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Clinical and therapeutic aspects of osteoporosis
European Journal of Radiology 71 (2009) 388–391
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Clinical and therapeutic aspects of osteoporosis Juliet Compston ∗ University of Cambridge School of Clinical Medicine, Box 157, Department of Medicine, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK
a r t i c l e
i n f o
Article history: Received 20 April 2008 Accepted 30 April 2008 Keywords: Osteoporosis Fracture Postmenopausal women Glucocorticoids Bisphosphonates
a b s t r a c t Osteoporosis is characterized by reduced bone mass and alteration in bone architecture, resulting in increased fracture risk. These fractures are a major cause of morbidity and mortality in the elderly and impose a huge economic burden on health services. Oestrogen deficiency plays a major role in the pathogenesis of bone loss and fracture in both women and men. Other pathogenetic factors include reduced physical activity and vitamin D insufficiency. A range of options is available for the prevention of fractures in high risk postmenopausal women. These include the bisphosphonates, strontium ranelate, raloxifene and parathyroid hormone peptides. Because of their broad spectrum of demonstrated anti-fracture efficacy, alendronate, risedronate, zoledronate and strontium ranelate are generally considered as front-line options for most women. The optimum duration of treatment has not been established but re-evaluation of risk and the need for continued therapy after 5 years of treatment may be appropriate. Compliance and persistence with long-term treatment is poor but may be improved by less frequent dosing regimens. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Osteoporosis is characterized by a reduction in bone mass and disruption of bone architecture, resulting in increased bone fragility and an increase in fracture risk. These fractures are a major health problem in the elderly population, leading to significant morbidity and mortality and resulting in an estimated annual cost to health services of £1.8 billion in the UK and D 30 billion in Europe. One in two women and one in five men over the age of 50 years will suffer a fracture due to osteoporosis during their remaining lifetime. Demographic changes over the next few decades will result in at least a doubling in the number of these fractures [1]. 2. Epidemiology The incidence of osteoporotic fractures increases markedly with age; in women, the median age for Colles’ fractures is 65 years and for hip fracture, 80 years. The age at which vertebral fracture incidence reaches a peak is less well defined but is thought in women to be between 65 and 80 years. In men, no age-related increase in forearm fractures is seen but hip fracture incidence rises exponentially after the age of 75 years. The prevalence of vertebral fractures rises with age in men, although less steeply than in women. Data from EVOS (European Vertebral Osteoporosis Study) have demonstrated
∗ Tel.: +44 1223 336867; fax: +44 1223 336846. E-mail address: [email protected]. 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2008.04.063
that the age standardized prevalence in the European population is 12.0% for women and 12.2% for men aged 50–79 years., with an overall age standardized incidence of 10.7 per 1000 person-years in women and 5.7 per person-years in men [2]. Both vertebral and hip fractures are associated with excess mortality, part of which is due to associated co-morbidities rather than to the fracture itself. 3. Clinical features Colles’ fractures of the radius typically occur after a fall forwards on to the outstretched hand. They cause considerable inconvenience, usually requiring 4–6 weeks in plaster and long-term adverse sequelae occur in up to one-third of patients. These include pain, sympathetic algodystrophy, deformity, and functional impairment. Vertebral fractures may occur spontaneously or as a result of normal activities such as lifting, bending, and coughing. A minority of vertebral fractures (possibly around one-third) present with acute and severe pain at the site of the fracture, often radiating around the thorax or abdomen. The natural history of this pain is variable; in general, there is a tendency for improvement with time but resolution is often incomplete. Multiple vertebral fractures result in spinal deformity (kyphosis), height loss, and corresponding alterations in body shape with protuberance of the abdomen and loss of normal body contours. These changes are commonly associated with loss of self-confidence and self-esteem, difficulty with daily activities, and increased social isolation. The clinical impact of vertebral fractures is thus substantial, although often underestimated.
J. Compston / European Journal of Radiology 71 (2009) 388–391
389
Table 1 Interventions that are approved for prevention/treatment of osteoporosis in postmenopausal women. Bisphosphonates Alendronate Etidronate Ibandronate Risedronate Zoledronate
Fig. 1. Lifetime changes in bone mass (BMD = bone mineral density).
Of all the osteoporotic fractures, hip fractures cause the greatest morbidity and mortality. They almost always follow a fall, usually either backwards or to the side, and require surgical treatment. Because hip fractures characteristically affect frail elderly people, postoperative morbidity and mortality are high; at 6 months after fracture, mortality rates of 12–20% have been reported. Only a minority of patients with hip fracture regain their former level of independence following a hip fracture and up to one-third require institutionalized care. 4. Pathogenesis Lifetime changes in bone mass are shown in Fig. 1. Peak bone mass is attained in the third decade of life and age-related bone loss is believed to start in both men and women around the beginning of the fifth decade; thereafter bone loss continues throughout life. In women, there is an acceleration of the rate of bone loss around the time of the menopause, the duration of which is poorly characterized but may be 5–10 years Bone mass in later life thus depends both on the peak bone mass achieved in early adulthood and on the rate of age-related bone loss. Genetic factors strongly influence peak bone mass, accounting for up to 70–80 per cent of its variance. A number of genes are likely to be involved; these include the collagen type IA1 gene, a polymorphism of which is associated both with low bone mineral density and fracture risk [3]. Sex hormone status, nutrition, and physical activity also influence peak bone mass. In postmenopausal women, oestrogen deficiency is the main cause of menopausal bone loss. In older men, oestrogen status is also significantly related to bone mineral density levels whereas the relationship between age-related bone loss and declining testosterone levels is less prominent. In the elderly, vitamin D insufficiency and secondary hyperparathyroidism are common and contribute to age-related bone loss, particularly in cortical bone. Other potential pathogenetic factors include declining levels of physical activity and reduced serum levels of insulin-like growth factors. 5. Pharmacological interventions
Calcitonin Calcitriol Hormone replacement therapy PTH[1–84] Raloxifene Strontium ranelate Teriparatide
Because of their broader spectrum of anti-fracture efficacy alendronate, risedronate, zoledronate and strontium ranelate are generally regarded as front-line options in the prevention of fractures in postmenopausal women [4]. This distinction is important because once a fracture occurs, the risk of a subsequent fracture at any site is increased independent of bone mineral density, and hence an intervention that covers all major fracture sites is preferable. Cost is also an important consideration. In countries where generic alendronate is available this is the most cost-effective option, although other bisphosphonates and strontium ranelate are also cost-effective in the secondary prevention of fracture and in primary prevention in high risk women [5]. Strontium ranelate has a particularly strong evidence base in the very elderly (women aged ≥80 years) [6] and is a useful option in frail individuals who are unable to comply with the dosing instructions for bisphosphonates. Alternatively, intravenous zoledronate may be considered in such patients. Because of the lack of evidence for efficacy against hip fractures, raloxifene and ibandronate are generally considered second-line options. The use of parathyroid hormone peptides is limited in many countries by their cost to women with severe vertebral osteoporosis who are intolerant to or appear to be unresponsive to other treatments. Reduction in fracture risk has been shown to occur within one year of treatment for bisphosphonates and strontium ranelate. This is particularly important in the case of vertebral fractures, since after an incident vertebral fracture there is a 20% risk of a further fracture occurring within the next 12 months, emphasizing the importance of prompt treatment once a fracture has occurred [7]. The optimum duration of treatment is uncertain. There are potential concerns that long-term treatment with potent antiresorptives may increase bone microdamage and suppress its repair, possibly resulting in increased bone fragility. However, this concern has to be counterbalanced against the possibility that increased bone turnover and bone loss after withdrawal of therapy may result in increased fracture risk. The current consensus is that treatment should be continued for a minimum of 5 years; in those who remain at high risk (based on bone mineral density [BMD] levels, incident fractures during treatment and the presence of other risk factors), longer treatment periods may be indicated.
5.1. General considerations 5.2. Bisphosphonates Interventions that are approved for the prevention and treatment of osteoporosis are shown in Table 1. Most of these are approved only for the treatment of postmenopausal osteoporosis. However, alendronate, etidronate, risedronate, zoledronate and teriparatide are approved for the prevention and treatment of glucocorticoid-induced osteoporosis in Europe and alendronate, risedronate and teriparatide are approved for the treatment of osteoporosis in men.
The bisphosphonates are synthetic analogues of the naturally occurring compound pyrophosphate and inhibit bone resorption. Alendronate, risedronate and ibandronate are available as oral formulations (70 mg once weekly, 35 mg once weekly and 150 mg once monthly respectively). Oral bisphosphonates are generally well tolerated. Upper gastrointestinal side-effects may occur with nitrogen-containing
390
J. Compston / European Journal of Radiology 71 (2009) 388–391
bisphosphonates (alendronate, risedronate and ibandronate), particularly if the dosing regimen is not adhered to. It is therefore important that patients take the drug according to the instructions, namely in the morning with a full glass of water, 30–60 min before food, drink, or other medications, and remaining standing or sitting upright for that time. Ibandronate and zoledronate are available as intravenous formulations. The former is given as an injection over 15–30 s every 3 months, whereas zoledronate is administered as an intravenous infusion over 15 min at a dose of 5 mg once yearly. An acute phase reaction may occur, particularly with the first injection, resulting in flu-like symptoms for 24–48 h. Anti-fracture efficacy has not been shown directly for the intravenous ibandronate formulation or for the 150 mg once monthly regimen, but is assumed from a bridging study based on bone mineral density changes [8]. Zoledronate has been demonstrated to reduce vertebral, non-vertebral and hip fractures in women with postmenopausal osteoporosis and also reduces the incidence of recurrent clinical fractures in patients who have suffered a hip fracture [9,10]. 5.3. Strontium ranelate Strontium ranelate is composed of two atoms of stable strontium with ranelic acid as a carrier. Although its mechanism of action remains to be fully defined, there is some evidence that it strengthens bone by altering its material properties. Its use is associated with a substantial increase in BMD in the spine and hip, although part of this increase is artefactual, due to incorporation of high atomic number strontium into bone. Strontium ranelate has been shown to reduce vertebral and nonvertebral fractures in postmenopausal women with osteoporosis [11,12]. In a post hoc analysis in older women with low hip bone mineral density, it was also shown to reduce hip fractures. It is taken as a single daily dose and is generally well tolerated. There is a small increase in the frequency of diarrhoea, nausea and headache. There is also a small increase in the risk of venous thrombo-embolic disease (OR 1.42 95% CI 1.02, 1.98). Very rarely, hypersensitivity reactions may occur. 5.4. Raloxifene Raloxifene is a selective oestrogen receptor modulator that has oestrogenic (antiresorptive) effects in the skeleton without the unwanted effects of oestrogen in the breast and endometrium. It is taken orally as a single daily dose. Reduction in vertebral, but not non-vertebral or hip, fractures has been demonstrated in postmenopausal women with osteoporosis [13]. Adverse effects include leg oedema, leg cramps, hot flushes and a two- to threefold increase in the risk of venous thromboembolism. Its use is associated with a significant decrease in the risk of breast cancer. A recent study indicates that raloxifene therapy results in a small increase in the risk of stroke [14]. 5.5. Parathyroid hormone peptides Teriparatide (recombinant human 1–34 parathyroid hormone peptide), and Preotact, (recombinant human 1–84 parathyroid hormone peptide) are administered by subcutaneous injection in daily doses of 20 g and 100 g, respectively. They have anabolic effects on bone, increasing bone formation and producing large increases in bone mineral density in the spine. Teriparatide has been shown to reduce both vertebral and non-vertebral fractures in postmenopausal women with osteoporosis after a median treatment period of 21 months, whereas reduction only in vertebral fractures was shown after 18 months treatment with Preotact [15,16]. Side-effects include nausea, headache and dizziness; in addition,
transient hypercalcaemia and hypercalciuria may occur, particularly with Preotact. 5.6. Hormone replacement therapy (HRT) Because the risk/benefit balance of HRT is generally unfavourable in older postmenopausal women, it is regarded as a second line-treatment option. However, it is an appropriate option in younger postmenopausal women at high risk of fracture, particularly those with vasomotor symptoms. 5.7. Calcium and vitamin D Available evidence does not support a role for calcium and vitamin D alone in prevention of osteoporotic fractures except in the institutionalized elderly population [17]. However, calcium and vitamin D supplements should be co-prescribed with other treatments for osteoporosis since the evidence base for their antifracture efficacy is derived from studies in which calcium and vitamin D were routinely administered. 5.8. Compliance and persistence Compliance and persistence with treatment for osteoporosis are poor; approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within 1 year [18]. Patient education is important in this respect and nurse-led monitoring early in the course of treatment has been shown to improve compliance. Whether monitoring by measurement of biochemical markers of bone turnover of bone mineral density provides additional benefits has not been established. 6. Future treatments A number of new treatments are currently under development. A human monoclonal antibody to receptor activator of NFB ligand (RANKL), a major regulator of osteoclast development and activity, has been developed and is now in Phase III studies [19]. Other approaches being evaluated include sclerostin inhibitors and other inhibitors of the Wnt pathway [20] and calcium sensing receptor antagonists, which result in intermittent increases in endogenous parathyroid hormone secretion. 7. Glucocorticoid-induced osteoporosis Osteoporosis is a common complication of oral glucocorticoid therapy. Bone loss is most rapid during the first few months of therapy, during which there is also a rapid increase in fracture rate. Observational data indicate that increased fracture risk occurs at all doses of oral prednisone, even those below 5 mg of oral prednisolone daily; however, higher doses are associated with more rapid bone loss and higher fracture risk [21]. The effects of inhaled glucocorticoids on bone are less certain but are potentially of great importance given their high level of use in the population. Cross-sectional data indicate that adverse effects on bone mineral density may occur, particularly when high doses are administered long-term. In both adults and children, a small increase in relative risk of fracture has been demonstrated with inhaled glucocorticoid use, but because similar increases are seen in those using only bronchodilators, it is likely that the underlying illness, rather than the glucocorticoids per se, is responsible for the observed increase [22]. In the context of glucocorticoid-induced osteoporosis, the term primary prevention is used to denote initiation of bone protective therapy at the time glucocorticoids are started, whereas secondary
J. Compston / European Journal of Radiology 71 (2009) 388–391
prevention implies that bone protection is started later in the course of glucocorticoid therapy. This distinction is important because of the rapid onset of bone loss and increase in fracture risk after glucocorticoid initiation, providing a strong rationale for early intervention in high-risk individuals. Although a number of interventions have been evaluated in the prevention and treatment of glucocorticoid-induced osteoporosis, the evidence base is much less robust than that which exists in postmenopausal women. Nevertheless, there is reasonable evidence that alendronate, etidronate, risedronate, zoledronate and teriparatide are effective and these are approved for this indication. National guidelines for the management of glucocorticoidinduced osteoporosis are available for a number of countries. In the UK, The Royal College of Physicians guidelines recommend primary prevention with a bisphosphonate in men and women committed to any oral dose of prednisolone for 3 months or more who are over the age of 65 years or who have sustained a previous fragility fracture. Bone densitometry is not required in such individuals. In others taking oral glucocorticoids for 3 months or more, bone densitometry is recommended and those with a bone mineral density T-score of −1.5 or lower should be considered for treatment. In addition, treatment should be advised for any individuals who sustain a fragility fracture during treatment [23]. References [1] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:1726–33. [2] O’Neill TW, Felsenberg D, Varlow, Cooper C, Kanis JA, Silman AJ. The prevalence of vertebral deformity in European men and women: the European Vertebral Osteoporosis Study. J Bone Miner Res 1996;11:1010–8. [3] McGuigan FE, Murray L, Gallagher A, et al. Genetic and environmental determinants of peak bone mass in young men and women. J Bone Miner Res 2002;17:1273–9. [4] Poole KE, Compston JE. Osteoporosis and its management. Brit Med J 2006;333:1251–6. [5] Kanis JA, Adams J, Borgström F, et al. The cost-effectiveness of alendronate in the management of osteoporosis. Bone 2008;42:4–15.
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[6] Seeman E, Vellas B, Benhamou C, et al. Strontium ranelate reduces the risk of vertebral and nonvertebral fractures in women eighty years of age and older. J Bone Miner Res 2006;21:1113–20. [7] Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001;285:320–3. [8] Delmas PD, Adami S, Strugala C, et al. Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the dosing intravenous administration study. Arthritis Rheum 2006;54:1838–46. [9] Black DM, Delmas PD, Eastell R, et al. Once yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809– 22. [10] Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799–809. [11] Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–68. [12] Reginster JY, Seeman E, de Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;90:2816–22. [13] Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomised clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637–45. [14] Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125–37. [15] Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434–41. [16] Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1– 84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis. Ann Intern Med 2007;146:326–39. [17] Francis RM. The vitamin D paradox. Rheumatol 2007;46:1749–50. [18] Compston JE, Seeman E. Compliance with osteoporosis therapy is the weakest link. Lancet 2006;368:973–4. [19] McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354:821–31. [20] Baron R, Rawadi G, Roman-Roman S. Wnt signalling: a key regulator of bone mass. Curr Top Dev Biol 2006;76:103–27. [21] Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000;15:993–1000. [22] Van Staa TP, Leufkens HG, Cooper C. Use of inhaled corticosteroids and risk of fractures. J Bone Miner Res 2001;16:581–8. [23] Compston JE. US and UK guidelines for glucocorticoid-induced osteoporosis: similarities and differences. Curr Rheumatol Rep 2004;6:66–9.
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Clinical and therapeutic aspects of osteoporosis Juliet Compston ∗ University of Cambridge School of Clinical Medicine, Box 157, Department of Medicine, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK
a r t i c l e
i n f o
Article history: Received 20 April 2008 Accepted 30 April 2008 Keywords: Osteoporosis Fracture Postmenopausal women Glucocorticoids Bisphosphonates
a b s t r a c t Osteoporosis is characterized by reduced bone mass and alteration in bone architecture, resulting in increased fracture risk. These fractures are a major cause of morbidity and mortality in the elderly and impose a huge economic burden on health services. Oestrogen deficiency plays a major role in the pathogenesis of bone loss and fracture in both women and men. Other pathogenetic factors include reduced physical activity and vitamin D insufficiency. A range of options is available for the prevention of fractures in high risk postmenopausal women. These include the bisphosphonates, strontium ranelate, raloxifene and parathyroid hormone peptides. Because of their broad spectrum of demonstrated anti-fracture efficacy, alendronate, risedronate, zoledronate and strontium ranelate are generally considered as front-line options for most women. The optimum duration of treatment has not been established but re-evaluation of risk and the need for continued therapy after 5 years of treatment may be appropriate. Compliance and persistence with long-term treatment is poor but may be improved by less frequent dosing regimens. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Osteoporosis is characterized by a reduction in bone mass and disruption of bone architecture, resulting in increased bone fragility and an increase in fracture risk. These fractures are a major health problem in the elderly population, leading to significant morbidity and mortality and resulting in an estimated annual cost to health services of £1.8 billion in the UK and D 30 billion in Europe. One in two women and one in five men over the age of 50 years will suffer a fracture due to osteoporosis during their remaining lifetime. Demographic changes over the next few decades will result in at least a doubling in the number of these fractures [1]. 2. Epidemiology The incidence of osteoporotic fractures increases markedly with age; in women, the median age for Colles’ fractures is 65 years and for hip fracture, 80 years. The age at which vertebral fracture incidence reaches a peak is less well defined but is thought in women to be between 65 and 80 years. In men, no age-related increase in forearm fractures is seen but hip fracture incidence rises exponentially after the age of 75 years. The prevalence of vertebral fractures rises with age in men, although less steeply than in women. Data from EVOS (European Vertebral Osteoporosis Study) have demonstrated
∗ Tel.: +44 1223 336867; fax: +44 1223 336846. E-mail address: [email protected]. 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2008.04.063
that the age standardized prevalence in the European population is 12.0% for women and 12.2% for men aged 50–79 years., with an overall age standardized incidence of 10.7 per 1000 person-years in women and 5.7 per person-years in men [2]. Both vertebral and hip fractures are associated with excess mortality, part of which is due to associated co-morbidities rather than to the fracture itself. 3. Clinical features Colles’ fractures of the radius typically occur after a fall forwards on to the outstretched hand. They cause considerable inconvenience, usually requiring 4–6 weeks in plaster and long-term adverse sequelae occur in up to one-third of patients. These include pain, sympathetic algodystrophy, deformity, and functional impairment. Vertebral fractures may occur spontaneously or as a result of normal activities such as lifting, bending, and coughing. A minority of vertebral fractures (possibly around one-third) present with acute and severe pain at the site of the fracture, often radiating around the thorax or abdomen. The natural history of this pain is variable; in general, there is a tendency for improvement with time but resolution is often incomplete. Multiple vertebral fractures result in spinal deformity (kyphosis), height loss, and corresponding alterations in body shape with protuberance of the abdomen and loss of normal body contours. These changes are commonly associated with loss of self-confidence and self-esteem, difficulty with daily activities, and increased social isolation. The clinical impact of vertebral fractures is thus substantial, although often underestimated.
J. Compston / European Journal of Radiology 71 (2009) 388–391
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Table 1 Interventions that are approved for prevention/treatment of osteoporosis in postmenopausal women. Bisphosphonates Alendronate Etidronate Ibandronate Risedronate Zoledronate
Fig. 1. Lifetime changes in bone mass (BMD = bone mineral density).
Of all the osteoporotic fractures, hip fractures cause the greatest morbidity and mortality. They almost always follow a fall, usually either backwards or to the side, and require surgical treatment. Because hip fractures characteristically affect frail elderly people, postoperative morbidity and mortality are high; at 6 months after fracture, mortality rates of 12–20% have been reported. Only a minority of patients with hip fracture regain their former level of independence following a hip fracture and up to one-third require institutionalized care. 4. Pathogenesis Lifetime changes in bone mass are shown in Fig. 1. Peak bone mass is attained in the third decade of life and age-related bone loss is believed to start in both men and women around the beginning of the fifth decade; thereafter bone loss continues throughout life. In women, there is an acceleration of the rate of bone loss around the time of the menopause, the duration of which is poorly characterized but may be 5–10 years Bone mass in later life thus depends both on the peak bone mass achieved in early adulthood and on the rate of age-related bone loss. Genetic factors strongly influence peak bone mass, accounting for up to 70–80 per cent of its variance. A number of genes are likely to be involved; these include the collagen type IA1 gene, a polymorphism of which is associated both with low bone mineral density and fracture risk [3]. Sex hormone status, nutrition, and physical activity also influence peak bone mass. In postmenopausal women, oestrogen deficiency is the main cause of menopausal bone loss. In older men, oestrogen status is also significantly related to bone mineral density levels whereas the relationship between age-related bone loss and declining testosterone levels is less prominent. In the elderly, vitamin D insufficiency and secondary hyperparathyroidism are common and contribute to age-related bone loss, particularly in cortical bone. Other potential pathogenetic factors include declining levels of physical activity and reduced serum levels of insulin-like growth factors. 5. Pharmacological interventions
Calcitonin Calcitriol Hormone replacement therapy PTH[1–84] Raloxifene Strontium ranelate Teriparatide
Because of their broader spectrum of anti-fracture efficacy alendronate, risedronate, zoledronate and strontium ranelate are generally regarded as front-line options in the prevention of fractures in postmenopausal women [4]. This distinction is important because once a fracture occurs, the risk of a subsequent fracture at any site is increased independent of bone mineral density, and hence an intervention that covers all major fracture sites is preferable. Cost is also an important consideration. In countries where generic alendronate is available this is the most cost-effective option, although other bisphosphonates and strontium ranelate are also cost-effective in the secondary prevention of fracture and in primary prevention in high risk women [5]. Strontium ranelate has a particularly strong evidence base in the very elderly (women aged ≥80 years) [6] and is a useful option in frail individuals who are unable to comply with the dosing instructions for bisphosphonates. Alternatively, intravenous zoledronate may be considered in such patients. Because of the lack of evidence for efficacy against hip fractures, raloxifene and ibandronate are generally considered second-line options. The use of parathyroid hormone peptides is limited in many countries by their cost to women with severe vertebral osteoporosis who are intolerant to or appear to be unresponsive to other treatments. Reduction in fracture risk has been shown to occur within one year of treatment for bisphosphonates and strontium ranelate. This is particularly important in the case of vertebral fractures, since after an incident vertebral fracture there is a 20% risk of a further fracture occurring within the next 12 months, emphasizing the importance of prompt treatment once a fracture has occurred [7]. The optimum duration of treatment is uncertain. There are potential concerns that long-term treatment with potent antiresorptives may increase bone microdamage and suppress its repair, possibly resulting in increased bone fragility. However, this concern has to be counterbalanced against the possibility that increased bone turnover and bone loss after withdrawal of therapy may result in increased fracture risk. The current consensus is that treatment should be continued for a minimum of 5 years; in those who remain at high risk (based on bone mineral density [BMD] levels, incident fractures during treatment and the presence of other risk factors), longer treatment periods may be indicated.
5.1. General considerations 5.2. Bisphosphonates Interventions that are approved for the prevention and treatment of osteoporosis are shown in Table 1. Most of these are approved only for the treatment of postmenopausal osteoporosis. However, alendronate, etidronate, risedronate, zoledronate and teriparatide are approved for the prevention and treatment of glucocorticoid-induced osteoporosis in Europe and alendronate, risedronate and teriparatide are approved for the treatment of osteoporosis in men.
The bisphosphonates are synthetic analogues of the naturally occurring compound pyrophosphate and inhibit bone resorption. Alendronate, risedronate and ibandronate are available as oral formulations (70 mg once weekly, 35 mg once weekly and 150 mg once monthly respectively). Oral bisphosphonates are generally well tolerated. Upper gastrointestinal side-effects may occur with nitrogen-containing
390
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bisphosphonates (alendronate, risedronate and ibandronate), particularly if the dosing regimen is not adhered to. It is therefore important that patients take the drug according to the instructions, namely in the morning with a full glass of water, 30–60 min before food, drink, or other medications, and remaining standing or sitting upright for that time. Ibandronate and zoledronate are available as intravenous formulations. The former is given as an injection over 15–30 s every 3 months, whereas zoledronate is administered as an intravenous infusion over 15 min at a dose of 5 mg once yearly. An acute phase reaction may occur, particularly with the first injection, resulting in flu-like symptoms for 24–48 h. Anti-fracture efficacy has not been shown directly for the intravenous ibandronate formulation or for the 150 mg once monthly regimen, but is assumed from a bridging study based on bone mineral density changes [8]. Zoledronate has been demonstrated to reduce vertebral, non-vertebral and hip fractures in women with postmenopausal osteoporosis and also reduces the incidence of recurrent clinical fractures in patients who have suffered a hip fracture [9,10]. 5.3. Strontium ranelate Strontium ranelate is composed of two atoms of stable strontium with ranelic acid as a carrier. Although its mechanism of action remains to be fully defined, there is some evidence that it strengthens bone by altering its material properties. Its use is associated with a substantial increase in BMD in the spine and hip, although part of this increase is artefactual, due to incorporation of high atomic number strontium into bone. Strontium ranelate has been shown to reduce vertebral and nonvertebral fractures in postmenopausal women with osteoporosis [11,12]. In a post hoc analysis in older women with low hip bone mineral density, it was also shown to reduce hip fractures. It is taken as a single daily dose and is generally well tolerated. There is a small increase in the frequency of diarrhoea, nausea and headache. There is also a small increase in the risk of venous thrombo-embolic disease (OR 1.42 95% CI 1.02, 1.98). Very rarely, hypersensitivity reactions may occur. 5.4. Raloxifene Raloxifene is a selective oestrogen receptor modulator that has oestrogenic (antiresorptive) effects in the skeleton without the unwanted effects of oestrogen in the breast and endometrium. It is taken orally as a single daily dose. Reduction in vertebral, but not non-vertebral or hip, fractures has been demonstrated in postmenopausal women with osteoporosis [13]. Adverse effects include leg oedema, leg cramps, hot flushes and a two- to threefold increase in the risk of venous thromboembolism. Its use is associated with a significant decrease in the risk of breast cancer. A recent study indicates that raloxifene therapy results in a small increase in the risk of stroke [14]. 5.5. Parathyroid hormone peptides Teriparatide (recombinant human 1–34 parathyroid hormone peptide), and Preotact, (recombinant human 1–84 parathyroid hormone peptide) are administered by subcutaneous injection in daily doses of 20 g and 100 g, respectively. They have anabolic effects on bone, increasing bone formation and producing large increases in bone mineral density in the spine. Teriparatide has been shown to reduce both vertebral and non-vertebral fractures in postmenopausal women with osteoporosis after a median treatment period of 21 months, whereas reduction only in vertebral fractures was shown after 18 months treatment with Preotact [15,16]. Side-effects include nausea, headache and dizziness; in addition,
transient hypercalcaemia and hypercalciuria may occur, particularly with Preotact. 5.6. Hormone replacement therapy (HRT) Because the risk/benefit balance of HRT is generally unfavourable in older postmenopausal women, it is regarded as a second line-treatment option. However, it is an appropriate option in younger postmenopausal women at high risk of fracture, particularly those with vasomotor symptoms. 5.7. Calcium and vitamin D Available evidence does not support a role for calcium and vitamin D alone in prevention of osteoporotic fractures except in the institutionalized elderly population [17]. However, calcium and vitamin D supplements should be co-prescribed with other treatments for osteoporosis since the evidence base for their antifracture efficacy is derived from studies in which calcium and vitamin D were routinely administered. 5.8. Compliance and persistence Compliance and persistence with treatment for osteoporosis are poor; approximately 50% of patients do not follow their prescribed treatment regimen and/or discontinue treatment within 1 year [18]. Patient education is important in this respect and nurse-led monitoring early in the course of treatment has been shown to improve compliance. Whether monitoring by measurement of biochemical markers of bone turnover of bone mineral density provides additional benefits has not been established. 6. Future treatments A number of new treatments are currently under development. A human monoclonal antibody to receptor activator of NFB ligand (RANKL), a major regulator of osteoclast development and activity, has been developed and is now in Phase III studies [19]. Other approaches being evaluated include sclerostin inhibitors and other inhibitors of the Wnt pathway [20] and calcium sensing receptor antagonists, which result in intermittent increases in endogenous parathyroid hormone secretion. 7. Glucocorticoid-induced osteoporosis Osteoporosis is a common complication of oral glucocorticoid therapy. Bone loss is most rapid during the first few months of therapy, during which there is also a rapid increase in fracture rate. Observational data indicate that increased fracture risk occurs at all doses of oral prednisone, even those below 5 mg of oral prednisolone daily; however, higher doses are associated with more rapid bone loss and higher fracture risk [21]. The effects of inhaled glucocorticoids on bone are less certain but are potentially of great importance given their high level of use in the population. Cross-sectional data indicate that adverse effects on bone mineral density may occur, particularly when high doses are administered long-term. In both adults and children, a small increase in relative risk of fracture has been demonstrated with inhaled glucocorticoid use, but because similar increases are seen in those using only bronchodilators, it is likely that the underlying illness, rather than the glucocorticoids per se, is responsible for the observed increase [22]. In the context of glucocorticoid-induced osteoporosis, the term primary prevention is used to denote initiation of bone protective therapy at the time glucocorticoids are started, whereas secondary
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prevention implies that bone protection is started later in the course of glucocorticoid therapy. This distinction is important because of the rapid onset of bone loss and increase in fracture risk after glucocorticoid initiation, providing a strong rationale for early intervention in high-risk individuals. Although a number of interventions have been evaluated in the prevention and treatment of glucocorticoid-induced osteoporosis, the evidence base is much less robust than that which exists in postmenopausal women. Nevertheless, there is reasonable evidence that alendronate, etidronate, risedronate, zoledronate and teriparatide are effective and these are approved for this indication. National guidelines for the management of glucocorticoidinduced osteoporosis are available for a number of countries. In the UK, The Royal College of Physicians guidelines recommend primary prevention with a bisphosphonate in men and women committed to any oral dose of prednisolone for 3 months or more who are over the age of 65 years or who have sustained a previous fragility fracture. Bone densitometry is not required in such individuals. In others taking oral glucocorticoids for 3 months or more, bone densitometry is recommended and those with a bone mineral density T-score of −1.5 or lower should be considered for treatment. In addition, treatment should be advised for any individuals who sustain a fragility fracture during treatment [23]. References [1] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:1726–33. [2] O’Neill TW, Felsenberg D, Varlow, Cooper C, Kanis JA, Silman AJ. The prevalence of vertebral deformity in European men and women: the European Vertebral Osteoporosis Study. J Bone Miner Res 1996;11:1010–8. [3] McGuigan FE, Murray L, Gallagher A, et al. Genetic and environmental determinants of peak bone mass in young men and women. J Bone Miner Res 2002;17:1273–9. [4] Poole KE, Compston JE. Osteoporosis and its management. Brit Med J 2006;333:1251–6. [5] Kanis JA, Adams J, Borgström F, et al. The cost-effectiveness of alendronate in the management of osteoporosis. Bone 2008;42:4–15.
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[6] Seeman E, Vellas B, Benhamou C, et al. Strontium ranelate reduces the risk of vertebral and nonvertebral fractures in women eighty years of age and older. J Bone Miner Res 2006;21:1113–20. [7] Lindsay R, Silverman SL, Cooper C, et al. Risk of new vertebral fracture in the year following a fracture. JAMA 2001;285:320–3. [8] Delmas PD, Adami S, Strugala C, et al. Intravenous ibandronate injections in postmenopausal women with osteoporosis: one-year results from the dosing intravenous administration study. Arthritis Rheum 2006;54:1838–46. [9] Black DM, Delmas PD, Eastell R, et al. Once yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809– 22. [10] Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799–809. [11] Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004;350:459–68. [12] Reginster JY, Seeman E, de Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;90:2816–22. [13] Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomised clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637–45. [14] Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006;355:125–37. [15] Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434–41. [16] Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1– 84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis. Ann Intern Med 2007;146:326–39. [17] Francis RM. The vitamin D paradox. Rheumatol 2007;46:1749–50. [18] Compston JE, Seeman E. Compliance with osteoporosis therapy is the weakest link. Lancet 2006;368:973–4. [19] McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354:821–31. [20] Baron R, Rawadi G, Roman-Roman S. Wnt signalling: a key regulator of bone mass. Curr Top Dev Biol 2006;76:103–27. [21] Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res 2000;15:993–1000. [22] Van Staa TP, Leufkens HG, Cooper C. Use of inhaled corticosteroids and risk of fractures. J Bone Miner Res 2001;16:581–8. [23] Compston JE. US and UK guidelines for glucocorticoid-induced osteoporosis: similarities and differences. Curr Rheumatol Rep 2004;6:66–9.