Search

Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumoral syndrome, featured by a combination of neoplasms of various endocrine and nonendocrine tissues. Approximately 33% of MEN1-related deaths are due to the malignant behaviour of well-differentiated neuroendocrine tumors (NETs), for which a preventive surgical treatment is not feasible. Somatostatin analogues (SSA) have been employed in the treatment of NETs in the stage of advanced or metastatic disease, in order to control the growth and secretion of tumor lesions. A longitudinal, open label study named "LARO-MEN1" was undertaken in order to assess whether early medical treatment with long-acting SSA could act as a preventive approach in small MEN1-related gastroenteropancreatic (GEP) NETs. Thirty consecutive patients affected by MEN1 were screened and 8 patients with small (<2 cm) NETs and abnormal laboratory values of at least one of the GEP hormones were administered octreotide acetate slow-release formulation (LAR) (10 mg i.m. every 28 days). Octreotide LAR was effective in decreasing GEP hormones and overall safe in the majority of patients up to six years of treatment, maintaining the disease stable also in terms of tumor size. The positive outcomes of this study in MEN1 patients reinforce the results obtained in advanced NETs on the use of SSA, opening to the opportunity for preventive use of octreotide LAR, aimed to delay or even avoid surgery in these patients., Competing Interests: Conflict of interest C.F., C.L., M.L., and G.F. declare that have no conflict of interest to disclose in general and regarding this paper. B.M.L. declares that has received grants and consulting fees from Alexion, Abiogen Pharma, Amgen, Bruno Farmaceutici, Eli Lilly, MSD, NPS, Shire, SPA, Servier.

According to European legislation, a disease can be considered rare or "orphan" when it affects less than 1 subject of 2000 (1). Often these diseases affecting the pediatric age, are complex diseases and chronically debilitating and for this motive need the intervention of multidisciplinary skills specific. Among the rare disease as affecting the skeleton more than 400 are characterized by dysplastic changes of the skeleton (2). Alongside the disorders affecting the skeleton primitively, many systemic diseases can have a bone involvement. Among these, the Gaucher disease (GD), an heterogeneous lysosomal storage determined by hereditary enzyme deficiency of β-glucosidase. Patients with this disease have skeletal disorders of varying severity (Erlenmeyer flask deformity, lytic lesions and osteonecrosis, pathological fractures) that affects both the bone marrow, both mineralized bone with progressive damage of the tissue. The bone disease is the most debilitating of GD and can have a significant impact on the quality of life of patients. Thorough evaluations by monitoring biochemical markers of bone turnover and instrumental, with a quantitative and qualitative evaluation of the bone, are of fundamental importance to intervene early so they can prevent complications irreversible.

Objectives: Sex steroids are important regulators of bone physiology and play an essential role in the maintenance of bone health throughout the life. Hormonal replacement therapy (HRT) is a treatment commonly used to relieve symptoms and some undesirable consequences of menopause such as osteoporosis. Osteoporosis, characterized by the loss of bone mass and deterioration of microarchitecture with a consequent higher risk of fragility fractures, is under genetic influence. A tetranucleotide (TTTA)n microsatellite repeat polymorphism, at intron 4 of the CYP19 (aromatase) gene, has been previously associated with higher lumbar spine bone mineral density (LS-BMD) and lower risk of spine fracture in postmenopausal women. Moreover, the ERα encoded by the ESR1 gene is another important candidate for the regulation of bone mass of menopause. Moreover prospective analysis from >18.000 subjects at the GENOMOS study indicated that XX homozygotes genotype had a reduced risk of fracture independently from BMD. In the present study, we investigated in postmenopausal Italian women, at baseline and after 1 year of HRT, whether ESR1 and CYP19 gene polymorphisms could affect BMD through different statistical models., Methods: This study has been performed on 100 post-menopausal Italian women, from a larger group of 250. The study group was administred HRT and LS-BMD was measured at baseline and after 1 year of therapy. Genetic analysis evaluating ESR1 and CYP19 gene polymorphisms was performed., Results: Generalized Linear Models (GLMs) test showed that women with normal LS-BMD at the baseline had a major statistically significant BMD increase of 0.1426 gr/cm(2) (p= 0.0001) with respect to the osteoporotic patients. In addition, subjects with genotype 1 and 2 of CYP19 gene had a lower modification in LS-BMD after 1 year of HRT (0.0837 gr/cm(2) and 0,076 g/cm(2); p=0.0470 and 0,0547 respectively) when compared to genotype 3. No influences of the aromatase genotypes were observed in the variable difference using both Anova and GLMs test. Regarding the ESR1 gene polymorphism, the LS-BMD after 1 year of HRT was influenced by the diagnosis at the baseline and height and ERα genotypes were able to influence difference with statistical significant results with both test., Conclusions: In the present study, we have demonstrated that CYP19 gene polymorphism is able to influence the effect of 1 year HRT on LS-BMD with no influence on pre-/ and post-/HRT LS-BMD differences. Although ESR1 gene polymorphism is not able to influence the LS-BMD after 1 year HRT, it influences the observed modifications during the year of therapy. These data underlie the complexity of the genetics of the bone mass and its importance in influencing the response to HRT.

Unlabelled: THE ROLE OF THE ORTHOPAEDIC SURGEON IN THE TREATMENT OF PATIENTS WITH FRAGILITY FRACTURES IS TWOFOLD: the conservative or surgical treatment of the fracture, and the prevention of further fractures, establishing diagnostic and therapeutic procedures for osteoporosis. We evaluated 72 patients treated surgically for fragility vertebral fracture and 801 patients treated surgically for fragility hip fracture, operated from 2009 to 2010 at O.U. Orthopaedics and Traumatology of S.M. Annunziata Hospital of Florence, that have followed a treatment for refractures prevention according to the TARGET (Appropriate Treatment for Refractures GEriatric in Tuscany) Project of Tuscany Region. The average follow-up was 34 months. Patients with vertebral fracture treated for refractures prevention were 58 (80.6%), while patients with hip fracture treated for refractures prevention were 307 (38.3)., Results: the number of patients with vertebral fracture who had a refracture in the first two years after surgery was 12 (16.6%), of which 9 patients were not treated for osteoporosis. The percentage of refracture at 1 year after surgery in patients with hip fractures was 3.19% in 2009 and 2.17% in 2010, compared to 5.16% of refracture of 2006 when the TARGET Project was not yet started. Mortality at 1 year after surgery in patients with hip fracture treated for osteoporosis was 19% compared to 25-31% in the patients not treated for osteoporosis.

Background: Osteoporosis is the most common metabolic bone disorder of the elderly, affecting the normal bone turnover with an increased bone resorption and subsequent higher risk of fragility fractures. Collagen type 1 is the most represented protein in bone matrix. A genetic variation (Sp1) in intron 1 of COL1A1 gene has been associated to modulation of expression of the alpha 1 chain of collagen type 1 and it is considered a candidate polymorphism for predisposition to osteoporosis status and fragility fractures. Association studies, in ethnically different populations, are needed to strongly confirm the role of this polymorphism in bone metabolism., Materials and Methods: We enrolled over 2,000 Italian individuals and studied their bone mineral density (BMD) and fractures in relation to age, sex and body mass index (BMI). Moreover, we analyzed the distribution of Sp1 polymorphism in these individuals and associated it to normal bone status, osteopenic condition or osteoporosis diagnosis, BMD and the presence of low-trauma fractures., Results: The most rare ss genotype showed a trend for osteoporosis diagnosis with respect to both normal and osteopenic status. The same genotype resulted to be associated to lower values of BMD both at spine and femur sites. No association was found with fractures., Discussion: In conclusion the presence of the homozygote ss genotype seemed to predispose to osteoporosis diagnosis and to be more frequent in subjects with lower spine and femur BMD values.

Bone alters its metabolic and anabolic activities in response to the variety of systemic and local factors such as hormones and growth factors. The responsiveness of bone is accomplished by the action of osteoblasts, osteoclasts and osteocytes through the process of bone remodeling. The importance of the nervous system on body homeostasis systems has been described (1) and has been suggested that organogenesis and tissue repair are under neuronal control.The first documentation of an anatomic relationship between nerves and bone was made via woodcut, by Charles Estienne in Paris in 1545, which demonstrated nerves entering and leaving the bones of a skeleton (2). Later, several authors showed that cortical bone is densely innervated (3) and differentiated myelinated and non-myelinated fibers are associated with the arterial vessels and venous sinusoids in bone (4). This began a steady flow of studies of various nerve types in bone by a number of different groups (2). The field has recently been reinvigorated by the observation of an important role of neural control of many aspects of bone metabolism (2).

Phosphate (Pi) homeostasis is under control of several endocrine factors that play effects on bone, kidney and intestine. The control of Pi homeostasis has a significant biological importance, as it relates to numerous cellular mechanisms involved in energy metabolism, cell signaling, nucleic acid synthesis, membrane function, as well as skeletal health and integrity. Pi is essential for diverse biological processes, and negative Pi balance resulting from improperly regulated intestinal absorption, systemic utilization, and renal excretion. As results of these functions, chronic Pi deprivation causes several biological alterations, such as bone demineralization with unmineralized osateoid typical of osteomalacia in adults and rickets in developing animals and humans (1). Phosphatonins are new hormones playing an important role in the control of Pi homeostasis together with parathyroid hormone (PTH) and 1,25-dihydroxy vitamin D(3). Most insight into the underlying mechanisms was established by defining the molecular basis of different inherited disorders that are characterized by an abnormal regulation of Pi homeostasis.

In today's society, citizens are called to play an increasingly active role in decision planning related to the various aspects of work, social and political life. This trend has been also confirmed in the health's field. In fact, the citizen is also required to have the skills to take responsibility for his/her own health, to have knowledge of the health care system, understand the advice and instructions of health professionals, actively participating with them in the therapeutical path. The lack or an inadequate level of these skills will affect both the health of the individual and the costs related to the National Health System. The nursing staff that interfaces between physicians and patients plays a key role in health's promotion as an important determinant of health and welfare of the patient-citizen. With regard to osteoporosis, due to better knowledge of its determining causes, it is now possible an easy access to diagnosis and treatment options before fragility fractures occur, providing a real prevention to such complications. Prevention must be addressed to two different, but related, objectives: 1) prevention of osteoporosis; and 2) prevention of fragility fractures in patients with osteoporosis. In the context of both primary and secondary prevention, the nurse can better informed the patients and/or citizens about either the risks related to an inappropriate behavior or situations and events particularly dangerous to health, as well as provide information to simply and effectively implement protective measures. This project aims to raise awareness and create competent and specialized nurse figures, with a good understanding of the bone diseases, through the organization of seminars and training courses. Thus, it will be create clinical pathways and welfare in which the figure of the "Bone Care Nurse" will be responsible for administration of questionnaires relating to lifestyle and, for patients in drug treatment, questionnaires designed to assess the relevance of the adherence/compliance to the prescribed therapy. The "Bone Care Nurse" will also provide specific information leaflets aimed at improving lifestyle, compliance and adherence to therapy prescribed by physician. Specifically, this program will cover not only the prevention of fragility fractures in patients with low bone mass but also will provide general information on healthy lifestyles, such as adequate diet and physical activity, helpful to prevent cardiovascular disease, diabetes, obesity. An increase patient's compliance in taking the antiosteoporotic therapy, as also other concomitant medications will be obtainable. The information collected will be stored in an electronic database, subject to statistical analysis and will be informative on both the degree of knowledge of disease by the patient at the first and follow-up meetings of the Bone Care Nurse project.

Breast cancer, mostly exhibiting an hormone-dependent pathogenesis, is a commonly diagnosed cancer in females.It is well known that sex steroids favor the process of carcinogenesis of breast tissue and anti-hormonal therapy of breast cancer aims to decrease the action of estrogens on this tissue. For this purpose, two different compounds are prevalently used: the Selective Estrogen Receptor Modulators, preventing the cancer cell to interact with estrogens, and Aromatase Inhibitors, inhibiting the tissue conversion of androgens into estrogens. Unfortunately, latter treatments negatively impact on bone mass leading to the onset of osteoporosis. For this purpose, we propose to build a database to afford, to store and analyze information about the effects of treatment with Selective Estrogen Receptor Modulators and/or Aromatase Inhibitors on bone metabolism in patients with breast cancer referred to Our Center. We will focus on the possibility of intervening to reduce the negative effects on bone both by the identification of modifiable risk factors and administration of specific therapies, in order to create a therapeutic, diagnostic standard workup for these diseases.

The "Fracture Unit" is one of the possible answers to the advanced health needs of the growing number of elderly in our Country, aimed at achieving effective and efficient management of fracture events due to osteoporosis or fragility fractures. Here we proposed an implementation model that can represent an ideal and virtuous path that should be dedicated to every fractured patient. This model should provide specific responses to the health needs of the fractured patient and specifically responses to the health needs of the subject as a frail patient. The goal of this model is therefore to define and structure "a priori" a multidisciplinary course where the patient should be automatically inserted at the time of contact with the health facility following the fracture event, to establish a similar structured course even for the post-acute phase, that is taken over by large social-health areas or districts; and meet the cost for the definition of the rehabilitation.An optimal communication between hospital and general practitioners, responsible necessarily of the continuous reassessment of the patient, and the monitoring of patient's adherence to treatment are needed for a successful outcome and application of the implementation's model.

Epidemiological studies suggest that consumption of isoflavones rich diets can improve several postmenopausal complications. The aim of this study was to investigate the absorption and the efficacy of isoflavonic supplementation in the treatment of menopausal symptoms.36 postmenopausal women received 75 mg/day of isoflavones in the form of tablets, for six months. 21 subjects concluded the treatment. Plasmatic and urinary samples were collected before and after the treatment, along with a dietary interview. Isoflavones were determined in biological samples and in commercial administered supplements by a HPLC/DAD system.Results showed the presence of genistein (from 0.043 to 1.820 micromol/L) in plasma samples, and of genistein (from 2.486 to 20.363 micromol/24h) and daidzein (from 11.106 to 98.091 micromol/24h) in the urines of the treated women. In the 21 completers the Greene Climateric scale value for hot flushes changed from 3 to 1 or 0. No changes of the endometrial thickness and of the breast tissue were detected. The analysis of the supplement content in the tablets was in agreement with what declared by the producer.Administration of isoflavone supplements produced a decrease of symptoms in this cohort of postmenopausal women monitored for isoflavone absorption.

At present chronic diseases are of crucial importance for all health services in the Western World for both their epidemic prevalence and the fact that they absorb a growing proportion of health service financial resources. Osteoporosis has clinical and public health importance because osteoporotic fractures are one of the most common causes of disability and an important contributor to medical costs in many regions of the world Increased longevity has resulted in the emergence of age-related fragility fractures as a major public health problem. Today several classes of effective drugs are available for osteoporosis. However, these drugs to be effective, need to be taken long-term. In the case of BPs data have shown that nearly 70% of patients on a daily, and almost 60% on a weekly treatment, stop taking medication before the end of 1 year. A poor adherence is associated to an increased probability of fractures with consequent higher likelihood of hospitalisation and higher costs. Since reasons for nonadherence may depend on individual beliefs and circumstances the strategy to improve adherence should be tailored according to the individual patient. These findings underline the key role played by the physicians, above all GPs, in a strategy to improve adherence which now could be supported by the avaibility of new drugs and innovative administration routes.

Introduction. It is evident from several studies that vitamin D inadequacy is widespread among women with osteoporosis across all continents regardless of season or latitude, with similar prevalence in patients treated for osteoporosis and in untreated women. These results underscore a need to improve physician and patient awareness of the importance of adequate vitamin D supplementation in postmenopausal women with osteoporosis.Materials and Methods. As the daily administration of vitamin D combined with 1 gr calcium is hampered by an insufficient patient adherence, we performed a longitudinal study in 90 randomly recruited postmenopausal women aged 65-75 years with inadequate calcium intake and circulating levels of 25-hydroxyvitamin D3 (lower than 30 ng/mL). The prevalence of secondary hyperparathyroidism (parathyroid hormone > 65 pg/mL) was 36% in the all population. The possible repercussion of oral single weekly or monthly calcidiol administration on phospho-calcium metabolism was observed after three months treatment (from April through July) with 500 mg calcium daily and with three different therapeutic regimens of calcidiol (Group I: 25 drops weekly; Group II: 50 drops monthly; and Group III: 100 drops monthly). The general baseline characteristics of the three groups were superimposable. We measured fasting morning serum 25-hydroxyvitamin D3, parathyroid hormone, calcium, phosphate, bone alkaline phosphatase, urinary deoxypyridinoline, and 24hr-calcium, - phosphate, and - creatinine.Results. The adherence to the weekly calcidiol treatment was over 80% in 90% of the patients. All three therapeutic regimens of calcidiol led to normalization of 25-hydroxyvitamin D3 after 3 months, yet with a significantly higher potency (P >0.01) of regimens I and III, when compared to Group II. Also the decrease of circulating levels of parathyroid hormone was significantly higher (P < 0.001) in Groups I and III versus Group II. No biochemically and clinically relevant adverse effects were observed at the end of the 90-day follow-up.ConclusionsIn postmenopausal women with inadequate circulating levels of 25-hydroxyvitamin D3, calcium and pulsed calcidiol supplementation normalized 25-hydroxyvitamin D3 levels and reduced circulating parathyroid hormone levels.

Osteoporosis is defined as a reduction in bone mass and disruption of bone architecture, resulting in reduced bone strength and increase of bone fractures and it is responsible for more than 1.5 million fractures annually, including 300,000 hip fractures, approximately 700,000 vertebral fractures, 250,000 wrist fractures, and more than 300,000 fractures at other sites. The lifetime risk for any fragility fractures in Caucasian women at age 50 years approaches 40% and 13% in men. During childhood and adolescence there is a rapid linear and appositional skeletal growth with a peak bone mass attained during the third decade of life. During adult life the mechanical integrity of the skeleton is maintained by the process of bone remodeling, in which old bone is removed by osteoclasts and subsequently replaced by new bone, formed by osteoblasts. In recent years, we have come to appreciate that the close association between bone and vasculature plays a pivotal role in the regulation of bone remodeling and fracture repair. Vitamin D, OPG/RANK/ RANK-L system, Matrix Gla-proteins (Mgp) and Fetuin-A/calcium phosphate mineral phase complex play an important role in the regulation of bone homeostasis and vascular calcifications. A greater understanding of the biological linkages may lead to new dual-purpose therapies that may ultimately prevent the adverse outcomes of osteoporosis and atherosclerosis.

The concentration of calcium in the extracellular fluid is crucial for several physiological functions in humans and in normal conditions its circulating levels are maintained between 8.5-10.5 mg/dl. Among the regulators of calcium homeostasis parathyroid hormone (PTH) acts though the G-protein coupled PTH receptor and a hormone-sensitive adenylate cyclase, with Gsα subunit (stimulatory guanine nucleotide-binding protein alpha-subunit) being responsible for the stimulation of the catalytic complex. Mutations of the Gsα encoding gene, GNAS1, are causal for some forms of congenital hypocalcemia. In the present study genetic variability in the GNAS1 gene was analyzed in a group of hypocalcemic patients collected through the Italian Register of Primary Hypoparathyroidism (RIIP). We identified a new intronic variant of the GNAS1 gene, consisting of a T>C polymorphism. This polymorphism was studied in a group of unrelated healthy subjects for a possible association with bone turnover biomarkers and bone mineral density. The T>C polymorphism was found in 18% of the studied populations, with 15% heterozygous TC and 3% homozygous CC (Pearson χ(2)analysis: p=0.04). A significant association with low serum calcium levels was found in healthy subjects carrying the T > C polymorphism (ANCOVA analysis: p=0.04). These results support segregation of a novel GNAS1 gene intronic variant with low calcium levels in primary hypoparathyroidism, pseudo-hypoparathyroidism and in the general population.

Objective. Osteoclast activation at the cartilage pannus junction is an essential step in the destruction of bone matrix in patients affected by rheumatoid arthritis (RA). Receptor activator of NFkappaB ligand (RANK-L) is responsible for osteoclast differentiation and activation. Osteoprotegerin (OPG) is an alternative, high-affinity soluble receptor for RANK-L which significantly inhibits osteoclastogenesis. Estrogens and the specific receptors α and β (ER-α and ER-α) are known to play an important role in the pathophysiology of osteoarthritis (OA). Scope of the present study is to investigate the role of ER-α and OPG gene polymorphisms in a group of women affected by RA.Materials and Methods. 139 consecutive RA patients (115 females and 34 males; median age 65.8 years) were selected. Bone mineral density (BMD) was measured by dual energy x-ray absorptinometry at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) and the presence of bone erosions was evaluated by conventional X-ray. ER-α gene polymorphisms were determined by PvuII and XbaI restriction endonuclease digestion of polymerase chain reaction (PCR) products. By convention, the presence of the endonuclease restriction site was indicated with lowercase (p and x) letters while the absence of the restriction site was indicated with uppercase letters (P and X). OPG gene polymorphism was determined by RsaI restriction endonuclease digestion of PCR products and the presence and absence of restriction fragment was identified as TT and CC respectively.Results. Pearson's χ(2)analysis for the ER-α gene polymorphism showed a prevalence of Pp genotype (58%) (p=0.04) and Xx (54%) (p=0.04) in the total population, without differences between males and females. We did not observed any significant differences between ER-α genotypes and LS-BMD. However subjects with xx or pp genotype had a lower LS-BMD in comparison with the opposite genotype.For OPG gene polymorphism, non significant differences in the distribution of the genotypes were observed between males and females. In addition, we did not observed significant differences on LS-BMD between the genotypes.Finally, we observed that patients with ER-α pp genotype was significant more represented in patients with hand erosions (p = 0.05). No significant correlation was observed for ER-α XbaI genotype, however a trend characterized by a correlation between xx and hand erosions was observed (p = 0.13). For OPG gene polymorphism, we found a statistical correlation between C allele of OPG and hands bone erosions (p = 0.02).Conclusion. We found a significant association between ER-α and OPG gene polymorphisms and the presence of bone erosions in RA patients. These preliminary data suggest a role of ER-α and OPG gene polymorphisms in bone turnover and disease progression.

Calcitonin (CT) is a polypeptide hormone with 32 aminoacids syntetized primarily by the thyroid.Several evidences support the existence of nonthyroidal CT like peptide. The CT gene transcript also encodes a distinct peptide known as calcitonin gene related peptide (CGRP) which is a potent vasodilator and responsible for the stimulation of the glomerular filtration rate. In addition, a 37 aminoacid peptide amylin has been originally isolated by pancreatic β-cells. Amylin is able to inhibit insulin secretion, glucose transport into the skeletal musculature and gluconeogenesis. It is also able to inhibit gastric emptying. In the kidney it is able to modulate Calcium (Ca(2+)) excretion and increases renin activity. Finally, high affinity amylin receptors have been identified in the brain of the rat. The calcitonin receptor (CTR) is a member of a subfamily of the seven-transmembrane domain G-protein coupled receptor super family that includes several peptides. Members of this family have a similar structure with other seven-membrane-spanning domain G-protein coupled receptors.The genetic contribution to osteoporosis susceptibility is well documented and many studies demonstrated that genetic factors play important roles in the regulation of bone metabolism. Restriction Fragment Length Polymorphisms (RFLPs) for the CTR gene have been described in the literature with a positive association with the lumbar bone mineral density (BMD), femoral neck BMD and with a lower incidence of vertebral fractures.

Diabetes mellitus and osteoporosis are two frequent multifactorial medical conditions with an increasing prevalence in the aging population. Patients with type 2 diabetes mellitus have an increased fracture risk despite a higher bone mineral density (BMD), which is mainly due to the increased risk of falls. Adequate glycemic control and prevention of diabetic complications are also the mainstay of therapy in type 2 diabetes mellitus. The thiazolidinediones (TZDs) have been demonstrated to improve insulin sensitivity and currently represent a widely prescribed treatment for type 2 diabetes. Their action is mediated by the binding to the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor- γ (PPAR- γ), regulating the activity of other transcription factors in the adipogenic differentiation and inflammatory response pathways. The activation of PPAR- γ by TZDs may also cause an increase in bone marrow adiposity and a decrease in osteoblastogenesis, resulting in reduced bone formation. Clinical data are pointing out that the intake of thiazolidinediones by older patients with type 2 diabetes correlates with both the decrease of bone mineral density in the femoral neck and hip and a higher risk for fractures. Thus, health care providers, not only physicians, should carefully check the existence of risk factors for osteoporosis and factures in their patients before selecting them for thiazolidinediones treatment. Moreover, an adequate clinical follow-up of treated subjects is strongly recommended.

The avascular necrosis of bone is characterized by an abnormality of tissue that can occur whenever a disease process causes major cell stress. Some evidence supports a role for genetic factors in some avascular necrosis suggesting that gene mutations could play a role in the pathogenesis of osteonecrosis. These genetic studies provide hope that tools for identifying high risk patients will be available in the future.