October 23, 2023- Revised April 29, 2026
“Good” Mutation? The “Unbreakable Bones” (LRP5 / LRP6)
Abstract
The argument critiques the common use of the LRP5/LRP6 “unbreakable bones” variant as a clear example of a beneficial mutation. While it is observable that certain variants of the LRP5 gene are associated with increased bone density, the claim that this mutation originated hundreds of millions of years ago through random processes is not directly observed but inferred from evolutionary models. The mutation itself affects the Wnt signaling pathway—an existing regulatory system—by increasing its activity, rather than creating a new biological function.
The text emphasizes that such mutations often involve trade-offs rather than pure advantages. Although higher bone density may seem beneficial, LRP5 variants are also linked to a range of disorders and structural abnormalities, reflecting the delicate balance of biological systems. Overall, the example is presented as a modification of existing processes with context-dependent outcomes, rather than evidence of new functional innovation or sustained evolutionary improvement.
When asked for a clear example of a beneficial mutation, the LRP5 / LRP6 variant associated with unusually high bone density is often presented as evidence. It is sometimes referred to as the “unbreakable bones” mutation.
At face value, this seems compelling. Osteoporosis-related fractures affect over 40% of women and more than 13% of men, so increased bone density appears advantageous. -4
However, this example is frequently overstated and does not tell the entire story.
What Is Observed vs. What Is Inferred
We can directly observe that certain LRP5 variants are associated with higher bone density in some individuals. -9
What we do not directly observe is the historical origin of this variant. The claim that it arose hundreds of millions of years ago through random mutation is an inference based on evolutionary models, not a directly observed event. -1, -8
This distinction matters. The present effect is observable. The origin story is reconstructed.
What the Mutation Actually Does
The LRP5 gene regulates the Wnt signaling pathway, which plays a central role in bone formation, cellular regulation, and tissue maintenance. -9
Variants such as LRP5-V171 are associated with increased Wnt signaling, which correlates with higher bone density. -9
But this pathway is tightly controlled. Both reduced and increased signaling are associated with disease.
Reduced Wnt signaling leads to conditions such as idiopathic juvenile osteoporosis, involving low bone density, fractures, and impaired mobility. -5, -6
At the same time, excessive or dysregulated Wnt signaling is also associated with abnormal bone growth and other physiological complications. -6
This is not the creation of a new function. It is a shift in the regulation of an existing system.
Trade-offs, Not Clean Gains
The key issue is whether this mutation represents a net fitness gain.
LRP5-related variants are associated with a wide range of outcomes, including osteoporosis, high bone mass syndromes, osteogenesis imperfecta, and osteoporosis-pseudoglioma syndrome, which includes bone fragility and vision loss. -4, -5
Even in cases of increased bone density, structural abnormalities can occur, such as thickened jawbones or cranial growths. -9
This reflects a common biological pattern: a change that enhances one trait can introduce costs elsewhere. These are trade-offs, not universally beneficial upgrades.
Variation vs. Novel Innovation
Another critical distinction is often overlooked.
Much of the variation in traits like bone density comes from existing allelic diversity passed through reproduction, not the continual generation of new functional information.
In the general population, moderate, balanced bone density is the dominant condition, expressed in roughly 65% of individuals. -4
More extreme variants, whether low or high, are less common and are frequently associated with dysfunction or instability. -4
This suggests that mutations more often shift systems away from equilibrium rather than construct new optimized systems.
What This Example Actually Demonstrates
Even if one accepts that this variant arose through mutation, what is actually being demonstrated?
- A modification of an existing regulatory pathway
- A change in output, not the creation of a new system
- A context-dependent effect with associated trade-offs
This is a far more limited claim than is often implied.
The Larger Argument
Mutations are observable. Their effects can be measured in real time.
What is consistently observed is that mutations:
- alter existing systems
- frequently disrupt regulation
- and often produce trade-offs or pathological outcomes
What is not directly observed is the step-by-step emergence of complex, integrated biological systems through mutations that consistently produce net gains in function over time.
Instead, claims about long-term constructive effects are largely inferred from models, not directly witnessed.
Conclusion
The “unbreakable bones” mutation is often presented as a clear example of beneficial evolution. However, a closer analysis shows:
- The present effect is observable, but the historical origin is inferred
- The mutation alters an existing regulatory system rather than creating a new one
- The outcome involves trade-offs and potential dysfunction, not a clean fitness gain
At minimum, this example does not demonstrate the kind of sustained, constructive biological innovation that is often claimed.
It shows that mutations can change systems, sometimes in ways that appear beneficial in isolation, but frequently with associated costs and without clear evidence of net functional advancement over time.
1- MacDonald BT, Semenov MV, Huang H, He X. Dissecting molecular differences between Wnt coreceptors LRP5 and LRP6. PLoS One. 2011;6(8):e23537. doi: 10.1371/journal.pone.0023537. Epub 2011 Aug 24. PMID: 21887268; PMCID: PMC3160902. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160902/
2- Xu GY, Qiu Y, Mao HJ. Common polymorphism in the LRP5 gene may increase the risk of bone fracture and osteoporosis. Biomed Res Int. 2014;2014:290531. doi: 10.1155/2014/290531. Epub 2014 Dec 14. PMID: 25580429; PMCID: PMC4279179. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279179/
3- Mizuguchi, T., Furuta, I., Watanabe, Y. et al. LRP5, low-density-lipoprotein-receptor-related protein 5, is a determinant for bone mineral density. J Hum Genet 49, 80–86 (2004). https://doi.org/10.1007/s10038-003-0111-6; https://www.nature.com/articles/jhg200413#citeas
4- Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE. Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites. Am J Hum Genet. 2004 May;74(5):866-75. doi: 10.1086/420771. Epub 2004 Apr 7. PMID: 15077203; PMCID: PMC1181981. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1181981/
5- Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity – BMC Medical Genetics
6- Korvala, J., Jüppner, H., Mäkitie, O. et al. Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity. BMC Med Genet 13, 26 (2012). https://doi.org/10.1186/1471-2350-13-26; https://www.science.org/doi/10.1126/scitranslmed.aau7137
7- Liu, J., Xiao, Q., Xiao, J. et al. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Sig Transduct Target Ther 7, 3 (2022). https://doi.org/10.1038/s41392-021-00762-6; https://www.nature.com/articles/s41392-021-00762-6#citeas
8- Mélanie Pruvost, Reinhard Schwarz, Virginia Bessa Correia, +5 “Freshly excavated fossil bones are best for amplification of ancient DNA” Jan, 2007, 104 (3) 739-744; https://doi.org/10.1073/pnas.0610257104
9- High Bone Density Due to a Mutation in LDL-Receptor–Related Protein 5, Lynn M. Boyden, Ph.D., Junhao Mao, Ph.D., Joseph Belsky, M.D., lyle Mitzner, M.D., Anita Farhi, R.N., Mary A. Mitnick, Ph.D., Dianqing Wu, Ph.D., Karl Insogna, M.D., and Richard P. Lifton, M.D., Ph.D.May 16, 2002 N Engl J Med 2002; 346:1513-1521, DOI: 10.1056/NEJMoa013444; https://www.nejm.org/doi/full/10.1056/nejmoa013444
10- J. C. Sanford, Book “Genetic Entropy and the Mystery of the Genome”, 3rd ed. (Waterloo, NY: FMS Publications, 2008).
