Clinical Parameters in Osteoporosis Patients Supplemented With PMA-Zeolite at the End of 5-Year Double-Blinded Clinical Trial.

Osteoporosis is among the most common pathologies. Associated complications in osteoporotic patients, in particular hip fractures and vertebral fractures, cause disabilities and significant quality of life deterioration. Standard treatment of osteoporosis, based on pharmacotherapy does still not yield adequate results, and the problem of osteoporosis remains incompletely solved. Additionally, adverse drug events and fractures after long-termed pharmacotherapy pose additional challenges within designing a proper therapy regimen. Improved clinical approach and new synergistic treatment modalities are consequently still needed. The rationale of the presented study was accordingly, to expand our preclinical animal study on human patients with osteoporosis, based on positive effects on bones observed in animals with osteopenia treated with PMA-zeolite. We specifically monitored effects of PMA-zeolite on the bone quality parameters, fracture risk and quality of life in a cohort of initially recruited 100 osteoporosis patients during a follow-up period of 5 years within a randomized, placebo-controlled and double blinded clinical study (TOP study). Obtained results provide evidence on the PMA-zeolite positive effects on the bone strength of osteoporotic patients as the risk of fractures was significantly decreased in PMA-zeolite-treated patients with respect to time before entering the study (p = 0.002). Statistical evidence point also to positive bone changes in the 5-years TOP study course as evidenced through osteocalcin and beta-cross laps values showing a prevalence of the bone-formation process (p < 0.05). BMD values were not significantly affected after the 5-years follow-up in PMA-zeolite-treated patients in comparison with the Placebo group. Results support the initial expectations based on our previously published preclinical studies on clinoptilolite product PMA-zeolite in animals that could be a new therapeutic option in osteoporosis patients.

Clinical Evaluation of a Defined Zeolite-Clinoptilolite Supplementation Effect on the Selected Blood Parameters of Patients.

The natural clinoptilolite material is an inorganic crystal mineral called zeolite. It has been extensively studied and used in industrial applications and veterinary and human medicine due to positive effects on health. Limited data is available in the scientific literature about its effects on the levels of physiologically relevant minerals in the human organism. Accordingly, we performed a comprehensive and controlled monitoring of the relevant mineral and contaminants levels in human subjects supplemented with a certified clinoptilolite material within three clinical trials with different supplementation regimens. Effects of a registered and certified clinoptilolite material PMA-zeolite on selected mineral and metal levels were determined by standard biochemical methods and inductively coupled plasma mass spectrometry (ICP-MS) in the blood of subjects enrolled in three clinical trials: short-term (28 days, Mineral Metabolism and selected Blood Parameters study MMBP), medium-term (12 weeks, Morbus Crohn study), and long-term (4 years, Osteoporosis TOP study) supplementation. Lower concentrations were observed for copper (Cu) in patients with osteoporosis, which normalized again in the long-term supplementation trial, whereas sodium (Na) and calcium (Ca) levels diminished below the reference values in patients with osteoporosis. In the short- and long-term supplementation trials, increased levels of lead (Pb) were observed in PMA-zeolite-supplemented subjects, which decreased in the continued long-term supplementation trial. Increased levels of aluminum (Al) or Pb attributable to eventual leakage from the material into the bloodstream were not detected 1 h after intake in the short-term supplementation trial. Nickel (Ni) and Al were statistically significantly decreased upon long-term 4-year supplementation within the long-term supplementation trial, and arsenic (As) was statistically significantly decreased upon 12-weeks supplementation in the medium-term trial. Alterations in the measured levels for Na and Ca, as well as for Pb, in the long-term trial are probably attributable to the bone remodeling process. Checking the balance of the minerals Cu, Ca, and Na after 1 year of supplementation might be prescribed for PMA-supplemented patients with osteoporosis. Clinical Trial Registration: [https://clinicaltrials.gov], identifiers [NCT03901989, NCT05178719, NCT04370535, NCT04607018].

X-Linked Osteogenesis Imperfecta Possibly Caused by a Novel Variant in PLS3.

Osteogenesis imperfecta (OI) represents a complex spectrum of genetic bone diseases that occur primarily due to mutations and deletions of the COL1A1 and COL1A2 genes. Recent molecular studies of the network of signaling pathways have contributed to a better understanding of bone remodeling and the pathogenesis of OI caused by mutations in many other genes associated with normal bone mineralization. In this paper, a case of a rare X-linked variant of OI with a change in the gene encoding plastin 3-a protein important for the regulation of the actin cytoskeleton, is presented. A 16-year-old patient developed ten bone fractures caused by minor trauma or injury, including a compression fracture of the second lumbar vertebra during his lifetime. Next-generation sequencing analysis did not show pathologically relevant deviations in the COL1A1 and COL1A2 genes. Targeted gene analyses (Skeletal disorder panel) of the patient, his father, mother and sister were then performed, detecting variants of uncertain significance (VUS) for genes PLS3, FN1 and COL11A2. A variant in the PLS3 gene were identified in the patient, his mother and sister. Since the PLS3 gene is located on the X chromosome, the mother and sister showed no signs of the disease. Although the variant in the PLS3 gene (c.685G>A (p.Gly229Arg)) has not yet been described in the literature, nor is its pathogenicity known, clinical findings combined with genetic testing showed that this variant may explain the cause of X-linked OI in our patient. This rare case of the PLS3 variant of X-linked OI might point to a novel target for personalized therapy in patients with this severe disease.

Treatment of osteoporosis with a modified zeolite shows beneficial effects in an osteoporotic rat model and a human clinical trial.

The severity of osteoporosis in humans manifests in its high incidence and by its complications that diminish quality of life. A societal consequence of osteoporosis is the substantial burden that it inflicts upon patients and their families. Several bone-modifying drugs have been prescribed to patients with osteoporosis. However, evidence for their anti-fracture efficacy remains inconclusive. To the contrary, long-term use of anti-osteoporotic drugs such as bisphosphonates and Denosumab, an RANKL inhibitor, have resulted in adverse events. We now present an alternative and adjuvant approach for treatment of osteoporosis. The data derive from in vivo studies in an ovariectomized rat model and from a randomized double blind, placebo-controlled human clinical study. Both studies involved treatment with Panaceo Micro Activation (PMA)-zeolite-clinoptilolite, a defined cation exchange clinoptilolite, which clearly improved all bone histomorphometric parameters examined from ovariectomized animals, indicative for increased bone formation. Moreover, intervention with PMA-zeolite-clinoptilolite for one year proved safe in humans. Furthermore, patients treated with PMA-zeolite-clinoptilolite showed an increase in bone mineral density, an elevated level of markers indicative of bone formation, a significant reduction in pain, and significantly improved quality of life compared with patients in the control (placebo) group. These encouraging positive effects of PMA-zeolite-clinoptilolite on bone integrity and on osteoporosis warrant further evaluation of treatment with PMA-zeolite-clinoptilolite as a new alternative adjuvant therapy for osteoporosis.

Nuclear magnetic resonance therapy (MBST) in the treatment of osteoporosis. Case report study.

Despite various pharmacological treatments, the problem of osteoporosis is not yet solved nor decreased. Drug's adverse event and fractures after long termed pharmacotherapy indicate a need for new treatment modalities. Nuclear magnetic resonance therapy could be a supplement to exercise and an alternative or supplement to pharmacotherapy. Number of clinical studies showed increase of BMD after nuclear magnetic resonance therapy and here presented case reports of eleven well-documented cases in which patients experienced severe trauma, having a huge hematoma around the hip but did not suffer any fracture, encourage this expectation. This case report study additionally presents case reports based on the follow-up of the incidence of fractures in a group of 450 patients (males n = 55, females n = 395) with a mean age of 68.4 years. All patients had been treated with MBST - therapeutic nuclear magnetic resonance, standard cycles of 10 days subsequently and followed during a five-year period. The data indicates that NMRT might reduce a risk of fractures in osteoporotic patients.

Postmenopausal Evaluation and Risk Reduction With Lasofoxifene (PEARL) trial: 5-year gynecological outcomes.

OBJECTIVE: The aim of this study was to establish the gynecological effects of 5 years of treatment with lasofoxifene versus placebo in postmenopausal osteoporotic women. METHODS: A total of 8,556 women aged 59 to 80 years with femoral neck or spine bone mineral density T scores of -2.5 or lower were randomized to receive lasofoxifene 0.25 mg/day, or lasofoxifene 0.5 mg/day, or placebo, for 5 years. RESULTS: Endometrial cancer was confirmed for two women in each lasofoxifene group and for three women in the placebo group. Endometrial hyperplasia occurred in three, two, and zero women in the lasofoxifene 0.25 mg/day, lasofoxifene 0.5 mg/day, and placebo groups, respectively. Vaginal bleeding occurred in 2.2% (P = 0.012 vs placebo), 2.6% (P = 0.001 vs placebo), and 1.3% of women treated with 0.25 mg/day lasofoxifene, 0.5 mg/day lasofoxifene, and placebo, respectively. Lasofoxifene treatment resulted in a small increase in endometrial thickness versus placebo (least-squares mean change from baseline 1.19 mm [P = 0.001], 1.43 mm [P < 0.001], and -0.72 mm for 0.25 mg/day lasofoxifene, 0.5 mg/day lasofoxifene, and placebo). Similar numbers of women required surgery for pelvic organ prolapse or urinary incontinence in the placebo and 0.5 mg/day lasofoxifene groups (1.2% vs 1.6%, P = 0.224; 0.25 mg/day group: 1.9%, P = 0.036). The absolute incidence rates of endometrial polyps were 8.8%, 5.5%, and 3.3% for lasofoxifene 0.25 mg/day (P = 0.003 vs placebo), lasofoxifene 0.5 mg/day (P = 0.163 vs placebo), and placebo groups, respectively. CONCLUSION: These findings indicate that 5 years of lasofoxifene treatment result in benign endometrial changes that do not increase the risk for endometrial cancer or hyperplasia in postmenopausal women.

Diversity of bone cell activity as a histomorphometric feature of idiopathic osteoporosis in men.

Although osteoporosis in men is an increasing health problem, studies on osteoporosis in males are still scarce. The aim of our study was to determine the characteristics of bone tissue and bone turnover in men with idiopathic osteoporosis. Transiliac crest bone samples were histomorphometrically analyzed after double tetracycline labeling in 32 men aged 37-65 years who were diagnosed with idiopathic osteoporosis by densitometry of the lumbar spine and hip. Bone volume, osteoid surface, osteoblast surface, eroded surface, osteoid thickness, trabecular thickness, trabecular number, trabecular separation, and mineral apposition rate (MAR) were determined in all trabecular bone specimens. Bone volume and structural parameters indicated trabecular bone loss in most patients. Cellular parameters and MAR indicated variations in bone cell actions. No age-related decrease in histomorphometric parameters was found. After the patients were grouped according to MAR values, osteoblast and eroded surfaces were found to be lower in the group with decreased MAR values and elevated in the group of patients with increased MAR parameter. Trabecular thickness was greater in patients with lower than normal MAR, due to reduced resorption and probably loss of very thin trabeculae. Our results suggest that idiopathic osteoporosis in man resembles many characteristics of postmenopausal osteoporosis in women resulting in impaired trabecular structure due to unbalanced cellular activity and bone turnover rate.

[Bone histology in postmenopausal osteoporosis--variations in cellular activity]. / Histologija kosti u postmenopauzalnoj osteoporozi--razlicitosti stanicnih zbivanja.

AIM: Modern understanding of the etiology of postmenopausal osteoporosis is based on the imbalance between bone resorption and formation due to estrogen deficiency, which may take several forms and combinations of decreased and/or increased activity of both or one cell type. Studies of postmenopausal osteoporosis have pointed to the existence of heterogeneity in the remodeling imbalance. Bone histology analyzed in a group of women with established postmenopausal osteoporosis undergoing bone biopsy is part of the diagnostic procedure. Data were compared and grouped according to the published histomorphometric classification of postmenopausal osteoporosis. METHODS: The study included 43 postmenopausal women aged 44-71 years with osteoporosis established by densitometry of the lumbar spine and hip. Secondary causes of osteoporosis were ruled out. Full thickness transiliacai bone biopsy specimens were obtained after double labeling regime with oxytetracycline (Geomycin, Pliva). Biopsy specimens were processed for undecalcified embedding in resin and sections stained by Goldner trichrome and toluidine blue, or used for fluorescence microscopy. A grid attached to the microscope eyepiece was used for histomorphometry. The following parameters were assessed according to the recommendations of the American Society for Bone and Mineral Research: bone volume (BV/TV, %), osteoid surface (OS/BS, %), osteoblast surface (Ob. S/BS, %), osteoid volume (OV/BV, %), osteoid thickness (O. Th, m), osteoclast surface (Oc. S/BS, %), mineral apposition rate (MAR, m/day). Thus obtained data were compared to published reference data for normal healthy population and also expressed as z-scores (the number of standard deviations by which the value differs from the mean of the normal age and sex matched controls). The study was approved by the hospital ethics committee. All patients signed an informed consent to take part in the clinical study. DISCUSSION: Histomorphometric analysis of bone biopsy demonstrated that on an average bone resorption, i.e. osteoclast surface, was considerably increased and osteoid volume moderately increased. The remaining histomorphometric parameters studied were generally normal for age and sex as compared to the published reference data. Increased osteoclast surface in 65% of patients indicated that bone loss was an active and prevailing process in these postmenopausal women, which was considerably more pronounced than in the normal age-matched population. Results of the histomorphometric analysis were categorized according to the published classification of postmenopausal osteoporosis. The percentage of patients in each group differed from literature data, most probably due to the sample size and choice. None of the patients had histomorphometric features of reduced osteoblastic and osteoclastic activity, but in 37% of postmenopausal women osteoclastic activity was increased while osteoblastic activity was normal, a feature not described in the original histomorphometric classification of postmenopausal osteoporosis. CONCLUSIONS: Histomorphometric analysis of bone biopsy in women with postmenopausal osteoporosis revealed bone resorption as a predominant finding. Different groups were recognized based on the diversity of bone cell activity. The difference in the frequencies in study groups, and observation of a distinct group not included in the histomorphometric classification of postmenopausal osteoporosis probably resulted from sample size and nonspecific population traits. Histomorphometric analysis of bone in postmenopausal osteoporosis is an important contribution to better understanding of this most common bone disorder.