Blocking antibody to the β-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis

Low estrogen levels undoubtedly underlie menopausal bone thinning. However, rapid and profuse bone loss begins 3 y before the last menstrual period, when serum estrogen is relatively normal. We have shown that the pituitary hormone FSH, the levels of which are high during late perimenopause, directly stimulates bone resorption by osteoclasts. Here, we generated and characterized a polyclonal antibody to a 13-amino-acid-long peptide sequence within the receptor-binding domain of the FSH β-subunit. We show that the FSH antibody binds FSH specifically and blocks its action on osteoclast formation in vitro. When injected into ovariectomized mice, the FSH antibody attenuates bone loss significantly not only by inhibiting bone resorption, but also by stimulating bone formation, a yet uncharacterized action of FSH that we report herein. Mesenchymal cells isolated from mice treated with the FSH antibody show greater osteoblast precursor colony counts, similarly to mesenchymal cells isolated from FSH receptor (FSHR)(-/-) mice. This suggests that FSH negatively regulates osteoblast number. We confirm that this action is mediated by signaling-efficient FSHRs present on mesenchymal stem cells. Overall, the data prompt the future development of an FSH-blocking agent as a means of uncoupling bone formation and bone resorption to a therapeutic advantage in humans.     

Paget’s disease of bone resembling bone metastasis from gastric cancer

A 74-year-old man had an endoscopic type 0′-IIc tumor in the upper gastric body on the greater curvature and biopsy showed the tumor to be a well-differentiated adenocarcinoma (Group 5). He was referred to us for endoscopic submucosal dissection (ESD). Endoscopy revealed fold convergency, fold swelling, and fusion of the fold, indicating tumor invasion into the submucosa, which was outside the indications for ESD. In addition, there was an increase of serum bone-type alkaline phosphatase (ALP-III and ALP-IV) and urinary cross-linked N-terminal telopeptide of type I collagen (a bone metabolism marker), while ¹⁸F-fluorodeoxyglucose positron emission tomography showed increased uptake in the left pelvis and Th10, suggesting bone metastases. We first diagnosed gastric cancer with bone metastases; however, the symptoms suggested pathological bone fracture and no bone pain. Therefore, a computed tomography-guided aspiration bone biopsy was performed to exclude the possibility of Paget’s disease of bone. Biopsy specimens revealed no tumor and a mosaic pattern. No increased uptake of ¹⁸F-FAMT (L-[3-¹⁸F] α-methyltyrosine) supported a diagnosis of no bone metastases from gastric cancer. We finally diagnosed gastric cancer accompanied by Paget’s disease of bone and performed a laparoscopy-assisted proximal gastrectomy. The pathological diagnosis was U less 0-IIb, and U post 0-IIc ypT1a (M) N0H0P0M0 yp stage IA. In gastric cancer patients with suspected bone metastasis, we also need to consider Paget’s disease of bone.     

Remodeling in bone without osteocytes: Billfish challenge bone structure–function paradigms

A remarkable property of tetrapod bone is its ability to detect and remodel areas where damage has accumulated through prolonged use. This process, believed vital to the long-term health of bone, is considered to be initiated and orchestrated by osteocytes, cells within the bone matrix. It is therefore surprising that most extant fishes (neoteleosts) lack osteocytes, suggesting their bones are not constantly repaired, although many species exhibit long lives and high activity levels, factors that should induce considerable fatigue damage with time. Here, we show evidence for active and intense remodeling occurring in the anosteocytic, elongated rostral bones of billfishes (e.g., swordfish, marlins). Despite lacking osteocytes, this tissue exhibits a striking resemblance to the mature bone of large mammals, bearing structural features (overlapping secondary osteons) indicating intensive tissue repair, particularly in areas where high loads are expected. Billfish osteons are an order of magnitude smaller in diameter than mammalian osteons, however, implying that the nature of damage in this bone may be different. Whereas billfish bone material is as stiff as mammalian bone (unlike the bone of other fishes), it is able to withstand much greater strains (relative deformations) before failing. Our data show that fish bone can exhibit far more complex structure and physiology than previously known, and is apparently capable of localized repair even without the osteocytes believed essential for this process. These findings challenge the unique and primary role of osteocytes in bone remodeling, a basic tenet of bone biology, raising the possibility of an alternative mechanism driving this process.Bone forms the stiff, load-bearing framework of the body of vertebrates. The current paradigm of bone biology is that the microdamage that accumulates in bone—the result of repeated loading over long periods of time—is prevented from reaching failure levels by “remodeling,” a physiologic maintenance process by which packets of damaged bone material are removed, then replaced by new, undamaged tissue (1). The most crucial role in the remodeling sequence is thought to be played by the osteocytes, the cells residing within the bone matrix, which sense local increases in strain (or strain energy density) caused by microcrack accumulation, then initiate and coordinate remodeling once a defined threshold is reached (2, 3). First, surface-residing osteoclasts (bone-resorbing cells) are recruited to invade and erode packets of damaged tissue within the bone material, a process that creates visible resorption cavities. Osteoblasts (bone-building cells) are then recruited to these eroded areas, and fill them concentrically from the periphery inwards with new bone, leaving only a small central canal for the passage of blood vessels and nerves (4). This “repair by replacement” process alters bone’s ultrastructural morphology, leaving behind lamellate, nearly circular “secondary osteons” (Fig. 1 A–D). Because subsequent secondary osteons do not respect each other’s borders, heavily remodeled tissue, which forms particularly in situations of large load magnitudes and/or cyclic loading, bears a characteristic morphology of overlapping osteons (Fig. 1 C and D), a structural record of vigorous remodeling (ref. 2; SI Text).Open in a separate windowFig. 1.Mammalian bone ultrastructure, showing morphological evidence for remodeling, compared with relatively “featureless” fish bone. (A) Cross-section of dog femoral midshaft with localized areas showing primary and remodeled bone (secondary osteons). (B) Higher magnification of the upper boxed region in A, showing isolated, nonoverlapping osteons (borders indicated by dashed lines) present in otherwise lamellar (layered) primary bone tissue. Every osteon is organized around a central Haversian canal (Ca); smaller black dots are osteocyte lacunae. (C) Higher magnification of the lower boxed region in A, showing much higher osteonal density, with many overlapping osteons (secondary osteons, shown by arrows, and in more detail in the inset image), indications of tissue remodeling. (D) Horse third metatarsal bone showing heavy remodeling, evidenced by extensive osteonal overlap. Inset polarized microscopy image illustrates how osteonal lamellae are “interrupted” by lamellae of new osteons (white arrows). The smaller Inset image highlights the high concentration of osteocyte lacunae (Os), visible as small black dots throughout the tissue. (E) Tilapia opercular bone which, like most fish bone examined to date, has a simple layered ultrastructure, even at higher magnification (Inset). This species is anosteocytic (i.e., lacks osteocytes entirely); in contrast, the mammalian tissues in A–D all have numerous osteocytes.Considering the pivotal role of osteocytes in remodeling and that remodeling is believed to be essential for the proper long-term function of bone, it is surprising that the bones of almost all members of the huge group of extant neoteleost fish—close to 50% of all vertebrates—are completely devoid of osteocytes (anosteocytic) (Fig. 1E) (5, 6). According to the current tenets of bone biology, because local internal strains are believed to be sensed by osteocytes alone (3, 7), remodeling in anosteocytic fish species would either not occur at all, be driven by something other than damage, or be stochastic in nature (i.e., “undirected”). The former option, lack of remodeling, is supported by the fact that the bone of most fish species examined to date has been shown to be featureless (i.e., to lack traces of remodeling; e.g., Fig. 1E), particularly in comparison with mammalian bone (e.g., Fig. 1 A–D) (5, 6, 8–11). From a functional point of view, however, there are many reasons to expect that both osteocytic and anosteocytic fishes should need to remodel their bones: Remodeling occurs in a wide assortment of aquatic and terrestrial amniote species (4, 12, 13); fish experience large loads on their skeletons (e.g., bite forces can exceed 300 N, and fish mass-specific bite forces are the highest recorded among vertebrates; ref. 14); and in vivo physiologic strains measured in fish bone are within the same range as those of mammals, and with considerably higher strain rates (15).Although fish (both osteocytic and anosteocytic) have been shown to respond to changing loading conditions by altering bone external morphology (the process of “modeling,” performed only on external and internal surfaces; see SI Text), there has been to date no definitive morphological evidence of remodeling within the bone material (SI Text). We examined the anosteocytic skeletons of billfishes, species with bone that we argue is at the extreme end of the need for remodeling (Fig. 2 and Fig. S1). The billfishes (Xiphiidae and Istiophoridae) have long life spans (up to several decades), and can reach large body sizes and high swimming speeds (up to 600 kg and 75 km/h, respectively, in some species) (16, 17). The large pointed rostra or “bills” from which the fishes get their common name—formed from sword- or spear-shaped, elongated upper jaw bones—are used to strike and stun a variety of prey (16, 18, 19). These factors suggest that the long rostra regularly sustain repeated high forces, which result in high stresses and strains and, therefore, have a substantial demand for superior bone material properties (e.g., unique resistance to failure) and/or remodeling to ensure long-term bone health and function. We focus our analysis on several billfish species, including some with bills reaching impressive lengths (∼0.5 m or a quarter of the body length of the fish in blue marlin, Makaira nigricans, and more than 1.0 m or half of body length in swordfish, Xiphias gladius) (Fig. 2 and Fig. S1). Billfish rostra therefore represent an extreme example of anosteocytic bone, loaded heavily and cyclically in cantilever bending over the animals’ long lifespans, and likely in need of regular remodeling to avoid failure. The five species examined provide a broad palette of body sizes and bill lengths in a closely related group of fishes (Fig. 2 and Fig. S1) and, therefore, are an ideal system to investigate correlations among body/bill size, reported activity level, and evidence for remodeling.Open in a separate windowFig. 2.Gross morphology and ultrastructure of billfish bone. Swordfish (SW) and blue marlin (BM) are shown here; tissue ultrastructure of the additional species examined (SB, shortbill spearfish; SF, sailfish; WM, white marlin) is shown in Fig. S1. The body plan of the fish is shown as a silhouette, with CT scan images beneath showing the skull in dorsal and lateral perspectives (white bars between CT scans = 10 cm). Light microscopy images of distal, whole bill transverse cross-sections are shown beneath CT scans, demonstrating an array of complex ultrastructures, with circular inset images providing a higher magnification of the acellular osteonal tissue (BM, backscatter electron image; SW, light microscopy image). CT scans of crania of the remaining three species in the lower left corner illustrate the variation in relative bill length among species. Two-letter acronyms for each species (in white circles in species’ silhouettes) are used also in subsequent figures.     

A case of early gastric cancer with bone metastases: are bone marrow micrometastases significant?

Gastric adenocarcinoma is currently the 14th cause of death worldwide. Early gastric cancer, defined as cancer not penetrating deeper than the submucosa, is considered to carry an excellent prognosis with 5-year survival rates reaching more than 90%. Cases of bone metastases due to intramucosal gastric cancer are very rarely described. A case of a 70-year old male presenting with confirmed bone metastases 7 years after a curative resection for a mucosal gastric carcinoma is discussed. The patient was investigated with bone marrow biopsy and bone scan and showed no other signs of disease. The clinicopathologic features included poor differentiation, signet ring cells presence, no lymph node involvement and a negative second laparotomy two years after the initial surgery. Studies concerning the presence of residual disease in the form of bone marrow micrometastases are briefly reviewed emphasizing that intramucosal gastric cancer still carries the p sibility for metastasis, many years after a curative resection, mandating long term alertness from the attending physician.     

How do bisphosphonates improve bone quality?

Accumulating evidence indicates that positive effects on bone mineral density of several promising drugs for osteoporosis do not completely account for their anti-fracture effects. Among anti-osteoporosis drugs, effects of bisphosphonates on the reduction in fracture risk are well correlated with those on the increase in bone mineral density. Even in bisphosphonates, at most 50% of their anti-fracture effect is estimated to be independent of the increase in bone mineral density. This suggests that bisphosphonates improve bone quality composed of bone architecture, matrix composition and mineralization. Bone quality is an emerging issue to be explored with an investigation of bone biopsy specimen and 3-dimensional structural analyses using micro computed tomography.     

Paget's disease of bone or osteopetrosis?

We report a previously undescribed case of diffuse, scan-negative, and low active form of bone disease carrying clinical, x-ray, and biochemistry signs of Paget's disease of bone, which is analyzed in comparison with different forms of osteopetrosis.     

Where is bone science taking us?

Bone science has over the last decades unraveled many important pathways in bone and mineral metabolism and the interplay between genetic factors and the environment. Some of these discoveries have led to the development of pharmacological treatments of osteoporosis and rare bone diseases. Other scientific avenues have uncovered a role for the gut microbiome in regulating bone mass, which have led to investigations on the possible therapeutic role of probiotics in the prevention of osteoporosis. Huge advances have been made in identifying the genes that cause rare bone diseases, which in some cases have led to therapeutic interventions. Advances have also been made in understanding the genetic basis of the more common polygenic bone diseases, including osteoporosis and Paget's disease of bone (PDB). Polygenic profiles are used for establishing genetic risk scores aiming at early diagnosis and intervention, but also in Mendelian randomization (MR) studies to investigate both desired and undesired effects of targets for drug design.     

Is osteoarthritis a systemic disorder of bone?

Objective

To describe the osteologic findings associated with osteoarthritis (OA) of a variety of joints.

Methods

We performed visual examination of 563 skeletons of which ≥80% of the skeleton was available, from an archaeologic site in England. The surfaces and margins of several different joints (shoulders, elbows, wrists, hips, hands, knees, and ankles) were studied for evidence of eburnation and osteophytes, respectively, and the entire skeleton was examined for evidence of generalized enthesophyte formation. Associations between changes in different joint sites and between enthesophyte formation and evidence of OA were sought.

Results

Eburnation and osteophyte formation at the hand, hip, and knee were strongly associated with eburnation and osteophytes at other joint sites not commonly thought to be prone to OA, including the elbow and wrist. Only the ankle was rarely involved. There was also a strong relationship between both bone eburnation and osteophytes and generalized enthesophyte formation. These findings remained statistically significant after adjustment for the age, sex, and historical period of the skeletons.

Conclusion

Our findings indicate that skeletal OA is more widespread in the body than is apparent from clinical studies and are consistent with other data suggesting that OA is a disease that is primarily dependent on systemic predisposition to a particular type of bone response to mechanical stress.

     

Is osteoarthritis a systemic disorder of bone?

OBJECTIVE: To describe the osteologic findings associated with osteoarthritis (OA) of a variety of joints. METHODS: We performed visual examination of 563 skeletons of which >/=80% of the skeleton was available, from an archaeologic site in England. The surfaces and margins of several different joints (shoulders, elbows, wrists, hips, hands, knees, and ankles) were studied for evidence of eburnation and osteophytes, respectively, and the entire skeleton was examined for evidence of generalized enthesophyte formation. Associations between changes in different joint sites and between enthesophyte formation and evidence of OA were sought. RESULTS: Eburnation and osteophyte formation at the hand, hip, and knee were strongly associated with eburnation and osteophytes at other joint sites not commonly thought to be prone to OA, including the elbow and wrist. Only the ankle was rarely involved. There was also a strong relationship between both bone eburnation and osteophytes and generalized enthesophyte formation. These findings remained statistically significant after adjustment for the age, sex, and historical period of the skeletons. CONCLUSION: Our findings indicate that skeletal OA is more widespread in the body than is apparent from clinical studies and are consistent with other data suggesting that OA is a disease that is primarily dependent on systemic predisposition to a particular type of bone response to mechanical stress.     

Can bone quality be assessed non-invasively?--Imaging--

Properties of "bone quality" contain "structural property" and "material property" . Most components of "material properties" cannot be visualized by current technology. Mineralization, one of material properties, can be evaluated using synchrotron radiation CT or contact microradiography with high spatial and density resolution, but they are invasive examinations. On the other hand, "structural property" can be radiographically delineated, even though only a few methods are available non-invasively. Assessments of macrostructure of bone by radiograms or CT, and trabecular microstructure by high resolution CT or MR can be done non-invasively, and provide valuable results in clinical studies. Bone scintigram provides limited but useful information of bone turnover.     

Long-term influence of inhaled corticosteroids on bone metabolism and density. Are biological markers predictors of bone loss?

Long-term effects of high doses of inhaled corticosteroids (ICS) on bone density and metabolism are still uncertain. Fifty-one patients (37 male, 14 female) using beclomethasone or budesonide at a daily dose > 800 microgram/d (high-dose group [Group HD] mean: 983 microgram/d [prescribed dose x estimated compliance]) or no or < 500 microgram/d (control group [Group C] mean: 309 microgram/d) for more than 5 yr were enrolled in this study. Each had, 3 yr ago and at this last evaluation, a clinical evaluation and measurements of expiratory flows and of bone density and bone metabolism markers. Lumbar spine bone density (last visit) was similar in the two groups with respective values of 0.94 +/- 0.03 (HD) and 0.96 +/- 0.03 g/cm2 (C) (p > 0.05). T and Z scores were -1.21 +/- 0.19 and -0.70 +/- 0.18 (HD), -0.95 +/- 0.25 and -0.47 +/- 0.21 (C) respectively (p > 0.05). A correlation was found between the decrease in bone density and the mean daily dose of corticosteroid in Group HD although these changes were quite small, mean bone density being unchanged over the 3-yr period. Serum and urinary parameters were similar in the two groups. Furthermore, neither initial bone density nor any of the biological parameters could predict changes in bone density over a period of 3 yr. In conclusion, bone density was similar in both study groups and not significantly different over a 3-yr period. Neither initial bone density nor biological markers of bone metabolism helped to predict changes in bone mass.     

Bone assessment in elderly women: what does a low bone ultrasound result tell us about bone mineral density?

Access to dual energy X-ray absorptiometry (DXA) can prove difficult for frail or elderly patients, and bone ultrasound may offer a practical alternative. Even after adjustment for bone mineral density (BMD), ultrasound readings are able to predict hip fracture in elderly women. We consider how bone ultrasound might contribute to bone assessment in a clinical setting. DXA remains the gold standard for bone assessment, with osteoporosis defined as a BMD result more than 2.5 S.D. below the young adult mean. Using an equivalent approach we defined an osteoporotic ultrasound result as broadband ultrasound attenuation (BUA)<54 dB/MHz. In 73 women aged 29-86 (mean 65) years DXA was used to measure BMD at lumbar spine and hip, and ultrasound to measure BUA at the heel. Correlation of BUA with BMD at femoral neck (r=0.64, P<0.001), and lumbar spine (r=0.55, P<0.001) was consistent with previously reported figures for this ultrasound system. All subjects with BUA below the 54 dB/MHz threshold value were shown to have low femoral neck BMD. Women (42%) aged over 65, but only 18% of younger women had low BUA results. In women over 65 years of age measurements of BUA achieved a sensitivity of 61% and specificity of 100% in prediction of low femoral neck BMD. Although a normal BUA did not exclude an osteoporotic BMD result at hip or lumbar spine, a low BUA appeared a highly specific predictor of low BMD at these sites. Since all those women identified as having a low BUA at the heel also had low BMD results, ultrasound appeared to identify a subgroup of elderly patients at a very high risk of fracture.     

Is HIV sequestered in bone? Possible implications of virological and immunological findings in some HIV-infected patients with bone disease

To determine the prevalence of CD4 lymphocyte levels less than 350 cells/mm3 accompanying viral loads (VL) less than 500 copies/ml (discordant CD4 lymphocyte levels/VL) in HIV-infected men with bone pathologies, we conducted a review of the records of 3512 men. We found discordant CD4 lymphocyte levels/VL in 26 (36.1%) out of 72 with bone pathologies, and in 704 (20.5%) out of 3440 without bone pathologies (P < 0.01), and concluded that HIV sequestered in bone was a possible explanation.