Pharmacotherapy For Osteoporosis

Pharmacotherapy for osteoporosis - eMedWiki
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Pharmacotherapy for osteoporosis

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Contents
1 Pharmacotherapy for Osteoporosis
2 Anti-catabolic agents
2.1 Bisphosphonates
2.2 Hormone replacement therapy (HRT)
2.3 Selective Estrogen Receptor Modulators (SERMs)
2.4 Calcitonin
3 Anabolic agents
3.1 Strontium Ranelate
3.2 Parathyroid hormone
4 Other considerations
4.1 Calcium and Vitamin D
4.2 Treatment in men
5 Future treatments
6 References
Pharmacotherapy for Osteoporosis

Osteoporosis is a disease of bone structure, where the bone becomes more porous as a result of reduced bone
mass. This decrease in bone mass leads to an increase in bone fragility and susceptibility to fractures [1].
Internationally, osteoporosis occurs in up to 1 in 2 women and 1 in 5 men over the age of 50 years and the most
common osteoporotic fractures occur in the vertebrae, hip and wrist bones [2]. In Australia approximately 10%
of the population are suffereing from osteoporosis and this is set to rise in coming years (Figure 1)[3]. It is most
commonly caused by post menopausal oestrogen deficiency and degeneration of bone homeostasis as a result of
the aging process. Other conditions (e.g. rheumatoid arthritis) and medications (e.g. glucocorticoids) can cause
secondary osteoporosis which often has a different treatment regime to primary osteoporosis [4].
http://php.med.unsw.edu.au/medwiki/index.php?title=Pharmacotherapy_for_osteoporosis
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Figure 1: Osteoporosis in Australia. [3].
The aim of pharmacotherapy in osteoporosis is to decrease the risk of osteoporotic fracture. There are two main
categories at present: anti-catabolic agents that target the osteoclast or anabolic agents that target the osteoblast
[5].
Anti-catabolic agents
Anti-catabolic agents decrease bone resorption and bone remodelling which results in increased bone strength
[6].
Table 1 shows the main anti-catabolic agents.
Table 1: Anti-catabolic agents [1][4][7]

Agent
Bisphosphonates
Use
Prevention and treatment of postmenopausal osteoporosis
Osteoporosis in males
Prevention and treatment of glucocorticoid induced osteoporosis
Hormone Replacement Therapy
Teatment of osteoporosis in postmenopausal women with vasomotor

symptoms
Selective Estrogen Receptor

Modulators
Treatment of postmenopausal osteoporosis

Calcitonin
Treatment of glucocorticoid induced osteoporosis

Treatment of osteoporosis in males
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Bisphosphonates
Figure 2: Mechanism of Action of Bisphosphonates [8].
Bisphosphonates are synthetic analogues of pyrophosphate that supress osteoclast function by interfering with
intracellular pathways. This ultimately leads to the deactivation and apoptosis of the osteoclasts (Figure 2 and
Figure 3). They are considered first-line therapy and there are several types used for the treatment of
osteoporosis (Table 2)[2][9].
Table 2: Current bisphosphonates[9] [10][11][12]

Bisphosphonate Efficacy (fracture risk reduction)
Vertebral: 44%
Alendronate
Hip: 51%
Vertebral: 49%
Risendronate
Non-vertebral: 39%
Use
Prevention and treatment of postmenopausal
osteoporosis
Treatment of osteoporosis in men Treatment of
glucocorticoid induced osteoporosis
osteoporosis
Treatment of osteoporosis in men Treatment of
glucocorticoid induced osteoporosis
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Ibandronate
Vertebral: 40%

osteoporosis
Zolendronic
acid
Significant reduction in both

vertebral and non-vertebral
There are two modes of administration for bisphosphonates: oral and intravenous (IV). When given orally, they
are poorly absorbed and can result in gastrointestinal side effects, including abdominal pain, nausea, dyspepsia
and heartburn [12]. IV administration can cause an acute reaction with flu-like symptoms as well as increase the
risk of atrial fibrillation (2%) and arthralgia [1]. It has also been associated with a slight increased risk of
osteonecrosis of the jaw in patients with certain cancers [11].
Alendronate can cause additional side effects such as esophagitis, esophageal ulcers and esophageal strictures
[4].
While the incidence is low, alendronate is contraindicated in patients with existing strictures or poor
esophageal emptying [13].
Hormone replacement therapy (HRT)

Post menopausal women are at an increased risk of developing osteoporosis (due to the reduction in oestrogen
levels) as oestrogen indirectly inhibits osteoclasts and counteracts bone resorption. For this reason oestrogen
replacments conserve BMD and reduce vertebral and non vertebral fracture risk [7] [10].
However due to the effect of estrogen on other systems, it can cause an increased risk of hormone-dependent
diseases such as breast cancer and cardiovascular disease (CVD) [4]. While HRT is no longer considered first
line treatment for osteoporosis, it may be used for postmenopausal women with vasomotor symptoms, who are
not already at risk for developing CVD [7]. When it is used, patients should be regularly monitored for any
complications and should only be on HRT for a short period [2].
Selective Estrogen Receptor Modulators (SERMs)

In order to target specific tissues, non hormonal agents were developed that acted on estrogen receptors. SERMs
bind to estrogen receptors and depending on the tissue may have an agonistic or antagonistic effect [14].
Raloxifene is a SERM that has an agonistic effect on bone and the cardiovascular system and an antagonistic
effect on the breast and uterus [1]. Within the bone it has an antiresorptive effect, causing an increase in
osteoclasts and a decrease in osteoblasts [4]. While data has shown a 30-50% decrease in vertebral fracture
occurrence, there has not been any evidence for the reduction of non-vertebral fractures [14]. The antagonistic
effects of Raloxifene means that it can reduce the incidence of estrogen receptor positive breast cancer and is
not associated with an increased risk of heart disease or uterine cancer [15]. Adverse effects include hot flushes,
leg cramps and an increased risk of venous thromboembolism and stroke in older patients [16].
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Calcitonin
Calcitonin is a peptide hormone that is produced by the C-cells of the thyroid gland and is involved in calcium
homeostasis [13]. It can be given subcutaneously, intramuscularly or by a nasal spray [9]. Calcitonin has three
major mechanisms; firstly it acts on osteoclasts to reduce numbers and inhibit bone resorption. Secondly, it
interacts with the cell brush border to interfere with calcium transport, thereby decreasing the amount of
calcium that is taken from the bone into the blood. Calcitonin also decreases tubular resorption of calcium in the
kidney [2].
Calcitionin has been shown to increase lumbar spine BMD and reduce the risk of vertebral fractures by 33% [5].
Limited studies on the use of calcitonin in men have been conducted, however two small studies showed a
similar efficacy to that found in women [17].
Adverse effects may occur at the site of injection/inhalation, with local inflammation or irritation, as well as
flushing, diarrhoea and nausea [12].
Anabolic agents
Anabolic agents increase bone remodelling which over time causes cortical thickening and an increase in the
number of trabecular elements, thus increasing bone strength [6].
Table 3: Anabolic agents [14] [18]

Agent
Use
Strontium ranelate
Parathyroid hormone Teatment in men and women
Strontium Ranelate
Strontium ranelate is a relatively new treatment for osteoporosis comprised of two strontium atoms and ranelic
acid as a carrier [19]. While the exact mechanism is not completely understood, it appears to have a dual action,
stimulating bone formation and decreasing bone resorption [18]. Strontium ranelate increases BMD in the spine
and hip (14.4% and 8.3% respectively), however approximately half of this is due to the incorporation of
strontium into the bone rather than an increase in bone mineralisation [11].
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Studies have shown a 30-40% reduction in vertebral fractures, 16% decrease in non-vertebral fracture risk and
36% reduction in hip fracture risk [15][19]. Whilst the drug is typically tolerated well, nausea and vomiting can
sometimes occur in the first three months of treatment. There is also a small increase in risk of venous
thromboembolisms and should be used with caution in those who are already at an increased risk [14].
Parathyroid hormone
Endogenous parathyroid hormone (PTH) is produced by the parathryroid gland and responsible for calcium
homeostasis. Chronic continuous elevation of PTH (e.g. hyperparathyroidism) is associated with an increase in
osteoclast activity, leading to bone resorption [13]. However intermittent injections of PTH exerts anabolic
effects on the bone increasing osteoblast number and activity. This leads to increased bone mass, structural
integrity and bone strength [12].
Teriparatide (recombinant PTH 1-34) has shown in several trials to reduce vertebral fracture risk by 65% and
non vertebral fracture risk by 53%, as well as increasing BMD in both the spine and hip [9]. PTH treatment can
lead to nausea, limb pain, headaches and dizziness as well as transient hypercalcaemia [1]. Contra-indications
include; bone malignancies, severe renal impairment, Paget's disease and during pregnancy [12][14]. Treatment
duration is restricted to 18-24 months as longer durations in rats have been associated with an increased
incidence of osteosarcoma [12].
Other considerations
Calcium and Vitamin D
Adequate calcium and vitamin D are essential for slowing age-related bone loss and maintaining calcium
homeostasis so as to prevent excessive bone resorption [16]. When prescribed in combination with other
therapeutic agents they are able to maximise the benefits and are thus a necessity in those who do not fulfil the
daily requirements [6].
Treatment in men
Osteoporosis is a significant problem for men as although the prevalence is lower, the mortality rate is higher
[17].
Despite this calcitonin and bisphosphonates are the only therapies that have been tested and universally
approved for men[20]. Newer agents such as teriparatide and strontium ranelate have only been approved for
men in some countries [17]. The bisphosphonates, alendronate and risendronate are considered first-line therapy
in male osteoporosis [11].
Future treatments
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Advances in the understanding of the functioning and regulation of osteoblast and osteoclast activity has led to
the development of targetted new therapies [18].
Figure 3: Mechanism of action for recombinant OPG, anti-RANKL antibodies and

bisphosphonates [4]
Denosumab, a human monoclonal antibody that inhibits RANK-L (Figure 3), blocking its actions on
osteoclastogenesis, is currently being trialled and preliminary results seem to show similar efficacies to current
therapies [15]. Other therapies being trialled include selective inhibitors of the enzyme cathepsin-K, recombinant
OPG and human monoclonal antibodies for sclerostin [12].
References
1. 1.0 1.1 1.2 1.3 1.4 Compston, J. (2009). Clinical and therapeutic aspects of osteoporosis. European Journal
of Radiology , 71, 388-391.
2. 2.0 2.1 2.2 2.3 Keen, R. (2007). Osteoporosis: strategies for prevention and management. Best Practice &
Research Clinical Rheumatology , 21 (1), 109-122.
3. 3.0 3.1 University of Melbourne (2007). The Burden of Brittle Bones: Epidemiology, Costs & Burden of
Osteoporosis in Australia -2007. Melbourne: Osteoporosis Australia.
4. 4.0 4.1 4.2 4.3 4.4 4.5 Rang, H., & Dale, M. (2007). Rang and Dale's pharmacology. Philadelphia:
Churchill Livingstone.
5. 5.0 5.1 Gasser, J. (2006). The relative merits of anabolics versus anti-resorptive compounds: where our
targets should be, and whether we are addressing them. Current Opinion in Pharmacology , 6, 313-318.
6. 6.0 6.1 6.2 Boonan, S., Vanderschueren, D., Haentjens, P., & Lips, P. (2006). Calcium and vitamin D in
the prevention and treatment of osteoporosis - a clinical update. Journal of Internal Medicine , 259, 539552.
7. 7.0 7.1 7.2 Goodman and Gilmans: Brunton, L., Lazo J. and Parker K. (n.d.) Goodman & Gilmans The
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Pharmacological Basis of Therapeutics (11th ed.). The McGraw-Hill Companies. Retrieved October 2nd
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Coxon, J., Oades, G., Colston, K. & Kirby, R. (2004). Advances in the use of bisphosphonates in the
prostate cancer setting Prostate Cancer and Prostatic Diseases, 7, 99-104.
9.0 9.1 9.2 9.3 Epstein, S. (2006). Update of Current Therapeutic Options for the Treatment of
Postmenopausal Osteoporosis. Clinical Therapeutics , 28 (2), 151-173.
10.0 10.1 Delaney, M. (2006). Strategies for the prevention and treatment of osteoporosis during early
postmenopause. American Journal of Obstetrics and Gynecology , 194, 12-23.
11.0 11.1 11.2 11.3 Bonnick, S. (2006). Osteoporosis in men and women. Clinical Cornerstone , 8 (1), 2839.
12.0 12.1 12.2 12.3 12.4 12.5 12.6 Brixen, K., Kassem, M., & Abrahamsen, B. (2009). Prevention and
treatment of osteoporosis in women: an update. Obstetrics, Gynaecology and Reproductive Medicine , 19
(6), 157-163.
13.0 13.1 13.2 Fauci, A., Braunwald, E., Kasper D., Hauser S., Longo D., Jameson J. and Loscalzo J.
(n.d.) Harrisons Principles of Internal Medicine (17th ed.). The McGraw-Hill Companies. Retrieved
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14.0 14.1 14.2 14.3 14.4 Kanis, J., Burlet, N., Cooper, C., Delmas, P., Reginster, J., Borgstrom, F., et al.
(2008). European guidance for the diagnosis and management of osteoporosis in postmenopausal women.
Osteoporosis International , 19, 399-428.
15.0 15.1 15.2 Shoback, D. (2007). Update in Osteoporosis and Metabolic Bone Disorders. The Journal of
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17.0 17.1 17.2 Ringe, J. (2007). Treatment of osteoporosis in men. Journal of Men's Health and Gender , 4
(3), 326-333.
18.0 18.1 18.2 Tuck, S., & Datta, H. (2007). Osteoporosis in the aging male: Treatment options. Clinical
Interventions in the Aging , 2 (4), 521-535.
19.0 19.1 Blake, G., & Fogelman, I. (2006). Strontium ranelate: a novel treatment for postmenopausal
osteoporosis: a review of safety and efficacy. Clinical Interventions in Aging , 1 (4), 367-375.
Vondracek, S., & Linnebur, S. (2009). Diagnosis and management of osteoporosis in the older senior.
Clinical Interventions in the Aging , 4, 121-136.
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