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A life-course study of bone density measured across the whole body, from childhood to old age, found 80 genetic loci — and that all but two of them act the same way no matter how old you are.
Total body bone mineral density (TB-BMD) is bone density measured across the entire skeleton by DXA scan, rather than at one site such as the hip or heel. This site already has three other bone-density pages, each built from a different measurement and a different question — this one is about whether the genetics of bone density change as a person ages.
Medina-Gomez et al. 2018 combined 30 genome-wide association studies — 66,628 people in total — split into five age groups, each spanning 15 years, from childhood through old age. They found 80 loci associated with TB-BMD, 36 of them newly discovered. Combined, these loci explain roughly 10% of the variation in TB-BMD and are linked to fracture risk. This page holds 38 of those loci.
The study's central question was not just where the loci are, but whether each one acts the same way across a lifetime, or shows up only at certain ages. The answer for nearly all of them was that the effect is set early and holds steady: of every locus tested, only variants near ESR1 and near RANKL showed a genetic effect that actually changed with age.
rs78667121, near TNFSF11 (the gene for RANKL), is one of this page's 38 loci — and one of only two loci in the entire study confirmed to have an age-dependent effect on bone density. RANKL is not just a GWAS hit: it is the direct drug target of denosumab, an approved osteoporosis medicine that works by blocking RANKL from telling bone-resorbing cells (osteoclasts) to activate.
Independently of what this particular study's own enrichment analysis reported, two more genes among this page's 38 loci are worth naming specifically: rs11228240, near LRP5, and rs66838809, near SOST. LRP5 is a WNT-signalling receptor on bone-building cells, and it is one of the most well-established genes in all of bone biology — rare gain-of-function mutations in it cause a high-bone-mass syndrome, and loss-of-function mutations cause the opposite, a bone-fragility condition called osteoporosis-pseudoglioma syndrome. SOST encodes sclerostin, a protein that normally holds that same WNT signal down; blocking sclerostin with the drug romosozumab — an approved osteoporosis treatment — releases the brake and increases bone formation.
Between them, RANKL and SOST are the targets of the two newest classes of approved osteoporosis drugs, and both turn up as genetic loci on this one page.
2026-07-10 · Chai RC, et al., Nature Genetics 2026, PMID:42432248
Which cells do the genes for bone density act in? This study mapped 34 distinct cell types in skeletal tissue with single-cell methods across species, then ranked them by enrichment for rare skeletal disorder genes and for bone-mineral-density genes from an extended UK Biobank genome-wide study (448,010 people of European ancestry in the GWAS Catalog's record), with functional validation in over 1,000 genetically modified mouse models. Beside the expected lineages that build and resorb bone — osteoblast, chondrocyte, osteoclast — two kinds of blood vessel cell, endothelial cells and vascular smooth muscle cells, emerged as newly relevant to skeletal disease. 249 of the study's positions are already on this site, 205 of them on the heel bone mineral density page, including rs7741021 (RSPO3), rs2982573 (ESR1) and rs4505759 (FGFRL1). PMID:42432248.
Bone density is diagnosed with a DXA scan, not a genotype. None of the 38 variants on this page are used by any guideline to assess an individual's fracture risk or bone health.
The age-dependency finding above is a population-level result from a meta-analysis of 66,628 people split into age strata — it describes how a genetic effect behaves on average across a population as it ages, not a prediction for what happens to any one person's bones over their own lifetime.
The studies behind these variants recruited participants from different ancestries — a result found in one population doesn't always transfer to another. Based on 98 of 105 linked studies with a resolved discovery ancestry.
Databases, guidelines and references
Licensed CC BY-NC 4.0: free to read, share and adapt for non-commercial use, naming MyGeneLog™ and linking the exact page. Commercial use, including training or serving a commercial AI system, needs a licence — https://www.mygenelog.com/license
Total Body Bone Mineral Density. MyGeneLog™. https://www.mygenelog.com/conditions/total-body-bone-mineral-density
Total body bone mineral density (TB-BMD) is bone density measured across the entire skeleton by DXA scan, rather than at a single site such as the hip or heel.
Mostly no. A life-course study spanning childhood to old age in 66,628 people found that nearly every one of 80 associated loci acts the same way at every age. Only variants near ESR1 and near RANKL showed an effect that actually changed with age.
One of this page’s own variants, rs78667121, sits near RANKL (gene symbol TNFSF11) and is one of only two loci in the whole study confirmed to have an age-dependent effect. RANKL is also the direct target of denosumab, an approved osteoporosis drug.
LRP5 is a WNT-signalling receptor central to building bone; SOST encodes sclerostin, which normally holds that signal down. Romosozumab, an approved osteoporosis medicine, works by blocking sclerostin — and both genes appear among this page’s 38 variants.
No. Bone density is diagnosed with a DXA scan, and no guideline uses these variants to assess an individual’s fracture risk. This is a population-level finding from 66,628 people, not an individual prediction.
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