VOL: 98, ISSUE: 10, PAGE NO: 52
Anne Sutcliffe, BSc, RGN, DN, RHV, is osteoporosis specialist nurse, Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS TrustAgents that decrease bone turnover include hormone replacement therapy (HRT), raloxifene, bisphosphonates, calcitonin, vitamin D and calcium supplements. Anabolic agents that increase bone mass include anabolic steroids, sodium fluoride and parathyroid hormone (PTH). The antiresorptive agents are used commonly in clinical practice in the UK, whereas the anabolic agents are given under specialist supervision.
Agents that decrease bone turnover include hormone replacement therapy (HRT), raloxifene, bisphosphonates, calcitonin, vitamin D and calcium supplements. Anabolic agents that increase bone mass include anabolic steroids, sodium fluoride and parathyroid hormone (PTH). The antiresorptive agents are used commonly in clinical practice in the UK, whereas the anabolic agents are given under specialist supervision.
Hormone replacement therapy
There has been a dramatic rise in the number of HRT preparations in the UK in the past five years. Currently more than 50 are available, offering a variety of dosing schedules and routes of administration. The literature demonstrates that if HRT is initiated at the onset of oestrogen deficiency it will prevent expected bone loss in the majority of women for the duration of therapy.
The extent to which bone density is maintained after cessation of therapy remains debatable, but epidemiological data now suggests that a proportion of the skeletal benefit will be lost in later years if HRT is discontinued.
Other potential benefits include a possible decrease in cardiovascular mortality and a possible delay in the development of Alzheimer's disease. Initial side-effects may include breast tenderness, fluid retention, abdominal bloating, leg cramps, nausea and mood swings. Many of these will subside with continuing treatment or may be resolved by changing to an alternative preparation.
HRT is also effective in treating established disease. It has been shown to increase spine bone density by 5% in older women with established osteoporosis ((Lufkin et al, 1992). This study also showed a 60% reduction in the number of further vertebral fractures. Long-term compliance with HRT for both prevention and treatment of osteoporosis remains poor because of the risks of breast cancer and thromboembolic disease. There is an association between duration of use and the risk of breast cancer that may limit the acceptable duration of therapy. Meta analyses suggest that this risk increases with more than five years' use of HRT (Collaborative Group on Hormonal Factors in Breast Cancer, 1997).
The withdrawal bleed from sequential therapy has commonly been cited for the reason for discontinuing treatment. Data on the use of continuous combined therapies have revealed compliance rates of 80% (Udoff, 1995), and it has been shown that three years' use of continuous combined therapy had a significantly better effect on bone mass density than sequential therapy (Nielsen et al, 1994). Data on the impact of continuous combined therapy on very long-term compliance are still unavailable, but its use may have major implications in the future.
The lay public is often tempted to use natural remedies, as they are perceived to be risk-free. Lee has suggested that progesterone, not oestrogen deficiency, is the major cause for excess bone loss. His work demonstrated that the use of natural progesterone cream, derived from the wild yam, increased bone density by approximately 15% (Lee, 1991). However, significant doubts have been cast on the scientific reliability of these findings. Leonetti et al showed that transdermal progesterone cream had no protective effect on bone density after one year (1999). Recent results have demonstrated that natural progesterone cream may alleviate vasomotor symptoms in some women but does not prevent bone loss among healthy postmenopausal women (Pearson et al, 2001).
Tibolone is a synthetic analogue of the gonadal steroids that has combined oestrogenic, progestogenic and androgenic properties.It is effective in controlling vasomotor symptoms and also prevents bone loss (Rymer et al, 1994). In women at least one year post-menopause it does not cause endometrial proliferation, so there is no withdrawal bleed.
Raloxifene is a selective oestrogen receptor modulator that exerts oestrogenic activity on bone. It prevents bone loss and significantly decreases vertebral fracture risk in postmenopausal women. The effects of raloxifene on coronary heart disease morbidity and mortality have not been established. However, it favourably lowers serum cholesterol (Cummings et al, 1999). The relative risk of breast cancer while taking raloxifene is significantly reduced, although this benefit is seen only for oestrogen receptor positive tumours (Cummings et al, 1999).
These are powerful antiresorptive agents that bind to hydroxyapatite crystals and reduce osteoclast function. As bisphosphonates persist in the skeleton for many months their duration of action is prolonged beyond the period of administration (Francis, 1995). Three bisphosphonates are now licensed for use in both postmenopausal and glucocorticoid-induced osteoporosis: cyclical etidronate, alendronate and risedronate. Etidronate is given cyclically and intermittently with calcium, and risedronate is given as a single 5mg daily dose without calcium. Alendronate is available as a 10mg daily dose but may also be prescribed as a once-weekly 70mg preparation. All drugs improve bone density in women with osteoporosis by 5-8% over two to three years and reduce the incidence of further vertebral fractures by about 60% (Harris et al, 1993; Liberman et al, 1995; Harris et al, 1999).
Daily alendronate increases femoral neck bone density by 4.1-5.9% in three years (Black et al, 1996) and is also very effective in reducing the incidence of other non-vertebral fractures (Pols et al, 1999). Clearly once-weekly medication offers a significant benefit to patients, and the efficacy of alendronate 70mg weekly is similar to that of the daily preparation (Schnitzer et al, 2000).
The results of a large study to investigate the efficacy of risedronate in prevention of hip fracture have recently been published in abstract form (Guesens et al, 2000). In risedronate-treated women with low femoral neck bone density there was a 39% reduction in hip fracture and in women with both low femoral neck bone density and a prevalent vertebral fracture the reduction in hip fracture was 58%.
Bisphosphonates are generally well tolerated but commonly cause mild gastrointestinal disturbance. More severe erosive oesophagitis has been reported with alendronate, although in the majority of cases, patients were not complying with the instructions on administration or had a past history of upper gastrointestinal disease (de Groen et al, 1996).
Calcitonin is a potent antiresorptive agent, having a rapid but short-lived effect on osteoclast function. In the UK it is given by subcutaneous or intramuscular injection but is available as a nasal spray in other countries.
Effects of calcitonin on fracture rates have recently been summarised in a systematic review (Kanis and McCloskey, 1999). This suggested that calcitonin treatment was associated with a significant decrease in the number of vertebral and non-vertebral fractures, but that these benefits may be lower than those from bisphosphonates. Parenteral calcitonin is expensive and associated with side-effects such as flushing, nausea, vomiting, diarrhoea, dizziness and headache. These side-effects are less with intranasal calcitonin, but as this is not available in the UK its clinical use is limited.
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 (Reid et al, 1993).
Calcium and vitamin D
With advancing age there is a reduction in cutaneous production and subsequent metabolism of vitamin D, which leads to a decrease in calcium absorption and PTH- mediated bone resorption.
A French study in nursing homes and apartment blocks for the elderly showed that 800mg of vitamin D3 and 1.2g of elemental calcium daily reduces the risk of hip fracture by 43% (Chapuy et al, 1992). In a recent placebo-controlled study of 389 men and women aged 65 and older 500mg of calcium and 700mg of vitamin D were associated with a 60% reduction in the incidence of all fractures over a three-year follow-up (Dawson-Hughes et al, 1997). These studies support the view that the use of calcium and/or vitamin D, even relatively late in life, may be beneficial.
Vitamin D and vitamin D metabolites
Vitamin D supplementation is probably most appropriate in frail and housebound elderly people who are at high risk of vitamin D deficiency and hip fractures.The vitamin D metabolites most widely used are calcitriol and alfacalcidol. Studies of the effect of treatment with vitamin D metabolites on bone loss and fractures in established osteoporosis have produced conflicting results, with some showing substantial increases in bone density, others showing little effect (Francis et al, 1996).
Anabolic steroids, such as stanozolol and nandrolone, increase bone mass in osteoporosis by 5-10% (Guesens et al, 1986). However, osteopoprosis is predominantly a problem of the female population and the masculinising effects of androgens in women make these unacceptable as a treatment for postmenopausal osteoporosis. Adverse effects and the lack of evidence of a beneficial effect on fracture incidence will limit the use of anabolic steroids in the management of osteoporosis.
Fluorides are not licensed in this country and are given only under specialist supervision. Although they have a marked anabolic effect on cancellous bone in the spine their efficacy remains controversial (Reginster et al, 1998). Toxic side-effects include nausea, vomiting, indigestion and lower-extremity bone pain (Riggs et al, 1990). The therapeutic window for fluoride remains narrow and this agent cannot be advocated for the management of osteoporosis.
The first indications that PTH might have an anabolic effect on the skeleton emerged over 60 years ago. Animal studies over the past 20 years have demonstrated positive effects on bone density, with an increase in structural strength at all sites. Evidence from recent clinical trials show encouraging results in postmenopausal women (Body et al, 2001) and in men with idiopathic vertebral osteoporosis (Kaufman et al, 2001). It is envisaged that PTH, in the form of a self-administered injection, may be available in UK within the next two years.
Choice of treatment
HRT, bisphosphonates and calcitonin are broadly comparable in efficacy in the treatment of vertebral osteoporosis, increasing spine bone density by 3-8% over three years and decreasing vertebral fracture incidence by 55-70% (Francis et al, 1995). The cost of these treatments varies widely, resulting in large differences in cost-effectiveness (Francis et al, 1995).
HRT is the treatment of choice for younger women with established osteoporosis, while bisphosphonates are useful in older women who may be unwilling or unable to take HRT. Raloxifene is an option for postmenopausal women with evidence of vertebral osteoporosis. Vitamin D supplementation plus calcium should be considered in frail and housebound elderly people, who are at high risk of vitamin D deficiency and hip fractures.
In an attempt to guide clinical practice the Royal College of Physicians (2000) has produced evidence-based guidelines detailing interventions for the prevention and treatment of osteoporosis. The grading of evidence base and effect of interventions are shown in Tables 1 and 2.
Implications for nursing practice
Although nurses are not yet in a position to prescribe drugs for the prevention and treatment of osteoporosis it is important they are aware of the efficacy, benefits and side-effects of treatment. The timing and method of administration may affect optimum effectiveness of drugs. For example, bisphosphonates are poorly absorbed and etidronate must be taken at least two hours before and after food, while alendronate and risedonate should ideally be taken at least 30 minutes before the first food of the day.
Therapies for the prevention or treatment of osteoporosis will need to be taken for several years, and therefore long-term compliance is essential.
If HRT is used the woman should be made aware of side-effects that commonly occur in the early months of treatment. Reassurance that these are often transient and may lessen with continuing treatment will aid initial compliance. Changing to a different HRT preparation may reverse persistent side-effects. Once HRT is established, it is still important to offer advice and information, when appropriate, to encourage long-term compliance.