Definition and management of very high fracture risk in women with postmenopausal osteoporosis: a position statement from the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Association of Bone Assessment and Metabolism (ABRASSO).

INTRODUCTION

In many chronic diseases, therapeutic inertia causes a considerable gap between recommended guidelines and treatment implementation in clinical practice ( 1 ). The treatment gap in osteoporosis leads to many preventable fractures that occur without appropriate treatment ( 2 ). After an episode of hip fracture, the rate of treatment initiation to prevent future fractures is low ( 3 ), despite robust evidence of a better outcome with pharmacological intervention ( 4 ).

Screening for osteoporosis is crucial for identifying high-risk patients who would benefit most from pharmacological treatment ( 5 ). In the SCOOP study, 12,483 postmenopausal women aged 70-85 years were randomized to a screening program using the Fracture Risk Assessment Tool (FRAX) or usual management ( 6 ). The women were identified from primary care centers and, in those at high risk of fractures, treatment was recommended. At the end of the first year, 15.3% of the participants in the screening group were on pharmacological treatment, compared with 4.5% of those in the control group. Over 5 years of follow-up, there was a 28% reduction in the rate of hip fracture in the screening group (hazard ratio [HR]: 0.72, 95% confidence interval [CI] 0.59-0.89; p = 0.002). This reduction was greater in women with a baseline FRAX probability of hip fracture in the 90th percentile (HR: 0.67, 95% CI 0.53-0.84; p = 0.002) ( 7 ). Among patients who were classified as being at high risk of fracture in the screening arm and who self-reported use of antiosteoporotic medication at 6 months, 38.2% remained on treatment at 60 months compared with 21.6% of controls ( 8 ).

In a recent meta-analysis of randomized studies evaluating the role of population screening for postmenopausal osteoporosis in preventing fracture, data from the SCOOP trial were combined with data from two other studies, i.e. , the ROSE and SOS studies, including 18,605 and 11,032 patients, respectively, aged 65-90 years ( 9 ). The FRAX probability of fracture was also used to identify high-risk patients ( 9 ). The proportion of patients who started pharmacological treatment and the mean follow-up period were, respectively, 11% and 5 years in ROSE, 15% and 4.8 years in SCOOP, and 18% and 3.7 years in SOS. There were significant reductions in the rates of major osteoporotic (HR: 0.91, 95% CI 0.84-0.98) and hip (HR: 0.80, 95% CI 0.71-0.91) fractures in screened patients compared with controls receiving usual care ( 9 ). These data reinforce the need for proper implementation of screening programs to reduce the fracture burden.

Several organizations have recommended risk stratification at screening as an important tool in osteoporosis management ( 10 - 14 ). These recently published guidelines have refined the fracture risk stratification to include a category of patients at a very high risk of fracture ( Table 1 ). Over the last decades, most patients requiring pharmacological intervention were offered antiresorptive drugs as first-line therapy, whereas anabolic agents were considered as last resource for those with therapeutic failure. Although bisphosphonates continue to be the first-line agents for long-term pharmacological therapy in high-risk patients ( 15 ), recent randomized trials comparing bone-forming agents with bisphosphonates have shown that anabolic agents reduce fractures to a greater extent than antiresorptive agents in patients with severe osteoporosis ( 16 , 17 ). Additionally, it became apparent that the reduction in fracture risk may be more pronounced when patients are treated with anabolic agents first, followed by an antiresorptive drug ( 18 , 19 ). In a meta-regression analysis of 38 randomized controlled trials of antiosteoporotic medications, Bouxsein and cols. ( 19 ) found that a 6% increase in total hip (TH) bone mineral density (BMD) was associated with a 66% reduction in vertebral fractures and 40% reduction in hip fractures. In this regard, for patients in the “very high risk” category (those who have a greater immediate risk of future fracture), starting with an anabolic followed by an antiresorptive agent would induce greater increases in femoral neck (FN) and TH BMD, which have been associated with a more pronounced reduction in fracture risk at any site, therefore avoiding a larger number of fracture than the single-antiresorptive strategy ( 13 ).

The aim of this document is to provide clinicians with a position from experts at the Brazilian Society of Endocrinology and Metabolism (SBEM) and the Brazilian Association of Bone Assessment and Metabolism (ABRASSO) on the evidence-based definition of very high fracture risk in postmenopausal women. It also aims to describe for whom anabolic agents should be considered as first-line therapy. The document also reviews the factors associated with increased fracture risk, the comparative trials of anabolic and antiresorptive agents, the efficacy of anabolic agents in patients who are treatment-naïve versus those previously treated with antiresorptive medications, and the safety of anabolic agents.

MATERIALS AND METHODS

Members of SBEM and ABRASSO performed a narrative review based on a rigorous literature search using PubMed. The literature search was limited to the English language and human subjects, and included original articles, systematic and narrative reviews, and guidelines by medical societies published between 2000 and 2021, as well as pertinent articles from authors’ libraries. Relevant articles were reviewed in detail. Panel members reached consensus after several virtual meetings to discuss the available data and finalize the non-graded recommendations presented in this review.

Clinical and densitometric findings associated with increased fracture risk

Recent and multiple fragility fractures

A prior fragility fracture is a very important, if not the main, risk factor for subsequent fractures. The time elapsed since the prior fracture, as well as characteristics specific to this fracture, are now recognized as important factors influencing subsequent risk. In a large cohort of 18,872 individuals, the risk of a second major osteoporotic fracture (MOF) was 2.7-fold higher than the risk of fracture in the background population within the first year following a MOF, and declined thereafter, yet not to the rates of the general population. In individuals with an incident fracture, a refracture occurred in 20% within 1 year and 34% within 2 years ( 20 ). The observation that the risk of a new fracture declines over time following an index fracture is in agreement with several studies ( 21 - 23 ) demonstrating up to 5-fold higher fracture risk within 1 year post-fracture ( 24 ).

Virtually all types of fragility fractures, including fractures in nonvertebral sites such as wrist and humerus, are followed by imminent fracture risk ( 25 - 27 ), but the magnitude of the risk of refracture varies by the location of the previous fracture ( Table 2 ). In three recent large cohorts of patients with an incident fracture, the incidence of subsequent fractures within 1-2 years was highest in those with an index vertebral fracture ( 28 - 30 ). Patients with an index wrist fracture had lower absolute risk relative to those with index fracture occurring at most of the other skeletal sites ( 29 ). The risk was lowest following prior tibia/fibula and ankle fracture ( 29 , 30 ). Importantly, the proportion of patients with a fragility fracture who fractured again increased with age in all these studies. Further, the risk of new vertebral fractures increases progressively with the number of prior vertebral fractures ( 31 - 33 ). In a large sample of participants of the Fracture Interventional Trial with prevalent vertebral fractures, the incidence of new vertebral fracture increased from 3.8% in women without prior vertebral fracture to 8.9%, 19.4%, 30.8%, or 54.2% in those with 1, 2, 3-4, or 5 or more prevalent vertebral fractures, respectively ( 33 ). Association between prior nonvertebral fractures and the risk of subsequent fractures was also investigated; in a cohort of 51,762 women, the subsequent 2-year fracture incidence was 10%, 16%, and 25% for women with one, two, or three or more prior fractures at any of 10 different skeletal sites. The increased risk was most dramatic for spine fractures; a history of ≥ 3 prior fractures carried a 9-fold risk of a subsequent vertebral fracture ( 34 ). Therefore, a recent fracture (within the past 2 years) is a predictor of imminent fracture risk and multiple fragility fractures; even when the fractures occurred remotely, they are associated with a very high risk of near-term fracture.

Bone mineral density T-score lower than -3.0 standard deviations

There is a strong inverse relationship between BMD and risk of fractures. For every 1 standard deviation (SD) decrease in age-adjusted BMD, the relative risk (RR) of fracture increases 1.6- to 2.6-fold ( 35 ). A low BMD is also a risk factor of imminent fracture ( i.e. , fracture within 1-2 years). A retrospective study of 3,228 women aged > 65 years from the Canadian Multicentre Osteoporosis Study identified four independent predictors of 2-year low-trauma nonvertebral fractures, including a T-score ≤ -3.5 at the TH (HR: 3.7; p < 0.001), two or more falls in the previous year (HR: 1.9; p < 0.001), at least one low-trauma fracture in the previous year (HR: 1.7; p = 0.055), and a low score in the physical component of the SF-36 quality of life questionnaire (HR: 1.6; p < 0.001) ( 36 ). Similar predictors of 1-year nonvertebral fractures were identified in a cohort of 1,470 women aged > 65 years from the Framingham Study original cohort, namely a hip T-score ≤ -2.5 (HR: 2.8; p < 0.001), a poor self-rated health (HR: 4.0; p = 0.04), and the use of nitrates in the previous year (HR: 2.6; p = 0.01) ( 37 ).

Thus, low BMD is a major predictor not only of long-term fracture risk ( 38 ) but also of imminent fracture. Since this concept of imminent fracture is central to the categorization of very high risk of fracture, one might consider a low T-score as an isolated criterion to define a very high risk of fracture. In fact, the recent guidelines of the American Association of Clinical Endocrinology (AACE) include a T-score ≤ -3.0 SD as characterizing patients at very high risk of fracture ( 10 ). Other authors suggest a T-score ≤ -3.5 SD as a criterion to define a very high fracture risk ( 39 ). However, especially for the imminent fracture risk, factors other than BMD are extremely important, such as advanced age, previous fracture, and high falling risk, among others ( 29 , 36 , 37 , 40 ). Thus, the present position statement considers that an isolated T-score ≤ -3.0 SD (without other predictive factors such as a prior fracture, advanced age, high risk of fall, or glucocorticoid use) may not be indicative of a very high fracture risk.

High risk of falls

Falls are the leading cause of injury-related morbidity and mortality among older adults ( 41 ), and over 50% of deaths due to falls are a result of complications following a hip fracture ( 42 ). A systematic review by Ganz and cols. concluded that older adults with a history of falls are likely to fall again (likelihood ratio [LR] 2.3-2.8), and that the most consistent predictor of future falls was a clinically detected gait or balance abnormality (LR 1.2-2.4) ( 43 ). Data on risk factors obtained from meta-analyses of observational studies have revealed the following odds ratios (ORs) and 95% CIs for any falls ( 44 ): gait problems, 2.06 (1.82-2.33) ( 45 ); balance impairment, 1.98 (1.6-2.46) ( 46 ); physical disability, 1.56 (1.22-1.99) ( 45 ); orthostatic hypotension, 1.50 (1.15-1.97) ( 47 ); depressive symptoms, 1.49 (1.24-1.79) ( 48 ); visual impairment, 1.35 (1.18-1.54) ( 45 ); and cognitive impairment, 1.32 (1.18-1.49) ( 49 ). The following medications are likewise related to risk factors for falls: antipsychotics, 2.30 (1.24-6.26) ( 50 ); antidepressants, 1.48 (1.24-1.77); benzodiazepines, 1.40 (1.18-1.66); and polypharmacy, 1.75 (1.27-2.41). Some of these factors increase not only the risk of falls but also the risk of fracture ( 40 , 51 ). In addition, the history of fall itself is a risk for imminent fracture ( 36 , 40 , 51 ). As previously mentioned, two or more falls in the previous year almost doubled the risk of osteoporotic nonvertebral fracture (HR: 1.9; p < 0.001) in the following 2 years in women aged > 65 years from the Canadian Multicentre Osteoporosis Study ( 36 ). A history of at least one fall in the previous 1 or 2 years also increased the risk of imminent fracture in two additional cohorts of older people (mostly women), with risk ratios ranging from 2.2 to 6.7 ( 40 , 51 ).

Therefore, it is important to consider the risk factors for falls in the previous year in the evaluation of patients at risk for fracture, since these factors are associated with imminent risk of fracture and may be useful to classify elderly women in the category of very high fracture risk. The present position statement considers that older women at high risk of falls are those who have had two or more falls in the previous year, or those with decreased physical and cognitive performance, with a high frailty status.

Risk stratification estimated by FRAX

FRAX is the most used fracture risk calculator incorporated into guidelines for the management of osteoporosis. In Brazil, as in many countries of Europe and Latin America, the approach used to define pharmacological treatment intervention with FRAX is based on an age-dependent intervention threshold adopted by the National Osteoporosis Guideline Group (NOGG) ( 52 - 55 ). Recently, the International Osteoporosis Foundation and European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (IOF-ESCEO) have published guidance recommending the use of FRAX to define a very high fracture risk ( 13 ). Using fully age-dependent intervention thresholds, a fracture probability calculated with or without BMD that exceeds the intervention threshold by 20% would categorize individuals at very high fracture risk. Thus, individuals eligible for treatment are categorized as being at high or very high risk of fracture if their fracture probability falls, respectively, below or above 1.2 times their age-specific intervention threshold ( 13 ).

This recommendation, however, may classify too many individuals into the category of very high fracture risk when the hybrid intervention threshold is used ( 56 ). Over the last few years, NOGG has adopted a “hybrid approach” defined as an age-dependent threshold up to the age of 70 years, with a fixed threshold thereafter ( 11 , 57 ), reducing the dependence on the existence of a prior fracture after this age. Recently, a NOGG working group has compared the impact of setting an upper intervention threshold (UIT) equivalent to 1.2, 1.6, and 2.0 times the preexisting age-dependent intervention threshold in a simulated UK population of women aged 55-90 years, to distinguish the “very high” from the “high” risk categories using the FRAX hybrid model ( 56 ). Among women eligible for treatment, the proportion of those at very high fracture risk was 55.7% (too high), 25.1%, and 12.1% (very low) using the UITs of 1.2, 1.6, and 2.0, respectively. The authors considered that a UIT of 1.6 would be more appropriate in the hybrid model. Indeed, using the UIT of 1.6, most participants in phase 3 trials of romosozumab and teriparatide (TPTD) would fall in the very-high-risk category ( 56 ).

The use of FRAX to identify individuals who are at very high risk of fracture has been questioned by some authors ( 58 ). The current version of FRAX does not consider the recency, site, or number of prior fractures − factors that have been shown to be important determinants of risk for imminent fractures ( 58 ). In addition, FRAX does not consider the risk of falls or the age when the fractures occurred. On the other hand, a recent post hoc analysis of the FRAME study has shown that, compared with placebo, the efficacy of romosozumab in reducing clinical, osteoporotic, and MOFs was greater in women with a higher FRAX probability of fracture at baseline ( 59 ). These data suggest that FRAX could be useful in identifying better responders to this anabolic agent.

The present position statement considers that, while the categorization of patients at very high risk of fracture should not be based solely on FRAX, this tool can be used as one of the criteria to identify these patients. The UIT of 1.2 to define patients at very high risk of fracture, as recommended by the IOF-ESCEO, appears to be appropriate for adoption in Brazil, since the FRAX Brazil uses the fully age-dependent intervention threshold rather than the hybrid model.

Fracture while on prolonged use of glucocorticoid

Glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis. Rapid bone loss and increased fracture risk may occur within the first 6 months of continuous use of glucocorticoid (GC), while fracture risk remains high during treatment, decreasing only after GC withdrawal ( 60 ). The risk of fracture in GIO is higher than in postmenopausal or senile osteoporosis at the same values of BMD ( 61 ). Vertebral fractures are more common in GIO, but nonvertebral and hip fractures may also occur ( 61 ). The risk of fracture is significantly associated with GC dose. Daily doses of prednisone < 2.5 mg, 2.5-7.5 mg, and > 7.5 mg lead to GIO RRs of 1.55, 2.59, and 5.18, respectively. Bone loss in GIO may lead to a very high risk of fracture ( 62 ).

Fracture while on antiosteoporotic treatment

The efficacy of the treatment response can be evaluated only in patients who have adhered to the treatment regimen (80% of doses taken) for at least 1 year, with calcium and vitamin D adequacy. Poor persistence is associated with loss of fracture risk reduction. Persistence is essential for the successful treatment of osteoporosis and can be improved by therapeutic education ( 63 ). In a systematic review, factors associated with poorer medication adherence included polypharmacy, older age, higher dosing frequency, medication side effects, and misconceptions about osteoporosis. The history of falls was associated with higher medication adherence ( 64 ). The IOF working group has defined that treatment failure in osteoporosis should be considered in the case of two or more incident fragility fractures (fractures of the hand, skull, digits, feet, and ankle are not considered as fragility fractures), significant bone loss (5% or more in at least two serial BMD measurements at the lumbar spine (LS) or 4% at the proximal femur), or nonresponse in bone turnover markers (decline of less than 25% from baseline levels for antiresorptive treatments, and less than 25% increase for TPTD after 6 months) in a patient who has been treated for more than 12 months and with no secondary causes of bone loss or fracture ( 65 ). The working group recommends that a weaker antiresorptive can be reasonably replaced by a more potent drug of the same class, an oral drug can be replaced by an injected drug, and a strong antiresorptive can be replaced by an anabolic agent ( 65 ).

More recently, the Endocrine Society suggested a greater change in bone turnover markers (~56% for serum C-telopeptide [CTX] and ~38% for procollagen type 1 N-terminal propeptide [P1NP]) to be considered an optimal response to treatment ( 12 ) and recommended that CTX or P1NP can be used to identify poor response or nonadherence to antiresorptive or anabolic therapy, respectively. While the authors agreed that having two or more fractures while on therapy is considered treatment failure, the occurrence of a single fracture in a compliant patient should raise the consideration for changing therapy ( 12 ). The AACE guideline for osteoporosis treatment suggests that the occurrence of fractures while on approved osteoporosis therapy is a criterion to define very high risk of fracture and recommends therapy with potent injected antiresorptive agents or anabolic drugs in these cases ( 10 ).

Head-to-head comparative trials of anabolic versus antiresorptive agents

Two bone-forming agents approved for treatment of postmenopausal osteoporosis are currently available in Brazil: TPTD (1-34 aminopeptide of PTH or PTH[1-34]), the foreshortened fragment of PTH( 1 - 84 ), and romosozumab, a monoclonal anti-sclerostin antibody. TPTD is an osteoanabolic agent that increases bone formation and resorption and is available in Brazil as a 20 µg subcutaneous (SC) daily dose, given for a maximum of 24 months. In contrast, romosozumab stimulates bone formation and inhibits bone resorption and is given as a 210 mg SC monthly dose for 12 months ( 66 ).

Anabolic therapy should be considered as initial treatment for very-high-risk patients. In these patients, rapid fracture risk reduction is required. Pivotal trial data and a few head-to-head studies indicate that anabolic agents produce a more rapid and greater reduction in nonvertebral fracture risk as well as a greater reduction in vertebral fracture risk compared with antiresorptive therapies over 1 to 2 years of treatment (described below) ( 16 , 17 , 67 , 68 ). However, these comparator studies utilized oral bisphosphonates (alendronate and risedronate) and not the most potent parenteral antiresorptive agents, denosumab or zoledronic acid.

Anabolic versus antiresorptive agents in postmenopausal women with low bone mineral density and previous fractures

A few anabolic/antiresorptive comparator clinical trials have evaluated fractures as primary outcomes, and they all included women with severe osteoporosis and prevalent vertebral or hip fracture ( Table 3 ) ( 16 , 17 , 68 ). In the VERO study, the antifracture efficacy of TPTD was compared with that of risedronate in postmenopausal women with severe osteoporosis ( 16 ). TPTD therapy led to a lower risk of new vertebral and clinical fractures compared with risedronate. TPTD reduced the incidence of vertebral fracture by 50% within 1 year (p = 0.01) and resulted in a trend toward reduced nonvertebral fracture incidence (p = 0.099) over 2 years ( 16 ).

In the ARCH study, fracture risk reductions with romosozumab versus alendronate were already apparent at 12 months, when romosozumab reduced the incidence of nonvertebral and vertebral fracture by 26% (p = 0.06) and 37% (p = 0.003), respectively, compared with alendronate. At 24 months, the risk of new vertebral fracture was reduced by 48% (p < 0.001) in patients treated with romosozumab followed by alendronate, when compared with alendronate alone. Moreover, nonvertebral fractures were reduced by 19% (p < 0.04) and hip fractures were reduced by 38% (p < 0.02) in patients who received romosozumab followed by alendronate compared with alendronate alone ( 17 ).

A post hoc analysis of the ACTIVE and its extension trials suggested a similar superiority of abaloparatide when compared with alendronate ( 69 ). The rates of vertebral fracture with 18 months of abaloparatide in the ACTIVE study were 71% lower than those observed with 24 months of alendronate during the ACTIVE extension trial ( 70 , 71 ). A trend toward lower nonvertebral fracture incidence was also observed with abaloparatide versus alendronate (45% risk reduction; p = 0.11).

Hadji and cols. studied 710 patients with active back pain due to vertebral fractures who were randomized to receive TPTD versus risedronate for 1 year. The incidence of recurrent vertebral fractures was 9% with risedronate and 4% with TPTD (p < 0.01), but there was no difference in nonvertebral fracture incidence ( 72 ). However, this study was designed to evaluate the effect of TPTD versus risedronate in reducing back pain, and the incidence of new vertebral fractures was a prespecified exploratory outcome.

Anabolic versus antiresorptive agents in individuals on chronic use of glucocorticoid

The mechanisms through which GCs decrease bone strength are complex, but the most consistent skeletal effects of GC are to inhibit osteoblastic function and promote osteoblast apoptosis. GIO is a typical bone formation disease ( 73 ). From a biological point of view, particularly in those patients receiving high dosages of GCs over the long term, the use of agents acting on osteoblasts and exerting an anabolic effect on bone seems appropriate. Bone quality and quantity may be restored to a greater extent with these compounds compared with inhibitors of bone resorption ( 74 ). To date, the only available osteoanabolic agent tested in a randomized clinical trial on GIO is TPTD. A head-to-head comparison of TPTD versus alendronate has been conducted in 428 men and women (80% women) with a mean age of 56 years, taking a median prednisone equivalent dose of 7.5 mg/day for 1.2-1.5 years. The mean BMD T-score was -2.6 at the LS and -2.0 at the TH. Overall, 27% of the participants had prevalent morphometric vertebral fractures, and 43% had nonvertebral fractures at baseline. Of note, only 9.3% of the study patients had been previously treated with bisphosphonates. The primary outcome was the change in BMD at the LS. The results showed that subjects with GIO treated with TPTD for 36 months had greater increases in BMD and fewer new vertebral fractures than those treated with alendronate (0.6% vs. 6.1%, respectively, p = 0.004), although the overall number of fractures was small ( 75 ).

Geusens and cols. performed a head-to-head comparison of TPTD versus risedronate in subgroups of the VERO trial, including GC-treated patients at a prednisone-equivalent dose of 5 mg/day or above (representing 9.3% of the cohort). They found consistent reduction in vertebral fracture risk in the TPTD group compared with the risedronate group, even in this subgroup of GIO patients ( 76 ).

The use in GIO has not yet been established for other osteoanabolic agents, such as abaloparatide and romosozumab, despite their use being approved for the treatment of postmenopausal osteoporosis. However, due to its combined anabolic and antiresorptive effect on bone, romosozumab may eventually become a promising treatment option in GIO ( 77 ).

Efficacy of bone-forming agents in treatment-naïve patients and in individuals previously treated with antiresorptive drugs

The prescription of antiresorptive drugs is a sine qua non after a cycle of anabolic drugs. On the other hand, there is a heterogeneous response to anabolic drugs after antiresorptive therapy. When TPTD treatment follows the use of less potent antiresorptive agents, such as hormone therapy or raloxifene, the TPTD-induced increase in BMD appears to be preserved ( 18 , 78 ). Differently, TPTD prescribed after alendronate leads to a transient bone loss in proximal femur and only a slight beneficial effect in BMD at this bone site following 2 years of therapy ( 18 , 79 ). However, in recent randomized clinical trials and meta-analyses, TPTD and abaloparatide have demonstrated increases in BMD at both trabecular and cortical sites, resulting in fracture risk reduction regardless of prior bisphosphonate treatment ( 16 , 76 , 80 ). Romosozumab following bisphosphonate therapy has demonstrated BMD gains at the LS and hip sites, although more modest than in treatment-naïve patients ( 81 , 82 ). A randomized trial comparing TPTD with romosozumab therapy for 12 months in postmenopausal women previously treated with bisphosphonates (mostly alendronate) for a mean period of 6 years has shown significant greater increments in BMD at the LS, TH, and FN with romosozumab than TPTD ( 83 ). This study, however, did not assess the difference in fracture incidence between the groups ( 83 ).

The transition from denosumab to anabolic therapy has the potential to increase bone turnover and decrease bone mass. In the DATA-Switch study, the use of TPTD after denosumab led to marked bone loss in proximal femur, which was attenuated during the second year of TPTD treatment. However, there was continuing bone loss at the 1/3 radius ( 84 ). There are no data on fracture risk in patients treated with denosumab followed by TPTD, but a recently published position statement on the management of discontinuation of denosumab therapy discourages monotherapy with TPTD after denosumab ( 85 ).

Kendler and cols. have shown in a small study, designed to evaluate a three-cycle therapy (romosozumab-denosumab-romosozumab regimen), that after 12 months of denosumab treatment, another romosozumab cycle promoted a small increase in BMD at the LS and maintenance of BMD at the TH ( 86 ). Two observational studies have shown that subjects with osteoporosis treated for 1 year with romosozumab after treatment with denosumab for a mean duration of 24 to 39 months presented significantly lower gains in LS and hip BMD than treatment-naïve subjects ( 81 , 82 ). Although romosozumab decreased bone resorption in treatment-naïve individuals, the opposite finding of increased level of bone resorption marker was observed in patients previously treated with denosumab, which may have blunted BMD improvements ( 81 , 82 ). No data are available on fracture risk in patients treated with romosozumab following denosumab therapy for longer periods (>2.5 years), and the safety of transitioning from long-term use of denosumab to romosozumab is unknown.

Ideal treatment sequences for patients at very high fracture risk

The aforementioned data suggest that the common practice of switching to bone-forming agents only after patients have an inadequate response to antiresorptive agents may not be the best approach to manage patients with severe osteoporosis. Indeed, there is evidence favoring the use of anabolic agents followed by potent antiresorptive therapy in patients at very high risk of fracture. Pivotal studies of anabolic and more potent parenteral antiresorptive agents suggest that the use of bone-forming compared with antiresorptive agents leads to a more rapid effect against all fractures, which is crucial in the management of patients with imminent risk of fractures ( 87 - 90 ). Moreover, recent data suggest that the use of anabolic followed by antiresorptive agents allows for greater increases in BMD ( 91 , 92 ). This is important considering new evidence showing that greater on-treatment increases in BMD, particularly at the femur, result in greater reduction in fracture risk ( 19 , 91 , 93 , 94 ).

Definition and management of very high fracture risk in postmenopausal women

Treatment-naïve women

Postmenopausal women with osteoporosis presenting any of the following criteria should be classified in the very-high-risk category and be considered for anabolic therapy as initial treatment:

BMD T-score ≤ -2.5 at the LS, FN, or TH associated with at least one osteoporotic vertebral fracture OR a fragility hip fracture, particularly when the fracture occurred within the last 24 months.

Multiple osteoporotic vertebral fractures OR two or more nonvertebral osteoporotic fractures, regardless of the skeletal site and the BMD T-score, even when the fractures occurred more remotely.

Fragility fracture while on long-term GC use (≥ 3 months of prednisone-equivalent dose of 5 mg/day or above).

A BMD T-score ≤ -3.0 associated with any other clinical risk factor, namely, advanced age (≥ 65 years), a previous fragility fracture, high risk of falls (see above), or prolonged use of GCs.

Patients with fracture risk 1.2 times above the age-specific intervention threshold, as assessed by FRAX Brazil calculated with or without BMD.

To determine if a woman falls into this very−high-risk category, vertebral imaging should be obtained. Both anabolic agents available in Brazil − TPTD and romosozumab − can be used as first-line treatment in patients at very high risk of fracture, apart from those on prolonged use of GCs and fractures. In these patients, TPTD should be preferred since the use of romosozumab in GIO has not yet been established.

Women previously treated with bisphosphonates

In patients who have been on long-term bisphosphonate use, one can consider switching to bone formation therapy if any of the following is present:

Women with adequate compliance and in whom secondary causes of osteoporosis have been ruled out, who continue to lose bone and sustain a fragility fracture, or those who sustain two or more fragility fractures.

Women with GIO who sustain a fracture while on bisphosphonate use with adequate compliance.

Vertebral imaging should be obtained in any woman on chronic use of bisphosphonates who presents symptoms or signs of vertebral fracture over the course of treatment, such as height loss or back pain ( 95 ). In those on prolonged use of GCs, vertebral imaging should be obtained every 6 months during the first year and then every 1-2 years ( 96 ). In patients switching from bisphosphonates to anabolic agents − with the exception of patients with GIO − romosozumab might be preferred, given the evidence of greater BMD improvements with this agent compared with TPTD ( 83 ). A transient decrease in hip BMD can be observed when transitioning from bisphosphonates to TPTD. This is, however, a recommendation based solely on BMD, and not on fracture data.

Women previously treated with denosumab

There are no data on fracture risk in patients treated with denosumab followed by TPTD or romosozumab. A small study has shown increased bone turnover and decreased bone mass in patients treated with denosumab followed by TPTD. Thus, despite the absence of fracture data, this position statement recommends against the use of TPTD following denosumab therapy.

Regarding the use of romosozumab after denosumab, small studies suggest that a short-term treatment of denosumab followed by romosozumab maintains or slightly increases bone mass. However, the safety of transitioning from a long-term denosumab therapy (>2.5 years) to romosozumab is unknown. Given the lack of data, this position statement makes no recommendation for or against the use of romosozumab following denosumab therapy.

Safety profile of anabolic agents

Prolonged treatment of rodents with TPTD has been linked to increased risk of osteosarcoma, although this has not been observed in long-term surveillance of patients treated with the drug ( 97 ). Yet, TPTD is not recommended for patients with existing risk factors for osteosarcoma (including Paget’s disease of bone, unexplained elevations of alkaline phosphatase, prior skeletal radiation, or personal or family history of osteosarcoma) or in those with bone metastasis, multiple myeloma, or other hematologic malignancies ( 98 ). In addition, the safety and efficacy of TPTD in postmenopausal osteoporosis have only been established for a 2-year period in clinical trials, so the use of this medication should not exceed 24 months. TPTD can cause hypercalcemia and is contraindicated in patients with primary hyperparathyroidism or other hypercalcemic states. Finally, TPTD has been associated with hypercalciuria, dizziness, palpitations, nausea, and headache ( 67 ).

Treatment with romosozumab can lead to hypocalcemia, hypersensitivity reactions, and mild injection site reactions ( 87 ). More importantly, in the ARCH study, the risk of major adverse cardiac events (MACE) was greater in the romosozumab than in the alendronate group ( 17 ). This observation has led to the recommendation by Regulatory Medical Agencies across many countries, including the ANVISA in Brazil, to avoid the use of romosozumab in patients who have had a myocardial infarction or stroke within the preceding year ( 99 , 100 ).

CONCLUSION

In conclusion, screening for osteoporosis, which includes clinical fracture risk assessment and BMD measurement, followed by pharmacological intervention in selected patients, reduces fracture risk. Recently, a step toward individualized treatment based on fracture risk stratification has been proposed. In postmenopausal women at very high risk of fracture, the use of a bone-forming agent as first-line therapy, followed by an antiresorptive agent, appears to reduce the fracture risk to a greater extent than antiresorptive drugs alone. This document proposes the definition of very high risk of osteoporotic fracture in postmenopausal women. It suggests bone-forming agents to be considered as first-line therapy for postmenopausal women presenting any of the following: a BMD T-score ≤ -2.5 associated with vertebral or hip osteoporotic fracture; multiple vertebral fractures or two or more nonvertebral osteoporotic fractures; a fragility fracture while on long-term GC use; a BMD T-score ≤ -3.0 associated with other clinical risk factors; or a fracture risk 1.2 times above the age-specific intervention threshold as assessed by FRAX. Additionally, anabolic agents should be considered in patients who fail bisphosphonate therapies, including those on long-term GC use. This new approach to osteoporosis treatment may reduce fracture-related morbidity and mortality.

REFERENCES

1 Phillips LS Branch WT Cook CB Doyle JP El-Kebbi IM Gallina DL Clinical inertia Ann Intern Med 2001 135 9 825 834 11694107 10.7326/0003-4819-135-9-200111060-00012

2 Compston J Reducing the treatment gap in osteoporosis Lancet Diabetes Endocrinol 2020 8 1 7 9 31757770 10.1016/S2213-8587(19)30378-X

3 Desai RJ Mahesri M Abdia Y Barberio J Tong A Zhang D Association of Osteoporosis Medication Use After Hip Fracture With Prevention of Subsequent Nonvertebral Fractures: An Instrumental Variable Analysis JAMA Netw Open 2018 1 3 e180826 30646034 10.1001/jamanetworkopen.2018.0826 PMC6324295

4 Lyles KW Colón-Emeric CS Magaziner JS Adachi JD Pieper CF Mautalen C Zoledronic acid and clinical fractures and mortality after hip fracture N Engl J Med 2007 357 18 1799 1809 17878149 10.1056/NEJMoa074941 PMC2324066

5 Clynes MA Harvey NC Curtis EM Fuggle NR Dennison EM Cooper C The epidemiology of osteoporosis Br Med Bull 2020 133 1 105 117 32282039 10.1093/bmb/ldaa005 PMC7115830

6 Shepstone L Lenaghan E Cooper C Clarke S Fong-Soe-Khioe R Fordham R Screening in the community to reduce fractures in older women (SCOOP): a randomised controlled trial Lancet 2018 391 10122 741 747 29254858 10.1016/S0140-6736(17)32640-5

7 McCloskey E Johansson H Harvey NC Shepstone L Lenaghan E Fordham R Management of Patients With High Baseline Hip Fracture Risk by FRAX Reduces Hip Fractures-A Post Hoc Analysis of the SCOOP Study J Bone Miner Res 2018 33 6 1020 1026 29480960 10.1002/jbmr.3411 PMC6004119

8 Parsons CM Harvey N Shepstone L Kanis JA Lenaghan E Clarke S Systematic screening using FRAX ® leads to increased use of, and adherence to, anti-osteoporosis medications: an analysis of the UK SCOOP trial Osteoporos Int 2020 31 1 67 75 31606826 10.1007/s00198-019-05142-z PMC6952271

9 Merlijn T Swart KMA van der Horst HE Netelenbos JC Elders PJM Fracture prevention by screening for high fracture risk: a systematic review and meta-analysis Osteoporos Int 2020 31 2 251 257 31838551 10.1007/s00198-019-05226-w PMC7010619

10 Camacho PM Petak SM Binkley N Diab DL Eldeiry LS Farooki A American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis-2020 Update Endocr Pract 2020 26 Suppl 1 1 46 10.4158/GL-2020-0524SUPPL 32427503

11 Compston J Cooper A Cooper C Gittoes N Gregson C Harvey N UK clinical guideline for the prevention and treatment of osteoporosis Arch Osteoporos 2017 12 1 43 43 28425085 10.1007/s11657-017-0324-5 PMC5397452

12 Eastell R Rosen CJ Black DM Cheung AM Murad MH Shoback D Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society* Clinical Practice Guideline J Clin Endocrinol Metab 2019 104 5 1595 1622 30907953 10.1210/jc.2019-00221

13 Kanis JA Harvey NC McCloskey E Bruyère O Veronese N Lorentzon M Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures Osteoporos Int 2020 31 1 1 12 10.1007/s00198-019-05176-3 PMC7018677 31720707

14 Shoback D Rosen CJ Black DM Cheung AM Murad MH Eastell R Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Guideline Update J Clin Endocrinol Metab 2020 105 3 10.1210/clinem/dgaa048 32068863

15 Bandeira F Dantas W Bilezikian JP Controversies in the treatment of postmenopausal osteoporosis: How long to treat with bisphosphonates? Arch Endocrinol Metab 2020 64 4 331 336 32725062 10.20945/2359-3997000000275 PMC10522084

16 Kendler DL Marin F Zerbini CAF Russo LA Greenspan SL Zikan V Effects of teriparatide and risedronate on new fractures in postmenopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial Lancet 2018 391 10117 230 240 29129436 10.1016/S0140-6736(17)32137-2

17 Saag KG Petersen J Brandi ML Karaplis AC Lorentzon M Thomas T Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis N Engl J Med 2017 377 15 1417 1427 28892457 10.1056/NEJMoa1708322

18 Cosman F Nieves JW Dempster DW Treatment Sequence Matters: Anabolic and Antiresorptive Therapy for Osteoporosis J Bone Miner Res 2017 32 2 198 202 27925287 10.1002/jbmr.3051

19 Bouxsein ML Eastell R Lui LY Wu LA de Papp AE Grauer A Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials J Bone Miner Res 2019 34 4 632 642 30674078 10.1002/jbmr.3641

20 Johansson H Siggeirsdóttir K Harvey NC Odén A Gudnason V McCloskey E Imminent risk of fracture after fracture Osteoporos Int 2017 28 3 775 780 28028554 10.1007/s00198-016-3868-0 PMC5338733

21 Center JR Bliuc D Nguyen TV Eisman JA Risk of subsequent fracture after low-trauma fracture in men and women JAMA 2007 297 4 387 394 17244835 10.1001/jama.297.4.387

22 Giangregorio LM Leslie WD Time since prior fracture is a risk modifier for 10-year osteoporotic fractures J Bone Miner Res 2010 25 6 1400 1405 20200950 10.1002/jbmr.35

23 Nymark T Lauritsen JM Ovesen O Röck ND Jeune B Short time-frame from first to second hip fracture in the Funen County Hip Fracture Study Osteoporos Int 2006 17 9 1353 1357 16823545 10.1007/s00198-006-0125-y

24 van Geel TA van Helden S Geusens PP Winkens B Dinant GJ Clinical subsequent fractures cluster in time after first fractures Ann Rheum Dis 2009 68 1 99 102 18677009 10.1136/ard.2008.092775

25 Huntjens KM Kosar S van Geel TA Geusens PP Willems P Kessels A Risk of subsequent fracture and mortality within 5 years after a nonvertebral fracture Osteoporos Int 2010 21 12 2075 2082 20162259 10.1007/s00198-010-1178-5 PMC2974915

26 Maravic M Briot K Roux C Burden of proximal humerus fractures in the French National Hospital Database Orthop Traumatol Surg Res 2014 100 8 931 934 25453923 10.1016/j.otsr.2014.09.017

27 Clinton J Franta A Polissar NL Neradilek B Mounce D Fink HA Proximal humeral fracture as a risk factor for subsequent hip fractures J Bone Joint Surg Am 2009 91 3 503 511 19255209 10.2106/JBJS.G.01529 PMC2669747

28 Toth E Banefelt J Åkesson K Spångeus A Ortsäter G Libanati C History of Previous Fracture and Imminent Fracture Risk in Swedish Women Aged 55 to 90 Years Presenting With a Fragility Fracture J Bone Miner Res 2020 35 5 861 868 31914206 10.1002/jbmr.3953 PMC9328134

29 Adachi JD Brown JP Schemitsch E Tarride JE Brown V Bell AD Fragility fracture identifies patients at imminent risk for subsequent fracture: real-world retrospective database study in Ontario, Canada BMC Musculoskelet Disord 2021 22 1 224 224 33637078 10.1186/s12891-021-04051-9 PMC7908684

30 Balasubramanian A Zhang J Chen L Wenkert D Daigle SG Grauer A Risk of subsequent fracture after prior fracture among older women Osteoporos Int 2019 30 1 79 92 30456571 10.1007/s00198-018-4732-1 PMC6332293

31 Ross PD Davis JW Epstein RS Wasnich RD Preexisting fractures and bone mass predict vertebral fracture incidence in women Ann Intern Med 1991 114 11 919 923 2024857 10.7326/0003-4819-114-11-919

32 Ross PD Genant HK Davis JW Miller PD Wasnich RD Predicting vertebral fracture incidence from prevalent fractures and bone density among non-black, osteoporotic women Osteoporos Int 1993 3 3 120 126 8481587 10.1007/BF01623272

33 Nevitt MC Ross PD Palermo L Musliner T Genant HK Thompson DE Association of prevalent vertebral fractures, bone density, and alendronate treatment with incident vertebral fractures: effect of number and spinal location of fractures. The Fracture Intervention Trial Research Group Bone 1999 25 5 613 619 10574584 10.1016/s8756-3282(99)00202-1

34 Gehlbach S Saag KG Adachi JD Hooven FH Flahive J Boonen S Previous fractures at multiple sites increase the risk for subsequent fractures: the Global Longitudinal Study of Osteoporosis in Women J Bone Miner Res 2012 27 3 645 653 22113888 10.1002/jbmr.1476 PMC4881741

35 Marshall D Johnell O Wedel H Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures BMJ 1996 312 7041 1254 1259 8634613 10.1136/bmj.312.7041.1254 PMC2351094

36 Adachi JD Berger C Barron R Weycker D Anastassiades TP Davison KS Predictors of imminent nonvertebral fracture in elderly women with osteoporosis, low bone mass, or a history of fracture, based on data from the population-based Canadian Multicentre Osteoporosis Study (CaMos) Arch Osteoporos 2019 14 1 53 53 31098708 10.1007/s11657-019-0598-x

37 Hannan MT Weycker D McLean RR Sahni S Bornheimer R Barron R Predictors of Imminent Risk of Nonvertebral Fracture in Older, High-Risk Women: The Framingham Osteoporosis Study JBMR Plus 2019 3 6 e10129 31346561 10.1002/jbm4.10129 PMC6636767

38 Lippuner K Johansson H Kanis JA Rizzoli R Remaining lifetime and absolute 10-year probabilities of osteoporotic fracture in Swiss men and women Osteoporos Int 2009 20 7 1131 1140 18974918 10.1007/s00198-008-0779-8

39 Ensrud KE Schousboe JT Anabolic Therapy for Osteoporosis JAMA 2021 326 4 350 351 34313699 10.1001/jama.2021.0233

40 Bonafede M Shi N Barron R Li X Crittenden DB Chandler D Predicting imminent risk for fracture in patients aged 50 or older with osteoporosis using US claims data Arch Osteoporos 2016 11 1 26 26 27475642 10.1007/s11657-016-0280-5 PMC4967418

41 Grossman DC Curry SJ Owens DK Barry MJ Caughey AB Davidson KW Interventions to Prevent Falls in Community-Dwelling Older Adults: US Preventive Services Task Force Recommendation Statement JAMA 2018 319 16 1696 1704 29710141 10.1001/jama.2018.3097

42 Deprey SM Descriptive analysis of fatal falls of older adults in a Midwestern county in the year 2005 J Geriatr Phys Ther 2009 32 2 67 72 20039585

43 Ganz DA Bao Y Shekelle PG Rubenstein LZ Will my patient fall? JAMA 2007 297 1 77 86 17200478 10.1001/jama.297.1.77

44 Ganz DA Latham NK Prevention of Falls in Community-Dwelling Older Adults N Engl J Med 2020 382 8 734 743 32074420 10.1056/NEJMcp1903252

45 Deandrea S Lucenteforte E Bravi F Foschi R La Vecchia C Negri E Risk factors for falls in community-dwelling older people: a systematic review and meta-analysis Epidemiology 2010 21 5 658 668 20585256 10.1097/EDE.0b013e3181e89905

46 Muir SW Berg K Chesworth B Klar N Speechley M Quantifying the magnitude of risk for balance impairment on falls in community-dwelling older adults: a systematic review and meta-analysis J Clin Epidemiol 2010 63 4 389 406 19744824 10.1016/j.jclinepi.2009.06.010

47 Mol A Bui Hoang PTS Sharmin S Reijnierse EM van Wezel RJA Meskers CGM Orthostatic Hypotension and Falls in Older Adults: A Systematic Review and Meta-analysis J Am Med Dir Assoc 2019 20 5 589.e5 597.e5 30583909 10.1016/j.jamda.2018.11.003

48 Kvelde T McVeigh C Toson B Greenaway M Lord SR Delbaere K Depressive symptomatology as a risk factor for falls in older people: systematic review and meta-analysis J Am Geriatr Soc 2013 61 5 694 706 23617614 10.1111/jgs.12209

49 Muir SW Gopaul K Montero Odasso MM The role of cognitive impairment in fall risk among older adults: a systematic review and meta-analysis Age Ageing 2012 41 3 299 308 22374645 10.1093/ageing/afs012

50 Seppala LJ van de Glind EMM Daams JG Ploegmakers KJ de Vries M Wermelink A Fall-Risk-Increasing Drugs: A Systematic Review and Meta-analysis: III. Others J Am Med Dir Assoc 2018 19 4 372.e1 372.e8 10.1016/j.jamda.2017.12.099 29402646

51 Yusuf AA Hu Y Chandler D Crittenden DB Barron RL Predictors of imminent risk of fracture in Medicare-enrolled men and women Arch Osteoporos 2020 15 1 120 120 32748034 10.1007/s11657-020-00784-7 PMC7399683

52 Kanis JA Harvey NC Cooper C Johansson H Oden A McCloskey EV A systematic review of intervention thresholds based on FRAX: A report prepared for the National Osteoporosis Guideline Group and the International Osteoporosis Foundation Arch Osteoporos 2016 11 1 25 25 27465509 10.1007/s11657-016-0278-z PMC4978487

53 Lekamwasam S Adachi JD Agnusdei D Bilezikian J Boonen S Borgstrom F A framework for the development of guidelines for the management of glucocorticoid-induced osteoporosis Osteoporos Int 2012 23 9 2257 2276 22434203 10.1007/s00198-012-1958-1

54 Clark P Denova-Gutierrez E Zerbini C Sanchez A Messina O Jaller JJ FRAX-based intervention and assessment thresholds in seven Latin American countries Osteoporos Int 2018 29 3 707 715 29273826 10.1007/s00198-017-4341-4

55 Lesnyak O Zakroyeva A Babalyan V Cazac V Gabdulina G Ismailov S FRAX-based intervention thresholds in eight Eurasian countries: Armenia, Belarus, Georgia, Kazakhstan, the Kyrgyz Republic, Moldova, the Russian Federation, and Uzbekistan Arch Osteoporos 2021 16 1 87 87 34089424 10.1007/s11657-021-00962-1

56 Kanis JA Johansson H Harvey NC Lorentzon M Liu E Vandenput L An assessment of intervention thresholds for very high fracture risk applied to the NOGG guidelines: A report for the National Osteoporosis Guideline Group (NOGG) Osteoporos Int 2021 32 10 1951 1960 33813622 10.1007/s00198-021-05942-2

57 McCloskey E Kanis JA Johansson H Harvey N Oden A Cooper A FRAX-based assessment and intervention thresholds – an exploration of thresholds in women aged 50 years and older in the UK Osteoporos Int 2015 26 8 2091 2099 26077380 10.1007/s00198-015-3176-0

58 Compston JE Drake MT Defining Very High Fracture Risk: Is FRAX Fit for Purpose? J Bone Miner Res 2020 35 8 1399 1403 32696997 10.1002/jbmr.4134

59 McCloskey EV Johansson H Harvey NC Lorentzon M Shi Y Kanis JA Romosozumab efficacy on fracture outcomes is greater in patients at high baseline fracture risk: a post hoc analysis of the first year of the frame study Osteoporos Int 2021 32 8 1601 1608 33537844 10.1007/s00198-020-05815-0 PMC8376732

60 Chotiyarnwong P McCloskey EV Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment Nat Rev Endocrinol 2020 16 8 437 447 32286516 10.1038/s41574-020-0341-0

61 Kaji H Yamauchi M Chihara K Sugimoto T The threshold of bone mineral density for vertebral fracture in female patients with glucocorticoid-induced osteoporosis Endocr J 2006 53 1 27 34 16543669 10.1507/endocrj.53.27

62 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 6 993 1000 10841167 10.1359/jbmr.2000.15.6.993

63 Confavreux CB Paccou J David C Mehsen N Leboime A Thomas T Defining treatment failure in severe osteoporosis Joint Bone Spine 2010 77 Suppl 2 S128 S132 21211750 10.1016/S1297-319X(10)70008-7

64 Yeam CT Chia S Tan HCC Kwan YH Fong W Seng JJB A systematic review of factors affecting medication adherence among patients with osteoporosis Osteoporos Int 2018 29 12 2623 2637 30417253 10.1007/s00198-018-4759-3

65 Diez-Perez A Adachi JD Agnusdei D Bilezikian JP Compston JE Cummings SR Treatment failure in osteoporosis Osteoporos Int 2012 23 12 2769 2774 22836278 10.1007/s00198-012-2093-8

66 Kaveh S Hosseinifard H Ghadimi N Vojdanian M Aryankhesal A Efficacy and safety of Romosozumab in treatment for low bone mineral density: a systematic review and meta-analysis Clin Rheumatol 2020 39 11 3261 3276 32385757 10.1007/s10067-020-04948-1

67 Cosman F Anabolic Therapy and Optimal Treatment Sequences for Patients with Osteoporosis at High Risk for Fracture Endocr Pract 2020 07 26 7 777 786 10.4158/EP-2019-0596 33471647

68 Hagino H Sugimoto T Tanaka S Sone T Nakamura T Soen S A randomized, controlled trial of once-weekly teriparatide injection versus alendronate in patients at high risk of osteoporotic fracture: primary results of the Japanese Osteoporosis Intervention Trial-05 Osteoporos Int 2021 32 11 2301 2311 34002252 10.1007/s00198-021-05996-2 PMC8563544

69 Leder BZ Mitlak B Hu MY Hattersley G Bockman RS Effect of Abaloparatide vs Alendronate on Fracture Risk Reduction in Postmenopausal Women With Osteoporosis J Clin Endocrinol Metab 2020 105 3 10.1210/clinem/dgz162 PMC7112966 31674644

70 Cosman F Miller PD Williams GC Hattersley G Hu MY Valter I Eighteen Months of Treatment With Subcutaneous Abaloparatide Followed by 6 Months of Treatment With Alendronate in Postmenopausal Women With Osteoporosis: Results of the ACTIVExtend Trial Mayo Clin Proc 2017 92 2 200 210 28160873 10.1016/j.mayocp.2016.10.009

71 Bone HG Cosman F Miller PD Williams GC Hattersley G Hu MY ACTIVExtend: 24 Months of Alendronate After 18 Months of Abaloparatide or Placebo for Postmenopausal Osteoporosis J Clin Endocrinol Metab 2018 103 8 2949 2957 29800372 10.1210/jc.2018-00163 PMC6097601

72 Hadji P Zanchetta JR Russo L Recknor CP Saag KG McKiernan FE The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures Osteoporos Int 2012 23 8 2141 2150 22159672 10.1007/s00198-011-1856-y

73 Lespessailles E Chapurlat R High fracture risk patients with glucocorticoid-induced osteoporosis should get an anabolic treatment first Osteoporos Int 2020 31 10 1829 1834 32780152 10.1007/s00198-020-05568-w

74 Canalis E Giustina A Bilezikian JP Mechanisms of anabolic therapies for osteoporosis N Engl J Med 2007 357 9 905 916 17761594 10.1056/NEJMra067395

75 Saag KG Shane E Boonen S Marin F Donley DW Taylor KA Teriparatide or alendronate in glucocorticoid-induced osteoporosis N Engl J Med 2007 357 20 2028 2039 18003959 10.1056/NEJMoa071408

76 Geusens P Marin F Kendler DL Russo LA Zerbini CA Minisola S Effects of Teriparatide Compared with Risedronate on the Risk of Fractures in Subgroups of Postmenopausal Women with Severe Osteoporosis: The VERO Trial J Bone Miner Res 2018 33 5 783 794 29329484 10.1002/jbmr.3384

77 Chiodini I Merlotti D Falchetti A Gennari L Treatment options for glucocorticoid-induced osteoporosis Expert Opin Pharmacother 2020 21 6 721 732 32004105 10.1080/14656566.2020.1721467

78 Ettinger B San Martin J Crans G Pavo I Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate J Bone Miner Res 2004 19 5 745 751 15068497 10.1359/JBMR.040117

79 Obermayer-Pietsch BM Marin F McCloskey EV Hadji P Farrerons J Boonen S Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment J Bone Miner Res 2008 23 10 1591 1600 18505369 10.1359/jbmr.080506

80 Barrionuevo P Kapoor E Asi N Alahdab F Mohammed K Benkhadra K Efficacy of Pharmacological Therapies for the Prevention of Fractures in Postmenopausal Women: A Network Meta-Analysis J Clin Endocrinol Metab 2019 104 5 1623 1630 30907957 10.1210/jc.2019-00192

81 Kobayakawa T Suzuki T Nakano M Saito M Miyazaki A Takahashi J Real-world effects and adverse events of romosozumab in Japanese osteoporotic patients: A prospective cohort study Bone Rep 2021 14 101068 101068 33981812 10.1016/j.bonr.2021.101068 PMC8085670

82 Ebina K Hirao M Tsuboi H Nagayama Y Kashii M Kaneshiro S Effects of prior osteoporosis treatment on early treatment response of romosozumab in patients with postmenopausal osteoporosis Bone 2020 140 115574 115574 32777516 10.1016/j.bone.2020.115574

83 Langdahl BL Libanati C Crittenden DB Bolognese MA Brown JP Daizadeh NS Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial Lancet 2017 390 10102 1585 1594 28755782 10.1016/S0140-6736(17)31613-6

84 Leder BZ Tsai JN Uihlein AV Wallace PM Lee H Neer RM Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial Lancet 2015 386 9999 1147 1155 26144908 10.1016/S0140-6736(15)61120-5 PMC4620731

85 Tsourdi E Zillikens MC Meier C Body JJ Gonzalez Rodriguez E Anastasilakis AD Fracture risk and management of discontinuation of denosumab therapy: a systematic review and position statement by ECTS J Clin Endocrinol Metab 2020 10 26 dgaa756 10.1210/clinem/dgaa756 33103722

86 Kendler DL Bone HG Massari F Gielen E Palacios S Maddox J Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab Osteoporos Int 2019 30 12 2437 2448 31628490 10.1007/s00198-019-05146-9 PMC6877701

87 Cosman F Crittenden DB Adachi JD Binkley N Czerwinski E Ferrari S Romosozumab Treatment in Postmenopausal Women with Osteoporosis N Engl J Med 2016 375 16 1532 1543 27641143 10.1056/NEJMoa1607948

88 Neer RM Arnaud CD Zanchetta JR Prince R Gaich GA Reginster JY Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis N Engl J Med 2001 344 19 1434 1441 11346808 10.1056/NEJM200105103441904

89 Black DM Delmas PD Eastell R Reid IR Boonen S Cauley JA Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis N Engl J Med 2007 356 18 1809 1822 17476007 10.1056/NEJMoa067312

90 Cummings SR San Martin J McClung MR Siris ES Eastell R Reid IR Denosumab for prevention of fractures in postmenopausal women with osteoporosis N Engl J Med 2009 361 8 756 765 19671655 10.1056/NEJMoa0809493

91 Cosman F Lewiecki EM Ebeling PR Hesse E Napoli N Matsumoto T T-Score as an Indicator of Fracture Risk During Treatment With Romosozumab or Alendronate in the ARCH Trial J Bone Miner Res 2020 35 7 1333 1342 32445228 10.1002/jbmr.3996 PMC9328657

92 Lewiecki EM Dinavahi RV Lazaretti-Castro M Ebeling PR Adachi JD Miyauchi A One Year of Romosozumab Followed by Two Years of Denosumab Maintains Fracture Risk Reductions: Results of the FRAME Extension Study J Bone Miner Res 2019 34 3 419 428 30508316 10.1002/jbmr.3622

93 Black DM Bauer DC Vittinghoff E Lui LY Grauer A Marin F Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials Lancet Diabetes Endocrinol 2020 8 8 672 682 32707115 10.1016/S2213-8587(20)30159-5

94 Ferrari S Libanati C Lin CJF Brown JP Cosman F Czerwinski E Relationship Between Bone Mineral Density T-Score and Nonvertebral Fracture Risk Over 10 Years of Denosumab Treatment J Bone Miner Res 2019 34 6 1033 1040 30919997 10.1002/jbmr.3722 PMC6852155

95 Borges JLC Sousa da Silva M Ward RJ Diemer KM Yeap SS Lewiecki EM Repeating Vertebral Fracture Assessment: 2019 ISCD Official Position J Clin Densitom 2019 22 4 484 488 31375350 10.1016/j.jocd.2019.07.005

96 Pereira RMR Perez MO Paula AP Moreira C Castro CHM Zerbini CAF Guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: an update of Brazilian Society of Rheumatology (2020) Arch Osteoporos 2021 16 1 49 49 33646403 10.1007/s11657-021-00902-z

97 Cipriani C Irani D Bilezikian JP Safety of osteoanabolic therapy: a decade of experience J Bone Miner Res 2012 27 12 2419 2428 23165426 10.1002/jbmr.1800

98 Tashjian AH Jr Gagel RF Teriparatide [human PTH(1-34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis J Bone Miner Res 2006 21 3 354 365 16491282 10.1359/JBMR.051023

99 Fixen C Tunoa J Romosozumab: a Review of Efficacy, Safety, and Cardiovascular Risk Curr Osteoporos Rep 2021 19 1 15 22 33409990 10.1007/s11914-020-00652-w

100 Vestergaard Kvist A Faruque J Vallejo-Yague E Weiler S Winter EM Burden AM Cardiovascular Safety Profile of Romosozumab: A Pharmacovigilance Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) J Clin Med 2021 04 13 10 8 1660 1660 33924496 10.3390/jcm10081660 PMC8070537