Advances in Non-Pharmacological and Pharmacological Management of Osteoporosis

    

    

    Figure 1:  Bone Remodeling.
    
    

The entire remodeling process takes about 100 days on an average. During this process, some of the osteoblasts remain inside the bone tissue and are converted to osteocytes. Once the new bone has been mineralized, the remodeling process is complete.

Bone remodeling continues throughout adulthood, with each remodeling process lasting 6-49 months. The balance between bone resorption and bone formation is usually maintained until the third or fourth decade of life [12]. Hormonal and nutritional deficiencies as well as age-related imbalance favor resorption over bone formation resulting into osteoporosis.

Approach for management of osteoporosis

The four major goals in the treatment of osteoporosis are:

• To prevent fractures
• To stabilize bone mass or achieve increased bone mass
• To relieve symptoms of fractures and skeletal deformity
• To maximize physical function

Non pharmacological management of osteoporosis

A comprehensive approach is required for the treatment of osteoporosis.

Both pharmacologic and non-pharmacologic approaches for treatment need to be considered.

1. Lifestyle modification can help in prevention of osteoporosis:

• Reduce alcohol consumption [13].
• Reduce caffeine consumption. Caffeine may interfere with calcium absorption.
• Quit smoking- the risk for osteoporosis diminishes after quitting smoking [14].

2. Exercise: In post menopausal women, it has been seen that weight-bearing exercise helps to prevent bone loss [15]. Exercise also has beneficial effects on neuromuscular function and it improves coordination, balance, and strength, thereby reducing the risk of falling.

Walking is a practical way to start. Swimming or water exercises also benefit by improving muscle strength. A combined exercise program (resistance + aerobic + impact) is recommended for an enhancement of spine BMD [16]. Exercise should be consistent, optimally at least three times a week.

3. Restoration of Calcium and vitamin D which are critical elements in bone homeostasis:

Calcium

The preferred source of calcium is dairy products. Dietary modification for calcium- Calcium rich food & exposure to sunlight is essential as a non-pharmacological approach to osteoporosis. Calcium supplements if needed, should be taken in doses <600 mg at a time, best taken with food as an adjuvant to other therapies. It reduces bone loss and suppresses bone turnover. The only adverse effects associated with calcium supplements are mild GI upset and constipation (mostly with carbonate salts).

Vitamin D

Presently, Vitamin D deficiency has been recognized as an epidemic [17]. Vitamin D is converted to its most active form, calcitriol, by hydroxylation in the liver and kidneys as follows (Figure 2).



Figure 2: Active form of Vitamin D.

    

    

    Figure 2:  Active form of Vitamin D.
    
    

Close

Active form of Vitamin D, Calcitriol increases plasma Ca²⁺ by mobilizing it from bone, increasing its absorption in the intestine and decreasing its excretion as well as increasing reabsorption by the kidney. Parathyroid hormone (PTH) increases blood Ca²⁺ by increasing calcitriol synthesis, mobilising Ca2+ from bone and reducing renal Ca²⁺ excretion. Paradoxically, small doses of PTH given intermittently increase bone formation through an anabolic effect. It promotes the recruitment of osteoclast precursor cells to resorption site and differentiation of osteoclasts. In osteoblasts, calcitriol induces production of several proteins, including osteocalcin, a vitamin K-dependent protein that contains g-carboxy glutamic acid residues, and Interleukin-1 (IL-1), a lymphokine that promotes bone resorption & calcification of matrix.

4. Fall prevention requires environmental modifications [18]:

In advanced age,in postmenopausal women& in individuals with low BMD some movements should be avoided like lifting heavy weights or lifting weight in forward bending position. Also pectoral stretching, deep breathing, back extension exercises& kyphotic posturing should be performed cautiously if needed.

5. Back braces and hip protectors, can help in the prevention and treatment of fractures.

6. Kyphoplasty is a minimally invasive procedure performed on spine in appropriately selected patients which improves pain and reduces occurrence of new vertebral fractures [19].

Pharmacological management

Currently used drugs for treatment of osteoporosis are:

• Calcium & Vitamin DeCalcium & Vitamin De. g. Calcium carbonate • Calcium citrate • Cholecalciferol
• Antiresorptive drugs-that decrease bone loss. e.g. Bisphosphonates, Calcitonin, Selective Estrogen Receptor Modulators (SERMs).
• Anabolic agents-that increase bone formation. e.g. PTH, Teriparatide, Cinacalcet, Fluoride.
• RANKL Antibody-Denosumab.
• Other Agents- Strontium ranelate, Sodium fluoride.

Management of the Underlying Disease with Drugs

Antiresorptive drugs

A. Bisphosphonates

Bisphosphonates haveappeared as the most effective & promising agents in the past decade. Daily Alendronate and Risedronate have reduced the risk of single and multiple spine fractures in women with low bone mineral density [20].

First generation - e.g. Etidronate, Tiludronate:

- Act by promoting apoptosis of osteoclasts.

- Less potent.

Second generation – e.g. Alendronate, Pamidronate, Ibandronate:

- 10-100 times more potent.

Third generation- e.g. Risedronate, Zolendronate:

- 10,000 times more potent.

Second & Third generation compounds are with N-containing side chains which prevent osteoclast action by inhibiting prenylation reactions required for membrane anchoring of functional proteins. They also interfere with metabolic mevalonate pathway and osteoclast function [21].

Bisphosphonates have a strong affinity for bone apatite. They are potent inhibitors of bone resorption and produce their effect by reducing the recruitment and activity of osteoclasts and increasing their apoptosis.

Strong affinity for calcium phosphate

↓

Concentrate in mineralized tissue

↓

Disrupt cytoskeleton and ruffled border of osteoclasts

↓

Acids secreted by osteoclast dissociates it from mineral

↓

Within osteoclast, blocks mevalonate pathway

↓

Osteoclast apoptosis

Uses-Alendronate, Risedronate, and Ibandronateare usedforprevention and treatment of postmenopausal osteoporosis while Risedronate and Alendronate for steroid-induced osteoporosis. Alendronate and Risedronate are alsopreferred for osteoporosis in men.

Adverse effects associated with these drugs are - Nausea, headache, abdominal pain, diarrhoea, occasionally may cause oesophagitis and oesophageal ulcer. Gastritis can be minimized by taking the drug on empty stomach in early morning with a glass full of water and patient is instructed not to lie down or take food for at least 30 min. They can also cause fever, joint pain, myalgia and ocular inflammation. Zolendronate is found to benephrotoxic. Higher doses of bisphosphonates can cause osteonecrosis of the jaw.

B. Hormones

1. Calcitonin- It is approved for the treatment of postmenopausal osteoporosis and bone resorption. It increases bone mass mainly in the spine. Intra nasal salmon calcitonin- 200 IU daily is more effective in preventing lamellar bone loss than cortical bone mass but it does not appear to be as effective as bisphosphonates. PROOF study (Prevent Recurrence of Osteoporotic Fracture) has proved that Salmon calcitonin nasal spray significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis [22].

2. Teriparatide- The recombinant form of PTH 1-34 is approved for the treatment of osteoporosis. It stimulates bone remodeling by inducing an increase in bone formation followed by a slower increase in bone resorption [23]. A dosage of 20 mcg subcutaneously daily increases BMD bone mass & bone strength by stimulating periosteal and endosteal bone formation. It is the first drug available with anabolic action on the bone. Teriparatide is approved for use for only 2 years for patients of osteoporosis. Trials examining the sequential use of teriparatide followed by a bisphosphonate after 1 or 2 years are in progress and look promising [24].

3. Estrogen-The majority of estrogen effects on bone resorption are mediated indirectly through paracrine factors produced by osteoblasts. They act by increasing IGF-1 and TGF- β & suppressing IL-1 (α and β), IL-6, TNF-, and osteocalcin synthesis.

Estrogen was used previously for treatment of post menopausal osteoporosis, however the concerns associated with its use i. e. development of breast cancer, endometrial carcinoma and failure to reduce the development of heart disease, have reduced enthusiasm for this form of therapy.

4. SERM- It prevents the risk of breast and uterine carcinoma associatedwith estrogen use while maintaining the benefit of estrogen to the bone.

Raloxifene - It causes dose dependent increase in osteoblastic activity and in osteoclastic activity. It protects against spine fractures but not against hip fracture unlike bisphosphate and teriparatide which protect against both [25].

It is used in the dose of 60 mg once daily for the prophylaxis of menopausal osteoporosis.

Adverse effects associated with this drug are - hot flushes, leg cramps & thromboembolic disease.

Hormone Replacement Therapy is preferred in early menopause symptoms while SERM is preferred in middle and late menopause.

Recent Advances

Strontium ranelate

Strontium ranelate is another treatment option for the prevention of osteoporosis. Strontium is laid down on the surface of newly formed bone where it decreases osteoclastic activity and reduces bone resorption [26]. Simultaneous administration of calcium and phosphatesis required for bone mineralization. At the same time, strontium induces the differentiation of pre-osteoblasts to osteoblasts and increases markers of bone formation. Overall, strontium increases bone mass and strength [27]. It has not been approved yet but clinical trials have found that strontium ranelate reduced the risk of new vertebral fractures by about 25% and non-vertebral fractures by 15%. Strontium may cause minor gastrointestinal problems but does not appear to have any serious adverse effects.

Denosumab

Denosumab is a human monoclonal antibody to RANKL (Receptor for activation of nuclear factor k ligand) that suppresses bone resorption by interfering with RANKL/RANK induction of osteoclast differentiation and function. Inactivation of the RANKL → RANK → NF-κB pathway by Denosumab inhibits gene expression required for osteoclast function and decreases bone resorption in both cortical and trabecular bone. The increase in BMD is higher than that obtained with the more potent bisphosphonates. Denosumab has produced reduction in the risk of vertebral, non vertebral and hip fractures in women with osteoporosis [28].

Romosozumab

Humanized monoclonal antibody

↓

Inhibits sclerosin

↓

Immediate increase in bone formation markers

↓

Moderate sustained reduction in bone resorption markers

Since, sclerosin genes are expressed only in skeletal tissue, it produces less adverse effects. There is no data on anti-fracture efficacy and long term safety of this drug. Currently it is in phase 3 trials and is administered by subcutaneous injection at monthly or 3 monthly intervals.

Osteoprotegerin (OPG)

Osteoblasts synthesise and release a molecule osteoprotegenin which inhibits RANKL binding to RANK. So, in near future, OPG analogue or agonist could be the potential the rapeutic agent for osteoporosis [29].

Thiazide diuretics

These decrease calcium excretion and are useful in preventing renal stones. They may also be useful in diminishing bone loss. Hence, a thiazide may be the preferred drug when osteoporotic patient also has hypertension and nephrolithiasis [30].

Statins

Statins have been seen to promote osteoclast apoptosis and synthesis activity in osteoblasts. Statins also inhibit mevalonate pathway, increase the gene expression for bone morphoenic protein 2 (BMP-2) and the bone formation. Hence, it seems that statins are going to be the future drug for treatment of osteoporosis [31].

Other sclerosin inhibitors

Sclerosin is produced by osteocytes and inhibits bone formation. In animal studies, treatment with monoclonal antibody that blocks sclerosin resulted in increase in BMD. Inhibitors of sclerosin hold promise as a therapy to bone mass [32].

Integrin antagonists

Adhesion of osteoclasts to bone surface is an important initial step for bone resorption. Intergrin mediates cell and cell matrix interaction. Thus, integrin inhibitors prevent osteoclast interaction with extracellular matrix and hence bone resorption [33].

Cathepsin k inhibitor

Cathepsin k is a cysteine protease that is expressed in osteoclasts. It plays a role in osteoclasts mediated bone resorption. Inhibition of cathepsin k may attenuate bone resorption without concurrent inhibition of bone formation [34].

Fluoride

Fluorides are potent stimulators of osteoprogenitor cells. They have been used in multiple osteoporosis studies with conflicting results, because of the use of varying doses and preparations. Flouride increases bone mass of up to 10%, but no consistent effects have been observed on vertebral or non vertebral fracture. Fluoride remains an experimental agent despite its long history and multiple studies [35].

Stem cell therapy

Mesenchymal Stem Cells (MSCs), obtained from bone marrow, adipose tissue and cord blood have been studied for osteoporosis. These are easily available, devoid of ethical issues, possess immunosuppressant properties, and are multipotent and safe. MSCs differentiate into osteoblasts upon systemic administration. Hematopoietic Stem Cells have also been found to produce osteoblasts [36].

Summary

Osteoporosis can be prevented by Calcium and Vitamin D supplementation along with life style modifications. A lifelong intake of adequate amounts of calcium and vitamin D is essential for optimal bone formation and maintenance. But once the osteoporosis develops, it can be treated with a Bisphosphonate drug, Calcitonin, Teriparatide, Estrogen, Raloxifene, Denosumab, or Strontium ranelate. Most drugs reduce bone resorption while Teriparatide stimulates bone formation and Strontium acts by both the mechanisms to reduce the risk of fractures in patients with osteoporosis.

References

1. Marwaha RK, Tandon N, Garg MK, Kanwar R, Narang A, Sastry A, et al. Bone health in healthy Indian population aged 50 years and above. Osteoporosis international. 2011; 22: 2829-2836.
2. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. Jama. 2009; 301: 513-521.
3. Pande KC. Prevalence of low bone mass in healthy Indian population. Journal of the Indian Medical Association. 2002; 100: 598-600.
4. Agrawal NK, Sharma B. Prevalence of osteoporosis in otherwise healthy Indian males aged 50 years and above. Archives of osteoporosis. 2013; 8: 1-7.
5. Holroyd C, Cooper C, Dennison E. Epidemiology of osteoporosis. Best Practice & Research Clinical Endocrinology & Metabolism. 2008; 22: 671-685.
6. Åkesson K. New approaches to pharmacological treatment of osteoporosis. Bulletin of the World Health Organization. 2003; 81: 657-663.
7. Bernabei R, Martone AM, Ortolani E, Landi F, Marzetti E. Screening, diagnosis and treatment of osteoporosis: a brief review. Clin Cases Miner Bone Metab. 2014; 11: 201-207.
8. Mauck KF, Clarke BL. Diagnosis, screening, prevention, and treatment of osteoporosis. In Mayo Clinic Proceedings. 2006; 81: 662-672.
9. Kanis JA, Johnell O. Requirements for DXA for the management of osteoporosis in Europe. Osteoporosis International. 2005; 16: 229-238.
10. Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson DO. Guidelines for diagnosis and management of osteoporosis. Osteoporosis International. 1997; 7: 390-406.
11. Datta HK, Ng WF, Walker JA, Tuck SP, Varanasi SS. The cell biology of bone metabolism. Journal of clinical pathology. 2008; 61: 577-587.
12. Christenson RH. Biochemical markers of bone metabolism: an overview. Clinical biochemistry. 1997; 30: 573-593.
13. Berg KM, Kunins HV, Jackson JL, Nahvi S, Chaudhry A, Harris KA, et al. Association between alcohol consumption and both osteoporotic fracture and bone density. The American journal of medicine. 2008; 121: 406-418.
14. Baron JA, Farahmand BY, Weiderpass E, Michaëlsson K, Alberts A, Persson I, et al. Cigarette smoking, alcohol consumption, and risk of hip fracture in women. Archives of internal medicine. 2001; 161: 983-988.
15. Todd JA, Robinson RJ. Osteoporosis and exercise. Postgraduate Medical Journal. 2003; 79: 320-323.
16. Moreira LD, Oliveira ML, Lirani-Galvo AP, Marin-Mio RV, Santos RN, Lazaretti-Castro M. Physical exercise and osteoporosis: effects of different types of exercises on bone and physical function of postmenopausal women. Arquivos Brasileiros de Endocrinologia & Metabologia. 2014; 58: 514-522.
17. Holick MF. The vitamin D epidemic and its health consequences. The Journal of nutrition. 2005; 135: 2739S-2748S.
18. Henderson NK, White CP, Eisman JA. The roles of exercise and fall risk reduction in the prevention of osteoporosis. Endocrinology and metabolism clinics of North America. 1998; 27: 369-387.
19. Grafe IA, Da Fonseca K, Hillmeier J, Meeder PJ, Libicher M, Nöldge G, et al. Reduction of pain and fracture incidence after kyphoplasty: 1-year outcomes of a prospective controlled trial of patients with primary osteoporosis. Osteoporosis International. 2005; 16.
20. Reginster JY, Minne HW, Sorensen OH, Hooper M, Roux C, Brandi ML, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporosis International. 2000; 11: 83-91.
21. Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporosis international. 2008; 19: 733-759.
22. Chesnut CH, Silverman S, Andriano K, Genant H, Gimona A, Harris S, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. The American journal of medicine. 2000; 109: 267-276.
23. Alkhiary YM, Gerstenfeld LC, Krall E, Westmore M, Sato M, Mitlak BH, et al. Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg Am. 2005; 87: 731-741.
24. Cranney A, Papaioannou A, Zytaruk N, Hanley D, Adachi J, Goltzman D, et al. Clinical Guidelines Committee of Osteoporosis Canada. Parathyroid hormone for the treatment of osteoporosis: a systematic review. Canadian Medical Association Journal. 2006; 175: 52-59.
25. D'Amelio P, Isaia GC. The use of raloxifene in osteoporosis treatment. Expert opinion on pharmacotherapy. 2013; 14: 949-956.
26. Bonnelye E, Chabadel A, Saltel F, Jurdic P. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone. 2008; 42: 129-138.
27. Ammann P, Shen V, Robin B, Mauras Y, Bonjour JP, Rizzoli R. Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats. Journal of bone and mineral research. 2004; 19: 2012-2020.
28. Cummings SR, Martin JS, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. New England Journal of Medicine. 2009; 361: 756-765.
29. Sattler AM, Schoppet M, Schaefer JR, Hofbauer LC. Novel aspects on RANK ligand and osteoprotegerin in osteoporosis and vascular disease. Calcified tissue international. 2004; 74: 103-106.
30. Feskanich D, Willett WC, Stampfer MJ, Colditz GA. A prospective study of thiazide use and fractures in women. Osteoporosis International. 1997; 7: 79-84.
31. Jadhav SB, Jain GK. Statins and osteoporosis: new role for old drugs. Journal of pharmacy and pharmacology. 2006; 58: 3-18.
32. Papapoulos SE. Targeting sclerostin as potential treatment of osteoporosis. Annals of the rheumatic diseases. 2011; 70: i119-122.
33. Hartman GD, Duggan ME. αvβ3 integrin antagonists as inhibitors of bone resorption. Expert opinion on investigational drugs. 2000; 9: 1281-1291.
34. Stoch SA, Wagner JA. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clinical Pharmacology & Therapeutics. 2008; 83: 172-176.
35. Pak CY. Fluoride and osteoporosis. Experimental Biology and Medicine. 1989; 191: 278-286.
36. Antebi B, Pelled G, Gazit D. Stem cell therapy for osteoporosis. Current osteoporosis reports. 2014; 12: 41-7.