Stefan Breer

Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.

Morphologic Analysis of Periprosthetic Fractures After Hip Resurfacing Arthroplasty

BACKGROUND Periprosthetic fractures have long been recognized as one of the major complications of hip resurfacing arthroplasty. The objective of this study was to develop a systematic and morphologic classification of the fracture mode based on pathogenesis. METHODS One hundred and seven retrieved specimens consisting of the femoral remnant and the femoral component of a total hip resurfacing arthroplasty that had failed as a result of a periprosthetic fracture were analyzed with regard to the morphologic failure mode. The location of the fracture line was used to differentiate the fractures. The fractures were also classified histopathologically as acute biomechanical, acute postnecrotic, or chronic biomechanical. RESULTS Fifty-nine percent (sixty-three) of the fractures occurred within the bone inside the femoral component. Fifty-one percent (fifty-five) of the fractures were classified morphologically as acute postnecrotic; 40% (forty-three), as chronic biomechanical; and 8% (nine), as acute biomechanical. Acute biomechanical fractures were found exclusively in the femoral neck and occurred earlier (mean time [and standard deviation] between implantation and revision, 41 +/- 57 days) than acute postnecrotic fractures (mean time between implantation and revision, 149 +/- 168 days; p = 0.002) or chronic biomechanical fractures (mean time between implantation and revision, 179 +/- 165 days; p = 0.001). The latter two fracture types both occurred predominantly in the bone inside the femoral component. CONCLUSIONS Three distinct fracture modes were characterized morphologically. Osteonecrosis was the most frequent cause of fracture-related failures. We suggest that an intraoperative mechanical injury of the femoral neck such as notching and/or malpositioning of the femoral component might lead to changes in the loading pattern or in the resistance to fracture of the femoral neck and may result in both acute and chronic biomechanical femoral neck fractures. These findings may serve as feedback information for the surgeon and possibly influence future therapeutic strategies.

68Ga DOTA-TATE PET/CT allows tumor localization in patients with tumor-induced osteomalacia but negative 111In-octreotide SPECT/CT

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia and low calcitriol levels as well as clinical symptoms like diffuse bone and muscle pain, fatigue fractures or increased fracture risk. Conventional imaging methods, however, often fail to detect the small tumors. Lately, tumor localization clearly improved by somatostatin-receptor (SSTR) imaging, such as octreotide scintigraphy or octreotide SPECT/CT. However, recent studies revealed that still a large number of tumors remained undetected by octreotide imaging. Hence, studies focused on different SSTR imaging methods such as 68Ga DOTA-NOC, 68Ga DOTA-TOC and 68Ga DOTA-TATE PET/CT with promising first results. Studies comparing different SSTR imaging methods for tumor localization in TIO are rare and thus little is known about diagnostic alternatives once a particular method failed to detect a tumor in patients with TIO. Here, we report the data of 5 consecutive patients suffering from TIO, who underwent both 111Indium-octreotide scintigraphy (111In-OCT) SPECT/CT as well as 68Ga DOTA-TATE PET/CT for tumor detection. While 111In-OCT SPECT/CT allowed tumor detection in only 1 of 5 patients, 68Ga DOTA-TATE PET/CT was able to localize the tumor in all patients. Afterwards, anatomical imaging of the region of interest was performed with CT and MRI. Thus, successful surgical resection of the tumor was achieved in all patients. Serum phosphate levels returned to normal and all patients reported relief of symptoms within weeks. Moreover, an iliac crest biopsy was obtained from every patient and revealed marked osteomalacia in all cases. Follow-up DXA revealed an increase in BMD of up to 34.5% 1-year postoperative, indicating remineralization. No recurrence was observed. In conclusion our data indicates that 68Ga DOTA-TATE PET/CT is an effective and promising diagnostic tool in the diagnosis of TIO, even in patients in whom 111In-OCT prior failed to detect a tumor.

Intraosseous lymphocytic infiltrates after hip resurfacing arthroplasty : a histopathological study on 181 retrieved femoral remnants.

To identify a possible role of lymphocytic infiltrates in failure mechanism of the metal-on-metal hip resurfacing arthroplasty, the extent of lymphocytic infiltration was compared with reasons for prosthesis failure in a series of retrieval specimens. One hundred eighty-one femoral head and neck remnants were subjected to thorough analysis of histological findings and clinical data. Lymphocytic infiltrates were considered weak to moderate in 52 (28.7%) and excessive in ten (5.5%) cases. Six cases with excessive lymphocytic infiltrates belonged to the group of 33 (18.2%) revisions without obvious cause (periprosthetic fracture, component loosening, and infection) for prosthesis failure. Excessive lymphocytic infiltrates were strongly linked to the presence of proliferative desquamative synovitis (p < 0.0001). Both the excessive lymphocytic infiltrates and proliferative desquamative synovitis were associated with female gender (p < 0.05). We hypothesize that a specific cause of groin pain might be related to excessive intraosseous lymphocytic infiltrates and explained possibly by the hypersensitivity reaction of the delayed type after the hip resurfacing arthroplasty. Proliferative desquamative synovitis might constitute another morphologic feature associated with the delayed type hypersensitivity reaction.

Analysis of retrieved hip resurfacing arthroplasties reveals the interrelationship between interface hyperosteoidosis and demineralization of viable bone trabeculae

Retrieved hip resurfacing arthroplasties (HRA) revised for causes other than osteonecrosis enable further insights into bone–cement interactions within the interface with only minimal biomechanical stresses. Our primary objective was to investigate the mineralization changes at the trabecular bone interface in retrieved hips using bright field and polarized light microscopy and by quantitative backscattered electron imaging. Because superficial seams of non‐mineralized bone tissue varied substantially, we defined hyperosteoidosis as an osteoid seam of more than 20 µm thickness. We hypothesized that interface hyperosteoidosis might be caused by the demineralization of previously mineralized bone tissue. One hundred and thirty‐one retrieved HRAs with viable bone remnant tissue were analyzed. Bone mineral density distribution obtained from backscattered signal intensities of the trabecular bone at the bone–cement interface was assessed in cases with and without interface hyperosteoidosis. In cases with interface hyperosteoidosis, the degree of trabecular mineralization was also analyzed in deeper areas of the femoral remnants. Thirty‐four cases showed hyperosteoidosis at the bone–cement interface, mostly in female patients. Bone trabeculae with hyperosteoidosis displayed a mineral density distribution pattern suggestive of the demineralization of a previously mineralized bone matrix. Our results demonstrate the localized disorder of the mineralization pattern of bone trabeculae at the bone–cement interface in a group of retrieved HRAs. In previously well‐fixed femoral components, potential adverse effects on the load‐bearing bone due to a decreased degree of mineralization at the bone–cement interface may affect the durability of the implants function.

Vitamin D deficiency intensifies deterioration of risk factors, such as male sex and absence of vision, leading to increased postural body sway.

INTRODUCTION Due to inconsistent findings, the influence of vitamin D on postural body sway (PBS) is currently under debate. This study evaluated the impact of vitamin D on PBS with regards to different foot positions and eye opening states in community-dwelling older individuals. METHODS In a cross-sectional study, we assessed PBS in 342 older individuals (264 females [average age (± SD): 68.3 ± 9.0 years], 78 males [65.7 ± 9.6 years]). A detailed medical history and vitamin D level were obtained for each individual. Fall risk was evaluated using the New York-Presbyterian Fall Risk Assessment Tool (NY PFRA). PBS parameters (area, distance, velocity, frequency) were evaluated on a pressure plate with feet in closed stance (CS) or hip-width stance (HWS), open eyes and closed eyes. Statistical analysis included logarithmic mixed models for repeated measures with the MIXED model procedure to test the influence of vitamin D (categorized in <10 μg/l, 10-20 μg/l, 21-30 μg/l, >30 μg/l), foot position, eye opening state, age, sex and frequency of physical activity on PBS. RESULTS Vitamin D was not an independent risk factor for falls experienced in the last 12 months. Nonetheless, PBS was higher in patients with vitamin D deficiency (<10 μg/l) in HWS (A/P p=0.028 and area p=0.037). Additionally, vitamin D deficiency intensified the deleterious effects of male sex (distance p=0.002) and absence of vision (area p<0.001) on PBS. CONCLUSION Independent risk factors for increased PBS like male sex and absence of vision are additionally compromised by vitamin D deficiency.