FRAX is based on a large sample of primary data of prospective population studies and takes into account variability in fracture probability between geographic regions. FRAX should not be considered a gold standard but rather a platform technology and provides an aid to enhance patient assessment. FRAX can be integrated in clinical practice in many countries worldwide, both in women and men. FRAX is therefore likely to become, in many countries, the most popular instrument for identifying women and men at highest risk for fractures.

FRAX has been included in guidelines as a tool for case finding for identifying postmenopausal women at high risk for fractures, for selecting subjects to measure BMD, and for treatment decisions. The National Osteoporosis Foundation (NOF) in the US and the National Osteoporosis Society (NOS) in the UK have recently updated their guidelines on postmenopausal osteoporosis in this context (Figure 1) 45. These groups have integrated FRAX and BMD for case finding of individuals at high risk for fracture and for treatment decisions. Both sets of guidelines make a clear distinction between postmenopausal women with and without a fracture history. This is a major step forward in the clinical applicability for postfracture treatment in patients presenting with a fracture. Based on the fracture risk profile, the NOS, together with the National Osteoporosis Guideline Group (NOGG) and the Royal College of Physicians, determined treatment thresholds at which fracture prevention became cost-effective (Figure 2) 25.

The NOS advocates drug treatment in all postmenopausal women with a history of any fragility fracture (defined as distal radius, proximal humerus, spine [including morphometric vertebral fracture], pelvis [pubic rami], tibia, and ankle) 5. The NOF advocates drug treatment in postmenopausal women with a vertebral or hip fracture (without need of BMD or FRAX for decisions about pharmacotherapy), but after a nonvertebral nonhip fracture, the NOF advocates performing a dual-energy x-ray absorptiometry (DXA) measurement and starting drug treatment in patients having osteoporosis and in patients with osteopenia when FRAX indicates a 10-year fracture probability of at least 3% for hip or at least 20% for major fractures. Thus, in postmenopausal women with a history of vertebral or hip fracture, neither set of guidelines uses FRAX for decisions about drug treatment (and neither does the NOS for after any fragility fracture), and both sets consider such fracture history by itself as a starting point for case finding and treatment decisions.

The NOS advocates applying FRAX (without BMD) in all postmenopausal women. Women at high risk according to FRAX without BMD are then considered candidates for drug treatment. Women with an intermediate risk according to FRAX without BMD are recommended to have a DXA measurement, and when FRAX with BMD is above the intervention threshold according to the NOGG, drug treatment should be considered.

The NOF advocates using DXA in all women older than 65 years and in postmenopausal women younger than 65 years in whom there is concern about their fracture risk based on the presence of clinical risk factors. This approach suggests that all postmenopausal women under 65 years of age should be clinically classified as having at least one of the risk factors of FRAX. Treatment is then recommended in patients with osteoporosis, in patients with osteopenia when the FRAX indicates a 10-year risk of greater than 3% for hip fractures or greater than 20% for major osteoporotic fractures, and in other patients considered at high risk (on glucocorticoids, total immobilization). These upgraded guidelines indicate that FRAX is an emerging tool in clinical decision making about case finding, selecting patients for DXA, and treatment decisions in postmenopausal women without a fracture history. Patients with a fracture are considered at high enough risk to make treatment decisions without additional need for using FRAX. It is expected that FRAX will also be helpful in designing fracture prevention studies and in reimbursement issues. In a study from Switzerland, profiles of patients at increased probability of fracture beyond currently accepted reimbursement thresholds for bone BMD measurement by DXA and osteoporosis treatment were identified and constitute an additional group of patients in whom treatment should be considered 6.

In spite of its solid scientific basis and clinical attractiveness, FRAX has several limitations, as acknowledged by the authors (Table 2) 2. Meanwhile, FRAX has been integrated in guidelines/guidance in the US, UK, Europe, Canada, Germany, and Japan 2, but with different approaches for diagnostic and treatment thresholds, as shown above for the NOS and the NOF 45. Fracture reduction has been demonstrated in randomized controlled clinical trials in patients selected on the basis of the presence of a morphometric vertebral fracture, hip fracture, or a low BMD, but not on the basis of FRAX. Therefore, of great interest is the finding that fracture reduction was greater at higher fracture probabilities based on FRAX, with or without BMD. Antifracture efficacy was evident when baseline fracture probabilities for major fractures were greater than 20% in the clodronate trial (in preventing major fractures) 7 and greater than 16% in the bazedoxifene trial (in preventing clinical fractures), irrespective of whether BMD was used in the fracture calculation 2. Further studies will be needed on the ability of treatment to reduce fracture risk in subjects at high risk for fractures based on FRAX in the absence of a morphometric vertebral fracture, hip fracture, or a low BMD, which is the case in most patients presenting with a nonvertebral fracture. Decisions on treatment thresholds will furthermore depend on factors related to health care providers and patients and the willingness of society to reimburse treatment as health economic aspects are becoming increasingly important to determine the cost-effectiveness of treatment. Meanwhile, the NOGG of the UK has indicated FRAX-based thresholds for measuring BMD and for treatment decisions, with and without BMD (Figure 2). The management algorithms proposed by the NOGG are underpinned by a health economic analysis applied to the epidemiology of fracture in the UK.

Fall-related risks were explicitly excluded from the FRAX calculations but were recognized as risks for fractures independently of bone-related risks, especially for non-vertebral fractures such as hip fractures. More than 80% of women and men presenting with a clinical fracture to the emergency unit have, beside bone-related risks, one or more fall-related risks and have, independently from BMD, a fourfold increased risk of a fall history during the previous year 1. In an integrated bone- and fall-related risk evaluation tool for the estimation of the 5- and 10-year ARs for fractures in patients using glucocorticoids, a history of falls had a greater impact on fracture risk than any other evaluated risk, and its contribution to fracture risk was similar to, and independent of, using a high dose of glucocorticoids (prednisone greater than 15 mg/day) 8. Thus, with FRAX, fracture risk calculation could be underestimated in patients with fall risks.

Estrogen has a direct effect on bone mass through receptors on osteoclasts and other bone cells and it results in lowered bone turnover and resorption. Observational studies have suggested a 25% to 70% risk reduction for fractures associated with the use of estrogen replacement therapy (ERT) 52535455. Results from the Women's Health Initiative (WHI), a study of over 16,000 postmenopausal women, convincingly confirmed a significant risk reduction of hip fractures attributed to combined conjugated equine estrogen and medroxyprogesterone (RR = 0.66, 95% confidence interval [CI] 0.45 to 0.98) 56 as well as estrogen alone in those women who had undergone hysterectomy 57. In addition to its beneficial effects on bone, ERT raises high-density lipoproteins and lowers low-density lipids in post-menopausal women 5859. Although a number of observational studies, including the Nurses Health Study 60, have reported a 35% to 80% reduction in cardiovascular events and prolonged survival among women with coronary heart disease compared with nonusers 6162636465, results from the WHI and other studies of both primary and secondary cardiovascular prevention refute this conclusion 56626667. Data from the WHI found a nearly 30% increased risk of coronary heart disease and an over 40% increased risk of stroke.

Beyond heart disease, three significant concerns with estrogen are an increased risk of thromboembolic events 68, hyperplastic effects on the endometrium (potentially leading to endometrial cancer), and a heightened risk for breast cancer. The WHI 56 and other studies 69 have shown a 26% to 35% increased risk of breast cancer. Some 70, but not all 71, studies suggest that invasive breast tumors that develop among estrogen users have a more favorable histologic prognosis and that lobular cancer is more common than ductal cancer 72.

The decision to initiate ERT should be individualized and based on a balanced assessment of risk and benefits by the physician and patient 7374. Lower-dose estrogen can increase bone mass, may have a lower adverse effect profile, and raises interest in further study of this possible approach 7576. The proven increased risks for breast cancer and hypercoagulability and the higher risks of both primary and secondary cardiovascular disease (at least among older women) offset bone benefits and have substantially diminished enthusiasm for long-term higher-dose estrogen historically used by many patients. Although questions about the relative benefit and risks of different estrogen types, routes of administration (oral versus transdermal), administration protocols (opposed by progestins versus unopposed), and variable risk profiles based on a woman's age and comorbidities persist, current recommendations support restricting the use of estrogen in most women to the perimenopausal period 7778 and not with the primary aim to prevent fractures in the context of treatment of osteoporosis. Furthermore, the growing array of alternative bone-directed medications now available further restrict the estrogen niche.

Selective estrogen receptor modulators (SERMs) are non-steroidal synthetic compounds that have estrogen-like properties on the bone and cardiovascular systems yet are estrogen antagonists to the breast and, in some cases, the endometrium. The first SERM developed both for breast cancer prevention and for osteoporosis, raloxifene, is now licensed in many countries for osteoporosis 79. After 3 years of follow-up in the Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter study of over 7,700 postmenopausal women with at least one vertebral fracture or osteoporosis on the basis of a T score of -2.5 or below, 60 mg/day of raloxifene reduced vertebral fracture risk by 30% 80. This decline in fracture risk at the spine was of a magnitude similar to that seen with more potent antiresorptive agents such as the aminobisphosphonates and emphasized the importance of attenuation of bone turnover, in addition to effects on BMD, for fracture risk reduction 8182. Similar to tamoxifen, the risk of invasive breast cancer was decreased by 72% during the MORE study 8384, particularly among women with higher estradiol levels 8586. Hot flashes and other menopausal symptoms may recur on raloxifene. Also similar to estrogen, with raloxifene, there is an increase in lower-extremity edema as well as a roughly threefold increased risk of deep venous thrombosis 80. Additional SERMs, such as bazedoxifene and lasofoxifene, are under development. Bazodoxifene decreases vertebral fracture risk to a degree similar to that of raloxifene (approximately 40% over a 3-year period 87) and, in a post hoc analysis, reduced the risk of nonspine fractures in a subgroup of patients with high risk for fractures based on the FRAX algorithm 2. Preliminary results from the PEARL (Postmenopausal Evaluation And Risk reduction with Lasofoxifene) trial showed significant reductions compared with placebo in vertebral and nonvertebral (but not hip) fracture risk as well as in estrogen receptor breast cancer with the 0.5 mg dose 88. This is the only SERM, to date, that has primary data on nonvertebral fracture risk reduction. Of potential concern, a small rise in overall mortality was reported in the 0.25 mg dose but not in the 0.5 mg dose.

Randomized controlled trials of both injectable 899091 and intranasal 92939495 calcitonin for treatment of established postmenopausal osteoporosis have consistently shown either stabilization of BMD or small, but significant, increases in vertebral BMD of approximately 1% to 3% on 200 IU daily for over 3 to 5 years. Beneficial BMD effects at the hip have not yet been reported. Modest increases in vertebral BMD with intranasal calcitonin are accompanied by significant declines in biochemical measures of bone resorption 96. A 5-year multicenter study of 1,255 postmenopausal women showed a 36% reduction in vertebral fractures in the 200 IU, but not in the 100 or 400 IU, dosage group. Interpretation of study results was further limited by an approximately 50% dropout rate 9798. Nasal calcitonin is generally well tolerated, with occasional rhinitis. Headache, flushing, nausea, and diarrhea have been reported more commonly with subcutaneous rather than with intranasal calcitonin. On the basis of data that are somewhat weaker than those of osteoporosis drugs (including the absence of data on hip or nonvertebral fracture risk reduction) along with emerging new therapeutic agents, calcitonin has been relegated to a second- or third-line agent for osteoporosis prevention and treatment.

Bisphosphonates are potent inhibitors of bone resorption and fractures when administered orally or by intravenous infusion 99. Variations in the structure of the amino side chains of these drugs affect their pharmacological activity. All oral bisphosphonates are poorly absorbed, with bioavailability of less than 1%. These agents bind tightly to hydroxyapatite crystals of bone, where they have a variable but generally long skeletal retention (approximately 10 years for alendronate). Over prolonged administration, a regional paracrine effect of continuously deposited and recycled bisphosphonates may partially account for a lack of rapid loss of BMD gains at some, but not all, skeletal sites when these agents are discontinued 100101102. The nitrogen-containing bisphosphonates (that is, alendronate, risedronate, and zolendronate) have variable affinity for bone and function as antiresorptive agents by variable enzyme inhibition, impairing cholesterol metabolism of the osteoclast and leading to cytoskeletal alterations and premature osteoclast cell death via apoptosis 103104.

As a class, oral bisphosphonates may lead to gastrointestinal (GI) intolerance, particularly at low pH 105. Most reported GI symptoms have been nonulcer dyspepsia, and in most clinical trials, there have not been significant differences between those exposed to bisphosphonates and those receiving placebo 106107. There have been rare reports of severe esophagitis 108 and case reports of esophageal cancer in patients taking oral bisphosphonates 109. Some small studies suggest that GI side effects may be fewer with risedronate than alendronate 110.

The most common bisphosphonates licensed and used internationally are alendronate, risedronate, ibandronate, and zoledronic acid. These drugs are used in osteoporosis, Paget disease, myositis ossificans progressiva, heterotopic ossification, multiple myeloma, other malignancies with bone metastasis, and hypercalcemia. Alendronate, risedronate, and zoledronic acid have all been shown to improve BMD among patients receiving glucocorticoids 111112113114.

Alendronate was the first aminobisphosphonate approved by the US Food and Drug Administration for the treatment and prevention of osteoporosis. Postmenopausal women receiving 10 mg/day of alendronate showed a lumbar spine BMD increase of 7% to nearly 9% over a 2-year period 115116. Smaller, but still significant, changes were seen at the femoral neck and trochanter. In early postmenopausal women, 5 mg/day of alendronate prevented the loss of BMD at the spine, hip, and total body 117. In a separate study, the 5 mg/day dose prevented bone loss to nearly the same extent as an estrogen-progestin combination (estrogen effect was 1% to 2% greater than 5 mg) 118. Increases in spinal BMD with alendronate continue for up to 7 years of daily therapy 119. Daily alendronate has a similar benefit and adequate tolerability even among older female residents of long-term care facilities 120. A once-weekly preparation of alendronate has greatly exceeded daily administration based on BMD efficacy, improved ease of use, and tolerability that is equivalent to or better than daily therapy 121122. Among 2,027 older women with at least one prior vertebral fracture and low femoral neck BMD in the Fracture Intervention Trial (FIT), alendronate had significant 47% and 51% reductions in morphometric vertebral and hip fractures, respectively 123. In FIT subjects without prevalent vertebral fractures, alendronate 10 mg decreased radiographic vertebral fractures by 44% 124. A multinational study of alendronate similarly identified a 47% risk reduction for nonvertebral fractures 125. A long-term extension to the FIT study found that, with the exception of clinical vertebral fractures, fracture risk reduction at other skeletal sites was statistically indistinguishable in those receiving 5 years on followed by 5 years off of alendronate versus a full 10 years of therapy 100. Further preliminary evaluation of these data has revealed that women with a femoral neck BMD T score of -2.5 or below at the 5-year mark had a higher risk of subsequent fractures 126. Thus, the decision about whether to stop therapy with alendronate after a finite period of time is a topic of current controversy and in need of additional scientific data. In addition to prior duration of therapy, past adherence to therapy informs the risk of subsequent fractures 127.

Combination approaches of bisphosphonates with either estrogen or SERMs have shown equivalent or better BMD than with either therapy alone 128129, although concerns of oversuppression of bone remodeling and potential risk of inadequate repair of bone microdamage persist 130. Alendronate can attenuate the loss of BMD seen after stopping hormone replacement therapy 131.

Alendronate clinical trials have shown no significant increases in serious adverse effects or significant GI adverse effects between treatment groups and placebo 106132. In a study of glucocorticoid-induced osteoporosis, there was a small increase in nonserious upper GI adverse effects in those taking 10 mg but not 5 mg or placebo 111. Results of bone histomorphometry indicate that alendronate decreases bone turnover in a dose-dependent manner but does not impair mineralization 121133134.

Risedronate is a pyridinyl bisphosphonate that increases bone mass and prevents fractures 135. In separate US 136 and multinational 137 VERT (Vertebral Efficacy with Risedronate Therapy) studies, 1,226 and 2,458 postmenopausal women with at least one prior vertebral fracture were treated with 5 mg of risedronate. Women receiving risedronate experienced significantly fewer new vertebral (41% US and 49% multinational) and nonvertebral (39% and 33% reduction, respectively) fractures over a 3-year period 136. In the Hip Intervention Program study, risedronate 5 mg significantly reduced hip fractures among women with confirmed low bone mass but not among those selected primarily on the basis of fall risks without documented osteoporosis 138. Similar to alendronate, combined treatment with risedronate and estrogen resulted in additive improvement in BMD and further reduction in bone turnover 139. Although the increases in BMD seen with risedronate were more modest compared with those of alendronate in one head-to-head comparator study 140, a fairly similar fracture effectiveness is believed to be due in part to the decrease in bone resorption, as evidenced by significant suppression of biochemical markers 141142. Risedronate is taken daily, weekly, or (more recently) monthly and is generally well tolerated, with no significant differences in upper GI adverse events between those receiving placebo and risedronate 136143.

Ibrandronate either orally (daily or monthly schedules) or intravenously successfully reduced markers of bone turnover, increased BMD 144145, and reduced fractures of the vertebra (relative risk reduction [RRR] = 52%) 146. Secondary analyses of persons in ibandronate studies with initial BMD at or below -3.0 showed that ibandronate had a protective effect on hip fracture risk reduction as well.

Zolendronic acid (zolendronate) is administered as a yearly intravenous infusion and significantly reduced both vertebral (RRR = 70%) and hip (RRR = 41%) fractures in a large multinational study 147. A subsequent study examined women and men who had experienced a prior hip fracture and showed a significant reduction in subsequent clinical fractures along with a reduction in mortality 148. Side effects may include an acute-phase response with myalgias and flu-like symptoms in 10% to 15% of patients receiving their first dose. These symptoms most commonly resolve within several days and are attenuated with acetaminophen, prior oral bisphosphonates, and repeated doses of the intravenous therapy. Patients receiving intravenous zoledronic acid must have adequate renal function (creatinine clearance of greater than 30 mL/minute) prior to getting this agent.

On the basis of largely uncontrolled reports of osteonecrosis of the jaw and newer questions about atypical femoral fractures, there is increasing scrutiny of particularly longer-term therapy with bisphosphonates as a class 149. Osteonecrosis of the jaw has been reported in an estimated 2% of cancer patients receiving higher doses of predominately intravenous bisphosphonates for patients with malignancies in particular 150. Cases also have been described in patients receiving bisphosphonates for osteoporosis. Although mechanisms are not confirmed for these two adverse outcomes, if a relationship is supported by further studies, this will have further impact on the idea of a 'drug holiday' 151.

In summary, there have been a large number of studies documenting the efficacy of several bisphosphonates in terms of BMD gains and, of more importance, with regard to reduction of both vertebral and nonvertebral fractures. As a class, bisphosphonates are the most efficacious anti-resorptive agents currently available for bone. Despite a significant duration of worldwide use of bisphosphonates, a number of questions such as the necessary duration of therapy, long-term safety, and use among women of child-bearing potential as well as among children remain 152.

When bone is exposed to elevated PTH levels continuously (e.g., hyperparathyroidism) it acts in a catabolic fashion. In contrast, exogenously administered intermittent PTH is anabolic stimulating skeletal remodeling and raising BMD both in rodent models and in human studies 153154. PTH (residues 1 to 34) (teriparatide) significantly decreased the risk of vertebral (65% risk reduction in those on 20 μg/day) and nonvertebral fractures and increased BMD at all sites investigated, except for the radial shaft 155. As a potential explanation for initial decreases in cortical bone density at sites such as the wrist, PTH initially increases intracortical porosity. It also leads to periosteal new bone formation and increases cross-sectional area, potentially increasing cortical bone strength 156157. Teriparatide increases BMD in the spine of men by nearly 6% 158. There is an enhanced effect on bone mass when PTH is sequentially followed by alendronate 159 or estrogen 160. When PTH is compared directly with alendronate, there is a greater BMD increase seen with PTH in postmenopausal 161 as well as glucocorticoid-associated 162 osteoporosis. Although BMD increases with PTH occur even in the presence of potent antiresorptive agents such as alendronate 163, antecedent oral bisphosphonates started concurrently with PTH may attenuate bone mass improvement seen with PTH 164165. PTH administered subcutaneously once a day has been associated with asymptomatic hypercalcemia, occasional nausea, and headache. Clinical trials of teriparatide were terminated early by the finding of osteosarcoma in Fisher rats 155. Selective parathyroid receptor agonists and antagonists are under investigation and may play a future role in osteoporosis 166. Due in part to the development of osteosarcoma in Fisher rats in the initial fracture trials (leading to their premature discontinuation), teriparatide at 20 μg/day is recommended for only a 24-month administration. It is used most commonly in adults with severe osteoporosis, many of whom have had fractures while on other antiosteoporotic agents or have had intolerance to bisphosphonates.

Daily intake of strontium ranelate has been shown to reduce the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis or a prevalent vertebral fracture or both. In a post hoc analysis in women over 74 years old with low BMD at the femoral neck, it reduces the risk of hip fractures 167168. Fracture reduction was still found after 5 years of treatment 169. In a post hoc analysis in women older than 80 years, strontium ranelate reduced the risk of vertebral and nonvertebral fractures 170. Strontium ranelate prevented quality-of-life impairment in postmenopausal women with established vertebral osteoporosis 171.

The discovery of the receptor activator of the nuclear factor-kappa B ligand RANKL/RANK/osteoprotegerin (OPG) pathway has opened new ways to target osteoclastic bone resorption. Clinical trials indicate that denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is effective in suppressing bone resorption, resulting in an increase in BMD in postmenopausal women with low BMD 172173174175. The effect of denosumab on BMD and markers of bone remodeling was more pronounced than with weekly alendronate 176. The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) study of nearly 8,000 women 177. As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture by 68%, with a cumulative incidence of 2.3% in the denosumab group versus 7.2% in the placebo group (risk ratio 0.32, 95% CI 0.26 to 0.41; P < 0.001). Denosumab significantly reduced the risk of hip fracture by 40% and also reduced significantly the risk of nonvertebral fracture by 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw.

In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which are, up until now, available up to 4 years. Since the RANKL/RANK/OPG pathway is involved in the development of the immune system, data on long-term safety, particularly with respect to bacterial infection and neoplasms, will be needed 172173174175176178.

Cathepsin K is the most abundant cysteine protease expressed in the osteoclast and is believed to be instrumental in the bone matrix degradation necessary for bone resorption. Cathepsin K inhibitors represent a novel target for developing agents to treat osteoporosis and other disorders characterized by increased bone resorption 179.

The discovery that the Wnt signaling is a major pathway in osteoblast activity has resulted in a revolution in our understanding of the molecular mechanisms that are involved in bone formation. Preclinical studies have shown that sclerostin has a pivotal role as a negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis 180.