Copyright © 2008 John Wiley & Sons, Ltd.Phytother. Res. 22, 518–523 (2008)DOI: 10.1002/ptr518G. BELCARO ET AL.Copyright © 2008 John Wiley & Sons, Ltd.PHYTOTHERAPY RESEARCHPhytother. Res. 22, 518–523 (2008)Published online in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/ptr.2376Treatment of Osteoarthritis with Pycnogenol®.The SVOS (San Valentino Osteo-arthrosis Study). Evaluation of Signs, Symptoms,Physical Performance and Vascular AspectsG. Belcaro, M. R. Cesarone, S. Errichi, C. Zulli, B. M. Errichi, G. Vinciguerra, A. Ledda,A. Di Renzo, S. Stuard, M. Dugall, L. Pellegrini, S. Errichi, G. Gizzi, E. Ippolito, A. Ricci,M. Cacchio, G. Cipollone, I. Ruffini, F. Fano, M. Hosoi and P. Rohdewald*Irvine2 Vascular Laboratory, Department of Biomedical Sciences, Chieti-pescara University and San Valentino VascularScreening Project, Institute Pharmaceutical Chemistry, Westfälische Wilhelms-Universität Münster, GermanyThe aim of this double-blind, placebo-controlled study was to evaluate the efficacy of 100mg Pycnogenol®daily (oral capsules) in a 3 month study in patients with osteoarthritis (OA). OA symptoms were evaluatedby WOMAC scores, mobility by recording their walking performance (treadmill). Treatment (77 patients) andplacebo group (79) were comparable for age, sex distribution, WOMAC scores, walking distances and use ofantiinflammatory drugs. The global WOMAC score decreased by 56% (p < < < < < 0.05) in the treatment groupversus 9.6% in the placebo group. Walking distance in the treadmill test was prolonged from 68m at the startto 198m after 3 months treatment (p < < < < < 0.05), under placebo, from 65m to 88m (NS). The use of drugsdecreased by 58% in the treatment group (p < < < < < 0.05) versus 1% under placebo. Gastrointestinal complicationsdecreased by 63% in the treatment group, but only 3% under placebo. Overall, treatment costs were reducedsignificantly compared with placebo. Foot edema was present in 76% of the patients of the treatment groupat inclusion and in 79% of the controls. After 3 months edema decreased in 79% of Pycnogenol patients(p < < < < < 0.05) vs 1% in controls. In conclusion, Pycnogenol offers an option for reduction of treatment costs andside effects by sparing antiinflammatory drugs. Copyright © 2008 John Wiley & Sons, Ltd.Keywords: osteoarthrosis; WOMAC; joints; pain; antiinflammatory agents; noninvasive investigations; muscular performance;edema; Pycnogenol®.Received 16 August 2007Revised 28 March 2007Accepted 4 September 2007INTRODUCTIONOsteoarthritis (OA) of the main joints is a diffusesocial problem altering the quality of life of millionsof older inhabitants in the most industrialized countriesand, at a younger age, of inhabitants of developingcountries (where severe bone and joint abnormalitiesmay be associated with nutritional and developmentalproblems). The increase in the average weight withage, the diffusion of sedentary habits, the decrease inregular exercise patterns cause a progressive decreasein physical fitness has contributed to aggravate the prob-lems due to OA.A multitude of treatment and management optionsare available to manage the symptoms of OA, particu-larly pain, and the disabilities related to this disease.The quantitative evaluation of the effects of OAon the quality of life of patients and a standardizedquantification of the effects of treatments has been animportant problem, considering the widespread clinicalsigns associated with several levels of handicap andalterations in the quality of life.The WOMAC (Western Ontario and McMasterUniversities) index is now generally used to assess patientswith OA of the hip or knee – two of the joints causingthe most frequent and severe motion handicaps – using 24 main parameters (Baron et al., 2007). The WOMACcan be used to monitor the course of the disease andhow OA affects the life of patients or to determine theefficacy of antirheumatic/antiinflammatory treatments.As a combination between OA and arterial or venousvascular problems and concomitant metabolic syndromeis relatively frequent, so the vascular aspects should bealso considered in the management of these subjects.Impaired motion causes some level of edema of theaffected limbs (i.e. in patients with chronic venous insufficiency or in subjects treated with antihypertensivedrugs). Stasis and low mobility cause a chronic increasein local, distal venous pressure, therefore transforminga mild level of venous disease into a severe, chronicvenous hypertension, often causing ulcerations. These,in turn, may contribute to the signs and symptomsof OA, altering mobility and social life and causingfurther handicaps.Therefore, vascular complications should be evaluatedtogether with aspects specifically concerning OA (i.e. pain, mobility) to judge the quality of life of OA patients.Four main components – all contributing to the clinicalpicture – may be considered in the treatment managementof OA:* Correspondence to: G. Belcaro, Irvine2 Vascular Laboratory, Departmentof Biomedical Sciences, Chieti-pescara University and San Valentino Vascu-lar Screening Project, G. SO Umberto I, 18, San Valentino, PE, Italy.E-mail: firstname.lastname@example.org
PYCNOGENOL FOR OSTEOARTHRITIS519Copyright © 2008 John Wiley & Sons, Ltd.Phytother. Res. 22, 518–523 (2008)DOI: 10.1002/ptr1.specific, OA-related, signs/symptoms (described bythe WOMAC score);2.inflammation causing a progression in the disease;3.alteration (and improvement by treatment) offatigue resistance and muscular performance;4.reversing and blocking the vascular problemsassociated with altered mobility (i.e. often leadingto edema and sometimes even to venous and stasisulcerations).These four aspects can all be considered as targets ofa treatment evaluation.Theoretically, treatment with a compound specificallyactive on all these four aspects could be highly effec-tive. Therefore, a study involving Pycnogenol® – as themain treatment – was planned to evaluate changes inthese main clinical aspects of OA.Pycnogenol® is the trademark of Horphag ResearchLtd, UK for a standardized extract from the bark ofthe French maritime pine. The extract is a concentrateof plant polyphenols, predominantly procyanidins.This compound has antiinflammatory actions in vitroand in vivo and scavenges free radicals (Rohdewald,2005; Devaraj et al., 2002; Durackova et al., 2003). Inthe context of treatment of OA, inhibition of matrixmetalloproteases (MMPs) is of great interest. After theintake of Pycnogenol®, release of MMP9 from macro-phages is inhibited (Cisar et al., 2006), thus blockingthe destructive activity of MMP on cartilage.Pycnogenol inhibits in vitro the activation of NFκB,a key element of inflammation (Grimm et al., 2006).Furthermore, plasma from volunteers inhibited signifi-cantly the activation of NFκB in inflammatory cellsex vivo, blocking subsequent steps of the inflammatoryreactions (Grimm et al., 2006). Cyclooxygenases initi-ate the production of pain-producing prostaglandins.Plasma from human volunteers inhibited cyclooxygenasesI and II following intake of Pycnogenol® (Schäfer et al.,2006). The sum of these antiinflammatory effects sug-gests that this compound may have a positive effectin reducing the symptoms of mild to moderate osteo-arthritis. Furthermore, Pycnogenol® demonstrated inseveral clinical trials its activity against edema forma-tion and chronic venous insufficiency (Rohdewald, 2005;Cesarone et al., 2005, 2006a, 2006b, 2006c; Belcaro et al.,2006). In a range of clinical trials, the unwanted effectsof Pycnogenol were minimal, mainly mild gastrointestinalsymptoms or dizziness, and transient in most cases(Cesarone et al., 1999). In the USA Pycnogenol obtainedthe GRAS status (Generally Recognized As Safe).The aim of this study was to evaluate the efficacyof 100mg Pycnogenol (oral capsules) in a 3-month,double-blind, placebo-controlled study in patientswith OA and disability due to pain of the major jointsaltering their quality of life. The mobility of thesepatients was also evaluated by recording their walkingperformance on a treadmill.PATIENTS AND METHODSA total of 156 patients with osteoarthritis grade I or II,confirmed by x-ray analysis were included in this study.Patients were recruited the San Valentino vascular screening project. Patients were informed about aim ofthe study and treatment procedure according to thedeclaration of Helsinki and gave written informedconsent. The study was approved by the ethical com- mittee of the University of Pescara. Patients were in- formed that they could leave the study any time withoutdifficulty.Inclusion criteria. Primary osteoarthritis grade I or IIin one or both knees was diagnosed by x-ray investiga-tion. There was mild to moderate pain not adequatelycontrolled with antiinflammatory drugs. Subjects hadto be able to perform the treadmill test and to under-stand all questions from the questionnaire.Exclusion criteria. Cardiovascular disease requiring drugtreatment, particularly coronary heart diseases, diabetes, overweight, severe metabolic disorders, surgery or arthros-copy 3 months before inclusion or radio- or chemo-therapy. Pregnancy, breast feeding, planned conception. Randomization. Patients were allocated to treatment groups using randomization by blocks. Block allocationsequences were created at random by using randomlygenerated numbers from a computer program. The randomization list covered twice the number of sub-jects planned to be recruited. Each patient enrolled inthe study received the respective lowest randomizationnumber available.Estimation of size of treatment groups. A recent study with a comparable population of osteoarthritis patients showed a significant response to Pycnogenol treatmentusing a group size of 37 patients (Farid et al., 2007).Taking into consideration a drop-out rate of 10–20%for a treatment period of 3 months, an alfa of 0.05 anda beta of 0.20 (power of 80%) a number of about80 patients in each group was calculated to obtain asignificant difference from the placebo.Evaluation of symptoms of osteoarthritis. To describeand rate the symptoms of osteoarthritis the question-naire developed by the Western Ontario and McMaster Universities (Baron et al., 2007) was applied. Thequestionnaire gives scores for the diverse symptoms ofosteoarthritis (WOMAC scores) (Baron et al., 2007).The status of osteoarthritis was evaluated by theinvestigator together with the patient at the start ofstudy and after 3 months of treatment.Evaluation of physical performance. Patients weretrainedhow to do the treadmill test in two tutorial tests. At thestart and after the end of treatment, the patient’s per-formance was evaluated by the treadmill test with aspeed of 3km/h and an inclination of 10%. The totaldistance which could be covered without pain was noted.Vascular aspects. The presence of any vascular (arte-rial, venous of lymphatic) problem was carefully evalu- ated to exclude the influence of vascular disease on thetreadmill performance (i.e. claudication) and on pain.Color-duplex, Doppler (at rest and after the treadmill test) excluded the presence of peripheral vascular dis-ease. After a treadmill test, in the presence of periph-eral arterial disease, the Doppler signal at the distaltibial arteries may disappear for a variable period oftime or become fainter with a decrease in tibial pressures
Copyright © 2008 John Wiley & Sons, Ltd.Phytother. Res. 22, 518–523 (2008)DOI: 10.1002/ptr520G. BELCARO ET AL.measured by Doppler. In the case of a normal arterialsystem the distal pressure is comparable to the pre-testvalue or higher (Belcaro et al., 1996; Belcaro andNicolaides, 2001). Also venous diseases and the pos-sible presence of venous obstruction were evaluatedbefore the inclusion and at the end of the study (Belcaroet al., 1996).Edema evaluation. Edema was scored by the investiga-tor using the following scores: 0, not visible; 1, edemaonly visible after long standing or in the evening; 2,edema visible during the day but relieved overnight; 3,edema visible during the day but only partially relievedovernight; 4, edema present all the time.Ankle/foot edema. Ankle/foot edema (foot edemalevels 2 and 3 only) was also evaluated in a quantitativeway by foot volumetry in a randomly selected subgroupof subjects within the two treatment groups. To nor-malize the values, the actual foot volume at inclusionwas defined as 100% (by immersion in water, using awater displacement method) (Belcaro et al., 1996;Belcaro and Nicolaides, 2001; Cesarone et al., 1999).The intra-individual, relative percent variations with thistest were within 8%, therefore any variation >10% canbe defined as caused by external factors (treatment,management). The foot volume values were definedat the end of the study and compared. The variations involume observed with this method can be consideredas the measurement of the level of edema involving the distal part of the leg (Cesarone et al., 1999). The plasticleggings included water up to the level of the knee(defined as the lower edge of the rotula, in these meas-urements). The leg was immersed in water and the waterlevel was defined by eliminating water from a lowerside tap down to the lower edge of the rotula. Therelative volume was defined as 100%. A variationof this volume was measured as a percentage of theindividual volume at the start.Evaluation of associated treatments needed to managearthrosis. A diary was kept to record the use of anyother drug prescribed by the patient’s GP, the useof which was free (with only a warning not to use anexcess of treatment).Evaluation of costs and side effects. The cost of treat-ments and other costs (including working disruptionand hospital admission) occurring during the trialperiod were recorded in a specific costing file.Medication. Pycnogenol and placebo tablets wereprepared by Manhattan Drug Company Inc, New York,USA. Verum and placebo tablets had an identical appearance, size and shape. Containers of study drugs– verum and placebo – were delivered by the producerlabeled as A and B and were identical in size, shapeand appearance. Emergency envelopes were provided to identify A and B in the case of severe adverse events.Treatment consisted of two tablets daily, taken afterbreakfast and after dinner, consisting either of placeboor 50mg Pycnogenol.Statistical evaluation. The results were evaluated usinganalysis of variance (ANOVA) and the non-parametricMann-Whitney U test.Table 1. Patient characteristics at inclusion
Mean global WOMAC score
Treadmill test mean
48.6 SD 8
47.8 SD 7.7
a Treadmill 8 km/h with an inclination of 10%.
RESULTSThe treatment group (77 patients) and placebo group(79 patients) did not differ in respect of age, male tofemale ratio, overall WOMAC score and performanceon treadmill test at the start of the study (Table 1).Six patients in the treatment group and five patientsin the placebo group left the study for non-medicalreasons such as moving to other places and work prob-lems. Two patients had a localized trauma from accidents.Symptoms of osteoarthritisThe results of the evaluation of treatment success after3 months by WOMAC scores are given in detail inTable 2.Scores for pain dropped significantly (p < 0.05) fol- lowing Pycnogenol intake from 17.3 to 7.7, the placebo had no significant effect.The scores for stiffness were reduced significantlyfrom 6.6 to 3.1 (p < 0.05), scores for the placeboremained unchanged after 3 months.Also the scores for physical function were morethan halved, reducing from 55.3 at the start to 23.8 inthe verum group (p < 0.05), the improvement underplacebo was not significant.The global WOMAC score (Table 2) decreased fol- lowing Pycnogenol treatment significantly from 79.2 to34.6, with the placebo insignificant from 76.9 to 69.5.Negative alterations of social functions by OAdecreased significantly in the treatment group (p > 0.05),but not in the placebo group (details in Table 3). The well-being of patients (emotional function) wassignificantly (p < 0.05) enhanced under verum treatment,as reflected in scores for emotional function (Table 3),the placebo produced a marginal improvement.In conclusion, all WOMAC scores improved signifi-cantly (p < 0.05) after 3 months treatment relative tothe start and versus the placebo. Muscular performance The results of the exercise test on the treadmill demon-strate a convincing increase of performance of patientsfollowing the 3 month treatment with Pycnogenol(Table 4). Patients could walk just 68m as mean dis-tance covered at the start, but could go for a mean of198m after treatment, versus only 65m to 88m in theplacebo group.
PYCNOGENOL FOR OSTEOARTHRITIS521Copyright © 2008 John Wiley & Sons, Ltd.Phytother. Res. 22, 518–523 (2008)DOI: 10.1002/ptrTable 2. Change of WOMAC scores after 3 months of treatment (mean and SD)
Pycnogenol groupPlacebo group
Symptoms and functionsInclusion3 monthsInclusion3 months
Sum of pain scores
Stiffness during the day
Sum of stiffness scores
Rising from sitting
Bending to floor
Walking on flat
Getting in or out of car
Putting on socks
Rising from bed
Taking off socks
Lying in bed
Getting on or off toilet
Heavy house duties
Light domestic duties
Sum of physical
Global WOMAC score
•Minimum total score: 0 (no symptoms)
•Minimum pain subscore: 0
•Minimum stiffness score: 0
•Minimum physical function score: 0
maximum total score: 96
maximum pain subscore: 20
maximum stiffness subscore: 8
maximum physical function subscore: 68
Table 3. Change of WOMAC scores for social functions and of emotional WOMAC scores during treatment
Pycnogenol groupPlacebo group
Inclusion3 monthsInclusion3 months
Negative alterations in:
Sum of emotional parameters
Copyright © 2008 John Wiley & Sons, Ltd.Phytother. Res. 22, 518–523 (2008)DOI: 10.1002/ptr522G. BELCARO ET AL.Table 4. Results of exercise test before and after 3 month treatment
Diff. Pycnogenol – Placebo
significance level Pycnogenol Placebo
68 m (0–133)
198 m (55–374)
65 m (12–98)
88 m (25–102)
Treadmill with an inclusion of 10% and speed of 8 km/h.
Table 5. Percentage reduction of health care costs under treatment with Pycnogenol and placebo
Diff. Pycnogenol – Placebo,
significance levelCosts Pycnogenol Placebo
Drugs and treatments
54% 11% p < 0.05
p < 0.05
p < 0.05
p < 0.05
p < 0.05
Vascular problemsA high percentage of patients (76% in the Pycnogenolgroup and 79% in the placebo group) showed visibleankle and foot edema at inclusion. At the end ofthe treatment period, edema decreased under verum in79% of the patients but only in 1% of patients under placebo.Foot volume, evaluated by the water-displacementmethod, decreased in a subgroup of 40 patients withslight to moderate edema after Pycnogenol (n = 20) by32% (19–69%), after placebo (n = 20) by 7% (0–22%).The difference with the placebo was significant (p >
0.05).Reduction of concomitant medicationPatients were allowed to use concomitant medicationduring treatment. The use of NSAIDs dropped by58% during treatment with Pycnogenol, whereas underplacebo NSAID use was reduced by only 1%. Thedifference between both treatments was significant(p > 0.05) (Table 5). Treatment costs evaluated frompatients files indicate a decrease in the need for drugs(other than NSAIDs) and treatment by 54% versus11% in the placebo group (Table 5).Decrease of management costsThe days spent in hospital and the number of hospitaladmissions decreased over the study period of 3 months by 60% in the treatment group versus 3% in the placebogroup. The decrease of non-drug related treatment costs as lost working days, consultations, insurance costs wasestimated as 55% versus 3.5% with placebo (Table 5).Unwanted effectsUnwanted effects of treatment were reported by patientsin diaries. Evaluation of data demonstrated a decreaseof gastrointestinal complications of 63% in the Pycno-genol group versus 3% in the placebo group.DISCUSSIONThe evaluation of treatment success of Pycnogenol byusing the WOMAC scores resulted in a very significantdecrease of OA symptoms by about 50%. This judge-ment by patients was supported by the objective test oftreadmill performance of OA patients, showing thatpatients could walk more than twice the distance afterPycnogenol treatment compared with placebo. Thus,this double-blind, placebo-controlled study confirmedthe hypothesis that Pycnogenol, due to its diverseantiinflammatory actions, could be used as an alter-native treatment of OA to relieve pain and increasemobility. The WOMAC questionnaire revealed notonly an improvement of physical function of patientsbut showed a gain of quality of life, by enabling thepatients to be engaged in social activities, staying inbetter mood.Another important advantage of the treatment withPycnogenol is the reduction of unwanted effects, mainlygastrointestinal troubles connected with the reduced use of NSAIDs.The improved symptoms of OA and enhanced thewell-being of patients leading to reduced treatmentcosts. The estimation of the sparing effect of Pycnogenolto treatment costs of OA point to the possibility of abetter cost management by adding the pine bark extract to regular treatment. However, studies with alarger population and for a longer treatment period areneeded to confirm the findings of this study on a broader basis.While some effects of OA can be easily calculated ascosts (as medical care/management) costs and disruptedor lost working days, other costs are not easy to detect.These hidden costs include quality of life, the need of afamily member support (who may alter his/her workingand life habits), the inability to enjoy leisure activitiesor a reduction in housekeeping activities. Therefore the
PYCNOGENOL FOR OSTEOARTHRITIS523Copyright © 2008 John Wiley & Sons, Ltd.Phytother. Res. 22, 518–523 (2008) DOI: 10.1002/ptrglobal impact of OA is often underestimated becauseof the difficulties in quantifying many of its con-sequences. New safe and cost-effective methods oftreatment – not associated with complications and sideeffects – which may be directly used by patients bothas a base treatment or as a substitute treatment for aperiod of time are useful for expanding the therapeutic range.In addition to the amelioration of OA symptoms, thestudy provided information about clinical effects whichhave been generally overlooked in previous studies onOA. The decrease of limb mobility is generally associ- ated with variable degrees of edema, limb swelling anddeterioration of microcirculation, which in turn leadsto a more severe level of disability. During Pycnogenoltreatment, edema of the lower legs and the foot vol-ume were significantly reduced compared with placebo,in accordance with our previous publications showingthe high efficacy of Pycnogenol in edema reduction (Cesarone et al., 2005, 2006a, 2006b, 2006c; Belcaro et al., 2006).The medication used in this protocol was thereforenot only characterized by its potential to improve thesymptoms of OA, but also by its efficacy in improvingperipheral vascular disease and controlling edema.The reduction of signs and symptoms of OA andof vascular problems may be attributed to the diverseantiinflammatory mechanisms of Pycnogenol, as theunspecific inhibition of cyclooxygenases I and II (Schäferet al., 2006) and the inhibition of matrix metalloproteases (Grimm et al., 2006).Further clinical studies have to clarify whether theincrease of muscular performance is due to inflamma-tion control or to a direct action on muscular function.CONCLUSIONSThis study provides a new window to the managementof OA by showing significant actions of Pycnogenol onfour main, clinical components of OA: 1.the signs/symptoms and disability; 2.inflammation causing a progression in the disease; 3.the altered fatigue resistance and muscularperformance;4.severe, vascular problems associated with alteredmobility (i.e. sometimes leading to venous and stasisulcerations).The study demonstrated an important clinical action ofPycnogenol on OA and shows an interesting potentialin the management of this diffuse disease.The aspects concerning cardiovascular toxicity ofantiinflammatory drugs used in OA (Stillman andStillman, 2007; Rahme and Nedjar, 2007) have receivedgreat attention lately. As many OA patients haveconcominant cardiovascular diseases, the use of Pycno-genol may reduce the load of antiinflammatory agentsand offers important alternative management solutionsfor cardiovascular patients.REFERENCES Download full-text
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