Bone-active Drugs Research Articles

Pregnancy and lactation associated osteoporotic vertebral fracture: the neurosurgical perspective through a multicentric study.

Pregnancy and lactation-associated osteoporosis is a rare form of osteoporosis occurring during late pregnancy and early lactation, featuring fragility fractures, primarily involving the vertebral bodies and leading to back pain. Its management involves osteoporosis treatment, complicated by potential drug-related dangerous effects on the fetus. Nevertheless, many controversies remain regarding diagnosis, prognosis, and treatment options. Herein, we propose a multicentric case series to provide a comprehensive neurosurgical, gynecological, and endocrinological perspective on the management of pregnancy and lactation-associated osteoporotic vertebral fractures.A multicenter retrospective study was conducted at the Neurosurgical Department of Università degli Studi di Napoli Federico II, the Neurosurgical Unit of Hopitaux Universitaires de Genève, and the Spine and Spinal Cord Surgery Unit of the University Hospital of Udine, collecting data from January 2014 to December 2022. The study has been approved by the ethical committee of each hospital.N = 11 patients with an overall number of 31 fractures were eligible, with a mean age of 36. N = 5 (16%) fractures in 4 patients (36%) developed during pregnancy, and N = 26 (84%) fractures in 7 (64%) patients occurred during lactation. The mean number of fractures per patient was 2,81. In 10 (90%) patients, fractures occurred at the first pregnancy, and 5 (45%) patients had uneventful subsequent pregnancies. The mean clinical signs and symptoms were back pain (92%), followed by loss of height (75%) and kyphosis (4 patients, 35%). One (9,09%) patient underwent in vitro fertilization (IVF), and one patient (9,09%) was receiving hormonal therapy (ethinylestradiol/drosiprenone). 10 out of 11 (90%) patients were treated conservatively, and 6 of them (60%) were managed with an orthosis. One (9,1%) patient underwent surgery for 5-level kyphoplasty. The mean average reduction of pain after one year of follow-up was 6,7 on the visual analogue scale (p-value 0,04).Pregnancy-related osteoporotic vertebral fractures are an emerging issue in developing countries, for which a conservative strategy ensures the best outcomes. The main goal is to improve bone mineral density through calcium and vitamin D supplementation and bone-active drugs as bisphosphonates or teriparatide. Surgery is warranted only in cases of a risk of severe deterioration of neurological functions.

Bone-active drugs in pre-menopausal women with breast cancer undergoing hormone deprivation therapies

Bone-active drugs in pre-menopausal women with breast cancer undergoing hormone deprivation therapies

Bone-active drugs in premenopausal women with breast cancer under hormone-deprivation therapies.

Bone health management in premenopausal women with breast cancer (BC) under hormone-deprivation therapies (HDTs) is often challenging, and the effectiveness of bone-active drugs is still unknown. This retrospective multicenter study included 306 premenopausal women with early BC undergoing HDTs. Bone mineral density (BMD) and morphometric vertebral fractures (VFs) were assessed 12 months after HDT initiation and then after at least 24 months. After initial assessment, bone-active drugs were prescribed in 77.5% of women (151 denosumab 60 mg/6 months, 86 bisphosphonates). After 47.0 ± 20.1 months, new VFs were found in 16 women (5.2%). Vertebral fracture risk was significantly associated with obesity (odds ratio [OR] 3.87, P = .028), family history of hip fractures or VFs (OR 3.21, P = .040], chemotherapy-induced menopause (OR 6.48, P < .001), preexisting VFs (OR 25.36, P < .001), baseline T-score less than or equal to -2.5 standard deviation (SD) at any skeletal site (OR 4.14, P = .036), and changes at lumbar and total hip BMD (OR 0.94, P = .038 and OR 0.88, P < .001, respectively). New VFs occurred more frequently in women untreated compared to those treated with bone-active drugs (14/69, 20.8% vs 2/237, 0.8%; P < .001) and the anti-fracture effectiveness remained significant after correction for BMI (OR 0.03; P < .001), family history of fractures (OR 0.03; P < .001), chemotherapy-induced menopause (OR 0.04; P < .001), and preexisting VFs (OR 0.01; P < .001). Premenopausal women under HDTs are at high risk of VFs in relationship with high BMI, densitometric diagnosis of osteoporosis, preexisting VFs, and family history of osteoporotic fractures. Vertebral fractures in this setting might be effectively prevented by bisphosphonates or denosumab.

Fat Body Mass and Vertebral Fracture Progression in Women With Breast Cancer

Women with early breast cancer (EBC) exposed to aromatase inhibitors (AIs) may experience fragility fractures despite treatment with bone-active drugs. Risk factors for fractures in patients receiving AIs and denosumab have not been explored to date. To evaluate whether an association exists between dual x-ray absorptiometry (DXA)-measured fat body mass (FBM) and vertebral fracture (VF) progression in postmenopausal women with EBC undergoing adjuvant therapy with AIs in combination with denosumab and to examine whether VF was associated with common risk factors for bone fracture and parameters of body composition other than FBM. For this prospective, single-center, cohort study, 237 patients with EBC who were undergoing adjuvant treatment with AIs and denosumab (60 mg every 6 months) were enrolled at the Breast Unit of the ASST Spedali Civili of Brescia from September 2014 to June 2018. Data analysis was conducted in June 2022. Body composition parameters, bone mineral density, and morphometric VFs were assessed by DXA at study entry and after 18 months of therapy. VF progression, defined as either new or worsening of preexisting VFs, between the 2 time points. Of the 237 patients enrolled (median [range] age, 61 [28-84] years), 17 (4.4%) reported VF progression. Univariable analysis found an association between VF progression and a history of clinical fractures (odds ratio [OR], 3.22; 95% CI, 1.19-8.74; P = .02), Fracture Risk Assessment Tool (FRAX) score for major fractures (OR, 4.42; 95% CI, 1.23-13.79; P = .04), percentage of FBM (OR, 6.04; 95% CI, 1.69-21.63; P = .006), and android fat (OR, 9.58; 95% CI, 1.17-78.21; P = .04) and an inverse association with appendicular lean mass index-FBM ratio (OR, 0.25, 95% CI, 0.08-0.82; P = .02). Multivariable analysis revealed percentage of FBM (OR, 5.41; 95% CI, 1.49-19.59; P = .01) and FRAX score (OR, 3.95; 95% CI, 1.09-14.39; P = .04) as independent variables associated with VF progression. The findings of this study suggest that baseline FBM is an independent factor for VF progression in patients with EBC treated with adjuvant AIs and denosumab. This observation is new and indicates that diet and exercise may synergize with denosumab in the management of bone health in this patient setting.

Risk prediction of second hip fracture by bone and muscle density of the hip varies with time after first hip fracture: A prospective cohort study

PurposePredictors of ‘imminent’ risk of second hip fracture are unknown. The aims of the study were to explore strength of hip areal bone mineral density (aBMD), and muscle area and density for predicting second hip fracture at different time intervals. MethodsData of the Chinese Second Hip Fracture Evaluation were analyzed, a longitudinal study to evaluate the risk of second hip fracture (of the contralateral hip) by using CT images obtained immediately after first hip fracture. Muscle cross-sectional area and density were measured of the gluteus maximus (G.MaxM) and gluteus medius and minimus (G.Med/MinM) and aBMD of the proximal femur at the contralateral unfractured side. Patients were followed up for a median time of 4.5 years. Separate Cox models were used to predict second hip fracture risk at different time intervals after first event adjusted for age, sex, BMI and diabetes. ResultsThe mean age of subjects with imminent (within 1st or 2nd year) second hip fracture was 79.80 ± 5.16 and 81.56 ± 3.64 years. In the 1st year after the first hip fracture, femoral neck (FN) aBMD predicted second hip fracture (HR 5.88; 95 % CI, 1.32–26.09). In the remaining years of follow-up after 2nd year, muscle density predicted second hip fracture (G.MaxM HR 2.13; 95 % CI, 1.25–3.65,G.Med/MinM HR 2.10; 95 % CI, 1.32–3.34). ConclusionsOur results show that femoral neck aBMD is an important predictor for second hip fracture within the first year and therefore suggest supports the importance concept of early and rapid-acting bone-active drugs to increase hip BMD. In addition, the importance of muscle density predicting second hip fracture after the second year suggest post hip fracture rehabilitation and exercise programs could also be important to reduce muscle fatty infiltration.

Denosumab improves trabecular bone score in relationship with decrease in fracture risk of women exposed to aromatase inhibitors.

Trabecular bone score (TBS) is a gray-level textural metric that has shown to correlate with risk of fractures in several forms of osteoporosis. The value of TBS in predicting fractures and the effects of bone-active drugs on TBS in aromatase inhibitors (AIs)-induced osteoporosis are still largely unknown. The primary objective of this retrospective study was to assess the effects of denosumab and bisphosphonates (BPs) on TBS and vertebral fractures (VFs) in women exposed to AIs. 241 consecutive women (median age 58years) with early breast cancer undergoing treatment with AIs were evaluated for TBS, bone mineral density (BMD) and morphometric VFs at baseline and after 18-24months of follow-up. During the study period, 139 women (57.7%) received denosumab 60mg every 6months, 53 (22.0%) BPs, whereas 49 women (20.3%) were not treated with bone-active drugs. Denosumab significantly increased TBS values (from 1.270 to 1.323; P < 0.001) accompanied by a significant decrease in risk of VFs (odds ratio 0.282; P = 0.021). During treatment with BPs, TBS did not significantly change (P = 0.849) and incidence of VFs was not significantly different from women untreated with bone-active drugs (P = 0.427). In the whole population, women with incident VFs showed higher decrease in TBS vs. non-fractured women (P = 0.003), without significant differences in changes of BMD at any skeletal site. TBS variation predicts fracture risk in AIs treated women. Denosumab is effective to induce early increase of TBS and reduction in risk of VFs.

Real-World Effectiveness of Denosumab and Bisphosphonates on Risk of Vertebral Fractures in Women with Breast Cancer Undergoing Treatment with Aromatase Inhibitors.

Bone-active drugs are recommended to protect the skeleton from detrimental actions of aromatase inhibitors (AIs). However, most of literature data are focused on bone mineral density (BMD), whereas data on fractures are scant. The aim of this prospective study was to investigate the real-life effectiveness of denosumab, oral bisphosphonates (BPs) and intravenous zoledronate on risk of vertebral fractures (VFs) induced by AIs. 567 consecutive women (median age 62years, range 28-83) with early breast cancer undergoing treatment with AIs were evaluated for morphometric VFs and BMD at baseline and after 18-24months of follow-up. After enrollment, 268 women (47.3%) started denosumab 60mg subcutaneously every 6months, 115 (20.3%) BPs (59 with oral BPs and, 56 with intravenous zoledronate 5mg/12months), whereas 184 women (32.5%) were not treated with bone-active drugs for several reasons. During follow-up, 54 women (9.5%) developed incident VFs in association with age of subjects (P &lt; 0.001), baseline FRAX scores for major fractures (P &lt; 0.001) and hip fractures (P = 0.003), pre-existing VFs (P &lt; 0.001), change in BMD at lumbar spine (P = 0.015), femoral neck (P = 0.003) and total hip (P &lt; 0.001). Risk of VFs was higher in subjects who were untreated as compared to those treated with bone-active drugs (32/184 vs. 22/383; P &lt; 0.001). Specifically, fracture risk was significantly decreased by denosumab [odds ratio (OR) 0.22; P &lt; 0.001] and zoledronate (OR 0.27; P = 0.035), but not by oral BPs (P = 0.317). These data suggest that in real-world clinical practice, denosumab and zoledronate can reduce AI-related risk of VFs after only 24months of treatment.

Impact of bone-active drugs and underlying disease on bone health after lung transplantation: A longitudinal study

Introductionthe effect of bone-active drugs on the risk of fragility fractures (Fx), bone mineral density (BMD) and trabecular bone score (TBS) changes in patients receiving lung transplantation (LTx) is largely unknown. This study assessed the bone-active drugs effect in patients undergoing LTx both with (CF) and without (nCF) cystic-fibrosis. MethodsWe evaluated incident Fx, both clinical and morphometric vertebral Fx by spinal X-ray, BMD and trabecular bone score (TBS) in 117 patients (CF=50, nCF n = 67) before and 24-months after LTx. A bone-active therapy was proposed to all LTx candidates. Results83.8% of patients started a bone-active drug. Lumbar-spine (LS) T-score improved significantly only in treated patients (-1.4 ± 1.0 vs -2.0±1.0, p = 0.0001), whereas femur BMD and TBS remained stable in treated and not treated subjects. The rate of incident Fx was 15.3%, with no difference between treated and not treated patients. After LTx, LS T-score improved significantly only in nCF group (-1.3 ± 1.0 vs -1.8 ± 1.1, p = 0.0001), while femur remained stable in both nCF and CF groups. Patients with CF showed a significant Z-TBS increase (-3.6 ± 1.7 vs -3.0 ± 1.7, p = 0.019) and a lower Fx incidence as compared with nCF patients (4.1% vs 24.2%, p =0.003). Incident Fx were associated with nCF diagnosis (OR 7.300, CI95% 1.385–38.461, p = 0.019) regardless of prevalent Fx, previous glucocorticoid therapy and bone-active therapy introduced at least 6 months before LTx. ConclusionsA prompt medical intervention helps in preventing BMD loss after LTx. As compared with nCF patients, CF patients show a TBS increase and a lower Fx risk after LTx.

Use of aromatase inhibitors in patients with breast cancer is associated with deterioration of bone microarchitecture and density.

To evaluate changes in bone density and architecture in postmenopausal women with breast cancer (BC) and use of aromatase inhibitor (AI). Thirty-four postmenopausal women with BC, without bone metastasis, renal function impairment and who were not receiving bone-active drugs were selected from a population of 523 outpatients treated for BC. According to the presence of hormonal receptors, HER2 and Ki67, seventeen had positive hormonal receptors and received anastrozole (AI group), and seventeen were triple-negative receptors (non-AI group), previously treated with chemotherapy. Areal bone mineral density (aBMD) and vertebral fracture assessment (VFA) analyses were performed by DXA; vBMD and bone microarchitecture were evaluated by HR-pQCT. Fracture risk was estimated using the FRAX tool. No patient referred previous low-impact fracture, and VFA detected one moderate vertebral fracture in a non-AI patient. AI patients showed lower aBMD and BMD T-scores at the hip and 33% radius and a higher proportion of osteoporosis diagnosis on DXA (47%) vs non-AI (17.6%). AI group had significantly lower values for vBMD at the entire, cortical and trabecular bone compartments, cortical and trabecular thickness and BV/TV. They also had a higher risk for major fractures and for hip fractures estimated by FRAX. Several HR-pQCT parameters evaluated at distal radius and distal tibia were significantly associated with fracture risk. AI is associated with alterations in bone density and microarchitecture of both the cortical and trabecular compartments. These findings explain the overall increase in fracture risk in this specific population.

Update on vertebral fractures in pituitary diseases: from research to clinical practice.

Derangement of pituitary hormone axes can induce changes in bone remodeling and metabolism with possible alterations in bone microarchitectural structure and increased susceptibility to fractures. Vertebral fractures (VFs), which are a hallmark of skeletal fragility, have been described in a very large number of patients with pituitary diseases. These fractures are clinically relevant, since they predispose to further fractures and may negatively impact on patients' quality of life. However, the management of skeletal fragility and VFs in the specific setting of pituitary diseases is a challenge, since the awareness for this disease is still low, prediction of VFs is uncertain, the diagnosis of VFs cannot be solely based on a clinical approach and also needs a radiological and morphometric approach, the risk of fractures may not be decreased via treatment of pituitary hormone disorders, and the effectiveness of bone-active drugs in this setting is not always evidence-based. This review is an update on skeletal fragility in patients with pituitary diseases, with a focus on clinical and therapeutic aspects concerning the management of VFs.

Treatment of acromegalic osteopathy in the real-life clinical practice: The baac (bone active drugs in acromegaly) multicenter study

Treatment of acromegalic osteopathy in the real-life clinical practice: The baac (bone active drugs in acromegaly) multicenter study

Treatment of Acromegalic Osteopathy in Real-life Clinical Practice: The BAAC (Bone Active Drugs in Acromegaly) Study.

Vertebral fractures (VFs) are a frequent complication of acromegaly, but no studies have been so far published on effectiveness of antiosteoporotic drugs in this clinical setting. To evaluate whether in real-life clinical practice bone active drugs may reduce the risk of VFs in patients with active or controlled acromegaly. Retrospective, longitudinal study including 9 tertiary care endocrine units. Two hundred and forty-eight patients with acromegaly (104 males; mean age 56.00 ± 13.60 years) were evaluated for prevalent and incident VFs by quantitative morphometric approach. Bone active agents were used in 52 patients (20.97%) and the median period of follow-up was 48 months (range 12-132). During the follow-up, 65 patients (26.21%) developed incident VFs in relationship with pre-existing VFs (odds ratio [OR] 3.75; P < .001), duration of active acromegaly (OR 1.01; P = .04), active acromegaly at the study entry (OR 2.48; P = .007), and treated hypoadrenalism (OR 2.50; P = .005). In the entire population, treatment with bone active drugs did not have a significant effect on incident VFs (P = .82). However, in a sensitive analysis restricted to patients with active acromegaly at study entry (111 cases), treatment with bone active drugs was associated with a lower risk of incident VFs (OR 0.11; P = .004), independently of prevalent VFs (OR 7.65; P < .001) and treated hypoadrenalism (OR 3.86; P = .007). Bone active drugs may prevent VFs in patients with active acromegaly.

Synthesis and Characterization of a Biocomposite Bone Bandage for Controlled Delivery of Bone-Active Drugs in Fracture Nonunions.

Fracture nonunions are common in orthopedics and their treatment often involves multiple surgical interventions. The aim of this study was to fabricate and characterize a gelatin-nano-hydroxyapatite membrane (GM)-based bone bandage for controlled delivery of bio-active molecules; recombinant human bone morphogenic protein-2 (rhBMP-2) and zoledronic acid (ZA) to promote osteoinduction and prevent callus resorption, respectively. In vitro cell-material interaction experiments using MC3T3 cells seeded on the GM indicated good biocompatibility. rhBMP-2-functionalized GM promoted osteogenic differentiation of MC3T3 cells and the rhBMP-2 bio-activity thus remained, as indicated by increased levels of alkaline phosphatase compared to only GM. The GM released a small amount (1.1%) of rhBMP-2 in vitro over a period of 5 weeks, demonstrating a strong interaction of rhBMP-2 with the GM. In the first animal study, the GM specimens loaded with rhBMP-2 or with the combination of rhBMP-2 + ZA were placed in the abdominal muscle pouch of rats. In the GM + rhBMP-2 + ZA group, significantly higher bone volume (21.5 ± 5.9 vs 2.7 ± 1.0 mm3) and area (3.3 ± 2.3 vs 1.0 ± 0.4 mm2) of bone were observed compared to GM + rhBMP-2 after 4 weeks, as indicated by micro-computed tomography and histomorphometry, respectively. Finally, a nonunion model in rats was used to evaluate the efficacy of the GM bandage and bio-active molecules in healing of fracture nonunions. The GM functionalized with rhBMP-2 + ZA led to higher bone formation around the fracture (63.9 ± 19.0 vs 31.8 ± 3.7 mm3) and stronger fracture callus (110.8 ± 46.8 vs 45.6 ± 17.8 N) compared to the empty controls. However, the overall union rate was only marginally improved. The GM alone or combined with ZA did not aid in bone healing in this model. Thus, this study shows that controlled delivery of rhBMP-2 + ZA via the developed GM is a promising approach that could aid in earlier full load bearing in patients with nonunion.

Vitamin D screening.

At present, there is no need and no sufficient evidence to support universal screening for vitamin D status. There are four categories of subjects in whom there is no requirement for screening, since a number of studies indicate beneficial effects of vitamin D supplementation; these are represented by children and adolescents, pregnant women, patients taking bone active drugs and subjects with documented hypovitaminosis D. In the remaining subjects, the utilization of adequate questionnaires will target with sufficient sensitivity and specificity those with hypovitaminosis D. These must be first supplemented and, at a later time, serum 25(OH)D assay should be requested to confirm attainment of sufficiency, independently of the threshold chosen. This strategy will cut costs deriving from both widespread use of vitamin D assays and vitamin D supplementation.

MANAGEMENT OF ENDOCRINE DISEASE: Bone disorders associated with acromegaly: mechanisms and treatment.

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) exert physiological actions on the skeleton throughout life, by stimulating longitudinal bone growth in children, the acquisition of bone mass during adolescence and the maintenance of skeletal architecture in adults. When GH and IGF-I are secreted in excess, bone remodeling is enhanced leading to deterioration of bone microstructure and impairment of bone strength. Indeed, acromegaly causes skeletal fragility, and vertebral fractures are reported in a remarkable number of subjects exposed to GH and IGF-I excess. The management of skeletal fragility in acromegaly is a challenge, since the awareness of this complication is low, the prediction of fracture risk is difficult to ascertain, the risk of fractures remains after the control of acromegaly and the effectiveness of bone-active drugs is unknown. This review is an update on bone disorders associated with acromegaly and provides a perspective of possible therapeutic approaches based on emerging pathophysiological and clinical information.

Low acceptance of osteoanabolic therapy with parathyroid hormone in patients with fragility fracture of the pelvis in routine clinical practice: a retrospective observational cohort study

IntroductionA recent randomized controlled trial has reported full patient compliance and no adverse events from therapy with parathyroid hormone (PTH) for osteoporosis and accelerated healing of fragility fractures of the pelvis. The purpose of the presented study was to evaluate if similar results can be achieved with comprehensive PTH therapy in routine clinical practice. We hypothesised that patients’ burden of PTH therapy is underestimated in the literature.Patients and methodsOsteoanabolic PTH therapy was recommended to 79 patients suffering from an acute fragility fracture of the pelvis (FFP). Case finding, initiation of therapy and follow-up were performed by a fracture liaison service team. Primary outcome was PTH initiation rate. Secondary outcomes were implementation rate of alternative antiresorptive pharmaceutical therapy for osteoporosis and participation rate in a bone metabolic workup. Adverse events and effects potentially related to the therapy with bone-active drugs were documented as exploratory outcomes.ResultsOsteoanabolic PTH therapy as suggested was accepted by 32%, whereas antiresorptive therapy was implemented in another 14% of the patients. DEXA scans were available in 38% of the patients (+ 27% when compared to baseline). A bone-specific laboratory analysis was done in 18 patients, uncovering 7 pathological findings. Two patients terminated PTH therapy early because of side effects.ConclusionThe experiences with PTH therapy in FFP patients with respect to, implementation rate, frequency of side effects and of pathological findings in laboratory controls as reported from a previous RCT could not be reproduced in routine clinical practice.

Biomodulation of an implant for enhanced bone-implant anchorage

Aseptic loosening of implants is the major cause for revision surgery. By modulating the bone-implant interface, early bone-implant anchorage could be improved. Implant surface manipulation by the addition of osteopromotive molecules locally and systemically to promote implant integration has been described with limited success. This study describes a novel approach by making the implant capable of biologically modulating its surroundings. It was hypothesized that the early implant fixation would improve by filling the interior of the implant with a carrier providing spatio-temporal release of bone active drugs with known osteogenic effect. The implant consisted of a threaded polyether ether ketone (PEEK) hollow chamber with holes at the bottom. The implant was filled with a calcium sulphate (CaS)/hydroxyapatite (HA) carrier, delivering two bone active molecules; zoledronic acid (ZA) and bone morphogenic protein-2 (BMP-2). At first, a rat abdominal muscle pouch model indicated a sustained in-vivo release of both 125I-rhBMP-2 (57%) and 14C-ZA (22%) from the CaS/HA carrier over a period of 4-weeks. The biomodulated implant was then inserted in the proximal tibia in rats with the following experimental groups: G1) Empty implant, G2) Implant + CaS/HA, G3) Implant + CaS/HA + ZA and G4) Implant + CaS/HA + ZA + rhBMP-2. Significantly higher bone volume (BV) was seen around the implant in groups G3 (3.3 ± 0.7 mm3) and G4 (3.1 ± 0.7 mm3) compared to the control (1.3 ± 0.4 mm3) using micro-computed tomography and qualitative histology. Group G3, also exhibited significantly higher pull-out force and absorbed energy when compared to the control group G1. These findings indicate that a low dose of ZA alone, released in a controlled manner from within a fenestrated implant is enough to improve implant anchorage without the need of adding rhBMP-2. This simple method of using a fenestrated implant containing a ceramic carrier releasing bone active molecules improved bone anchorage and could clinically reduce prosthetic failure. Statement of SignificanceAseptic loosening remains as a major cause for implant revisions and early reaction of surrounding bone to the prosthesis is important for longevity. A novel approach to enhance early bone-implant anchorage is presented.The implant is filled with a carrier providing controlled release of bone active molecules. In an animal model, a calcium sulphate (CaS)/hydroxyapatite (HA) carrier was used to provide a spatio-temporal release of bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA). Significantly better bone-implant integration was achieved using ZA alone, thereby eliminating the need for adding BMP-2. The developed method of implant biomodulation holds potential to prevent implant loosening and is an alternative to prosthetic coatings or systemic drug treatment. Importantly, all constituents are approved for clinical use.

Understanding and managing secondary osteoporosis

ABSTRACTIntroduction: The term secondary osteoporosis (SO) identifies a reduction of bone mass related to a well-established disease or pharmacological agent. The identification of the underlying disease often represents a challenging situation in clinical practice.Areas covered: The prevalence of SO in the real world may vary, ranging from 17% to 80%; therefore, search for a form of SO represents a pillar when evaluating patients with osteoporosis. Guidelines for treatment of specific secondary forms of osteoporosis, such as glucocorticoid-induced osteoporosis, have been published even though often neglected in clinical practice. For the majority of SO, there are currently no specific guidelines concerning treatment with only few trials showing the effect of bone-active drugs on fracture risk reduction.Expert opinion: Healthcare professionals should be aware of the secondary forms of osteoporosis, in particular when the reason for reduced skeletal resistance is uncertain or when bone mineral density results are unsatisfactory in a patient compliant to therapy. In a few cases (such as, for example: no response to therapy, better classification of bone involvement in patients with kidney failure, suspicion of rare metabolic bone disease) bone biopsy is needed to investigate the patient. This review highlights recent advances in understanding and managing SO.

Targeted Drug Delivery from Titanium Implants: A Review of Challenges and Approaches.

Titanium implants are considered the gold standard of treatment for dental and orthopedic applications. Biocompatibility, low elasticity, and corrosion resistance are some of the key properties of these metallic implants. Nonetheless, a long-term clinical failure of implants may occur due to inadequate osseointegration. Poor osseointegration induces mobility, inflammation, increased bone resorption, and osteolysis; hence, it may result in painful revision surgeries. Topographical modifications, improvement in hydrophilicity, and the development of controlled-release drug-loading systems have shown to improve cellular adhesion, proliferation, and differentiation. Surface modifications, along with drug coating, undoubtedly demonstrate better osseointegration, especially in challenged degenerative conditions, such as osteoporosis, osteoarthritis, and osteogenesis imperfecta. Anabolic bone-acting drugs, such as parathyroid hormone peptides, simvastatin, prostaglandin-EP4-receptor antagonist, vitamin D, strontium ranelate, and anti-catabolic bone-acting drugs, such as calcitonin, bisphosphonates, and selective estrogen receptor modulators, expedite the process of osseointegration. In addition, various proteins, peptides, and growth factors may accessorize the idea of localized therapy. Loading these substances on modified titanium surfaces is achieved commonly by mechanisms such as direct coating, adsorption, and incorporating in biodegradable polymers. The primary approach toward the optimum drug loading is a critical trade-off between factors preventing release of a drug immediately and those allowing slow and sustained release. Recent advances broaden the understanding of the efficacy of adsorption, hydrogel coating, and electrospinning layer-by-layer coating facilitated by differential charge on metallic surface. This review discusses the existing approaches and challenges for the development of stable and sustained drug delivery systems on titanium implants, which would promote faster and superior osseointegration.

Femoral neck cortical bone in female and male hip fracture cases: Differential contrasts in cortical width and sub-periosteal porosity in 112 cases and controls.

To quantitate differences between cases of hip fracture and controls in cortical width around the mid-femoral neck in men and women. Over 5 years, 64 (14 male) participants over age 55 (mean 79) years, who had never taken bone-active drugs and suffered intra-capsular hip fracture treated by arthroplasty, donated their routinely discarded distal intra-capsular femoral neck bone for histomorphometry. After embedding, complete femoral neck cross sections from the cut surface near the narrowest part of the neck were stained with von Kossa and cortical width was measured radially every 5 degrees of arc. Control material (n = 48, 25 male) was available through consented post mortems prior to the year 2000. Cortical widths were averaged for circumferential octants, each representing 45 degrees of arc. Divergence of individual cortical widths from their means was also examined. Because sections were required to have a complete cortex, sampling was biased towards cases with sub-capital versus trans-cervical fractures. Compared to sex- and age matched controls, male cases showed larger relative differences in cortical widths than female cases. Unexpectedly, cortical widths in female but not male cases also showed marked over-representation of extremely narrow (<0.1 mm) cortical widths, located mainly posteriorly. The numbers of these very narrow cortical widths observed per subject retrospectively predicted female fracture status in logistic regression independently of mean cortical width values. Together with mean cortical width differences, the numbers of measured cortical widths <0.1 mm (out of 72 measured) raised the sensitivity of predicting fracture status in women from 48 to 80% at 80% specificity. In almost all cases, very narrow cortical widths were identified in regions enclosing a cortical pore roofed on its endosteal surface by thin structural bone defined a priori as trabecular. Cortical widths <0.1 mm probably reflect zones where endosteal cortex has been trabecularised through expansion of an un-refilled sub-endosteal canal close to the periosteum. Persistent cortical defects occurring near the periosteal surface, where mechanical loading exerts its greatest stresses, are likely to result in extremes of localized concentrations of stress during a fall, unknown in young normal fallers. Such defects have the potential to help explain the excess of hip fractures among elderly women. Prevention of sub-periosteal tunnelling by osteoclasts might explain in part the additional benefits, beyond an increase in bone density, of treatments that reduce excessive bone resorption or else stimulate new bone formation on previously resorbed surfaces.