Neuropathic and Nociplastic Pain Profiles are Common in Adult Chronic Nonbacterial Osteitis (CNO).

Chronic nonbacterial osteitis (CNO) is a rare musculoskeletal disease causing chronic bone pain. It is known that chronic musculoskeletal pain may involve other mechanisms than nociceptive pain only. We investigate the prevalence of neuropathic and nociplastic pain in adult CNO and their association with clinical characteristics and treatment outcomes. Survey study among the Dutch adult CNO cohort (n = 84/195 participated), including PAIN-detect for neuropathic pain, and the Central Sensitization Inventory (CSI), Fibromyalgia Rapid Screening Tool (FiRST), and ACTTION-APS Pain Taxonomy (AAPT) for nociplastic pain. Clinical characteristics and CNO-related bone pain scores were compared between patients with exclusive nociceptive pain and those with nociceptive pain plus neuropathic and/or nociplastic pain (mixed pain). 31% (95% CI 21-41) of patients classified as likely having neuropathic pain according to PAIN-detect. 53% (41-64) of patients displayed central sensitization on CSI, 61% (50-72) screened positive for fibromyalgia on FiRST and 14% (7-23) of patients fulfilled the AAPT criteria, all indicative of nociplastic pain. Mixed pain was associated with longer diagnostic delay (mean difference 2.8 years, 95% CI 0.4-5.2, p = 0.023), lower educational level (72% versus 20%, p < 0.001), and opioid use (37% versus 13%, p = 0.036). Despite comparable disease severity and extent, patients with mixed pain reported significantly higher CNO-related bone pain scores. This study demonstrates the high prevalence of mixed pain in adult CNO, in which neuropathic and nociplastic pain exist alongside nociceptive inflammatory bone pain. Disease burden in CNO may extend beyond inflammatory activity, highlighting the need for a multifaceted management approach.

Clinical and therapeutic diversity in adult chronic nonbacterial osteomyelitis (CNO) of the sternocostoclavicular region: a meta-analysis.

OBJECTIVES: Chronic nonbacterial osteomyelitis (CNO) is a rare inflammatory bone disease. The distinct CNO subtype that affects the anterior chest wall is descriptively named sternocostoclavicular hyperostosis (SCCH) and mainly occurs in adults. Literature on CNO/SCCH is scattered and lacks diagnostic and therapeutic consensus. METHODS: Systematic review and meta-analysis aiming to characterize clinical presentation and therapeutic modalities applied in adult CNO/SCCH patients. Untransformed numerical data and double-arcsine transformed proportional data were pooled in a random effects model in R-4.0.5; proportions were reported with 95% CI. RESULTS: Forty studies were included, containing data on 2030 and 642 patients for aim 1 and 2, respectively. A female predisposition (67%, 95% CI 60, 73) and major diagnostic delay (5 years 95% CI 3, 7) were noted. Clinical presentation included chest pain (89%, 95% CI 79, 96) and swelling (79%, 95% CI 62, 91). Patients suffered from pustulosis palmoplantaris (53%, 95% CI 37, 68), arthritis (24%, 95% CI 11, 39) and acne (8%, 95% CI 4, 13). Inflammatory markers were inconsistently elevated. Autoantibody and HLA-B27 prevalence was normal, and histopathology unspecific. Increased isotope uptake (99%, 95% CI 96, 100) was a consistent imaging finding. Among manifold treatments, pamidronate and biologicals yielded good response in 83%, 95% CI 60, 98 and 56%, 95% CI 26, 85, respectively. CONCLUSION: CNO/SCCH literature proves heterogeneous regarding diagnostics and treatment. Timely diagnosis is challenging and mainly follows from increased isotope uptake on nuclear examination. Biopsies, autoantibodies and HLA status are non-contributory, and biochemical inflammation only variably detected. Based on reported data, bisphosphonates and biologicals seem reasonably effective, but due to limitations in design and heterogeneity between studies the precise magnitude of their effect is uncertain. Fundamentally, international consensus seems imperative to advance clinical care for CNO/SCCH.

Reference Intervals for Bone Impact Microindentation in Healthy Adults: A Multi-Centre International Study.

Impact microindentation (IMI) is a novel technique for assessing bone material strength index (BMSi) in vivo, by measuring the depth of a micron-sized, spherical tip into cortical bone that is then indexed to the depth of the tip into a reference material. The aim of this study was to define the reference intervals for men and women by evaluating healthy adults from the United States of America, Europe and Australia. Participants included community-based volunteers and participants drawn from clinical and population-based studies. BMSi was measured on the tibial diaphysis using an OsteoProbe in 479 healthy adults (197 male and 282 female, ages 25 to 98 years) across seven research centres, between 2011 and 2018. Associations between BMSi, age, sex and areal bone mineral density (BMD) were examined following an a posteriori method. Unitless BMSi values ranged from 48 to 101. The mean (± standard deviation) BMSi for men was 84.4 ± 6.9 and for women, 79.0 ± 9.1. Healthy reference intervals for BMSi were identified as 71.0 to 97.9 for men and 59.8 to 95.2 for women. This study provides healthy reference data that can be used to calculate T- and Z-scores for BMSi and assist in determining the utility of BMSi in fracture prediction. These data will be useful for positioning individuals within the population and for identifying those with BMSi at the extremes of the population.

Osteoporosis in children and adolescents: how to treat and monitor?

Osteoporosis is a condition of increased bone fragility associated with fractures. Apart from primary genetic osteoporotic conditions, secondary osteoporosis in children is being increasingly recognized. As a result, there is growing interest in its prevention and treatment. Important goals of care are to prevent fractures, increase bone mass and trabecular and cortical thickness, reshape vertebral fractures, prevent (or correct) skeletal deformities, and improve mobility, independence, and quality of life. Secondary pediatric osteoporosis is often of multifactorial origin since affected children frequently have more than one acquired factor that is detrimental to bone health. Typical conditions causing osteoporosis are leukemias, progressive muscle or neurological disorders, as well as chronic inflammatory conditions and their treatment. Management of children with osteoporosis involves a multidisciplinary team involving pediatric experts from different subspecialties. With regard to prevention and early intervention, it is important to provide optimal management of any underlying systemic conditions including avoidance, or dose-reduction, of osteotoxic medications. Basic supporting life-style measures, such as appropriate nutrition, including adequate calcium intake and vitamin D, and physical activity are recommended, where possible. When pediatric treatment criteria for osteoporosis are met, antiresorptive drugs constitute the first pharmacological line treatment. CONCLUSION: This clinical review focuses on the prevention, treatment, and follow-up of children with, or at risk of developing, osteoporosis and the transition from pediatric to adult care. WHAT IS KNOWN: • Osteoporosis and associated fractures can cause significant morbidity and reduce the quality of life. • The developing skeleton has huge potential for recovery and reshaping, thus early detection of fractures, assessment of recovery potential, and treatment of children with osteoporosis can prevent future fractures, deformities, and scoliosis, improve function and mobility, and reduce pain. WHAT IS NEW: • Osteoporosis in children and adolescents requires a multidisciplinary approach with a thorough assessment of recovery potential, and indication for therapy should be personalized. • Although bisphosphonates still represent the drug most commonly used to increase bone mass, improve mobility, and reduce pain and recurrence of fractures, new agents are being developed and could be beneficial in children with specific conditions.

Osteoporosis in children and adolescents: when to suspect and how to diagnose it.

Early recognition of osteoporosis in children and adolescents is important in order to establish an appropriate diagnosis of the underlying condition and to initiate treatment if necessary. In this review, we present the diagnostic work-up, and its pitfalls, of pediatric patients suspected of osteoporosis including a careful collection of the medical and personal history, a complete physical examination, biochemical data, molecular genetics, and imaging techniques. The most recent and relevant literature has been reviewed to offer a broad overview on the topic. Genetic and acquired pediatric bone disorders are relatively common and cause substantial morbidity. In recent years, there has been significant progress in the understanding of the genetic and molecular mechanistic basis of bone fragility and in the identification of acquired causes of osteoporosis in children. Specifically, drugs that can negatively impact bone health (e.g. steroids) and immobilization related to acute and chronic diseases (e.g. Duchenne muscular dystrophy) represent major risk factors for the development of secondary osteoporosis and therefore an indication to screen for bone mineral density and vertebral fractures. Long-term studies in children chronically treated with steroids have resulted in the development of systematic approaches to diagnose and manage pediatric osteoporosis. CONCLUSIONS: Osteoporosis in children requires consultation with and/or referral to a pediatric bone specialist. This is particularly relevant since children possess the unique ability for spontaneous and medication-assisted recovery, including reshaping of vertebral fractures. As such, pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children. WHAT IS KNOWN: • Both genetic and acquired pediatric disorders can compromise bone health and predispose to fractures early in life. • The identification of children at risk of osteoporosis is essential to make a timely diagnosis and start the treatment, if necessary. WHAT IS NEW: • Pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children and children at risk of osteoporosis. • We offer an extensive but concise overview about the risk factors for osteoporosis and the diagnostic work-up (and its pitfalls) of pediatric patients suspected of osteoporosis.

Comparative Effect of Zoledronate at 6 Versus 18 Months Following Denosumab Discontinuation.

Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures.Trial Registration: NCT02499237; July 16, 2015.

Practice variation in the treatment of patients with renal hyperparathyroidism: a survey-based study in the Netherlands.

BACKGROUND: Renal hyperparathyroidism is a disease entity that is complex and poorly understood. Although there are guidelines regarding how to manage this patient group, evidence is scarce. Therefore, this survey-based study aims to map the physicians' attitude in terms of preference for management of renal hyperparathyroidism and the influence of patient and respondent factors. METHODS: A survey was sent to Dutch societies of nephrology, endocrinology, and surgeons with interest in endocrine surgery. The survey consisted of eight case vignettes of renal hyperparathyroidism patients who were on hemodialysis and suitable for kidney transplantation, and varied in one of three patient variables import for decision making: age (40 vs. 65 years), parathyroid hormone (40 vs. 90 pmol/L), and serum calcium level (2.25 vs. 2.8 mmol/L). For each case, respondents could choose between maintaining conservative treatment (active vitamin D metabolites), calcimimetics, or subtotal parathyroidectomy as their treatment of choice. Categorical multilevel logistic models were used to investigate the association of patient and respondent variables with treatment preference. The influence of patient variables was determined independently of each other and by means of logistic regression the probabilities of treatment choice were calculated. RESULTS: In total, 115 surveys were included in the analysis. In 6 out of 8 cases, less than two-thirds of respondents agreed on the most favoured treatment. Among patient characteristics, the main disincentive for respondents not to choose conservative therapy was an elevated serum calcium level (subtotal parathyroidectomy vs conservative OR 93.1, 95%-CI: 48.39-179.07 and calcimimetics vs conservative OR 31.2 95%-CI: 18.58-52.30). Additionally, the most significant treatment differences were found between medical specialties and the experience of the respondents, expressed as the amount of cases the physician was involved in during the past year. CONCLUSIONS: Elevated serum calcium levels were widely recognized and the prime reason for respondents to abandon conservative treatment. However, considerable disagreement in treatment preferences remained throughout the cases, demonstrating the current literature available being inconclusive in guiding physicians. Therefore, a high-quality trial comparing subtotal parathyroidectomy to medical treatment is needed to determine optimal treatment.

Increased Bone Resorption during Lactation in Pycnodysostosis.

Pycnodysostosis, a rare autosomal recessive skeletal dysplasia, is caused by a deficiency of cathepsin K. Patients have impaired bone resorption in the presence of normal or increased numbers of multinucleated, but dysfunctional, osteoclasts. Cathepsin K degrades collagen type I and generates N-telopeptide (NTX) and the C-telopeptide (CTX) that can be quantified. Levels of these telopeptides are increased in lactating women and are associated with increased bone resorption. Nothing is known about the consequences of cathepsin K deficiency in lactating women. Here we present for the first time normalized blood and CTX measurements in a patient with pycnodysostosis, exclusively related to the lactation period. In vitro studies using osteoclasts derived from blood monocytes during lactation and after weaning further show consistent bone resorption before and after lactation. Increased expression of cathepsins L and S in osteoclasts derived from the lactating patient suggests that other proteinases could compensate for the lack of cathepsin K during the lactation period of pycnodysostosis patients.

Quantifying skeletal burden in fibrous dysplasia using sodium fluoride PET/CT.

PURPOSE: To quantify Na18F-PET/CT uptake in relation to clinical and biochemical parameters of fibrous dysplasia (FD) severity and healthy bone (HB) metabolism. Secondary aims: comparing normalization for volume of distribution and determining reproducibility of Na18F-PET/CT uptake parameters in HB and FD. Relating Na18F uptake to skeletal burden score (SBS), bisphosphonate therapy and pain measured by Brief Pain Inventory (BPI). METHODS: In a prospective cohort study (n = 20), Na18F-PET/CT parameters of HB and FD were assessed by two independent readers to determine the cutoff defining increased bone uptake, optimized normalization, and interobserver agreement (ICC) and were related to SBS, serum biomarkers, medication, and clinical parameters. RESULTS: Physiological bone standardized uptake value (SUV) was best normalized but displayed large interpatient variation (total range 4.1-13.7 g/mL), with very high interobserver agreement (ICC = 0.964). FD burden defined by patient-specific SUV cutoffs reached near-perfect agreement for SUVpeak (ICC = 0.994) and total lesion fluorination (TLF) (ICC = 0.999). TLF correlated weakly with SBS (R2 = 0.384, p = 0.047). TLF correlated positively with serum alkaline phosphatase (R2 = 0.571, p = 0.004) and procollagen type 1 N-terminal propeptide (R2 = 0.621, p = 0.002), SBS did not (p > 0.06). SBS and TLF both correlated with increased fibroblast growth factor-23 (R2 = 0.596, p = 0.007 and R2 = 0.541, p = 0.015, respectively). TLF was higher in use of bisphosphonates (p = 0.023), SBS was not. Average BPI scores correlated to increased FGF-23 (R2 = 0.535, p = 0.045), work-related BPI scores to higher SBS (R2 = 0.518, p = 0.024), higher TLF (R2 = 0.478, p = 0.036), and higher levels of FGF-23 (R2 = 0.567, p = 0.034). CONCLUSIONS: Individualized Na18F-PET/CT SUV cutoffs reproducibly discriminated HB from FD and were well-normalized. The strong relations of bone formation serum markers with Na18F-PET/CT FD burden measurements suggest clinical relevance over SBS as an adjunct instrument in FD patients. The correlation of both imaging modalities with increased work-related BPI scores also indicates clinical applicability. Moreover, SBS is known to remain stationary irrespective of use of medication, whereas TLF on Na18F-PET/CT was higher in baseline patients using bisphosphonates. This makes Na18F-PET/CT a promising tool to quantitatively measure treatment efficacy in FD.

Patients With Isolated Craniofacial Dysplasia Report Better Quality of Life Compared With Those With Craniofacial Dysplasia and Extracranial Involvement.

PURPOSE: Craniofacial fibrous dysplasia (CFD) is a subtype of fibrous dysplasia/McCune-Albright syndrome (FD/MAS) characterized by FD lesions in one or more of the skull bones. The orbit is often involved, with facial pain, facial deformity, and increased risk of compressive optic neuropathy as associated clinical manifestations possibly leading to altered illness perceptions and impairments in quality of life(QoL). The aim of this study was to evaluate illness perceptions and QoL in patients with CFD among our FD/MAS cohort. METHODS: One hundred ninety-one patients were included. Illness perceptions and QoL were assessed by using validated questionnaires, that is, the Illness Perceptions Questionnaire-Revised and the Short-Form 36. Patients were first grouped as CFD versus non-CFD, a second selection was based on the presence of "Isolated CFD" versus "CFD+PFD/MAS." Non-CFD patients were grouped as monostotic fibrous dysplasia "MFD" versus polyostotic "PFD/MAS." RESULTS: Patients with isolated CFD attributed less symptoms to their disease compared with patients with CFD+PFD/MAS (p < 0.05). Furthermore, patients with isolated CFD reported better QoL on all domains (except role emotional and mental health) compared with patients with CFD+PFD/MAS (p < 0.05). Patients with isolated CFD also reported better QoL compared with non-CFD groups (on 3 out of 8 subscales) (p < 0.05). CONCLUSIONS: Patients with isolated CFD attribute less symptoms to their disease and report better QoL compared with patients with CFD with extracranial involvement or FD without cranial involvement. These findings indicate that craniofacial involvement alone is not sufficient to cause negative illness perceptions and impairments in QoL. Therefore, it can be postulated that isolated CFD should be considered a unique patient subtype within the spectrum of FD/MAS patients.

Clinical and translational pharmacological aspects of the management of fibrous dysplasia of bone.

Fibrous dysplasia (FD) is a genetic, noninheritable rare bone disease caused by a postzygotic activating mutation of the α subunit of the stimulatory G-protein causing increased abnormal bone formation leading to pain, deformity and fractures. To date, no cure has been identified for FD/McCune-Albright syndrome (MAS) and treatment is symptomatic and aimed at decreasing pain and/or local bone turnover. Various drugs have been used to achieve clinical improvement in FD/MAS patients including bisphosphonates and denosumab, however further translational studies are also warranted to address unresolved pathophysiological issues and explore novel pharmacological targets for the management of FD/MAS. In this article, we review literature on the medical treatment of FD/MAS, discuss the unresolved pathophysiological issues and explore novel pharmacological targets for the management of FD/MAS.

Timing of Parathyroidectomy Does Not Influence Renal Function After Kidney Transplantation.

BACKGROUND: Parathyroidectomy (PTx) is the treatment of choice for end-stage renal disease (ESRD) patients with therapy-resistant hyperparathyroidism (HPT). The optimal timing of PTx for ESRD-related HPT-before or after kidney transplantation (KTx)-is subject of debate. METHODS: Patients with ESRD-related HPT who underwent both PTx and KTx between 1994 and 2015 were included in a multicenter retrospective study in four university hospitals. Two groups were formed according to treatment sequence: PTx before KTx (PTxKTx) and PTx after KTx (KTxPTx). Primary endpoint was renal function (eGFR, CKD-EPI) between both groups at several time points post-transplantation. Correlation between the timing of PTx and KTx and the course of eGFR was assessed using generalized estimating equations (GEE). RESULTS: The PTxKTx group consisted of 102 (55.1%) and the KTxPTx group of 83 (44.9%) patients. Recipient age, donor type, PTx type, and pre-KTx PTH levels were significantly different between groups. At 5 years after transplantation, eGFR was similar in the PTxKTx group (eGFR 44.5 ± 4.0 ml/min/1.73 m2) and KTxPTx group (40.0 ± 6.4 ml/min/1.73 m2, p = 0.43). The unadjusted GEE model showed that timing of PTx was not correlated with graft function over time (mean difference -1.0 ml/min/1.73 m2, 95% confidence interval -8.4 to 6.4, p = 0.79). Adjustment for potential confounders including recipient age and sex, various donor characteristics, PTx type, and PTH levels did not materially influence the results. CONCLUSIONS: In this multicenter cohort study, timing of PTx before or after KTx does not independently impact graft function over time.

Pain in fibrous dysplasia: relationship with anatomical and clinical features.

Background and purpose - Fibrous dysplasia (FD) is a rare bone disorder associated with pain, deformities, and pathological fractures. The pathophysiological mechanism of FD-related pain remains ill-understood. We evaluated the degree of pain and the potential contributory factors in 2 patient cohorts from Austria and the Netherlands. Patients and methods - 197 patients (16-85 years) with FD (Graz n = 105, Leiden n = 92) completed a survey concerning the presence and severity of pain at their FD site. Sex, age, type of FD, and localization of FD lesions were examined for a relationship with the presence and severity of pain. Results - Of 197 patients from the combined cohort (61% female, mean age 49 (SD 16) years, 76% monostotic) who completed the questionnaires, 91 (46%) reported pain at sites of FD lesions. Severity of pain was higher in patients with lesions of the lower extremities and ribs compared with upper extremity or craniofacial lesions. Severe subtypes of FD (polyostotic/McCune-Albright syndrome) were more often associated with pain, often severe. Interpretation - Our data suggest that almost 50% of patients with FD report pain at FD sites, thus representing a major clinical manifestation of the disorder, importantly also in patients with monostotic lesions. Lesions in lower extremities and ribs were more painful.

Safety and efficacy of subtotal or total parathyroidectomy for patients with secondary or tertiary hyperparathyroidism in four academic centers in the Netherlands.

PURPOSE: Hyperparathyroidism (HPT) is a common abnormality in patients with end-stage renal disease (ESRD). Since the introduction of cinacalcet in 2004, a shift from surgery toward predominantly medical treatment has occurred. Surgery is thought to be associated with more complications than oral medication. The aim of this retrospective study was to evaluate 30-day outcomes and effectiveness of parathyroidectomy (PTx) in ESRD patients in the Netherlands. METHODS: A national database containing data from four academic medical centers in the Netherlands of patients with ESRD-related HPT, who had undergone PTx and kidney transplantation between 1994 and 2015, was established. Primary endpoints were 30-day mortality and complication rate. Secondary endpoints were biochemical measurements. RESULTS: We identified 187 HPT patients undergoing PTx, with a median age of 46 years. Median preoperative PTH level was 866 pg/mL (interquartile range [IQR] 407-1547 pg/mL). At 3 months, the median PTH drop from baseline was 93% (IQR, 71-98%) to a median of 61 pg/mL (IQR, 23-148 pg/mL, p < 0.001). Over the 25-year inclusion period, 13 patients (7.0%) required re-exploration for persistent or recurrent disease. Thirty-day mortality and complication rate were 0.0% and 7.9% respectively. Median serum calcium levels improved significantly postoperatively from 2.6 (2.4-2.8) mmol/L to 2.3 (2.1-2.5) mmol/L (p < 0.001). CONCLUSIONS: PTx is a safe and effective procedure in the frail ESRD population. These data show that there should be no reluctance for surgical intervention and when indicated, nephrologists can safely refer these patients for PTx.

What Is the Role of Allogeneic Cortical Strut Grafts in the Treatment of Fibrous Dysplasia of the Proximal Femur?

BACKGROUND: Fibrous dysplasia of the proximal femur is a progressive, often recurrent condition of bone that can cause skeletal deformity, fractures, and pain [corrected]. Allogeneic cortical strut grafting to minimize the risk of fracture or as part of fracture treatment is a promising treatment option, but evidence is scarce on the intermediate- to long-term results of this procedure and there are no data on factors associated with graft failure. QUESTIONS/PURPOSES: The purposes of this study were (1) to evaluate the revision-free survivorship; (2) radiographic findings; (3) factors associated with failure; and (4) complications associated with cortical strut allograft to prevent or treat fractures of the proximal femur in patients with fibrous dysplasia. METHODS: Between 1980 and 2013 we performed cortical strut allografting in 30 patients for impending or actual fractures of the proximal femur, of whom 28 (93%) were available for followup at a minimum of 2 years (mean, 13 years; range, 4-37 years) and of whom 22 (73%) had also been evaluated within the last 5 years. During that time, the indications for cortical strut allografting were an impending fracture of the proximal femur, persistent pain, or an actual nondisplaced femoral fracture. In patients who presented with a diaphyseal fracture, a fracture with severe dislocation of severe varus deformity, which required an osteotomy, placement of a blade plate was instead performed and these patients are not included here. During that time, for patients with diaphyseal fractures, and in patients with a displaced femoral fracture of the proximal femur, placement of a blade plate without strut grafting was instead performed; these patients are not included here. The primary outcome was the success rate of allogeneic cortical strut grafting surgery as assessed by the absence of revision surgery for a newly sustained fracture, resorption of the graft, or progressive deformity of the proximal femur. The association of possible contributing factors to graft failure such as gender, age at surgery, preoperative fracture, and anchoring distances of the graft in healthy bone was also evaluated using Cox regression analysis. RESULTS: Revision surgery was performed in 13 patients, resulting in a mean survival time of 13 years (Kaplan-Meier 95% confidence interval [CI], 10-16). Radiological resorption of the graft was observed in 15 of 28 patients (54%). However, revision surgery was not performed in all patients who developed graft resorption, because of the absence of a risk for fracture on the basis of the anatomical site of resorption. Identified risk factors for graft failure included preoperative fractures (hazard ratio [HR], 4.5; 95% CI, 1.2-17.2; p = 0.028) and insufficient proximal anchoring of the graft in healthy bone (HR, 6.02; 95% CI, 1.3-27; p = 0.02). One patient sustained a refracture after surgery resulting from an in-hospital fall. The fracture was treated without further surgery, and it healed. CONCLUSIONS: Our findings from this study suggest that cortical strut allografting may be a viable option for treatment of fibrous dysplasia of the proximal femur a without previous pathological fracture. Surgeons should pay particular attention to the proximal fixation point of the allograft to decrease the risk of failure. Patients with a fracture have an increased risk of failure and reoperation and so should be treated with an osteosynthesis. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Sclerostin Inhibition in the Management of Osteoporosis.

The recognition of the importance of the Wnt-signaling pathway in bone metabolism and studies of patients with rare skeletal disorders characterized by high bone mass identified sclerostin as target for the development of new therapeutics for osteoporosis. Findings in animals and humans with sclerostin deficiency as well as results of preclinical and early clinical studies with sclerostin inhibitors demonstrated a new treatment paradigm with a bone building agent for the management of patients with osteoporosis, the antifracture efficacy, and long-term tolerability of which remain to be established in on-going phase III clinical studies. In this article we review the currently available preclinical and clinical evidence supporting the use of sclerostin inhibitors in osteoporosis.

Decompressive surgery in a patient with hyperostosis corticalis generalisata for relief of cognitive disability and dysaesthesia.

A 28-year-old man with genetically confirmed hyperostosis corticalis generalisata (Van Buchem disease) suffered from headache and progressive cognitive and sensibility disorders. Bone formation of the skull was ongoing, leading to narrowing of the intracranial space and foramen magnum. A large bilateral frontoparietal craniotomy and decompression of the foramen magnum resulted in almost complete relief of his symptoms. This is the first report on successful decompressive surgery as a treatment of cognitive impairment and dysaesthesia.

Effects of up to 15 years of recombinant human GH (rhGH) replacement on bone metabolism in adults with growth hormone deficiency (GHD): the Leiden Cohort Study.

BACKGROUND: Growth hormone deficiency (GHD) in adulthood may be associated with a decreased bone mineral density (BMD), a decreased bone mineral content (BMC) and an increased fracture risk. Recombinant human GH (rhGH) replacement induces a progressive increase in BMD for up to 5-7 years of treatment. Data on longer follow-up are, however, scarce. METHODS: Two hundred and thirty-adult GHD patients (mean age 47·1 years, 52·6% female), of whom 88% patients had adult-onset (AO) GHD, receiving rhGH replacement for ≥5 years were included in the study. Most patients had multiple pituitary hormone deficiencies. Bone turnover markers, BMC and BMD and T-scores at the lumbar spine and femoral neck were evaluated at baseline, and after 5, 10 and 15 years of rhGH replacement. In addition, clinical fracture incidence was assessed. RESULTS: Mean lumbar spine BMD, lumbar spine BMC and T-scores gradually increased during the first 10 years of rhGH replacement and remained stable thereafter. Largest effects of rhGH supplementation were found in men. In the small subset of patients using bisphosphonates, use of bisphosphonates did not impact additional beneficial effects in the long term. Low baseline BMD positively affected the change in BMD and BMC over time, but there was a negative effect of high GH dose at 1 year on the change in BMD and BMC over time. Clinical fracture incidence during long-term rhGH replacement was 20.1/1000 py. CONCLUSIONS: Fifteen years of rhGH replacement in GHD adults resulted in a sustained increase in BMD values at the lumbar spine, particularly in men, and stabilization of BMD values at the femoral neck. Clinical fracture incidence was suggested not to be increased during long-term rhGH replacement.

Osteopetrosis and related osteoclast disorders in adults: A review and knowledge gaps On behalf of the European calcified tissue society and ERN BOND.

Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.