Individualized treatment with denosumab in children with osteogenesis imperfecta – follow up of a trial cohort

Abstract

Background Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1 year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually. Methods Ten patients (age range: 6.16–12.13 years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1 mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12 month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting. Results During follow-up mean relative change of lumbar aBMD was − 6.4%. Lumbar spine aBMD z-Scores decreased from − 1.01 ± 2.61 (mean ± SD) to − 1.91 ± 2.12 (p = 0.015). Mobility changed not significantly (GMFM-88 -6.49 ± 8.85% (p = 0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12 weeks previously to 20.3 weeks. Conclusions On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1 year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children.

A bedridden young lady with hypophosphatemic rickets treated with denosumab: a case report

“…The patient did not develop any side effects from the denosumab such as hypocalcemia most likely due to the associated primary hyperparathyroidism in this patient. On reviewing the literature there were no cases reported on using denosumab for hypophosphatemic rickets but is has been used in a case of hypophosphatemic osteomalacia which was drug induced [ 6 ] it also has been reported to be used in cases of osteogenesis imperfecta [ 7 ]. Denosumab, in addition to other drugs are currently being investigated in phase III trials for use in hypophosphatemic rickets, hypophosphatasia and fibrodysplasia ossificans progressiva [ 8 ].…”

Management of primary and secondary osteoporosis in children

“…Despite stable laboratory findings for bone resorption markers, patients presented with a significant reduction of areal BMD during the follow-up year, but there were no new VF and vertebral shape further improved. 139 However, a 23-month-old boy with type 6 OI who was treated with denosumab had a persistent decline in BMD and continued to fracture over a 12-month treatment period. 140 In contrast to bisphosphonates, denosumab's effect on bone turnover is rapidly reversible.…”

Denosumab in pediatric bone disorders and the role of RANKL blockade: a narrative review

“…In 2016, a prospective study involving 10 children with OI treated with denosumab was published. The authors evaluated the safety and efficacy of denosumab for the treatment of different types of OI by which denosumab's dose interval varied from 3 to 12 months (1 mg/kg BW) (14). All the children studied could safely tolerate denosumab therapy; only 1 child with asymptomatic hypocalcemia was observed during the therapy period, and coincidentally, mild asymptomatic hypercalcemia was observed in several patients prior to the fourth dose of denosumab.…”

“…The investigators administered denosumab at a dose of 1 mg/kg body weight to 10 pediatric patients with OI and, for the first time, used urinary deoxypyridinoline (DPD) levels as a marker to assess osteoclastic activity and to personalize the interval of denosumab injection. When the level of DPD/creatinine (CREA) prior to injection of denosumab was increased, a second dose of denosumab was administered (17). All 10 children tolerated denosumab therapy, and only a few patients reported muscle and joint pain during the treatment period, with these cases all being relieved without intervention.…”