Osteoporosis: A review of current recommendations and emerging treatment options

October 1, 2011

Osteoporosis is a widespread condition with significant morbidity and mortality affecting millions of people in the United States and worldwide. Incidence is expected to increase as the population ages.

Key Points


Osteoporosis is a widespread condition with significant morbidity and mortality affecting millions of people in the United States and worldwide. Incidence is expected to increase as the population ages. Treatment guidelines are available from many organizations throughout the world; in the United States these include those from the National Osteoporosis Foundation, American Association of Clinical Endocrinologists, North American Menopause Society, and the American College of Rheumatologists. Current treatment options include bisphosphonates, calcitonin, parathyroid hormone, raloxifene, and denosumab. Future therapies include drugs with new mechanisms of action and new dosage forms. All therapies require an analysis of their risk-benefit profile prior to patient-specific treatment selection. Bisphosphonates, despite several controversies, remain the foundation of therapy. (Formulary. 2011; 46:432-446.)

Osteoporosis is among the most common bone diseases. Multiple definitions exist, for example, osteoporosis is defined by the National Osteoporosis Foundation (NOF) as "porous bone," by the World Health Organization (WHO) based on diagnostic test results, and by the National Institute of Health as "a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture."1-3

In addition to being a common disease, osteoporosis significantly increases healthcare costs. The American Association of Clinical Endocrinologists (AACE) noted that direct costs associated with osteoporotic fractures approached $17 billion in 2005. As the population ages and osteoporosis likely becomes more common, costs are projected to reach nearly $25 billion by 2025.4


Human bone undergoes a continuous remodeling process mediated by osteoblasts and osteoclasts.5 Osteoblasts generate new bone tissue, and osteoclasts break down bone tissue. Throughout normal growth in childhood and adolescence, the activity of osteoblasts surpasses that of osteoclasts, allowing bone density to increase. Bone remodeling is affected by various hormones, including parathyroid hormone, calcitriol, calcitonin, estrogen, testosterone, growth hormone, insulin-like growth factor, thyroid hormone, and cortisol. Dietary calcium and vitamin D are also critical for bone health. Calcium serves as an essential component of bone tissue, and vitamin D facilitates adequate calcium absorption from the gut. Bone mass is at its greatest between the ages of 20 and 30 years. At this age, osteoclast activity and osteoblast activity are equivalent for some time, allowing bone density to be maintained. Then the activity of osteoclasts begins to surpass that of osteoblasts, and bone mass declines. This decline in bone density may progress to osteoporosis.5




Calcitonin-salmon is also an antiresorptive therapy for osteoporosis, and affects BMD by inhibiting the activity of osteoclasts. It is available in a non-oral (nasal spray) formulation for the treatment of osteoporosis. It should be administered daily in alternating nostrils. Common side effects are local, and include nasal irritation and occasionally epistaxis.18

Calcitonin has demonstrated positive effects on spinal BMD, but has not been shown to significantly affect hip BMD. The Prevent Recurrence of Osteoporotic Fractures (PROOF) study in 2000 was a landmark multicenter clinical trial for calcitonin.19 The population of the trial was more than 1,200 subjects randomly assigned to calcitonin or placebo for 5 years. At the conclusion of the PROOF study, a 36% relative risk reduction in vertebral fractures was noted. Also in 2000, a review was undertaken to analyze the impact of calcitonin on corticosteroid-induced osteoporosis, including data from 9 trials and 221 patients.20 Results were not dramatic, with calcitonin showing a 3% improvement (over placebo) in lumbar BMD. No fracture data were reported in this review. In addition to its effects on spinal BMD, calcitonin has been shown to alleviate pain from vertebral osteoporotic compression fractures. The mechanism of calcitonin-produced analgesia remains unclear, but it has been proposed to include beta endorphins and prostaglandins.21

Raloxifene is a selective estrogen receptor modulator (SERM). It antagonizes estrogen receptors in some tissues and agonizes estrogen receptors at other tissues, such as bone tissue. Estrogen affects the balance of osteoclast and osteoblast activity, and its deficiency is associated with an increase in osteoclastic activity. Raloxifene is administered as a once-daily oral formulation. Side effects include hot flashes, especially during the first 6 months of therapy. Raloxifene has been associated with an increase in thromboembolic events, and carries a black box warning about this risk.22 The Multiple Outcomes of Raloxifene Evaluation (MORE) study evaluated raloxifene versus placebo in nearly 8,000 women for 3 years with a 1-year extension.23 Results from the MORE study included a 55% relative risk reduction in first vertebral fractures and a 30% relative risk reduction in secondary vertebral fractures.22

Teriparatide is parathyroid hormone produced using recombinant DNA technology. Teriparatide has anabolic effects on bone, stimulating the activity of osteoblasts. It is administered as a once-daily subcutaneous injection. Side effects include orthostatic hypotension, nausea, myalgia, and arthralgia. Teriparatide has a black box warning regarding risk of osteosarcoma. Osteosarcoma was observed in rats exposed to teriparatide at doses much higher than the currently approved dose.24 A study of more than 1,600 women randomly assigned to daily subcutaneous teriparatide or placebo reported a 53% relative risk reduction in nonvertebral fragility fractures.25 Teriparatide is not recommended for use beyond 2 years due to lack of safety and efficacy data. After 2 years, some studies suggest that the addition of bisphosphonates helps continue increase in BMD or helps maintain BMD gained during teriparatide treatment.26

Denosumab, an antiresorptive therapy, prevents the activation of receptor activator of nuclear factor kappa B ligand (RANKL) receptors on the surface of osteoclasts. The RANK receptor plays a role in formation, function, and survival of osteoclasts. Denosumab is administered by a healthcare professional as a twice-yearly subcutaneous injection. The most commonly reported side effects include back and musculoskeletal pain, pain in extremity, cystitis, and hypercholesterolemia. Serious reported side effects include serious infections and osteonecrosis of the jaw (ONJ). Patients at risk of infection (including patients on immunosuppressive therapy) should have a risk-benefit evaluation prior to considering denosumab therapy.27 Denosumab improves BMD and decreases fractures. A study of nearly 8,000 osteoporotic women randomized to denosumab or placebo revealed a 68% relative risk reduction in vertebral fractures and a 40% relative risk reduction in hip fractures.28

No head-to-head comparative trials exist to guide selection of osteoporosis therapy for a specific patient. Of the guidelines discussed previously, there is discordance on which therapies are used as first-line treatment (Table 1).4,6-8 The NOF guidelines simply list the agents that have been approved for osteoporosis treatment.6 AACE indicates that alendronate, risedronate, zoledronic acid, and denosumab are considered first-line therapy due to their proven efficacy against fractures. The AACE guidelines do not offer any recommendations for choosing between these 4 agents.4 The NAMS and ACR guidelines recommend use of bisphosphonates as first-line therapy, but offer no suggestion on choosing a specific bisphosphonate.7,8 Practitioners must rely on their own analysis of efficacy, safety, and cost when deciding between currently available therapies.


Several controversies confound treatment of osteoporosis, particularly with the use of bisphosphonates. Key controversies associated with bisphosphonates use include treatment duration and risk of rare but serious adverse effects, such as ONJ and atypical femur fracture. These controversies are connected, as published data point to a relationship between medication exposure and occurrence of serious adverse effects.29-34 ONJ is literally death of the bony tissue of either the maxilla or the mandible. ONJ attributed to bisphosphonate use was initially reported in 2003.29 ONJ has been reported with all 4 bisphosphonates used for osteoporosis, but the incidence is rare. Risk factors for ONJ include intravenous bisphosphonates; cancer and anti-cancer therapy; dental extraction, oral bone manipulating surgery, poor fitting dental appliances, intraoral trauma; duration of exposure to bisphosphonate treatment; glucocorticoids; comorbid conditions (ie, malignancy); alcohol and/or tobacco abuse; and pre-existing dental or periodontal disease.30 Reviews indicate an incidence of less than 1 per 1,000 individuals treated with an oral bisphosphonate for osteoporosis. The risk may be as much as 4 times higher in individuals with risk factors receiving a parenteral bisphosphonate.31 The labeling of bisphosphonates used for osteoporosis includes information on the risk of ONJ.10-13

A more recent concern with bisphosphonates is the occurrence of atypical femur fractures. In 2008, a Danish database study found an increased risk in atypical femur fractures in patients exposed to alendronate.32 These findings prompted FDA to request information regarding atypical fractures from bisphosphonate manufacturers. In 2010, FDA issued 2 safety communications about these effects, and required information about the risk of atypical femur fractures to be added to bisphosphonate labeling.35,36 During that same year, a task force of the American Society for Bone and Mineral Research stated that in most patients the benefits of treating osteoporosis with bisphosphonates outweigh risk of atypical fractures.33 A Swedish database study evaluating the risk of atypical femur fractures reported an absolute increase in risk of 5 cases per 10,000 patient-years exposed to bisphosphonates.34 The same study noted that the relative risk of atypical femur fracture decreased significantly each year after discontinuation of bisphosphonates.34

Both ONJ and atypical femur fracture have been associated with increased exposure to bisphosphonates, bringing into question the appropriate duration of bisphosphonate treatment. Osteoporosis is a chronic condition, in that BMD continues to decline with age without pharmacologic intervention. The concept of a bisphosphonate drug holiday remains controversial, and current guidelines do not address appropriate duration of bisphosphonate therapy. Practitioners and patients must weigh the risks of declining bone density with the risk of continued bisphosphonate therapy. The Fracture Intervention Trial Long-term Extension (FLEX) trial most specifically addressed this issue, evaluating the BMD and fracture outcomes of women who either continued alendronate therapy past 5 years of initial treatment or discontinued alendronate after 5 years.37 There were no significant differences in the rate of nonvertebral fractures between the groups after an additional 5 years of observation. Another review found that the risk of fracture was increased in women who discontinued bisphosphonate therapy after 2 years.38


Several therapies for osteoporosis are currently being investigated. These include oral calcitonin, odanacatib, and oral parathyroid hormone.39-42 Oral calcitonin is being studied in postmenopausal women for both prevention and treatment of osteoporosis. End points do not include fractures, but are limited to BMD and urinary bone-turnover markers as a surrogate indicator of effects on BMD.39 Odanacatib is a cathepsin-K inhibitor. Cathepsin K is an enzyme that affects the function of osteoclasts, meaning that odanacatib will also be an antiresorptive agent. Odanacatib is being evaluated as an oral weekly formulation in both men and women with osteoporosis. End points include both BMD and fractures.40,41 Oral parathyroid hormone is currently undergoing safety and efficacy studies for osteoporosis treatment. End points include urinary bone-turnover markers as a surrogate indicator of effects on BMD.42 If approved, these therapies offer both new mechanisms of treating low BMD as well as new formulations that may be more palatable.

Dr McBane is assistant clinical professor, UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, Calif.

Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.


Osteoporosis is a widespread condition with significant morbidity and mortality affecting millions of people in the United States and worldwide. Incidence is expected to increase as the population ages. Guidelines are available from many organizations throughout the world; key guidelines in the United States include those from the National Osteoporosis Foundation, American Association of Clinical Endocrinologists, North American Menopause Society, and the American College of Rheumatologists. Pharmacists can contribute to the overall care of patients with osteoporosis by familiarizing themselves with these guidelines and the available treatment options. All therapies require an analysis of their risk-benefit profile. Bisphosphonates, despite several controversies, remain the foundation of therapy.


1 Fast facts. The National Osteoporosis Foundation. Updated October 25, 2010. Available at: http://www.nof.org/node/40/. Accessed September 11, 2011.

2 WHO Scientific Group on the Assessment of Osteoporosis at Primary Health Care Level. Summary Meeting Report. Brussels, Belgium, 5-7 May 2004. Available at: http://www.who.int/chp/topics/Osteoporosis.pdf. Accessed September 9, 2011.

3 Osteoporosis Prevention, Diagnosis, and Therapy. National Institutes of Health Consensus Development Conference Statement. March 27-29, 2000. Available at: http://consensus.nih.gov/2000/2000Osteoporosis111html.htm. Accessed September 9, 2011.

4 Watts NB, Bilezikian JP, Camacho PM, et al; AACE Osteoporosis Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2010;16(suppl 3):1–37.

5 Bone health and osteoporosis: A report of the Surgeon General. US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; Washington, DC. Available at: http://www.surgeongeneral.gov/library/bonehealth/content.html. Accessed September 9, 2011.

6 National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010. Available at: http://www.nof.org/professionals/clinical-guidelines/. Accessed September 9, 2011.

7 Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause. 2010;17:25–54.

8 Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis. Arthritis Rheum. 2001;44:1496–1503.

9 WHO Fracture Risk Assessment Tool: FRAX. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK. Available at: http://www.shef.ac.uk/FRAX/index.jsp. Accessed September 9, 2011.

10 Fosamax (alendronate sodium) [prescribing information]. Whitehouse Station, NJ: Merck; revised 2011.

11 Actonel (risedronate sodium) [prescribing information]. Rockaway, NJ: Warner Chilcott; revised 2011.

12 Boniva (ibandronate sodium) [prescribing information]. South San Francisco, CA: Genentech; revised 2011.

13 Reclast (zoledronic acid) [prescribing information]. East Hanover, NJ: Novartis; revised 2011.

14 Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD001155.

15 Wells GA, Cranney A, Peterson J, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 2008;(1):CD004523.

16 Cranney A, Wells GA, Yetisir E, et al. Ibandronate for the prevention of nonvertebral fractures: a pooled analysis of individual patient data. Osteoporos Int. 2009;20:291–297.

17 Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799–1809.

18 Mialcacin (calcitonin-salmon) [prescribing information]. East Hanover, NJ: Novartis; revised 2009.

19 Chestnut CH 3rd, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: The prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med. 2000;109:267–276.

20 Cranney A, Welch V, Adachi JD, et al. Calcitonin for the treatment and prevention of corticosteroid-induced osteoporosis. Cochrane Database Syst Rev. 2000;(2):CD001983.

21 Blau LA, Hoehns JD. Analgesic efficacy of calcitonin for vertebral fracture pain. Ann Pharmacother. 2003;37:564–570.

22 Evista (raloxifene hydrochloride) [prescribing information]. Indianapolis, IN: Lilly USA; Revised 2011.

23 Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282:637–645.

24 Forteo (teriparatide) [prescribing information]. Indianapolis, IN: Eli Lilly; revised 2010.

25 Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434–1441.

26 Tashjian AH Jr, Gagel RF. Teriparatide [human PTH(1-34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res. 2006;21:354–365.

27 Prolia (denosumab) [prescribing information]. Thousand Oaks, CA: Amgen; revised 2011.

28 Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765.

29 Rizzoli R, Burlet N, Cahall D, et al. The impact of osteonecrosis of the jaw on osteoporosis management: Executive summary of a European Society on Clinical and Economic Aspects of Osteoporosis and Foundation for Research on Osteoporosis and other Bone Diseases Working Group Meeting. Liege, Belgium: ESCEO, 2007.

30 Khosla S, Burr D, Cauley J, et al; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479–1491.

31 Abrahamsen B. Bisphosphonate adverse effects, lessons from large databases. Curr Opin Rheumatol. 2010;22:404–409.

32 Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: A register-based national cohort study. J Bone Miner Res. 2009;24:1095–1102.

33 Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2010;25:2267–2294.

34 Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364:1728-1737.

35 FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical subtrochanteric femur fractures. 03-10-2010. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203891.htmAccessed September 9, 2011.

36 FDA Drug Safety Communication: Safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. 10-13-2010. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm229009.htm. Accessed September 9, 2011.

37 Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: The Fracture Intervention Trial Long-term Extension (FLEX): A randomized trial. JAMA. 2006;296:2927–2938.

38 Curtis JR, Westfall AO, Cheng H, Delzell E, Saag KG. Risk of hip fracture after bisphosphonate discontinuation: Implications for a drug holiday. Osteoporos Int. 2008;19:1613–1620.

39 A study comparing oral calcitonin to nasal spray calcitonin in postmenopausal osteoporotic women (ORACAL). http://clinicaltrials.gov/ identifier: NCT00959764. Accessed September 9, 2011.

40 A study to evaluate the safety, tolerability, and efficacy of odanacatib (MK0822) in postmenopausal women previously treated with a bisphosphonate (0822-042). http://clinicaltrials.gov/ identifier: NCT00885170. Accessed September 9, 2011.

41 A study to assess safety and efficacy of odanacatib (MK-0822) in men with osteoporosis (MK-0822-053 AM1). http://clinicaltrials.gov/ identifier: NCT01120600. Accessed September 9, 2011.

42 Safety, tolerability, pharmacokinetics and pharmacodynamics of oral doses of PTH134 in post-menopausal women. http://clinicaltrials.gov/ identifier: NCT01224717. Accessed September 9, 2011.