Management of patients at very high risk of osteoporotic fractures through sequential treatments

Abstract

Osteoporosis care has evolved markedly over the last 50 years, such that there are now an established clinical definition, validated methods of fracture risk assessment and a range of effective pharmacological agents. Currently, bone-forming (anabolic) agents, in many countries, are used in those patients who have continued to lose bone mineral density (BMD), patients with multiple subsequent fractures or those who have fractured despite treatment with antiresorptive agents. However, head-to-head data suggest that anabolic agents have greater rapidity and efficacy for fracture risk reduction than do antiresorptive therapies. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) convened an expert working group to discuss the tools available to identify patients at high risk of fracture, review the evidence for the use of anabolic agents as the initial intervention in patients at highest risk of fracture and consider the sequence of therapy following their use. This position paper sets out the findings of the group and the consequent recommendations. The key conclusion is that the current evidence base supports an "anabolic first" approach in patients found to be at very high risk of fracture, followed by maintenance therapy using an antiresorptive agent, and with the subsequent need for antiosteoporosis therapy addressed over a lifetime horizon.

Keywords: Anabolic; Antiresorptive; Epidemiology; Fracture; Imminent; Osteoporosis.

Fig. 1

Crystal Bone: Use of Machine Learning driven methods for fracture prediction. Crystal Bone used techniques applied in natural language processing to screen electronic healthcare records from a US population (Optum), covering 91 million patients to predict first and second fracture at the spine, pelvis, clavicle, humerus, radius, ulna, hip, femur, tibia, fibula, and ankle. Sequences of ICD codes were used as inputs to implement two distinct frameworks: (1) ICD code vectorization and long short-term memory networks, and (2) patient-level vectorization and extreme gradient boosting decision trees. The figure shows exploration of model interpretability by comparison of various characteristics of the input data for the 4 prediction cohorts of the confusion matrix (FN false negative, FP false positive, TN true negative, TP true positive). UMAP: uniform manifold approximation and projection (this allows encoded vectors to be projected onto a 2D space for dimension reduction). ICD codes predictive of future fracture (TP) include, for example 73,313 (collapsed vertebra), 81,200 (closed fracture of upper humerus), 81,342 (closed fracture of distal radius), 82,100 (closed fracture of femur). Reproduced with permission from [29]. https://www.jmir.org/2020/10/e22550/

Fig. 2

The characterisation of fracture risk according to FRAX major osteoporotic fracture probability in postmenopausal women. Initial risk assessment is performed using FRAX with clinical risk factors alone. FRAX probability in the red zone indicates very high risk, in which pathway C may be appropriate (anabolic agent followed by an inhibitor of bone resorption). FRAX probability in the green zone suggests low risk, in which pathway A should be followed, with advice to be given on lifestyle, calcium and vitamin D nutrition and menopausal hormonal treatment considered. FRAX probability in the orange zone (intermediate, between the upper assessment threshold, UAT, and lower assessment threshold, LAT) should be followed by BMD assessment and recalculation of FRAX probability including femoral neck BMD. After recalculation, risk may, therefore, be in the red zone (very high risk), orange zone (high risk, pathway B, which suggests initial antiresorptive therapy), reproduced with permission from [10].

Fig. 3

The VERO study of teriparatide vs risedronate; fracture incidence was measured over 24 months. A Incidence of new vertebral fractures after 24 months (primary endpoint) and 12 months. At 24 months, new vertebral fractures occurred in 28 (5.4%) of 680 patients in the teriparatide group and 64 (12.0%) of 680 patients in the risedronate group (B) Kaplan–Meier estimates of the cumulative incidence of the first clinical fracture, a composite of non-vertebral and symptomatic vertebral fracture. Reproduced with permission from [13]

Fig. 4

Outline of a recommended approach to sequential therapy: in a patient with severe osteoporosis at high imminent risk of fracture following fracture risk assessment, a bone-forming agent for 1–2 years is recommended (duration according to prescribing guidelines). Following this, bone-forming therapy, a consolidation period of antiresorptive therapy (such as a bisphosphonate or denosumab) is recommended. Monitoring, including assessment of treatment adherence and reassessment of fracture risk, is required