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

Sandra Kraljević Pavelić, Vedran Micek, Dragica Bobinac, Edo Bazdulj, Alessandra Gianoncelli, Dalibor Krpan, Marta Žuvić, Sandra Eisenwagen, Peter J Stambrook, Krešimir Pavelić, Sandra Kraljević Pavelić, Vedran Micek, Dragica Bobinac, Edo Bazdulj, Alessandra Gianoncelli, Dalibor Krpan, Marta Žuvić, Sandra Eisenwagen, Peter J Stambrook, Krešimir Pavelić

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03901989.

Keywords: Zeolite; clinoptilolite Panaceo Micro Activation; clinoptilolite tuff; double-blinded clinical trial; osteoporosis; ovariectomized rats.

Conflict of interest statement

Declaration OF CONFLICTING INTERESTS: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SKP and KP are independent scientific advisors of Panaceo International Gmbh, Austria. SE is employed at Panaceo International Gmbh, Austria. Other authors do not have any competing interest to declare.

Figures

Figure 1.
Figure 1.
Comparison of markers of tibia metaphysis bone integrity between control untreated ovariectomized rats and ovariectomized rats treated with zeolite A (Ovx + zeo A), PMA-zeolite-clinoptilolite + 10% dolomite (Ovx + clino/dol), and PMA-zeolite-clinoptilolite (Ovx + PMA) by ex vivo µCT. Panel A compares levels of markers of bone integrity at 16 weeks between sham-operated (group #1) and untreated ovariectomized rats (Ovx, group #2). Markers include (A) BV/TV%, (B) BS density based on TV presented as BS/TV 1/mm, (C) trabecular thickness (Tb.th mm), (D) trabecular number (Tb. N. 1/mm), (E) trabecular separation (Tb. Sp. mm), (F) SMI, (G) total porosity (Pot(tot)%), and (H) connectivity density (Conn. dn. 1/mm3). Data are presented as mean ± standard error of mean. *Significantly different from sham (analysis of variance (ANOVA) Duncan post hoc, P < 0.05, n = 9–10 in both groups). Panel B compares bone integrity between Ovx controls (group #2), animas treated with zeolite A (Ovx + zeo A, group #4), with PMA-zeolite-clinoptilolite + dolomite (Ovx + clino/dol, group #5), or with PMA-zeolite-clinoptilolite alone (Ovx + PMA, group #6). The markers include (A) percent BV BV/TV%, (B) BS density BS/TV 1/mm, (C) trabecular number (Tb. N. 1/mm), (D) SMI, (E) total porosity (Pot(tot)%). Panel C compares bone mineral density and bone mineral content after 16 weeks between untreated ovariectomized rats (Ovx control) with ovariectomized animals treated with zeolite A (Ovx + zeoA), with PMA-zeolite-clinoptilolite with addition of 10% dolomite (Ovx + clino/dol), or with PMA-zeolite-clinoptilolite alone (Ovx + PMA). In all cases, the data are presented as the mean ± standard error of the mean with an N = 9 or 10 in all groups. The asterisk denotes statistically significant difference from untreated ovariectomized controls (Ovx control) based on ANOVA Duncan post hoc, P < 0.05. BV: bone volume; BS: bone surface; TV: total volume; PMA: Panaceo Micro Activation; SMI: structure model index.
Figure 2.
Figure 2.
Ex vivo µCT images of proximal tibia metaphysis in control, untreated ovariectomized rats and ovariectomized rats treated with zeolite A (Ovx + zeo A), PMA-zeolite-clinoptilolite + 10% dolomite (Ovx + clino/dol), and PMA-zeolite-clinoptilolite (Ovx + PMA). Images show horizontal sections of proximal tibia metaphysis in ovariectomized (Ovx control, group #2) and treated groups. Red area represents measured region of interest. From left to right: control (group #2), Ovx + Zeolite A (group #4), Ovx + Clino/dol (group #5), and Ovx + PMA-zeolite-clinoptilolite (group #6). PMA: Panaceo Micro Activation. (A color version of this figure is available in the online journal.)
Figure 3.
Figure 3.
Measures of bone integrity at the start and end of the study on osteoporosis patients within the presented clinical trial. A: BMD values at the beginning and the end of the study, measured in PMA-zeolite-clinoptilolite-treated group (Verum, Blue) and control (Placebo, Red) group. B: Osteocalcin values at the beginning and the end of the study, measured in PMA-zeolite-clinoptilolite-treated group (Verum, Blue) and control (Placebo, Red) group. C: Beta-cross laps values at the beginning and the end of the study, measured in PMA-zeolite-clinoptilolite-treated group (Verum, Blue) and control (Placebo, Red) group. Mean values with 95% confidence interval are presented. BMD: bone mineral density. (A color version of this figure is available in the online journal.)
Figure 4.
Figure 4.
BMD, osteocalcin, and Betacross laps values at the beginning and the end of the clinical study on osteoporosis patients, measured in PMA-zeolite-clinoptilolite-treated group (Verum) and control (Placebo) group. Mean values with 95% confidence interval are presented. BMD: bone mineral density. (A color version of this figure is available in the online journal.)

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