a review of current treatment options for osteoporosis in bulgaria

www.wjpps.com Vol 4, Issue 05, 2015.

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Petkova et al. World Journal of Pharmacy and Pharmaceutical Sciences

A REVIEW OF CURRENT TREATMENT OPTIONS FOR

OSTEOPOROSIS IN BULGARIA

Pankova Stefka1, Vasileva Lili

2 and Petkova Valentina

3*

1Department of Pharmacognosy and Pharmaceutical Chemistry, Medical University Plovdiv,

Bulgaria.

2Department of Pharmacology and Clinical Pharmacology, Medical University Plovdiv

Bulgaria.

3Department of Social Pharmacy, Faculty of Pharmacy, Medical University – Sofia,

Bulgaria.

ABSTRACT

Bone undergoes a continuous remodeling process involving resorption

and formation. Any process that disrupts this balance by increasing

resorption relative to formation may results in osteoporosis.

Osteoporosis is defined as abnormal loss of bone predisposing to

fractures. Osteoporosis is characterized by low bone mineral density

(BMD) and loss of the structural and biomechanical properties that are

required to maintain bone homeostasis. This review aims to enlighten

the current trends in prevention and treatment of osteoporosis in

Bulgaria. Recent studies suggest potential role of physical exercises in

prevention and management of osteoporosis. Management of

osteoporosis includes non-pharmacological treatment - diet rich of

calcium and vitamin D, healthy lifestyle, proper exercise plan, and pharmacological therapy.

Combination of non-pharmacological and pharmacological treatment options have to be

considered for prevention of osteoporosis and minimization of the risk of fractures. More

randomized control trial should be done using variable combined methods of treatment.

KEYWORDS: Osteoporosis, treatment, prevention, pharmacology, exercises.

INTRODUCTION

Bone undergoes a continuous remodeling process involving resorption and formation. Any

process that disrupts this balance by increasing resorption relative to formation may results in

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Article Received on

11 March 2015,

Revised on 02 April 2015,

Accepted on 23 April 2015

*Correspondence for

Author

Dr. Petkova Valentina

Department of Social

Pharmacy, Faculty of

Pharmacy, Medical

University – Sofia,

Bulgaria.


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osteoporosis. Osteoporosis is defined as abnormal loss of bone predisposing to fractures.

Osteoporosis is characterized by low bone mineral density (BMD) and loss of the structural

and biomechanical properties that are required to maintain bone homeostasis.[1]

It is most

common in postmenopausal women but also occurs in men. The social burden and annual

direct medical cost of fractures in older people is increasing as our population age

worldwide.[2-5]

It is expected that the number of osteoporotic fractures would double by

2050.[3]

The biggest epidemiological study in Bulgaria was done in 2001 showing the bone

mineral density (BMD) of 8869 women.[3]

Osteoporosis is most commonly associated with

loss of gonadal functions in menopause but may also occur as medication-induced,

idiopathic, or as a consequence of alcohol abuse and smoking. Long-term administration of

glucocorticoids, proton pump inhibitors, selective serotonin receptor inhibitors, androgen

deprivation therapy, thiazolidinediones, heparin, calcineurin inhibitors, and some

chemotherapies such as methotrexate have deleterious effects on bone health.[1]

Management

of osteoporosis includes non-pharmacological treatment - diet rich of calcium and vitamin D,

healthy lifestyle, proper exercise plan, and pharmacological therapy.

RISK FACTORS FOR OSTEOPOROSIS

Age and menopause in women are the two main determinants of osteoporosis and predispose

to low bone mass. In particular, estrogen is a systemic hormone with direct effects on bone

that plays an important role in osteoporosis. In postmenopausal women, the deficiency of

estrogen leads to an upregulation of RANKL on bone marrow cells, resulting in an increase

in bone resorption.[3,5]

The extraskeletal effects of estrogen deficiency are mainly based on

increased renal calcium excretion and decreased intestinal calcium absorption. The risk of

osteoporosis is determined by several independent factors in addition to low bone mass and

decreased estrogen. Family history of fractures, high bone turnover, overweight or too low

body mass index, lack of physical activity, tobacco use, and alcohol abuse, are the most

important factors to be considered.[2,6]

Genetic and nutritional factors (e.g. calcium intake and

vitamin D repletion) play significant roles.[7]

Calcium homeostasis is normally well regulated

such that increased calcium loss via the urine leads to increased calcium absorption from the

gut. However, the duration of this adaptive process may be greater than that of many of the

studies demonstrating that increased salt intake leads to both increased sodium and calcium in

the urine. In any case, higher urinary calcium output appears to be seen only in a minority of

humans in response to increased salt intake. Therefore overuse of salt in the diet is also risk

factor for development of osteoporosis.[6]


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A quantitative predictor of osteoporotic fractures in postmenopausal women without a

previous fracture is bone mineral density (BMD). The WHO operational definition defines an

osteoporotic woman on the basis of a BMD measurement (spine or hip) showing a T-score

below -2.5. The term “severe or established osteoporosis” habitually denotes a T-score below

-2.5 in the presence of one or more fragility fractures. Osteopenia is defined as a BMD T-

score between -1 and -2.5.[8, 9]

However, BMD alone has a limited value to predict the risk of fractures. The incidence of

osteoporotic fractures increases with age. The predictive value of BMD becomes weaker with

age. It has become evident that fracture risk is also driven by parameters including bone size

and shape, bone turnover, micro-architecture, damage accumulation (micro cracks), and

degree of mineralisation or collagen structure, all playing a role in bone strength, and hence

in the risk of osteoporotic fractures. Several epidemiological studies showed that a large

proportion of incident fragility fractures occur in postmenopausal women who have a BMD

T-score above -2.5. The use of bone-related independent risk factors for fractures combined

with BMD values provides a global assessment of future fracture risk, allowing the

identification of women who should benefit from a treatment to prevent the occurrence of

osteoporotic fractures.[4, 10]

MANAGEMENT AND PREVENTION

Management of osteoporosis includes non-pharmacological treatment - diet rich of calcium

and vitamin D, healthy lifestyle, proper exercise plan, and pharmacological therapy. Both

types of treatment could be implemented for prevention as well as for treatment of

established osteoporosis.

Non-pharmacological treatment

Recent studies suggest potential role of physical exercises in prevention and management of

osteoporosis.[3,5,11-13]

Weight-bearing exercise is associated with increases in bone density.[11]

Krasnova et al report that regular sport activities provided good prophylactic for osteoporosis

within women.[5]

In Bulgaria according to National Guidelines for management of

Osteoporosis 2006-2010 a net of local osteoporosis centers was established.[3]

Prevention

should be initiated early at age by establishing proper sports in schools for children and

adolescents.[13]

The information about risk factors for osteoporosis among young people is


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important for prevention of letter development of bone problems. Good rehabilitation was

provided with significant decrease in the number of fractures risk patients.[12]

In addition to increase in the physical activity in most elderly patients, alcohol, caffeine and

tobacco use should also be eliminated. These lifestyle modifications can reduce the risk of

fractures. Daily diet should be enriched with calcium and vitamin D.[14]

Numerous studies

have demonstrated the importance of vitamin K in bone health. The results of recent studies

have suggested that concurrent use of menaquinone and vitamin D may substantially reduce

bone loss.[15]

Increased intakes of various nutritional factors (potassium, magnesium, zinc,

vitamin C), fibre and alkaline-producing fruit and vegetables also favour adult bone health.[16]

Pharmacological treatment

Hormone replacement therapy (HRT)

HRT has been shown to reduce the risk of fracture, but increases the risk of breast cancer and

cardiovascular diseases.[4,8,10]

Oestrogens have been used for prevention of bone loss. The

prevailing hypothesis advanced to explain these observations is that estrogens reduce the

bone-resorbing action of PTH. Estrogen receptors have been found in bone, and estrogen has

direct effects on bone remodeling. Case reports of men who lack the estrogen receptor or who

are unable to produce estrogen because of aromatase deficiency noted marked osteopenia and

failure to close epiphyses. This further substantiates the role of estrogen in bone

development, even in men. However, due to recent discussions/developments, there has been

a shift in thinking about the use of medicinal products in osteoporosis. New developments

only for prevention of bone loss after menopause are no longer seen as a goal. The use of

estrogens in this indication is left to local treatment guidelines, which will take into account

both existing data for efficacy and safety.[3]

Selective estrogen receptor modulators (SERMs) have been developed to retain the beneficial

effects on bone while minimizing deleterious effects on breast, uterus, and the cardiovascular

system. Tamoxifen was the first SERM to be widely used in clinical practice, based on its

now well-recognized estrogen antagonist activity in the breast. The prolonged use of

tamoxifen was associated with an increase in uterine cancer, leading to the search for other

SERMs with different pharmacological profiles.[8-10]

Thus, raloxifene, a new SERM, was

developed for the treatment and prevention of postmenopausal osteoporosis, with the goal of

improving the drug safety profile. Raloxifene has a spectrum of tissue-specific agonist-

antagonist effects on estrogen target tissues but acts on bone as an estrogen agonist. This drug


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has been extensively studied and data support its estrogen agonist profile in the skeletal

system.[10]

The drug specifically acts on estrogenic receptor-a and estrogenic receptor-b,

binding to the receptors in the same ligand-binding pocket as does estradiol, and causes the

C-terminal a-helix of the receptor to change its conformation to block access to the activation

function-2 region of the receptor. This event in turn likely blocks access to the transcriptional

coactivators necessary to facilitate the activation of estrogen-responsive genes. In the

ovariectomized (OVX) rat model, raloxifene acts as an anti-resorptive, with preservation of

both bone mineral density (BMD) and bone strength. It has been demonstrated that raloxifene

modulates the homeostasis of bone cells in vitro by inhibiting osteoclastogenesis and bone

resorption.[17]

Nonhormonal therapy

Nonhormanal forms of therapy for osteoporosis with proven efficacy in reducing fracture risk

include the following pharmacological groups: bisphosphonates, teriparatide, denosumab,

stroncium renalate, calcitonin, calcium and vitamin D.

Biphosphonates

The group of bisphosphonates includes etidronate, pamidronate, alendronate, risedronate,

tiludronate, ibandronate, and zoledronate. Biphosphonates have been conclusively shown to

increase bone density and reduce fractures over at least 5 years when used continuously.[17]

Side-by-side trials between alendronate and calcitonin indicated a grated efficacy of

alendronate. Biphosphonates are poorly absorbed and must be given on an empty stomach or

infused intravenously. At higher oral doses used in the treatment of Paget`s disease,

alendronate causes gastric irritation, but this is not a significant problem at the doses

recommended for osteoporosis. All of these drugs inhibit bone resorption with secondary

effects to inhibit bone formation. They owe at least part of their clinical usefulness and

toxicity to their ability to retard formation and dissolution of hydroxyapatite crystals within

and outside the skeletal system. Some of the newer bisphosphonates appear to increase bone

mineral density well beyond the 2-year period predicted for a drug whose effects are limited

to slowing bone resorption. This may be due to their other cellular effects, which include

inhibition of vitamin D production, inhibition of intestinal calcium transport, metabolic

changes in bone cells such as inhibition of glycolysis, inhibition of cell growth, and changes

in acid and alkaline phosphatase activity. Amino bisphosphonates such as alendronate and

risedronate inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway


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that appears to be critical for osteoclast survival. With the exception of the induction of a

mineralization defect by higher than approved doses of etidronate and gastric and esophageal

irritation by the oral bisphosphonates, these drugs have proved to be remarkably free of

adverse effects when used at the doses recommended for the treatment of osteoporosis.

Esophageal irritation can be minimized by taking the drug with a full glass of water and

remaining upright for 30 minutes or by using the intravenous forms of these compounds.

Biphosphonate-associated maxillary bone osteonecrosis (BPMO) is a complication related to

nitrogen-containing biphosphonate therapy such as zolendronate. This adverse effect

occasionally appears in patients who are administered biphosphonates through intravenous

infusion for the treatment of cancer involving bone metastases. It can also present, in a lesser

degree, in patients who take these drugs orally for the treatment of osteoporosis.[18,19]

More

recently, concern has been raised about over-suppressing bone turnover, and case reports

have appeared describing unusual subtrochanteric (femur) fractures in patients on long-term

bisphosphonate treatment. This complication appears to be rare, comparable to that of

osteonecrosis of the jaw, but has led some authorities to recommend a “drug holiday” after 5

years of treatment if the clinical condition warrants it.[18]

Teriparatide

As osteoporosis is mostly due to bone loss, antiresorptive therapy, mainly bisphosphonates,

are a cornerstone of therapy. However, as a result of their different mode of action, anabolic

drugs have increased the options in the treatment of osteoporosis. Postmenopausal women

and men with severe and progressive osteoporosis despite antiresorptive therapy as well as

patients with glucocorticiod-induced osteoporosis need to be evaluated for a treatment course

with osteoanabolic drugs such as teriparatide. [20]

The recombinant parathormone (PTH) 1-34

teriparatide directly stimulates bone formation. It must be administered daily by subcutaneous

injection. Its efficacy is preventing fractures is at least as great as that of the

bisphosphonates.[17]

Trials examining the sequential use of teriparatide followed by a

bisphosphonate after 1 or 2 years are in progress and look promising. Use of teriparatide with

a bisphosphonate has not shown greater efficacy than the bisphosphonate alone. In all cases,

adequate intake of calcium and vitamin D needs to be maintained.

Calcium

In patients whose dietary intakes do not cover the recommended daily allowances

supplementation with calcium and vitamin D (at daily doses of 1 gr and 800 IU) is needed.[21]


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Calcium preparations are available for intravenous, intramuscular, and oral administration.

Calcium gluceptate (0.9 mEq calcium/mL), calcium gluconate (0.45 mEq calcium/mL), and

calcium chloride (0.68–1.36 mEq calcium/mL) are available for intravenous therapy.

Calcium gluconate is preferred because it is less irritating to veins.[17]

Oral preparations

include calcium carbonate (40% calcium), calcium lactate (13% calcium), calcium phosphate

(25% calcium), and calcium citrate (21% calcium). Calcium carbonate is often the

preparation of choice because of its high percentage of calcium, ready availability, low cost,

and antacid properties. The association between calcium supplementation and adverse

cardiovascular events has recently become a topic of debate. Several reports indicate that

there is a significant increase in adverse cardiovascular events following supplementation

with calcium; however, a number of experts have raised several issues with these reports such

as inconsistencies in attempts to reproduce the findings in other populations and questions

concerning the validity of the data due to low compliance, biases in case ascertainment,

and/or a lack of adjust- ment. Further studies investigating the risk-benefit profiles of calcium

supplementation in various populations are required to develop population-specific guidelines

for individuals of different genders, ages, ethnicities, and risk profiles around the world.[22]

Vitamin D

Vitamin D alone appears unlikely to be effective in preventing osteoporotic fractures, but in

combination with calcium reduces the risk of new fractures.[3,4,9,14]

When rapidity of action is

required, 1,25(OH) 2 D 3 (calcitriol), 0.25–1 mcg daily, is the vitamin D metabolite of choice

because it is capable of raising serum calcium within 24–48 hours. Calcitriol also raises

serum phosphate, although this action is usually not observed early in treatment. The

combined effects of calcitriol and all other vitamin D metabolites and analogs on both

calcium and phosphate make careful monitoring of these mineral levels especially important

to prevent ectopic calcification secondary to an abnormally high serum calcium × phosphate

product.[17]

Calcitonin

The calcitonin secreted by the parafollicular cells of the mammalian thyroid is a single-chain

peptide hormone with 32 amino acids and a molecular weight of 3600. A disulfide bond

between positions 1 and 7 is essential for biologic activity. The ability of calcitonin to block

bone resorption and lower serum calcium makes it a useful drug for the treatment of Paget’s

disease, hypercalcemia, and osteoporosis. Calcitonin is approved for use in the treatment of


8


postmenopausal osteoporosis.[4,17]

It has been shown to increase bone mass and reduce

fractures, but only in the spine. It does not appear to be as effective as bisphosphonates or

teriparatide.[21]

Denosumab

Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been

approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which

is responsible for osteoclastic activation, thus reducing bone resorption. Naturally RANKL is

molecule produced by osteoblasts. It stimulates osteoclastogenesis via RANK, the receptor

for RANKL that is present on osteoclasts. Denosumab inhibits osteoclast formation and

activity.[23]

It is at least as effective as the potent bisphosphonates in inhibiting bone

resorption and has recently been approved for treatment of postmenopausal osteoporosis and

some cancers (prostate and breast). The latter application is to limit the development of bone

metastases or bone loss resulting from the use of drugs suppressing gonadal function.

Denosumab is administered subcutaneously every 6 months, which avoids gastrointestinal

side effects.[17]

The drug appears to be well tolerated but two concerns remain. First, a

number of cells in the immune system also express RANKL, suggesting that there could be

an increased risk of infection associated with the use of denosumab. Second, because the

suppression of bone turnover with denosumab is similar to that of the potent bisphosphonates,

the risk of osteonecrosis of the jaw and subtrochanteric fractures may be increased, although

this has not been reported in the clinical trials leading to its approval by the FDA.[23]

Stroncium renalate

Furthermore, there are several other forms of therapy in the pipeline. In Europe, strontium

renalate, a drug that appears to stimulate bone formation and inhibit bone resorption, has been

used for several years with favorable results in large clinical trials. However, European

Pharmacovigilance Risk Assessment Committee (PRAC) recommends restriction in the use

of strontium ranelate, based on a routine benefit-risk assessment of the medicine, which

included data showing an increased risk of heart problems, including heart attacks.[4]

On

January 10, 2014 PRAC has recommended that Protelos/Osseor should no longer be used to

treat osteoporosis.[5]

Strontium ranelate is composed of two atoms of strontium bound to an organic ion, ranelic

acid. In Europe, strontium renalate, a drug that appears to stimulate bone formation and

inhibit bone resorption, has been used for several years with favorable results in large clinical


9


trials for the treatment of osteoporosis.[4,24]

Strontium ranelate appears to block differentiation

of osteoclasts while promoting their apoptosis, thus inhibiting bone resorption. At the same

time, strontium ranelate appears to promote bone formation. Unlike bisphosphonates,

denosumab, or teriparatide, this drug increases bone formation markers while inhibiting bone

resorption markers.[17]

Large clinical trials have demonstrated its efficacy in increasing bone

mineral density and decreasing fractures in the spine and hip. However, European

Pharmacovigilance Risk Assessment Committee (PRAC) recommends restriction in the use

of strontium ranelate, based on a routine benefit-risk assessment of the medicine, which

included data showing an increased risk of heart problems, including heart attacks.[24]

On

January 10, 2014 PRAC has recommended that strontium ranelate should no longer be used

to treat osteoporosis.[25-28]

Additional promising new treatments undergoing clinical trials include an antibody against

sclerostin (a protein produced by osteocytes that inhibits bone formation), that has been

shown to stimulate bone formation, and inhibitors of cathepsin K, an enzyme in osteoclasts

that facilitates bone resorption.[17]

DISCUSSION AND CONCLUSION

In conclusion to decrease the risk of osteoporosis the EU guidelines for treatment should be

updated regularly. Patients should be informed in details about the risk factors for fractures.

Establishing a net of local osteoporosis centers in Bulgaria has provided better prophylaxis of

osteoporosis.[3]

Recent Bulgarian studies report that regular sport activities provided good

prophylactic for osteoporosis within women.[5, 12, 13]

Combination of non-pharmacological

and pharmacological treatment options have to be considered for prevention of osteoporosis

and minimization of the risk of fractures.[3, 5, 29-31]

More randomized control trials should be

done using variable combined methods of treatment.

REFERENCES

1. Panday, K., Gona,A ,& Humphrey, M. B. Medication-induced osteoporosis: screening

and treatment strategies. Therapeutic Advances in Musculoskeletal Disease, 2014: 6(5):

185–202.

2. Becker DJ, Kilgore ML, Morrisey MA The societal burden of osteoporosis.Curr

Rheumatol Rep,2010; 12: 186.

3. Национална програма за ограничаване на остеопорозата в България. 2010; 1–18.


10


4. European Medicines Agency. Guideline on the Evaluation of Medicinal Products in the

Treatment of Primary Osteoporosis. Guideline, 2006; 1–10.

5. Dimitrova Dimitrova Z., Vasilev Todorov T, Vasilev Mitov K. Ivanova Petrova G.,

Computerised system for effective stock control management, First congress of pharmacy

of the republic of Macedonia, Skopie, 1995; 41(1-2): 432.

6. Bartlett, J. G., & Thorner, A. R. Risk factors and prevention of, J Musculoskelet Neuronal

Interact.2010; 7: 268–272.

7. Prentice A. Diet, nutrition and the prevention of osteoporosis. Public Health Nutrition,

2004; 7: 227–243.

8. Halldorsson, B. V., Bjornsson, A. H., Gudmundsson, H. T., Birgisson, E. O., Ludviksson,

B. R., & Gudbjornsson, B. A Clinical Decision Support System for the Diagnosis,

Fracture Risks and Treatment of Osteoporosis. Computational and Mathematical

Methods in Medicine, 2015; 1–7.

9. Berry, S. D., Kiel, D. P., Donaldson, M. G., Cummings, S. R., Kanis, J. a., Johansson, H.,

& Samelson, E. J. Application of the national osteoporosis foundation guidelines to

postmenopausal women and men: The Framingham osteoporosis study. Osteoporosis

International, 2010; 2(1): 53–60.

10. Sale, J. E. M., Gignac, M. a, Hawker, G., Frankel, L., Beaton, D., Bogoch, E., & Elliot-

Gibson, V. Decision to take osteoporosis medication in patients who have had a fracture

and are “high” risk for future fracture: a qualitative study. BMC Musculoskeletal

Disorders, 2011; 12(1): 92.

11. Te, H., Shea, B., Lj, D., Downie, F., Murray, a, Ross, C. Exercise for preventing and

treating osteoporosis in postmenopausal women (Review). Cochrane Database Syst Rev.

2011; 6(7): CD000333.

12. Kasnakova P., Velikov Y. Methodology of complex rehabilitation in cases of disk

nemiation. Trakia Journal of Sciences, 2012; 10(3): 185-187.

13. Kasnakova P., Krushkova P., Kostov S., Slavcheva N. Importance of sports and aerobic

exercise for prevention of obesity among children and adolescents. Proceeding book XVI

International Scientific Congress “Olympic Sport and Sport for All” & VI International

Scientific Congress “Sport, Stress, Adaptation”, Sofia May, 2012; 17-19, 479-481.

14. Avenell, a, Wj, G., Ld, G., Connell, O. D., Avenell, A., Gillespie, W. J, Connell, D. O.

Vitamin D and vitamin D analogues for preventing fractures associated with involutional

and post-menopausal osteoporosis ( Review ) Cochrane Database Syst Rev. 2009; (3): 2–

4.

http://www.ncbi.nlm.nih.gov/pubmed/17947811





11


15. Adams, J., & Pepping, J. Vitamin K in the treatment and prevention of osteoporosis and

arterial calcification. American Journal of Health-System Pharmacy : AJHP : Official

Journal of the American Society of Health-System Pharmacists, 2005; 62(15): 1574–81.

16. Cohen, A., Roe, F. J. Review of risk factors for osteoporosis with particular reference to a

possible aetiological role of dietary salt. Food and Chemical Toxicology, 2000; 38(2-3):

237–253.

17. Katzung, B. G., Masters, S. B., & Trevor, A. J. Basic and clinical Pharmacology.

18. López-D’alessandro, E., Mardenlli, F., & Paz, M. Oral bisphosphonate-associated

osteonecrosis of maxillary bone: A review of 18 cases. Journal of Clinical and

Experimental Dentistry, 2014; 6(5): e530–4.

19. Polymenidi, I., Trombetti, A., & Carballo, S. The risk of bisphosphonate-related

osteonecrosis of the jaw]. Revue Médicale Suisse, 2014; 10(446): 1930–4.

20. Meier, C., Lamy, O., Krieg, M., Mellinghoff, H., Felder, M., Ferrari, S., & Rizzoli, R.

The role of teriparatide in sequential and combination therapy of osteoporosis, 2014; 1–6.

21. Reginster, J.-Y., Neuprez, A., Lecart, M. P., Sarlet, N., Distèche, S., & Bruyère, O.

[Treatment of post-menopausic osteoporosis: what’s new in 2014?]. Revue Médicale de

Liège, 2014; 69(7-8): 441–53.

22. Shin, C. S., & Kim, K. M. Review Article The Risks and Benefits of Calcium

Supplementation, Endocrinology and Metabolism,2015; 30: 27–34.

23. Nardone, V., D’Asta, F., Brandi, M. L. Pharmacological management of osteogenesis.

Clinics (São Paulo, Brazil), 2014; 69(6): 438–46.

24. European Medicines Agency PRAC recommends suspending use of Protelos / Osseor

( strontium ranelate ) Recommendation by PRAC to be considered by CHMP for final

opinion, 2014; 44: 1–2.

25. European Medicines Agency PRAC recommends suspending use of Protelos / Osseor (

strontium ranelate ) Recommendation by PRAC to be considered by CHMP for final

opinion, 2014; 44: 1–2.

26. Dimitrova Dimitrova Z., Vasilev Todorov T, Vasilev Mitov K. Ivanova Petrova G.,

Computerised system for effective stock control management, First congress of pharmacy

of the republic of Macedonia, Skopie, 1995; 41(1-2): 432.

27. Kamusheva M., Mitov K., G. Petrova. Еconomic impact of the influenza prophylaxis with

influenza vaccine (split virion, inactivated) among elderly patients >65 years old in

Bulgaria. World journal; of pharmacy and pharmaceutical sciences, 2015; 4 (3): 24-36.


12


28. Georgieva Svetla, Maria Kamusheva, Dragana Lakic, Konstantin Mitov, Alexandra

Savova, Guenka Petrova, The health related quality of life for kidney transplant patients

in bulgaria – a pilot study, Biotechnology & Biotechnol. Eq, 2012, 26(3): 3062-3065.

29. Naseva E., T. Kundurzhiev. Tabular and graphical presentation of data. In: Occupational

Medicine and Public Health, Part Three Statistics in occupational medicine, Edited by

prof. N. Tsacheva, MU-Sofia, 2015; 21-32. ISBN 978-954-9493-92-4.

30. Kundurzhiev T., F. Naseva. Parametric methods for hypotheses testing. In: Occupational

Medicine and Public Health, Part Three Statistics in occupational medicine, Edited by

prof. N. Tsacheva, MU-Sofia, 2015; 60-66. ISBN 978-954-9493-92-4.

31. Gardeva M., E. Naseva. Needs assessment of health services in practice for immediate

assistance and distribution of regulatory standards. Medical meridians, 2013; 2: 24-31.

a review of current treatment options for osteoporosis in bulgaria

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