Bone Quality in Paget’s Disease of Bone

Paget’s disease of bone is produced by a localized increase in osteoclastic and osteoblastic activity which can progress slowly to involve an entire bone if untreated. A common feature is enlarged bones which are deformed, particularly in weight-bearing regions of the skeleton such as the lower extremity. Pathologic fractures may be a consequence, and nonunion of femoral fractures is not uncommon. Analyses of bone biopsies from patients with Paget’s disease indicate that there is a lower, heterogeneous degree of bone mineralization and a younger tissue age than that found in control bone. Pagetic bone also has less resistance to plastic deformation and a straighter crack path than control bone.     

Does Quantitative Ultrasound of Bone Reflect More Bone Mineral Density Than Bone Microarchitecture?

Relationships among quantitative ultrasound of bone (QUS), bone mineral density (BMD) and bone microarchitecture have been poorly investigated in human calcaneus.Twenty-four specimens, from 12 men and 12 women (mean age 78 +/- 10 years; range 53-93), removed from cadavers were studied. The feet were axially sectioned above the ankle. Two variables were measured for QUS (Achilles, Lunar): broadband ultrasound attenuation (BUA) and speed of sound (SOS). A third variable, the stiffness index (SI), which is a combination of both BUA and SOS, was also calculated. BMD (a lateral view) was measured on a QDR 2000 densitometer (Hologic). Bone microarchitecture was assessed by computed tomography (CT) using a conventional CT-system. Fifteen sagittal sections (1 mm in width and 2 mm apart) were selected for CT. Methods used for characterizing bone microarchitecture consisted in structural (trabecular network characterization) and a fractal analyses. The relationships between QUS and bone microarchitecture were assessed by simple linear regression analysis with and without adjustment for BMD (partial correlation) and by backward stepwise regression analysis. Strong relationships were found between BMD and QUS. Adjusted r(2) values were 0.545 for SOS and 0.717 for SI. Two microarchitectural variables were also significantly correlated with both SOS and SI: apparent trabecular separation (App Tr Sp) and trabecular bone pattern factor (App TBPF). After adjustment for BMD few correlations between QUS and microarchitectural variables were always significant. Adjusted squared semipartial coefficients of correlation (rsp2) values between SOS and bone microarchitecture were 6%, 6.8%, 13.2% and 4.6% for App BV/TV, App Tr Sp, App TBPF and fractal dimension (FD), respectively. For SI, corresponding figures were 3.7%, 4.1%, 5.2% and 3.2%. Backward stepwise regression analysis using BMD and microarchitecture showed a slight increase of r(2) values that varied from 8.4% for SI to 17.8% for SOS, compared with BMD alone. The current study suggests that although BMD is a major determinant of acoustic properties of human calcaneus, significant density independent relationships with bone microarchitecture should also be taken into account.     

Does Quantitative Ultrasound of Bone Reflect More Bone Mineral Density Than Bone Microarchitecture?

Relationships among quantitative ultrasound of bone (QUS), bone mineral density (BMD) and bone microarchitecture have been poorly investigated in human calcaneus. .Twenty-four specimens, from 12 men and 12 women (mean age 78 ± 10 years; range 53–93), removed from cadavers were studied. The feet were axially sectioned above the ankle. Two variables were measured for QUS (Achilles®, Lunar): broadband ultrasound attenuation (BUA) and speed of sound (SOS). A third variable, the stiffness index (SI), which is a combination of both BUA and SOS, was also calculated. BMD (a lateral view) was measured on a QDR 2000 densitometer (Hologic). Bone microarchitecture was assessed by computed tomography (CT) using a conventional CT-system. Fifteen sagittal sections (1 mm in width and 2 mm apart) were selected for CT. Methods used for characterizing bone microarchitecture consisted in structural (trabecular network characterization) and a fractal analyses. The relationships between QUS and bone microarchitecture were assessed by simple linear regression analysis with and without adjustment for BMD (partial correlation) and by backward stepwise regression analysis. Strong relationships were found between BMD and QUS. Adjusted r² values were 0.545 for SOS and 0.717 for SI. Two microarchitectural variables were also significantly correlated with both SOS and SI: apparent trabecular separation (App Tr Sp) and trabecular bone pattern factor (App TBPF). After adjustment for BMD few correlations between QUS and microarchitectural variables were always significant. Adjusted squared semipartial coefficients of correlation (rs_p²) values between SOS and bone microarchitecture were 6%, 6.8%, 13.2% and 4.6% for App BV/TV, App Tr Sp, App TBPF and fractal dimension (FD), respectively. For SI, corresponding figures were 3.7%, 4.1%, 5.2% and 3.2%. Backward stepwise regression analysis using BMD and microarchitecture showed a slight increase of r² values that varied from 8.4% for SI to 17.8% for SOS, compared with BMD alone. The current study suggests that although BMD is a major determinant of acoustic properties of human calcaneus, significant density independent relationships with bone microarchitecture should also be taken into account.     

Genetics of Paget’s Disease of Bone

Paget’s disease of bone (PDB) is a common condition, which is characterised by focal areas of increased and disorganized bone remodeling. Genetic factors play an important role in the disease. In some cases, Paget’s disease is inherited in an autosomal dominant manner and the most common cause for this is a mutation in the SQSTM1 gene. Other familial cases have been linked to the OPTN locus on Chromosome 10p13 and still other variants have been identified by genome wide association studies that lie within or close to genes that play roles in osteoclast differentiation and function. Mutations in TNFRSF11A, TNFRSF11B and VCP have been identified in rare syndromes with PDB-like features. These advances have improved understanding of bone biology and the causes of PDB. The identification of genetic markers for PDB also raises the prospect that genetic profiling could identify patients at high risk of developing complications, permitting enhanced surveillance and early therapeutic intervention.     

Are Bone Turnover Markers Capable of Predicting Callus Consolidation During Bone Healing?

The aim of this study was to determine the ability of the following bone turnover markers to monitor the course of callus consolidation during bone healing: Carboxy-terminal propeptide of procollagen type I (PICP), skeletal alkaline phosphatase (sALP), and amino-terminal propeptide of type III procollagen (PIlINP). Since interfragmentary movements have been proven to possess the ability to document the progression of bone healing in experimental studies, correlations between bone turnover markers and interfragmentary movements in vivo were investigated. Therefore, two different types of osteosyntheses representing different mechanical situations at the fracture site were compared in an ovine osteotomy model. Blood samples were taken preoperatively and postoperatively in weekly intervals over a nine-week healing period. At the same intervals, interfragmentary movements were measured in all sheep. After nine weeks, animals were sacrificed and the tibiae were evaluated both mechanically and histologically. Wide interindividual ranges were observed for all bone turnover markers. The systemic PICP level did not increase with callus consolidation. The bone-healing model seemed to influence the systemic level of PIIINP and sALP but no general correlation between bone turnover markers and interfragmentary movements could be detected. No differences between the different types of osteosyntheses and thus the different mechanical situations were observed. All analyzed markers failed as general predictors for the course of callus consolidation during bone healing.     

Giant Cell–Containing Tumors of Bone

Giant cell–containing tumors of bone are characterized morphologically by the presence of numerous osteoclastic giant cells. Correlation of clinical, radiologic, and laboratory findings is required for accurate histopathologic diagnosis and treatment of a giant cell–containing tumor of bone. In differential diagnosis, it is particularly important to note the age of the patient and the skeletal location of the lesion. This article considers the range of neoplastic and nonneoplastic lesions, which histologically contain numerous osteoclastic giant cells, and focuses on several lesions that frequently enter into the differential diagnosis.     

Repairing of goat Tibial Bone Defects with BMP-2 Gene–Modified Tissue-Engineered Bone

Bone defects larger than a critical size are major challenges in orthopedic medicine. We combined tissue-engineered bone and gene therapy to provide osteoprogenitor cells, osteoinductive factors, and osteoconductive carrier for ideal bone regeneration in critical-sized bone defects. Goat diaphyseal bone defects were repaired with tissue and genetically engineered bone implants, composed of biphasic calcined bone (BCB) and autologous bone marrow derived mesenchymal stem cells (BMSC) transduced with human bone morphogenetic protein-2 (hBMP-2). Twenty six goats with tibial bone defects were divided into groups receiving implants by using a combination of BCB and BMSCs with or without the hBMP-2 gene. In eight goats that were treated with BCB that contained hBMP-2 transduced BMSC, five had complete healing and three showed partial healing. Goats in other experimental groups had only slight or no healing. Furthermore, the area and biochemical strength of the callus in the bone defects were significantly better in animals treated with genetically engineered implants. We concluded that the combination of genetic and tissue engineering provides an innovative way for treating critical-sized bone defects.     

Osteonecrosis of the Jaw—a Bone Site-Specific Effect of Bisphosphonates

A known complication that can occur in patients using bisphosphonates (BPs) is osteonecrosis of the jaw (ONJ). ONJ features bone exposure that may be associated with severe pain, swelling, local infection, and pathological fracture of the jaw. Current literature indicates that a complex combination of factors is necessary to induce ONJ. Several hypotheses about the pathophysiology of ONJ were previously reported. Here, we review these hypotheses and introduce new ideas and suggestions on this topic, focusing on bone site-specific cells, and the effect that BPs and other anti-resorptive drugs have on those cells. Gaining more insight into bone site-specific effects may help to better understand the pathogenesis ONJ, and contribute to the development of new bone site-specific anti-resorptive drugs.     

SQSTM1 and Paget’s Disease of Bone

Mutations in the Sequestosome 1 gene (SQSTM1; also known as p62) have recently been identified as the cause of 5q35-linked Pagets disease of bone (PDB). All of the mutations identified to date affect the ubiquitin-associated (UBA) domain of SQSTM1, a region of the protein that binds noncovalently to ubiquitin. In this review we consider the possible functional significance of the SQSTM1-ubiquitin interaction, and consequences of the SQSTM1 UBA domain mutations. Clarification of the in vivo roles of SQSTM1 in bone-cell function will be central to improving our understanding of the molecular pathogenesis of PDB and related conditions.     

A Combination of Low Doses of 17β-Estradiol and Norethisterone Acetate Prevents Bone Loss and Normalizes Bone Turnover in Postmenopausal Women

The effects of 17β-estradiol (E₂) 1 mg combined with low doses of norethisterone acetate (NETA) on postmenopausal bone loss and turnover were investigated in a 2-year, randomized, double-masked, placebo-controlled trial. A total of 135 postmenopausal women with a lumbar spine bone mineral density (BMD) T-score between −2 and +2 were randomized to daily treatment with an oral tablet of either placebo, E₂ 1 mg/NETA 0.25 mg, or E₂ 1 mg/NETA 0.5 mg. Significant (p<0.001) increases in BMD at the lumbar spine (L1–4) were observed with E₂ 1 mg/NETA 0.25 mg (5.2%) and E₂ 1 mg/NETA 0.5 mg (5.4%) compared with placebo (−0.9%). The total hip BMD increased significantly in the E₂ 1 mg/NETA 0.25 mg (3.1%) and E₂ 1 mg/NETA 0.5 mg groups (3.3%) compared with placebo. At the femoral trochanter, the increase in BMD in the E₂ 1 mg/NETA 0.5 mg group (6.3%) was significantly different from the placebo group (0.8%), while that in the E₂ 1 mg/NETA 0.25 mg group (3.3%) was not. No statistical differences were found between the active groups and placebo for the change in BMD at the femoral neck. Significant increases in BMD at the distal radius and total body were found for both E₂ 1 mg/NETA 0.25 mg (0.9% and 2.5%, respectively) and E₂ 1 mg/NETA 0.5 mg (2.1% and 3.0%, respectively) compared with placebo (−0.7% and 0.4%, respectively).  At the end of the treatment, urinary pyridinoline type I collagen C-telopeptide had decreased by 65% and 60% in the E₂ 1 mg/NETA 0.25 mg and E₂ 1 mg/NETA 0.5 mg groups, respectively, while the mean serum concentrations of osteocalcin had decreased by 39% and 34%, bone-specific alkaline phosphatase by 32% and 29%, and C-terminal propeptide of type I collagen by 21% and 19% had decreased by 34-39%, 29-32%, and 19-21% in the E₂ 1 mg/NETA 0.25 mg and E₂ 1 mg/NETA 0.25 mg groups, respectively.  In conclusion, combinations of E₂ 1 mg and NETA 0.25 or 0.5 mg prevent bone loss in postmenopausal women at the lumbar spine, hip, distal radius and total body, and normalize bone turnover. Received: 12 March 1998 / Accepted: 31 August 1999     

A Comparison between Xenogenic Deproteinized Bone Substitute Pyrost? and Autologous Bone Graft in the Surgical Management of Simple Bone Cysts

Background: The basic principle of surgical treatment of simple bone cysts has remained unchanged over the years, with curettage followed by packing of the defect with autogenic bone graft. With the introduction of ceramic biomaterials, an alternative packing material is available, avoiding the complications associated with cancellous bone harvesting or the use of a bioceramic implant. The aim of this study was to compare bony union and recurrence rate after packing of surgically treated simple bone cysts with either Pyrost^® or autogenic spongiosa. Patients and Methods: 58 patients with simple bone cysts were treated by curettage followed by packing of the cavity with either high-porosity hydroxyapatite (Pyrost^®) inoculated with locally aspirated autogenic bone marrow (n = 26) or autogenic spongiosa (n = 32). Minimum X-ray follow-up was 36 months. Results: No recurrence of the bone cyst was seen in 44 (75.9%) patients. According to Neer's criteria, complete obliteration was observed in 43.1% and residuals were found in 53.4%. The remaining 3.4% required subsequent operation due to recurrence. Entire packing of the cavity with xenogenic deproteinized bone substitution was radiologically confirmed in 80.8%. There were no significant differences (p = 0,76) between the use of autogenic spongiosa and the xenogenic deproteinized bone substitute concerning the rate of recurrency and radiographically verified complete bone consolidation. Conclusions: Pyrost^® can be considered an alternative to conventional bone grafting in the treatment of simple bone cysts. The primary advantages of bone substitute materials ar their abundance and the avoidance of morbidity associated with bone harvesting. Questions concerning long-term biocompatibility and biomechanical aspects of the composite of unabsorbed bone substitute and bone warrant further investigation.     

Radioprotectant and Radiosensitizer Effects on Sterility of γ-irradiated Bone

Gamma radiation is widely used to sterilize bone allografts but may impair their strength. While radioprotectant use may reduce radiation damage they may compromise sterility by protecting pathogens. We assessed the radioprotective potential of various agents (L-cysteine, N-acetyl-L-cysteine, L-cysteine-ethyl-ester and L-cysteine-methyl-ester) to identify those which do not protect spores of Bacillus subtilis. We hypothesized charge of these agents will affect their ability to radioprotect spores. We also determined ability of these radioprotectants and a radiosensitizer (nitroimidazole-linked phenanthridinium) to selectively sensitize spores to radiation damage by intercalating into the nucleic acid of spores. Spores were treated either directly in solutions of these agents or treated after being embedded and sealed in bone to assess the ability of these agents to diffuse into bone. L-cysteine and L-cysteine-ethyl-ester did not provide radioprotection. Positively charged L-cysteine-methyl-ester protected the spores, whereas positively charged L-cysteine-ethyl-ester did not, indicating charge does not determine the extent of radioprotection. The spores were sensitized to radiation damage when irradiated in nitroimidazole-linked phenanthridinium solution and sensitization disappeared after rinsing, suggesting nitroimidazole-linked phenanthridinium was unable to intercalate into the nucleic acid of the spores. Some cysteine-derived radioprotectants do not shield bacterial spores against gamma radiation and may be suitable for curbing the radiation damage to bone grafts while achieving sterility. One or more of the authors (OA, JS, SAK) has received funding from a research grant from the Musculoskeletal Transplant Foundation.     

Ewing’s Family of Tumors of the Sinonasal Tract and Maxillary Bone

The Ewing’s family of tumors (EFT) are malignant neoplasms affecting children and young adults. Most cases arise in the long bones or the pelvis. Primary EFT of head and neck is uncommon and primary sinonasal EFT is even rarer. Previous studies have not focused on the sinonasal region specifically, and the published literature on sinonasal EFT consists of sporadic case reports. Fourteen cases of sinonasal EFT were available and had H&Es for review and immunohistochemical stains for CD99, S100, keratins, synaptophysin and desmin. FISH or RT-PCR was performed for EWSR1 abnormalities on 8 cases. The 14 identified patients included 5 males and 9 females, ranging from 7–70 years of age (mean 32.4 years). Tumors involved nasal cavity (5), sinuses (5) or both (4). Five patients had dural, orbital or brain involvement. The majority involved bone radiologically and/or microscopically. All cases were composed of small cells with variable cytoplasmic clearing. Focal or prominent nesting was noted in most cases. All cases were positive for CD99. Keratins (AE1/3 and/or CAM5.2), S100 and synaptophysin were positive in 4, 3 and 5 cases, respectively. All cases were negative for desmin. The 8 cases tested by FISH or RT-PCR were positive for EWSR1 abnormalities. Follow-up in 8 patients ranged from 1–168 months (average 11.3 m) showing 1 death due to metastatic disease, 1 death due to local disease, 1 patient alive with metastases and 5 patients disease-free at last follow-up. Interestingly, however, an analysis of the literature suggests a better prognosis for sinonasal EFT than EFT overall.     

Increased Arterial Calcification in Paget’s Disease of Bone

When examining radiographs of patients with Paget’s disease of bone (PD), we often observed calcification of the aorta and iliac or femoral arteries. The processes of extraosseous calcification or mineralization are very close to the mechanisms regulating mineralization of bone tissue. The aim of our study was to quantify the number, extent (length and thickness), and type (arteriosclerotic or medial arterial calcification) of vascular calcification in patients with Paget’s disease and to compare them with those of controls, in order to discover whether PD is accompanied by increased calcification. Vascular calcification was quantified on the aorta, the iliac arteries, and their branches, the femoral, gluteal, and pelvic arteries of 42 patients with Paget’s disease and 36 control subjects. Of the PD subjects, 52.4% had arteriosclerotic calcification versus 30.6% of controls (P = 0.05), and 38.6% of PD patients had medial arterial calcification versus 11.1% of controls (P = 0.05). The mean length of calcification was greater in PD patients: 1.93 ± 2.85 cm versus 0.84 ± 1.69 cm in controls (P = 0.04). The thickness of calcification was also greater in PD patients: 1.24 ± 1.30 mm versus 0.56 ± 0.94 mm (P = 0.01). Patients with Paget’s disease more frequently had medial arterial or arteriosclerotic calcification than controls. These calcifications were longer and thicker. Our clinical study therefore confirms that abnormal vessel wall calcification and bone remodeling in Paget’s disease are probably linked, although the mechanism of this relation is as yet unexplained.     

Effects of Nicotine Administration and Nicotine Cessation on Bone Histomorphometry and Bone Biomarkers in Sprague–Dawley Male Rats

Nicotine is a major alkaloid of tobacco, which can increase free radical formation, leading to osteoporosis. The effects of nicotine administration and cessation on bone histomorphometry and biomarkers were studied in 28 Sprague–Dawley male rats. Rats aged 3 months and weighing 250–300 g were divided into four groups: control (C, normal saline for 4 months), nicotine for 2 months (N2), nicotine for 4 months (N4), and nicotine cessation (NC). The NC group was given nicotine for the first 2 months and then allowed to recover for the following 2 months without nicotine. Histomorphometric analysis was done using an image analyzer. ELISA kits were used to measure serum osteocalcin (bone formation marker) and pyridinoline (PYD, bone resorption marker) levels at month 0, month 2, and month 4. All test groups showed a significant decrease in BV/TV, Ob.S/BS, dLS/BS, MAR, BFR/BS, and osteocalcin levels and an increase in sLS/BS and PYD levels compared to group C. No significant differences were observed in all parameters measured among the test groups, except for MAR and BFR/BS. In conclusion, nicotine administration at a dose of 7 mg/kg for 2 and 4 months has detrimental effects on bone metabolism. Nicotine administration at 7 mg/kg for 2 months is sufficient to produce significant effects on bone histomorphometric parameters and biomarkers. In addition, prolonging the treatment for another 2 months did not show any significant differences. Cessation of nicotine for 2 months did not reverse the effects.