Management of established osteoporosis

Transcription

1 Br J Clin Pharmacol 1998; 45: Musculoskeletal Unit, Freeman Hospital, Newcastle upon Tyne, NE7 7DN Introduction individuals whose bone density is lower than expected for their age and who are at greater risk of osteoporotic fractures. Osteoporosis is characterized by a reduction in the amount Although precise and accurate measurements of lumbar of bone in the skeleton, associated with skeletal fragility and spine and femoral neck BMD can be made using DEXA, an increased risk of fractures after minimal trauma. The population-based bone density screening cannot be advo- major osteoporotic fractures are those of the forearm, cated for the prevention of osteoporotic fractures. vertebral body and femoral neck. The lifetime risk of Nevertheless, BMD measurements may be useful in the symptomatic fracture for a 50 year old white woman in the assessment of individuals at high risk of osteoporosis, because UK has been estimated to be 13% for the forearm, 11% for of factors such as early menopause or prolonged oral steroid the vertebra, and 14% for the hip, whilst the corresponding therapy [7]. Bone densitometry may also be helpful in figures for a 50 year old man are 2%, 2%, and 3%, patients with history of peripheral fractures after minimal respectively [1]. It has also been suggested that trauma or those with apparent reduced bone density on forearm fractures, symptomatic vertebral fractures X-ray [7]. and hip fractures occur each year in the UK [2]. Osteoporotic fractures are associated with excess mortality, substantial morbidity and health and social service costs of at least 742 million annually in the UK [2]. Diagnosis of osteoporosis Investigation of osteoporosis Prior to the development of techniques which accurately measure bone density, osteoporosis was usually only diagnosed after a fracture had occurred. The term osteoporosis was therefore reserved for the fracture syndrome resulting from reduced bone density. With the advent of dual energy X-ray absorptiometry (DEXA) bone densitometry and the antigen in men [8, 9]. therapeutic possibility of preventing bone loss, the term osteoporosis is now increasingly used to describe reduced Secondary causes of osteoporosis should be sought by careful history, physical examination and appropriate investigation, as treatment of underlying conditions such as hyperthyroidism, hypogonadism and hyperparathyroidism may reverse the osteoporotic process and increase bone density. Investigations may include full blood count, ESR, biochemical profile, thyroid function tests and serum and urine electrophoresis, together with serum testosterone, sex hormone binding globulin, gonadotrophins and prostate specific Treatment of osteoporosis bone density before fractures have occurred. There is a strong inverse relationship between bone mineral density Treatments for osteoporosis may be classified into antiresorptive (BMD) and fracture risk, with a 2 3 fold increase in fracture agents, such as oestrogens, other hormonal agents, incidence for each standard deviation reduction in bone bisphosphonates, calcitonin, vitamin D and calcium supplements, density [3, 4]. BMD measurements may be expressed as and anabolic agents like anabolic steroids, sodium standard deviation units above or below the mean value for fluoride and parathyroid hormone (PTH). Although antiresorptive normal young adults or relative to the mean value for agents decrease bone resorption, the transient control subjects of the same age, to give T and Z scores uncoupling of bone resorption and formation may lead to a respectively [5, 6]. The T score reflects current fracture risk, modest increase in bone density of 5 10%. In contrast, whereas the Z score predicts life-time fracture risk, although anabolic agents increase bone density by up to 50%, although the relative merits of T and Z scores in clinical practice this is not necessarily associated with a decreased risk remains controversial [6]. of fractures. The World Health Organization (WHO) has defined osteoporosis as a BMD 2.5 standard deviations or more below the mean value for young adults (T score< 2.5), Hormone replacement therapy whilst the term severe or established osteoporosis indicates The use of hormone replacement therapy (HRT) for 5 to that there has also been one or more fragility fracture [5]. 10 years at the time of the menopause prevents the rapid Although the WHO definition is useful for the diagnosis of bone loss that occurs at this time and substantially decreases osteoporosis, it does not necessarily represent a threshold for the risk of fractures [10 12]. Nevertheless, the benefits of treatment. This is important as 70% of women above the previous long term HRT may be lost by the age of 75 years age of 80 years have a T score of less than 2.5, but only [13]. HRT has also been shown to increase spine bone a proportion will sustain an osteoporotic fracture [5]. For density by 5% in older women with established osteoporosis these reasons there has been a trend to use Z scores in [14, 15]. One of these small studies has also shown a 60% interpreting BMD measurements in older people, to identify reduction in the number of further vertebral fractures [14]. HRT is the treatment of choice in younger women with osteoporosis, because of its beneficial effect on climacteric Correspondence: Dr, Musculoskeletal Unit, Freeman Hospital, Newcastle upon Tyne, NE7 7DN. symptoms, ischaemic heart disease and possibly Alzheimer s 1998 Blackwell Science Ltd 95

2 disease. Long term compliance with HRT is often poor, fracture incidence in 70 postmenopausal women receiving because of the return of the menses and concern about the cyclical etidronate, but was inadequately powered to risks of breast cancer and thromboembolic disease. The accurately assess the effect of treatment on overall fracture advent of continuous combined oestrogen progestogen rate [27]. There is also evidence that cyclical etidronate preparations may improve the situation, as they offer the prevents bone loss in normal postmenopausal women benefits of HRT without the need for a regular monthly [30, 31]. bleed. Many women however will experience patchy Cyclical etidronate is now licensed in the UK for the bleeding during the first few months of treatment, although treatment of osteoporosis, the prevention of bone loss in 90% of women are amenorrhoeic after 1 year s treatment. postmenopausal women who are considered at risk of developing osteoporosis and the prevention and treatment Tibolone of corticosteroid-induced osteoporosis, whilst alendronate is currently licensed for the management of osteoporosis in This synthetic agent has weak oestrogenic, progestogenic postmenopausal women. Other bisphosphonates are under and androgenic properties and does not usually cause investigation for the management of osteoporosis, including menstrual bleeding if used in older postmenopausal women. clodronate, pamidronate, tiludronate and risedronate. In addition to relieving climacteric symptoms, it prevents Bisphosphonates are generally well tolerated, but commonly bone loss in normal postmenopausal women [16, 17]. There cause mild gastrointestinal disturbance. More severe is no information on the effect of tibolone on fracture erosive oesophagitis has been reported with aminobisphosphonates incidence, but it has been licensed for the prevention of such as alendronate, although in the majority of postmenopausal osteoporosis. cases, patients were not complying with the recommended instructions on administration or had a past history of upper Selective oestrogen receptor modulators (SERMs) gastrointestinal disease [32]. Whilst high dose or continuously administered etidronate may impair bone mineralisation, no Although tamoxifen is used in the management of breast clinical evidence of osteomalacia has been found with cancer because of its action as an oestrogen antagonist, it intermittent cyclical etidronate therapy [20]. acts as an oestrogen agonist on the skeleton and cardiovascular system, reducing bone loss and decreasing the risk of ischaemic heart disease [18]. There is growing interest in Calcitonin the development of agents with selective oestrogen agonist Calcitonin is a potent antiresorptive agent, having a rapid and antagonist actions on different target tissues. Raloxifene but short lived effect on osteoclast function. A dose-response is a SERM currently under investigation for the management study of intranasal calcitonin in the treatment of women of postmenopausal osteoporosis. It appears to decrease bone with reduced forearm bone density showed significant turnover and has a beneficial effect on serum lipids, without increases in spine bone density of 1 3% over 2 years, stimulating the endometrium [19]. associated with a reduction in the number of vertebral fractures [33]. Another study in postmenopausal women Bisphosphonates with vertebral crush fractures demonstrated that cyclical i.m. calcitonin and calcium supplements decreased the incidence These are powerful antiresorptive agents, which although of vertebral fractures by 60% over 2 years, compared with poorly absorbed by mouth, localise preferentially in bone. an increase in 35% in a group receiving calcium alone [34]. They bind to hydroxyapatite crystals and reduce osteoclast Calcitonin is expensive and associated with side-effects such recruitment and function. As bisphosphonates persist in the as flushing, nausea, vomiting, diarrhoea, dizziness and skeleton for many months, their duration of action is headache. These side-effects may be less with the intranasal prolonged beyond the period of administration [20]. route of administration, although this is not currently Intermittent cyclical etidronate therapy and continuous available in the UK. alendronate treatment both increase spine bone density in women with osteoporosis by 5 8% over 2 to 3 years and reduce the incidence of further vertebral fractures by about Vitamin D 60% [21 25]. Alendronate also increases femoral neck bone With advancing age there is a reduction in cutaneous density by % in 3 years, compared with 1.4% with production and subsequent metabolism of vitamin D. This cyclical etidronate [23, 24, 25]. Recent data from the large leads to a decrease in calcium absorption and PTH mediated Fracture Intervention Trial shows that alendronate treatment bone resorption. A French study in nursing homes and in women with low hip bone density and at least one apartment blocks for the elderly, showed that 800 iu vitamin vertebral fracture significantly increases bone density in the D 3 and 1.2 g elemental calcium daily reduces the risk of hip forearm, spine and femoral neck and decreases the incidence fracture by 43% [35]. A smaller American study of older of fractures at these sites [25]. men and women living at home demonstrated that 700 iu Small controlled studies indicate that cyclical etidronate vitamin D 3 and 500 mg elemental calcium daily had a prevents bone loss from the lumbar spine in patients starting modest beneficial effect on bone density and decreased the oral steroid therapy [26, 27], whilst significantly increasing incidence of non-vertebral fractures [36]. It is unclear if the spine bone density in patients on long term steroids with evidence of osteoporosis [28, 29]. The largest of these studies also showed a significant reduction in vertebral benefits of treatment seen in these studies were due to vitamin D, calcium or the combination of both, but a Finnish study showed that an annual i.m. injection of Blackwell Science Ltd Br J Clin Pharmacol, 45, 95 99

3 iu vitamin D decreases the risk of fractures in elderly people by 25% [37]. In contrast, a Dutch study Fluoride salts showed a small increase in hip bone density with 400 iu Initial studies showed that sodium fluoride increased spine vitamin D 3 daily, but no effect on the incidence of hip bone density by up to 35% over 4 years in women with fractures in elderly people [38]. Vitamin D supplementation vertebral osteoporosis, although this appeared to be at the is probably most appropriate in frail and housebound elderly expense of cortical bone loss [46, 47]. Furthermore, there people, who are at high risk of vitamin D deficiency and was no reduction in vertebral or non-vertebral fracture hip fractures. incidence with fluoride. These studies also showed that sodium fluoride is potentially toxic, causing nausea, vomiting, indigestion and lower extremity bone pain [46, 47]. A Vitamin D metabolites European study using a lower dose of sodium fluoride or monofluorophosphate with calcium and vitamin D Patients with vertebral fractures have lower calcium absorption supplements showed increases in spine bone density of than age-matched control subjects, which may be due 10.8% after 2 years compared with 2.4% with calcium and to reduced serum 1,25 dihydroxyvitamin D concentrations vitamin D alone, but no beneficial effect on fracture or to relative resistance to the action of vitamin D incidence was seen [48]. In contrast, another study using metabolites on the bowel [39]. Malabsorption of calcium in low dose, slow release sodium fluoride shows small increases osteoporosis does not usually respond to physiological doses in spine and hip bone density associated with a reduction in of vitamin D, but may be corrected by low doses of the vertebral fracture incidence [49]. The later studies showed vitamin D metabolites, calcitriol and alfacalcidol [39]. Studies none of the side effect profile described with the higher of the effect of treatment with vitamin D metabolites on dose treatment. Nevertheless, the therapeutic window for bone loss and fractures in established osteoporosis have fluoride appears narrow and this agent cannot yet be produced conflicting results [39]. A study comparing advocated for the management of osteoporosis. calcitriol 0.25 mg twice daily with calcium 1 g daily has shown a significantly lower vertebral fracture incidence with calcitriol, although this was due mainly to an increase in Parathyroid hormone fracture rate with calcium rather than a reduction with PTH increases trabecular bone density by as much as 50%, calcitriol [40]. Subsequent analysis of this study suggests that but as with fluoride this may be at the expense of cortical the beneficial effect of calcitriol on vertebral fractures is bone [50]. More recent work suggests that the combination only seen in women over the age of 65 years. This study also showed a significant reduction in non-vertebral fractures with calcitriol compared with calcium supplements. Treatment with vitamin D metabolites is associated with an increased risk of hypercalcaemia, but this did not appear to be a major problem in this study [40]. Calcium supplements of PTH with calcitonin or oestrogen may increase spine bone density without adverse effects on cortical bone mass at the femoral neck [51, 52]. Selection of patients and choice of treatment The development of effective treatments for osteoporosis, which afflicts large numbers of older men and women, raises important questions about who should be treated. This will depend on the financial resources available, the absolute risk of fracture in the individual, the efficacy of the treatment in reducing fracture incidence and the costs of the therapeutic intervention and that of any fractures averted. The risk of fracture may be assessed by BMD measurement, as there is a 2 3 fold increase in fracture incidence for each standard Although calcium supplements were previously used alone in the treatment of osteoporosis, this is probably no longer appropriate as a number of more effective treatments are now available. Calcium supplements decrease bone loss, but not to the same extent as other antiresorptive agents [41, 42]. There is limited evidence that calcium supplements deviation reduction in bone density [3, 4]. For any given alone may decrease the risk of vertebral fractures in bone density, the risk of fracture is also doubled in the vitamin D replete elderly people [43]. presence of a previous osteoporotic fracture [3]. It is therefore particularly worthwhile targeting treatment on older individuals with lower than expected BMD (Z score < 1.0) and those with a past history of fragility fracture. Anabolic steroids HRT, bisphosphonates and calcitonin are broadly comparable Anabolic steroids such as stanozolol and nandrolone increase in efficacy in the treatment of established vertebral bone mass in osteoporosis by 5 10% [44, 45]. This has osteoporosis, increasing spine bone density by 3 8% over previously been attributed to increased bone formation, but three years and decreasing vertebral fracture incidence by may be due to decreased bone resorption. Anabolic 55 70% [53]. The cost of these treatments varies widely, steroids are associated with androgenic side-effects and fluid resulting in large differences in cost-effectiveness [53]. The retention, whilst prolonged administration may lead to cost of each vertebral fracture averted is for abnormal liver function tests and even hepatocellular HRT, 1880 for cyclical etidronate and for tumours. These adverse effects and the lack of evidence of calcitonin [53]. Further cost-effectiveness work is required a beneficial effect on fracture incidence may limit the use to examine the number of patients needing to be treated to of anabolic steroids in the management of osteoporosis. avert vertebral and hip fractures at different BMD levels 1998 Blackwell Science Ltd Br J Clin Pharmacol, 45,

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