Calcitonin Treatment Research Articles

My, How Things Have Changed in Multiple Endocrine Neoplasia Type 2A!

The history of medullary thyroid carcinoma (MTC) has been characterized by several distinct phases. The initial descriptive phase originated with the 1961 report from John Sipple describing the association of thyroid carcinoma and pheochromocytoma (1). Subsequent investigators correctly identified the thyroid malignancy as MTC, showed that the tumor produced the newly discovered hormone calcitonin, and further categorized this syndrome into its two major subtypes—multiple endocrine neoplasia (MEN) types 2A and 2B (2–4). The second phase began in the late 1960s with the use of serum calcitonin measurements to identify MTC and successful treatment of the malignancy by total thyroidectomy and lymph node dissection. In the 1970s and 1980s, investigators questioned whether MTC could be identified in children at risk for inheriting the disease through the use of provocative calcitonin testing and treatment by early thyroidectomy (5, 6). These studies identified well-defined kindreds with MEN2, an essential resource for the genetic linkage analysis to map the causative gene. The third phase began in 1993 with the identification of RET proto-oncogenemutations inMEN2and theuseof this information to identify affected children (7, 8). The fourth phase began in 2002 with the recognition that small organic molecules that inhibit phosphorylation of RET (and other kinase receptors) have therapeutic efficacy for treatment of metastatic MTC (9), leading to recent Food and Drug Administration approval of two agents for this purpose (10, 11). Machens and Dralle (12), in their insightful report published in this issue, summarize their substantial lifetime contributions to this field and, through their experience, chronicle the changes that have occurred over the past 50 years. Perhaps the most significant observation made by the authors in their report has been the impact of early thyroidectomy on the presence of disease and identifiable metastasis, assessed by histological evaluation of the thyroid gland and lymph nodes removed for treatment of MTC. For those non-index patients with American Thyroid Association (ATA)-labeled level C (high-risk) mutations (13), the percentage with MTC found in the thyroid gland at thyroidectomy has fallen from 100% in the 1985–1989 period to 19% in the 2010–2014 period. This dramatic decrease was caused initially by provocative testing that lowered the age of thyroidectomy to an average of 13 years, with a drop from 100% MTC to approximately 50% in the series of cases that encompassed the period from 1971–1988 (6). The decline was further accelerated by the rapid adoption of genetic testing and the acceptance of the recommendation that children with level C mutations undergo thyroidectomy by age 5 or 6 years. Interestingly, there has not been a comparable decline in the MTC or node positivity in the level A or B mutations, a point to which we will return later. Another important observation, highlighted by their data, is the shift in frequency of specific mutations over the past 20 years. In the classic report by Eng et al (14) in 1996, approximately 80% of mutations identified in MEN2 occurred at codon 634 of the RET proto-oncogene (Figure 1). Sipple’s syndrome, or classic MEN2A, the association of MTC, pheochromocytoma, and hyperparathyroidism caused most commonly by a codon 634 RET mutation, came to attention in 1961 (1) because it is a “noisy” syndrome with as many patients initially identified based on the presence of hypercalcemia or pheochromocytoma as MTC, facilitating its identification in the pregenetic era. Subsequent reports by Yip et al (15) in 2003 and Frank-

Calcitonin suppresses intervertebral disk degeneration and preserves lumbar vertebral bone mineral density and bone strength in ovariectomized rats

We investigated the effect of calcitonin (CT) on lumbar intervertebral disk degeneration (LIDD) in rats with ovariectomy-induced osteopenia. CT protected ovariectomized rats from LIDD by, at least in part, modifying extracellular matrix metabolism of the disks and preserving the microarchitecture and biomechanical properties of adjacent vertebrae. The present study aimed to investigate the effect of CT on lumbar vertebral bone mineral density and intervertebral disk degeneration in ovariectomized (OVX) rats. We first subjected 50 3-month-old female rats to either OVX (n = 30) or sham (n = 20). Twelve weeks later, ten OVX and ten sham rats were necropsied. The remaining OVX rats began to receive either saline vehicle (OVX + V, n = 10), or salmon CT (OVX + CT, 16 IU/kg/2 days, n = 10). After 12 weeks of treatment, necropsy was conducted and bone mineral density was determined in L3-4 and L5-6 vertebrae. The microstructure and biomechanical properties of L3 vertebrae were detected by micro-computed tomography and compression test, respectively. L5-6 was also used to measure intervertebral disk height and observe intervertebral disk histological changes by Van Gieson staining and histological scores, as well as immunohistochemistry (IHC) analysis of matrix metalloprotease (MMP)-1, MMP-13, and collagen II expression. At 12 weeks post-OVX, OVX rats had lower BV/TV and Tb.N and higher intervertebral disk histological score than sham rats. After 24 weeks, OVX + CT rats had higher BMD, BV/TV, Tb.N, and bone biomechanical strength values than OVX + V rats. Histological analysis showed OVX + CT rats had significantly lower disk degeneration scores than OVX + V rats. IHC analysis revealed CT treatment decreased expression of MMP-1 and MMP-13 and increased expression of collagen II compared with OVX + V rats. Our data demonstrate that CT-treated OVX rats display less intervertebral disk degeneration and favorable changes in intervertebral disk metabolism, associated with higher trabecular bone mass, better trabecular microarchitecture, and better biomechanical strength when compared to vehicle-treated OVX rats.

Calcitonin-Induced Acute Pancreatitis: A Case-Report

A 68 years old woman was admitted for abdominal pain, acute pancreatitis complicated with peripancreatic fluid collections. She has received steroid treatment during 12 months for pulmonary fibrosis, 60 mg/day Prednisone in the last months. Three weeks before her admission calcitonin treatment was introduced for osteoporotic vertebral fracture. The pancreatitis followed a benign clinical course; oral diet was reintroduced in two weeks. Some days later, calcitonin treatment was also reinitiated, followed by a recurrence of abdominal pain on the third day, accompanied by a second increase in blood pancreatic enzymes. On the fourth week of the acute exacerbation of pancreatitis the patient presented fever: bacterial infection of the demarcated fluid collections was confirmed by fine needle aspiration. The infected pseudocysts were drained percutaneously, guided by CT scan, with favorable evolution, almost complete disappearence of them in two weeks. The patient died three months later, as a consequence of her pulmonary disease. The acute pancreatitis developed in the second week after initiation of calcitonin treatment and an acute recurrence was observed after a three-day “accidental rechallenge”. No other known etiology of acute pancreatitis was detected. We conclude that calcitonin should be considered as a probable cause of a drug-induced pancreatitis

Effects of salmon calcitonin treatment on serum and synovial fluid bone formation and resorption markers in osteoporosis patients.

This study aimed to evaluate the effects of salmon calcitonin, and calcium and vitamin D treatment on bone mineral density, serum and synovial fluid bone formation and resorption markers in patients with osteoporosis. The study was completed with twenty-five osteoporosis patients divided into two groups: The 15 patients comprising Group I (1 male and 14 females; mean age: 67.0±12.0) were administered calcitonin treatment in addition to calcium and vitamin D. The 10 patients in Group II (3 males and 7 females; mean age 68.0±16.0) were administered calcium and vitamin D only. Serum and synovial fluid calcium phosphorus, alkaline phosphatase, calcitonin, C-telopeptide (CTx), N-telopeptide (NTx) and sialoprotein levels, and bone densitometries were determined at the beginning and at the end of one year of treatment. In the calcitonin and calcium and vitamin D treatment group (Group I), femoral neck density scores were decreased and vertebrae scores were increased after one-year treatment. Both scores were increased in the non-calcitonin group (Group II). In Group I, synovial fluid levels of calcitonin, sialoprotein and NTx were decreased, and synovial fluid CTx levels showed no change. The only decrease that was statistically significant was that in calcitonin levels. In Group II, synovial fluid calcitonin levels were decreased, synovial fluid CTx levels were increased and synovial fluid NTx and sialoprotein level were unchanged. These changes were not statistically significant. Serum changes in the parameters were not statistically significant in either group. In osteoporosis, salmon calcitonin treatment affects synovial fluid bone formation and absorption marker levels. Advanced studies are needed to evaluate the mechanisms by which this takes place, and to explain the relationship between osteoporosis and articular cartilage metabolism.

Calcitonin treatment is associated with less severe osteoarthritis and reduced toll-like receptor levels in a rat model

Background Studies indicate that inflammation promotes progression of osteoarthritis. Cartilage damage is aggravated by the binding of toll-like receptors and endogenous ligands that release large amounts of cytokines and inflammation mediators. Calcitonin can inhibit degeneration of articular cartilage, by inhibiting activation of toll-like receptors and generation of endogenous ligands. To study the effect of calcitonin in the pathogenesis of osteoarthritis and the underlying molecular mechanism, we monitored levels of toll-like receptors during osteoarthritis progression, and after calcitonin injection.Methods Male Sprague–Dawley rats were randomly assigned to either a surgery-only or a calcitonin-treatment group (n = 35, each). To induce osteoarthritis, the anterior cruciate ligament and the medial meniscus were cut in the right knees of both groups. Rats in the calcitonin-treatment group received a subcutaneous injection of 15 IU/kg calcitonin once every other day, starting one day post-surgery, until euthanised. Signs of osteoarthritic changes were noted. The amount of collagen II was measured by antibody staining. The amounts of MMP1 and MMP3 in cartilage were measured by use of ELISA. RNA from operated and matched control knee cartilage was extracted to determine expression levels of Col2a1, ACAN, Tlr2, Tlr3, and Tlr4.Results Signs of osteoarthritis were less severe in rats treated with calcitonin. In the surgery-only group, Tlr2 levels increased early after surgery and then decreased substantially by the latter stages. Tlr3 levels gradually increased and correlated with the severity of osteoarthritis. Tlr4 levels were high but fluctuated over the experimental period. Calcitonin treatment was associated with lower Tlr3 and Tlr4 levels than in the surgery-only group whereas Tlr2 expression was initially lower but increased 28 days after administration of calcitonin.Conclusion Calcitonin treatment may lessen the severity of osteoarthritis in the rat model, perhaps by inhibition of Tlr expression in cartilage.

Nonuremic calciphylaxis precipitated by teriparatide [rhPTH(1–34)] therapy in the setting of chronic warfarin and glucocorticoid treatment

Calciphylaxis occurs rarely in the absence of end stage renal disease. Predisposing factors for nonuremic calciphylaxis (NUC) include hyperparathyroidism, coagulopathies, connective tissue disease, liver disease, glucocorticoid use, and malignancy. Warfarin can facilitate vascular calcification by reducing vitamin K-dependent carboxylation of matrix-Gla proteins. An 86-year-old Caucasian woman with a history of polymyalgia rheumatica, two spontaneous deep venous thromboses (DVTs) and multiple fractures was treated with calcium, vitamin D, prednisone, and warfarin. The patient's low bone density was treated initially with estrogen, then oral bisphosphonate, which was discontinued due to upper gastrointestinal symptoms. Nasal calcitonin was initiated. After 10 years of calcitonin treatment, she was changed to teriparatide. Two months after initiating teriparatide, she developed lower extremity edema and painful erythematous nodular lesions on her calves bilaterally, that progressed to necrotic ulcers despite antibiotic therapy. Biopsy of the lesions showed calcification in the media of small blood vessels and subcutaneous fat with fat necrosis, consistent with calciphylaxis. Teriparatide was discontinued. Aggressive wound care, antibiotics, and intravenous zoledronic acid were initiated. With cessation of teriparatide therapy and intensive wound care, the patient's lesions resolved over 8 months. We report the first case of NUC precipitated by teriparatide therapy. Our patient had multiple underlying predisposing factors including a connective tissue disorder, glucocorticoid therapy, warfarin use, and possible underlying coagulopathy given her history of multiple DVTs. In such patients, alternative osteoporosis therapies may be preferred.

The Potential Protective Effects of Calcitonin Involved in Coordinating Chondrocyte Response, Extracellular Matrix, and Subchondral Trabecular Bone in Experimental Osteoarthritis

Previous reports indicate a potential role for calcitonin (CT) in the treatment of osteoarthritis (OA). To evaluate this potential therapeutic role, we investigated the effect of CT pretreatment on the activation of mitogen-activated protein kinase (MAPK) signaling and the expression of matrix metalloproteinase-13 (MMP-13) in interleukin-1β (IL-1β)-induced chondrocytes, and further assessed its protective effect in a rat model of anterior cruciate ligament transection (ACLT), using sham-operated and saline-treated controls. Using western blotting in vitro, we found that CT pretreatment inhibited the IL-1β-induced phosphorylation of 38,000-dalton protein (p38) and extracellular regulated protein 1/2 (ERK1/2) and reduced the expression of MMP-13 protein. For the in vivo experiment, 30 male rats were randomly divided into three groups of 10, subjected to bilateral ACLT or sham surgery, and then treated for 12 weeks with subcutaneous injections of CT or normal saline. Histological observations showed that CT treatment reduced the severity of the cartilage lesions stemming from the ACLT surgery and provided a lower Mankin score when compared with that determined for rats in the saline-treated ACLT group. Immunohistochemical staining revealed that CT treatment increased type II collagen expression and decreased MMP-3 and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) expression when compared with the saline-treated group. Subchondral bone analysis indicated that CT treatment inhibited the reduction in bone mineral density observed in the saline-treated ACLT group and reduced the ACLT-induced destruction to the subchondral trabecular microstructure. Our data demonstrate that CT induces its protective effects by reducing the chondrocyte response to inflammatory stimuli, cartilage extracellular matrix degradation, and subchondral trabecular microstructure damages brought on by OA.

Changes in Blood Pressure after the First Dose of Calcitonin (Elcatonin)

We had found previously that calcitonin treatment (elcatonin once a week for 10 weeks) results in significant decreases in blood pressure. The aim of the present study was to determine whether these effects were due to a cumulative effect of elcatonin or could be elicited by treatment with a single dose. To this end, we recruited 62 patients (eight men, 54 women; mean age 83 years; range 67-101 years) with a chief complaint of lower back pain to the present study and examined changes in blood pressure following administration of the first dose of elcatonin. All subjects in the study had been hospitalized either at our institution or an affiliated hospital. After acute phase symptoms had settled, subjects received 1 U (1mL), i.m., elcatonin S20. Blood pressure was measured the day before the first scheduled treatment and on the day of treatment. Both systolic and diastolic blood pressure decreased from 2 h after administration, and dropped significantly 4 and 6 h after administration. Therefore, elcatonin decreased blood pressure without first having to be accumulated in the body. There are several possible explanations for the results, including effects mediated by changes in concentrations of calcitonin gene-related peptide and calcium ions, as well as involvement of the parasympathetic nervous system. In conclusion, calcitonin inhibits bone resorption and pain, lowers blood pressure, and is easy to use in elderly patients who exhibit age-related increases in blood pressure.

One-time injection of calcitonin induces glucose intolerance in children with the first degree obesity

The effect of calcitonin on the blood glucose level in glucose-tolerance test of children with the first degree obesity was studied. Initial blood glucose level was normal and glucose-tolerance test per os didn’t expose glucose tolerance impairment in children under control. Calcitonin didn’t change initial glucose concentration but evoked impairment of glucose tolerance. The girls with the first degree obesity were more sensitive to hyperglycemic effect of calcitonin than the boys. Sex specificities must be taken into consideration in calcitonin treatment. Besides one ought mean that the increasing secretion of calcitonin occurs in stress-reactions. In these conditions endogenous calcitonin can make the same effect on the regulation of carbohydrate metabolism as exogenous injections of hormone.

Administration of calcitonin promotes blastocyst implantation in mice by up-regulating integrin 3 expression in endometrial epithelial cells

Does exogenous calcitonin improve the efficiency of implantation in mice by increasing uterine receptivity? The administration of calcitonin could improve the efficiency of implantation by increasing the expression of several receptivity-related genes in endometrial epithelial cells (EECs). Calcitonin is one of the biomarkers of uterine receptivity, which is transiently produced in the uterine epithelia during the period of implantation both in humans and mouse. Hormone-replaced mice were used for in vivo experiments. To evaluate the effect of calcitonin on uterine receptivity, the expression of endometrial genes was analyzed 36 h after i.p. injection of 0.5 IU calcitonin in a treatment group versus saline in the control. To evaluate the effect of calcitonin on implantation efficiency in vivo, two groups received 0.5 IU or 2 IU calcitonin (i.p.) 24 h before embryo transfer, and a control group received saline (i.p.) (n = 18 mice per group). Implantation sites were counted 7 days after embryo transfer. The RL95-2 human endometrial carcinoma cell line was used to study the mechanisms underlying the effect of calcitonin on gene expression in the endometria. Using an in vitro model of endometrium-trophoblast interaction, established with RL95-2 cells and JAR (human choriocarcinoma cell line) trophoblast, endometrial receptivity was evaluated by comparing attachment and outgrowth of JAR spheroids in control and treatment groups. Uterine receptivity in ovariectomized mice was induced by injection of estradiol and progesterone. Expression of eight genes in murine endometrium and RL95-2 cells was analyzed by real-time RT-PCR, western blot, immunohistochemical analysis, flow cytometry and enzyme-linked immunosorbent assay. We tested the effects of a protein kinase C inhibitor, matrigel and an antibody against integrin αvβ3 using RL95-2 cells and performed attachment and outgrowth assays using the in vitro model of endometrium-trophoblast interaction. Implantation efficiency was evaluated by counting the implantation sites after embryo transfer. Calcitonin up-regulated αvβ3 in RL95 cells, which in turn resulted in increased levels of the leukemia inhibitory factor (LIF) and heparin binding-epidermal growth factor (HB-EGF) mRNA (both P < 0.01 versus control) and protein (both P < 0.05 versus control). The attachment and expansion of JAR spheroids was promoted by pretreatment of EECs with calcitonin (P < 0.05 versus control) together with significantly increased expression of αvβ3, LIF and HB-EGF. Moreover, the injection of calcitonin in the preimplantation phase increased the total number of implantation sites in treatment groups (55 in control versus 78 and 85 in 0.5 and 2 IU groups, respectively). Compared with the control group (3.11 ± 2.14), the average number of implantation sites in the 2 IU calcitonin treatment group increased (4.72 ± 1.87, P = 0.022). Experiments were performed in mice and human cell lines but not in primary cultures of human endometrial cells. The findings presented here have important implications, in that calcitonin administration (currently used for treatment of hypercalcemia or osteoporosis) may have clinical benefits in assisted reproduction programs, by facilitating endometrial receptivity and embryo implantation. However, further studies are required to confirm these findings. This work was supported by National Science Foundation of China (No. 81170619). There are no financial or commercial conflicts in this study.

The role of the ERK1/2 pathway as an alternative to the aging-diminished cyclic AMP pathway in calcitonin-mediated chondrogenesis in human nucleus pulposus

Human disc degeneration initiated by aging in the central nucleus pulposus (hNP) is an irreversible process and the recovery has become seriously emerging. In this study, the related mechanisms of calcitonin on the regeneration of hNP and the effects of calcitonin on the age-related alterations were examined. The harvested hNP population was designated as YhNP (from young donor, age <50) and OhNP (from old donor, age >50). Primary OhNP cells showed more hypertrophic phenotypes than YhNP. However, calcitonin (10−8–10−6 M) was able to induce the same chondrogenesis in both YhNP and OhNP by elevating chondrogenic specific-mRNA and protein expressions. Their cell viabilities were increased with calcitonin treatment. No significant differences of calcitonin receptor (CTR) were expressed between YhNP and OhNP cells. Interestingly, in calcitonin-induced pathways for chondrogenesis, highly increased cyclic AMP (cAMP) was detected in YhNP but was strongly diminished by aging in OhNP after calcitonin treatment. However, to maintain the chondrogenesis, calcitonin-induced an alterative phosphorylated ERK1/2 (p-ERK) in both cells. After inhibiting ERK1/2 by PD98059, calcitonin-induced chondrogenesis in OhNP was almost restrained while YhNP cells were not affected. Our results demonstrated that the regeneration of calcitonin on hNP was maintained with aging which was satisfied by an alternative signaling pathway. Therefore, calcitonin shows great potential for clinical therapy for disc regeneration without aging considerations.

Effects of calcitonin on knee osteoarthritis and quality of life

There has been a recent interest in calcitonin as a potential treatment for osteoarthritis, based on its metabolic activities in both bone turnover and cartilage. The aim of this study was to evaluate the effects of nasal form calcitonin on knee osteoarthritis and quality of life in women who receive calcitonin treatment for postmenopausal osteoporosis. Two hundred and twenty postmenopausal women, aged between 55 and 65 years with knee pain and knee osteoarthritis, graded II-III by using Kellgren-Lawrence radiographic scoring system, were included. Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, the quality of life questionnaire of the European Foundation for Osteoporosis (QALEFFO-41) and visual analog scale were used for the algofunctional assessments. Need of rescue analgesic was recorded. Pain (P < 0.001), stiffness (P < 0.05), functional capability (P < 0.05) and total score of WOMAC (P < 0.05) revealed statistically significant improvements after 3 months of the treatment and remained consistent throughout 1 year of the treatment period. Participants experienced significant reductions in WOMAC perceptions of pain (-53 %), joint stiffness (-44 %) and limitations in physical function (-49 %) at the end of 1 year of calcitonin treatment. Need of rescue analgesic intake was reported to have decreased approximately by 60 % at the end of the 1-year treatment period. QUALEFFO_41 scores improved: 37.6 (baseline), 30.9 (3 months), 28.0 (6 months) and 24.4 (1 year). In conclusion, nasal calcitonin treatment provided dual action on osteoporosis and osteoarthritis with significant improvements in quality of life and algofunctional results in knee osteoarthritis.

Concurrent Parathyroid Carcinoma and Hyperplasia in Hyperparathyroidism

Concurrent Parathyroid Carcinoma and Hyperplasia in Hyperparathyroidism

The diagnosis and management of giant cell lesions of the jaws

This article will review current thoughts with regard to the etiology, histopathology, diagnosis, and management of giant cell lesions of the jaws. It will attempt to point out the differences between these lesions and giant cell lesions elsewhere in the body and also the current techniques for medical management of these conditions including steroid injections, calcitonin treatment, and alpha interferon treatment.

Hormone-stimulated modulation of endocytic trafficking in osteoclasts

A precise control of vesicular trafficking is crucial not only for osteoclastic bone resorption, but also for the crosstalk between osteoclasts and osteoblasts, which regulates bone homeostasis. In addition to the release of growth factors and modulators, such as glutamate, flux through the intracellular trafficking routes could also provide the osteoclast with a monitoring function of its resorption activity. To establish the signaling pathways regulating trafficking events in resorbing osteoclasts, we used the bone conserving hormone calcitonin, which has the unique property of inducing osteoclast quiescence. Calcitonin acts through the calcitonin receptor and activates multiple signaling pathways. By monitoring trafficking of a fluorescent low molecular weight probe in mature, bone resorbing osteoclasts we show for the first time that calcitonin blocks endocytosis from the ruffled border by phospholipase C (PLC) activation. Furthermore, we identify a requirement for polyunsaturated fatty acids in endocytic trafficking in osteoclasts. Inhibition of PLC prior to calcitonin treatment restores endocytosis to 75% of untreated rates. This effect is independent of protein kinase C activation and can be mimicked by an increase in intracellular calcium. We thus define an essential role for intracellular calcium levels in the maintenance of endocytosis in osteoclasts.

REGIONAL MIGRATORY OSTEOPOROSIS IN OLDER ADULTS: A NEW TWIST TO AN OLD DISEASE

To the Editor: A 72-year-old man presented with pain and limited motion in the right hip joint for the last 50 days. He described the symptoms as occurring mainly during walking and prolonged upright stance but not at rest. He denied any antecedent injury, and his current medical history was noncontributory. Further review of his medical files revealed that 20 years earlier he had two episodes of regional migratory osteoporosis (RMO) in the left hip (1989) (Figure 1A) and right knee (1990). He had a complete recovery under calcitonin treatment combined with a rehabilitation protocol of initial limited weight bearing followed by therapeutic exercise. (A) Anterior view from bone scintigram (1989) demonstrating avid radiotracer uptake mainly in the left hip joint. (B) Anteroposterior X-ray (2010) showing initial demineralization of right femoral head. (C) Coronal T1-weighted magnetic resonance imaging (2010) showing low signal intensity in the right femoral head and neck (bone marrow edema). His current physical examination revealed mild tenderness on palpation over the right groin area and upper thigh, atrophy of the quadriceps, pain-induced restriction in hip range of motion, and antalgic gait. Laboratory analysis, including complete blood count; erythrocyte sedimentation rate; liver, kidney, and thyroid function tests; and parathyroid hormone and vitamin D levels, was unremarkable. Hip X-ray performed 5 to 6 weeks after the onset of symptoms showed initial demineralization of the right femoral head with a thin but intact subchondral line and preserved joint space (Figure 1B). Bone mineral densitometry (lumbar quantitative computed tomography) was normal. Bone scintigraphy and magnetic resonance imaging (MRI) (Figure 1C) were consistent with transient osteoporosis of the hip (TOH),1 and overall he was diagnosed as having a recurrence of RMO, after a lapse of 20 years. He was started on a combination of alendronate, calcium, and vitamin D, with a rehabilitation protocol consisting of limited weight bearing (use of two crutches) associated with progressive non-weight-bearing strengthening exercises. After 2 months, pain and limping disappeared. RMO is an uncommon condition characterized by migrating arthralgia of the weight-bearing joints in the lower extremities associated with severe focal osteoporosis. Secondary joints are generally involved within the first year of the initial episode. Middle-aged men are most commonly affected.2 Early radiographic changes are often subtle and lag behind the clinical symptoms by 3 to 6 weeks.3 Bone scintigraphy and MRI are crucial for early diagnosis. Management is conservative and mainly directed toward pain management, osteoporosis treatment, limited weight bearing, and therapeutic exercise. TOH and RMO have been histologically considered to be a form of “high remodeling” osteoporosis,3 but their pathophysiology is under debate. It has not been established whether TOH and RMO represent distinct conditions or are part of a common spectrum of “bone marrow edema” syndromes3,4 that range from these self-limiting clinical entities to more-severe conditions, such as subchondral fractures4,5 and avascular necrosis.6 The reason this case is being reported is twofold. First, to the knowledge of the authors, this case represents the longest duration between two RMO episodes; before this, the longest interim reported in the literature was 11 years.3 Second, bearing in mind the devastating scenarios linked to some hip pathologies in older adults, physicians' attention should be drawn to the clinical problem of TOH and RMO (which can easily be overlooked), its differential diagnosis (particularly with subchondral fractures and incipient osteonecrosis of the femoral head3–6), and its possible severe complications (e.g., hip fracture), also often overlooked.7 Thus, especially in older adults with a positive history of RMO, long-term follow-up is of paramount importance. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Study concept and design: GF, LÖ, FF. Acquisition of subjects and data: GF, FF. Analysis and interpretation of data: GF, LÖ, FF. Preparation of manuscript: GF, LÖ, FF. Sponsor's Role: None.

Oral salmon calcitonin reduces cartilage and bone pathology in an osteoarthritis rat model with increased subchondral bone turnover

Traumatic osteoarthritis (OA) is possibly augmented by effects from loss of sex hormones. Salmon calcitonin is shown to reduce OA pathogenesis and bone resorption. We investigated the effects of oral salmon calcitonin treatment and ovariectomy on cartilage and bone pathology in a traumatic OA model. Six groups with 10 7-month-old female Sprague Dawley rats each were subjected to bilateral meniscectomy (MNX), ovariectomy (OVX) or Sham surgery and treated for 8 weeks with oral salmon calcitonin (CT) or vehicle (V) in the following way: (1) Sham+V; (2) MNX+V; (3) MNX+CT; (4) OVX+V; (5) MNX/OVX+V; (6) MNX/OVX+CT. Weights were recorded weekly and CTX-II was measured in serum. At termination 56 days post-surgery, the right tibia was analyzed for changes in articular cartilage thickness, extent of cartilage damage and subchondral bone changes in predefined zones, as recommended in the novel OARSI histopathology score. The combined MNX/OVX model produced a significantly reduced cartilage thickness (P=0.033) in the outer zone (Z1) of the tibial plateau and increased calcified cartilage damage (P=0.0004) and serum CTX-II (P=0.003). Addition of OVX to MNX significantly increased the width of matrix damage at the surface (P=0.025) and 50% cartilage depth (P=0.004). Treatment with oral salmon calcitonin counteracted the loss of cartilage thickness (P=0.055), significantly reduced subchondral bone damage score (P=0.019) and reduced the type II collagen degradation (P=0.009). Addition of ovariectomy augmented site-specific traumatic OA pathology, which was reduced by oral salmon calcitonin treatment. Treatments for OA might ideally affect both bone and cartilage.

Calcitonin-induced alterations to the ultimobranchial and parathyroid glands in the garden lizard Calotes versicolor

Calotes versicolor specimens were divided into 2 groups of equal quantity (groups A and B). Group A was injected daily with 0.1 mL/50 g bw of vehicle. Group B was injected daily with 0.5 \mug/50 g bw of salmon calcitonin. Lizards in each group were sacrificed 2 h after the last injection on the 1st, 3rd, 5th, 10th, and 15th day of treatment. After collection of blood samples, ultimobranchial and parathyroid glands were fixed. The plasma calcium level in the lizards treated with calcitonin decreased on day 1. This response progressed up to day 5; thereafter the level was elevated, so that on day 15 a normal plasma calcium level was achieved. No change in plasma phosphate levels from day 1 was observed following calcitonin treatment. Progressive hypophosphatemia was observed from day 3 to 5; thereafter the level tended to rise and resulted in normophosphatemia on day 15. The ultimobranchial gland in the lizards treated with calcitonin did not exhibit any histological alterations up to day 5. The nuclear volume of ultimobranchial cells decreased on day 10 and persisted until day 15. Additionally, few degenerating cells were observed after 15 days of calcitonin treatment. The parathyroid gland in C. versicolor was unaffected up to day 3 following calcitonin treatment. A progressive increase in the nuclear volume of parathyroid cells was observed from day 5 until the end of the experiment (day 15); the gland became compact on days 10 and 15. In addition, few degenerating cells were observed after 15 days of calcitonin treatment.

Biochemical markers identify influences on bone and cartilage degradation in osteoarthritis - the effect of sex, Kellgren-Lawrence (KL) score, Body Mass Index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation

BackgroundOsteoarthritis (OA) involves changes in both bone and cartilage. These processes might be associated under some circumstances. This study investigated correlations between bone and cartilage degradation in patients with OA as a function of sex, Kellgren-Lawrence (KL) score, Body Mass Index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation.MethodsThis study was a 2-week, double-blind, double-dummy, randomized study including 37 postmenopausal women and 36 men, aged 57-75 years, with painful knee OA, and a KL-score of I - III. Subjects were allocated to one of three treatment arms: 0.6 mg or 0.8 mg oral sCT, or placebo given twice-daily for 14 days. Correlations between gender, KL score, or BMI and the bone resorption marker, serum C-terminal telopeptide of collagen type I (CTX-I), or the cartilage degradation marker, urine C-terminal telopeptide of collagen type II (CTX-II) were investigated.ResultsAt baseline, biomarkers indicated women with OA experienced higher bone and cartilage degradation than men. CTX-I levels were significantly higher, and CTX-II levels only marginally higher, in women than in men (p = 0.04 and p = 0.06, respectively). Increasing KL score was not correlated with bone resorption, but was significantly associated with the cartilage degradation CTX-II marker in both men and women (p = 0.007). BMI was significantly and negatively correlated to the bone resorption marker CTX-I, r = -0.40 (p = 0.002), but showed only a borderline positive correlation to CTX-II, r = 0.25 (p = 0.12). Before morning treatments on days 1 and 14, no correlation was seen between CTX-I and CTX-II in either the sCT or placebo group. However, oral sCT and food intake induced a clear correlation between these bone and cartilage degradation markers. Four hours after the first sCT dose on treatment days 1 and 14, a significant correlation (r = 0.71, p < 0.001) between changes in both CTX-I and CTX-II was seen. In the placebo group a weakly significant correlation between changes in both markers was found on day 1 (r = 0.49, p = 0.02), but not on day 14.ConclusionBone resorption was higher in females than males, while cartilage degradation was correlated with increasing KL-score and only weakly associated with BMI. Bone and cartilage degradation were not correlated in untreated individuals, but dosing with oral sCT with or without food, and a mid-day meal, decreased bone and cartilage degradation and induced a correlation between both markers. Changes in bone and cartilage markers may aid in the identification of potential new treatment opportunities for OA.Trial RegistrationClinical trial registration number (EUDRACT2006-005532-24 & NCT00486369)

Novel oral calcitonin treatment reduces cartilage loss in OA rat model with increased subchondral bone turnover

Novel oral calcitonin treatment reduces cartilage loss in OA rat model with increased subchondral bone turnover