## 7 Therapy
In practice, there are still two other questions regarding the treatment with bisphosphonates in children with permanent risk factors: when should we start bisphosphonates, and how long should patients be on bisphosphonates therapy? When should we start bisphosphonates? As said before, treatment with intravenous bisphosphonates should be considered in children fulfilling the ISCD criteria. However, in children with significant risk factors for bone fragility due to chronic illness, even a single low-trauma long bone or vertebral fracture (in the absence of a \"low BMD\") may be sufficient to diagnose the child with osteoporosis, as discussed in a recent paper by [PERSON] et al. [7]. recently [PERSON] et al. published a study of the treatment with bisphosphonates in 48 with primary osteoporosis, 46 with secondary osteoporosis without glucocorticoids and 29 children with glucocorticoid-induced osteoporosis [56]. They treated 19% of the patients with intravenous bisphosphonates without these patients fulfilling the ISCD criteria for osteoporosis. One of these indications was low, declining BMD without a history of fractures; another was low BMD in association with kidney stones in children with ongoing risk factors. In addition, [PERSON] et al. treated children on a ketogenic diet with ongoing risk factors with bisphosphonates out of the ISCD criteria [68]. How long should patients be on bisphosphonate therapy? Some observations in children with both primary and secondary osteoporosis have provided answers to these questions [69]. After discontinuing bisphosphonate therapy in children with open growth plates and persistent risk factors for osteoporosis, the newly formed bone has a low density. This may cause a point of increased bone fragility because of the \"density differential\" between the high-density bone (formed under treatment with bisphosphonates) and the low-density bone [70], leading to fractures in the transition zone between treated and untreated bone [71; 72]. So, if bisphosphonate therapy should be continued, for how long? A possible answer followed from a study in children with osteogenesis imperfecta [71]. In children with still open growth plates and discontinuing bisphosphonate therapy, the BMD z-scores declined. However, discontinuing therapy in children with closed growth plates had no effect on the BMD z-scores two years later. This has led to the recommendation of continuation of bisphosphonate therapy until the closure of the growth plates in those with persistent risk factors (such as congenital/genetic disorders and long-term acquired risk factors, such as chronic glucocorticoid therapy). Starting with a higher dose until the patient is clinically stable and tapering the dose or frequency is often implemented in order to avoid over-treatment in the context of long-term therapy considered [39; 73]. In summary, treatment with intravenous bisphosphonates should be considered in children fulfilling the ISCD criteria (intended for otherwise healthy children with clinically significant fractures and low, appropriately size-adjusted BMD parameters). However, it should also be considered in high-risk patients outside of this conservative approach who have even a single-low-trauma long bone or vertebral fracture, a known increased risk for bone fragility, and limited potential for spontaneous recovery [39; 68]. It is important to keep in mind that not all children with secondary osteoporosis require bisphosphonate therapy following a fragility fracture; those with transient risk factors for vertebral or long bone fractures and potential for spontaneous recovery due to younger age or less severe vertebral collapse typically do not need osteoporosis intervention, unless they have significant bone pain interfering with the quality of life. A proposition for screening, prevention, and therapy of secondary osteoporosis is given in Figure 1.  
Figure 1: Recommendation for investigation and treatment of secondary osteoporosis in children.