Forum on aging and skeletal health: Summary of the proceedings of an ASBMR workshop
Sundeep Khosla1, khosla.sundeep@mayo.edu
Teresita M Bellido2,
Marc K Drezner3,
Catherine M Gordon4,
Tamara B Harris5,
Douglas P Kiel6,
Barbara E Kream7,
Meryl S LeBoff8,
Jane B Lian9,
Charlotte A Peterson10,
Clifford J Rosen11,
John P Williams12,
Karen K Winer13,
Sherry S Sherman14, shermans@nia.nih.gov
1 College of Medicine, Mayo Clinic
2 Indiana University School of Medicine
3 University of Wisconsin–Madison
4 Children's Hospital Boston, Harvard Medical School
5 Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging
6 Institute for Aging Research, Hebrew SeniorLife and Harvard Medical School
7 University of Connecticut Health Center, Farmington, CT
8 Brigham and Women's Hospital, Harvard Medical School
9 University of Massachusetts Medical School, Department of Cell Biology
10 College of Health Sciences, University of Kentucky
11 Maine Medical Center Research Institute
12 National Institute on Aging, NIH
13 Eunice Kennedy Shriver National Institute of Child Health and Human Development
14 National Institute on Aging, NIH

Journal of Bone and Mineral Research, Vol. 26 Issue 9

With the aging of the population, the scope of the problem of age-related bone loss and osteoporosis will continue to increase. As such, it is critical to obtain a better understanding of the factors determining the acquisition and loss of bone mass from childhood to senescence. While there have been significant advances in recent years in our understanding of both the basic biology of aging and a clinical definition of age-related frailty, few of these concepts in aging research have been evaluated adequately for their relevance and application to skeletal aging or fracture prevention.

The March 2011 Forum on Aging and Skeletal Health, sponsored by the NIH and ASBMR, sought to bring together leaders in aging and bone research to enhance communications among diverse fields of study so as to accelerate the pace of scientific advances needed to reduce the burden of osteoporotic fractures. This report summarizes the major concepts presented at that meeting and in each area identifies key questions to help set the agenda for future research in skeletal aging.

Following two items were clipped from PDF attached at bottom of this page

Effects of vitamin D on bone in children and mouse models

Humans and mice with impaired vitamin D action have hypocalcemia and secondary hyperparathyroidism, accompanied by hypophosphatemia. This results in osteomalacia and, in a growing skeleton, expansion of the cartilaginous growth plate (rickets).14 In children with vitamin D receptor (VDR) mutations, intravenous administration of mineral ions (ie, phosphorus and calcium) leads to resolution of osteomalacia and rickets. Mouse models of VDR ablation were developed to determine which actions of the VDR are direct and which resulted from altered mineral homeostasis.14 Experiments in VDR null mice have shown that rickets stems from impaired apoptosis of cells within the late hypertrophic chondrocyte region. Prevention of abnormal mineral ion levels leads to a normal skeleton in this model. Studies in a murine model of X-linked hypophosphatemia (associated with high serum fibroblast growth factor 23 [FGF-23] levels) and in mice with diets inducing hypercalcemia/hypophosphatemia demonstrated that low circulating phosphate levels were responsible for impaired hypertrophic chondrocyte apoptosis. Studies in cellular models demonstrated that phosphate induces hypertrophic, but not proliferative, chondrocyte apoptosis through a capase-9-dependent mitochondrial apoptotic pathway. Phosphate treatment of hypertrophic, but not proliferative, chondrocytes led to a decrease in mitochondrial membrane potential and Erk1/2 phosphorylation. Prevention of Erk1/2 phosphorylation inhibited hypertrophic chondrocytes apoptosis. Mice lacking Npt2a (a renal sodium-dependent phosphate transporter) also develop hypophosphatemia, but growth plate abnormalities resolve in association with increased 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] production.15 However, VDR/Npt2a double knockout mice exhibit severe rickets. Therefore, receptor-dependent actions of 1,25(OH)2D3 can compensate for hypophosphatemia and lead to normal growth plate development.
Research gaps and questions identified were:

1. Within the growth plate, what is the mechanism of action of liganded VDR on growth?
2. What is the effect of hyperphosphatemic states on hypertrophic chondrocyte apoptosis, and how is the system modulated by vitamin D analogues and bisphosphonates?
3. What is the effect of the liganded VDR in the setting of hypophosphatemia on bone mineralization and biomechanical integrity? and
4. What is the role of FGF-23 in a growing and adult skeleton?

Relation of vitamin D to falls in the elderly

In an early, large trial of institutionalized seniors in France treated with vitamin D and calcium, the risk for fracture was reduced within the first 6 months, suggesting that the intervention may have reduced falls. In observational studies addressing the relation between serum 25-hydroxyvitamin D 25(OH)D concentrations and falls, there has been a clear increase in risk for falls when concentrations are below 25?nmol/L.30 In later intervention studies, the effect of vitamin D and calcium on fractures and falls was less clear. Several meta-analyses of these studies on the effect of vitamin D on falls showed a significant decrease in fall incidence of between 5% and 20%. There was a suggestion that doses greater than 700 or 800?IU were required for the prevention of falls and that the very frail institutionalized population responded to a greater extent.31 Recently, data from an Australian study suggested that very large doses administered infrequently (500,000?IU once per year) actually might have adverse effects on fall risk.32

The mechanism by which vitamin D status affects fall risk is not well understood, although some studies have demonstrated an association between serum concentrations of vitamin D and physical performance, strength, and balance.33 Improvement in these domains in vitamin D intervention studies has not been clearly shown.
Areas for further research include

1. defining the mechanism of how vitamin D might prevent falls,
2. defining a dose-response effect and whether higher doses prevent more falls as well as whether a calcium supplement is necessary,
3. determining whether falls are associated with polymorphisms of vitamin D–related genes, and
4. defining whether vitamin D prevents falls in the general population of older persons or only in the frail?