Growth factor-mediated augmentation of long bones: evaluation of a BMP-7 loaded thermoresponsive hydrogel in a murine femoral intramedullary injection model.

BACKGROUND: Due to our aging population, an increase in proximal femur fractures can be expected, which is associated with impaired activities of daily living and a high risk of mortality. These patients are also at a high risk to suffer a secondary osteoporosis-related fracture on the contralateral hip. In this context, growth factors could open the field for regenerative approaches, as it is known that, i.e., the growth factor BMP-7 (bone morphogenetic protein 7) is a potent stimulator of osteogenesis. Local prophylactic augmentation of the proximal femur with a BMP-7 loaded thermoresponsive hydrogel during index surgery of an osteoporotic fracture could be suitable to reduce the risk of further osteoporosis-associated secondary fractures. The present study therefore aims to test the hypothesis if a BMP-7 augmented hydrogel is an applicable carrier for the augmentation of non-fractured proximal femurs. Furthermore, it needs to be shown that the minimally invasive injection of a hydrogel into the mouse femur is technically feasible. METHODS: In this study, male C57BL/6 mice (n = 36) received a unilateral femoral intramedullary injection of either 100 µl saline, 100 µl 1,4 Butan-Diisocyanat (BDI)-hydrogel, or 100 µl hydrogel loaded with 1 µg of bone morphogenetic protein 7. Mice were sacrificed 4 and 12 weeks later. The femora were submitted to high-resolution X-ray tomography and subsequent histological examination. RESULTS: Analysis of normalized CtBMD (Cortical bone mineral density) as obtained by X-ray micro-computed tomography analysis revealed significant differences depending on the duration of treatment (4 vs 12 weeks; p < 0.05). Furthermore, within different anatomically defined regions of interest, significant associations between normalized TbN (trabecular number) and BV/TV (percent bone volume) were noted. Histology indicated no signs of inflammation and no signs of necrosis and there were no cartilage damages, no new bone formations, or new cartilage tissues, while BMP-7 was readily detectable in all of the samples. CONCLUSIONS: In conclusion, the murine femoral intramedullary injection model appears to be feasible and worth to be used in subsequent studies that are directed to examine the therapeutic potential of BMP-7 loaded BDI-hydrogel. Although we were unable to detect any significant osseous effects arising from the mode or duration of treatment in the present trial, the effect of different concentrations and duration of treatment in an osteoporotic model appears of interest for further experiments to reach translation into clinic and open new strategies of growth factor-mediated augmentation.

Beware of bone pain with bisphosphonates.

A 71-year-old woman who had been taking ibandronate for 10 years presented to an Endocrinology Department with persistent mid-thigh pain. Pelvic X-ray showed bilateral femoral cortical expansion, indicating impending atypical femoral fractures (AFFs). AFFs have been linked to long-term bisphosphonate therapy and have morbidity and mortality similar to that of hip fractures. Such fractures can be averted by regular reviews of bisphosphonate therapy and vigilance for prodromal symptoms. This patient's bisphosphonate therapy was stopped, and fractures were avoided by treatment with vitamin D and parathyroid hormone.

Medication management after intramedullary nailing of atypical fractures.

Long term use of bisphosphonates (BPs) in osteoporotic patients may be associated with stress fractures of the sub-trochanteric and shaft area of the femur, so called "atypical" femoral fractures (AFF). Specific diagnosis criteria have been defined with 5 major features; the presence of four of them characterizes the AFF. Once a complete fracture occurred, the best surgical treatment is closed reduction and intra medullary nailing. The BPs treatment should be stopped immediately after an AFF occurred. Dietary calcium and vitamin D status should be assessed, and adequate supplementation prescribed. Principle of combination of a systematic bone anabolic treatment is strongly debated. The recombinant parathyroid hormone 1-34 or Teriparatide ® (TPTD) has an anabolic effect on bone and prevent osteoporotic fractures. Available preclinical and clinical data have also demonstrated the role played by TPTD to enhance bone fracture healing and the potential beneficial effect in impaired fracture healing or specific clinical condition like AFFs. Some authors have proposed in incomplete BP use stress fractures different medical management according the MRI findings. Bone anabolic agents may be promising both to prevent healing complications in AFFs and to promote healing in conservative treatment of incomplete AFFs. More clinical studies are needed to confirm this hypothesis.

Spectacular improvement in vitamin D status in elderly osteoporotic women: 8-year analysis of an osteoporotic population treated in a dedicated fracture liaison service.

UNLABELLED: In a population of postmenopausal women with a fragility fracture, we found a drastic reduction in the proportion of women with severe (<25 nmol/L) and moderate (25 to 75 nmol/L) hypovitaminosis D, especially from 2009 onwards. These results show that supplementation has been very widely integrated into current practice. INTRODUCTION: Vitamin D (25(OH)D) is essential for bone health. In institutionalised osteoporotic women, it reduces the risk of fragility fractures. Numerous articles suggesting the possibility of extraosseous effects have generated a growing number of publications and recommendations on more widespread administration, to limit the risks of moderate or severe hypovitaminosis D. We assessed the impact on clinical practice of these recommendations concerning 25(OH)D supplementation in elderly at-risk populations. METHODS: A total of 1486 postmenopausal osteoporotic women were seen in the context of a fracture liaison service (i.e. a rheumatology consultation following a peripheral fragility fracture), between May 2005 and December 2012. Of these, 1107 had a 25(OH)D assay (femur, n = 520; humerus, n = 207; wrist, n = 380). RESULTS: The average age of the total population was 76.7 ± 9.9 years, while for women with an available 25(OH)D assay, the average age was 75.1 ± 11.8 years. The average 25(OH)D (nmol/L) level was similar for the three fracture sites: femur, 30 ± 36.2; humerus, 27.5 ± 24; and wrist, 31 ± 26. A drastic reduction in the proportion of women with severe (<25 nmol/L) and moderate (25 to 75 nmol/L) hypovitaminosis D was observed, especially from 2009 onwards, with a mean prevalence of 69 and 30 % respectively before that year and 35 and 52 % thereafter. Conversely, the proportion of women with 25(OH)D at the threshold value of 75 nmol/L increased from 1.2 to 24 %. Overall, mean serum 25(OH)D levels were significantly higher when comparing the two periods 2005-2008 and 2009-1012 (17.6 ± 14.6 and 48.4 ± 39.2 nmol/L, respectively; p < 0.0001). CONCLUSION: These results show that supplementation has been very widely integrated into current practice. We can expect it to yield beneficial effects in osseous and extraosseous terms in osteoporotic women, particularly the very elderly.

Atypical femoral fractures: a review of the literature.

Bisphosphonates are the most commonly used drugs worldwide for treating osteoporosis. Atypical femoral fractures most commonly are associated with prolonged bisphosphonate use. They also may occur with denosumab use or in patients without a history of using these drugs. In this article, we provide a comprehensive review of the mechanism of action of bisphosphonate and the definition, incidence, epidemiology, pathogenesis, diagnosis, management, and prevention of atypical femoral fractures.

Antiresorptive drugs (bisphosphonates), atypical fractures and rebound effect: new evidence of similitude.

BACKGROUND: Homeopathy is based on treatment by similitude ('like cures like') administering to sick individuals substances that cause similar symptoms in healthy individuals, employing the secondary and paradoxical action of the organism as therapeutic response. This vital or homeostatic reaction of the organism can be scientifically explained by the rebound effect of drugs, resulting in worsening of symptoms after suspension of treatment. Bisphosphonates (BPs) reduce 'typical' fractures in patients with osteoporosis, but recent studies report 'atypical' fractures of the femur after stopping the BPs, a rebound effect may be the causal mechanism. METHOD: Review of the literature concerning the relationship between atypical femoral fractures and antiresorptive drugs (bisphosphonates), identifying the pathogenesis of this adverse event. RESULTS: Several studies have described multiple cases of 'atypical' low-impact subtrochanteric stress fractures or complete fractures of the femur. These fractures are often bilateral, preceded by pain in the affected thigh, may have a typical X-ray appearance, and may delayed healing. Rebound of osteoclastic activity after suspension of antiresorptive drugs is a plausible mechanism to explain this phenomenon. CONCLUSION: As for other classes of drugs, the rebound effect of antiresorptive drugs supports Hahnemann's similitude principle (primary action of the drugs followed by secondary and opposite action of the organism), and clarifies this 'unresolved' issue. Unfortunately, the rebound effect is little discussed among health professionals, depriving them of important knowledge ensure safe management of drugs.

Can martial arts techniques reduce fall severity? An in vivo study of femoral loading configurations in sideways falls.

Sideways falls onto the hip are a major cause of femoral fractures in the elderly. Martial arts (MA) fall techniques decrease hip impact forces in sideways falls. The femoral fracture risk, however, also depends on the femoral loading configuration (direction and point of application of the force). The purpose of this study was to determine the effect of fall techniques, landing surface and fall height on the impact force and the loading configuration in sideways falls. Twelve experienced judokas performed sideways MA and Block ('natural') falls on a force plate, both with and without a judo mat on top. Kinematic and force data were analysed to determine the hip impact force and the loading configuration. In falls from a kneeling position, the MA technique reduced the impact force by 27%, but did not change the loading configuration. The use of the mat did not change the loading configuration. Falling from a standing changed the force direction. In all conditions, the point of application was distal and posterior to the greater trochanter, but it was less distal and more posterior in falls from standing than from kneeling position. The present decrease in hip impact force with an unchanged loading configuration indicates the potential protective effect of the MA technique on the femoral fracture risk. The change in loading configuration with an increased fall height warrant further studies to examine the effect of MA techniques on fall severity under more natural fall circumstances.

Supracondylar femur fracture after knee manipulation: a report of 3 cases.

Supracondylar femur fracture is a rare but devastating complication of knee manipulation following total knee arthroplasty (TKA). Avoidance of this complication can be achieved by careful attention to the indications and contraindications, timing, and technique of closed manipulation. We performed a retrospective chart and radiographic review to identify all patients who underwent closed manipulation under anesthesia for a diagnosis of aseptic arthrofibrosis after TKA. This article presents 3 cases of supracondylar femur fracture following closed knee manipulation of stiff TKAs that occurred at our institution over a 4-year period (1999-2002). Patient age ranged from 44 to 73 years. All patients underwent cruciate retaining TKA. Time from TKA to manipulation ranged from 3 months to 3 years. Two patients sustained an extension type supracondylar fracture. Two of the 3 patients were treated with closed reduction and casting/bracing. At a minimum 8-month follow-up after fracture, range of motion was poor with average flexion to 77 degrees and average flexion contracture of 13 degrees . In our patients, risk factors for fracture included prolonged time from arthroplasty to manipulation, arthrofibrosis, radiographic osteopenia, and rheumatoid arthritis. To our knowledge, this represents the largest case series of iatrogenic supracondylar femur fractures reported in the literature. Two manipulation techniques are described in detail. The alternative manipulation technique is highlighted with no fractures or complications over the same period. We believe that the alternative manipulation technique is a safe and effective technique to manipulate stiff TKA's and has been used for over >10 years by the senior surgeon (J.V.B.).

[Osteoporosis in the elderly]. / Ostéoporose chez le sujet âgé.

Osteoporosis is a frequent disease among the elderly and has major consequences in terms of mortality, morbidity and cost. Guidelines for diagnostic procedures are often difficult to apply in frail, elderly patients with multiple comorbidities. Bisphosphonates are the reference treatment for the elderly, combined with vitamin D and calcium supplementation. Vitamin D deficiency must also be treated to prevent falls and fractures. Strontium ranelate is a promising treatment in this population. Fall prevention is a major part of osteoporosis management. The potential benefit of hip protectors is questionable, even in institutionalized patients.

Fracture and fortified breast milk in an extremely preterm infant.

Metabolic bone disease (MBD) in the newborn predominantly affects preterm infants. The risk of MBD is inversely proportional to gestational age and birthweight, and directly related to postnatal complications. Poor bone mineralization has been shown in 55% of infants born at less than 1000 g. Optimal nutrition for very preterm infants is thought to be mother's own milk but supplementation is required to meet dietary requirements. However, there is insufficient evidence to determine that supplementation of human milk with commercial fortifiers has an effect on bone mineral content. We report a case of severe MBD with fractures in an extremely preterm infant who was fed with fortified mother's milk.

[Study of the antiosteoporosis effects of bushenqianggu capsule].

OBJECTIVE: To study the antiosteoporosis effects of Bushenqianggu capsule. METHOD: Observing the pharmacological effects of Bushenqianggu capsule with blank and positive control, and then analyzing the data with biological statistics. RESULT: The testis and uterus weight index of "the kidney assessed" model mice, weight of thighbone and blood concentration of Ca2+ increased significantly. Meanwhile, the thighbone mass density of castrated rats was improved and the incidence of the thighbone fracture in the osteoporosis model rats induced by retinoic acid was reduced. Besides, it had analgesia and anti-inflammatory effects. CONCLUSION: Bushenqianggu capsule has a good effect on osteoporosis, which provides evidence for clinical use.

[Physiopathology and prevention of fractures of the proximal end of the femur]. / Physiopathologie et prévention des fractures de l'extrémité supérieure du fémur.

Hip fracture is the most important skeletal problem in elderly people. Its two main determinants are falls and bone loss leading to an intrinsic bone fragility. Bone fragility results from postmenopausal and senile bone loss. The latter is increased by the secondary hyperparathyroidism of elderly persons which is induced by a combination of vitamin D deficiency and calcium intake, both very common in old age, particularly in Europe. Prophylactic strategies should be based on prevention of falls and of bone fragility. The latter includes the optimization of peak bone mass during childhood, postmenopausal oestrogen replacement therapy and a late prevention of senile secondary hyperparathyroidism by vitamin D and calcium supplements which have recently been shown to reduce by 25% the number of hip fractures in a prospective study performed in a large population of institutionalized women. Therefore, it is never too early to pay attention to the risk of osteoporosis, and never too late to prevent hip fractures.

Ipriflavone improves bone density and biomechanical properties of adult male rat bones.

To assess the potential impact of ipriflavone on the biomechanical properties and mineral composition of bone, we administered two doses (200 or 400 mg/kg bw) of the drug orally to adult male rats for 1 month. Bone biomechanics were evaluated by vibration damping, an index of strain energy loss, and impact strength (the amount of energy required to fracture after a single impact). At the higher dose, ipriflavone significantly decreased vibration damping of rat femurs by 23.0 +/- 9.8% compared with control, vehicle-treated animals, suggesting a higher capacity to withstand dynamic stress. This result was confirmed by the impact strength studies showing that a higher energy (49.6 +/- 21.3% above control) was required to fracture femurs of rat treated with 400 mg/kg bw ipriflavone. The high dose of ipriflavone increased bone mineral density, assessed by both volume displacement and ash analysis (4.2% and 2.5% above controls, respectively). The relative content of calcium, phosphorus, and magnesium in the ashes was not different among the treated and untreated groups, indicating that no gross abnormalities in mineral composition of bone occurred after ipriflavone administration. Similarly, there were no differences in serum calcium and magnesium levels between treated and control animals at the end of the study, whereas lower circulating phosphorus levels were detected in the latter. Ipriflavone treatment was not associated with significant changes in serum alkaline phosphatase nor type I collagen telopeptide levels, two markers of bone turnover. In summary, 1-month treatment with ipriflavone increased bone density and improved the biomechanical properties of adult rat male bones without altering mineral composition.(ABSTRACT TRUNCATED AT 250 WORDS)

[Secondary hyperparathyroidism in the elderly. Apropos of 200 assays of intact parathormone]. / L'hyperparathyroïdie secondaire du sujet âgé. A propos de 200 dosages de parathormone intacte.

OBJECTIVES: To evaluate the frequency of high levels of intact parathormone in an elderly population of hospitalized patients and to determine whether there are any correlations with different factors involved in phosphocalcium metabolism, nutritional status and renal function. METHODS: Intact parathormone was assayed in all patients admitted to a geriatric ward (n = 200). Other laboratory tests included serum phosphorus, calcium, total albumin, prealbumin, ionized calcium, creatinine with calculation of the clearance and in 50 patients radioimmunoassay for 25 hydroxyvitamin D. RESULTS: Intact parathormone was abnormally high (> 65 pg/ml) in 40 patients. Mean levels increased significantly with age and reached 70.5 pg/ml in patients 90 years of age and over. No correlation was found between intact parathormone and total serum calcium, corrected serum calcium, albumin or prealbumin. Inversely there was a significant correlation with serum phosphorus and creatinine and creatinine clearance. Serum levels of 25 hydroxyvitamin D were abnormally low in 82% of the patients. There was a constant and significant decrease in intact parathormone level 15 days after calcium and calcifediol substitution therapy in 13 patients. CONCLUSION: The frequency of hyperparathyroidism increases with age to affect nearly 1 out of 2 subjects over 90. It would be useful to determine a threshold level for elderly subjects with a major risk of bone fracture.