## 7 Therapy  
Currently, the most widely used agents for treating secondary osteoporosis in children are bisphosphonates [39]. Bisphosphonates are synthetic analogs of pyrophosph. Classically, treatment with intravenous bisphosphonates should be considered in children with a formal diagnosis of secondary osteoporosis that manifests as at least one low-trauma vertebral or long bone fracture and limited potential for spontaneous (i.e., medication-unassisted) recovery due to older age and/or persistence of osteoporosis risk factors [6; 60]. In previous years, the ISCD criteria for otherwise healthy children were erroneously applied to some children with risk factors for osteoporosis, which meant that bisphosphonate therapy was withheld from, for example, boys with DMD who had a single femur fracture (instead of two or more long-bone fractures by 10 years of age or three or more long bone fractures by 19 years of age plus a low BMD) [61; 62]. However, it is now understood that these criteria were intended for otherwise healthy children so as not to over-diagnose osteoporosis in this population, and even a single low-trauma long bone fracture can represent an osteopororotic event in children with risk factors for osteoporosis [39]. Low-trauma long bone fractures and symptomatic vertebral fractures (or asymptomatic VF in high-risk settings such as CP, DMD, and glucocorticoid-treated disorders) are the most frequent indications for treatment with intravenous bisphosphonates. The primary function of bisphosphonates is to inactivate osteoclasts, resulting in cortical and trabecular bone thickening. This makes bones wider, denser, and stronger. There has been much discussion in the literature on the use of oral versus intravenous therapy with bisphosphonates. At this time, the scientific data support the use of the (more potent) intravenous bisphosphonates over oral bisphosphonates. This article is not the place for a thorough discussion on this theme, but we refer those wanting to know more to [PERSON] et al. [39]. There are different regimens to prescribe the most-used intravenous bisphosphonate, panidronate. The most frequently used regimen is 1 mg/kg/day for three days every four months (in total, 9 mg/kg/year). However, a regimen of 1 mg/kg every three months (in total, 4 mg/kg/year) in children with primary osteoporosis has shown a comparable effect on BMD and reduction of fragility fractures [63]. Other studies also showed a comparable effect [64; 65]. A different intravenous bisphosphonate, zoledronic acid, is also used in children. Zoledronic acid can be given every six months and is preferred by some because of its greater convenience with respect to the shorter duration of the infusion and longer duration of action compared with panidronate. [PERSON] et al. showed that zoledronic acid has a comparable efficacy compared to panidronate in children with osteogenesis imperfects [66]. Additionally, [PERSON] et al. found no difference in effect on BMD Z scores between Pamidronate and zoledronic acid in patients with primary, secondary, and glucocorticoid-induced osteoporosis [61]. Furthermore, the costs of zoledronic acid are lower [66]. Conversely, Pamidronate probably has fewer adverse drug reactions, predominantly hypocalcemia [61], nausea, and vomiting. It is important to note that the first-infusion reactions of intravenous bisphosphonate therapy can precipitate adrenal insufficiency in glucocorticoid-treated children. For this reason, steroid stress dosing is recommended in children at risk for adrenal suppression in this context. In a recent study of intravenous zoledronic acid versus intravenous placebo in glucocorticoid-treated children, 25% of children in the placebo group had at least one adverse event following the first zoledronic acid infusion [67]. This observation provided evidence that not all health eventsfollowing the first intravenous bisphosphonate infusions are bisphosphonate-related but may be linked to underlying chronic illnesses.