Rescue of High Glucose Impairment of Cultured Human Osteoblasts Using Cinacalcet and Parathyroid Hormone.

Patients with type 2 diabetes mellitus (T2DM) experience a higher risk of fractures despite paradoxically exhibiting normal to high bone mineral density (BMD). This has drawn into question the applicability to T2DM of conventional fracture reduction treatments that aim to retain BMD. In a primary human osteoblast culture system, high glucose levels (25 mM) impaired cell proliferation and matrix mineralization compared to physiological glucose levels (5 mM). Treatment with parathyroid hormone (PTH, 10 nM), a bone anabolic agent, and cinacalcet (CN, 1 µM), a calcimimetic able to target the Ca2+-sensing receptor (CaSR), were tested for their effects on proliferation and differentiation. Strikingly, CN+PTH co-treatment was shown to promote cell growth and matrix mineralization under both physiological and high glucose conditions. CN+PTH reduced apoptosis by 0.9-fold/0.4-fold as measured by Caspase-3 activity assay, increased alkaline phosphatase (ALP) expression by 1.5-fold/twofold, increased the ratio of nuclear factor κ-B ligand (RANKL) to osteoprotegerin (OPG) by 2.1-fold/1.6-fold, and increased CaSR expression by 1.7-fold/4.6-fold (physiological glucose/high glucose). Collectively, these findings indicate a potential for CN+PTH combination therapy as a method to ameliorate the negative impact of chronic high blood glucose on bone remodeling.

Osteoporosis in the age of COVID-19.

As the world grapples with the crisis of COVID-19, established economies and healthcare systems have been brought to their knees. Tough decisions regarding redirection of resources away from the management of conditions deemed "nonessential" are being made. How can we balance urgent resourcing of our acute crisis while not abandoning the real need of patients with osteoporosis? This article offers a few practical solutions.

Establishing an Operational Definition of Sarcopenia in Australia and New Zealand: Delphi Method Based Consensus Statement.

BACKGROUND: Globally there are several operational definitions for sarcopenia, complicating clinical and research applications. OBJECTIVE: The objective of the Australian and New Zealand Society for Sarcopenia and Frailty Research (ANZSSFR) Task Force on Diagnostic Criteria for Sarcopenia was to reach consensus on the operational definition of sarcopenia for regional use by clinicians and researchers. METHOD: A four-Phase modified Delphi process was undertaken in which 24 individuals with expertise or a recognised interest in sarcopenia from different fields across Australia and New Zealand were invited to be Task Force members. An initial face-to-face meeting was held in Adelaide, South Australia, in November 2017, followed by two subsequent online Phases conducted by electronic surveys. A final Phase was used to approve the final statements. Responses were analysed using a pre-specified strategy. The level of agreement required for consensus was 80%. RESULTS: In Phase 2, 94.1% of Task Force respondents voted in favour of adopting an existing operational definition of sarcopenia. In Phase 3, 94.4% of respondents voted in favour of adopting the European Working Group on Sarcopenia in Older People (EWGSOP) definition as the operational definition for sarcopenia in Australia and New Zealand. CONCLUSION: With consensus achieved, the ANZSSFR will adopt, promote and validate the EWGSOP operational definition of sarcopenia for use by clinicians and researchers in Australia and New Zealand.

1,25-Dihydroxycholecalciferol (calcitriol) modifies uptake and release of 25-hydroxycholecalciferol in skeletal muscle cells in culture.

The major circulating metabolite of vitamin D3, 25-hydroxycholecalciferol [25(OH)D], has a remarkably long half-life in blood for a (seco)steroid. Data from our studies and others are consistent with the hypothesis that there is a role for skeletal muscle in the maintenance of vitamin D status. Muscle cells internalise vitamin D-binding protein (DBP) from the circulation by means of a megalin/cubilin plasma membrane transport mechanism. The internalised DBP molecules then bind to actin and thus provide an intracellular array of high affinity binding sites for its specific ligand, 25(OH)D. There is evidence that the residence time for DBP in muscle cells is short and that it undergoes proteolytic degradation, releasing bound 25(OH)D. The processes of internalisation of DBP and its intracellular residence time, bound to actin, appear to be regulated. To explore whether 1,25-dihydroxycholecalciferol (calcitriol) has any effect on this process, cell cultures of myotubes and primary skeletal muscle fibers were incubated in a medium containing 10-10M calcitriol but with no added DBP. After 3h pre-incubation with calcitriol, the net uptake of 25(OH)D by these calcitriol-treated cells over a further 4h was significantly greater than that in vehicle-treated control cells. This was accompanied by a significant increase in intracellular DBP protein. However, after 16h of pre-incubation with calcitriol, the muscle cells showed a significantly depressed ability to accumulate 25(OH)D compared to control cells over a further 4 or 16hours. These effects of pre-incubation with calcitriol were abolished in fibers from VDR-knockout mice. The effect was also abolished by the addition of 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), which inhibits chloride channel opening. Incubation of C2 myotubes with calcitriol also significantly reduced retention of previously accumulated 25(OH)D after 4 or 8h. It is concluded from these in vitro studies that calcitriol can modify the DBP-dependent uptake and release of 25(OH)D by skeletal muscle cells in a manner that suggests some inducible change in the function of these cells.