Oxford University Press (OUP)

Nghiên cứu này dự đoán gánh nặng của các chấn thương liên quan đến loãng xương và chi phí tại Hoa Kỳ, phân theo giới tính, nhóm tuổi, chủng tộc/dân tộc và loại chấn thương, từ năm 2005 đến 2025. Tổng số chấn thương vượt quá 2 triệu, với chi phí gần 17 tỷ USD vào năm 2005. Nam giới chiếm hơn 25% gánh nặng. Sự gia tăng nhanh chóng trong gánh nặng bệnh tật được dự đoán ở các nhóm không phải người da trắng.

Giới thiệu: Sự lão hóa của dân số Hoa Kỳ có thể dẫn đến tỷ lệ loãng xương cao hơn. Các nhà hoạch định chính sách cần các dự đoán chính xác về gánh nặng bệnh tật theo các nhóm nhân khẩu học và các vị trí xương để nhắm mục tiêu hiệu quả các chương trình can thiệp và điều trị loãng xương.

Vật liệu và Phương pháp: Một mô hình quyết định Markov chuyển trạng thái đã được sử dụng để ước tính tổng số chấn thương phát sinh và chi phí theo tuổi, giới tính, chủng tộc/dân tộc, và vị trí xương cho dân số Hoa Kỳ từ 50 tuổi trở lên trong giai đoạn 2005–2025.

Kết quả: Hơn 2 triệu chấn thương phát sinh với chi phí 17 tỷ USD được dự đoán cho năm 2005. Tổng chi phí bao gồm các chấn thương phổ biến hơn 19 tỷ USD. Nam giới chiếm 29% số chấn thương và 25% tổng chi phí. Tổng số chấn thương phát sinh theo vị trí xương là: cột sống (27%), cổ tay (19%), hông (14%), xương chậu (7%), và các vị trí khác (33%). Tổng chi phí theo loại chấn thương là: cột sống (6%), hông (72%), cổ tay (3%), xương chậu (5%), và các vị trí khác (14%). Đến năm 2025, số lượng chấn thương và chi phí hàng năm được dự đoán sẽ tăng gần 50%. Tăng trưởng nhanh nhất được ước tính cho những người từ 65–74 tuổi, với mức tăng >87%. Dự đoán rằng nhóm dân số Tây Ban Nha và các nhóm khác sẽ có mức tăng gần 175%.

Fracture healing is a unique postnatal repair process in which the events of endochondral and intramembranous bone formation follow a definable temporal sequence. The temporal patterns of messenger RNA (mRNA) expression for members of the transforming growth factor β (TGF-β) superfamily were examined over a 28-day period of fracture healing in mouse tibias. Bone morphogenetic protein 2 (BMP-2) and growth and differentiation factor 8 (GDF8) showed maximal expression on day 1 after fracture, suggesting their roles as early response genes in the cascade of healing events. Restricted expression of GDF8 to day 1, in light of its known actions as a negative regulator of skeletal muscle growth, suggests that it may similarly regulate cell differentiation early in the fracture healing process. GDF5, TGF-β2, and TGF-β3 showed maximal expression on day 7, when type II collagen expression peaked during cartilage formation. In contrast, BMP-3, BMP-4, BMP-7, and BMP-8 showed a restricted period of expression from day 14 through day 21, when the resorption of calcified cartilage and osteoblastic recruitment were most active. TGF-β1, BMP-5 and BMP-6, and GDF10 were constitutively expressed from day 3 to day 21. However, during the same time period, GDF3, GDF6, and GDF9 could not be detected, and GDF1 was expressed at extremely low levels. These findings suggest that several members of the TGF-β superfamily are actively involved in fracture healing and although they are closely related both structurally and functionally, each has a distinct temporal expression pattern and potentially unique role in fracture healing.

Qualitative and quantitative bone features were determined in nondecalcified and decalcified bone from 20 predetermined bone sites in each of 44 patients who died with castration-resistant prostate cancer (CRPC), some of which received bisphosphonate treatment (BP) in addition to androgen-deprivation therapy (ADT). Thirty-nine of the 44 patients (89%) had evidence of bone metastases. By histomorphometric analysis, these bone metastases were associated with a range of bone responses from osteoblastic to osteolytic with a wide spectrum of bone responses often seen within an individual patient. Overall, the average bone volume/tissue volume (BV/TV) was 25.7%, confirming the characteristic association of an osteoblastic response to prostate cancer bone metastasis when compared with the normal age-matched weighted mean BV/TV of 14.7%. The observed new bone formation was essentially woven bone, and this was a localized event. In comparing BV/TV at metastatic sites between patients who had received BP treatment and those who had not, there was a significant difference (28.6% versus 19.3%, respectively). At bone sites that were not invaded by tumor, the average BV/TV was 10.1%, indicating significant bone loss owing to ADT that was not improved (11%) in those patients who had received BPs. Surprisingly, there was no significant difference in the number of osteoclasts present at the metastatic sites between patients treated or not treated with BPs, but in bone sites where the patient had been treated with BPs, giant osteoclasts were observed. Overall, 873 paraffin-embedded specimens and 661 methylmethacrylate-embedded specimens were analyzed. Our results indicate that in CRPC patients, ADT induces serious bone loss even in patients treated with BP. Furthermore, in this cohort of patients, BP treatment increased BV and did not decrease the number of osteoclasts in prostate cancer bone metastases compared with bone metastases from patients who did not receive BP. © 2013 American Society for Bone and Mineral Research

Bone metastases place patients at increased risk of skeletal-related events (SREs), including pathologic fractures, spinal cord compression, severe pain requiring radiotherapy or surgery, and hypercalcemia, because of increased osteoclast-mediated bone resorption. Denosumab, a fully human monoclonal antibody, decreases bone resorption by inhibiting RANKL, which mediates osteoclast activity. We compared the effects of denosumab in two phase 2 studies in patients with bone metastases naive to intravenous bisphosphonate therapy (IV BP; n = 255) and those with elevated levels of the bone resorption marker urinary N-telopeptide (uNTX) despite ongoing IV BP treatment (n = 111). Patients were randomized to receive IV BP every 4 weeks or subcutaneous denosumab every 4 weeks (30/120/180 mg) or every 12 weeks (60/180 mg). Patients treated with denosumab experienced a rapid and sustained reduction in bone turnover regardless of prior IV BP exposure. After 25 weeks, the median uNTX reduction was 75% (IV BP-naive) and 80% (prior IV BP) after denosumab treatment and 71% (IV BP-naive) and 56% (prior IV BP) in the IV BP arms. Denosumab patients with prior IV BP exposure had marked suppression of the osteoclast marker TRAP-5b (median reduction: denosumab 73%, IV BP 11%). SRE incidence was low across both studies. In patients previously treated with BPs, the rate of first on-study SRE was lower in the denosumab groups (8%) than the IV BP group (17%). Denosumab appeared to be well tolerated in both studies. Denosumab suppresses bone resorption markers independently of prior BP treatment, even in patients who appear to respond poorly to BPs. © 2010 American Society for Bone and Mineral Research.

Nghiên cứu này điều tra các tác động của kyphoplasty đối với cơn đau và khả năng vận động ở bệnh nhân loãng xương và gãy xương đốt sống đau, so với quản lý y tế thông thường.

Giới thiệu: Điều trị dược phẩm cho bệnh nhân loãng xương nguyên phát không ngăn ngừa đau và suy giảm hoạt động ở bệnh nhân bị gãy xương đốt sống đau đớn. Vì vậy, chúng tôi đã đánh giá kết quả lâm sàng sau khi thực hiện kyphoplasty ở bệnh nhân bị gãy xương đốt sống và đau mãn tính kèm theo trong hơn 12 tháng.

Vật liệu và Phương pháp: Sáu mươi bệnh nhân loãng xương nguyên phát và gãy xương đốt sống đau đớn trình diện trên 12 tháng đã được bao gồm trong nghiên cứu tiến cứu không ngẫu nhiên này. Hai mươi bốn giờ trước khi thực hiện kyphoplasty, bệnh nhân tự xác định việc tham gia vào nhóm kyphoplasty hoặc nhóm kiểm soát do đó 40 bệnh nhân được điều trị bằng kyphoplasty, trong khi 20 làm nhóm kiểm soát. Nghiên cứu này đánh giá thay đổi hình thái học trên X-quang, chỉ số đau theo thang đo analog hình ảnh (VAS), các hoạt động hàng ngày (thang đo của Nghiên cứu Loãng Xương Đốt Sống châu Âu [EVOS]), số lượng gãy xương đốt sống mới và việc sử dụng dịch vụ y tế. Các kết quả được đánh giá trước điều trị và tại thời điểm 3 và 6 tháng theo dõi. Tất cả bệnh nhân đều nhận được điều trị y tế tiêu chuẩn (1g canxi, 1000 IE vitamin D3, liều tiêu chuẩn của aminobisphosphonate uống, thuốc giảm đau, vật lý trị liệu).

Kết quả: Kyphoplasty tăng chiều cao đốt sống ở vị trí giữa của các thân đốt sống được điều trị lên 12,1%, trong khi ở nhóm kiểm soát, chiều cao đốt sống giảm xuống 8,2% (p = 0.001). Tăng cường và ổn định bên trong bằng kyphoplasty dẫn đến giảm đau lưng. Chỉ số đau VAS được cải thiện trong nhóm kyphoplasty từ 26,2 ± 2 đến 44,2 ± 3.3 (SD; p = 0.007) và ở nhóm kiểm soát từ 33,6 ± 4.1 đến 35.6 ± 4.1 (không có ý nghĩa thống kê), trong khi điểm số EVOS tăng trong nhóm kyphoplasty từ 43,8 ± 2.4 đến 54.5 ± 2.7 (p = 0.031) và ở nhóm kiểm soát từ 39,8 ± 4.5 đến 43.8 ± 4.6 (không có ý nghĩa). Số lượt khám bác sĩ liên quan đến đau lưng trong khoảng thời gian theo dõi 6 tháng giảm đáng kể sau khi kyphoplasty so với nhóm kiểm soát: trung bình 3.3 lượt khám/bệnh nhân ở nhóm kyphoplasty và trung bình 8.6 lượt khám/bệnh nhân ở nhóm kiểm soát (p = 0.0147).

Kết luận: Kết quả của nghiên cứu này cho thấy chiều cao đốt sống tăng đáng kể, giảm đau và cải thiện khả năng vận động ở bệnh nhân sau kyphoplasty. Kyphoplasty thực hiện ở những bệnh nhân loãng xương được chọn lọc phù hợp với gãy xương đốt sống đau đớn là một bổ sung đầy hứa hẹn cho liệu pháp y tế hiện nay.

A major limitation of total joint arthroplasty is that up to 20% of patients require revision surgery to correct prosthetic loosening. Aseptic loosening is believed to result from the phagocytosis of wear debris particles by macrophages, which secrete proinflammatory cytokines that stimulate osteolysis. Tumor necrosis factor α (TNF-α) has been shown to be one of the prominent cytokines in this cascade and to be involved critically in the generation of particle-induced osteolysis. Etanercept is a soluble inhibitor of TNF-α, which is widely used for the treatment of rheumatoid arthritis. Here, we show this agent's ability to prevent wear debris-induced osteolysis. In vitro we show that Etanercept can inhibit directly osteoclastic bone resorption in a bone wafer pit assay, as well as cytokine production from titanium (Ti)-stimulated macrophages. Using a quantitative in vivo model of wear debris-induced osteolysis, we show that Etanercept prevents bone resorption and osteoclastogenesis. In mice treated with Etanercept at the time of osteolysis induction, bone resorption and osteoclast numbers were reduced to background levels in both normal and human TNF-α (hTNF-α) transgenic mice. In an effort to evaluate its effect on established osteolysis, Etanercept was administered 5 days after Ti implantation, and we observed that further osteolysis was prevented. These data support the concept that TNF-α is involved critically in osteoclastogenesis and bone resorption during periprosthetic osteolysis and suggest that soluble TNF-α inhibitors may be useful as therapeutic agents for the treatment of prosthetic loosening in humans.

Osteoclast formation in bone is supported by osteoblasts expressing receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) expression. Numerous osteotropic factors regulate expression levels of RANKL and the RANKL decoy receptor osteoprotegerin (OPG) in osteoblasts, thereby affecting osteoclast differentiation. However, not only is RANKL widely expressed in soft tissues, but osteoclasts have been noted in extraskeletal lesions. We found that cultured skin fibroblastic cells express RANKL, M-CSF, and OPG messenger (mRNA). Stimulation by 1α,25 dihydroxyvitamin D3 [1,25(OH)2D3] plus dexamethasone (Dex) augmented RANKL and diminished OPG mRNA expression in fibroblastic cells and caused the formation of numerous osteoclasts in cocultures of skin fibroblastic cells with hemopoietic cells or monocytes. The osteoclasts thus formed expressed tartrate-resistant acid phosphatase (TRAP) and calcitonin (CT) receptors and formed resorption pits in cortical bone. Osteoclast formation also was stimulated (in the presence of Dex) by prostaglandin E2 (PGE2), interleukin-11 (IL-11), IL-1, tumor necrosis factor-α (TNF-α), and parathyroid hormone-related protein (PTHrP), factors which also stimulate osteoclast formation supported by osteoblasts. In addition, granulocyte-macrophage-CSF (GM-CSF), transforming growth factor-β (TGF-β), and OPG inhibited osteoclast formation in skin fibroblastic cell-hemopoietic cell cocultures; CT reduced only osteoclast nuclearity. Fibroblastic stromal cells from other tissues (lung, respiratory diaphragm, spleen, and tumor) also supported osteoclast formation. Thus, RANKL-positive fibroblastic cells in extraskeletal tissues can support osteoclastogenesis if osteolytic factors and osteoclast precursors are present. Such mesenchymally derived cells may play a role in pathological osteolysis and may be involved in osteoclast formation in extraskeletal tissues.

Human recombinant tumor necrosis factors α and β (TNF-α and TNF-β), at and above 1 ng/ml (≅ 70 pM), caused a dose- and time-dependent enhancement of 45Ca release from neonatal mouse calvarial bones in vitro. In addition, TNF-α and TNF-β (3–100 ng/ml) caused a dose-dependent stimulation of prostaglandin E2 (PGE2) formation in the calvarial bones. TNF-α also enhanced the biosynthesis of PGI2, as assessed by analysis of the stable breakdown product 6-keto-PGF1α. The stimulatory actions of TNF-α and TNF-β on PGE2 formation was maximal at 12 h. Indomethacin, flurbiprofen, and meclofenamic acid, three structurally unrelated nonsteroidal antiinflammatory drugs, abolished PGE2 biosynthesis induced by TNF-α and TNF-β (100 ng/ml). The 45Ca release stimulated by TNF-α and TNF-β (100 ng/ml), however, was only slightly reduced by indomethacin, flurbiprofen, and meclofenamic acid. The partial inhibitory effect of indomethacin on 45Ca release was seen over a wide range of TNF-α concentrations, without affecting the concentration producing half-maximal stimulatory response. TNF-α and TNF-β (100 ng/ml) stimulated bone matrix breakdown, as assessed by analysis of the release of 3H from bone prelabeled with [3H]proline. Also, the stimulatory effect of TNF-α and TNF-β on bone matrix degradation was partially reduced by indomethacin. Hydrocortisone (1 μM) and dexamethasone (0.1 μM) abolished TNF-α- and TNF-β-induced production of PGE2. In contrast to the cyclooxygenase inhibitors, the corticosteroids did not affect the stimulatory action by the cytokines on 45Ca release. These observations suggest that TNF-α and TNF-β can stimulate bone resorption in vitro by prostaglandin-independent mechanisms.

Osteopenia is an important clinical manifestation of hyperprolactinemia. Bone loss in these patients has mainly been attributed to concomitant deficiency of gonadal hormones rather than to hyperprolactinemia per se. Parathyroid hormone-related peptide (PTHrP) is expressed in human mammary tissue, and elevated circulating PTHrP levels as well as concomitant hypercalcemia have been described during lactation. We sought to determine circulating PTHrP levels in patients with long-standing hyperprolactinemia and whether PTHrP may exert possible systemic effects on bone and mineral metabolism. We studied 45 patients (30 women and 15 men) with persisting hyperprolactinemia 6 ± 4 years (mean ± SD) after trans-sphenoidal surgery for prolactin-producing pituitary adenomas. PTHrP levels in 117 healthy controls were 10.6 ± 73 pmol-eq/l (mean ± SD). In hyperprolactinemic patients, plasma PTHrP was elevated to 303 ± 13.4 pmol-eq/l (p < 0.001, n = 45), and in patients with humoral hypercalcemia of malignancy PTHrP levels were 52.9 ± 29.6 (p < 0.001 to controls and hyperprolactinemic patients). Fifty-three percent of hyperprolactinemic patients (n = 24) had clearly elevated PTHrP levels (>2 SD). Retrospective immunocytochemical studies of the removed pituitary adenomas from 19 patients generally showed a higher degree of immunoreactivity for PTHrP (1–34) in all but one case when compared with normal pituitary tissue. Patients with elevated circulating PTHrP levels showed in most instances strong immunoreactivity to PTHrP in 70–100% of tumor cells. PTHrP was significantly correlated to blood pressure (systolic: r = –0.42, p < 0.005; diastolic: r = –0.41, p < 0.01), serum calcium (r = 0.40, p < 0.01), parathyroid hormone (r = –0.43, p < 0.005), and bone density measurements (r = –0.41, p < 0.005). Patients taking low doses of bromocriptine (n = 15) had similar reductions in bone mineral density despite lower prolactin levels (p < 0.005), and there was no correlation between either prolactin levels or estrogen status and bone mineral density measurements (r = –0.12 and r = –0.28, respectively). Our data demonstrate that circulating PTHrP levels are clearly elevated in approximately 50% of patients with pituitary hyperprolactinemia and suggests the pituitary adenomas to be the major source of PTHrP production. Independent of gonadal function and the degree of hyperprolactinemia, PTHrP functions as an active hormone and contributes substantially to bone loss seen in these patients.

Decorin (dcn) and biglycan (bgn), two members of the family of small leucine-rich proteoglycans (SLRPs), are the predominant proteoglycans expressed in skin and bone, respectively. Targeted disruption of the dcn gene results in skin laxity and fragility, whereas disruption of the bgn gene results in reduced skeletal growth and bone mass leading to generalized osteopenia, particularly in older animals. Here, we report that bgn deficiency leads to structural abnormality in collagen fibrils in bone, dermis, and tendon, and to a “subclinical” cutaneous phenotype with thinning of the dermis but without overt skin fragility. A comparative ultrastructural study of different tissues from bgn- and dcn-deficient mice revealed that bgn and dcn deficiency have similar effects on collagen fibril structure in the dermis but not in bone. Ultrastructural and phenotypic analysis of newly generated bgn/dcn double-knockout (KO) mice revealed that the effects of dcn and bgn deficiency are additive in the dermis and synergistic in bone. Severe skin fragility and marked osteopenia characterize the phenotype of double-KO animals in which progeroid changes are observed also in the skin. Ultrastructural analysis of bone collagen fibrils in bone of double-KO mice reveals a complete loss of the basic fibril geometry with the emergence of marked “serrated fibril” morphology. The phenotype of the double-KO animal mimics directly the rare progeroid variant of human Ehlers-Danlos syndrome (EDS), in which skin fragility, progeroid changes in the skin (reduced hypodermis), and osteopenia concur as a result of impaired glycosaminoglycan (GAG) linking to bgn and dcn core proteins. Our data show that changes in collagen fibril morphology reminiscent of those occurring in the varied spectrum of human EDS are induced by both bgn deficiency and dcn deficiency in mice. The effects of an individual SLRP deficiency are tissue specific, and the expression of a gross phenotype depends on multiple variables including level of expression of individual SLRPs in different tissues and synergisms between different SLRPs (and likely other macromolecules) in determining matrix structure and functional properties.