Disease of the skeletal system

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Osteoporosis is a disease of the skeletal system due to low bone mass and structural deterioration of bone tissue, causing bone mineral density (BMD) to be reduced and bone's micro architecture to be disrupted. (1) (2) (3) Thus, osteoporotic bone appears to be more porous as in Figure 1.

Figure Normal bone versus osteoporotic bone (1)

The onset of the disease is primarily due to ageing besides gender, hormonal change and use of glucocorticosteroid medicine being other risk factors.(4) (5) It is normally diagnosed based on the BMD measurement by dual energy X-ray absorptiometry (DXA). According to World Health Organization (WHO), a person with osteoporosis has a value of BMD 2.5 standard deviations or more below the adult mean. (7) (8) (9)

Today, osteoporosis has become a global issue, being the second leading health care problem after cardiovascular diseases. (5) (10) Its ratio is one in three women and one in five men worldwide. (11) (12) Osteoporosis can be treated and prevented but can never be cured completely. So, what are the current available treatments for osteoporosis?

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SOLUTION

Osteoporosis Medications

As osteoporosis is due to the imbalance between bone resorption and formation, osteoporosis drugs are classified into antiresorptive and bone anabolic agents based on their functions in balancing them up as follows. (3) (4)

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Figure Bone remodelling cycle (9)

Figure Chemical structure of biphosphonate (14)

Bisphosphonates are the most effective antiresorptive agent. (3) (4) (5) (7) (15) They are synthetic analogues of pyrophosphate as shown with two phosphonate groups on the side, thereby inhibiting activation of enzymes which utilize pyrophosphate. Their specificity comes from the phosphonate groups which coordinates the calcium ions by 'sticking' and binding to them. (5) (14) They then attach to bone and are ingested by osteoclasts over bone cells. Consequently, they inhibit bone digestion and encourage apoptosis of osteoclasts instead. (15) Among all, alendronate (Fosamax by Merck) is most effective in reducing osteoporotic fractures.

Intervention

BMD

Vertebral fracture

Non-vertebral fracture

Hip fracture

Calcium

A

B

B

D

Calcium + Vitamin D

A

-

A

A

Estrogens

A

A

A

A

Tibolone

A

-

-

-

Alendronate

A

A

A

A

Etidronate

A

-

D

D

Risendronate

A

A

B

A

Ibandronate

A

-

-

-

Calcitonin

A

C

C

D

Fluride

A

C

-

-

Anabolic steroids

A

-

-

D

Calcitriol

C

C

C

-

Alfacaldcidol

C

C

-

D

Raloxifene

A

A

-

-

Ipriflavone

B

-

-

-

Menatetrenone

B

B

-

-

Evidence A, positive evidence from one or more, adequately powered, randomized controlled trials; B, positive evidence from smaller non-definitive randomized controlled trials; C, inconsistent results from randomized controlled trials; D, positive results from observational studies; -, efficacy not established or not tested.

Table Evidence for efficacy of osteoporosis therapies (12)

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Table 1 shows a 3-year study by WHO showing that alendronate works best for osteoporosis, having grade A for all categories. In the study, alendronate was prescribed to osteoporotic women, 5mg daily for 2 years and 10mg daily for the third year or with placebo for 3 years. The treatment is shown to reduce the incidence of clinical vertebral, hip and wrist fractures by about 50% besides increasing the BMD at all measured sites. (5) (12) The Fosamax International Trial (FOSIT) study also demonstrated a reduction in non-vertebral fracture incidence in women, further confirming alendronate decreases clinical fractures as suggested.(18) Thus, Fosamax is now the first-line osteoporosis drugs, normally taken in 5-10mg daily, to treat both male and female osteoporosis and recently, also the glucocorticosteroid-associated osteoporosis.. (4) (17)

Figure 4 Bisphosphonates versus teriparatide (4)

As for bone formation deficiency, bone anabolic agents help in building bones. The most effective one is teriparatide (Forteo by Eli Lilly), normally given as daily injection. (3) (19) It is a recombinant parathyroid hormone (PTH) which regulates calcium and phosphate metabolism in bone. Exposure to Forteo activates osteoblasts more than osteoclasts. (4) Thus, it stimulates new bone formation, raising BMD level unlike biphosphonates which kill cells that degrade bone as shown. (15) (19) It is used mostly for those with established osteoporosis or cannot tolerate bisphosphonates. (4)

Graphs 1 and 2 Effect of alendronate and PTH in bone remodeling cycle (20)

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Both graphs show change in bone markers which detect products of bone remodeling during alendronate, PTH (representing teriparatide) and combined therapy. Graph 1 shows that teriparatide results in great increase of bone formation markers, to as high as 150% while alendronate and combined therapy lead to suppression in the median change in both graphs, confirming that teriparatide enhances bone formation effectively. Another study below too proves its effectiveness as postmenopausal women with osteoporosis treated with Forteo shows increase in BMD as compared to that of placebo. (20)

Mean Percent Change in BMD in Postmenopausal Women with Osteoporosis, Treated with Forteo or Placebo for 19 Months

FORTEO

N=541

Placebo

N=544

Lumbar spine BMD

9.7b

1.1

Femoral neck BMD

2.8c

-0.7

Total hip BMD

2.6c

-1.0

Trochanter BMD

3.5c

-0.2

Intertrochanter BMD

2.6c

-1.3

Ward's triangle BMD

4.2c

-0.8

Total body BMD

0.6c

-0.5

Distal 1/3 radius BMD

-2.1

-1.3

Ultradistal radius BMD

-0.1

-1.6

aIntent-to-treat analysis, last observation carried forward.

bp <0.001 compared with placebo.

cp <0.05 compared with placebo.

Table 2 Effect of Forteo on BMD (20)

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For maximum effectiveness of osteoporosis drugs, calcium and vitamin D supplements are usually prescribed along. According to Women's Health Initiative (WHI), both supplements are found to increase BMD by 1% and supports bone healing. This parallels with result from WHO study in Table 1.With additional healthy lifestyles such as exercising, avoiding smoking and alcohol consumption, osteoporosis drugs can function at their best. (3) (7) (15)

"It came as a complete shock to me that men even have it. I come about it by being pro-active, by doing weight bearing exercises, by the supplements, by the actual drug that I particularly use, the kind of food that I eat, and I do try and booze a little less."

Mark Holden, songwriter and performer (13)

IMPLICATIONS

Social implication

Figure VCF (6)

Osteoporosis accounts for millions of fractures annually, especially involving vertebra, hip and wrist. (4) (5) (11) Hip fractures causes chronic pain and immobility. (21) Following that, 40% of the patients are unable to walk independently and 60% requiring total assistance in mobility. (22) Thus, patients may find themselves dependent on caregivers. Immobility increases the risk of complications such as deep vein thrombosis and pneumonia which raises the morbidity and mortality rate. For example, hip fractures is said to cause mortality rates up to 20-24%. (3) (22) Such impact will bring about great distress among people around them. Vertebral compression fractures (VCFs) bring about radiculopathic pain, ie. shooting pain due to nerve root compression, immobility and even deformity. (2) (4) (5) There is evidence that quality of life following vertebral fractures is reduced more severely than other fractures. Furthermore, multiple VCFs result in kyphosis, ie. severe hunch back with stooped posture. (4) (5) (23) Patients may have low self-esteem and depressed with their distorted body image, exerting social impacts. In more severe cases, kyphosis exerts pressure on internal organs impairing patient's breathing ability and causing death.. (6) (23)

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Economic implication

Figure Burden of disability (24)

The direct costs for osteoporosis treatment are high, up to $2.7 billion annually in USA as reported by IOF. (24) WHO analysis has shown hip fractures have the highest costs due to long duration of hospitalization. (5) Another study showed 10-20% of patients require long term nursing care, following a fracture. (22) Such hospitalization and long term care pose financial burden to patients and their family. Futhermore, osteoporosis medications today are costly with evidence showing bisphosphonates particularly, are more costly compared with other treatments like supplements. (25) The rising direct costs for treatment are parallel with the rising indirect cost when patients lose their independence and require care. Osteoporosis-related disability confines patients to more immobile days than other diseases as shown. (5) (21) Such immobility leads to great fall of patients' productivity in work as they cannot work as much as before and may even lose their jobs. Furthermore, if premature death of osteoporosis occurs, the supply of workforce in the economic field will be greatly reduced too.

BENEFITS & RISKS

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Osteoporotic drugs are beneficial in alleviating patients' BMD. (18) (26) Besides reducing bone resorption, bisphosphanates result in significant reductions in fractures risks especially Fosamax. FOSIT study demonstrated a reduction of non-vertebral fracture in postmenopausal women by about 50% after treatment. (5) Such reduction enhances patients' quality of life. However, this approach imposes side effects on health mainly in the gastrointestinal tract. (3) (7) (14) Oral biphosphonates often leads to oesophagal inflammation. Thus, it must be taken at least one and a half hour before first food with only plain water and remained seated upright for 30-60 minutes. On 31 December 2008, FDA reported that 23 cases of oesophageal cancer are possibly linked to the use of the drug, since its 1995 market debut. (18)

Just like bisphosphonates, Forteo reduces risk of fracture comparably. It is the drug of choice when patients cannot tolerate bisphosphonates. (4) (27) In addition, it is found to be a more effective treatment for glucocorticoid-induced osteoporosis as compared to Fosamax. (16) (26) (28) However, it was associated with increased risk of osteosarcoma, ie. bone cancer. (3) (15) In July 2006, Eli Lilly disclosed the first human case of osteosarcoma in a postmenopausal women in her second year of Forteo treatment. Since then, its manufacturer provide guidelines to avoid prescription to patients with increased risk of osteosarcoma including those with Paget's Disease (ie. elevations of serum alkaline phosphate resulting in excessive breakdown and formation of bone tissue), had prior skeleton radiation therapy and children. Avoiding usage for more than two years can reduce the side effects. (19) (27)

ALTERNATIVE SOLUTIONS

Hormone replacement therapy(HRT)

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Hormone replacement therapy is a good alternative when patients continue to encounter bone loss while taking osteoporotic drugs. (4) (5) (7) (13) HRT aims to improve the reproductive hormones imbalance as we age. Normally, HRT is available in oral tablets or skin patches. (15) HRT in postmenopausal women involves combination of estrogen and progestin. (30) (31) It works by replacing both hormones which are no longer being produced during menopause back to premenopausal levels. As osteoblasts contain oestrogen receptors, oestrogen increases osteoblasts, encouraging slower bone loss and faster bone growth simultaneously. Addition of progestin lowers risk of uterus cancer caused by estrogen. (3) (5) According to evidence provided by WHO in Table 1, estrogen increases BMD and reduces osteoporotic fractures in postmenopausal women. (12) (30) (32) Another controlled study in 164 women found no fractures in HRT group but 7 fractures in placebo group in the first 10 years of treatment. (5) For men, adequate testosterone is responsible in maintaining BMD. (33) Testosterone replacement therapy has been shown to improve bone quantity and quality. (4)

Kyphoplasty and Vertebroplasty

Figure Kyphoplasty (34)

Kyphoplasty and vertebroplasty are two relatively new treatments that relieve pain caused by VCFs when osteoporosis medications failed to do so. (6) Kyphoplasty, derived from vertebroplasty is more common. Inflatable balloon tamps are used to create a cavity in the fractured vertebra. Acrylic cement is then injected into the cavity under X-ray guidance as in Figure 8. (35) However, there is no balloon used and no cavity created in vertebroplasty. (36) The cement will then restore the vertebral body height, correct the angular deformity and stabilize the fractured vertebra. Consequently, radiculopathic pain is relieved. However, the risks are that the vertebra directly below can be crushed due to the expansion of the vertebra above or leakage of acrylic cement may occur. The Journal of the American Academy of Nurses Practitioners (JAANP) revealed that both treatments are effective in treating pain associated with VCFs. In addition, another study shows more than 95% patients have rated kyphoplasty a success and it is effective in preventing future fractures. (37)

EVALUATION

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Biphosphonates had been found to be the main pharmacological treatment for osteoporosis from reference (3) Sim, Dr Yeap Swan. The Beginning of 'O' (Osteoporosis). Health Today. October, 2009 , an article published in conjunction with World Osteoporosis Day 20 October 2009. This source is reliable because it agrees with sources (4), (5), (7) - an introductory orthopaedics textbook written by 3 reputable orthopaedic surgeons in UK and (15). Being published in Health Today, a leading consumer health magazine in Asia Pacific, owned by CMPMedica which specializes in healthcare education and information also proves its reliability as the information should be factual and accurate. In addition, it is written by a consultant rheumatologist based on kreferences which are ensured valid and cited in the article.

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I have found source (11) About Osteoporosis. [Online] [Cited: November 31, 2009.] http://www.iofbonehealth.org/ very reliable in providing in-depth information on osteoporosis. Sources (8), (13), (22) containing information on diagnosis, treatment and statistics of osteoporosis are all from it. This website contains a lot of reviews, articles, researches and even past experiences from patients on the disease. It is very reliable as it is managed by the International Osteoporosis Foundation (IOF), the largest global non-governmental organization dedicated for this disease. Its information also agrees with other sources. For example, HRT as an alternative to osteoporosis medications is agreed by sources (4), (5) and (7).

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