A Systematic Skeletal Disorder Biology Essay

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INTRODUCTION

Osteoporosis is a systematic skeletal disorder characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (EMEA, 2006).

Osteoporosis disease causes potential economic burden; specially vertebral and hip fragility and fractures cause increase rate of morbidity and mortality.

The clinical manifestation of the disease is frequent fractures specially hip and vertebral fracture. There are no clinical signs of the disease, till it has reached its clinical manifestation. However it is well known now that age and menopause are the two major determinants of the disease.

PATHOPHYSIOLOGY OF Osteoporosis

The underlying mechanism in all cases of osteoporosis is an imbalance between bone resorption and bone formation. Skeletal fragility can result from (Lawrence and Raisz, 2005):

Failure to produce a skeleton of optimal mass and strength during growth;

Excessive bone resorption resulting in decreased bone mass and microarchitectural deterioration of the skeleton; and

An inadequate formation response to increased resorption during bone remodeling.

The bone remodeling process is a very important factor and determinant of the disease as it can results in more bone resorption and less bone formation. Thus it is important to understand the mechanism by which bone remodeling occur.

(A) Bone Remodeling

Pathophysiology

The bone remodeling process occurs in the bone multicellular unit (BMU) as first described by Frost in 1963.

Osteoblasts are activated via growth hormones, PTH and IL-1 and IL-6 (figure 1). They induce various molecular signals to activate hematopoietic precursors to become osteoclasts. One of the well known regulators of osteoclasts is the Receptor Activator for Nuclear kB ligand, RANK.

Once osteoclasts are activated, various mediators are produced such as growth factors (IGF-I, IGF-2 and IGF-BP) and collagen that activates new osteoblast to form and differentiate from the stromal cell. Then the new osteoblast produces a new complex matrix and start the bone mineralization process (see figure 1).

Figure 1: The bone remodeling cycle (Clifford, 2007).

Bone formation is regulated by master genes, such as cbfa1, and by growth factors such as members of the transforming growth factor β super family, which includes the bone morphogenetic proteins (Mueller and Russell, 2003).

Apoptosis (programmed cell death) is emerging as a major means of regulating the life span of bone cells of all lineages: osteoclasts, osteoblasts and osteocytes (Mueller and Russell, 2003).

It is very important to understand that the cycle is regulated by various hormones, growth factors and prostaglandins agents such as estrogens and androgens, parathyroid hormone, growth factors (IGF-I & IGF-II), transforming growth factors, vitamin D and calcium and members of the tumor necrosis factor known as RANK .

Calcium plays an important role during bone growth; thus a deficiency in calcium serum level will affect the peak bone mass and will lead to osteoporosis. Vitamin D is important to induce calcium absorption from the GIT.

One of the main recognized hormones that have an important role is the parathyroid hormone (PTH). The hormone is produced by the parathyroid gland when the calcium level is decreased. The PTH triggers the breakdown of bone via osteoclasts stimulations. Further the PTH increase the calcium level through activation of vitamin D, which increase the absorption of calcium from the gastrointestinal tract and maintain its level.

PTH activates bone remodeling through stimulation of growth factors IGF-I and collagen production and appears to increase osteoblast number by stimulating replication, enhancing osteoblast recruitment, and inhibiting apoptosis (Harrison, Chapter 348).

It is published that the most effect of estrogen on the bone resorption process (that is decreasing the bone resorption) is mediated indirectly via the paracrine factors produced by osteoblasts. These actions include: (1) increasing IGF-I and TGF-b, and (2) suppressing IL-1 (a and b), IL-6, TNF-a, and osteocalcin synthesis. (Harrison, Chapter 348).

So how can a change in the resorption and formation process can lead to osteoporosis?

Osteoporosis can eventually occur during the bone remodeling cycle due to the fact that the resorption process and the reversal process are very short compared to the period required for osteoblasts to replace new bones.

This huge difference and any increase into the resorption and reversal processes will lead to eventual bone mass loss and thus bone become fragile.

Further excessive resorption will lead to loss of the bone trabecular structure

Any changes to the regulated hormones and growth factors will lead to inadequacy in the bone formation process and will increase the resorption rate.

(B) Other Major Risk Factors

B.1 Hormonal Factors

As discussed in the bone remodeling section, there are many hormones that contribute to the cycle in many ways;

Deficiency of estrogen is amongst the well known cause factor of osteoporosis in women.

Changes in the parathyroid hormone will lead to less bone formation and thus will cause more bone resorption. It will also affect the stimulation of other growth factors (such as IGF-I) that induce the activation of osteoblasts.

PTH will also affect on the absorption of calcium

B.2 Chronic Diseases and Medications

Chronic diseases can lead to osteoporosis such as;

Crohn's disease interfere with the absorption of calcium

Hyperthyroidism can result in increase in bone turnover

Hyperparathyroidism lead to vitamin D insufficiency.

Diabetes may cause less bone formation

Cushing's syndrome lead to inhibition of bone formation

Multiple myeloma causes stimulation of osteoclasts and may also inhibit osteoblast reaction.

Malabsorption can also interfere with calcium and vitamin D absorption.

Deficiency in lactase directly affects absorption of calcium.

Renal and hepatic impairment diseases.

Medications can induce the speed rate of osteoporosis. Some of the well known are:

Glucocorticoids - induce osteocyte apoptosis and are one of the most well known drugs that cause osteoporosis.

Gonadotropin releasing hormone analogs

Thyroid Hormone analogs - speed up the rate of remodeling and cause bone loss

Immunosuppressants - concurrent intake with Glucocorticoids in transplantation also lead to bone loss

Heparin and many other medications

B.3 Ageing Factor

Increase in age is a common cause of osteoporosis as bone tissue is increasingly lost.

Women at menopause age are highly susceptible to osteoporosis risk.

Concurrent illnesses are common and cause bone loss.

Decrease in growth hormone with increase in age also contributes to the risk of osteoporosis.

B.4 Others Risks that can contribute to Osteoporosis

Genetic factors

Smoking decrease estrogen productions

Excessive alcohol lead to inhibition of the activity of osteoblast and also increase the risk of falling which lead to fracture

High caffeine level can cause loss of calcium

Less physical activities can lead to weak bone

Low level of calcium intake and vitamin D

Race and ethnicity

Menopause

Frequent falls

Nutrition and life style

DIAGNOSIS

Most of the techniques are used to diagnosis the disease measure the bone mineral density of the bone which utilizes the use of radiation such as:

Dual Energy X-ray Absorptiometry (DEXA)

Single-Photon Absorptiometry (SPA) and Dual-Photon Absorptiometry (DPA)

Quantitative CT (QCT)

Ultrasound

The above mentioned techniques are used to:

determine whether the bone is of low density or not

determine whether there is bone loss

determine type of treatment that will be of great benefit to the patient

Treatment

(A) Antiresorptive THERAPY

Bisphosphonates

Bisphosphonates are synthetic analogues of pyrophosphate that bind to the hydroxyapatite found in bone. Bisphosphonates specifically inhibit the osteoclast function. The current available bisphosphonates therapies in the Australian market are:

Alendronate and alendronate plus vitamin D3 (brand names Fosamax and Fosamax plus D and their generics equivalents)

Ibandronate (brand name Bonviva Injections)

Risedronate and risedronate with calcium (brand names Actonel and Actonel with Calcium and their generics equivalents)

Zoledronic Acid (brand name Zometa, Osteovan and Aclasta injections)

(B) Hormone Replacement THERAPY

Estrogen therapy (ET) and estrogen with progesterone hormone therapy (HT) are approved for the prevention of osteoporosis in postmenopausal women such as Raloxifene (brand name Evista Tablets).

(C) Bone Forming (Anabolic) THERAPY

Parathyroid Hormone

Teriparatide (brand name Forteo®) is a recombinant parathyroid hormone with the active fragment (1-34) of endogenous human PTH. It is approved for the treatment of osteoporosis in postmenopausal women and in men who have very low BMD or are at high risk for a fracture.

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