Osteoporosis is the name given to the characteristic age-related loss of bone mass and strength. The extracellular matrix of bone tissue is constantly remodeled, created by osteoblasts and broken down by osteoclasts. The proximate cause of osteoporosis is a tilt in the balance of these processes, favoring osteoclast activity and thus slow loss of bone structure.

Today’s research materials discuss a most intriguing result: in mice, maintaining a higher environmental temperature slows the progression of osteoporosis. Interesting, but is it a path to therapy? As is always the case when looking at metabolic responses to environmental differences in mice, there is the question of whether similar effects in humans are anywhere near as large All too many examples of this sort of thing are, unfortunately, clearly of little interest as a basis for human therapies because larger mammals respond less strongly. Here, however, a range of epidemiological data from hotter versus colder regions of the world suggests that, yes, the effect of temperature on osteoporosis in humans may be large enough to care about.

Perhaps the most interesting part of this work is the investigation into underlying mechanisms. It appears that the effect of temperature on osteoporosis is mediated by differences in the gut microbiome. In hotter climates, there is a greater microbial production of the metabolite polyamine, known to beneficially affect bone tissue maintenance. Transplanting gut microbes from high temperature environment mice to mice with osteoporosis modestly reverses the progression of the condition, improving bone density, but this benefit is not realized in mice in which polyamine production is inhibited.

Stronger bones thanks to heat and microbiota

Many biologists are familiar with Allen’s Rule, according to which animals living in warm areas have a larger surface area in relation to their volume than animals living in colder environment. Indeed, a larger skin surface allows better evacuation of body heat. By placing several groups of adult mice in a warm environment, scientists observed that while bone size remained unchanged, bone strength and density were largely improved.

What about human beings? The research team analysed global epidemiological data on the incidence of osteoporosis in relation to the average temperature, latitude, calcium consumption, and vitamin D levels. Interestingly, they found that the higher the temperature, the fewer hip fractures – one of the main consequences of osteoporosis – regardless of other factors.

Scientists wanted to understand the role of the gut microbiome in these metabolic modifications. To this end, they transplanted the microbiota of mice living in a 34°C environment to osteoporotic mice, whose bone quality was rapidly improved. Thanks to the state-of-the-art metagenomic tools developed in their laboratory, the scientists then succeeded in understanding the role played by microbiota. When adapts to heat, it leads to a disruption in the synthesis and degradation of polyamines, molecules that are involved in ageing, and in particular in bone health.

Warmth Prevents Bone Loss Through the Gut Microbiota

Osteoporosis is the most prevalent metabolic bone disease, characterized by low bone mass and microarchitectural deterioration. Here, we show that warmth exposure (34°C) protects against ovariectomy-induced bone loss by increasing trabecular bone volume, connectivity density, and thickness, leading to improved biomechanical bone strength in adult female, as well as in young male mice. Transplantation of the warm-adapted microbiota phenocopies the warmth-induced bone effects. Both warmth and warm microbiota transplantation revert the ovariectomy-induced transcriptomics changes of the tibia and increase periosteal bone formation.

Combinatorial metagenomics / metabolomics analysis shows that warmth enhances bacterial polyamine biosynthesis, resulting in higher total polyamine levels in vivo. Spermine and spermidine supplementation increases bone strength, while inhibiting polyamine biosynthesis in vivo limits the beneficial warmth effects on the bone. Our data suggest warmth exposure as a potential treatment option for osteoporosis while providing a mechanistic framework for its benefits in bone disease.