Osteoporosis is a disease characterised by reduction in bone mass and disruption of skeletal architecture, which ultimately leads to fragility fractures.
Based on the 2007–08 National Health Survey (NHS), it is estimated that 3.4 per cent of the Australian population have osteoporosis as diagnosed by a medical practitioner.1 However, this is almost certainly an underestimate of the true prevalence, as investigation for osteoporosis generally only occurs after a fracture. Moreover, two-thirds of spinal fractures are silent and thus mostly not detected. Fracture results in significant morbidity, cost and premature mortality that is not just limited to hip fractures. The associated mortality risk increase is greatest in the first five years post-fracture before returning to that of the general population.2 However, not only are less than 20 per cent of women and fewer men with minimal trauma investigated for underlying causes, but also less than 30 per cent of women and ten per cent of men are on treatment once they have had a fracture.3
Risk factors for osteoporosis can be classified as modifiable and non-modifiable (see Table 1). All individuals should be investigated after a minimal trauma fracture, but individuals with risk factors listed in Table 1 should be investigated earlier.
Bone mineral density
The most common method of measuring bone mineral density (BMD) is by dual energy absorptiometry (DXA). There are different DXA manufacturers (GE-Lunar, Norland and Hologic) and comparisons of actual BMD values are not valid between the different systems. However, BMD results are also reported as T-scores (number of standard deviations below that of a young normal individual) and Z-scores (number of standard deviations below an age-, sex- and, in some cases, weight-adjusted individual) and comparisons of these scores can provide an idea of trend.
Table 1. Risk factors for osteoporosis.
|Non modifiable||Potentially modifiable|
|Age||Sex hormone deficiency (oestrogen in females, testosterone in males)|
|Family history of osteoporosis||Alcohol excess|
|Previous minimal trauma fracture||Medical conditions (eg malabsorption, coeliac disease, chronic lung disease)|
|Low body weight|
|Prolonged low dietary calcium intake|
|Medications (eg glucocorticoids, anti-epileptics, aromatase inhibitors)|
|Endocrine disorders (Cushingâ€™s syndrome, hyperprolactinaemia, hyperthyroidism)|
The WHO definition of osteoporosis is based on a T-score ≤ -2.5. A T-score between -1 and -2.5 is defined as osteopenia, while scores ≥ -1 are considered normal. Serial BMD measurements can be used for monitoring changes with age or treatment response. Secondary causes of osteoporosis should be investigated for particularly in individuals with low Z-scores. A recommendation of the laboratory tests has been summarised in Table 2.
Regular weight-bearing exercise and resistance training improves muscle strength and may help to preserve bone density. Strategies for fall prevention – such as balance training and provision of vision aids – are also beneficial. It should be noted that there is no randomised controlled trial (RCT) evidence for exercise having a direct effect in preventing fractures.
The recommended daily intake of calcium is 1000–1300mg (three to four serves of dairy products). Ideally, the RDI of calcium should be achieved through dietary means; however, this is often not possible. A calcium supplement may be taken to make up the shortfall. There has been recent controversy surrounding calcium supplement (but not dietary) intake and possible increase rate of heart attacks in some4-6, but not all studies.7 Despite the controversy, we would recommend taking a calcium supplement with food if there was inadequate dietary intake but not to exceed the RDI.
Adequate vitamin D level is essential for calcium absorption. Formation of vitamin D occurs after exposure to ultraviolet light. The recommended skin exposure is five to 15 minutes of sunlight, depending on time of year and latitude, four to six times a week, longer for people with darker skin. Individuals with limited sunlight exposure – for instance, institutionalisation, long indoor working hours and cultural dress – are more likely to be vitamin D deficient. A serum level >75nmol/l is considered as optimal for skeletal health. A recent meta-analysis showed that vitamin D supplementation of greater than 800IU was associated with a 30 per cent reduction in hip fractures and 14 per cent reduction in non-vertebral fractures.8
Table 2. Recommended laboratory tests.
|Serum biochemistry||Exclude hyper/hypocalcaemia, renal, liver dysfunction|
|Serum 25-hydroxy vitamin D||Exclude vitamin D deficiency|
|Serum parathyroid hormone||Exclude hyperparathyroidism|
|Protein electrophoresis||Exclude multiple myeloma|
|Anti endomyseal anti-tissue transglutaminase antibodies and Ig A level||Exclude coeliac disease|
|Urinary free cortisol (24 hour)||Exclude Cushingâ€™s syndrome if clinical suspicion|
|Serum prolactin||Exclude prolactinoma if clinical suspicion|
The recommended skin exposure is five to 15 minutes of sunlight, depending on time of year and latitude, four to six times a week, longer for people with darker skin. Individuals with limited sunlight exposure – for instance, institutionalisation, long indoor working hours and cultural dress – are more likely to be vitamin D deficient. A serum level >75nmol/l is considered as optimal for skeletal health. A recent meta-analysis showed that vitamin D supplementation of greater than 800IU was associated with a 30 per cent reduction in hip fractures and 14 per cent reduction in non-vertebral fractures.8
Levels below 25nmol/l are considered as severely deficient, 25–50nmol/l are deficient and 50–75nmol/l are insufficient. Supplementation should be commenced at 3000–5000IU of cholecalciferol for 12 weeks for the moderate to severely deficient, while 1000 to 2000IU is likely to be adequate for insufficiency. The 25(OH)D level should be rechecked three months after commencement of supplementation.
Available pharmocological therapies are primarily anti-resorptive with one anabolic therapy (teriparetide) available. Most therapies have been shown to reduce vertebral fractures by up to 50 per cent and peripheral fractures by 15–40 per cent.9-19
Table 3. Current PBS indications.
|Bisphosphonates||Primary prevention: Aged â‰¥ 70 years and T score â‰¤ 2.5 for alendronate, others T score < 3.0
Secondary prevention: Patients with minimal trauma fractures at any T score
Corticosteroid induced osteoporosis: T score â‰¤ 1.5
|HRT||Not PBS listed for fracture prevention|
|Tibolone||Not PBS listed for fracture prevention|
|Denosumab||Only PBS listed for use in women for the following: Primary prevention: Aged â‰¥ 70 years and T score â‰¤ 3.0 Secondary prevention: Patients with minimal trauma fractures at any T score|
|Strontium ranelate||Only PBS listed for use in women for the following: Primary prevention: T score â‰¤|
|Teriparatide||In patients with established osteoporosis:
Three criteria: T score â‰¤ 3.0 and two minimal trauma fractures and one year of continuous anti-resorptive therapy
Can only be initiated by specialists
Alendronate (Fosamax) and risedronate (Actonel) are the two oral bisphosphonates available in Australia.9-12 Both agents are available as daily and once-weekly doses, with risedronate being available as a once-monthly preparation as well. These agents are also available in various combination packs with Vitamin D and calcium.
Bisphosphonates are poorly absorbed enterally (less than one per cent) and must to be taken after an overnight fast with a glass of water in an upright position, at least 30 minutes before food or other drink. The relatively new enteric-coated delayed-release risedronate (Actonel EC) overcomes some of these restrictions as it can be taken with or immediately after breakfast. However, it must not be taken with other tablets, particularly calcium, and subjects should remain upright for 30 minutes after taking it.
Zoledronic acid (Aclasta or Zometa) is a long-acting intravenous bisphosphonate approved as a once yearly infusion. As well as reducing fracture incidence, it also decreased mortality following hip fractures.20 Although approved as an annual infusion, its action can last 18 months or more in many people.
A common side-effect of oral bisphosphonates is gastrointestinal irritation and with intravenous bisphosphonates flu-like symptoms are associated with the first infusion. This commonly lasts not more than 48 hours and should settle with paracetamol.
Osteonecrosis of the jaw (ONJ) is a serious, but very rare, side-effect. The estimated incidence in people taking bisphosphonates for osteoporosis is one in 10,000 to 100,000 person-years and has mainly been reported after major dental work such as tooth extraction. Other risk factors include poor dental hygiene, corticosteroids and diabetes. ONJ is more common in cancer patients on much higher bisphosphonate doses.
Atypical femoral stress fractures have been rarely reported since 2005 in long-term bisphosphonate users.21,22 However, the risk reduction in typical hip fractures far outweighs the risk of atypical fractures.23
Raloxifene (Evista) is a Selective Estrogen Receptor Modulator (SERM) that has similar effects on bone as oestrogen, inhibiting bone resorption. Its use can exacerbate menopausal symptoms such as hot flushes. There is evidence for reduction in vertebral fractures however there is limited evidence for peripheral fracture reduction.13
Hormone replacement therapy (HRT) is an option for women
peri-menopausal and early post-menopause. HRT is effective in preserving BMD and reducing vertebral and peripheral fracture risk.
Tibolone (Livial) is a selective tissue oestrogenic activity regulator that is an alternative to HRT for postmenopausal women. Tibolone has been shown to reduce the risk of vertebral and peripheral fractures without the increased breast cancer or clotting risk seen with traditional HRT.14 However, it was associated with a small risk of stroke in older women.14
Denosumab (Prolia) is a fully human monoclonal antibody to the nuclear factor kB ligand. By blocking the binding of RANK to the ligand, it inhibits the development and activity of osteoclasts. It is administered subcutaneously every six months. Denosumab has been shown to reduce vertebral, non-vertebral and hip fractures.15 The effects of the drug wear off after six months thus must be given regularly or bone loss will ensue. Denosumab can be safely used in people with stage I to IV chronic kidney disease without dose reduction. There was some initial concern with people commencing on denosumab having a higher incidence of skin infections, however, this has been negated on longer follow-up.16
Strontium ranelate (Protos) is an oral form of strontium taken as a powder mixed with water.17,18 It needs to be taken two hours after the evening meal for maximal absorption. Side-effects include nausea, diarrhoea, headache and rashes. These should resolve quickly. Thromboembolism is a rare, but serious, side-effect thus consideration should be given in patients with history of thromboembolic disorders.
Teripartide (Forteo) is a recombinant form of human parathyroid hormone, given as a subcataneous injection daily. Teriparatide is an anabolic agent that stimulates bone formation.19 It is approved for a once-only lifetime course of 18 months. Upon completion of the 18-month course, patients should be commenced on an anti-resorptive therapy.
In conclusion, osteoporosis is a common disorder that is associated with significant cost, morbidity and increased mortality risk. Treatment has been shown to decrease fracture risk with minimal side-effects. There are a variety of treatment options available; hence treatment can be tailored to an individual’s needs. It is no longer acceptable that only a small proportion of people with osteoporosis and fracture are actively treated.
- A snapshot of osteoporosis in Australia 2011. Canberra: AustralianInstitute of Health and Welfare, 2011 Contract No.: Cat. no.PHE137.
- Biliuc D NN, Milch VE, Nguyen TV et al. Mortality risk associatedwith low-trauma osteoporotic fracture and subsequent fracture inmen and women. The Journal of the American Medical Association2009;301(5):513-21.
- Eisman J CS, Kehoe L. Osteoporosis prevalence and levels oftreatment in primary care: the Australian BoneCare study. Journal ofBone and Mineral Research 2004;19(12):1969-75.
- Bolland MJ AA, Baron JA, Grey A et al. Effect of calciumsupplements on risk of myocardial infarction and cardiovascularevents: meta-analysis. BMJ 2010;341.
- Bolland MJ GA, Avenell A, Gamble GD, Reid IR. Calciumsupplements with or without vitamin D and risk of cardiovascularevents: reanalysis of the Women’s Health Initiative limited accessdataset and meta-analysis. BMJ 2011;342.
- It is no longer acceptable thatonly a small proportion of peoplewith osteoporosis and fracture areactively treated.’6 Li K KR, Linseisen J, Rohrmann S. Associations of dietary calciumintake and calcium supplementation with myocardial infarction andstroke risk and overall cardiovascular mortality in the Heidelbergcohor of the European Prospective Investigation into Cancer andNutrition study (EPIC- Heidelberg). Heart. 2012;98:920-5.
- Lewis JR CJ, Zhu K, Flicker L, Prince RL. Calcium supplementationand the risks of atherosclerotic vascular disease in older women:results of a 5-year RCT and a 4.5-year follow-up. Journal of Boneand Mineral Research. 2011;26(1):35-41.
- Bischoff-Ferrari HA WW, Orav EJ, Lips P et al. A pooled analysis ofvitamin D dose requirements for fracture prevention. N Engl J Med.2012;367(1):40-9.
- Watts NB JR, Hamdy RC, Hughes RA et al. Risedronate preventsnew vertebral fractures in postmenopausal women at highrisk. The Journal of Clinical Endocrinology and Metabolism.2003;88(2):542-9.
- McClung MR GP, Miller PD, Zippel H et al. Effect of risedronateon the risk of hip fracture in elderly women. N Engl J Med.2001;344(5):333-40.
- Harris ST WN, Genant HK, McKeever CD et al. Effects ofrisedronate treatment on vertebral and nonvertebral fractures inwomen with postmenopausal osteoporosis. The Journal of theAmerican Medical Association 1999;282(14):1344-52.
- Black DM TD, Bauer DC, Ensrud K et al. Fracture risk reduction withalendronate in women with osteoporosis: The Fracture InterventionTrial. The Journal of Clinical Endocrinology and Metabolism2000;85(11):4118-124.
- Ensrud KE SJ, Barrett-Connor E, Grady D et al. Effects of raloxifeneon fracture risk in postmenopausal women: the raloxifeneuse for the heart trial. Journal of Bone and Mineral Research2008;23(1):112-20.
- Cummings SR EB, Delmas PD, Kenemans P et al. The effectsof tibolone in older postmenopausal women. N Engl J Med.2008;359(7):697-708.
- Cummings SR SMJ, McClung MR, Siris ES et al. Denosumab forprevention of fractures in postmenopausal women with osteoporosis.N Engl J Med 2009;361(8):756-65.
- Papapoulos S CR, Libanati C, Brandi ML et al. Five years ofdenosumab exposure in women with postmenopausal osteoporosis:results from the first two years of the FREEDOM extension. AmericanSociety for Bone and MIneral Research 2012;27(3):694-701.
- Reginster JY SE, Vernejoul MCD, Adami S et al. Strontium ranelatereduces the risk of nonvertebral fractures in postmenopausal womenwith osteoporosis treatment of peripheral osteoporosis (TROPOS)study. The Journal of Clinical Endocrinology and Metabolism2005;90(5):2816-22.
- Meunier PJ RC, Seeman E, Ortolani S et al. The effects ofstrontium ranelate on the risk of vertebral fracture in women withpostmenopausal osteoporosis. N Engl J Med 2004;350(5):459-68.
- Neer RM AC, Zanchetta JR, Prince R et al. Effect of parathyroidhormone (1-34) on fractures and bone mineral density inpostmenopausal with osteoporosis. N Engl J Med 2001;344:1434-41.
- Lyles KW C-ECMJ, Adachi JD, Pieper DF et al. Zoledronic acidand clinical fractures and mortality after hip fracture. N Engl J Med2007;357(18):1799-809.
- Kim SY SS, Katz JN, Levin R, Solomon DH. Oral bisphosphonatesand risk of subtrochanteric or diaphyseal femur fractures in apopulation-based cohort. Journal of Bone and Mineral Research2011;26(5):993-1001.
- Black DM KM, Genant HK, Palermo L et al. Bisphosphonates andFractures of the Subtrochanteric or Diaphyseal Femur. N Engl JMed.2010;362(19):1761-71.
- Schilcher J MK, Aspenberg P. Bisphosphonate Use and atypicalfracture of the femoral shaft. N Engl J Med. 2011;364(18):1728-37.