Parathyroid hormone and trabectedin have differing effects on macrophages and stress fracture repair.

Stress fractures occur as a result of repeated mechanical stress on bone and are commonly found in the load-bearing lower extremities. Macrophages are key players in the immune system and play an important role in bone remodeling and fracture healing. However, the role of macrophages in stress fractures has not been adequately addressed. We hypothesize that macrophage infiltration into a stress fracture callus site promotes bone healing. To test this, a unilateral stress fracture induction model was employed in which the murine ulna of four-month-old, C57BL/6 J male mice was repeatedly loaded with a pre-determined force until the bone was displaced a distance below the threshold for complete fracture. Mice were treated daily with parathyroid hormone (PTH, 50 µg/kg/day) starting two days before injury and continued until 24 h before euthanasia either four or six days after injury, or treated with trabectedin (0.15 mg/kg) on the day of stress fracture and euthanized three or seven days after injury. These treatments were used due to their established effects on macrophages. While macrophages have been implicated in the anabolic effects of PTH, trabectedin, an FDA approved chemotherapeutic, compromises macrophage function and reduces bone mass. At three- and four-days post injury, callus macrophage numbers were analyzed histologically. There was a significant increase in macrophages with PTH treatment compared to vehicle in the callus site. By one week of healing, treatments differentially affected the bony callus as analyzed by microcomputed tomography. PTH enhanced callus bone volume. Conversely, callus bone volume was decreased with trabectedin treatment. Interestingly, concurrent treatment with PTH and trabectedin rescued the reduction observed in the callus with trabectedin treatment alone. This study reports on the key involvement of macrophages during stress fracture healing. Given these observed outcomes on macrophage physiology and bone healing, these findings may be important for patients actively receiving either of these FDA-approved therapeutics.

A rare side effect of methotrexate therapy: drug-induced osteopathy with multiple fractures of the lower limb.

Methotrexate is associated with bone lesions that are rare and, although presenting with a typical localisation to the lower extremities and appearing with a characteristic radiologic morphology, largely unknown and often misdiagnosed as osteoporotic insufficiency fractures. The correct and early diagnosis, however, is key for treatment and prevention of further osteopathology. Here, we present a patient with rheumatoid arthritis who developed multiple painful insufficiency fractures in the left foot (processus anterior calcanei, tuber calcanei) and in the right lower leg and foot (anterior and dorsal calcaneus and at the cuboid and distal tibia) during therapy with methotrexate, which were all misdiagnosed as osteoporotic. The fractures occurred between 8 months and 35 months after starting methotrexate. Discontinuation of methotrexate resulted in rapid pain relief and no further fractures have occurred. This case powerfully demonstrates the importance of raising awareness of methotrexate osteopathy in order to take appropriate therapeutic measures, including and perniciously discontinuing methotrexate.

Recombinant fibroblast growth factor-18 (sprifermin) enhances microfracture-induced cartilage healing.

Posttraumatic osteoarthritis is a disabling condition impacting the mostly young and active population. In the present study, we investigated the impact of intra-articular sprifermin, a recombinant truncated fibroblast growth factor 18, on the outcome of microfracture treatment, a widely used surgical technique to enhance cartilage healing at the site of injury. For this study, we created a cartilage defect and performed microfracture treatment in fetlock joints of 18 horses, treated joints with one of three doses of sprifermin (10, 30, or 100 µg) or with saline, hyaluronan, and evaluated animals functional and structural outcomes over 24 weeks. For primary outcome measures, we performed histological evaluations and gene expression analysis of aggrecan, collagen types I and II, and cartilage oligomeric matrix protein in three regions of interest. As secondary outcome measures, we examined animals' lameness, performed arthroscopic, radiographic, and computed tomography (CT) scan imaging and gross morphology assessment. We detected the highest treatment benefit following 100 µg sprifermin treatment. The overall histological assessment showed an improvement in the kissing region, and the expression of constitutive genes showed a concentration-dependent enhancement, especially in the peri-lesion area. We detected a significant improvement in lameness scores, arthroscopic evaluations, radiography, and CT scans following sprifermin treatment when results from three dose-treatment groups were combined. Our results demonstrated, for the first time, an enhancement on microfracture outcomes following sprifermin treatment suggesting a cartilage regenerative role and a potential benefit of sprifermin treatment in early cartilage injuries.

Teriparatide and stress fracture healing in young adults (RETURN - Research on Efficacy of Teriparatide Use in the Return of recruits to Normal duty): study protocol for a randomised controlled trial.

BACKGROUND: Stress fractures are a common and potentially debilitating overuse injury to bone and occur frequently among military recruits and athletes. Recovery from a lower body stress fracture typically requires several weeks of physical rehabilitation. Teriparatide, a recombinant form of the bioactive portion of parathyroid hormone (1-34 amino acids), is used to treat osteoporosis, prevent osteoporotic fractures, and enhance fracture healing due to its net anabolic effect on bone. The study aim is to investigate the effect of teriparatide on stress fracture healing in young, otherwise healthy adults undergoing military training. METHODS: In a two-arm, parallel, prospective, randomised controlled, intention-to-treat trial, Army recruits (n = 136 men and women, 18-40 years) with a magnetic resonance imaging (MRI) diagnosed lower body stress fracture (pelvic girdle, sacrum, coccyx, or lower limb) will be randomised to receive either usual Army standard care, or teriparatide and usual Army standard care. Teriparatide will be self-administered by subcutaneous injections (20 µg/day) for 16 weeks, continuing to 24 weeks where a fracture remains unhealed at week 16. The primary outcome will be the improvement in radiological healing by two grades or more, or reduction to grade zero, 8 weeks after randomisation, assessed using Fredericson grading of MRI by radiologists blind to the randomisation. Secondary outcomes will be time to radiological healing, assessed by MRI at 8, 10, 12, 14, 16, 20 and 24 weeks, until healed; time to clinical healing, assessed using a clinical severity score of injury signs and symptoms; time to discharge from Army physical rehabilitation; pain, assessed by visual analogue scale; health-related quality of life, using the Short Form (36) Health Survey; and adverse events. Exploratory outcomes will include blood and urine biochemistry; bone density and morphology assessed using dual-energy X-ray absorptiometry, peripheral quantitative computed tomography (pQCT), and high-resolution pQCT; physical activity measured using accelerometers; and long-term future fracture rate. DISCUSSION: This study will evaluate whether teriparatide, in addition to standard care, is more effective for stress fracture healing than standard care alone in Army recruits who have sustained a lower body stress fracture. TRIAL REGISTRATION: ClinicalTrials.gov NCT04196855 . Registered on 12 December 2019.

Treatment of an Acromial Stress Fracture After Reverse Total Shoulder Arthroplasty With Teriparatide: A Case Report.

CASE: A 78-year-old woman who underwent reverse total shoulder arthroplasty (RTSA) for proximal humerus fracture developed a Type-3 acromial stress fracture, resulting in increased pain and decreased function 9 months post-op. She was managed nonoperatively with adjunctive teriparatide (FORTEO), and after a 4-month course, she had regained excellent motion and achieved union. CONCLUSION: Teriparatide is a viable adjunct in treating patients nonoperatively with acromial stress fractures after RTSA.

Successful treatment for bilateral femoral neck insufficiency fractures: a rare lesion case report and an updated review of the literature.

BACKGROUND: The incidence of insufficiency fracture (IF) at femoral neck is low, accounting for about 5% of all insufficiency fractures, and IF at bilateral femoral neck is less common with more occurrence in athlete or serviceman. With the aging of populations, more cases of bilateral femoral neck IF have occurred recently, while the standard clinical treatment still remains lacking due to the complexity of these patients. CASE PRESENTATION: A 55-year-old male patient complained pain in his bilateral hip, with no history of trauma, glucocorticoid hormone consumption or radiotherapy, and imaging examination revealed fracture nonunion and shortening in his left femoral neck, and double fracture line on the right femoral neck. The patient received a cementless THA for the left femoral neck fracture and conservative treatment for the right side, followed by Elcatonin injection and oral administration of Carbonate D3 Granules. After 4 months of fellow-up, the patient presented improved functional scorings in bilateral hip joints, with no signs of prothesis infection or loosening. CONCLUSION: We present a rare case of bilateral femoral neck IF in a middle-aged male and the treatment is successful. The timely CT and MRI examinations of bilateral hip joints for patients was necessary for orthopedists to select proper therapeutic regimen. In addition, the choice for therapeutic regimen of bilateral femoral IF should not only be based on the professional judgement of orthopedists, but also on the wishes of patients.

British Army recruits with low serum vitamin D take longer to recover from stress fractures.

BACKGROUND: Recruits undergoing military training experience a particularly high incidence of stress fractures. The role of combined calcium and vitamin D (25-OHD) deficiency and subsequent supplementation has been well described in the literature, but the role of 25-OHD deficiency alone is less well understood, particularly its influence on recovery once a stress fracture has been incurred. METHODS: Retrospective data of recruits who had incurred stress fractures were collected (n=37). Independent-samples t-tests were conducted in Microsoft Excel to investigate the association between serum-25 OHD and the time taken to recover. RESULTS: Significant differences (p<0.05) were found in the mean time taken to recover from stress fractures when participants were grouped according to serum 25-OHD level. Sufficient levels of serum 25-OHD (>50 nmol/L) at the time of injury resulted in shorter recovery times than all other groups. CONCLUSION: The study demonstrated an association between serum 25-OHD level and the time taken to recover from a stress fracture. The sample population of this study was too small to contribute to the discussion about whether a minimum serum 25-OHD status should be met before entering British Army training, but a larger prospective study should be able to provide the data required for a cost benefit analysis to be conducted and a decision made.

Delayed-Union of Acetabular Stress Fracture in Female Gymnast: Use of Teriparatide to Augment Healing.

Pelvic stress fractures are rare and present unique challenges for medical personnel. Delayed healing can lead to increased physical, psychological, and social stress for athletes. Recent literature suggests effective use of a synthetic derivative of parathyroid hormone, teriparatide, to augment healing of delayed-union stress fractures. We present a case of a female National Collegiate Athletic Association Division I gymnast successfully returned to play after a 12-week course of teriparatide injections for an ischioacetabular stress fracture.

Effects of tranexamic acid on the recovery of osteochondral defects treated by microfracture and acellular matrix scaffold: an experimental study.

BACKGROUND: Microfracture and scaffold application in the treatment of osteochondral defects is still one of the most frequently used methods in the clinic. The most important step in this treatment method is the stabilization of fibrin clot. Tranexamic acid (TA) is an antifibrinolytic agent commonly used in orthopedic surgery in recent years. This study evaluated the effect of local TA application on healing of experimentally induced osteochondral defects on rabbits. METHODS: This paper contains an animal in vivo data and histological outcomes on the effect of TA. Eighteen New Zealand white rabbits were treated unilaterally and cylindrical defects having a width of 4 mm and depth of 5 mm were created in the weight-bearing surfaces of the medial and lateral condyles of the right femur. They were divided into two groups, as group 1 study and group 2 control groups, respectively. One milliliter (ml) of TA was injected into the knee joints of the subjects in group 1. All animals were sacrificed for the extraction of the femur condyles for histologic study at the fourth and eighth weeks after surgery. Histological evaluations were performed by Brittberg and O'Driscoll scores to all samples. Data were organized in a Standard Statistical Package System v.22 software package (SPSS/PC Inc., Chicago, IL.) and reported as mean and median (min-max). Repeated measures ANOVA test was used to compare groups and condyle effects together for each week. p values below 0.05 were considered as statistically significant. RESULTS: Samples were taken in the fourth and eighth weeks. The regularity of the surface in group 1 was smoother, and the tissue stability was more robust. Mean Brittberg scores in both weeks were statistically higher in group 1 when compared with group 2. In the microscopic evaluation, it was observed that the regeneration of subchondral and cartilage tissues were more rapid and organized in group 1, and the mean O' Driscoll scores in both weeks were statistically higher in group 1. CONCLUSIONS: Application of TA improves the healing time and tissue stability in osteochondral defects which are implanted a-cellular scaffold after microfracture and should be applicable to humans for the treatment of osteochondral defects.

Single injection of PTH improves osteoclastic parameters of remodeling at a stress fracture site in rats.

Stress fractures (SFx) result from repetitive cyclical loading of bone. They are frequent athletic injuries and underlie atypical femoral fractures following long-term bisphosphonate (BP) therapy. We investigated the effect of a single PTH injection on the healing of SFx in the rat ulna. SFx was induced in 120 female Wistar rats (300 ± 15 g) during a single loading session. A single PTH (8 µg.100g-1 ) or vehicle (VEH) saline injection was administered 24 h after loading. Rats were divided into four groups (n = 15) and ulnae were examined 1, 2, 6, or 10 weeks following SFx. Two Toluidine Blue and TRAP-stained sections of the SFx were examined for histomorphometric analysis using Osteomeasure™ software. An increase in osteoclast number (N.Oc) and perimeter (Oc.Pm) was observed two weeks following PTH treatment (p < 0.01). At 6 weeks, bone formation was the main activity in BMUs. At 10 weeks, the proportion of healing along the SFx line remained 50% greater in PTH groups (p = 0.839), leading to a 43% reduction in the porosity area of BMU (p = 0.703). The main effect of time was a significant variable along the entire SFx remodeling cycle, with significant interactions between time and treatment type affecting (N.Oc) (p = 0.047) and (Oc.Pm) (p = 0.002). We conclude that a single PTH injection increases osteoclastogenesis by the second week of the remodeling cycle in a SFx in vivo. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

[Teriparatide as a therapy approach in sacral insufficiency fractures]. / Teriparatid als Therapieansatz bei Sakruminsuffizienzfrakturen.

As a result of immense heterogeneity with regard to morphology and stability, the recent literature lacks consensus concerning the treatment of sacral insufficiency fractures. We report the case of a 79-year-old woman with bilateral sacral insufficiency fractures following anterior pelvic ring fractures who was treated with teriparatide. During a two-week hospital stay, the patient was successfully mobilised and the regularly conducted pelvic X­ray controls showed full consolidation of the fractures.

Clinical and imaging outcome of osteochondral lesions of the talus treated using autologous matrix-induced chondrogenesis technique with a biomimetic scaffold.

BACKGROUND: The purpose of our study was to assess the clinical and imaging outcome of autologous matrix-induced chondrogenesis (AMIC) technique consisting of microfractures followed by the filling of osteochondral lesions of the talus (OLTs) with a cell-free biphasic collagen-hydroxyapatite osteochondral scaffold (MaioRegen). METHODS: Sixteen patients (eight males, age: 42.6 ± 18.4, range 14-74) with OLT repaired using AMIC technique, with implantation of MaioRegen, were clinically evaluated through the American Orthopedic Foot and Ankle Society Score (AOFAS) and a 10-point Visual Analogue Scale (VAS) pain score after a mean follow-up of 30 ± 16.9 months. The MRI examinations were performed 12 and 24 months after surgery. A paired t-test was applied to compare pre- and post-operative clinical findings (VAS and AOFAS) and Magnetic resonance observation of cartilage repair tissue (MOCART) score changes in the follow-up. To assess the correlation between variation of AOFAS and MOCART scores, the Pearson's correlation coefficient was calculated. RESULTS: No complications after surgery were encountered. From pre-operative to post-operative values, there was a significant (P < 0.001) reduction of mean VAS pain score (6.3 ± 0.9,range: 4-8 and 2.9 ± 1.8,range: 0-6, respectively) and increase of AOFAS score (60.2 ± 7.8,range: 50-74 and 77.4 ± 16.2,range: 50-100, respectively). Among 16 patients, six (37%) were not satisfied at the end of follow-up, six (37%) were moderately satisfied and four (25%) were highly satisfied. The treatment was considered failed in five out of 16 patients (31%). Among them, four (25%) required re-interventions with implantation of ankle prostheses, whereas one patient was treated with a further AMIC technique combined with autologous bone graft and platelet-rich plasma. The mean MOCART score was 41.9 ± 14.6 (25-70) 12 months after surgery and 51.9 ± 11.6 (30-70) after 24 months, with a statistically significant increase (P = 0.012). However, no correlation was seen between AOFAS and MOCART changes (r = 0.215, p = 0.609). CONCLUSION: The high rates of treatment failure encountered in our study using MaioRegen need to be confirmed by larger studies and should induce the scientific community questioning the reliability of this biomimetic scaffold for the treatment of OLTs.

Teriparatide Treatment in Elderly Patients With Sacral Insufficiency Fracture.

Context and Objective: Pain-related immobility because of insufficiency fractures may result in serious complications and a high mortality rate in senile patients with preexisting comorbidities. This study aimed to evaluate the efficacy of teriparatide in patients with sacral insufficiency fractures. Design, Setting, and Participants: This retrospective, case-controlled, single center study, performed from 2009 to 2014, included 41 patients who underwent radiographs, magnetic resonance imaging, and/or bone scans to document sacral insufficiency fractures. Intervention: The intervention involved teriparatide at a once-daily subcutaneous dose of 20 µg within 2 days of hospital admission (21 patients). Twenty patients (control group) did not receive teriparatide. Main Outcome Measures: Functional outcome was assessed using a visual analog scale for pain and the time to mobilization. Pelvic anteroposterior radiographs were repeated at 0, 1, 4, 8, 12, and 16 weeks until radiographic evidence of cortical bridging at the fracture site was confirmed. Results: From the date of admission to 4 weeks, the mean visual analog scale score improved between the 2 groups. The mean time to mobilization was 1.2 ± 0.4 weeks in patients who received teriparatide treatment, compared with 2.0 ± 0.3 weeks in controls (P < 0.001). At 8 weeks, all fractures in the teriparatide treatment group and 4 fractures in the control group had healed. Conclusions: In senile patients with preexisting comorbidities who have sacral insufficiency fractures, teriparatide treatment may achieve earlier pain reduction and mobilization and reduce healing time.

Transdermal drug delivery: feasibility for treatment of superficial bone stress fractures.

Transdermal drug delivery offers the promise of effective drug therapy at selective sites of pathology whilst reducing systemic exposure to the pharmaceutical agents in off-target organs and tissues. However, that strategy is often limited to cells comprising superficial tissues of the body (rarely to deeper bony structures) and mostly indicated with small hydrophobic pharmacological agents, such as steroid hormones and anti-inflammatory gels to skin, muscle, and joints. Nonetheless, advances in transdermal liposomal formulation have rendered the ability to readily incorporate pharmacologically active hydrophilic drug molecules and small peptide biologics into transdermal dosage forms to impart the effective delivery of those bioactive agents across the skin barrier to underlying superficial tissue structures including bone, often enhanced by some form of electrical, chemical, and mechanical facilitation. In the following review, we evaluate transdermal drug delivery systems, with a particular focus on delivering therapeutic agents to treat superficial bone pain, notably stress fractures. We further introduce and discuss several small peptide hormones active in bone (such as calcitonins and parathyroid hormone) that have shown potential for transdermal delivery, often under the added augmentation of transdermal drug delivery systems that employ lipo/hydrophilicity, electric charge, and/or microprojection facilitation across the skin barrier.

Intravenous bisphosphonates and vitamin D in the treatment of bone marrow oedema in professional athletes.

INTRODUCTION: The goal of this retrospective study was to evaluate the safety and efficacy of ibandronate for bone marrow oedema (BMO) syndrome and stress fracture cases, and to demonstrate an additional field of therapeutic importance-the high-performance athlete. PATIENTS AND METHODS: This retrospective study included twenty-five high-performance athletes. Sixty per cent of the athletes were European soccer players and 40.0% other high-class international athletes (3 women and 22 men with an average age of 25.0±4.2), with BMO of the lower trunk or extremity diagnosed by magnetic resonance imaging (MRI). The treatment regimen consisted of high-dose vitamin D supplementation and intravenous ibandronate therapy. RESULTS: The time between the onset of pain and proper diagnosis of BMO was 106.3±104.1 days. Excellent pain reduction (pain at rest and under strain) and improved mobility was reported within the first two weeks after the first ibandronate administration by sixteen patients (64%). The time from first treatment until return to competition (RTC) was on average 102.6±65.2 days in total. If the time from onset of pain until diagnosis was within 40 days, the RTC was significantly reduced (p≤0.05) to almost 50% (63.8±48.1 days) when compared to the athletes with later diagnosis (124.4±63.2 days). CONCLUSIONS: The here-applied therapy regimen of intravenous BPs application and vitamin D supplementation in BMO syndrome has a beneficial effect for high-performance athletes. An early diagnosis and rapid treatment start can reduce the RTC significantly. An optimal bone metabolism with sufficient daily calcium and vitamin D intake is crucial and should not only be strived for the professional but also for the recreational athlete.

Recurrent bone fractures due to tenofovir-induced renal phosphate wasting.

A 42-y-old HIV-infected man suffered from several stress fractures due to tenofovir-induced proximal tubular injury. Laboratory examination revealed hypophosphatemia due to renal phosphate wasting. Therefore, more attention has to be paid to the monitoring of serum phosphate and alkaline phosphatase levels, since tenofovir-related nephrotoxicity increases the risk of osteomalacia.

Vitamin D supplementation in athletes.

It is well recognized that vitamin D is necessary for optimal bone health. Emerging evidence is finding that vitamin D deficiency can have a profound effect on immunity, inflammation and muscle function. Studies in athletes have found that vitamin D status varies among different populations and is dependent on skin color, early- or late-day training, indoor training and geographic location. Although dietary assessment studies have found that athletes worldwide do not meet the dietary intake recommendations for vitamin D, the most probable reason for poor status is inadequate synthesis due to lack of sun exposure. Studies in athletic populations suggest that maintaining adequate vitamin D status may reduce stress fractures, total body inflammation, common infectious illnesses, and impaired muscle function, and may also aid in recovery from injury. Given that compromised vitamin D status can potentially impact an athlete's overall health and training efficiency, vitamin D status should be routinely assessed so that athletes can be coached to maintain serum 25(OH)D concentration of ≥30 and preferably ≥40 ng/ml. Recommendations will be dependent on the athlete's current 25(OH)D concentration, but can include regular safe sun exposure and/or dietary supplementation combined with increased vitamin D intake.