Browsing by Subject "Bone histomorphometry"
Item A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation(Wiley, 2021-03-03) Coffman, Abigail A.; Basta-Pljakic, Jelena; Guerra, Rosa M.; Ebetino, Frank H.; Lundy, Mark W.; Majeska, Robert J.; Schaffler, Mitchell B.; Anatomy, Cell Biology and Physiology, School of MedicineBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE‐58025, risedronate, or PBS vehicle for 3 months to test effectiveness in preventing long‐term bone loss. Bone microarchitecture, histomorphometry, and whole‐bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped, and bone was assessed up to 3 months post‐treatment. NE‐58025 and RIS inhibited long‐term OVX‐induced bone loss, but NE‐58025 antiresorptive effects were more pronounced. Withdrawing NE‐58025 treatment led to the rapid onset of trabecular resorption with a 200% increase in osteoclast surface and bone loss within 1 month. Cessation of risedronate treatment did not lead to increases in resorption indices or bone loss. These results show that NE‐58025 prevents OVX‐induced bone loss, and its effects reverse quickly following cessation treatment in vivo. Low‐HAP affinity BPs may have use as reversible, antiresorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long‐term BP treatment.Item Burosumab for the Treatment of Tumor‐Induced Osteomalacia(Wiley, 2021-04) Jan de Beur, Suzanne M.; Miller, Paul D.; Weber, Thomas J.; Peacock, Munro; Insogna, Karl; Kumar, Rajiv; Rauch, Frank; Luca, Diana; Cimms, Tricia; Scott Roberts, Mary; Martin, Javier San; Carpenter, Thomas O.; Medicine, School of MedicineTumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia.Item Classical and Nonclassical Manifestations of Primary Hyperparathyroidism(Wiley, 2022-08-19) El-Hajj Fuleihan, Ghada; Chakhtoura, Marlene; Cipriani, Cristiana; Eastell, Richard; Karonova, Tatiana; Liu, Jian-Min; Minisola, Salvatore; Mithal, Ambrish; Moreira, Carolina A.; Peacock, Munro; Schini, Marian; Silva, Barbara; Walker, Marcella; El Zein, Ola; Marcocci, Claudio; Medicine, School of MedicineThis narrative review summarizes data on classical and nonclassical manifestations of primary hyperparathyroidism (PHPT). It is based on a rigorous literature search, inclusive of a Medline search for systematic reviews from 1940 to December 2020, coupled with a targeted search for original publications, covering four databases, from January 2013-December 2020, and relevant articles from authors' libraries. We present the most recent information, identify knowledge gaps, and suggest a research agenda. The shift in the presentation of PHPT from a predominantly symptomatic to an asymptomatic disease, with its varied manifestations, has presented several challenges. Subclinical nephrolithiasis and vertebral fractures are common in patients with asymptomatic disease. The natural history of asymptomatic PHPT with no end organ damage at diagnosis is unclear. Some observational and cross-sectional studies continue to show associations between PHPT and cardiovascular and neuropsychological abnormalities, among the different disease phenotypes. Their causal relationship is uncertain. Limited new data are available on the natural history of skeletal, renal, cardiovascular, neuropsychological, and neuromuscular manifestations and quality of life. Normocalcemic PHPT (NPHPT) is often diagnosed without the fulfillment of rigorous criteria. Randomized clinical trials have not demonstrated a consistent long-term benefit of parathyroidectomy (PTX) versus observation on nonclassical manifestations. We propose further refining the definition of asymptomatic disease, into two phenotypes: one without and one with evidence of target organ involvement, upon the standard evaluation detailed in our recommendations. Each of these phenotypes can present with or without non-classical manifestations. We propose multiple albumin-adjusted serum calcium determinations (albumin-adjusted and ionized) and exclusion of all secondary causes of high parathyroid hormone (PTH) when establishing the diagnosis of NPHPT. Refining the definition of asymptomatic disease into the phenotypes proposed will afford insights into their natural history and response to interventions. This would also pave the way for the development of evidence-based guidance and recommendations.Item L-BAIBA Synergizes with Sub-Optimal Mechanical Loading to Promote New Bone Formation(Wiley, 2023-04-24) Prideaux, Matt; Smargiassi, Alberto; Peng, Gang; Brotto, Marco; Robling, Alexander G.; Bonewald, Lynda F.; Anatomy, Cell Biology and Physiology, School of MedicineThe L-enantiomer of β-aminoisobutyric acid (BAIBA) is secreted by contracted muscle in mice, and exercise increases serum levels in humans. In mice, L-BAIBA reduces bone loss with unloading, but whether it can have a positive effect with loading is unknown. Since synergism can be more easily observed with sub-optimal amounts of factors/stimulation, we sought to determine whether L-BAIBA could potentiate the effects of sub-optimal loading to enhance bone formation. L-BAIBA was provided in drinking water to C57Bl/6 male mice subjected to either 7 N or 8.25 N of sub-optimal unilateral tibial loading for 2 weeks. The combination of 8.25 N and L-BAIBA significantly increased the periosteal mineral apposition rate and bone formation rate compared to loading alone or BAIBA alone. Though L-BAIBA alone had no effect on bone formation, grip strength was increased, suggesting a positive effect on muscle function. Gene expression analysis of the osteocyte-enriched bone showed that the combination of L-BAIBA and 8.25 N induced the expression of loading-responsive genes such as Wnt1, Wnt10b, and the TGFb and BMP signaling pathways. One dramatic change was the downregulation of histone genes in response to sub-optimal loading and/or L-BAIBA. To determine early gene expression, the osteocyte fraction was harvested within 24 hours of loading. A dramatic effect was observed with L-BAIBA and 8.25 N loading as genes were enriched for pathways regulating the extracellular matrix (Chad, Acan, Col9a2), ion channel activity (Scn4b, Scn7a, Cacna1i), and lipid metabolism (Plin1, Plin4, Cidec). Few changes in gene expression were observed with sub-optimal loading or L-BAIBA alone after 24 hours. These results suggest that these signaling pathways are responsible for the synergistic effects between L-BAIBA and sub-optimal loading. Showing that a small muscle factor can enhance the effects of sub-optimal loading of bone may be of relevance for individuals unable to benefit from optimal exercise.Item Micropetrosis in hemodialysis patients(Elsevier, 2021-11-27) Yajima, Aiji; Tsuchiya, Ken; Burr, David B.; Murata, Taro; Nakamura, Masaki; Inaba, Masaaki; Tominaga, Yoshihiro; Tanizawa, Tatsuhiko; Nakayama, Takashi; Ito, Akemi; Nitta, Kosaku; Anatomy, Cell Biology and Physiology, School of MedicineMicropetrosis develops as a result of stagnation of calcium, phosphorus and bone fluid, which appears as highly mineralized bone area in the osteocytic perilacunar/canalicular system regardless of bone turnover of the patients. And microcracks are predisposed to increase in these areas, which leads to increased bone fragility. However, micropetrosis of hemodialysis (HD) patients has not been discussed at all. Micropetrosis area per bone area (Mp.Ar/B·Ar) and osteocyte number per micropetrosis area (Ot.N/Mp.Ar) were measured in nine HD patients with renal hyperparathyroidism (Group I), twelve patients with hypoparathyroidism within 1 year after the treatment of renal hyperparathyroidism (Group II) and seven patients suffering from hypoparathyroidism for over two years (Group III). And bone mineral density (BMD) and tissue mineral density (TMD) were calculated using μCT to evaluate bone mineral content of iliac bone of the patients. These parameters were compared among the three groups. Only Mp.Ar/B·Ar was statistically greater in Group II and III compared to Group I in the parameters of bone mineral content and micropetrosis. However, the other parameters were not statistically different among the three groups. In long-term HD patients, BMD and TMD may be modified by the causes of renal insufficiency and the treatment of renal bone disease. We concluded that Mp.Ar/B·Ar was greater in patients with long-term hypoparathyroidism than both those with short-term hypoparathyroidism and with renal hyperparathyroidism. Special attention should be paid to avoid long-term hypoparathyroidism of the patients from the view point of increased fracture risk caused by increased micropetrosis area.