Margaret Seton

Osteosarcoma in Paget's Disease of Bone

Pagets disease of bone (PDB) is a focal disorder of bone metabolism first described by Sir James Paget in 1876. It is presumed benign in nature and mediated by abnormal osteoclast function. The incidence of osteosarcomas complicating PDB is estimated at <1%. These cancers occur mostly in persons with long‐standing, polyostotic disease and affect patients in their seventh decade or when osteosarcoma is remarkably rare in the general population. Epidemiological studies suggest that this late peak of osteosarcomas is absent in regions where Pagets is infrequently reported. Whereas PDB has a predilection for the axial skeleton, skull, femurs, and tibias, pagetic osteosarcoma tend to spare the spine, and are reported more commonly in the pelvis, femur, humerus, and skull. A molecular basis for the association of osteosarcoma with Pagets disease is unclear. These osteosarcomas are osteogenic in origin, consistently arise in sites of pagetic bone, and may present as metachronous, multifocal lesions. On histopathology, the lesions are usually osteoblastic, and the tumor phenotype is sometimes characterized as an exaggerated, chaotic form of the accelerated bone remodeling that characterizes PDB. New insights from the biology of adolescent osteosarcomas, VCP and SQSTM1 mutations now defined in patients with Pagets disease, and emerging evidence that stromal lesions are present in patients with Pagets disease are changing the way we think about the pathogenesis of PDB and the rare complication of pagetic osteosarcomas.

Analysis of environmental factors in familial versus sporadic Paget's disease of bone: the New England Registry for Paget's disease of bone

A registry for Pagets Disease (PD) was created to study the environmental and familial features of this disorder. This study examines the first 202 people enrolled. Those with a family history of PD (20%) suffered earlier deformity and fracture, and tended to have grandparents born abroad. These findings suggest heritage is important in PD; the role of environment remains unclear.

Somatic Mutations in SQSTM1 Detected in Affected Tissues From Patients With Sporadic Paget's Disease of Bone

Pagets disease of bone (PDB) is a focal disorder of bone remodeling that leads to overgrowth of affected bone, with rare progression to osteosarcoma. Extensive studies of familial PDB showed that a majority of cases harbor germline mutations in the Sequestosome1 gene (SQSTM1). In contrast, little is known about the mutational status of SQSTM1 in sporadic PDB. We hypothesized that somatic SQSTM1 mutations might occur in the affected tissues of sporadic PDB and pagetic osteosarcoma. We used laser capture microdissection to capture homogeneous populations of cells from the affected bone or tumor of patients with sporadic PDB or pagetic osteosarcoma, respectively. DNA from these samples and appropriate controls was used for sequence analysis and allelic discrimination analysis. Two of five patients with sporadic PDB had SQSTM1C1215T mutations detected in their affected bone but not in their blood samples, indicating a somatic origin of the mutations. Samples from three of five sporadic pagetic osteosarcoma patients had the SQSTM1C1215T mutation, whereas the normal adjacent tissue from two of these tumors clearly lacked the mutation, again indicating an occurrence of somatic events. No SQSTM1 mutations were found in primary adolescent osteosarcomas. The discovery of somatic SQSTM1 mutations in sporadic PDB and pagetic osteosarcoma shows a role for SQSTM1 in both sporadic and inherited PDB. The discovery of somatically acquired mutations in both the diseased bone and tumor samples suggests a paradigm shift in our understanding of this disease.

Should bisphosphonates be used for long‐term treatment of glucocorticoid‐induced osteoporosis?

Skeletal mass is a reflection of the relative activities of bone synthesizing osteoblasts and resorbing osteoclasts. When the activity of the latter supersedes that of the former, bone loss occurs, which if profound, eventuates into osteoporosis (1). While their clinical manifestations may be similar, the causes of osteoporosis are many, the most common attending menopause. Estrogen-deficiency typically prompts a high turnover form of osteoporosis in which both formation and resorption are accelerated but the relative activity of the osteoclast is greater than that of the osteoblast (2–3). Thus, suppression of the osteoclast using hormone replacement was standard of care for decades. With the realization that estrogens increase risk of breast cancer and cardiovascular complications in older women, bisphosphonates have become the most common treatment for post-menopausal osteoporosis. Given the absolute increase in osteoclast activity in estrogen-deficient osteoporosis, the effectiveness of bisphosphonates is not surprising. Alendronate, for example, maintains bone mass and reduces fracture risk of post-menopausal, osteoporotic women for as long as a decade with minimal complications in the great majority of patients (4).

Third generation bisphosphonates for treatment of sensorineural hearing loss in otosclerosis

Objective To evaluate hearing outcomes in patients treated with third generation bisphosphonates for otosclerosis-related sensorineural hearing loss (SNHL). Hypothesis Otosclerosis is a disease of abnormal bone remodeling in the otic capsule. In recent years, third generation bisphosphonates, with more powerful anti-resorptive properties and increased bone affinity, have demonstrated effectiveness in the treatment of osteoporosis and other metabolic bone diseases. We hypothesized that newer generation bisphosphonates, such as risedronate and zoledronate, would be effective in slowing the progression of SNHL in patients with otosclerosis. Study Design Retrospective review. Setting Tertiary referral center, ambulatory care. Interventions Risedronate or zoledronate administration. Main Outcome Measures Bone conduction pure tone threshold averages (PTAs) and word recognition (WR) scores were examined for each ear before and after bisphosphonate treatment. Criteria for significant change were defined as greater than 10 decibels in PTA or between 4% and 18% in WR based on binomial variance. Results All 10 patients had audiometric progression of SNHL in the pretreatment monitoring interval and 12 ears met criteria for significant progression. All 10 patients (19 ears) showed at least no significant progression of SNHL (i.e., stabilization) at an average follow-up of 13 months. Two patients (3 ears) showed improvement by defined audiometric criteria. There were no major complications. Conclusion Treatment with zoledronate or risedronate stabilized progressive SNHL related to otosclerosis in this small group of patients. Further evaluation of third-generation bisphosphonate treatments is warranted.

Paget's disease of bone: the skeletal distribution, complications and quality of life as perceived by patients.

CONTEXT Pagets disease of bone (PDB) is a focal disorder of bone metabolism with overgrowth of affected bone resulting in the skeletal complications of this disease. OBJECTIVE This study examines what patients know about the skeletal distribution of their PDB, and correlates this with their reports of complications and quality of life. DESIGN The New England Registry for PDB (NRPD) is a voluntary registry with a questionnaire linked to a radiographic database. Data were collected by mail beginning in 2001. SETTING Ambulatory population. PATIENTS Any patient with PDB living in New England was eligible to enroll; 285 elected to participate, mean age 73.2 years. MAIN OUTCOME MEASURES Patients were asked what bones were affected by PDB, and whether they suffered complications from PDB. Radiographic studies were sought to corroborate their responses. An SF-12 was administered. RESULTS Compared to the general population, they reported substantially lower levels of physical health (Physical Component Score (PCS) mean=40), and slightly better mental health (Mental Component Score (MCS) mean=52). There were more instances of agreement on disease presence and fewer instances on disagreement (p=0.001). Radiographic studies supported the presence of a complication from PDB when deformity, fracture and joint replacement had occurred, but were less correlative when headache or hearing loss was reported. CONCLUSIONS Most patients with PDB are aware of the skeletal distribution of their disease; there is a reasonable correlate between complications ascribed to PDB and the presence of PDB on the radiograph except when headache or hearing loss is reported.

Autosomal dominant hypophosphatemic rickets in an 85 year old woman: Characterization of her disease from infancy through adulthood

BACKGROUND Autosomal dominant hypophosphatemic rickets (ADHR) is a rare genetic disorder of phosphate homeostasis characterized, when severely expressed, by osteomalacia, suppressed levels of calcitriol, and renal phosphate wasting due to elevated levels of fibroblast growth factor 23 (FGF23). The disease is caused by heterozygous FGF23 mutations at the RXXR site that prevent cleavage of the intact hormone. OBJECTIVES An FGF23 mutation was identified in the proband an 85-year-old woman with elevated FGF23 levels, and her clinical course was characterized. Medical records revealed she was treated for rickets as an infant. She was then asymptomatic until soon after her 4th pregnancy, when she suffered incapacitating bone pain and weakness, age 37. Symptoms remitted with brief treatment. RESULTS The proband and one son, but not other family members, were found to be heterozygous for the R176Q mutation in FGF23. Expression of this germ line mutation was strikingly different in both individuals in terms of skeletal health, FGF23 levels and disease activity. CONCLUSIONS The identified FGF23 mutation in two members of this family raises questions about molecular mechanisms that have led to intermittent increases in FGF23 synthesis and secretion, and disease expression.

Low 25-Hydroxyvitamin D and Osteopenia Are Prevalent in Persons ≥55 Yr With Fracture at Any Site: A Prospective, Observational Study of Persons Fracturing in the Community

Ethnic diversity and lower socioeconomic populations are poorly captured in most studies of osteoporosis and fracture risk. This article describes a prospective, observational study designed to analyze risk factors for fracture in an ambulatory, ethnically diverse, urban population aged > or =55 yr. The goal of the study was to determine the number of fractures associated with hypovitaminosis D (< or =15 ng/mL serum 25-hydroxyvitamin D) and osteopenia (T-score <-1.5) by bone mineral density (BMD). From January 1 to July 31, 2001, we identified 262 persons who fractured in our community; 83 chose to enroll in the study. Enrolled patients had a BMD examination at two sites; their blood was drawn for 25-hydroxyvitamin D (25VitD), calcium, phosphorus, albumin, and alkaline phosphatase. At the completion of the study a letter was sent to the patients detailing the findings, and a copy sent to their physician. Of the 83 persons enrolled, 73 (88%) had evidence of osteopenia or osteoporosis (T-score <-1.5) and/or low 25VitD. All fractures in the community in person > or =55 yr, with or without a history of antecedent trauma, should be assessed with BMD and screening for 25VitD.

Case 26-2013: A 46-Year-Old Woman with Muscle Pain and Swelling

Dr. Luke A. Neilans (Medicine): A 46-year-old woman was seen in the emergency department at this hospital because of muscle pain and swelling in her arms and lower legs. The patient had been well until approximately 3 weeks before admission, when a deep ache developed in her left triceps, in the absence of trauma. During the following weeks, the pain persisted, gradually spreading to both arms and both legs, and was exacerbated by movement; she began having difficulty rising from chairs and climbing stairs because of pain. Two weeks before admission, examination by her primary care physician at another hospital reportedly revealed no focal muscle weakness. Red-cell indexes and blood levels of electrolytes, calcium, and glucose were normal, as were renal-function tests; testing for parvovirus B19 IgG and IgM antibodies was negative; other test results are shown in Table 1. Three days before admission, pain and swelling in the left arm worsened. She returned to the other hospital. Blood levels of alkaline phosphatase, direct and total bilirubin, total protein, albumin, and thyrotropin were normal, and testing for antibodies to the human immunodeficiency virus and Borrelia burgdorferi were negative; other test results are shown in Table 1. The patient returned home, with persistent symptoms. Three days later, she came to the emergency department at this hospital. The patient reported restricted range of motion of her arms because of pain, as well as stiffness in her proximal arm muscles that was worse in the morning. She also reported intermittent nondrenching night sweats that she attributed to menopause. She reported no muscle weakness, fever, chills, malaise, dysphagia, nasal regurgitation, synovitis, weight loss, numbness or tingling in her hands, shortness of breath, chest pain, changes in bowel or bladder function, nausea, vomiting, photosensitivity, or rash. A diagnosis of uterine fibroids with menorrhagia had been made 2 years earlier. Routine mammograms had been normal. Her only medication was megestrol acetate, taken midcycle (10 days per month). She had no known allergies. She was single, physically active, and had traveled widely. She drank alcohol in moderation, and she did not smoke or use illicit drugs. Her mother had had breast cancer at age 65 years, and her father had had a myocardial infarction at age 57 years. There was no family history of rheumatologic or neuromuscular disorders.

Case 26-2013

Dr. Luke A. Neilans (Medicine): A 46-year-old woman was seen in the emergency department at this hospital because of muscle pain and swelling in her arms and lower legs. The patient had been well until approximately 3 weeks before admission, when a deep ache developed in her left triceps, in the absence of trauma. During the following weeks, the pain persisted, gradually spreading to both arms and both legs, and was exacerbated by movement; she began having difficulty rising from chairs and climbing stairs because of pain. Two weeks before admission, examination by her primary care physician at another hospital reportedly revealed no focal muscle weakness. Red-cell indexes and blood levels of electrolytes, calcium, and glucose were normal, as were renal-function tests; testing for parvovirus B19 IgG and IgM antibodies was negative; other test results are shown in Table 1. Three days before admission, pain and swelling in the left arm worsened. She returned to the other hospital. Blood levels of alkaline phosphatase, direct and total bilirubin, total protein, albumin, and thyrotropin were normal, and testing for antibodies to the human immunodeficiency virus and Borrelia burgdorferi were negative; other test results are shown in Table 1. The patient returned home, with persistent symptoms. Three days later, she came to the emergency department at this hospital. The patient reported restricted range of motion of her arms because of pain, as well as stiffness in her proximal arm muscles that was worse in the morning. She also reported intermittent nondrenching night sweats that she attributed to menopause. She reported no muscle weakness, fever, chills, malaise, dysphagia, nasal regurgitation, synovitis, weight loss, numbness or tingling in her hands, shortness of breath, chest pain, changes in bowel or bladder function, nausea, vomiting, photosensitivity, or rash. A diagnosis of uterine fibroids with menorrhagia had been made 2 years earlier. Routine mammograms had been normal. Her only medication was megestrol acetate, taken midcycle (10 days per month). She had no known allergies. She was single, physically active, and had traveled widely. She drank alcohol in moderation, and she did not smoke or use illicit drugs. Her mother had had breast cancer at age 65 years, and her father had had a myocardial infarction at age 57 years. There was no family history of rheumatologic or neuromuscular disorders.