Osteoporosis affects over 200 million people worldwide and it is estimated that 30% of all postmenopausal women suffer from it in the United States of America as well as in Europe.1 It was also found that about 40% of the postmenopausal women having osteoporosis and an approximate 20-30% of men were likely to suffer at least one fracture soon after.2,3 The major complication of this disease is the development of fragility fractures which lead to morbidity, reduced quality of life and eventually mortality. In 2000, it was roughly estimated that there were 3.79 million osteoporotic fractures sustained only in Europe itself.4
Osteoporosis can be split into two categories, primary and secondary. Primary osteoporosis is a metabolic disorder that affects the bones systemically and is presented by low bone density and a degeneration of the microarchitecture of the bone tissues.5 This result in brittle and fragile bones which will then eventually lead to high fracture risks. This loss in bone mass and density is directly related to an increase in age in men and women who suffer no other chronic diseases, which include a reduced activity of the gonads in postmenopausal women. Secondary osteoporosis however is caused by other chronic diseases or medications, specifically steroids, which indirectly results in loss of bone mass. Osteoporosis is known as a ‘silent disease' as the thinning of bones is asymptomatic and many are unaware that they are suffering from osteoporosis only until they sustain a fracture due to brittle bones. Fragility fractures are the clinically evident consequence of this disease. Figure 1 shows the difference between a normal bone and one with osteoporosis. The most common bone breaking sites are located at the hips, wrists and spine. Other effects of osteoporosis include chronic pain caused by vertebrae compression, physical deformities such as Dowager's hump, which is the curving of the spinal column forward resulting in a stooped posture and a general loss of height.
The main cause of osteoporosis is simply an imbalance in bone formation and bone resorption. There are several mechanisms that contribute to this imbalance. Firstly, it is the insufficient peak bone mass which in other words means that during growth, the skeletal bones have inadequate strength and mass. Bone mass peaks by 30 years of age and thereafter, it will then gradually decline. The major factor that confers to osteoporosis is that maximum bone strength is not achieved by the third decade of life. Apart from that, the other two mechanisms involved include an excess in bone resorption as well as insufficient new bone formation during the remodeling process. In an average adult, bones continually undergo remodeling in order to sustain bone strength. Fundamentally, osteoclasts, originating from the bone marrow, are responsible for bone resorption whereas osteoblasts function to form new bones. Osteocytes (differentiated osteoblasts), which are located in mineralized bone are involved in regulation of time and location of remodeling. The reason to why bone formation and resorption are so closely inter-related is because osteoblasts, not only produce and mineralize osteoids for bone formation but they are also found to govern the bone resorption process of osteoclasts. Due to the fact that there is a difference in time duration of both processes, i.e. bone resorption take weeks whereas bone formation require a matter of months, an acceleration of bone remodeling will generate a nett loss in bone mass over a period of time.7 This accelerated remodeling is seen during postmenopausal periods and hence there is high chance of fractures occurring as the bones have less minerals, therefore less densed, and also accompanied with damaged collagen maturation.8 Not only that, hormonal factors come into play as well in the pathogenesis of osteoporosis as they are one of the driving forces for the rate of bone resorption. Estrogen deficiency increases the rate of bone resorption as well as reducing the rate of bone formation in both men and women, particular those who are postmenopausal. It also enhances bone sensitivity to PTH (parathyroid hormone) effects. PTH effects are directly linked to calcium levels in the body and due to this, calcium is also crucial in bone remodeling. When calcium levels are particularly low, the parathyroid glands are stimulated to release PTH which then leads to an increase in bone resorption, in order counter the low calcium levels and to maintain adequate amounts of calcium in the body. This response is known as secondary hyperparathyroidism and can also be caused by vitamin D deficiency.9
There are several pharmalogical treatment options for osteoporosis. Firstly, drugs that reduce or prevent bone resorption may be used. These antiresorptive agents include drugs such as bisphosphonates, estrogen analogues via HRT (hormonal replacement therapy), raloxifene, and calcitonin. Bisphosphonates are widely used in both treatment and prophylaxis of osteoporosis and they work by adsorbing onto hydroxyapatite crystals in the bone, slowing their growth rate and dissolution rate, and ultimately reducing the rate of bone turnover.10 Some examples of bisphosphonates include alendronic acid, disodium etidronate, disodium pamidronate, ibandronic acid, risedronate sodium, sodium clodronate, tiludronic acid, and zoledronic acid. Bisphosphonates are available in a number of dose frequencies varying from daily, weekly, twice monthly, monthly, once every three months or even once yearly, depending on the route of administration, either orally or via an intravenous injection. However, side effects of bisphosphonates have been reported to occur and these for oral bisphosphonates include severe oesophageal reactions such as retrosternal pain, dysphagia, and gastrointestinal problems such as heartburn. This may be minimized by remaining upright for at least 30 minutes after administration. Common side effects of intravenous bisphosphonates on the other hand include fever and influenza-like symptoms, headaches, nausea, vomiting and diarrhoea have been said to occur but should go away within a few days. Osteonecrosis of the jaw has been reported in patients receiving both intravenous and oral bisphosphonates and hence, oral hygiene must be maintained throughout treatment with bisphosphonates. Recent studies have shown that the use of bisphosphonates contributes as a risk factor for atrial fibrillation in women however the causal explanation for that is still unclear and that the benefits still outweigh the risks for that of bisphosphonate.11 HRT is an option where other therapies are contra-indicated, cannot be tolerated, or if there is lack of response.10 The CSM (Committee on Safety of Medicines) has also advised that HRT should not be considered as first-line therapy for the long-term prevention of osteoporosis in women above 50 years, but is most beneficial in prophylaxis of postmenopausal osteoporosis if started early during menopause and continued for up to 5 years. However, bone resorption recurs on discontinuation of HRT, with possibility at it occurring at a higher rate instead. Raloxifene is licensed for both treatment and prevention of postmenopausal osteoporosis, and it differs from HRT as it does not lessen the vasomotor symptoms of menopause.10 It is an oral SERM (selective estrogen receptor modulator) which means that it has selective activity in different sites, that is, exerting agonistic oestrogen actions on the bone, whilst having antagonistic effects on the uterine and breast. This augments the clinical effects on the bone and diminishes adverse side effects on other sites of the body. The common side effects of raloxifene are hot flushes, leg cramps, peripheral oedema and influenza-like symptoms. However, according to the NICE guidance, raloxifene is not a recommended treatment option in postmenopausal women for primary prevention of osteoporotic fractures. Calcitonin is involved with PTH in bone remodeling regulation as well as calcium balance and homeostasis. Based on a recent study, it has been explained that calcitonin acts on osteoclasts hence reducing bone resorption and bone turnover.11 It is also said that calcitonin may provide analgesia in patients suffering from fractures although this remains controversial. Calcitonin can be administered subcutaneously, intramuscularly or even nasally. Side effects of calcitonin include gastrointestinal disturbances, flushing, dizziness, headache, and with nasal spray, nose and throat irritation, rhinitis, sinusitis and epistaxis.
Apart from antiresoptive agents, drugs that stimulate bone formation may be used, and they are also known as bone anabolic agents. Examples of these are human recombinant parathyroid hormone and teriparatide. Human recombinant parathyroid hormone is used for the treatment of postmenopausal osteoporosis aimed to reduce the risk of vertebral fractures and is administered subcutaneously. However, in February of 2007, The Scottish Medicines Consortium has advised that parathyroid hormone should only be initiated by specialist experienced in osteoporosis treatment. Teriparatide is a recombinant fragment of PTH and is also administered subcutaneously. The FDA (Food and Drug Association) though has included a black box warning denoting that there may be a slight chance that teriparatide may cause an increased risk in osteosarcoma, a primary malignancy of the bone, but has also concluded that clinical trials support the dosage administrations of teriparatide of 20μg per day being effective and safe, in addition to it improving the microarchitecture of the bones as well as increasing bone density and for preventing fractures. The setback of these two treatment options is that they are extremely expensive with the price of Preotact® (parathyroid hormone) at approximately ₤130.20 per 14-dose cartridge and Forsteo® (teriparatide) at about ₤271.88 per 28-dose prefilled pen.
Lastly, strontium ranelate may be used and it is a unique drug as it stimulates bone formation and decreases resorption of bone simultaneously. The Scottish Medicines Consortium has advised in July 2005 that strontium ranelate should only be used if bisphosphonates are contra-indicated or not tolerated, and then in women over 75 years with previous fractures and low bone mineral density, or in other women at similar risks.10 Severe allergic reactions have been reported with the use of strontium ranelate and these include DRESS (drug rash with eosinophilia and systemic symptoms), which can be fatal.
A routine aspect of treatment for osteoporosis is calcium and vitamin D supplements. Surveys have shown that many do not consume enough calcium in their daily diet and insufficient calcium supply over time leads to osteoporosis. According to the National Institute of Health, 1,300mg of calcium per day is recommended for those above 50 and in osteoporosis, twice the recommended amount of calcium intake slows down the rate of bone loss.10, 13 Vitamin D is a term used for a group of compounds that include ergocalciferol (calciferol, vitamin D2), colecalciferol (vitamin D3), dihydrotachysterol, alfacalcidol (1α-hydroxycholecalciferol), and calcitriol (1,25-dihydroxycholecalciferol).10 Vitamin D is converted to its active form in the kidneys, and its hydroxylated derivatives are alfacalcidol and calcitriol. Calcitriol regulates calcium in the body via two ways. It stimulates calcium absorption from food in the intestines as well as calcium reabsorption to the bones from the kidneys. Calcitriol is licensed for the management of established postmenopausal osteoporosis.10
Referring to the case scenario stated above, the elderly patient has suffered at least 2 fractures and cannot tolerate bisphosphonates. This instantly rules out the recommended first-line treatment option for this case, the secondary prevention of osteoporotic fractures in postmenopausal women who has established osteoporosis, which is alendronate. The second alternative would be risedronate and etidronate but since this patient is intolerant of bisphosphonates altogether, the third option would be to use either strontium ranelate or raloxifene.14
If considering strontium ranelate as the treatment option, the patient's renal profile should be measured prior to treatment as strontium ranelate is contra-indicated in patients with severe renal impairment. It should also be used in caution if she is predisposed to thromboembolism. The recommended dosage for strontium ranelate would be 2g once daily in water, preferably at bedtime. Food and antacids containing aluminium and magnesium hydroxides should be avoided 2 hours before and after administration, especially calcium-containing products such as milk as this will reduce absorption of the drug. 28-sachets, each containing 2g of strontium ranelate costs ₤25.60, which amounts to an approximate of ₤330 annually. Several trials have shown that strontium ranelate reduced risk of both vertebral and non-vertebral fractures and provided advantages in improving QALY (quality adjusted life-years) but there was also significant risk of adverse effect of venous thromboembolism associated with it.14 From two multinational trial studies; the SOTI (Spinal Osteoporosis Therapeutic Intervention) and the TROPOS (Treatment of Peripheral Osteoporosis) studies, results showed significant reduction in the relative risk of experiencing first new vertebral and non-vertebral fracture, and hip fracture.15, 16 Not only that, the adverse effects of strontium ranelate did not show significant difference as compared to placebo.16
If raloxifene was to be considered as treatment, the patient must not have had a history of venous thromboembolism, undiagnosed uterine bleeding, endometrial cancer, hepatic impairment, or cholestatis as these are contra-indications of raloxifene treatment.10 Raloxifene is given as raloxifene hydrochloride tablets at a recommended dose of 60mg once daily. Sold in packs of 28 for ₤17.06 or in an 84-tablet pack for ₤59.59, treatment would cost an average of about ₤240 yearly. From the MORE (Multiple Outcomes of Raloxifene Evaluation) study, risk of new vertebral fractures was reduced as was the risk of breast cancer in postmenopausal women with the use of raloxifene. In addition to that, BMD (bone mineral density) was increased and maintained with 3 years of raloxifene therapy.17, 18 In order to determine which of these two drugs should be used, there is a need to balance the clinical effectiveness and patient's tolerability to it as different individuals respond differently to each treatment.19
The next alternative treatment option, should the patient be intolerant of strontium ranelate, would be teriparatide.19 Symptoms of intolerance of strontium ranelate include persisting nausea or diarrhoea. As stated previously, teriparatide is administered by subcutaneous injection in the recommended dose of 20μg daily, and the maximum duration of treatment should only be 18 months and not to be repeated. As teriparatide costs ₤271.88 for a 3ml prefilled pen intended for 28 doses, one year's treatment would cost approximately ₤3,500. Teriparatide is contraindicated if the patient has severe renal impairment, pre-existing hypercalcaemia, skeletal malignancies or bone metastases, metabolic bone diseases, including Paget's disease and hyperparathyroidism, unexplained raised alkaline phosphatase, or previous radiation to the skeleton.10 Several studies have shown that with teriparatide treatment, there was significant BMD and BMC (bone mineral content) increase in both men and postmenopausal women.20 However, continuous monitoring should be carried out for adverse effects like hypercalcaemia and urinary calcium excretion as there was evidence showing effects of that with teriparatide therapy.21 There was a study which showed that teriparatide treatment had high compliance and patient acceptance, and although it is very expensive, it may be cost-effective in some patients.22, 23
At the same time, the patient should also be given calcium and vitamin D supplements. Adcal-D3® tablets are now the product of choice since Calcichew-D3® Forte was removed due to Adcal-D3® being evidence based equivalent at a lower cost. One tablet should be taken once daily to maintain adequate amounts of both calcium and vitamin D in the body. Adcal-D3® contains 1.5g of calcium carbonate (calcium 600mg or Ca2+ 15mmol) and 10μg of colecalciferol (400 units).10 Based on two meta-analyses carried out in 2005 and 2007, there was significant evidence showing that calcium and vitamin D supplementation lead to positive clinical benefits in reducing fracture risk and bone loss in osteoporosis.24, 25
Ultimately, the choice of treatment would rely on both clinician and patient, considering other factors such as the relative efficacy, adverse effects, costs, route of administration of treatment, and patient monitoring. The patient's condition including compliance factors, and co-morbidities should also be taken into consideration prior to determining the ideal choice of treatment for her.