It’s been a while since the last post…but this work has reinvigorated me. This recent paper, brought to us from the lab of Jerry Feng suggests we need to recalibrate the way we think about bone development/growth. Most all of us were taught and continue to teach, the hypertrophic cells of the growth plate are an afterthought of the growth process, essentially becoming trapped in the matrix, starved of oxygen, and destined to die off. Through a series of elegant experiments they show that this is only part of the story and that a significant portion of these cells actually transform into osteogenic cells. It’s a great read – along with the accompanying editorial. Hopefully this work, and others like it, will stimulate others to challenge ‘what we know’….
It has long been thought – and for a while known – that micro cracks in bone are removed by remodeling. Over time, loading your skeleton causes tiny linear cracks (about as large as a human hair is thick). In addition to these cracks, the bone forms more amorphous regions of damage, called diffuse damage. This damage exists as an area that has many tiny cracks (1/100th the size of linear cracks). Both linear cracks and diffuse damage reduce the mechanical properties of the bone meaning that if they are not repaired, and enough are formed, than fracture would occur.
Significant work has gone into studying linear microdamage. We know that these cracks are repaired by the body through a process of remodeling (osteoclasts come in and remove the damaged region and then osteoblasts replace the void space with new bone. I (and I think probably most others) thought/assumed that disuse damage was also repaired in the same way. We appear to have been wrong.
A new interesting article from the lab of Mitch Schaffler has shown that diffuse damage heals without remodeling. How this happens is not clear. Are the osteocytes orchestrating the healing (since they do not appear to be dying), does the mineral simply become re-deposited, are non-collagenous proteins in the matrix able to pull the tiny cracks closed, or is it simply magic? Only future work will provide the answer but given Dr. Schaffler’s track record – it shouldn’t be long before we know.
A great article by two prominent skeletal biologists focused on reproducibility in preclinical science. It’s worth a read by all as it highlights shortcomings at several levels of the scientific process – from granting agencies, to journals, to principal investigators. Worth a few minutes to read and a bit longer to think about and determine what action you can take to put us all back on the right track…
Bisphosphonates are the most common drug used to treat osteoporosis. They greatly reduce the risk of fracture and some forms of the drug can be taken once per year making them quite convenient (although you have to get an IV infusion; if that isn’t your thing you can take them orally weekly). The emergence of a few rare, yet significant, side effects of these agents has raised the question of how long patients should be treated with these drugs. Because bisphosphonates are retained in the bone, they exert efficacy on some bone parameters long after treatment is stopped. The large unknown is whether or not patients are protected from fracture after treatment is stopped. Answering this question is complicated because so many factors play into the outcome (how long a patient took the bisphosphonate, how responsive they were to the drug, what their fracture risk is, etc) and clinical studies are unlikely to ever be conducted. Yet the field yearns for some data to drive clinical decisions.
Hernandez et al turned to computer simulations to estimate how various bone parameters would be affected by taking a ‘drug holiday’. Some parameters (mean tissue age) that are changed by bisphosphonates are estimated to differ 15 years post-cessation, while others (bone density) return to normal more quickly. This is important because density is easily measured clinically, while mean tissue age is not – meaning that traditional ways to assess bone health clinically may not capture some of the important retained effects of bisphosphonates. While computer simulations have limitations, they provide a starting point for addressing complex questions and designing future experiments The work of Hernandez does this for what is a very important topic in the bone field.
Bisphosphonates, the most common pharmacological agent used to combat metabolic bone disease and skeletal disease associated with cancer, have been associated with a rare side effect known as atypical femoral fractures. These fractures often occur with minimal trauma and are catastrophic. We have little insight into why they occur although many theories exist. A recent paper by Ken Iwata and colleagues adds a new piece of data to the potential pathophysiological underpinnings of atypical femoral fractures. They performed histological assessment of microdamage on a biopsy specimen taken from near the atypical fracture site and found it to be 28x higher than a reference level from previous literature. While there are certainly limitations of the case report (single subject, no way to know if the damage was pre-existing or occurred subsequent to the fracture), the data are intriguing and are supported by preclinical work we have conducted in our lab (some of which Dr. Iwata was involved in during his time here).
This blog has highlighted several papers on mechanical properties and how advances in technology have permitted the assessment of these properties in vivo. Others have done it in humans and we recently reported results in a large animal model. Our labs most recent work asked the basic question of whether or not we could extend this technology to rodents, one of the most popular preclinical animal models in scientific research but who’s size presents unique challenges for reference point indentation (RPI). We found that while there was modest variability both within and among animals, the technique can effectively measure properties in rats. This work provides a foundation to help researchers design future studies in this animal model.
One of the lesser appreciated complications of chronic kidney disease (CKD), to those outside of the field, is the dramatic effects on bone health. Fracture rates in folks with CKD are several-fold higher, as are the rates of mortality associated with fracture, compared to the general population. A recent paper in JBMR highlights the idea that CKD has a dramatic effect on cortical bone – with really no effect on trabecular bone. This is district from what most think of for conditions such as post-menopausal bone loss – where dramatic loss of trabecular bone is most notable. Studying individuals with various causes of CKD, the authors used high-resolution CT of the distal radius and tibia to measure properties at baseline and then after ~ 1.5 years. The most striking finding (Figure 1) was that at both the radius and tibia there was an increase of ~ 4% cortical porosity per year. Trabecular bone was essentially unchanged. Those patients on dialysis had even greater rates of porosity increase compared to non-dialysis patients. Although several correlations were assessed to look for biomarkers of cortical porosity – nothing really popped out.
These clinical data are a nice clinical confirmation of our ongoing work in an animal model of CKD. We have found the cortex is where the action is – with the trabecular bone, at least in the tibia, being spared at the expense of the cortex (see image). Always good when the preclinical work actually translates to the clinic!