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Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation.

ABSTRACT: Denosumab is an anti-RANKL Ab that potently suppresses bone resorption, increases bone mass, and reduces fracture risk. Discontinuation of denosumab causes rapid rebound bone resorption and bone loss, but the molecular mechanisms are unclear. We generated humanized RANKL mice and treated them with denosumab to examine the cellular and molecular conditions associated with rebound resorption. Denosumab potently suppressed both osteoclast and osteoblast numbers in cancellous bone in humanized RANKL mice. The decrease in osteoclast number was not associated with changes in osteoclast progenitors in bone marrow. Long-term, but not short-term, denosumab administration reduced osteoprotegerin (OPG) mRNA in bone. Localization of OPG expression revealed that OPG mRNA is produced by a subpopulation of osteocytes. Long-term denosumab administration reduced osteocyte OPG mRNA, suggesting that OPG expression declines as osteocytes age. Consistent with this, osteocyte expression of OPG was more prevalent near the surface of cortical bone in humans and mice. These results suggest that new osteocytes are an important source of OPG in remodeling bone and that suppression of remodeling reduces OPG abundance by reducing new osteocyte formation. The lack of new osteocytes and the OPG they produce may contribute to rebound resorption after denosumab discontinuation.

SUBMITTER: Fu Q

PROVIDER: S-EPMC10561722 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation.

Fu Qiang Q Bustamante-Gomez Nancy C NC Reyes-Pardo Humberto H Gubrij Igor I Escalona-Vargas Diana D Thostenson Jeff D JD Palmieri Michela M Goellner Joseph J JJ Nookaew Intawat I Barnes C Lowry CL Stambough Jeffrey B JB Ambrogini Elena E O'Brien Charles A CA

JCI insight 20230922 18

Denosumab is an anti-RANKL Ab that potently suppresses bone resorption, increases bone mass, and reduces fracture risk. Discontinuation of denosumab causes rapid rebound bone resorption and bone loss, but the molecular mechanisms are unclear. We generated humanized RANKL mice and treated them with denosumab to examine the cellular and molecular conditions associated with rebound resorption. Denosumab potently suppressed both osteoclast and osteoblast numbers in cancellous bone in humanized RANKL ...[more]

PMID: 37581932

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Project description:Stopping denosumab after 8 years of continued treatment was associated with bone loss during a 1-year observation study in patients who were not prescribed osteoporosis treatment. Bone loss was attenuated in patients who began another osteoporosis therapy. Treatment to prevent bone loss upon stopping denosumab should be considered.IntroductionThis study aimed to understand osteoporosis management strategies during a 1-year observational follow-up after up to 8 years of denosumab treatment in a phase 2 study.MethodsDuring the observational year, patients received osteoporosis management at the discretion of their physician and returned to the clinic for BMD assessment and completion of an osteoporosis management questionnaire. Incidence of serious adverse events and fractures was collected. Analyses were descriptive.ResultsOf 138 eligible patients, 82 enrolled in and completed the observation study. Most (65 [79%]) did not receive prescription osteoporosis medication, with "my doctor felt I no longer needed a medication" being the most common reason (23 [35%]). Of the 17 patients who took osteoporosis medications, 8 discontinued therapy during the observation study. In patients treated with denosumab for 8 years (N = 52), BMD decreased during the 1-year observation study (6.7% [lumbar spine], 6.6% [total hip]). Those who took osteoporosis medication during the observation study showed a smaller decline in BMD than those who did not. No new safety concerns were identified. Eight patients (9.8%), all of whom had at least one predisposing risk factor, experienced 17 fractures. This included seven patients who experienced one or more vertebral fractures.ConclusionsConsistent with denosumab's mechanism of action, treatment cessation led to reversal of the drug's effect on BMD and perhaps fracture risk. For patients who took osteoporosis therapy, bone loss was attenuated. For patients at high fracture risk, switching to another osteoporosis therapy if denosumab is discontinued seems appropriate.

Project description:Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas brain tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased c-Fos expression in midbrain 5-HT (TPH2 positive) neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT1A receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT1A autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study reports evidence that, across a range of experiments, SSRI discontinuation triggers a rebound activation of 5-HT neurons. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.

Project description:Osteoarthritic (OA) pain affects 18% of females and 9.6% of males aged over 60 worldwide, with 62% of all OA patients being women. The molecular drivers of sex-based differences in OA are unknown. Bone is intricately coupled with the sensory nervous system and one of the only joint tissues known to show changes that correlate with patient pain in OA. There are fundamental sex differences in pain sensation and bone biology which may be intrinsic to OA disease progression, however these differences are vastly under researched. We have utilised three data sets to investigate the hypothesis that potential mediators responsible for sex dependent pain mechanisms displayed in OA are derived from mechanically stimulated osteocytes. Our published dataset of the in vitro human osteocyte mechanosome was independently compared with published data from, sex-based gene expression differences in human long bone, the sex-based gene expression differences during the skeletal maturation of the mouse osteocyte transcriptome and sex specific OA risk factors and effector genes in a large human GWAS. 80 of the 377 sex-specific genes identified in the mouse osteocyte transcriptome were mechanically regulated in osteocytes with enrichment associated with neural crest migration and axon extension, and DISEASES analysis enrichment for the rheumatoid arthritis pathway. 3861 mechanically regulated osteocytic genes displayed sex-specific differences in human long bone with enrichment for genes associated with the synapse, sensory perception of pain, axon guidance, immune responses, distal peripheral sensory neuropathy, sensory neuropathy, and poor wound healing. 32 of 77 effector genes and 1 of 3 female specific OA risk factor genes identified in the human GWAS were differentially expressed in the osteocyte mechanosome and male and female bone. This analysis lends support to the hypothesis that mechanically regulated genes in osteocytes could influence sex specific differences in osteoarthritic pain and highlights pain pathways with approved drugs that could potentially treat elevated pain susceptibility in females with OA.

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Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation.

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Reduced osteoprotegerin expression by osteocytes may contribute to rebound resorption after denosumab discontinuation.

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