Off-label uses of denosumab in metabolic bone diseases

Polyzos, Stergios A.; Makras, Polyzois; Tournis, Symeon; Anastasilakis, Athanasios D.

doi:10.1016/j.bone.2019.115048

Cited by 41 publications

(29 citation statements)

References 146 publications

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“…Perhaps the most important aspect regarding the off-label practice, and one of the main advantages, is that it fulfills the unmet medical needs by the conventional therapeutic approaches, increasing the access to medication for special categories of patients. In agreement with the EC report on off-label use, the literature reveals that off-label practice is widespread in rare diseases [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ], oncology [ 12 , 13 , 14 , 15 , 16 ], pediatrics [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ], and psychiatry (especially in pediatric and elderly populations) [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. It is difficult to establish a prevalence or a pattern of general off-label prescribing, since it embraces many forms, and it is divided into many categories.…”

Section: Introductionsupporting

confidence: 76%

Off-Label Medication: From a Simple Concept to Complex Practical Aspects

Rusz

Ősz

Jîtcă

et al. 2021

IJERPH

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Off-label use of drugs is widely known as unapproved use of approved drugs, and it can be perceived as a relatively simple concept. Even though it has been in existence for many years, prescribing and dispensing of drugs in an off-label regimen is still a current issue, triggered especially by unmet clinical needs. Several therapeutic areas require off-label approaches; therefore, this practice is challenging for prescribing physicians. Meanwhile, the regulatory agencies are making efforts in order to ensure a safe practice. The present paper defines the off-label concept, and it describes its regulation, together with several complex aspects associated with clinical practices regarding rare diseases, oncology, pediatrics, psychiatry therapeutic areas, and the safety issues that arise. A systematic research of the literature was performed, using terms, such as “off-label”, ”prevalence”, ”rare diseases”, ”oncology”, ”psychiatry”, ”pediatrics”, and ”drug repurposing”. There are several reasons for which off-label practice remains indispensable in the present; therefore, efforts are made worldwide, by the regulatory agencies and governmental bodies, to raise awareness and to ensure safe practice, while also encouraging further research.

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Section: Introductionsupporting

confidence: 76%

Off-Label Medication: From a Simple Concept to Complex Practical Aspects

Rusz

Ősz

Jîtcă

et al. 2021

IJERPH

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“…An imbalance in RANK-RANKL-OPG signaling is also observed in many rare bone diseases such as Juvenile Paget disease, fibrous dysplasia, Hajdu Cheney syndrome, and Langerhans cell histiocytosis ( 199 ). Therefore, denosumab has also been used off-label in rare metabolic bone diseases, including Paget's disease, osteogenesis imperfecta, and aneurysmal bone cysts ( 200 ). Bisphosphonate treatment prevents bone loss and fractures caused by rare bone disease-mediated osteogenesis imperfecta ( 201 – 203 ).…”

Section: Therapies To Improve Osteocyte Functionmentioning

confidence: 99%

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

2020

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Osteocytes are the most abundant (~95%) cells in bone with the longest half-life (~25 years) in humans. In the past osteocytes have been regarded as vestigial cells in bone, since they are buried inside the tough bone matrix. However, during the last 30 years it has become clear that osteocytes are as important as bone forming osteoblasts and bone resorbing osteoclasts in maintaining bone homeostasis. The osteocyte cell body and dendritic processes reside in bone in a complex lacuno-canalicular system, which allows the direct networking of osteocytes to their neighboring osteocytes, osteoblasts, osteoclasts, bone marrow, blood vessels, and nerves. Mechanosensing of osteocytes translates the applied mechanical force on bone to cellular signaling and regulation of bone adaptation. The osteocyte lacuno-canalicular system is highly efficient in transferring external mechanical force on bone to the osteocyte cell body and dendritic processes via displacement of fluid in the lacuno-canalicular space. Osteocyte mechanotransduction regulates the formation and function of the osteoblasts and osteoclasts to maintain bone homeostasis. Osteocytes produce a variety of proteins and signaling molecules such as sclerostin, cathepsin K, Wnts, DKK1, DMP1, IGF1, and RANKL/OPG to regulate osteoblast and osteoclast activity. Various genetic abnormality-associated rare bone diseases are related to disrupted osteocyte functions, including sclerosteosis, van Buchem disease, hypophosphatemic rickets, and WNT1 and plastin3 mutation-related disorders. Meticulous studies during the last 15 years on disrupted osteocyte function in rare bone diseases guided for the development of various novel therapeutic agents to treat bone diseases. Studies on genetic, molecular, and cellular mechanisms of sclerosteosis and van Buchem disease revealed a role for sclerostin in bone homeostasis, which led to the development of the sclerostin antibody to treat osteoporosis and other bone degenerative diseases. The mechanism of many other rare bone diseases and the role of the osteocyte in the development of such conditions still needs to be investigated. In this review, we mainly discuss the knowledge obtained during the last 30 years on the role of the osteocyte in rare bone diseases. We speculate about future research directions to develop novel therapeutic drugs targeting osteocyte functions to treat both common and rare bone diseases.

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“…The drug theoretically offers a causative treatment option for patients with JPD. Denosumab is approved for the treatment of a number of conditions in adults only (in Germany), but it has been used off-label in the treatment of different rare bone diseases in pediatric patients worldwide, such as osteogenesis imperfecta, giant cell tumors, juvenile osteoporosis, and others [11-14], and also in adult and pediatric patients with JPD [15, 16]. However, so far, no information regarding potential side effects on growth and final height in humans is available.…”

Section: Introductionmentioning

confidence: 99%

Rhizomelia and Impaired Linear Growth in a Girl with Juvenile Paget Disease: The Natural History of the Condition

et al. 2021

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In ultra-rare bone diseases, information on growth during childhood is sparse. Juvenile Paget disease (JPD) is an ultra-rare disease, characterized by loss of function of osteoprotegerin (OPG). OPG inhibits osteoclast activation via the receptor activator of nuclear factor-κB (RANK) pathway. In JPD, overactive osteoclasts result in inflammatory-like bone disease due to grossly elevated bone resorption. Knowledge on the natural history of JPD, including final height and growth, is limited. Most affected children receive long-term antiresorptive treatment, mostly with bisphosphonates, to contain bone resorption, which may affect growth. In this study, we report the follow-up of height, growth velocity, and skeletal maturation in a 16-year-old female patient with JPD. The patient was treated with cyclic doses of pamidronate starting at 2.5 years of age and with 2 doses of denosumab at the age of 8 years, when pamidronate was paused. In the following years, a sustainable decline in a height <i>z</i>-score and a stunted pubertal growth spurt; despite appropriate maturation of the epiphyseal plates of the left hand, the proximal right humerus and both femora were observed. Whether this reflects the growth pattern in JPD or might be associated to the antiresorptive treatments is unclear, since there is very limited information available on the effect of bisphosphonates and denosumab on growth and the growth plate in pediatric patients. Studies are needed to understand the natural history of an ultra-rare bone disease and to assess the effects of antiresorptive treatment on the growing skeleton.

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Off-label uses of denosumab in metabolic bone diseases

Cited by 41 publications

References 146 publications

Off-Label Medication: From a Simple Concept to Complex Practical Aspects

Off-Label Medication: From a Simple Concept to Complex Practical Aspects

The Osteocyte as the New Discovery of Therapeutic Options in Rare Bone Diseases

Rhizomelia and Impaired Linear Growth in a Girl with Juvenile Paget Disease: The Natural History of the Condition

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