700 Annals ofthe Rheumatic Diseases 1996;55:700-714 REVIEW Ann Rheum Dis: first published as 10.1136/ard.55.10.700 on 1 October 1996. Downloaded from Current and potential future drug treatments for osteoporosis Sanjeev Patel Osteoporosis is the most common metabolic ture risk increases by a factor of 1.5 to 3.0.6 bone disease in the developed world and is Other determinants of osteoporotic fracture increasingly recognised as an important public are shown in table 1. health problem.' There is marked worldwide Drugs active on bone can be simplistically variation in its incidence. It is predicted that classified as those that inhibit bone resorption the incidence of hip fractures caused by or those that stimulate bone formation (table osteoporosis will increase, particularly in 2). The effects of these drugs on bone mineral developing countries.2 The human burden of density are summarised in fig 1. Drugs that osteoporosis is considerable, with increased stimulate bone formation lead to a direct morbidity and mortality, especially following increase in bone mineral density, whereas those osteoporotic hip fractures.' The current finan- that inhibit bone resorption result in limited cial burden is substantial, with estimated yearly increases in bone mineral density by costs of £750 million in the UK,' $10 billion in uncoupling bone turnover and allowing forma- the USA, and FF3.7 billion in France.3 The tion to continue in excess of resorption. This ability to measure bone mineral density and leads to an increase in bone mineral density thereby monitor response to intervention has due to filling in of the remodelling space (the been vital in the development ofpharmacologi- remodelling transient).7 It has been suggested cal treatments. In this review I aim to discuss that beyond this increase (5-10%), there is lit- current issues surrounding the use of tle potential for further increases in density, http://ard.bmj.com/ established and newly licensed drugs, as well as giving rise to the term "the remodelling examining agents that are in the early stages of barrier".8 However, more recent evidence sug- development. gests that this may not be the case, and that bone mineral density may continue to increase Background beyond the first year of treatment with The cycle of bone resorption by osteoclasts antiresorptive drugs.9 In addition, decreases in followed by bone formation by osteoblasts is fractures do occur, partly due to increases in on September 25, 2021 by guest. Protected copyright. essential for modelling (resorption followed by bone mineral density leading to increased bone formation at a distant skeletal site resulting in strength as well as to a lower rate of trabecular changes in architecture and growth), and perforation associated with reduced bone remodelling (resorption followed by formation turnover. at the same skeleton site). In the first 20-25 Interventions aimed at decreasing fractures years of life, bone mineral density increases by influencing bone mineral density can either with age until peak density is achieved. It then prevent low mineral density (by maximising remains relatively constant until, in women, the peak density and decreasing rate ofloss ofbone menopause is reached, after which there is a in later life), or they can treat established low phase of rapid oestrogen dependent bone loss mineral density (osteoporosis). There are few for 5-10 years, and then a less rapid phase of data on pharmacological interventions capable age related bone loss. Prospective studies of influencing peak bone mineral density, suggest that the latter may accelerate in the although prospective cohort studies are under very old, particularly at the hip.' In men there way examining several variables including is no rapid phase of bone loss. Whether bone calcium supplements.'01' In established osteo- Osteoporosis Unit, mineral density will decrease below the so porosis, drugs that increase bone formation Department of called fracture threshold in later life is depend- and mass are required; in practice, because of a Rheumatology, St George's Hospital, ent on the absolute magnitude of peak density Table 1 Determinants ofosteoporoticfracture London SW17 OQT, and subsequent rate ofbone loss. Bone mineral United Kingdom density is highly correlated with bone strength Bone mineral density S Patel of variance in bone is Gait and propensity to fall (75-80% strength Geometry (especially at the hip) Correspondence to: explained by bone density)5 and at a given Bone dimensions Dr Sanjeev Patel. skeletal site it predicts future fracture risk. For Bone "quality" deviation which bone Bone architecture Accepted for publication every standard by ? Trochanteric fat (padding) 28 June 1996 mineral density is below peak bone mass, frac- Drug treatments for osteoporosis 701 Table 2 Current andpotentialffuture drug treatments for loss of trabecular connectivity that is seen in osteoporosis severe osteoporosis (fig 2). Ann Rheum Dis: first published as 10.1136/ard.55.10.700 on 1 October 1996. Downloaded from Drugs which suppress bone resorption Hormone replacementt (oestrogens, progestagens, tibolone, Bone resorption inhibitors tamoxifen and derivatives) HORMONE REPLACEMENT THERAPY (HRT) Anabolic steroidst Oestrogen replacement attenuates bone loss Bisphosphonatest Calcitonint that occurs after the menopause and reduces Calcium and vitamin Dt osteoporotic fractures.5 Despite this, and a Activated vitamin Dt Ipriflavonet reduction in coronary heart disease and Integrin antagonists* strokes, compliance is poor.'2 Reasons for this Proton pump inhibitors* are multiple and include the need for monthly Amylin* withdrawal bleeds (at least for non-continuous Drugs which simulate boneformation combined HRT) to prevent uterine cancer, Fluoridet anxiety regarding weight gain, breast Bone growth factors Growth hormone tenderness, and more importantly concern Parathyroid hormone regarding the increased risk of breast cancer. Parathyroid hormone receptor agonists (theoretical)* Previous meta-analyses have suggested a Vitamin D analogues* Zeolite A* relative risk of 1.0 (no increased risk) to as high Stronium salts as 1.6 for breast cancer with HRT.'2 Recent * Not tested on humans. studies do not seem to clarify this issue, show- t Licenced in some countries. ing either no increase in risk,'3 to an increase in risk with longer duration of use and age.'4 20 These differing results could be due to numer- ous factors including methodological design Stimulators of and differing HRT regimens studied in bone formation different populations. Thus whether HRT is suitable for an 10 a individual is dependent on the aim of m treatment and what is in practice a difficult Inhibitors of risk-benefit analysis, with the patient's own 0) bone resorption views and preferences playing a substantial 0o role. That is, treatment benefits such as relief of .C menopausal symptoms and reduction in cardiovascular disease and osteoporotic fractures have to be weighed against side No intervention effects, past medical and family history of -10 L cardiovascular disease, osteoporosis, and 0 1 2 3 breast cancer, as well as other risk factors and http://ard.bmj.com/ Time (years) patient preferences. For the female population, Figure 1 Influence ofvarious treatments on bone mass although more older women die of heart (see textfor details). disease than ofbreast carcinoma, the beneficial effect of HRT on cardiovascular mortality may lack of such agents (apart from fluoride) bone be negated by increased deaths from breast resorption inhibitors are used. However, it cancer. Definitive data may be provided by a should be noted that increasing trabecular long term prospective study examining the net on September 25, 2021 by guest. Protected copyright. thickness by stimulating bone formation or health effects of HRT that is being carried out inhibiting bone resorption does not reverse the in the USA under the auspices of the Women's Health Initiative. The timing and duration of HRT is also controversial. Maximum protection against High CM osteoporosis would be provided by taking life- long HRT from the menopause, although this would have to be weighed against long term side effects, as discussed above. An alternative is to start HRT after a fracture, thus allowing 0 easy identification of patients at risk who may cen\ comply with treatment. However, preventable ._.V\N fractures would occur with this strategy and Low there may be limited response due to extensive Low Normal disruption of bone architecture. A third Bone mineral density possibility is to start HRT many years after the Figure 2 Schematic relations between bone mineral menopause and to continue indefinitely there- density, trabecular connectivity, andfracture risk. As bone after. For example, starting HRT at the age of mineral density decreases from normal (A) to moderate 70-75 years may be adequate intervention to osteoporosis (B), where there is some disruption in reduce fracture since the median trabecular connectivity, fracture risk increases. Treatment at hip rates, age B will restore bone mineral density and reducefracture risk of hip fracture is 80 years and bone density at back to A. However, in severe osteoporosis (C), where bone this site continues to decrease, although mineral density is very low and trabecular connectivity is compliance in this age group is likely to be low disrupted, treatment increases trabecular thickness and bone mineral density (D), but since trabecular connectivity is and many individuals would have