Parkinson’s disease: Accelerated bone loss, fractures and mortality in older men

Data from case-control studies as well as from a cross-sectional study suggest an independent association between Parkinson’s disease (PD) and prevalent lower bone mineral density. Among older PD patients in randomized trials, control group participants experienced bone mineral density (BMD) loss exceeding 4% per year, suggesting that PD is associated with rapid incident bone loss. Retrospective and case-control studies have suggested that PD increases risk for fractures. However, prospective data are limited. The objective of this study [1] was to examine the association of PD with bone loss and fractures in older men. This prospective cohort study analyzed data from 5937 community dwelling men aged >65 years at six clinical centers of the Osteoporotic Fractures in Men (MrOS) study. At baseline and visit two (mean interval 4.6 years), community-diagnosed PD was ascertained by self-report and hip BMD was measured using dual energy x-ray absorptiometry (DXA). Incident fractures were self-reported. Fractures and deaths were centrally adjudicated.
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Fat or bone? The answer is in the Wnt

Adipocytes and osteoblasts derive from the same mesenchymal stem cells. During differentiation, gene expression programs decide the fate of these cells. One of the key mediators of adipogenesis is the nuclear hormone receptor PPAR-γ (peroxisome proliferator activated receptor γ). When stimulated by its ligand, PPAR-γ enhances expression of target genes that force differentiation into adipocytes. By contrast, expression of the major osteogenic determinants, the transcription factors Runx2 and Osterix, produce osteoblasts. The control and signaling mechanisms that lead to an adipogenic or osteogenic cell-lineage decision remain largely elusive. Canonical Wnt signalling is crucial for bone formation. In the Wnt signaling cascade, Wnt family members bind to their receptors on the cell membrane, and LRP5 (low density lipoprotein receptor related protein 5) or LRP6 are required as coreceptors (see Osteoscoop entitled “PTH does not need Lrp5 to stimulate bone formation in mice”). Activation of the receptor complex leads to the intracellular accumulation of β-catenin, and this increase leads to translocation of β-catenin to the nucleus where it serves as a cofactor for a transcription factor. Disruption of the canonical Wnt signalling cascade severely impairs bone formation. For example, mutations in LRP5 result in altered bone mass in mice and humans. Deletion of β-catenin in osteoblasts also leads to multiple skeletal defects.
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RANKL inhibition with osteoprotegerin increases bone strength in ovariectomized rats

Ovariectomy results in bone loss caused by increased bone resorption. RANKL is an essential mediator of bone resorption. The purpose of a recent study [1] was to examine whether the RANKL inhibitor osteoprotegerin (OPG) would preserve bone volume, density, and strength in ovariectomized rats. Rats were ovariectomized or sham-operated at 3 mo of age. Sham controls were treated for 6 wk with vehicle. Ovariectomized rats were treated with vehicle or human OPG-Fc (10 mg/kg, 2/wk). Serum RANKL and TRACP5b, an osteoclast marker, was measured by ELISA. BMD of lumbar vertebrae (L1–L5) and distal femur was measured by DXA. Right distal femurs were processed for bone histomorphometry. Left femurs and the fifth lumbar vertebra (L5) were analyzed by µCT and biomechanical testing, and L6 was analyzed for ash weight.

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Central control of bone remodeling by neuromedin U

Bone remodeling, which is affected in osteoporosis, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms.

A recent study [1] shows that neuromedin U-deficient mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that neuromedin U acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling.
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