Signing of the Stars and Coach Jim Harbaugh

What I learned from the University of Michigan Signing of the Stars and Coach Jim Harbaugh

by Allan Mishra
@bloodcure

Seek a unique perspective.
Harbaugh and his expert production team took a rather mundane event (signing of high school football players) and turned it into an Oscar-like event.  The day inspired not only the Michigan football program but the entire university.

Embrace diversity.
The crowd supporting the newly signed Michigan players included Tom Brady, Derek Jeter, Denard Robinson, Jordon Kovacs, Charles Woodson, wrestler Rick Flair, world champion poker player Phil Hellmuth, rap group Migos, Owen Wilson, Vince Vaughn, Coach Mike Ditka, and many others.  The collective value of the group to the signees and audience was staggering.

Sometimes you just have to ask.
Former Notre Dame Coach Lou Holtz helped carry the event with excellent one liners.  Why did a coach from another school come to a Michigan football event?  Simply because Jim Harbaugh asked him.  To the new Michigan players Holtz said:  "You didn't just make a four year decision, you made a 40 year decision"  He understands and articulated how the new players would be part of Michigan for the rest of their lives---a powerful message.

"Some people think less is more, I believe more is more."---Jim Harbaugh
Jim Harbaugh doesn't like meetings and discusses strategy on the field with this players and coaches during marathon four hour practices.  We all should have less meetings and execute instead of engaging in perpetual discussion.

"Those who stay will be champions"-----Coach Bo Schembechler
Harbaugh added a corollary to that famous Michigan axiom.  "Try hard and you will stay".  He has written this above the exit sign from the Michigan locker room.  The implication is clear.  Work as hard as you can and you will stay.  Stay and you will be a champion.  Embracing this mindset could help all of us in our chosen professions.


"Attack each day with an enthusiasm unknown to mankind."---Jim Harbaugh 
Harbaugh and his team gave a swag bag full of gear emblazoned with his motto to all the presenters.  After the star-studded event was over around 1 pm, Harbaugh, true to form, was quoted by the Michigan daily as saying:  “We’ll be back to work at 2.30.”  Translation---have some fun but then return to the relentless pursuit of being one of the leaders and best.

Video montage of the event produced by VisionVideo360




AM
@bloodcure
TotalTendon

Respect Your Future Health (#BodyIRA)

Body Individual Retirement Account (BodyIRA)

When I was in medical school and about 22 years old, an erudite 50-year old professor made a claim that the warranty on the human body wears out at age 45.  As I fidgeted in my uncomfortable back row seat in a packed classroom, I thought to myself---what an old man.  I couldn't even contemplate what it would feel like to be 45 or 50.  I can now attest to the validity of my professor's claim because I have seen friends, family members and patients endure unexpected medical issues in their 40s.  I have a suggestion:  Open a BodyIRA.

What is a BodyIRA?  It's not a financial investment, but an investment in good health practices. Think of a BodyIRA as a bridge to your future health.  Just like a retirement savings account, a BodyIRA is a gift you give to yourself, by taking care of yourself now so you can be healthy far into the future.  And just like retirement savings, the sooner you begin to contribute to your  BodyIRA, the more benefits you will reap later in life.

Request to join the BodyIRA LinkedIn Group 
(Goal:  share ideas about health and fitness)

Four Starter Recommendations for your BodyIRA

1.  Maintain or work toward your ideal body weight (Keep a daily record of your weight)

2.  Stretch your hamstrings and develop strong legs  (See the PowerKnee Program)

3.  Focus on your posture (Sit up and Stand up straight)

4.  Get 7-8 hours of sleep per night or more

Consistent exercise, a healthy diet coupled with stable sleep patterns are like buying index funds for your future health.  In our twenties, we are told to begin contributing to a retirement savings plan like a 401k or an individual retirement account (IRA).  Put away a little money each month and you will see it grow into millions of dollars over the course of the next 40 years.  We need to emulate that sage advice and translate it to our health.

BodyIRA leads to dramatic dividends later.  One profound example is bone density in women.  Women in their teens and early twenties are building their bony framework.  In their thirties and beyond, they will make withdrawals from this bone bank.  If they do not deposit enough early on, they pay a heavy price later in the form of osteoporosis.

We have all heard this type of advice before but let's make it actionable.  Don't just take it from a friend or a medical professional.  Take it directly from your future self.  What would your ten-years-older self have to say to your current self?  If that older you limped in the door and looked at what you were doing, he or she might just scream at you to get your butt off the couch, stop bingeing on Netflix and get some exercise.  Begin by committing to writing down your weight daily and doing some simple leg exercises.  (See PowerKnee Program)  If you can initiate the habit of contributing to your BodyIRA for two weeks, you will experience some immediate benefits and also be contributing to your future health.

Importantly,  it's never too late to open a BodyIRA.  Don't worry if you are in your 30s, 40s, 50s or even beyond 60, you can still work toward a better physical and mental situation.  Much like a "catch up" contribution to your 401k or IRA, if you start later, you will need to pay more.  Also, as we age, the body requires more maintenance.  Don't get mad about it and neglect your aging engine and wheels.   Respect your future health and start your own BodyIRA today.  You will reap the priceless reward of future well-being.  


AM
TotalTendon

Will Biologics Revolutionize Musculoskeletal Care?

The economic costs of musculoskeletal care in the United States is approaching $800 billion or about 5.7% of annual GDP.  (Ref)  These costs are expected to increase significantly as our population ages.  This is clearly not a sustainable path.  A recent article published by the American Academy of Orthopedic Surgeons (AAOS) suggests the "early evidence is promising" for biologics to revolutionize musculoskeletal care.  (AAOS Article in full)

Biologic therapies represent a rapidly evolving frontier similar to arthroscopy in the 1970s and 1980s.  There will always be a need for continued research and development but the data supporting treatments such as platelet rich plasma (PRP) and stem cell treatments for tendinopathy and arthritis is increasing significantly.  PRP is now a recognized treatment for chronic tennis elbow that has been shown to be better than surgery.  (See Ref)  The number of PRP articles on PubMed now is over 8000 and the Google Trends for PRP is rising rapidly. (See Graph)

Biologic orthopedic procedures are in the process of revolutionizing the options available for patients for difficult problems such as arthritis.  It is an exciting time to execute on these point-of-care biologic treatments.   Continued progress will demand hard work and innovation by elite motivated teams in order to produce transformative outcomes for patients.


AM
TotalTendon

Top 7 Life Lessons from Steve Martin

A few years back I was very lucky and blessed to play poker with Steve Martin in Las Vegas with my friend Phil Hellmuth.  The three of us also had a fantastic dinner discussion that has made an enduring impression on my life. 

Mr. Martin is a superb writer, musician, actor, and producer.  He also recently hosted the Saturday Night Live 40th reunion show and expertly managed the egos of dozens of elite stars from music, TV and the movies. We can all learn from his sublime approach to work and life. 

7 Life Lessons from American icon Steve Martin

1.  “Be so good, they can’t ignore you”

2.  “It’s pain that changes our lives” 

From Shopgirl

3.  “Thankfully, persistence is a great substitute for talent”

From Born Standing Up, A Comic’s Life

4.  “I thought yesterday was the first day of the rest of my life but it turns out today is.”

5.  “I have found that-- just as in real life--imagination sometimes has to stand in for experience.”

From, An Object Of Beauty

 6.  “I just believe that the interesting time in a career is pre-success, what shaped things, how did you get to this point?”

From, Born Standing Up: A Comic's Life

7.  “Were they beautiful? We were all beautiful. We were in our twenties.”

Thank you Mr. Martin for sharing your immense talent with the world.  Please share his wisdom with your network.

AM

Ref:   http://www.goodreads.com/author/show/7103.Steve_Martin

Visit the site for more Steve Martin quotes

Microfracture Surgery Jadaveon Clowney

The Houston Texans' Jadeveon Clowney recently underwent "microfracture" surgery on his ailing right knee.  (See ESPN report)

The report suggests the talented Mr. Clowney will be out for 9 months or more.  Just what is microfracture surgery and why does it take as long to recovery as it does for a baby to born?

Microfracture Surgery

Let's start with the basics.  There are two types of cartilage in the knee.  The surface cartilage which covers the bone.  This is known as articular cartilage and can be thought of a type of cap or covering of the end of the bone.  This cartilage is present in any joint.  In the knee, there is another type of cartilage, the meniscus cartilage.  There are two menisci in the knee--medial (inside) and lateral (outside).  When the surface "articular" cartilage is damaged, the knee can become quite painful especially with loading and twisting.  Think rushing a passer for example.  Similar symptoms can occur when the meniscus is torn.  It is often difficult to distinguish between the two in terms of which one is the pain generator.

Microfracture surgery is an attempt to create a tire patch over a cartilage defect by poking a hole in the end of the bone and creating an access channel to the bone marrow.  The bone marrow then leaks out via the holes that are created and forms a clot which over time can help cover the defect.  It takes time, many months, for this surgery to work because the "patch" needs to mature.  This technique is useful for small defects in the cartilage but hasn't proven to be great for larger defects.  We do not know the size of Mr. Clowney's knee cartilage injury.

Recent evidence suggests that the addition of platelet-rich plasma can enhance microfracture surgery results.  This has been shown in basic science, preclinical and now clinical studies.

This type of surgery at such a young age is clearly not a good sign.  In the long run, he may require further intervention.  Please read the post below for further information about why we need to accelerate our regenerative medicine efforts.  Mr. Clowney is one of tens of millions of people worldwide with symptomatic cartilage damage.  We need to maximize outcomes of today's surgical techniques and develop new procedures to help keep our athletes and patients in the game.

AM

TotalTendon

Platelet Rich Plasma (PRP) Helps Patients

Platelet Rich Plasma (PRP) has been used now for more than a decade to treat a variety of orthopedic conditions.  Hundreds of thousands of patients have been treated with a stellar safety record.  The efficacy of PRP has evolved over the years but there are now multiple randomized controlled trials supporting the use of PRP.  This data has been presented at major medical conferences all over the world and published in peer reviewed elite journals such as the American Journal of Sports Medicine.

Below are the highlights from a few of the published papers:


Large Randomized Controlled Trial using PRP for Chronic Tennis Elbow Patients
American Journal of Sports Medicine 2014 

82.1% had successful treatment using PRP  compared to 60.3% in the active control group at six months.  (P = 0.008)  (See Figure)

There was also significantly less elbow tenderness in the PRP treated patients compared to the active control group at six months. (P = 0.009)

PRP Beats Cortisone for Chronic Tennis Elbow at 2 year Follow up
American Journal of Sports Medicine 2011 (100 patient trial)
Patients treated with PRP had dramatically better success rates at 2 years compared to cortisone.
(P < 0.001)

These two trials used the same protocol and same PRP device (Biomet GPS PRP).  There were no significant complications in either study.   Successfully treated patients were able to avoid more invasive and expensive surgical interventions.  This is clear evidence supporting the use of PRP for chronic tennis elbow.

PRP More Effective than Placebo in the Treatment of Knee Osteoarthritis
American Journal of Sports Medicine 2013 (156 knees)
50% improvement in pain scores was noted using PRP compared to worsening of pain in the placebo group at 6 months.  (P < 0.001)

There are now over 7400 references to PRP on PubMed with more than 500 publications last year alone.  This is an indication of the worldwide interest in this topic.   There are literally hundreds of published papers supporting the use of PRP and other blood components to treat disease.  More research and development will always be needed but using a patient's own blood to treat their injuries and disorders simply makes intuitive and scientific sense.  

Patients and providers with experience with platelet rich plasma or other biologic treatments are encouraged to post comments below.

AM
TotalTendon

Survivor Blood to be used as an Ebola Treatment

The Ebola epidemic is spreading and there is no cure.  Treatment options even in the United States are limited because there are no approved drugs and even the supply of experimental ones have been exhausted.  (See Washington Post Article)

Is it possible that blood could cure Ebola?

That is exactly what the New York Times (read full article here) is reporting as a possible treatment.  The concept is actually pretty simple.  Patients who have been infected with Ebola and survive develop antibodies to the virus.  These virus destroying proteins live in the serum of the blood.  A transfusion of serum or perhaps even whole blood may be the best option as a stop gap measure to treat the expanding number of patients with the disease.  The World Health Organization even has a specific guidance document on the topic.  (WHO convalescent blood for Ebola)

In this space over many years, I have discussed how to use blood therapeutically for regenerative medicine.  Discussions about platelet-rich plasma, bone marrow concentrates and stem cells from peripheral blood have focus primarily on orthopedic injuries and disorders.  Blood as a treatment for Ebola will receive more attention in this blog.  Anyone with blood expertise of any kind should do whatever they can to help.  Please post comments or send me information about how blood is being used to treat Ebola:   @bloodcure on Twitter.

The potential restorative powers of blood are considerable and if it is possible to stop the epidemic or at least slow it down by using the serum of survivors as a treatment, we should do everything we can do execute on that strategy in addition to pursuing containment, supportive care, and experimental drugs.

AM
TotalTendon

Kobe returns to Germany for another Knee Arthritis Treatment

KobeTeam.com

Kobe Bryant returned to Germany this past week to be treated with a blood derived treatment (Orthokine) again for his knee.  He has had this treatment in the past at least twice before.  It involves drawing blood and incubating it over a 24 hour period and then reinjecting a component of blood that has anti-inflammatory properties.  It is similar but not exactly the same as platelet-rich plasma therapy.  It would be most interesting to learn about how this has helped him over the years and in what specific ways. He clearly has thousands of miles of basketball on his knees and is also recovering from multiple other injuries.  We do not, however, have any data about the status of his knee cartilage or joint before or after any of these treatments.  Here is a detailed description of the "Orthokine" treatment.  

Kobe has with his travel and his wallet voted in favor of this treatment.  It will be quite interesting to see how he plays this year in the NBA.   It will also be instructive to follow Kobe's future medical interventions as a way of measuring the value of the one he just had in Germany.

AM

TotalTendon

Can Curry Cure Knee Arthritis?

It sounds like a plot for a silly Bollywood movie, but published data actually supports the idea that one of the key components of curry powder can help alleviate pain for patients with knee arthritis.

Curcumin, a bright yellow spice found in curry powder, recently was found to have the same efficacy as ibuprofen (the active ingredient in Motrin and Advil) for patients with knee arthritis.  In a recently published study of 367 knee arthritis patients, researchers found 1500 mg of Curcuma domestica extract had the same effectiveness in terms of pain reduction as 1200 mg of ibuprofen at four weeks (Kuptnirataikul et al). Importantly, the curcumin treated patients had less episodes of abdominal pain or discomfort compared to the ibuprofen patients.  Importantly, another published study of of the same dosage of curcumin (1500 mg) was found to have significant improvements in terms of pain and physical function when compared to placebo at six weeks (Panahi et al).   Curcumin has been noted to block several substances involved in the inflammatory pathway and also inhibits activation of free radicals.  This could help explain why the spice works to reduce pain in arthritis patients.  

So next time your knee starts to hurt, put down the ibuprofen and hobble over to your favorite Indian or Thai restaurant for a tasty curry meal.  It may just help your knees feel better.

On a more serious note, the published data supports trying a curcumin supplement 1500 mg per day divided in three doses for 4-6 weeks for patients with knee arthritis.  (See chart below)

AM
TotalTendon

Pain Reduction in Patients with Knee ArthritisKuptnirataikul et al

Platelet Rich Plasma, Stem Cells and Biologic Orthopedics on Dr. Radio

On Monday May 12th, I will be on Sirius-XM Doctor Radio (Channel 81, 7 pm EST, 4 pm PST) discussing platelet-rich plasma, stem cells and other biologic orthopedic treatments.  It is an exciting time for this topic because research in these areas has progressed significantly just in the last few months.  Also, patients and payers are demanding less invasive and more effective treatments for difficult problems such as knee osteoarthritis and degenerative disc disease.  So, tune in at 7 pm EST, 4 pm PST on Monday May 12th to learn more about the frontiers of musculoskeletal medicine and surgery.  

AM

TotalTendon

Best Initial Knee Stretch "The Hammy" (Knee OA, Part 3)

Your hamstring tendons start on your pelvis and insert behind and below your knee. In almost every person, these tendons tighten with time.  Stretching your hamstring tendons is one of the best exercises you can do for your knee and back.  One study found "individuals with and without osteoarthritis of the knee are able to demonstrate immediate beneficial adaptations to a stretching intervention."
Reference

I recommend do a set of 3 hamstrings stretches, 3 times PER DAY.  Stretching multiple times per day is better than stretching only once a day or not at all.  You may be surprised with your improved flexibility if you are consistent about stretching.  See the video below for a simple stretch that can done anywhere.  I call it the "Hammy Stretch".



Start by placing your leg on a step, or low table.  Keep your back straight and your toes pointed toward the ceiling.  Then, simply hinge forward at your waist.  You will likely feel the stretch in the back of your thigh, knee and calf.

Consistency is the key to improvement.  Try this simple exercise and it will help your overall knee health and improve your ability to straightening your knee.  Hamstring stretching is like sunscreen, it is best to start early and continue to stretch throughout your life.

As always, check with your own doctor before beginning any exercise program.

Next time, we reveal the simple yet highly effective way to strengthen all of the muscle of your legs.

AM
TotalTendon

Platelet Rich Plasma Update, JBJS Webinar

Worldwide interest in Platelet-Rich Plasma is increasing significantly.  471 new publications have appeared on PubMed about platelet-rich plasma in just the last year, making it quite challenging to keep up with the published literature.  There has also been a dramatic rise in Google "hits" for PRP to over 1.3 million.  (See the graphs below)   New data recently accepted for publication to the American Journal of Sports Medicine confirms the value of PRP in the treatment of chronic tennis elbow.  See American College of Surgeons Report on the paper.

Tonight the Journal of Bone and Joint Surgery will be holding a webinar on the topic.  Over 1000 professionals have already signed up for the event.  This is totally unprecedented for a major, elite journal to sponsor a discussion on a single specific biologic orthopedic topic.  Follow Dr. Mishra:  @BloodCure for real time updates about tonight's webinar.

Or, consider joining the Biologic Orthopedic Society Group on LinkedIN to participate in a discussion about the webinar and other biologic orthopedic topics.

AM

TotalTendon

Platelet Rich Plasma Eyedrops for Chemical Eye Injuries

In the study outlined below, platelet rich plasma eyedrops were used to augment standard treatment of chemical injuries to the eye.  The researchers found PRP to be "safe and effective, and it promotes rapid reepithelialization of ocular surface"

Novel and interesting application of PRP.

Allan Mishra

TotalTendon

Topical Autologous Platelet-Rich Plasma Eyedrops for Acute Corneal Chemical Injury.

Panda A, Jain M, Vanathi M, Velpandian T, Khokhar S, Dada T.

Source

Cornea. 2012 Jul 2. 

Abstract

PURPOSE:

Evaluation of efficacy of autologous platelet-rich plasma eyedrops as an adjunct to standard medical treatment as compared with standard medical treatment with artificial tears in acute ocular chemical injury.

METHODS:

Twenty eyes with grade III to grade V chemical injury were randomly assigned to 2 groups. Group I (10 eyes) received autologous platelet-rich plasma eyedrops along with standard medical treatment, and group II (10 eyes) received standard medical treatment alone. Follow-up was on days 3, 7, 14, 21, 30, 60, and 90. Chi-square test for categorical variables and Mann-Whitney test for quantitative variables were applied for statistical analysis.

RESULTS:

The mean time between exposure and presentation was 2.15 ± 0.93 days (group I, 2.2 ± 0.73 days; group II, 2.1 ± 0.98 days; P = 0.81). Complete epithelialization was achieved in all the eyes. The mean ± SD and median (range) time to complete epithelialization were 40 ± 31.57 days and 25.5 (7-90) days in group I and 47 ± 26.15 days and 30.0 (21-90) days in group II (P = 0.29). For grade III injuries, mean ± SD and median (range) time to complete epithelialization were 14 ± 7 days and 14 (7-21) days in group I and 28.5 ± 3.67 days and 28.5 (21-30) days in group II (P = 0.006) [Wilcoxon rank sum (Mann-Whitney) test]. At 3 months, corneal clarity showed significant improvement in grade I compared with grade II (P = 0.048). Similarly, the percentage improvement in best-corrected visual acuity was 63.64 ± 55.75 and 37.74 ± 9.66 for grades I and II, respectively (P = 0.082).

CONCLUSIONS:

Topical autologous platelet-rich plasma therapy is safe and effective, and it promotes rapid reepithelialization of ocular surface and can be administered along with standard medical therapy.

Kobe Bryant Regenokine Orthokine Treatment Explained

Kobe Bryant (LA Lakers) is having another Orthokine or Regenokine treatment after averaging 29 points per game in his 15th season in the NBA.  Is it because of a blood derived treatment he had done on his knee?  Other elite athletes such as Alex Rodriguez (NY Yankees) and Fred Couples (PGA Golfer)  have been treated with Orthokine in Germany.  But what is Orthokine?  That is a question that needs to be answered.

Orthokine is a form of autologous conditioned serum (ACS) that contains a high concentration of a molecule called IL-1 RA.  This stands for interleukin-1 receptor antagonist (IL-1 RA).  Interleukin-1 (IL-1) is an important mediator of inflammation and tissue damage.  Balancing IL-1 with IL-1 RA is important.  Read more about IL-1/IL-1 RA

Orthokine to the best of my knowledge is only available in Germany and has mainly been used to treat knee osteoarthritis.  A study of 376 patients was done comparing Orthokine (ACS) with hyaluronic acid (HA) and saline injections for knee osteoarthritis.  The "effects of ACS were significantly superior to those of HA and saline for all outcome measures and time points."  See Abstract of Article

From the available evidence, it appears as though this is a reasonable treatment.  I do not, however, know many of the details.  This treatment is not available in the United States.  It is produced by incubating a patient's blood in a sterile container with beads over a period of 6-8 hours or more.  The IL-1 RA and other growth factors are concentrated and injected back into the patient.

This is different than platelet rich plasma (PRP) in that PRP is made at the point of care and can be delivered back to the patient within 15-20 minutes.  No incubation period is needed.  

Allan Mishra, MD

@BloodCure

Sports Press about Kobe and the treatment:  
http://www.hoopsworld.com/kobe-readying-for-german-knee-procedure

Platelet Rich Plasma Significantly Improves Pain and Function for Patellar Tendonitis

In a randomized controlled trial, platelet rich plasma significantly improved pain and function in patients with patellar tendinopathy (also known as patellar tendonitis).  In the study, PRP was compared to dry needling.  The PRP used in the study contained concentrated platelets and white blood cells, also known as leukocytes (prepared via the Biomet Biologics GPS system).   Both groups were also given an eccentric exercise program.

“Importantly, we also showed that PRP is both clinically and statistically significantly better than dry needling based on the Victorian Institute of Sports Assessment  (VISA) score of patella tendinopathy symptoms.”  (See Full Article)

MRI showing significant patellar tendinopathy

This important data contributes significantly to the growing body of evidence suggesting PRP has value in the treatment of tendon related disorders.  


AM (@bloodcure)
Total Tendon

Genes Identified that are Associated with Risk of Fracture

In the study outlined below, genes were identified that are associated with increased risk of fracture.  Importantly, six genes NOT known to have a role in bone biology were found to correlate with bone mineral density.  This speaks to the importance of looking for diseases related genes within AND outside of known pathways.  See abstract below.

AM

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

• Karol Estrada,
• Unnur Styrkarsdottir,
• Evangelos Evangelou,
• Yi-Hsiang Hsu,
• Emma L Duncan,
• Evangelia E Ntzani,
• Ling Oei,
• Omar M E Albagha,
• Najaf Amin,
• John P Kemp,
• Daniel L Koller,
• Guo Li,
• Ching-Ti Liu,
• Ryan L Minster,
• Alireza Moayyeri,
• Liesbeth Vandenput,
• Dana Willner,
• Su-Mei Xiao,
• Laura M Yerges-Armstrong,
• Hou-Feng Zheng,
• Nerea Alonso,
• Joel Eriksson,
• Candace M Kammerer,
• Stephen K Kaptoge,
• Paul J Leo
• et al.

Nature Genetics

 

44,

 

491–501

 

(2012)

Received

 

07 October 2011 

Accepted

 

16 March 2012 

Published online

 

15 April 2012

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10⁻⁸). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10⁻⁴, Bonferroni corrected), of which six reached P < 5 × 10⁻⁸, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.