures at the end of the four- and five-year periods was 33% and 24% respectively. In relation to non-vertebral fractures, the reduction in the relative incidence of fracture with strontium ranelate was 16% at the end of the three-year period and 15% at the end of the five-year period. A later assessment of these results in a subset of 1,977 subjects with high fracture risk (≥74 years old and a T-score of ≤-2.4) indicated a decrease in the incidence of vertebral fracture of 36% at the end of the three-year period and 43% at the end of the five-year period [87, 90].
Strontium ranelate was deployed in a widespread manner across Europe up to February 2014, when the European Medicines Agency (EMA) advised that the use of the drug be limited to cases which cannot use other treatments approved for osteoporosis, and that subjects with high risk for ischemic cardiac disorders should be excluded from this treatment option. This decision was grounded in a study carried out by the Pharmacovigilance Risk Assessment Committee (PRAC) that highlighted doubts about cardiovascular security which went beyond the risk, already known, of venous thromboembolism. On the basis of the PRAC analysis, an elevated incidence of serious cardiac disorders (including myocardial infarction) was pinpointed and steps were put forward to minimize the risk, specifically targeting the highlighted issue, in April 2013.
As set out in this review, there are several treatment options for osteoporosis. Unfortunately the choices are more restricted in daily clinical practice as treatments have been removed or their use restricted. Table 2 provides a summary of those treatments currently available to practitioners.
\n\t\t\t\t | \n\t\t
Current available osteoporosis therapies
Cathepsin K is expressed in the main in osteoclasts and a variety of other multinucleated cells including giant foreign body cells and Langhans cells. To a lesser extent it is present in macrophages, synovial fibroblasts, and fibroblasts at sites of wound repair or inflammation, chondrocytes, various epithelial cells of the human fetus, adult lung airway epithelium, thyroid epithelium, and potentially in low levels within smooth muscle cells. When the enzyme has been synthesised, it is separated into lysosomes and can be introduced into the extracellular environment. It is introduced particularly into the resorption lacuna below actively resorbing osteclasts where it is causes the degradation of the collagen type I dominated organic bone matrix. Thus, in a similar manner to pycnoidisostosis, removal of cathepsin K from osteoclasts prevents bone resorption. Inhibitors of cathepsin K are reported to have a less significant impact on osteoclast–osteoblast interaction, causing a lower inhibition of bone formation than available bisphosphonate antiresorptive drugs. Human cathepsin K inhibitors have been proven to stop bone loss in ovariectomized mice without reducing the anabolic effeciveness of parathyroid hormone (PTH) [91].
Whilst no CatK inhibitor is licensed for osteoporosis treatment or prevention at the present time, trials of three CatK inhibitors for the management of osteoporosis have been published: balicatib, relacatib, and odanacatib.
Balicatib is extremely selective for CatK in enzyme potency tests but has a reduced selectivity in living tissue. Clinical trials of balicatib have shown elevated BMD in postmenopausal women, but the drug was linked with cutaneous adverse effects. The first presentation of the efficacy of cathepsin K inhibitors on human bone density was witnessed with balicatib. This study, released by Adami et al. at an ASBMR meeting in 2009 (Denver, CO, USA), was a multi-centre, randomised, controlled, 12 month, dose-range identifying trial of 675 postmenopausal subjects with lumbar spine T-score less than 2.0. In the cohort treated with 50mg of balicatib daily, markers of bone resorption were reduced by over 55% with no reduction in markers of bone formation (osteocalcin, bone-specific alkaline phosphatase and N-terminal propeptide of type I collagen). The lumbar spine BMD was elevated 4.46%, that of the total hip was elevated 2.25%. Cutaneous reactions, including pruritus and morphea-like alterations, were observed in a low number of subjects. In a limited Japanese study, intact PTH levels were demonstrated to be elevated by 50% with balicatib treatment [92].
Relacatib is a powerful but nonselective inhibitor of cathepsins K, L, V, and S for which no clinical data in humans has been made public. The use of relacatib with ovariectomized and control monkeys caused an acute and rapid decrease in bone markers, and the impact of this lasted for a maximum of 48 hours, according to the dosage administered [93].
On the basis of the adverse effects, especially the cutaneous reactions, the production of all cathepsin K inhibitor drugs has been discontinued or put on hold, with the exception of odanacatib and, at present, ONO 5334
Odanacatib is a potent, selective inhibitor with an ability to inhibit cathepsin K in osteoclasts [91].
Two trials have been undertaken to assess the effectiveness and security of odanacatib, a phase I study to determine the dosage and a phase II study to assess the security and effectiveness. In the Phase I study a cohort of 49 women was used to assess a weekly dose. Doses of 5mg, 25mg, 50mg, and 100mg were used and 12 subjects were placed in the control cohort. A cohort of 30 women was created to enable the evaluation of the daily dosage. Doses of 0.5, 2.5, and 10mg were deployed, with six subjects placed in the control cohort. All treatments were given under fasting conditions. Odanacatib had an extended half-life of between 66 and 93 hours for all the treatments and dosages assessed. The effectiveness of both weekly and daily dosages in altering the markers was assessed. The impact was dose-dependant but not in proportion to the dosage level. Decreases in resorption markers were highest for weekly doses >50mg and daily doses ≥2.5mg. The greatest suppression was witnessed between days 3 and 5 with the weekly dose and this level remained elevated until the subsequent treatment [95].
The Phase II trial presented by Cusick et al. at the ASBMR meeting in 2009 (Denver, Co, USA), was a double-blind, randomised, controlled study lasting one year, with an expected extension period of two years. It looked at 399 postmenopausal women (postmenopausal (5yr) or bilateral oophorectomy) aged 45 to 85 years, presenting a T-score <-2 but not less than -3.5 in any one location. Subjects were assigned to five different cohorts with differing dosage levels: placebo, 3mg/week, 10mg/week, 25mg/week and 50mg/week. The variations in BMD at the lumbar spine were analysed and taken as the main outcome. In addition, variations in bone remodeling, variations in BMD in other locations and side effects were assessed in turn. The data indicated a elevation in BMD in all locations, which was related to the dose level. The more significant improvement was achieved with the highest dose. Weekly treatments of 50mg of odanacatib augmented bone mass by 5.7% in the lumbar spine, 4.1% in the total hip, 4.7% in the femoral neck, 5.2% in the trochanter and 2.9% in the distal third of the radius at the two-year point. Resorption markers dropped relative to the dose from the start of the therapy and stayed lower over the initial six-month period, at which point they increased to a similar level as those in the control group.
The data from the extension period of the phase II study to the three-year point (reported by Eisman et al. at the ASBMR meeting 2009 in Denver), looked at 169 women randomly assigned to weekly doses of odanacatib 50mg or a placebo. In the odanacatib cohort, BMD continued to rise (lumbar spine 7.5%, total hip 5.5%, femoral neck 5.5% and trochanter 7.4%). The urine NTX resorption marker was reduced by 50% versus the placebo, while the BSAP (bone specific alkaline phosphatase) formation marker remained unchanged. At the three-year point, formation markers had not only not decreased, but had in fact risen by 18% above baseline values.
ONO5334 is a new cathepsin K inhibitor. An initial trial has been carried out to assess its effectiveness and security in the treatment of postmenopausal osteoporosis. This was a year-long, randomised, double-blind, placebo and active-controlled parallel-group trial carried out across 13 locations in six European states. The study looked at 285 postmenopausal women from 55 to 75 years old with osteoporosis. Patients were randomly assigned to one of five dosage groups: placebo; 50mg twice daily, 100mg once daily, or 300mg once daily of ONO-5334; or alendronate 70mg once a week. After 12 months of monitoring all ONO-5334 doses and alendronate demonstrated a marked elevation of BMD at the lumbar spine, total hip (except the 100mg/day cohort), and femoral neck. There was little or no evidence that ONO-5334 suppressed bone-formation markers versus the alendronate, however the suppressive action on bone-resorption markers were comparable. There were no security issues of any clinic consequence. With a marked elevation in BMD, ONO-5334 also heralds a new mechanism in the treatment of osteoporosis. This new agent increases the range of treatments available both in the class of cathepsin K inhibitors as the second apparently available agent, and also across the full range of osteoporosis treatment [94].
We can conclude that Cathepsine K inhibitors are a new class of treatment that adds to the range of therapies available for the treatment and prevention of fractures, the most hazardous consequence of osteoporosis. Being able treat this condition at a variety of points along the resorption pathway is an asset and it provides clinicians with the opportunity to reduce the risk of fractures more effectively than before.
Sclerostin is a protein encoded by the SOST gene [96, 97]. It is identified as an important inhibitor of osteoblast-mediated bone formation [98, 99]. Loss-of-function mutations in this gene are linked with sclerosteosis, which results in progressive bone overgrowth and elevated bone mass and BMD.
A similar condition is van Buchem disease, a less severe form of sclerostosis resulting from by a deletion downstream of this gene, and leading to reduced sclerostin expression. SOST gene knockout mice no longer produce sclerostin and have an elevated bone mass, which demonstrates the impact this protein has on bone mass and BMD levels. In addition to elevated bone mass and BMD levels resulting from sclerostin deficiency, it is notable that no fractures have been reported in patients with either sclerosteosis or van Buchem disease [99, 100].
Sclerostin binds to low-density lipoprotein receptor-related protein (LRP) 5/6 and intercepts Wnt-signaling, governing bone formation in a negative manner and preventing osteoblast differentiation, proliferation, and activity [101].
At the present there are three separate humanized sclerostin antibodies under investigation: romosozumab (AMGEN & UCB), blozosumab (Eli Lilly) and BPS804 (Novartis). Romosozumab is a high affinity immunoglobulin G2 (IgG2) monoclonal antibody. It is produced through the humanisation of a mouse sclerostin monoclonal antibody that neutralizes sclerostin. The first-in-human single-dose trial in healthy men and postmenopausal women was carried out to assess pharmacokinetics, pharmacodynamics, tolerance and security of romosozumab doses of 0.1, 0.3, 1, 3, 5 or 10mg/kg delivered sub-cutaneously and 1 or 10mg/kg delivered intravenously. Seventy-two subjects in total took part in the trial and were subsequently monitored for a maximum of 85 days. The pharmacokinetics of this agent were not relative to the dosage levels. Dose-related rises in bone formation markers and falls in bone resorption markers were noted. A small proportion of subjects presented anti-investigational product bodies however the majority of these were non-neutralizing antibodies. The data indicated that the agent was well-tolerated [102].
In a phase II, multi-centre, multi-dose, controlled, parallel groups clinical study, 419 postmenopausal women with poor BMD were randomly assigned to the treatment to assess the effectiveness of romosozumab versus alendronate, teriparatide and a placebo, over a one year course of therapy. The main outcome was BMD change. All the dosage levels of romosozumab causes a marked elevation in the BMD at the lumbar spine, femoral neck and total hip together with a short-term rise in the bone formation markers and a durable fall in the bone resorption markers [103]. Data from the phase III studies is to be published soon.
A randomised, double-blind, controlled phase II clinical study of blosozumab in postmenopausal women with poor BMD was recently made available. Subjects were given subcutaneously administered blosozumab 180mg Q4W, 180mg Q2W, 270mg Q2W or equivalent placebo over a period of one year. In total, 120 women took part. Dosage levels across the range of blosozumab augmented lumbar spine and total hip BMD. Bone formation markers rose rapidly during the therapy while bone resorption markers fell at an early point in the therapy and continued at low level through to the end of the trial [104].
A comparable study was carried out using BPS804 with a similar cohort, however no data is yet published from this trial.
We can conclude that anti-sclerostin antibodies may be the most efficacious agent in the treatment of osteoporosis and bone defect related conditions.
Over the last decade, new drugs have come forward as potential pharmacological treatments for osteoporosis. More recent options are part of new classes of agent which present optimised modes of action, allowing practioners to replace patients’ lost bone mass more quickly and efficaciously than with older treatments. Nonetheless, it is important to be aware that all drugs have their appropriate uses and also a wide range of side effects, factors which must be considered in any clinical decision-making process. Furthermore, it is vital that practitioners ensure that, as required by the majority of therapies, treatments for osteoporosis are administered alongside adjustments in a patient’s lifestyle and/or calcium and vitamin D supplementation. New treatments are now coming into use that are likely to enable practitioners to opt for shorter courses of therapy which result in better outcomes for patients.
Stability constant of the formation of metal complexes is used to measure interaction strength of reagents. From this process, metal ion and ligand interaction formed the two types of metal complexes; one is supramolecular complexes known as host-guest complexes [1] and the other is anion-containing complexes. In the solution it provides and calculates the required information about the concentration of metal complexes.
Solubility, light, absorption conductance, partitioning behavior, conductance, and chemical reactivity are the complex characteristics which are different from their components. It is determined by various numerical and graphical methods which calculate the equilibrium constants. This is based on or related to a quantity, and this is called the complex formation function.
During the displacement process at the time of metal complex formation, some ions disappear and form a bonding between metal ions and ligands. It may be considered due to displacement of a proton from a ligand species or ions or molecules causing a drop in the pH values of the solution [2]. Irving and Rossotti developed a technique for the calculation of stability constant, and it is called potentiometric technique.
To determine the stability constant, Bjerrum has used a very simple method, and that is metal salt solubility method. For the studies of a larger different variety of polycarboxylic acid-, oxime-, phenol-containing metal complexes, Martel and Calvin used the potentiometric technique for calculating the stability constant. Those ligands [3, 4] which are uncharged are also examined, and their stability constant calculations are determined by the limitations inherent in the ligand solubility method. The limitations of the metal salt solubility method and the result of solubility methods are compared with this. M-L, MLM, and (M3) L are some types of examples of metal-ligand bonding. One thing is common, and that is these entire types metal complexes all have one ligand.
The solubility method can only usefully be applied to studies of such complexes, and it is best applied for ML; in such types of system, only ML is formed. Jacqueline Gonzalez and his co-worker propose to explore the coordination chemistry of calcium complexes. Jacqueline and et al. followed this technique for evaluate the as partial model of the manganese-calcium cluster and spectrophotometric studies of metal complexes, i.e., they were carried calcium(II)-1,4-butanediamine in acetonitrile and calcium(II)-1,2-ethylendiamine, calcium(II)-1,3-propanediamine by them.
Spectrophotometric programming of HypSpec and received data allows the determination of the formation of solubility constants. The logarithmic values, log β110 = 5.25 for calcium(II)-1,3-propanediamine, log β110 = 4.072 for calcium(II)-1,4-butanediamine, and log β110 = 4.69 for calcium(II)-1,2-ethylendiamine, are obtained for the formation constants [5]. The structure of Cimetidine and histamine H2-receptor is a chelating agent. Syed Ahmad Tirmizi has examined Ni(II) cimetidine complex spectrophotometrically and found an absorption peak maximum of 622 nm with respect to different temperatures.
Syed Ahmad Tirmizi have been used to taken 1:2 ratio of metal and cimetidine compound for the formation of metal complex and this satisfied by molar ratio data. The data, 1.40–2.4 × 108, was calculated using the continuous variation method and stability constant at room temperature, and by using the mole ratio method, this value at 40°C was 1.24–2.4 × 108. In the formation of lead(II) metal complexes with 1-(aminomethyl) cyclohexene, Thanavelan et al. found the formation of their binary and ternary complexes. Glycine,
Using the stability constant method, these ternary complexes were found out, and using the parameters such as Δ log K and log X, these ternary complex data were compared with binary complex. The potentiometric technique at room temperature (25°C) was used in the investigation of some binary complex formations by Abdelatty Mohamed Radalla. These binary complexes are formed with 3D transition metal ions like Cu2+, Ni2+, Co2+, and Zn2+ and gallic acid’s importance as a ligand and 0.10 mol dm−3 of NaNO3. Such types of aliphatic dicarboxylic acids are very important biologically. Many acid-base characters and the nature of using metal complexes have been investigated and discussed time to time by researchers [7].
The above acids (gallic and aliphatic dicarboxylic acid) were taken to determine the acidity constants. For the purpose of determining the stability constant, binary and ternary complexes were carried in the aqueous medium using the experimental conditions as stated above. The potentiometric pH-metric titration curves are inferred for the binary complexes and ternary complexes at different ratios, and formation of ternary metal complex formation was in a stepwise manner that provided an easy way to calculate stability constants for the formation of metal complexes.
The values of Δ log K, percentage of relative stabilization (% R. S.), and log X were evaluated and discussed. Now it provides the outline about the various complex species for the formation of different solvents, and using the concentration distribution, these complexes were evaluated and discussed. The conductivity measurements have ascertained for the mode of ternary chelating complexes.
A study by Kathrina and Pekar suggests that pH plays an important role in the formation of metal complexes. When epigallocatechin gallate and gallic acid combine with copper(II) to form metal complexes, the pH changes its speculation. We have been able to determine its pH in frozen and fluid state with the help of multifrequency EPR spectroscopy [8]. With the help of this spectroscopy, it is able to detect that each polyphenol exhibits the formation of three different mononuclear species. If the pH ranges 4–8 for di- or polymeric complex of Cu(II), then it conjectures such metal complexes. It is only at alkaline pH values.
The line width in fluid solutions by molecular motion exhibits an incomplete average of the parameters of anisotropy spin Hamilton. If the complexes are different, then their rotational correlation times for this also vary. The analysis of the LyCEP anisotropy of the fluid solution spectra is performed using the parameters determined by the simulation of the rigid boundary spectra. Its result suggests that pH increases its value by affecting its molecular mass. It is a polyphenol ligand complex with copper, showing the coordination of an increasing number of its molecules or increasing participation of polyphenol dimers used as ligands in the copper coordination region.
The study by Vishenkova and his co-worker [8] provides the investigation of electrochemical properties of triphenylmethane dyes using a voltammetric method with constant-current potential sweep. Malachite green (MG) and basic fuchsin (BF) have been chosen as representatives of the triphenylmethane dyes [9]. The electrochemical behavior of MG and BF on the surface of a mercury film electrode depending on pH, the nature of background electrolyte, and scan rate of potential sweep has been investigated.
Using a voltammetric method with a constant-current potential sweep examines the electrical properties of triphenylmethane dye. In order to find out the solution of MG and BF, certain registration conditions have been prescribed for it, which have proved to be quite useful. The reduction peak for the currents of MG and BF has demonstrated that it increases linearly with respect to their concentration as 9.0 × 10−5–7.0 × 10−3 mol/dm3 for MG and 6.0 × 10−5–8.0 × 10−3 mol/dm3 for BF and correlation coefficients of these values are 0.9987 for MG and 0.9961 for BF [10].
5.0 × 10−5 and 2.0 × 10−5 mol/dm3 are the values used as the detection limit of MG and BF, respectively. Stability constants are a very useful technique whose size is huge. Due to its usefulness, it has acquired an umbrella right in the fields of chemistry, biology, and medicine. No science subject is untouched by this. Stability constants of metal complexes are widely used in the various areas like pharmaceuticals as well as biological processes, separation techniques, analytical processes, etc. In the presented chapter, we have tried to explain this in detail by focusing our attention on the applications and solutions of stability of metal complexes in solution.
Stability or formation or binding constant is the type of equilibrium constant used for the formation of metal complexes in the solution. Acutely, stability constant is applicable to measure the strength of interactions between the ligands and metal ions that are involved in complex formation in the solution [11]. A generally these 1-4 equations are expressed as the following ways:
Thus
K1, K2, K3, … Kn are the equilibrium constants and these are also called stepwise stability constants. The formation of the metal-ligand-n complex may also be expressed as equilibrium constants by the following steps:
The parameters K and β are related together, and these are expressed in the following example:
Now the numerator and denominator are multiplied together with the use of [metal-ligand] [metal-ligand2], and after the rearranging we get the following equation:
Now we expressed it as the following:
From the above relation, it is clear that the overall stability constant βn is equal to the product of the successive (i.e., stepwise) stability constants, K1, K2, K3,…Kn. This in other words means that the value of stability constants for a given complex is actually made up of a number of stepwise stability constants. The term stability is used without qualification to mean that the complex exists under a suitable condition and that it is possible to store the complex for an appreciable amount of time. The term stability is commonly used because coordination compounds are stable in one reagent but dissociate or dissolve in the presence of another regent. It is also possible that the term stability can be referred as an action of heat or light or compound. The stability of complex [13] is expressed qualitatively in terms of thermodynamic stability and kinetic stability.
In a chemical reaction, chemical equilibrium is a state in which the concentration of reactants and products does not change over time. Often this condition occurs when the speed of forward reaction becomes the same as the speed of reverse reaction. It is worth noting that the velocities of the forward and backward reaction are not zero at this stage but are equal.
If hydrogen and iodine are kept together in molecular proportions in a closed process vessel at high temperature (500°C), the following action begins:
In this activity, hydrogen iodide is formed by combining hydrogen and iodine, and the amount of hydrogen iodide increases with time. In contrast to this action, if the pure hydrogen iodide gas is heated to 500°C in the reaction, the compound is dissolved by reverse action, which causes hydrogen iodide to dissolve into hydrogen and iodine, and the ratio of these products increases over time. This is expressed in the following reaction:
For the formation of metal chelates, the thermodynamic technique provides a very significant information. Thermodynamics is a very useful technique in distinguishing between enthalpic effects and entropic effects. The bond strengths are totally effected by enthalpic effect, and this does not make any difference in the whole solution in order/disorder. Based on thermodynamics the chelate effect below can be best explained. The change of standard Gibbs free energy for equilibrium constant is response:
Where:
R = gas constant
T = absolute temperature
At 25°C,
ΔG = (− 5.708 kJ mol−1) · log β.
The enthalpy term creates free energy, i.e.,
For metal complexes, thermodynamic stability and kinetic stability are two interpretations of the stability constant in the solution. If reaction moves from reactants to products, it refers to a change in its energy as shown in the above equation. But for the reactivity, kinetic stability is responsible for this system, and this refers to ligand species [14].
Stable and unstable are thermodynamic terms, while labile and inert are kinetic terms. As a rule of thumb, those complexes which react completely within about 1 minute at 25°C are considered labile, and those complexes which take longer time than this to react are considered inert. [Ni(CN)4]2− is thermodynamically stable but kinetically inert because it rapidly exchanges ligands.
The metal complexes [Co(NH3)6]3+ and such types of other complexes are kinetically inert, but these are thermodynamically unstable. We may expect the complex to decompose in the presence of acid immediately because the complex is thermodynamically unstable. The rate is of the order of 1025 for the decomposition in acidic solution. Hence, it is thermodynamically unstable. However, nothing happens to the complex when it is kept in acidic solution for several days. While considering the stability of a complex, always the condition must be specified. Under what condition, the complex which is stable or unstable must be specified such as acidic and also basic condition, temperature, reactant, etc.
A complex may be stable with respect to a particular condition but with respect to another. In brief, a stable complex need not be inert and similarly, and an unstable complex need not be labile. It is the measure of extent of formation or transformation of complex under a given set of conditions at equilibrium [15].
Thermodynamic stability has an important role in determining the bond strength between metal ligands. Some complexes are stable, but as soon as they are introduced into aqueous solution, it is seen that these complexes have an effect on stability and fall apart. For an example, we take the [Co (SCN)4]2+ complex. The ion bond of this complex is very weak and breaks down quickly to form other compounds. But when [Fe(CN)6]3− is dissolved in water, it does not test Fe3+ by any sensitive reagent, which shows that this complex is more stable in aqueous solution. So it is indicated that thermodynamic stability deals with metal-ligand bond energy, stability constant, and other thermodynamic parameters.
This example also suggests that thermodynamic stability refers to the stability and instability of complexes. The measurement of the extent to which one type of species is converted to another species can be determined by thermodynamic stability until equilibrium is achieved. For example, tetracyanonickelate is a thermodynamically stable and kinetic labile complex. But the example of hexa-amine cobalt(III) cation is just the opposite:
Thermodynamics is used to express the difference between stability and inertia. For the stable complex, large positive free energies have been obtained from ΔG0 reaction. The ΔH0, standard enthalpy change for this reaction, is related to the equilibrium constant, βn, by the well thermodynamic equation:
For similar complexes of various ions of the same charge of a particular transition series and particular ligand, ΔS0 values would not differ substantially, and hence a change in ΔH0 value would be related to change in βn values. So the order of values of ΔH0 is also the order of the βn value.
Kinetic stability is referred to the rate of reaction between the metal ions and ligand proceeds at equilibrium or used for the formation of metal complexes. To take a decision for kinetic stability of any complexes, time is a factor which plays an important role for this. It deals between the rate of reaction and what is the mechanism of this metal complex reaction.
As we discuss above in thermodynamic stability, kinetic stability is referred for the complexes at which complex is inert or labile. The term “inert” was used by Tube for the thermally stable complex and for reactive complexes the term ‘labile’ used [16]. The naturally occurring chlorophyll is the example of polydentate ligand. This complex is extremely inert due to exchange of Mg2+ ion in the aqueous media.
The nature of central atom of metal complexes, dimension, its degree of oxidation, electronic structure of these complexes, and so many other properties of complexes are affected by the stability constant. Some of the following factors described are as follows.
In the coordination chemistry, metal complexes are formed by the interaction between metal ions and ligands. For these type of compounds, metal ions are the coordination center, and the ligand or complexing agents are oriented surrounding it. These metal ions mostly are the transition elements. For the determination of stability constant, some important characteristics of these metal complexes may be as given below.
Ligands are oriented around the central metal ions in the metal complexes. The sizes of these metal ions determine the number of ligand species that will be attached or ordinated (dative covalent) in the bond formation. If the sizes of these metal ions are increased, the stability of coordination compound defiantly decreased. Zn(II) metal ions are the central atoms in their complexes, and due to their lower size (0.74A°) as compared to Cd(II) size (0.97A°), metal ions are formed more stable.
Hence, Al3+ ion has the greatest nuclear charge, but its size is the smallest, and the ion N3− has the smallest nuclear charge, and its size is the largest [17]. Inert atoms like neon do not participate in the formation of the covalent or ionic compound, and these atoms are not included in isoelectronic series; hence, it is not easy to measure the radius of this type of atoms.
The properties of stability depend on the size of the metal ion used in the complexes and the total charge thereon. If the size of these metal ions is small and the total charge is high, then their complexes will be more stable. That is, their ratio will depend on the charge/radius. This can be demonstrated through the following reaction:
An ionic charge is the electric charge of an ion which is formed by the gain (negative charge) or loss (positive charge) of one or more electrons from an atom or group of atoms. If we talk about the stability of the coordination compounds, we find that the total charge of their central metal ions affects their stability, so when we change their charge, their stability in a range of constant can be determined by propagating of error [18]. If the charge of the central metal ion is high and the size is small, the stability of the compound is high:
In general, the most stable coordination bonds can cause smaller and highly charged rations to form more stable coordination compounds.
When an electron pair attracts a central ion toward itself, a strong stability complex is formed, and this is due to electron donation from ligand → metal ion. This donation process is increasing the bond stability of metal complexes exerted the polarizing effect on certain metal ions. Li+, Na+, Mg2+, Ca2+, Al3+, etc. are such type of metal cation which is not able to attract so strongly from a highly electronegative containing stable complexes, and these atoms are O, N, F, Au, Hg, Ag, Pd, Pt, and Pb. Such type of ligands that contains P, S, As, Br and I atom are formed stable complex because these accepts electron from M → π-bonding. Hg2+, Pb2+, Cd2+, and Bi3+ metal ions are also electronegative ions which form insoluble salts of metal sulfide which are insoluble in aqueous medium.
Volatile ligands may be lost at higher temperature. This is exemplified by the loss of water by hydrates and ammonia:
The transformation of certain coordination compounds from one to another is shown as follows:
A ligand is an ion or small molecule that binds to a metal atom (in chemistry) or to a biomolecule (in biochemistry) to form a complex, such as the iron-cyanide coordination complex Prussian blue or the iron-containing blood-protein hemoglobin. The ligands are arranged in spectrochemical series which are based on the order of their field strength. It is not possible to form the entire series by studying complexes with a single metal ion; the series has been developed by overlapping different sequences obtained from spectroscopic studies [19]. The order of common ligands according to their increasing ligand field strength is
The above spectrochemical series help us to for determination of strength of ligands. The left last ligand is as weaker ligand. These weaker ligand cannot forcible binding the 3d electron and resultant outer octahedral complexes formed. It is as-
Increasing the oxidation number the value of Δ increased.
Δ increases from top to bottom.
However, when we consider the metal ion, the following two useful trends are observed:
Δ increases with increasing oxidation number.
Δ increases down a group. For the determination of stability constant, the nature of the ligand plays an important role.
The following factors described the nature of ligands.
The size and charge are two factors that affect the production of metal complexes. The less charges and small sizes of ligands are more favorable for less stable bond formation with metal and ligand. But if this condition just opposite the product of metal and ligand will be a more stable compound. So, less nuclear charge and more size= less stable complex whereas if more nuclear charge and small in size= less stable complex. We take fluoride as an example because due to their smaller size than other halide and their highest electro negativity than the other halides formed more stable complexes. So, fluoride ion complexes are more stable than the other halides:
As compared to S2− ion, O22− ions formed more stable complexes.
It is suggested by Calvin and Wilson that the metal complexes will be more stable if the basic character or strength of ligands is higher. It means that the donating power of ligands to central metal ions is high [20].
It means that the donating power of ligands to central metal ions is high. In the case of complex formation of aliphatic diamines and aromatic diamines, the stable complex is formed by aliphatic diamines, while an unstable coordination complex is formed with aromatic diamines. So, from the above discussion, we find that the stability will be grater if the e-donation power is greater.
Thus it is clear that greater basic power of electron-donating species will form always a stable complex. NH3, CN−, and F− behaved as ligands and formed stable complexes; on the other hand, these are more basic in nature.
We know that if the concentration of coordination group is higher, these coordination compounds will exist in the water as solution. It is noted that greater coordinating tendency show the water molecules than the coordinating group which is originally present. SCN− (thiocynate) ions are present in higher concentration; with the Co2+ metal ion, it formed a blue-colored complex which is stable in state, but on dilution of water medium, a pink color is generated in place of blue, or blue color complex is destroyed by [Co(H2O)6]2+, and now if we added further SCN−, the pink color will not appear:
Now it is clear that H2O and SCN− are in competition for the formation of Co(II) metal-containing complex compound. In the case of tetra-amine cupric sulfate metal complex, ammonia acts as a donor atom or ligand. If the concentration of NH3 is lower in the reaction, copper hydroxide is formed but at higher concentration formed tetra-amine cupric sulfate as in the following reaction:
For a metal ion, chelating ligand is enhanced and affinity it and this is known as chelate effect and compared it with non-chelating and monodentate ligand or the multidentate ligand is acts as chelating agent. Ethylenediamine is a simple chelating agent (Figure 1).
Structure of ethylenediamine.
Due to the bidentate nature of ethylenediamine, it forms two bonds with metal ion or central atom. Water forms a complex with Ni(II) metal ion, but due to its monodentate nature, it is not a chelating ligand (Figures 2 and 3).
Structure of chelating configuration of ethylenediamine ligand.
Structure of chelate with three ethylenediamine ligands.
The dentate cheater of ligand provides bonding strength to the metal ion or central atom, and as the number of dentate increased, the tightness also increased. This phenomenon is known as chelating effect, whereas the formation of metal complexes with these chelating ligands is called chelation:
or
Some factors are of much importance for chelation as follows.
The sizes of the chelating ring are increased as well as the stability of metal complex decreased. According to Schwarzenbach, connecting bridges form the chelating rings. The elongated ring predominates when long bridges connect to the ligand to form a long ring. It is usually observed that an increased a chelate ring size leads to a decrease in complex stability.
He interpreted this statement. The entropy of complex will be change if the size of chelating ring is increased, i.e., second donor atom is allowed by the chelating ring. As the size of chelating ring increased, the stability should be increased with entropy effect. Four-membered ring compounds are unstable, whereas five-membered are more stable. So the chelating ring increased its size and the stability of the formed metal complexes.
The number of chelating rings also decides the stability of complexes. Non-chelating metal compounds are less stable than chelating compounds. These numbers increase the thermodynamic volume, and this is also known as an entropy term. In recent years ligands capable of occupying as many as six coordination positions on a single metal ion have been described. The studies on the formation constants of coordination compounds with these ligands have been reported. The numbers of ligand or chelating agents are affecting the stability of metal complexes so as these numbers go up and down, the stability will also vary with it.
For the Ni(II) complexes with ethylenediamine as chelating agent, its log K1 value is 7.9 and if chelating agents are trine and penten, then the log K1 values are 7.9 and 19.3, respectively. If the metal ion change Zn is used in place of Ni (II), then the values of log K1 for ethylenediamine, trine, and penten are 6.0, 12.1, and 16.2, respectively. The log βMY values of metal ions are given in Table 1.
Metal ion | log βMY (25°C, I = 0.1 M) |
---|---|
Ca2+ | 11.2 |
Cu2+ | 19.8 |
Fe3+ | 24.9 |
Metal ion vs. log βMY values.
Ni(NH3)62+ is an octahedral metal complex, and at 25 °C its log β6 value is 8.3, but Ni(ethylenediamine)32+ complex is also octahedral in geometry, with 18.4 as the value of log β6. The calculated stability value of Ni(ethylenediamine)32+ 1010 times is more stable because three rings are formed as chelating rings by ethylenediamine as compared to no such ring is formed. Ethylenediaminetetraacetate (EDTA) is a hexadentate ligand that usually formed stable metal complexes due to its chelating power.
A special effect in molecules is when the atoms occupy space. This is called steric effect. Energy is needed to bring these atoms closer to each other. These electrons run away from near atoms. There can be many ways of generating it. We know the repulsion between valence electrons as the steric effect which increases the energy of the current system [21]. Favorable or unfavorable any response is created.
For example, if the static effect is greater than that of a product in a metal complex formation process, then the static increase would favor this reaction. But if the case is opposite, the skepticism will be toward retardation.
This effect will mainly depend on the conformational states, and the minimum steric interaction theory can also be considered. The effect of secondary steric is seen on receptor binding produced by an alternative such as:
Reduced access to a critical group.
Stick barrier.
Electronic resonance substitution bond by repulsion.
Population of a conformer changes due to active shielding effect.
The macrocyclic effect is exactly like the image of the chelate effect. It means the principle of both is the same. But the macrocyclic effect suggests cyclic deformation of the ligand. Macrocyclic ligands are more tainted than chelating agents. Rather, their compounds are more stable due to their cyclically constrained constriction. It requires some entropy in the body to react with the metal ion. For example, for a tetradentate cyclic ligand, we can use heme-B which forms a metal complex using Fe+2 ions in biological systems (Figure 4).
Structure of hemoglobin is the biological complex compound which contains Fe(II) metal ion.
The n-dentate chelating agents play an important role for the formation of more stable metal complexes as compared to n-unidentate ligands. But the n-dentate macrocyclic ligand gives more stable environment in the metal complexes as compared to open-chain ligands. This change is very favorable for entropy (ΔS) and enthalpy (ΔH) change.
There are so many parameters to determination of formation constants or stability constant in solution for all types of chelating agents. These numerous parameters or techniques are refractive index, conductance, temperature, distribution coefficients, refractive index, nuclear magnetic resonance volume changes, and optical activity.
Solubility products are helpful and used for the insoluble salt that metal ions formed and complexes which are also formed by metal ions and are more soluble. The formation constant is observed in presence of donor atoms by measuring increased solubility.
To determine the solubility constant, it involves the distribution of the ligands or any complex species; metal ions are present in two immiscible solvents like water and carbon tetrachloride, benzene, etc.
In this method metal ions or ligands are present in solution and on exchanger. A solid polymers containing with positive and negative ions are ion exchange resins. These are insoluble in nature. This technique is helpful to determine the metal ions in resin phase, liquid phase, or even in radioactive metal. This method is also helpful to determine the polarizing effect of metal ions on the stability of ligands like Cu(II) and Zn(II) with amino acid complex formation.
At the equilibrium free metal and ions are present in the solution, and using the different electrometric techniques as described determines its stability constant.
This method is based upon the titration method or follows its principle. A stranded acid-base solution used as titrate and which is titrated, it may be strong base or strong acid follows as potentiometrically. The concentration of solution using 103− M does not decomposed during the reaction process, and this method is useful for protonated and nonprotonated ligands.
This is the graphic method used to determine the stability constant in producing metal complex formation by plotting a polarograph between the absences of substances and the presence of substances. During the complex formation, the presence of metal ions produced a shift in the half-wave potential in the solution.
If a complex is relatively slow to form and also decomposes at measurable rate, it is possible, in favorable situations, to determine the equilibrium constant.
This involves the study of the equilibrium constant of slow complex formation reactions. The use of tracer technique is extremely useful for determining the concentrations of dissociation products of the coordination compound.
This method is based on the study of the effect of an equilibrium concentration of some ions on the function at a definite organ of a living organism. The equilibrium concentration of the ion studied may be determined by the action of this organ in systems with complex formation.
The solution of 25 ml is adopted by preparing at the 1.0 × 10−5 M ligand or 1.0 × 10−5 M concentration and 1.0 × 10−5 M for the metal ion:
The solutions containing the metal ions were considered both at a pH sufficiently high to give almost complete complexation and at a pH value selected in order to obtain an equilibrium system of ligand and complexes.
In order to avoid modification of the spectral behavior of the ligand due to pH variations, it has been verified that the range of pH considered in all cases does not affect absorbance values. Use the collected pH values adopted for the determinations as well as selected wavelengths. The ionic strengths calculated from the composition of solutions allowed activity coefficient corrections. Absorbance values were determined at wavelengths in the range 430–700 nm, every 2 nm.
For a successive metal complex formation, use this method. If ligand is protonate and the produced complex has maximum number of donate atoms of ligands, a selective light is absorbed by this complex, while for determination of stability constant, it is just known about the composition of formed species.
Bjerrum (1941) used the method stepwise addition of the ligands to coordination sphere for the formation of complex. So, complex metal–ligand-n forms as the following steps [22]. The equilibrium constants, K1, K2, K3, … Kn are called stepwise stability constants. The formation of the complex metal-ligandn may also be expressed by the following steps and equilibrium constants.
Where:
M = central metal cation
L = monodentate ligand
N = maximum coordination number for the metal ion M for the ligand
If a complex ion is slow to reach equilibrium, it is often possible to apply the method of isotopic dilution to determine the equilibrium concentration of one or more of the species. Most often radioactive isotopes are used.
This method was extensively used by Werner and others to study metal complexes. In the case of a series of complexes of Co(III) and Pt(IV), Werner assigned the correct formulae on the basis of their molar conductance values measured in freshly prepared dilute solutions. In some cases, the conductance of the solution increased with time due to a chemical change, e.g.,
It is concluded that the information presented is very important to determine the stability constant of the ligand metal complexes. Some methods like spectrophotometric method, Bjerrum’s method, distribution method, ion exchange method, electrometric techniques, and potentiometric method have a huge contribution in quantitative analysis by easily finding the stability constants of metal complexes in aqueous solutions.
All the authors thank the Library of University of Delhi for reference books, journals, etc. which helped us a lot in reviewing the chapter.
IntechOpen publishes different types of publications
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