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Osteoporosis is known as a disease with distinguished low bone density and bone microarchitecture deterioration, leading to increase bone fragility and risk of fracture. Osteoporosis affects both men and women especially the elderly with higher prevalence in postmenopausal women.1, 2 The loss of bone density itself is asymptomatic but it causes complications such as painful fractures and deformities in the bones.2 Thus, it was estimated that in UK one in three women and one in twelve men over the age 50 will suffer an osteoporotic fracture. These numbers are likely to grow due to increasing elderly population and inactive lifestyles of the people. Currently, it costs UK health board â‚¤1.7 billion annually to treat these osteoporotic fractures, not accounting personal costs of each patient.1
Osteoporotic fractures could lead to pain, disability and/or deformity. Severity of these complications depends on the site of fracture. Long bone fractures such as fractures on the arms, forearms, thighs and lower legs are often associated with dislocations. This indicates the need of much medical attention; thus, reducing patient from self-reliant to full reliance on care from others. On the other hand, vertebral wedging and compression not only causes severe pain but also kyphosis, also known as hunchback. Although patient may not need much medical attention, there is a decrease ability of patient to take care themselves and decrease in quality of life.2 The most important complication of osteoporosis is fracture to the hip as it requires hospitalisation and surgery.2,3 50% of these patients will not recover previous mobility and independence while 20% dies within first 6 months.1 Most of these deaths accounts for the complications arise during surgery.2 In UK, it was estimated that the cost of treating hip fractures in postmenopausal women will rise above £2 billion by 2020.4
Other complications of osteoporosis arise due to the nature of the fall as the patient may have been lying unattended on the ground for a period of time and this exposes the patient to the risk of pneumonia and exacerbation of coexisting illness. Moreover, resulting immobility from the fall could lead to development of venous thrombosis which could progress to pulmonary embolism.2 Besides that, patients also suffer from psychological symptoms such as anxiety, anger and depression as they try to cope with the pain, lifestyle limitations and physical deformities.5 Hence, preventive measures against incidence of fracture will be beneficial to individuals, the community and health care board.
In this case, Mrs. X most likely was osteoporotic due to presenting clinical features of low bone density and fractures. Moreover, she presented with osteoporosis risk factors such as her age and gender. According to guidelines, there was an increase occurrence of fractures with every passing decade after the age of 60. It was also proven that women bear greater risk of osteoporosis because they have smaller bone mass and significant loss of bone mass after menopause.1 A study show that generally women had greater bone loss compared to men with an average bone loss of 0.86% to 1.21% vs. 0.04% to 0.09%.6 An official diagnosis could be performed by measuring Mrs. Xs bone mineral density (BMD) with a Dual-energy X-ray Absorptiometry (DXA). Osteoporotic patients have a BMD more than 2.5 standard deviations below the young normal subjects of the same gender (i.e. T < -2.5).1, 2 Other laboratory investigations should be done to eliminate underlying causes such as hyperthyroidism, renal impairment, osteomalacia and cancer.2 In this case, it was assumed that Mrs. X had undergone these tests and was diagnosed with osteoporosis without underlying causes. Below are some of the pharmacological interventions used in fracture prevention.
Bisphosphonates are analogues of pyrophosphonates and are divided into two classes: simple bisphosphonates and nitrogen-containing bisphosphonates (NBPs).7 Simple bisphosphonates such as clodronate and etidronate are the first derived antiresorptive bisphosphonates. They are prodrugs that are converted in vivo to methylene-containing (AppCp-type) metabolites which would then be taken intracellularly by osteoclasts and incorporated into ATP analogues to promote cell apoptosis. Meanwhile, NBPs such as alendronate and ibandronate were proven to inhibit farnesyl diphosphate (FPP) synthase by mimicking analogs of isoprenoid diphosphatelipids lipids. This inhibits the production of isoprenoid lipids and blocks the activity of small GTPase signaling proteins involved in formation of ruffles borders of osteoclasts. Inability to form ruffled borders prevents attachment of osteoclasts onto bones and hinder subsequent resorption.7,8 All bisphosphonates are absorbed into the bone matrix and osteoclasts would be exposed to high concentrations of drug upon bone resorption.7 Therefore, bisphosphonates are effective osteoporosis management because of its' ability to prevent loss of bone mass.
The efficacy of bisphosphonates is well-established with the publications of various studies. For instance in the Fracture Intervention Trial, 3658 postmenopausal women of 55-80 years of age were selected and randomly assigned with placebo or alendronate treatment. The outcome of the study showed significant relative risk reduction (95% confidence interval (CI) does not include 1) in incidence of hip fractures (47%), vertebral fractures (55%) and overall clinical fractures (70%).9 In a 3 year randomized clinical trial (RCT), 1226 postmenopausal women with two or more vertebral fractures were selected for risedronate vs. placebo therapy. Results indicated that significant risk reduction (p < 0.001) of 49% for occurrence of new vertebral fractures.10 Both studies were conducted with large numbers of subjects that has similarities with this case scenario (i.e. age, gender, postmenopausal and multiple fractures).9,10 Thus, these findings are valid and relevant to the case. With that said, it could be concluded the use of bisphosphonates is valid and beneficial for Mrs. X.
Bisphosphonates have long duration of action as 50% of dose accumulates into the bone matrix and only released when the bones are resorbed.7 This is evident when a study determined that there were still residual alendronate action up to 2 years after discontinuation. However, persistent to therapy is needed for continuous benefits from therapy.11 Common oral bisphosphonates currently used include alendronate, risedronate and etidronate. They have very poor bioavailability and impaired absorption when ingested with food. Intravenous formulations such as zoledronic acid are used in malignant conditions.3, 7 All bisphosphonates cause gastrointestinal disturbances while alendronate and risedronate cause esophageal reactions such as oesophagitis and esophageal ulcers. Thus, oral bisphosphonates should be taken with plenty of water on an empty stomach first thing in the morning with subsequent abstain of food for 30 minutes. After ingestion patient should remain in an upright position for 30 minutes In addition, disodium etidronate is taken cyclically because of its' reduced bone calcification, increasing risk of fracture.7, 12
A study indicated the need for at least 50% compliance to observe any outcome in bisphosphonate therapy.13 Poor compliance to bisphosphonates could be caused by their side effects, cumbersome dosing regimens and lack of immediate outcome. In a retrospective administrative database analysis, it was implied that cost of wasted drugs per patient was $25.87 for primary prevention group and $30.52 for secondary prevention group. Thus, resulting in further cost of $62.95/patient in primary prevention group and $330.84/patient in secondary prevention group for there were 110 and 19 additional avoidable fractures respectively.14 Consequently, the efficacy of bisphosphonates do not rely on drug alone but also the patients' full compliance to medication.
Strontium ranelate is a combination compound of two strontium atoms and ranelic acid. The exact mode of action of this drug is unknown but is thought to curb bone resorption and promote bone formation 3,7; hence, its efficacy in fracture prevention. In a phase 3 clinical trial, 1649 postmenopausal women who were osteoporotic and presented with one or more vertebral fractures were selected and received placebo or strontium ranelate. The clinical outcome presented significant risk reduction of 41% (Relative Risk (RR):0.59; 95% Confidence interval (CI): 0.48 to 0.73) in new vertebral fractures over 3 years. Strontium ranelate also show significant risk reductions (p < 0.001) of lumbar spinal fractures (14.4%) and femoral neck fractures (8.3%).15 The risk reduction of new vertebral fracture in strontium ranelate (41%) 15 and in risedronate (49%)10 are comparable. Thus, implying both regimens has comparable effect. However this statement maybe inconclusive because strontium ranelate is a fairly new drug and not much research has been conducted on comparison on both classes of drugs.
Strontium ranelate have a similar pharmacokinetic profile as calcium in regards of gastrointestinal absorption, renal elimination and bone matrix incorporation.7 Consequently, ingestion of calcium-containing products and antacids would impair absorption of medication. Thus, 2g of strontium ranelate in water should be taken once daily with 2-hour fasting before and after consuming medication (best taken at bedtime).7,12 Furthermore, strontium ranelate was reported to have mild gastrointestinal side effects.7 In the same phase 3 clinical trial, the most reported complain was diarrhea, 6.1% incidence in strontium ranelate and 3.6% in placebo group (p=0.02). It was also reported that symptoms of diarrhea ceased after 3 months. The study also showed compliance rate of 83% and 85% for strontium ranelate and placebo group.15 This proves that the drug is well-tolerated by patients. Unfortunately, there were reports of rare but fatal allergic reactions with strontium ranelate consumption. The allergic reaction causes drug rash with eosinophilia and systemic symptoms (DRESS) which could affect the kidneys, lungs and liver.12,16 Hence, patients who develop skin rashes are advised to stop medication immediately and seek medical attention.
In conclusion, strontium ranelate is beneficial in fracture prevention and has mild, transient gastrointestinal side effects but can cause rare yet severe allergic reactions.
Hormone Replacement Therapy (HRT)
Oestrogens are thought to increase bone formation and calcium absorption while they reduce bone resorption and renal excretion of calcium. Thus, indicating the benefits of starting HRT in postmenopausal patients. A meta-analysis of 13 RCTs, showed that HRT caused a risk reduction of vertebral fractures by 33% (95% CI: 45% to 98%).17 However, the correlation between HRT and fracture risk reduction was not strong due to large CI and most of the trials involved did not use incidence of fractures as the endpoint measurement. Meanwhile, in a population-based case study, there was a substantial decline in HRT efficacy after 5 years with risk of fractures increase from 7% to 48%.18 Moreover, in a Lancet study of four randomized trials established that HRT significantly increased the prevalence of breast cancer, stroke or pulmonary embolism with additional incidence of these diseases in 6 per 1000 patients aged 50-59 and 12 per 1000 patients aged 60-69 within 5 years. Contrarily, there was a decrease of colorectal cancer or femoral neck fractures of 1.7 per 1000 patients aged 50-59 and 5.5 per 1000 aged 60-69 within 5 years.19 These findings showed the increased incidence of adverse outcome outweigh the benefits of using HRT.
Selective oestrogen receptor modulators (SERMS)
Since HRT utilizes natural and synthetic hormones of oestrogens and progestogens, HRT affects multiple systems. This lead to the discovery of non-hormonal agent known as selective oestrogen receptor modulators (SERMS) which selectively acts on bones and the cardiovascular system to increase oestrogen production while acting on endometrium and breast to decrease oestrogen production.7 Raloxifene is the only drug under this class that is licensed for use in postmenopausal osteoporosis.12 In a Multiple Outcome of Raloxifene Evaluation (MORE) study, there was significant decline in risk of vertebral fracture in both 60mg/d (RR:0.7, 95% CI 0.5-0.8) and 120mg/d (RR: 0.5, 95%: 0.4-0.7) regimes of raloxifene. In this study it was also indicated that raloxifene group had significant higher risk of venous thromboembolism vs. placebo (RR: 3.1; 95% CI: 1.5-6.2). On the other hand, raloxifene have a lower incidence of breast cancer vs. placebo group and did not report complain of vaginal bleeding or breast pains. However, raloxifene did not show more beneficial effect in reducing non-vertebral fractures compared to placebo (RR, 0.9; 95% CI 0.8-1.1).20 Moreover, extension of this study determined that there was no difference in the risk reduction on the 4th year alone compared to previous 3 year therapy.21 Thus, indicating the better efficacy and lesser adverse effect in long-term use of raloxifene compared to long-term use of HRT.
Teriparatide is a recombinant human parathyroid hormone that acts to increase osteoblast production and activation yet reduces osteoblasts' programmed cell-death. In a RCT, it was evident that teriparatide produced significant increase (p < 0.001) in BMD of 12 % just after 3 months of therapy. The trial even implied that the action of BMD increment was significantly more effective in teriparatide compared to alendronate (p-value < 0.001). The study also reported significantly lesser (p < 0.05) incidence of non-vertebral fractures in teriparatide group vs. alendronate.22 However, these outcomes could not give a strong correlation on teriparatides' efficacy in fracture prevention because the sample size was relatively small (n=146 for teriparatide study vs. n=3658 for alendronate study) and duration of study was relatively short (14 months vs. average 3 year study).9,22 Moreover, this study uses BMD as endpoint measurement and not fracture risk reductions.
Teriparatide is only licensed for therapeutic use up to an 18 months period with specialists recommendation for certain group of patients: severe osteoporotic postmenopausal women and men or glucocorticoid-induced osteoporosis.3,12,16 The strict rules in using teriparatide is due to the reported increased occurrence of osteosarcoma in male and female rats tested on teriparatide.23 In a follow-up study, a sustained teriparatide effect on risk reduction of vertebral fractures for at least 18 months was indicated though therapy was discontinued. Despite the sustained effect of teriparatide after therapy discontinuation, there is still the need of other drugs for long-term fracture prevention.24
Moreover, teriparatide is one of the most expensive osteoporosis drugs with estimated monthly expenditure of $515.79 compared to other drugs such as bisphosphonates and SERMS with estimated monthly expenditure of $65.23 Furthermore, the drug is administered through subcutaneous injections which pose potential compliance problem.16 Although the use of teriparatide is beneficial in prevention of fractures, the potential occurrence of osteosarcoma limits the therapy use to certain patients and also limits the time period of the therapy.
Calcium and vitamin D supplements.
Calcium and vitamin D are often used as adjuncts to osteoporosis therapy unless the patient has adequate intake of calcium in daily diet and was already on vitamin D supplements.16 There was a significant fracture risk reduction of all types by 12% (p=0·0004) in a meta-analysis study. Also in this study it was proven that minimum doses of 800 IU of vitamin D and 1200 mg of calcium were needed for optimal therapeutic outcome.25
According to guidelines, the first line treatment is bisphosphonates as they reduce fracture risk at all sites and their efficacy is well-established.1,26 Not only does previously mentioned clinical trials support this statement9,10, but a meta-analysis showed that both alendronates and risendronates significantly reduce risk of vertebral and non-vertebral fractures (p ≤ 0.01).27 These results are well-grounded as this study included substantial amount of subjects and specific data on risk reduction of fractures at all sites.
However, Mrs. X was not tolerating bisphosphonates and the nature of intolerance is unknown. If she was not complying with the dosing regimen, there are weekly or even monthly preparations of bisphosphonates that are as effective as daily preparations. In a randomized open-label trial, significantly more subjects (p < 0.0001) preferred once-monthly ibandronate (61%) compared to the once-weekly alendronate (25%) with 17% of subjects who preferred ibandronate group find the side-effects more tolerable.28
With that said, if she was intolerant to bisphosphonates due to side effects of the drugs, there is no beneficial effects of switching to another bisphosphonates as a study showed the switch to second bisphosphonates due to side effects of the first bisphosphonates would have an increased rate of discontinuation on the second bisphosphonates due to side effects (p < 0.05).29 In this situation, the guidelines suggests strontium ranelate or raloxifene as alternative options.26 Strontium ranelate not only has distinguished effect on reducing risk of vertebral fractures but also of non-vertebral fractures.15 This further proven in a RCT where there was relative risk reduction of 16% for all non-vertebral fractures (p=0.04).30 This justifies the use of strontium ranelate as alternative to bisphosphonates as it also causes risk reduction of fractures at multiple sites with lesser gastrointestinal side effects.
Raloxifene was also considered as second-line therapy but it only has significant effect in vertebral fractures.20 This is further proven in a meta-analysis study that determined raloxifenes' significant risk reduction of vertebral fractures (p = 0.01) but not of non-vertebral fractures (p= 0.24).27 Therefore, it could be extrapolated that raloxifene is not a beneficial preventive treatment of fractures at all sites. Moreover, raloxifene posed a threat of venous thromboembolism in osteoporotic patients who already has a high risk of venous thromboembolism.20 Hence, raloxifene is not as suitable as strontium ranelate to replace bisphosphonates. According to guideline 3rd line therapy would be teriparatide.26 Although teriparatide showed risk reduction of fractures at multiple site, its' high cost, side effect and limited period therapy makes it a lesser option compared to strontium ranelate. Moreover, the comparison of efficacy of drugs through outcome of different clinical trials maybe crude as heterogeneity between RCTs maybe large but there are little or even no RCTs done with direct comparison between these drugs. This maybe because drug choice are mostly influenced by drug formulation, cost of therapy, patients' tolerability and compliance to treatment.3,16
In conclusion, Mrs. X will be suggested with a weekly or monthly bisphosphonate if her intolerance is due to poor compliance. However, if Mrs. X is intolerant to bisphosphonates due to its' side effects, Mrs. X will be suggested to use strontium ranelate as it decreases the risk of fractures at all sites and show mild gastrointestinal side effects. Yet, if Mrs. X develops allergic reactions to strontium, it should discontinue immediately and the use of reloxifene or teriparatide will be considered. Additionally, patient should also be counseled on non-pharmacological interventions such as the use of external hip protectors, exercise consistently, decreased alcohol intake and smoking cessation.3,16 It would also benefit Mrs. X if her living quarters could be assessed for potential hazards and improved them. Thus, risk of falling could be reduced.16