INTRODUCTION
Osteoporosis, a skeletal disease having characteristic bone mass
reduction and bone micro architecture deterioration including bone
fragility and high risk of fractures. Fractures are more prone due to
decrease in bone mineral density and has some importance in both men and
women [1]. Osteoporosis has become major health
problem with the advancement in socioeconomical conditions and delay of
humanoid life span. Bone mass maintained by bone resorption and dynamic
balance of bone formation, when lost results in osteoporosis[2].
Fastest growing population in the world are elderly age, bone mass
decline and risk of fractures increases as age increases. As population
longevity in developing countries continues to increase likelihood of
osteoporosis will increase in these countries [3].The prevalence of osteoporosis that is reported in women in United
Kingdom, France and Germany, United States of America, and Japan, as
9%, 15%, 16% and 38% respectively; whereas in men, United Kingdom,
Japan, Canada and France as 1%, 4%, 3%, 8% respectively. In 2000,
around 9.0 million osteoporotic fractures were stated, 1.6, 1.7 and 1.4
million of which found at the hips, forearm and vertebral fractures[4]. It was concluded that in Pakistan there are
9.90 million osteoporotic patients (7.19 million are women and 2.7
million are male) and these numbers will increase to 11.3 million in
2020 and 12.9 million in 2050; after conducting the large countrywide
study using the quantitative ultrasound in Pakistan[5].
In osteoporosis patients, care of patients and underlying drug
development continues to improve with increased understanding of bone
loss. In a co-ordinated and continuous fashion old bones are removed by
osteoclast and new bones are formed by osteoblast and process is called
bone remodeling. With certain diseases and aging among old and new bone
incomplete replacement occurs [6]. A new mechanism
for osteoporosis recently suggested is imbalance between
osteoblastogensis and adipogenesis of mesenchymal stem cells of bone
marrow. The comprehensiveness and exhaustiveness of this mechanism is
still uncertain [7].
Osteoporosis can be classified in two main categories; primary
osteoporosis and secondary osteoporosis. Primary osteoporosis can occur
both in males and females but occur oftenly in postmenopausal women,
also happens in men’s life later. Use of medications (glucocorticoid,
immunosuppressant’s), disease (Cushing’s syndrome, hyperthyroidism),
other conditions (vitamin D deficiency and hypogonadism) results in
secondary osteoporosis[8]. Primary osteoporosis is
the most commonly found type of disease and it has sub types as:
post-menopausal osteoporosis or type-I and senile osteoporosis or
type-II [9]. At menopause ovarian function reduces
that give consequences as limited estrogen production and parallel
increasing follicle stimulating hormone. A significant bone resorption
and quick bone loss is result of combined effect of estrogen decrease
and increase in FSH; this is the basic for onset of post-menopausal
osteoporosis [10] .Senile osteoporosis is also
called Involutional osteoporosis (type-II) and is related to bone mass
loss due to cortical and trabicular bones aging[11]. Secondary osteoporosis is characterized by
micro architectural bone changes causes fragility fractures accompanied
by underlying disease or medication associated with low bone mass[12] .Medical conditions or treatments that
interfere with the attachment of peak bone mass and/or may predispose to
accelerated bone loss results in secondary osteoporosis. Secondary
osteoporosis is becoming more frequently diagnosed despite of being less
common. It shows similar prevalence among men and women[13].
In osteoporosis major component of fragile bone is low bone mass
resulting from: (1) A small peak bone mass at young adult hood. (2) At
menopause or later ages as increased bone loss. (3) Combination of both.
Peak bone mass and subsequent bone loss is influenced by many factors
that are physical in activity, genetic factors, nutritional factors and
hormonal factors [14] .Development or appearance
of osteoporosis is due to many causes. When cause is natural it is known
as primary osteoporosis. Idiopathic osteoporosis develops when cause is
unknown [15] .Low estrogen level, genetic
predispositions, low body weight, smoking, excessive consumption of
coffee and long periods of immobilization are contributing factors
towards osteoporosis. Deficiency of calcium, 1.25 dihydroxy vitamin D
and proteins are dietary factors which increase the risk of osteoporosis[16]. Many of the nutrients and food components we
consume influence bones by various mechanisms that include bone
structure alterations, bone metabolism rate, the endocrine system,
homeostasis of calcium and other bone active mineral elements. These
dietary factors include inorganic minerals (e.g. calcium, magnesium,
phosphorus, sodium, potassium and various trace elements), vitamins
(vitamin A, D, E, K, C and certain B vitamins) and macronutrients such
as proteins and fatty acids increase risk of osteoporosis[17]. Osteoporosis is diagnosed clinically or
radio graphically. Low impact fractures or fragility fractures may
present with osteoporosis. T-score of -1.25 or below as determined by
DEXA scan of the total hip, femoral, neck or lumbar spine is most common
method for diagnosis of osteoporosis. BMD can be assessed by
quantitative computed tomography by radiation exposure and cost has been
limited [18].
The whole population must focus on nutritional and life style changes
for prevention of osteoporosis. Increase awareness through patient
education about the modifiable risks of osteoporosis is an important
primary care role [19] .As described women
(especially post-menopausal) are osteoporotic in high ratio, so
preventive measures are taken in women to avoid osteoporosis. Ensuring
that women reach their peak bone mass (PBM) and minimize bone loss
through their early adult years is primary prevention goal in
osteoporosis. In women who have osteoporosis or osteopenia by bone
density measurement, fracture prevention is basic focus of secondary
prevention. In women who have already sustained fractures in
osteoporosis, preventing future fractures is tertiary prevention
strategy [20].
By assessment of bone mineral density by DEXA scan in vast majority of
cases; those at high risks of osteoporotic fractures should be targeted
for treatment. The treatment can be started without measuring BMD in
people with two or more vertebral fractures and having high risks of
future fractures. Goals of treatment are fracture prevention,
stabilization and achievement of an increase bone mass, relieving
fractures and skeletal deformity and physical function minimization[21] .Bracing, exercise programs, calcium and
vitamin D supplementation, fall prevention and kyphoplasty are
non-pharmacological therapies for managing osteoporosis and have
significant role in fractures minimization [22].Various pharmacological treatments are also available for treatment of
osteoporosis. In alphabetic order, bisphosphonates (alendronate,
alendronate plus D, risedronate and zoledronic acid) calcitonin,
estrogen (estrogen and/or hormone therapy), estrogen agonists, tissue
selective estrogen complex, parathyroid hormone (PTH, teriperatide) and
receptor activator of nuclear factor kappa-B, ligand inhibitor
denosumab; are current FDA approved pharmacological treatment of
osteoporosis [23]
Osteoporosis pharmacological treatment comprises of two main classes;
antiresorptive agents and anabolic agents. Bone resorption is limited
through inhibition of osteoclasts activity by use of anti resorptive
agents such as bisphosphonates. Active building of bone mass is promoted
using anabolic agents such as parathyroid hormone[24].
Various physiochemical effects on bone salt crystals and biological
effects on mineralization and resorption of bones are biological actions
of bisphosphonates [25] .Bisphosphonates are
reported as most potent and effective inhibitors of bone resorption.
Extended use of bisphosphonates in all conditions such as excessive
osteoclast-mediated bone resorption such as steroid induced osteoporosis
has been reported in clinical use [26].Bisphosphonates discovery and development for the treatment of bone
diseases is fascinating story extended over three decades. The bone
resorption inhibitors bisphosphonates are “P-C-P” structures i.e. two
phosphonates groups attached to single carbon atom. Bisphosphonates are
therefore stable analogs of naturally occurring pyrophosphonate
compounds helpful in intracellular and extra cellular mode of action[27].
Bisphosphonates as anti resorptive agents are most broadly consumed
drugs group for osteoporosis. By inhibiting recruitment of osteoclasts
bisphosphonates straightaway diminish the count of osteoclasts and also
inhibit osteoclast stimulating activity of osteoblasts. In patients with
osteoporosis, bisphosphonates normalize bone turn over, reduce number of
bone remodeling unit, restore the balance of bone remodeling, prevent
bone loss and deterioration of bone structure and reduce fracture
risks.[1] In many clinical trials of
postmenopausal women suffering osteoporosis, efficacy of bisphosphonates
is thoroughly researched and reported. Large number of meta-analysis of
bisphosphonates have been performed but recently adverse effects related
reviews are found and few reviews on clinical impact in population for
future prevention [28]. Adverse effect such as
gastro esophageal irritation was recognized early on with
bisphosphonates therapy. Short term adverse effects include: upper GI
adverse effects, acute phase reaction, severe musculoskeletal pain,
hypocalcaemia, esophageal cancer with oral use and ocular inflammation.
Long term adverse effects include: osteonecrosis of jaw, atrial
fibrillation, severe suppression of bone turn over and subtrochanteric
femoral fractures [29].
In mammals maintenance of calcium homeostasis is central role played by
human parathyroid hormone that is an 84-amino acid peptide. The primary
mechanism through which this class of drug operates is inhibition of
bone remodeling. Decline in remodeling rate have several beneficial
effects such as bone density improvement through decrease in remodeling
space size, cancellous bone architecture prevention, decrease in
resorption cavities number and cortical porosity decrease[30]. Teriperatide is amino-terminal fragment of
parathyroid hormone and is a potent bone formation agent. Teriperatide
increases the number of osteoblasts and rate of new bone formation by
increasing osteoblasts birth rate and preventing osteoblasts apoptosis.
Teriperatide is administered parenterally; subcutaneously[31].
Injection site pain and swelling (<3.3% of patients), nausea
(8.5%), headache (7.5%), leg cramps (2.6%) and dizziness (8%) are
most common adverse effects of parathyroid hormone; Teriperatide.
Hypocalcaemia associated with Teriperatide is an uncommon side effect.
In less than 1 in 1000 teriperatide recipients allergic reactions
including dyspnea, urticaria and chest pain have occurred. In patients
with risk of osteocarcoma such as Paget’s disease, teriperatide use
should be avoided. Drug should not be use more than two years[32].
Another major cause of osteoporosis is malnutrition. Calcium intake less
than 500mg/day contributes to low bone mass, like wise osteoporosis may
also be caused by high intake of caffeine, tea, soft drink, sodium
chloride, cigarette smoking, protein and alcohol[33].
Large intake of salt is another major risk factor for development of
osteoporosis because excretion of sodium and calcium both increased in
urine due to excessive salt intake. Salt intake at a level of 9g/day
contributes osteoporosis [34].
Like all developed and developing countries, osteoporosis is also very
common in Pakistan especially in elderly population. Different treatment
options are offered to the patients by their treating physician.