1100304-口服玻尿酸改善膝關節炎症狀之效果-台灣人體臨床試驗研究

1. 口服玻尿酸改善膝關節炎症狀及功能之效果
<台灣臨床人體試驗研究結果發表>
1
王世杰 醫師/教授
Shyu-Jye Wang, MD

2. 王世杰 醫師/教授
2
現職
•台北市私立宏恩醫院、私立中山醫院
經歷
•中國醫藥大學附設醫院 骨科部 主治醫師/顧問醫師/教授
•美國梅約臨床醫學中心 研究員
•國防醫學院 骨科學科主任
•三軍總醫院 骨科部主任
•三軍總醫院 創傷骨科主任
•中華民國骨科及外科專科醫師
教職
•國防醫學院 副教授
•中國醫藥大學骨科、運動醫學系 教授
專長
•關節重建
•創傷骨科
•運動醫學

3. 3
Shyu-Jye Wang, MD*, Ya-Hui Wang, MD, Liang-Chen Huang,
MD
Clinical Trial Registration:
NCT04352322.

4. Background
4
 The discomfort of the intraarticular injection of high
molecular HA in knee OA patients[1]
 The efficacy of low molecular weight HA ingestion in knee
OA has been investigated in several studies and the
results remain controversial[2-3]
 To investigate the efficacy of an oral low molecular weight
liquid HA in the relief of symptoms and improvement of the
quality of life (QoL) in patients with knee OA

5. Study design
5
 A randomized, double-blind, placebo-controlled, 8- week study designed
to evaluate the effectiveness of oral low molecular weight A+HA for
symptom relief and improvement QoL in Taiwanese knee OA patients
 The A+HA is a 20mL liquid combination supplement containing, 50mg
of HA with low molecular weight (5×104 _ 5×105 Da) , 750mg of
glucosamine, and 250mg of chondroitin
 Subjects were randomized to administer either a bottle contained 20mL
of A+HA or a bottle contained 20mL of placebo daily for 8 weeks.
Efficacy assessments were performed at week 2, week 4, and week 8
after randomization
Ethics
This was a single center study took place in China Medical University
Hospital under the approval of China Medical University and Hospital
Research Ethics Committee (DMR101-IRB2–033)

6. Eligibility
6
Male or female age ≥ 40 years, diagnosed with knee OA
which met the definition of Ahlbäck classification[4]
and had
knee joint symptoms within 30 days prior to enrollment
were eligible
Ahlback S. Acta Radiol Diagn (Stockh) 1968;(suppl):7–2.
Ahlbäck classification
Stage and Radiographic change：
Stage 1： Joint space narrowing
Stage 2：Joint space obliteration
Stage 3：Bone contact less than 5 mm
Stage 4：Bone contact 5-10 mm , posterior osteophytes
Stage 5：Severe subluxation , anterior subluxation of tibia more than 10 mm

7. Excluded
7
 Administered glucosamine 1 month prior to enrollment
 Known allergy to oral HA
 Body mass index ≥ 40kg/m2, or their knee OA was caused by
occupational hazard or sports injury
 Patients with known other causes of arthritis (infectious rheumatoid or
psoriatic arthritis)
 Bony or soft tissue malignancy or peripheral neuropathy involving the
lower extremities
 Cardiopulmonary disease which limited walking more than knee pain
 Knee instability defined as a report of knee buckling or locking within
the past month of the study knee
 Major neurological deficit that affected gait, psychiatric illness that
limited informed consent or Parkinsonism
 Women in pregnancy and wheel chair users

8. Original study design
Moderate knee pain
Mild knee pain
All subjects had used oral analgesic
or any other medications for knee OA
concomitantly due to moderate to
severe knee pain during the study
period
8
OA
All subjects had Voren gel for
knee OA concomitantly due to
mild knee pain during the study
period

9. Study flow diagram
9

10. Outcome
10
 The patient’s knee OA symptoms were assessed by the
Western Ontario and McMaster Universities (WOMAC)
Osteoarthritis Index. [2]
 WOMAC: The higher the score, the greater the severity
 Pain(5 items)
 stiffness (2 items)
 physical function (17 items)
a maximum total score of 96

11. 11
 WOMAC: The higher
the score, the greater
the severity
 Pain(5 items)
 stiffness (2 items)
 physical function (17 items)
a maximum total score of 96

12. Outcome
12
 The patient’s QoL was evaluated by the 36-Item Short
Form Survey (SF-36) [5]
 SF-36: A higher score indicates a better QoL
 physical functioning (10 items), role limitations due to physical health
(4 items), pain (2 items), general health (5 items), vitality (4 items),
social functioning (2 items), role limitations due to emotional problems
(3 items), and emotional well-being (5 items)

13. 13
 SF-36: A higher score
indicates a better QoL
 physical functioning (10
items)
 role limitations due to
physical health (4 items)
 pain (2 items)
 general health (5 items)
 vitality (4 items)
 social functioning (2
items)
 role limitations due to
emotional problems (3
items)
 emotional well-being (5
items)

14. 14
SF-36

15. 15
SF-36

16. Study population
16
Baseline demographics and clinical characteristics of all randomized subjects

17. WOMAC scores during the 8-week study period
17
Over the 8-week study period, the A+HA group
showed a gradual improvement in WOMAC index
∗P <.05

18. Mean change from baseline in WOMAC
18
Total score Pain
Stiffness Physical function
∗P value<.05
against placebo
group
#P value<.01
against baseline

19. SF-36 scores during the 8-week study period
19

20. SF-36 scores at the week 8
20
The A+HA group achieved a significant improvement
in physical functioning sub-score at Week 8

21. Results
21
 At Week 8, significant reductions from baseline in the WOMAC pain
(–2.6±1.68, P<.0001), stiffness (–1.2±1.50,P=.007), physical function
(–5.8±4.39, P<.0001), and total (–9.4±5.82, P<.0001) scores were
observed in the A+HA group but not in the placebo group
 Significant differences in the mean change of WOMAC scores from
baseline at Week 8 between groups were detected (P<.01)
 At Week 8, the A+HA group also showed significant improvements in
SF-36 physical functioning (2.7±3.10, P=.001)

22. Conclusions
22
Oral administration of low molecular weight liquid HA
appeared to be effective for knee OA patients with mild
knee pain (VAS≦3) in the relief of knee OA symptoms,
particularly in pain and physical function

23. Discussion (I)
23
 For the symptoms relief in knee OA, the reduction in WOMAC pain
and physical function sub-scores were significant at 2 weeks after
randomization and persisted until the end of our study
 We found that HA ingestion did not improve much in the mental
health dimension in SF-36 (vitality, social functioning, role
limitations due to emotional problem[6]
, and emotional well-being
domains) and only modest but significant improvement was
observed in the SF-36 physical functioning domain at the end of
our study, in line with the results of HA ingestion
 HA ingestion offers an advantage over HA injection in avoiding
potential complications at the injection site and discomfort
associated with repeated injections

24. Discussion (II)
24
 This oral liquid formulation of HA may overcome the problem of
difficulty of swallowing solid oral dosage forms and offer a better
compliance in elderly knee OA patients[7]
 As the supplement contains glucosamine and chondroitin which are
usually consumed as chondroprotective agents, the potential effects
of ingredients other than HA on knee OA symptom relief cannot be
denied. However, the beneficial effects of this oral liquid low molecular
HA OA supplement on knee OA patients with mild knee pain symptom
were confirmed in this study
 At the study period, squatting, kneeing, up and down stairs activities,
and heavy duty loading motions of the OA knees were suggested to
be decreased as possible as they could. Beside, walking, cycling, and
swimming activities were encouraged if they could

25. Summary
25
Oral administration of liquid low molecular weight HA
appeared to be effective in the alleviation of knee OA
patients with mild knee pain symptoms, particularly in
pain and physical functions, and the effect is apparent
as early as 2 weeks after first administration

26. References
26
[1] Oe M, Tashiro T, Yoshida H, et al. Oral hyaluronan relieves knee pain: a review. Nutr J
2016;15:11.
[2] Nelson FR, Zvirbulis RA, Zonca B, et al. The effects of an oral preparation ontaining
hyaluronic acid (Oralvisc(R)) on obese knee osteoarthritis patients determined by pain,
function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses.
Rheumatol Int 2015;35:43–52.
[3] Tashiro T, Seino S, Sato T, et al. Oral administration of polymer hyaluronic acid
alleviates symptoms of knee osteoarthritis: a doubleblind, placebo- controlled study
over a 12-Month period. ScientificWorldJournal 2012;2012:167928.
[4] Ahlback S. Osteoarthrosis of the knee. A radiographic investigation. Acta Radiol Diagn
(Stockh) 1968;(suppl):7–2.
[5] Lu J-FR, Tseng H-M, Tsai Y-J. Assessment of health-related quality of life in Taiwan
(I): development and psychometric testing of SF-36 Taiwan version. Taiwan J Public
Health 2003;22:501–11.
[6] Farr Ii J, Miller LE, Block JE. Quality of life in patients with knee osteoarthritis: a
commentary on nonsurgical and surgical treatments. Open Orthop J 2013;7:619–23.
[7] Schiele JT, Quinzler R, Klimm HD, et al. Difficulties swallowing solid oral dosage forms
in a general practice population: prevalence, causes, and relationship to dosage forms.
Eur J Clin Pharmacol 2013;69:937–48.

27. 消炎止痛、修復軟骨、潤滑關節
退化性關節炎的治療方案
運動
體重控制
休息及關節護理
藥物
輔助替代療法
手術
1995-2012 by the American Academy of Orthopaedic Surgeons.

28. 消炎止痛、修復軟骨、潤滑關節
口服玻尿酸與葡萄糖胺差異
葡萄糖胺經過糖的代謝路徑，轉化成乙醯葡萄糖胺，再經
由玻尿酸合成酵素促成與體內葡萄糖醛酸結合，最後合成
玻尿酸，故葡萄糖胺是人體合成玻尿酸的原料
Glucuronic acid
葡萄醣醛酸
N-acetylglucosamine
乙醯葡萄糖胺
玻尿酸
Hyaluronic Acid

29. 消炎止痛、修復軟骨、潤滑關節
葡萄糖胺-合成玻尿酸的原料之一
年紀越大玻尿酸的合成酵素活性會下降且會大量缺乏，
導致無法合成所需的玻尿酸，所以補充再多的葡萄糖
胺也於事無補
OA 病患通常年紀較大，所以口服葡萄糖胺效果有限
(小分子玻尿酸)
(葡萄糖醛酸)
(乙醯葡萄糖胺)
+
人體合成

30. 消炎止痛、修復軟骨、潤滑關節
玻尿酸是老化的指標
25歲的玻尿酸含量只有嬰兒期的65%，到了60歲只剩25%

31. 消炎止痛、修復軟骨、潤滑關節
口服玻尿酸有用嗎?
與針劑一樣,不但對關節軟骨有潤滑、覆蓋、保護的作
用,還可以刺激關節的滑液膜細胞再製造出新的玻尿酸
軟骨組成結構

32. 消炎止痛、修復軟骨、潤滑關節
口服玻尿酸之吸收實驗-美國
在口服30分鐘後，即可在血液中偵測到
該報告證明口服玻尿酸可以順利被哺乳類吸收，堆積
於血液，肌肉，硬骨組織，排出體外者僅小於5%
This study examined the absorption, excretion and distribution of
radiolabeled hyaluronan (HA) after a single oral administration in
Wistar rats and Beagle dogs. To date its therapeutic use has
been limited to injections or topical applications, but there is no
data on pharmacokinetics after oral intake. The gamma emitting
isotope 99mtechnetium (Tc) was coupled to HA ……
Less than 5% of the radioactivity appeared in feces after 72 hours
in rats. Radioactivity was seen in blood, muscles, salivary glands
and bone as early as 30 minutes, and peaked 4-6 hours in all
non-alimentary tissues examined after oral administration.
There were transient increases in radioactivity in shoulder joints
and vertebrae 4 hours after oral administration of HA in both rats
and Beagle dogs. Residence time (t) in Beagle blood was 0.0134
hours. These results demonstrate that HA is absorbed and
distributed to organs and joints after a single oral administration.
Molecular weight was approximately 1.1−1.5 MDa for each HA.
200 mcg HA were administered to 150-200 gram Wistar rats, and
10 mg HA were administered to 10-15 kg Beagle dogs.
J. Agric. Food Chem. 2008, 56, 10582–10593

33. 消炎止痛、修復軟骨、潤滑關節
decreasing pain, improving physical function, and enhancing several aspects of quality of life.
口服玻尿酸之臨床有效性
HA mixture at 80mg (HA 48mg; MW 1000 k) daily for 2 months.

34. 消炎止痛、修復軟骨、潤滑關節
口服玻尿酸顯著改善疼痛及僵硬

35. 消炎止痛、修復軟骨、潤滑關節
口服玻尿酸之臨床有效性
2012 日本 Oral HA 人體臨床試驗
HA at 200mg (MW 900 k) daily for 12 weeks.

36. 消炎止痛、修復軟骨、潤滑關節
Conclusion
The population is aging rapidly around the world. In addition to medical
treatment, self-medication is more commonly practiced to reduce patient
burden and enhance QOL. HA is a safe raw material and the efficacy of
oral HA in relieving knee pain was demonstrated in several clinical trials.
HA as a dietary supplement exhibits mild efficacy and no side effects. By
utilizing these characteristics, HA dietary supplements provide at least
some possibility for the treatment and prevention of serious conditions in
patients with OA exhibiting mild knee pain. This review may improve the
understanding of HA dietary supplements and it is expected that HA will
emerge as a modality for treating knee pain that can be safely used by patients.
Oe et al. Nutrition Journal (2016) 15:11
DOI 10.1186/s12937-016-0128-2
口服玻尿酸提供輕度關節疼痛病患，治療與預防更嚴重狀況產生，
且安全無任何副作用
口服玻尿酸之臨床有效性
2016 review paper

37. 消炎止痛、修復軟骨、潤滑關節
Oe et al. Nutrition Journal (2016) 15:11
DOI 10.1186/s12937-016-0128-2
口服玻尿酸之臨床有效性
2016 review paper
Oral HA人體臨床試驗安全、無副作用

38. 消炎止痛、修復軟骨、潤滑關節
Many randomized, double-blind, placebo-
controlled trials have demonstrated the
effectiveness of dietary HA in alleviating
knee pain since 2008 in the US, EU, and
Asia (Table 1).
口服玻尿酸之臨床有效性
2016 review paper
2008-2015美國、
歐洲與亞洲許多
人體臨床試驗
(RCT)皆證實能
有效改善OA及
膝關節疼痛現象

39. 消炎止痛、修復軟骨、潤滑關節
1. 補充關節滑液，潤滑關節
2. HA在軟骨基質與軟骨素形成蛋白聚醣，修復軟骨、
吸水緩衝、提供養分
3. 減少 collagen 裂解，並抑制軟骨細胞的凋亡，逆轉
關節慢性發炎
4. HA覆蓋和保護痛覺感受器，而緩解疼痛
口服 HA可達成治療骨關節炎的目標
Arthritis Res Ther 2003,5:54-67
2008 Orthopaedic Research Society.J Orthop Res
January 2008;Accepted:10MARCH 2008

40. 消炎止痛、修復軟骨、潤滑關節
小分子液體口服玻尿酸
(Hyaluronic acid)
針對骨關節炎病患量身訂做的醫療級新配方，擷取最適合人體吸收的
分子量大小，且被證實玻尿酸確實分佈至關節、眼、皮膚等組織中
果汁般的液體，服用方便、簡單，水飽和狀態的玻尿酸，吸收更快
用喝的玻尿酸有最多的附加效益，全身關節都受惠、眼睛不再乾澀、
皮膚水嫩光滑，一兼三顧
吃維骨力沒有效果的病人應直接補充玻尿酸
A+HA 兩週見效，效果快，病人感受明顯
A+HA 針對骨關節炎添加軟骨素、葡萄糖胺、維他命C，效果更佳

42. 消炎止痛、修復軟骨、潤滑關節
早上空腹服用
2週即有感受
一個療程2個月
2個月後可改成2天喝一
瓶保養
眼睛不再酸澀
關節不再疼痛
皮膚水嫩光滑
A+HA 2,2,2法則

43. 消炎止痛、修復軟骨、潤滑關節
產
品 口服玻尿酸 葡萄糖胺 膠原蛋白
原
料 純雞冠萃取或發酵 甲殼素 豬皮、魚皮
成
分
玻尿酸 + 葡萄糖胺 +
軟骨素 + 維他命C
葡萄糖胺 + (軟骨素) 膠原蛋白+(胺基酸)
劑
型 單瓶20CC液體 膠囊,錠劑,大瓶裝液體 粉末,錠劑,液體
作
用
直接補充關節液
*片段小分子玻尿酸
形成玻尿酸的原料
補充膠原蛋白
(均衡飲食即可補充)
效
果 關節保養,乾眼症,皮膚
一兼三顧
關節保養 關節保養
口服玻尿酸 VS 葡萄糖胺 VS 膠原蛋白

44. 消炎止痛、潤滑關節、跪拜自如
法規開放原料來源：茹素者福音

45. 消炎止痛、潤滑關節、跪拜自如
小分子液體口服玻尿酸
有效消炎止痛，潤滑關節，提升肌耐力，是針對
素食族群所設計最完美的全素食口服玻尿酸!
玻尿酸 HA(發酵來源)
→潤滑關節，增加眼球角膜的潤滑、及皮膚的保水性
素食葡萄糖胺(玉米鬚萃取物)
→提供合成玻尿酸的原料、促進軟骨中蛋白聚醣的生成
輔酵素Q10
→提供細胞能量、清除體內自由基、增強肌耐力
鳳梨酵素
→減輕關節疼痛、抑制發炎因子、協助體內環保

46. 消炎止痛、潤滑關節、跪拜自如
YES HA 包裝與外觀

47. 47
Thank you
for your attention~