Rabbit Study Suggests Antibiotic-Releasing Implant Coating Could Cut Infection Risk
A study by Miller et al. in the February 20, 2019 issue of JBJS provides preclinical proof of concept that antibiotic-loaded coatings on orthopaedic implants could eventually reduce the incidence of implant-associated infection.
The researchers used in vivo bioluminescence imaging (BLI) and ex vivo analysis of colony-forming units (CFUs) to show the efficacy of an implant coating that released linezolid-rifampin over a 7-day period. Through a parapatellar arthrotomy, researchers reamed the femoral canal of 12 rabbits and inoculated the canals with a bioluminescent strain of MRSA. They then inserted a surgical grade titanium peg into each canal. All of the pegs were coated with a nanofiber coating; 6 of the pegs were loaded with the antibiotic coating and 6 were not.
Implants coated without antibiotics were associated with significantly increased in vivo BLI signals and significantly increased knee width, relative to implants with the antibiotic-releasing coatings. The animals were killed on day 7, and ex vivo analysis of CFUs isolated from soft tissue, bone, and implant specimens showed significantly increased CFUs in the specimens without the antibiotic-releasing coating, while CFUs were undetectable in the implants with antibiotics.
This larger-animal model to assess bacterial burden employed a clinically used orthopaedic implant and replicated a medial parapatellar arthrotomy in humans. According to the authors, the coating used is “highly versatile, and the polymers or drug concentrations could be modified for more rapid or longer release.” This rabbit model should be amenable to studying additional antibiotic-releasing strategies for possible translation to clinical research in humans.
Residual Pain after Joint Replacement
This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
In the absence of infection and aseptic loosening, significant postoperative pain persists in up to 20% of joint-replacement patients. In one study related to this predicament, investigators studied 3 groups of individuals: 1) those without a total joint replacement (TJR) and no self-reported pain, 2) patients with a well-functioning TJR and no self-reported pain (mean implant time of 1.5 years), and 3) patients with a painful TJR (self-reported pain of >8 on a 0 to10 VAS scale; mean implant time of 1.76 years)1.
Peripheral blood mononuclear cells were collected for use in a lymphocyte reactivity assay to detect anti-inflammatory (IL-1ra, IL-10, IL-13 and IL-11) and inflammatory cytokines or receptors (IL-1rII and TNFR1). In general, anti-inflammatory cytokine markers in patients with post-TJR pain were decreased compared to controls and to individuals with no pain following TJR, with IL-10 and IL-13 significantly decreased among painful TJR patients. TNFR1 was significantly elevated in those with painful TJRs, and IL-1rII was modestly elevated. The authors note that treating this “1-2 punch” of elevated proinflammatory cytokines and decreased anti-inflammatory cytokines may require “a complex pattern” of both inhibition of proinflammatory mechanisms as well as anti-inflammatory medications.
In a separate study, investigators used scanning electron microscopy (SEM) to try to determine whether implant corrosion was secondary to inflammatory cellular reactions or to the effects of electrocautery used in near proximity to metallic surfaces2. Twelve knee prostheses taken at necropsy were compared to an off-the-shelf cobalt-chromium knee implant intentionally exposed to Bovie and Aquamantys electrocautery sources. SEM data was collected using an identical method to that of the retrieved implants. Five of the 12 necropsy retrievals showed signs of inflammatory cell-induced corrosion. Compared to the necropsy-retrieved implants, the iron/carbon ratio of the Bovie electrocautery-damaged implant was significantly higher, suggesting that the mechanism by which immune cells corrode implants is different than the mechanism of electrocautery damage.
In a third study, which compared results of lymphocyte transformation testing (LTT) for metal sensitivity with histological and clinical findings in 27 cases of primary total knee arthroplasty (TKA), researchers found that LTT results alone were insufficient for the diagnosis of TKA pain-relief failure due to an immune reaction3. A positive LTT might not indicate that an immune reaction is the cause of pain and stiffness post-TKA.
It will take more research to determine whether there is a connection between surface pitting and chronic knee pain in metal-sensitive persons, whether the elevated macrophage response is an associated risk factor, and whether that is associated with metallic material response.
References
- Lauryn S, Caicedo M, Jacobs J, Hallab NJ. Do TJR Patients with High Self-Reported Pain Levels Exhibit Decreased Serum Anti-inflammatory Cytokine Markers? Abstract 0135 Orthopaedic Research Society 2019
- Sorrels JA, Heise G, Morrow B, Arnholt C, Kurtz S, Mihalko WM. Inflammatory Cell- Induced Corrosion and Electrocautery Damaged TKA Implants. Abstract 0131 Orthopaedic Research Society 2019
- Yang S, Dipane M, Lu CH, Schmalzried TP, McPherson EJ. Lymphocyte Transformation Testing (LTT) in Cases of Pain Following Total Knee Arthroplasty: Little Relationship to Histopathologic Findings and Revision Outcomes. J Bone Joint Surg Am. 2019 Feb 6;101(3):257-264. doi: 10.2106/JBJS.18.00134. PMID: 30730485
In Chronic Sciatica, Gabapentin Quells Nerve Pain Better than Pregabalin
This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
Orthopaedic surgeons may not be at the forefront of dealing with nonoperative nerve pain, but many of our patients who are not candidates for surgery suffer from spine-related nerve pain in their limbs, such as sciatica. Both gabapentin (GBP, Neurontin) and pregabalin (PGB, Lyrica) are used to treat chronic sciatica (CS).
Gamma-aminobutyric acid (GABA) is an important pain-related neurotransmitter, although neither GBP nor PGB affect the GABA receptor. Instead, both drugs associate with the ligand of the auxiliary α2δ-1 and α2δ-2 subunits of certain voltage-dependent calcium channels in nerves. Among other uses, Neurontin is prescribed to treat diabetic peripheral neuropathy, and Lyrica is commonly used to treat fibromyalgia.
Investigators reporting in JAMA Neurology sought to help guide practitioners in the initial choice of drug. Eighteen patients with MRIs corroborating single-sided nerve-root sciatic pain of at least 3 months duration were evaluated in an interim analysis as part of a randomized, double-blind, double-dummy crossover trial of PGB vs GBP (8 weeks of exposure to each drug with a 1-week washout in between). The primary outcome was pain intensity measured with a 10-point visual analog scale (VAS) at baseline and 8 weeks. Secondary outcomes included disability as measured with the Oswestry Disability Index and the severity and frequency of adverse events.
Relative to baseline, both drugs showed significant VAS pain reductions and disability-score improvements, However, head-to-head, GBP showed superior VAS pain reduction (mean [SD], GBP: 1.72 [1.17] vs PGB: 0.94 [1.09]; P = 0.035), regardless of the order in which it was given. There were no between-drug differences in disability scores, but adverse events for PGB were more frequent (PGB, 31 [81%] vs GBP, 7 [19%]; P = 0.002), especially when PGB was taken first.
The authors conclude that GBP was superior with fewer and less severe adverse events, and they suggest that gabapentin should be commenced before PGB to permit optimal crossover of medicines.
Reference
Robertson K, Marshman LAG, Plummer D, Downs E. Effect of Gabapentin vs Pregabalin on Pain Intensity in Adults WIth Chronic Sciatica: A Randomized Clinical Trial. JAMA Neurol. 2018 Oct 15. doi: 10.1001/jamaneurol.2018.3077. [Epub ahead of print] PMID: 30326006
Keeping Your Bones Pumped Up
This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
While a reasonable amount of “pumping iron” exercise has proven beneficial for musculoskeletal health, long-term use of acid-suppressing proton pump inhibitors (PPIs) may have the opposite effect on bone. Many people are currently taking PPIs, most commonly for gastrointestinal disorders such as heartburn and gastroesophageal reflux. Fortunately, many are occasional PPI users, taking the drugs only when symptoms arise. However, PPIs are often prescribed long term for preventive reasons.1
The same proton-pump mechanism present in the GI tract is seen in the vacuolar H+-ATPases that are present in high concentrations on the ruffled border of osteoclasts.2 Years of PPI use may therefore interfere with normal and essential bone remodeling. PPIs are also prescribed in the pediatric population for reflux symptoms. The effect of PPIs on future fracture or long-term osteoporosis in these very young patients is not clear.
The consequences for adult and elderly patients are clearer. Femoral bone mineral density is significantly decreased in PPI users. Also, patients with peptic ulcer disease using PPIs have a higher risk for osteoporosis than peptic ulcer patients not using PPIs. Among younger adults, the risk of fracture was significantly higher in those using PPIs than in those not using PPIs.
In 2010, the FDA issued a communication alerting healthcare professionals that users of PPIs have a possible increased risk of fractures of the hip, wrist, and spine, and that they should weigh the known benefits against the potential risks when recommending use of these medications. In 2011, the FDA refined its language somewhat: “Following a thorough review of available safety data, FDA has concluded that fracture risk with short-term, low dose PPI use is unlikely.” Still, when fractures are the outcome of interest, the data implicates long-term use of PPIs in having deleterious effects on bone.
Although data on human fracture healing in association with PPI use are sparse, animal studies do show that PPIs have a negative impact on normal fracture healing, with a decrease in the expression of important markers of bone formation, including bone morphogenetic protein (BMP)-2, BMP-4, and cysteine-rich angiogenic inducer (CYR)61.
It is time to question the need for chronic use of PPIs by our patients. Orthopaedists should encourage their patients who take PPIs to discuss this matter with their primary care physician.
References
- Eom CS, Park SM, Myung SK, Yun JM, Ahn JS. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med. 2011 May-Jun;9(3):257-67. doi: 10.1370/afm.1243. PMID: 21555754
- Wagner SC. Proton Pump Inhibitors and Bone Health: What the Orthopaedic Surgeon Needs to Know. JBJS Rev. 2018 Dec 18. doi: 10.2106/JBJS.RVW.18.00029. [Epub ahead of print] No abstract available. PMID: 30562209
Epiphyseal Etiology for Juvenile Osteochondritis Dissecans?
Most patients with clinically apparent juvenile osteochondritis dissecans (JOCD) are between 12 and 19 years of age. Often the disease can be treated successfully with nonoperative modalities, but even in cases where the initial lesion resolves, patients may be predisposed to osteoarthritis later in life. While repetitive microtrauma is suspected to be involved in the development of JOCD, the exact etiology remains poorly understood, even 130 years after the condition was first described.
In the December 19, 2018 issue of The Journal, Toth et al. histologically examined 59 biopsy samples from the central condyles of 26 pediatric cadavers to look for areas of epiphyseal cartilage necrosis. Hypothesizing that such evaluation would reveal some lesions similar to those found in animals, the authors did indeed identify 6 samples with 1 or more areas of necrotic cartilage, which were either incorporated into subchondral bone or associated with focal failure of endochondral ossification. Those characteristics are consistent with a similar disease process called osteochondrosis manifesta seen in pigs and horses. While the clinical significance of these findings remains to be determined, the authors suggest that they may help explain an epiphyseal etiology of JOCD, and the data suggest that these microscopic changes (some of which are rendered in this article as whole-slide images) are probably present in young people 5 to 10 years prior to the clinical manifestations of JOCD.
These findings lend credence to the theory that the underlying etiology of JOCD primarily involves the epiphyseal growth plate rather than subchondral bone. Furthermore, the similarities between these cadaveric specimens and osteochondrosis manifesta lesions in porcine and equine femoral condyles may help us develop improved models to better diagnose, prevent, and treat this pathology.
Chad A. Krueger, MD
JBJS Deputy Editor for Social Media
What’s New in Musculoskeletal Basic Science 2018
Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.
This month, Matthew J. Allen, VetMB, PhD, author of the December 5, 2018 Specialty Update on Musculoskeletal Basic Science, focuses on the five most compelling findings from among the more than 60 noteworthy studies summarized in the article.
Gene Editing in Orthopaedics
–Gene-editing tools such as CRISPR-Cas9 have great potential as a means of introducing therapeutic genes into mesenchymal stem cells that can then be targeted to tissues in vivo. These researchers1 reported on genetically modified stem cells that have the potential to differentiate into chondrocytes encoding a natural inhibitor of interleukin-1, providing an opportunity for localized release of immunomodulatory factors.
Managing Orthopaedic Infections
–A novel study2 in which transmission electron microscopy was used to identify viable bacteria deep within the canalicular structure of cortical bone, remote from the site of an infected implant, suggests that effective debridement requires the removal of not just necrotic tissue, but also of adjacent, apparently unaffected bone.
Computational Modeling of Human Movement
–This report3 presented a human musculoskeletal model that provided extremely accurate predictions of ground reaction forces during simulated walking and squatting. As similar models are developed and validated, surgeons will have improved tools for evaluating patients, planning surgery, and making decisions about which procedure/implant is most appropriate for an individual patient.
Sex-Related Differences
–This report4 demonstrated sexually dimorphic regulation of gene-expression profiles in bone marrow osteoprogenitor cells that could partly explain clinical observations in sex differences in peak bone mass, bone remodeling, and immunomodulation.
Biological Enhancement of Ligament Healing
–Among several basic science papers focused on the optimal healing and durable fixation of tendons and ligaments, this notable work5 reported on the translation of bridge-enhanced ligament repair for the anterior cruciate ligament.
References
- Brunger JM, Zutshi A, Willard VP, Gersbach CA, Guilak F. CRISPR/Cas9 editing of murine induced pluripotent stem cells for engineering inflammation-resistant tissues. Arthritis Rheumatol.2017 May;69(5):1111-21. Epub 2017 Mar 31.
- de Mesy Bentley KL, Trombetta R, Nishitani K, Bello-Irizarry SN, Ninomiya M, Zhang L, Chung HL, McGrath JL, Daiss JL, Awad HA, Kates SL, Schwarz EM. Evidence of Staphylococcus aureus deformation, proliferation, and migration in canaliculi of live cortical bone in murine models of osteomyelitis. J Bone Miner Res.2017 May;32(5):985-90. Epub 2017 Jan 26.
- Jung Y, Koo YJ, Koo S. Simultaneous estimation of ground reaction force and knee contact force during walking and squatting. Int J Precis Eng Manuf.2017;18(9):1263-8.
- Kot A, Zhong ZA, Zhang H, Lay YE, Lane NE, Yao W. Sex dimorphic regulation of osteoprogenitor progesterone in bone stromal cells. J Mol Endocrinol.2017 Nov;59(4):351-63. Epub 2017 Sep 4.
- Perrone GS, Proffen BL, Kiapour AM, Sieker JT, Fleming BC, Murray MM. Bench-to-bedside: bridge-enhanced anterior cruciate ligament repair. J Orthop Res.2017 Dec;35(12):2606-12. Epub 2017 Jul 9.
Comparing the Potential of Cartilage-Cell Therapies
This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs.Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
Other than by using shell allografts, it is not possible to replant whole cartilage or cells that even come close to a biological construct matching original cartilage. The old adage that cartilage, unlike bone, cannot repair itself holds true, as the natural damage repair of cartilage leads to the formation of “scar” cartilage (fibrocartilage).
However, there are connective tissue progenitor cells that can be found in multiple different tissues, and chondrogenic connective-tissue progenitors (CTP-Cs) are found within articular cartilage, even if it is osteoarthritic. Investigators recently designed a study to quantitatively define the CTP-Cs resident in cartilage and to compare overall cartilage-cell concentration, CTP-C prevalence, and biological potential of cells in tissues taken from patients with different grades of osteoarthritis.
Investigators procured samples of osteoarthritic articular cartilage from 23 patients undergoing elective total knee arthroplasty. All patients had grade 3-4 osteoarthritis on the medial side and grade 1-2 on the lateral side. Each patient sample was assessed for mean cell concentration and CTP prevalence by subjecting cells from a unit measure of cartilage to specific conditions to promote colony formation. The biological potential of the CTPs was measured using sophisticated imaging analysis.
Cell concentration was significantly greater (p < 0.001) in grade 3-4 cartilage than in grade 1-2 cartilage. This matches findings from previous histologic reports. Although the prevalence of CTP-Cs varied widely, it trended lower in grade 3-4 than grade 1-2 cartilage samples (p = 0.078). The biological performance of CTP-Cs from grade 1-2 and grade 3-4 cartilage was comparable. Increased cell concentration was a significant predictor of decreased CTP-C prevalence (p = 0.002). Sex was not a predictor of cell concentration, but age correlated negatively with prevalence of CTP-Cs. The number of cells per colony varied widely across the 23 patients, implying a highly individualized capacity.
This research contributes to our understanding of what might constitute appropriate cell selection for combination with biochemical interventions that could lead to robust cartilage repair that has greater longevity.
Disrupting “Quorum Sensing” Could Help Fight Biofilms
This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
A biofilm is a complex combination of extracellular carbohydrates, proteins, lipids, and one or more species of bacteria that may adhere to an orthopaedic implant and surrounding tissue (see related OrthoBuzz post). Staphylococci bacteria are believed to account for more than 50% of all biofilm infections of medical devices.
Researchers recently summarized what we know about the biofilm formation process.1 In the attachment phase, free-floating bacteria attach to a prosthetic surface via proteins. Extracellular DNA from autolysis add to the mix. Then begins the irreversible attachment phase, during which the initial bacteria are incarcerated while more free-floating bacteria are added. During this phase, autoinducers are expressed, which serve as inter- and intrabacterial signals.
In the presence of an adequate quorum of bacteria, the maturation phase begins, during which the bacterial population cohesively shifts from replication to expression of virulence factors such as secretion systems, toxins, or biofilm formation. A mature biofilm is immune-resistant, although bacterial replication decreases. In the dispersal phase bacteria become planktonic again, potentially available to repeat the process.
Once a biofilm has formed, antibiotic administration becomes problematic because of the toxicity of the high doses needed to treat biofilm colonies. An underlying challenge with pharmacologic intervention is the variety of quorum-sensing communication pathways between bacterial species. The authors suggest that a future biofilm-fighting strategy may be to force bacteria into biofilm-forming behavior before they reach the necessary critical density to become virulent, although this notion remains unexplored. Researchers are investigating other possible strategies to disrupt the quorum-sensing communication among bacteria that enable them to behave as a “social” group.
Reference
- Mooney JA, Pridgen EM, Manasherob R, Suh G, Blackwell HE, Barron AE, Bollyky PL, Goodman SB, Amanatullah DF. Periprosthetic bacterial biofilm and quorum sensing. J Orthop Res. 2018 Sep;36(9):2331-2339. doi: 10.1002/jor.24019. Epub 2018 May 24.
Surgical Infection Prevention: Local Antibiotic Powders Beat IV Agents in Rats
When it comes to preventing infections associated with orthopaedic procedures, the question of which antibiotic to use is only one of several concerns. How and where to administer antibiotics is another relevant question, not only in terms of infection-fighting effectiveness but also in terms of combatting the proliferation of antibiotic-resistant microbes.
In the September 19, 2018 issue of The Journal of Bone & Joint Surgery, Sweet et al. report on findings from a study in rats that compared the infection-prevention efficacy of intravenous (IV) cefazolin (n = 20) and IV vancomycin (n = 20) with local application of 4 antimicrobials—vancomycin powder (n = 20), cefazolin powder (n = 20), tobramycin powder (n = 20), and dilute Betadine lavage (n = 20).
The researchers induced infection by surgically implanting a polytetrafluoroethylene vascular graft near each rat’s thoracic spine and inoculating it with methicillin-sensitive Staphylococcus aureus (MSSA). After 7 days, all of the rats in each of the IV cefazolin, IV vancomycin, and Betadine lavage groups had grossly positive cultures for MSSA, “with bacterial colonies too numerous to count.” Ninety percent of the rats in the local cefazolin-powder group also had positive cultures, but the infection rates with vancomycin and tobramycin powder were much lower than those with the other four approaches (p <0.000001).
In addition to the main “disclaimer” about this study (namely, that its findings cannot be extrapolated to clinical practice in humans), the authors caution that “the effect of locally applied antibiotics on the emergence of resistant organisms is unknown,” while citing evidence that systemic administration of antibiotics is “associated with the emergence of resistant organisms at an alarming rate.”
Sweet et al. say they plan to follow up this study with a similar model to investigate the efficacy of local antimicrobials against the more problematic methicillin-resistant Staphylococcus aureus (MRSA)—and they suggest further that “clinical studies should be considered to determine the relative clinical efficacy of local versus systemic antibiotics for surgical infection prophylaxis in humans.”
BOG Fracture-Risk Score Combines DNA Info with Physiological Factors
This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
During childhood and adulthood, we often put ourselves at risk for future fractures based on our activity, diet, and social habits. Many factors affect the risk of both stress fractures in younger people and fragility fractures later in life. Everyone—but especially athletes and active-duty military personnel—could benefit from an early heads-up regarding their genetic and phenotypic predisposition to stress fractures. Later in life, the FRAX index is a very useful multifactor risk score, but it is usually calculated only after a sentinel event, such as a fragility fracture.
Ultrasound is a readily available and inexpensive way to obtain an estimated heel bone mineral density (eBMD). Many common genetic variants contribute to the genetic basis for the eBMD phenotype. These variants are most commonly characterized by single nucleotide polymorphisms (SNPs, pronounced “snips”). Stanford researcher Stuart Kim developed the BMD Osteoporosis Genetic (BOG) risk score by combining 22,886 SNPs with data on height, weight, sex, and age.1 The correlation between actual eBMD and the BOG algorithm was 0.496, which was higher than the correlations achieved using the 22,886 genetic predictors or the four covariates alone.
Individuals with low BOG scores had a 17.4-fold increased risk for osteoporosis compared to those with the median BOG score. Low BOG scores were also associated with a 1.9-fold higher risk for bone fractures compared to median BOG values. However, the algorithm’s ability to discriminate cases from controls in the overall population was modest. The receiver operator area under the curve for predicting osteoporosis or fracture by the BOG algorithm was 0.78 and 0.57, respectively.
Although the effect of an individual SNP may be inconsequential, the cumulative effect from many SNPs can be large. The author stated that “an algorithm such as the BOG risk score might be useful to screen the general population…to identify individuals that warrant closer examination, such as BMD measurement via DXA [dual-energy X-ray absorptiometry].”
Reference
- Kim SK. Identification of 613 new loci associated with heel bone mineral density and a polygenic risk score for bone mineral density, osteoporosis and fracture. PLoS One. 2018 Jul 26;13(7):e0200785. doi: 10.1371/journal.pone.0200785. eCollection 2018. PMID: 30048462
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