Update on the treatment of post-menopausal osteoporosis

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1 Published Online May 12, 2008 Update on the treatment of post-menopausal osteoporosis Zoë Cole, Elaine Dennison, and Cyrus Cooper * MRC Epidemiology Resource Centre, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK Background: Osteoporosis has a huge impact on public health, through the increased morbidity, mortality and economic costs associated with resultant fractures. The goal is to evaluate and identify those that are at risk of osteoporotic fracture in order to start preventative and therapeutic measures to reduce their risk of fracture. Sources of data: This article reviews the data from randomized controlled trials for the current therapeutic agents available in the UK. It also reviews new trial data for promising osteoporosis therapies, in particular Denosumab, a monoclonal antibody against RANK ligand. Areas of agreement: Bisphosphonates are the current recommended first-line treatments for patients with osteoporosis. Areas of controversy/growing points: There are a number of patients where bisphosphonates are contraindicated. Under these circumstances, it is important that clinicians have access to alternative treatments. The long-awaited National Institute for Health and Clinical Excellence (NICE) technology appraisals for both primary and secondary prevention and the clinical guidelines will clarify this. Treatment decisions should be based on risk factors and pharmaceutical intervention given to those with the highest risks. Areas timely for developing research: Future studies are required to look at these agents in combination to see whether anti-fracture efficacy can be improved. Keywords: osteoporosis/fracture/prevention/treatment/risk Accepted: April 17, 2008 *Correspondence to: Professor Cyrus Cooper MRC Epidemiology Resource Centre, Southampton General Hospital, Southampton SO16 6YD, UK cc@ mrc.soton.ac.uk British Medical Bulletin 2008; 86: DOI: /bmb/ldn017 & The Author Published by Oxford University Press. All rights reserved. For permissions, please journals.permissions@oxfordjournals.org

2 Z. Cole et al. Introduction Bisphosphonates Fig. 1 Impact of osteoporosis-related fractures in Europe. Osteoporosis is the most common clinical disorder of bone metabolism. It occurs when there is an increase in bone breakdown relative to bone formation and is characterized by microarchitectural deterioration, low bone mass and increased risk of fractures. Despite its high prevalence within the UK post-menopausal population, relatively few adults with fractures are evaluated and/or treated for osteoporosis. The lifetime incidence of any fracture in a 50 year old in Britain is 40% for women and 13% for men (see K. Walker-Bone et al. in Osteoporosis. In Silman AJ, Hochberg M (eds) Epidemiology of the Rheumatic Diseases, Oxford: Oxford University Press). (Fig. 1). The annual cost of osteoporosis is 1.7 billion in the UK alone (see Walker-Bone et al.). Thus, increased knowledge about how to treat osteoporosis is critical to change the practice of care. In this clinical review, we summarize the existing treatment options and promising new therapies for the prevention and treatment of osteoporosis. Bisphosphonates have revolutionized our ability to manage osteoporosis and, over the last 20 years, have continually evolved to give increased efficacy. They are stable analogues of pyrophosphate that have a strong affinity for bone hydroxyapatite. They reduce bone resorption by reducing the recruitment and activity of osteoclasts and increasing apoptosis. 1,2 Increases in bone mineral density (BMD) are caused by a decrease in the remodelling space, reduction in resorption cavities and increases in secondary mineralization of preformed osteons. Bisphosphonates have proven efficacy for prevention of bone loss caused by ageing, oestrogen deficiency and glucocorticoid use, and are licensed for prevention of fractures in post-menopausal women and 130 British Medical Bulletin 2008;86

3 Update on the treatment of post-menopausal osteoporosis glucocorticoid-induced osteoporosis. Four bisphosphonates (alendronate, risendronate, ibandronate and zolendronate) are currently approved by the UK MRHA for the prevention and treatment of osteoporosis. Alendronate Risedronate Several randomized controlled studies show that oral alendronate increases BMD and decreases the risk of osteoporotic fractures in postmenopausal women. It is also effective for the treatment of osteoporosis in men, steroid-induced osteoporosis in men and women. The vertebral fracture arm of the Fracture Intervention trial (FIT) was the first randomized trial to show a reduction in fractures with any agent. A total of 2027 women with prevalent fractures received either alendronate (5 mg/day for 2 years, 10 mg/day for 1 year) or placebo. The incidence of new fractures was reduced by 50% with alendronate treatment compared with placebo (47, 48 and 51% for radiographic vertebral, wrist fractures and hip fractures, respectively). 3 In the clinical fracture arm of FIT, 4432 women without prevalent vertebral fractures showed a decrease of 50% in the first incident vertebral fracture and a 12% reduction in clinical vertebral fracture (not significant, P ¼ 0.07). 4 In post hoc analysis, both non-vertebral and hip fractures (36%) were significantly reduced in those with a hip BMD T-score of,2.5. Studies with continued alendronate for as long as 10 years show that BMD increases are maintained for at least that long. 5 Alendronate reduces bone turnover markers by 50 70%, and these decreases are maintained as long as treatment is continued. BMD and bone turnover effects of 10 mg/day are similar to those for 70 mg/week, 6 and based on these results the weekly dose was approved in Risedronate is another potent bisphosphonate that also produces very positive effects on bone mass and bone turnover, with lumbar spine BMD increasing by 7% and hip BMD by 4% versus placebo over 3 years. 7 Risedronate 5 mg/day was shown to reduce vertebral fractures by 40 50% in two 3-year studies of over 3600 women with prevalent vertebral fractures. 7,8 The Hip Intervention Program (HIP) study (2.5 and 5 mg/day risedronate versus placebo) studied 9331 women (age.70 years) at high risk of hip fracture and showed a 30% overall reduction in hip fractures. 9 In the subset of women aged years with a very low BMD (hip T-score, below 3), there was a 40% reduction. However, British Medical Bulletin 2008;86 131

4 Z. Cole et al. among those over 80 years, there was only a non-significant trend towards hip fracture reduction (20%); however, it should be noted that these patients did not necessarily have low BMD but, instead, had at least one non-skeletal risk factor for hip fracture. Post hoc analyses of the Phase 3 trials suggest that risedronate decreases the incidence of non-vertebral fractures within 6 months of starting 10 treatment. Ibandronate Zoledronic acid Ibandronate has more recently been approved for use in the UK for the treatment and prevention of osteoporotic fractures in post-menopausal women. Given as a daily dose of 2.5 mg/day, it has been shown to increase spine BMD by 5% and hip BMD by 3 4% over 3 years. 11 Recent evidence suggests that superior increases in BMD can be achieved with the monthly preparation (150 mg). 12 A 3-year randomized controlled trial of 2946 post-menopausal women with prevalent vertebral fracture compared ibandronate (2.5 mg daily or 20 mg every other day for 12 doses, every 3 months) with placebo. 11 Patient taking 2.5 mg a day showed a 50% reduction in incident vertebral fractures, there was no overall reduction in non-vertebral fractures. Post hoc analysis of patients with a hip BMD T-score less than 23 (15% of study population), there was a 69% reduction in non-vertebral fracture. Ibandronate can also be given as an i.v. preparation, which is particularly useful for patients with severe gastrointestinal symptomatology. A recent trial compared 3 mg i.v. ibandronate with oral 2.5 mg/day, and found equivalent gains in BMD and similar bone suppression that lasted up to 3 months. On this evidence, i.v. ibandronate has been approved for use. 13 Zoledronic acid is the most recently licensed bisphosphate (in 2007). A single annual intravenous infusion of 5 mg zoledronic acid given over 15 min reduced bone markers by 30 60%. In a randomized controlled trial of 3889 patients with established osteoporosis, there was a 70% reduction in vertebral fracture and 41% reduction in hip fracture compared with placebo. 14 The results seem sustained over the 3-year follow-up and clearly offer the potential of improved compliance as well as convenience for patients. There was a small increase in the treated group of patients developing atrial fibrillation. A more recent study looked at the effect of giving 5 mg zoledronic acid to patients who had sustained a hip fracture within the last 90 days. There was a 132 British Medical Bulletin 2008;86

5 Update on the treatment of post-menopausal osteoporosis 35% risk reduction of any clinical fracture with zoledronic acid. A 28% reduction in deaths was also seen over the mean 1.9-year follow-up compared with placebo. 15 Dosing, side effects and safety issues Bisphosphonates taken orally are very poorly absorbed even under ideal conditions. Absorption is completely abolished in the presence of divalent cations and dairy products. All bisphosphonates must be taken in the fasting state, with nothing but water orally for at least 30 min after ingestion. To minimize the chance of oesophageal irritation, the tablet should be taken with water and the patient should remain upright until after eating in order to avoid reflux of the drug into the oesophagus. A significant proportion (10 30%) of patients receiving their first intravenous dose of bisphosphonates experience acute phase reactions (fever, myalgia, etc.); these rarely occur with repeated administration. Pre-treatment with histamine blockers, antipyretics or corticosteroids may reduce these symptoms. There have been recent reports of osteonecrosis of the jaw associated with bisphosphonate use, but these have been primarily confined to oncology patients, receiving frequent large doses of intravenous bisphosphonates. The risk of osteonecrosis of the jaw in the treatment of osteoporosis seems very low, but it is prudent for patients awaiting dental surgery to have this performed before starting on a bisphosphonate. Optimal effectiveness of bisphosphonates requires that patients engage in weight bearing exercise and have adequate calcium and vitamin D nutrition. Bisphosphonates are contraindicated in patients with hypocalcaemia and should be used in caution in those individuals with low serum 25-hydroxyvitamin D because this can prompt severe hypocalcaemia. There had also been a concern that potent anti-resorptive agents such as bisphosphonates might turn off remodelling completely, leading to frozen bone and eventually increased bone fragility. There is no evidence that this actually occurs with the doses used clinically. Fracture healing in patients treated with chronic bisphosphonates therapy does not appear to be a problem, although there are few studies addressing this important issue. The optimal duration of treatment of women with post-menopausal osteoporosis is uncertain. A US trial of 1099 women that had previously where they received a mean 5 years of treatment with alendonate as part of the FIT trial were enrolled into an extension in which they received alendronate 5 or 10 mg/day or placebo for 5 years. 16 British Medical Bulletin 2008;86 133

6 Z. Cole et al. Other drug therapies Strontium ranelate After 5 years, the cumulative risk of non-vertebral fractures was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. However, in those who did continue, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; but no significant reduction in morphometric vertebral fractures). These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase the fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. Bisphosphonates are the recommended first-line treatments for the majority of patients with osteoporosis. However, there will be a number of patients where bisphosphonates are contraindicated, or who develop side effects attributable to the medication. Under these circumstances, it is important that clinicians have access to alternative treatments (Fig. 2). The long-awaited National Institute for Health and Clinical Excellence (NICE) technology appraisals for both primary and secondary prevention and the clinical guidelines will clarify this (Fig. 3). At present, other available agents include strontium ranelate, raloxifene and parathyroid hormone (PTH). Strontium (Sr) is chemically similar to calcium, but twice the atomic weight, it is bound to ranelic acid. Sr is incorporated into bone at the same rate as calcium and has a long half life. It is preferentially distributed at sites of trabecular rich bone and in new bone. The exact mechanisms of action for strontium ranelate are unclear, but there appear to Fig. 2 Comparison of effect of current treatment licensed for use in UK on vertebral, nonvertebral and hip fractures. 134 British Medical Bulletin 2008;86

7 Update on the treatment of post-menopausal osteoporosis Fig. 3 Suggested guidelines from National Institute of Clinical Excellence (NICE), still under review. be both effects on inhibition of osteoclast recruitment and activity, but also an increase of osteoblast proliferation and differentiation. 17 This, in turn, leads to increased trabecular bone volume. As strontium has a higher atomic number than calcium, it attenuates more X-rays compared with calcium; this attenuation can result in overestimation of BMD that requires an adjustment for bone strontium content. 18 Two major randomized controlled trials have evaluated efficacy and tolerability of 2 g daily strontium ranelate compared with placebo in post-menopausal women. These studies were the Spinal Osteoporosis therapeutic Intervention Trial (SOTI) and the Treatment of Peripheral Osteoporosis study (TROPOS). In SOTI, 1649 women with established osteoporosis were evaluated. Lumbar BMD (adjusted for strontium content) increased 6.8% over baseline in the active group; over a 3-year study period, there was a 41% lower risk of incident vertebral fracture. 19 In TROPOS, 5091 women were studied for 5 years. 20 After 3 years, there was a 16% decrease in peripheral fracture compared with placebo. Subgroup analysis from TROPOS demonstrated a 36% reduction in hip fracture risk in women aged 74 years or more with hip BMD T-score of less than 23. A pre-planned pooling of data from both SOTI and TROPOS demonstrated significant effects in the elderly (women aged between 80 and 100 years). In this subgroup, strontium ranelate was associated with a 59% reduction of vertebral fracture after 1 year and 32% after 3 years. In addition, there was a reduced incidence of nonvertebral fractures by 41% at 1 year and 31% after 3 years. 21 Strontium ranelate is relatively well tolerated. Side effects include nausea, diarrhoea and a headache, which usually resolves over time. British Medical Bulletin 2008;86 135

8 Z. Cole et al. There has been a recent evidence linking strontium ranelate to DRESS syndrome (rash with eosinophilia and systemic symptoms). This is a very rare, but severe hypersensitivity reaction occurring within 1 8 weeks of starting treatment and has resulted two deaths out of patients years exposure. This should be balanced against Steven Johnson syndromes observed with raloxifene or bisphosphonates. If a rash is seen soon after starting the drug, it should be stopped immediately. Selective oestrogen receptor modulators Selective oestrogen receptor modulators (SERMs) are non-steroidal partial oestrogen agonists that act preferentially as agonists in bone, but as antagonists in reproductive tissues. Raloxefine is the only SERM currently licensed for the treatment and prevention of osteoporosis. In the Multiple Outcomes of Raloxifene Evaluation (MORE) trial involving 7705 post-menopausal women treated with raloxifene (60 or 120 mg) increased lumbar BMD (2.6 and 2.7%, respectively) and reduced the incidence of spinal fracture (30 and 50%, respectively). Although raloxifene increased femoral neck BMD by a similar magnitude, it did not reduce the risk of non-vertebral fractures and in particular hip fracture. This lack of efficacy at the hip has meant that raloxefine has fared badly in health economic analyses performed by NICE as to date no allowance has been made for the 76% reduction in the risk of breast cancer seen in these women. Raloxifene is associated with some oestrogen antagonist effects outside the skeleton. These include worsening of menopausal symptoms. Oestrogen agonist effects include an increase in risk in deep vein thrombosis, but not pulmonary embolisms; there is no increase in cardiovascular disease. Additional SERMs including arzoxifene, lasofoxifene, bazedoxifene, droloxifene and ospemifene are currently being investigated in Phases II and III trials. Parathyroid hormone Parathyroid hormone is an 84 amino acid peptide that is secreted by the parathyroid gland and is critical to calcium homeostasis. PTH increases renal re-absorption of calcium, enhances intestinal calcium absorption via its effect on one hydroxylation of 25(OH)D3 and increases bone remodelling. The net effect of PTH on skeletal architecture depends upon the pattern of exposure. Continuous secretion of 136 British Medical Bulletin 2008;86

9 Update on the treatment of post-menopausal osteoporosis PTH, as in primary hyperthyroidism, decreases bone mass, especially cortical bone; however, intermittent secretion of exogenous PTH increases bone mass. Intermittent PTH has a stimulatory effect on bone turnover that appears to be via stimulation of the activation frequency. There is greater increase in formation markers over resorption markets early in treatment. In addition, PTH has other effects on bone material properties and structure that can enhance strength. Recombinant human PTH is now available as a treatment for postmenopausal osteoporosis. There are currently two formulations for use in the UK: Teriparide (Forsteow), it contains the first 34 amino acids of the PTH molecule, and Preotactw, a full-length molecule. In a study of 1637 post-menopausal women with two or more prior vertebral fracture, a subcutaneous once daily dose of 20 mg teriparide (hpth 1 34) decreased the occurrence of new vertebral fractures by 65% compared with placebo and 53% reduction in the risk of new non-vertebral fracture after a mean of 18 months therapy. 22 This pivotal study was inadequately powered to detect positive treatment effect at any individual site. Lumbar BMD increased by 9% and femoral neck BMD by 3% over the same period. After termination of the study, the patients who were subsequently followed up still showed a significant reduction in risk for both vertebral and non-vertebral fractures. hpth(1 84) has been studied in 2532 post-menopausal women with osteoporosis. 23 Treatment was associated with significant reduction (58%) in vertebral fracture risk. There were no data showing an effect of hpth(1 84) on non-vertebral risk. It is worth noting that the women in this study had a lower baseline risk of fracture than the women treated with hpth(1 34) as only 19% of them had radiological evidence of vertebral fracture. Hypercalciuria and hypocalcaemia were more common in women who took the drug, and current monitoring of calcium is recommended in the initial months of therapy. Both forms of PTH are also associated with side effects that include headache, nausea, dizziness and mild transient increases in serum and urine calcium. There is some evidence to suggest that high lifetime doses of teriparatide induced osteogenic sarcomas in rat studies. Although this has not been observed in humans, this therapy is limited to 18 months and is not approved for patients at risk of osteosarcoma including children, patients with a previous history of radiation therapy and Paget s disease. In most countries, PTH therapy is currently targeted to patients at high risk for fracture. Issues related to the cost-effectiveness of treatment rather than to clinical effectiveness are driving this. Research is looking at whether it is most appropriate for patients to receive PTH therapy as a single course, or if dosing can be intermittent and cyclical. British Medical Bulletin 2008;86 137

10 Z. Cole et al. The effect of pre-treatment with bisphosphonates and the role of combination therapy are currently being evaluated. It should be noted that PTH should currently not be recommended to be given in combination with bisphosphonates. Calcitonin Vitamin D and calcium Calcitonin is a peptide produced by thyroid C cells that inhibits bone resorption by inhibiting osteoclast activity. In the Prevent Recurrence of osteoporotic Fractures (PROOF) study, nasal calcitonin 200 IU reduced the incidence of vertebral fractures by 33%. There was no effect on non-vertebral fractures. 24 There was no dose effect observed, neither was there an effect on bone metabolism or BMD. Given its relatively weak anti-fracture efficacy, calcitonin is generally not considered as first-line therapy for treatment of osteoporosis. Vitamin D is a steroid hormone that plays an important role in the regulation of calcium homeostasis and mineralization of bone. Despite fortification of various dietary sources, there is a pandemic of vitamin D insufficiency, particularly in the older population of several European countries. Very low levels have been reported in up to 57% of patients with hip fractures. In the largest trial of its kind, 3270 women (mean age 84 years) in French nursing homes were randomized to 1200 mg and 800 IU vitamin D 3 daily or placebo. After 3 years, the incidence of hip fractures in the treated group was 29% lower and all non-vertebral fractures 24% lower. 25 This is a population at particularly high risk of vitamin D deficiency and hence may explain the results seen. However, other vitamin D intervention trials have given inconsistent results. The Women s Health Initiative (WHI), a US study of post-menopausal women aged years, showed that calcium 1000 mg daily and vitamind3400iudailyhadnoreductioninhipfracturesintheintention to treat analysis. 26 However, in women who were compliant with the supplements, there was a 29% reduction in fracture. In the Randomized Evaluation of Calcium or Vitamin D (RECORD) study from the UK, there was no reduction in fractures although compliance was poor. 27 Calcium and vitamin D supplementation is advocated as the basic minimum for treatment of osteoporosis and secondary fracture prevention in post-menopausal women. The ongoing MRC RECORD trial of 6000 men and women with a previous fragility fracture aims to look at 138 British Medical Bulletin 2008;86

11 Update on the treatment of post-menopausal osteoporosis the role of calcium and vitamin D in respect to secondary fracture prevention. Fall prevention Physical activity Approximately 30% of individuals aged.60 years fall at least once a year, with an increase in incidence in people aged 80 and over. 28 Falls have a serious consequences in patients with osteoporosis or osteopenia as they can lead directly to fractures. Therefore, prevention of falls should be a priority in older patients. All patients with osteoporosis should be assessed for risk factors for falls including previous falls, fainting or episodes of loss of consciousness, muscle weakness, impaired balance, poor sight and certain medications (e.g. sedatives, antihypertensives). Environmental factors such as poor lighting may also increase the risk of falls. Overall, no interventions so far that aim at reducing the risk of fall has ever resulted in a decrease in fracture incidence. Hip protectors have been used in elderly patients who live in nursing homes. However, multi-centre randomized controlled trials provide conflicting results. 29 The use of these hip protectors is limited largely by compliance and comfort. Physical activity is particularly important for the accrual of optimal peak bone mass in young adulthood. It is also important in the middle and later years but for different reasons. Conflicting evidence exists regarding the optimum exercise for post-menopausal bone loss. A systematic review and meta-analysis undertaken to evaluate the effects of randomized controlled trials of progressive, high-intensity resistance training on BMD among post-menopausal women showed a significant increase in lumbar BMD. In contrast, marked heterogeneity was apparent within the studies evaluating femoral neck BMD. 30 However, exercise, even low impact (walking), is recommended because it improves mobility, muscle function, and balance and consequently is likely to reduce the risk of falling. New therapies There are several new and promising osteoporosis therapies in various stages of development, including calcium-sensing receptor antagonists, sclerostin inhibitors, integrin antagonists and cathepsin K inhibitors. British Medical Bulletin 2008;86 139

12 Z. Cole et al. Denosumab, a monoclonal antibody against RANK ligand, is furthest in development and is discussed below. Monoclonal antibodies against RANK ligand Conclusions The receptor activator of nuclear factor kb ligand (RANKL) is an important regulator of osteoclast activation. The binding of RANKL to its receptor on osteoclast precursors results in increased osteocyte differentiation and proliferation. A human monoclonal antibody to RANKL prevents its binding to its receptor. In 412 post-menopausal women, treatment for 1-year increased BMD at the lumbar spine (3 7%) and total hip (2 4%) compared with placebo. 31 Treatment decreased markers of bone turnover; the duration of the decrease was dose dependant. In animal studies, RANKL antibody appeared to improve cortical and bone strength. Phase III studies are currently in progress. More data are needed to show the long-term safety and fracture prevention efficacy of this therapy in humans. Osteoporosis is an increasing health problem in both women and men resulting in significant morbidity and mortality through the consequences of fracture. Most patients require pharmacological therapy to reduce the risk of fracture. Treatment decisions should be based upon risk factors Fig. 4 Management algorithm for post-menopausal osteoporosis based on World Health Organization (WHO) fracture probability. 140 British Medical Bulletin 2008;86

13 Update on the treatment of post-menopausal osteoporosis Funding References Fig. 5 Cost-effectiveness ( 000/QALY gained) of treatment of women aged years by the presence or absence of a prior fracture. The solid horizontal line indicates the threshold for cost-effectiveness. Adapted from Kanis et al. 32 and bone densitometry (Fig. 4). Pharmacological intervention is most appropriate when fracture risk is highest (Fig. 5). Bisphosphonates remain the primary treatment of osteoporosis. Teriparatide, a potent anabolic agent which improves bone architecture and decreases both vertebral and non-vertebral fractures, is currently limited to those with severe osteoporosis at high risk of fracture. Future studies are required to look at these agents in combination to see whether anti-fracture efficacy can be improved. The management of osteoporosis will continue to evolve as emerging therapies show great promise. Dr Zoe Cole is currently funded by the Arthritis Research Campaign as a clinical research fellow. 1 Carano A, Teitelbaum SL, Konsek JD, Schlesinger PH, Blair HC. Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J Clin Invest 1990, 85, Hughes DE, Wright KR, Uy HL et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res 1995, 10, Black DM, Cummings SR, Karpf DB et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996, 348, British Medical Bulletin 2008;86 141

14 Z. Cole et al. 4 Cummings SR, Black DM, Thompson DE et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998, 280, Bone HG, Hosking D, Devogelaer JP et al. Ten years experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004, 350, Schnitzer T, Bone HG, Crepaldi G et al. Therapeutic equivalence of alendronate 70 mg onceweekly and alendronate 10 mg daily in the treatment of osteoporosis. Alendronate Once-Weekly Study Group. Aging (Milano) 2000, 12, Harris ST, Watts NB, Genant HK et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. JAMA 1999, 282, Reginster J, Minne HW, Sorensen OH et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporos Int 2000, 11, McClung MR, Geusens P, Miller PD et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med 2001, 344, Harrington JT, Ste-Marie LG, Brandi ML et al. Risedronate rapidly reduces the risk for nonvertebral fractures in women with postmenopausal osteoporosis. Calcif Tissue Int 2004, 74, Chesnut CH III, Skag A, Christiansen C et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004, 19, Miller PD, McClung MR, Macovei L et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res 2005, 20, 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, Black DM, Delmas PD, Eastell R et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007, 356, Lyles KW, Colon-Emeric CS, Magaziner JS et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007, 357, Black DM, Schwartz AV, Ensrud KE et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006, 296, Marie PJ, Hott M, Modrowski D et al. An uncoupling agent containing strontium prevents bone loss by depressing bone resorption and maintaining bone formation in estrogen-deficient rats. J Bone Miner Res 1993, 8, Nielsen SP, Slosman D, Sorensen OH et al. Influence of strontium on bone mineral density and bone mineral content measurements by dual X-ray absorptiometry. J Clin Densitom 1999, 2, 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, 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, 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, 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, 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: a randomized trial. Ann Intern Med 2007, 146, British Medical Bulletin 2008;86

15 Update on the treatment of post-menopausal osteoporosis 24 Chesnut CH III, Silverman S, Andriano K et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med 2000, 109, Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. Br Med J 1994, 308, Jackson RD, LaCroix AZ, Gass M et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006, 354, Grant AM, Avenell A, Campbell MK et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005, 365, O Loughlin JL, Robitaille Y, Boivin JF, Suissa S. Incidence of and risk factors for falls and injurious falls among the community-dwelling elderly. Am J Epidemiol 1993, 137, Kiel DP, Magaziner J, Zimmerman S et al. Efficacy of a hip protector to prevent hip fracture in nursing home residents: the HIP PRO randomized controlled trial. JAMA 2007, 298, Martyn-St JM, Carroll S. High-intensity resistance training and postmenopausal bone loss: a meta-analysis. Osteoporos Int 2006, 17, McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006, 354, Kanis JA, Burlet N, Cooper C et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2008, 19, British Medical Bulletin 2008;86 143