Osteomyelitis is an infection, usually by bacteria, of bone and bone marrow. It is relatively rare in developed countries but is more common in children, most often affecting the long arm and leg bones and vertebrae; in adults, it usually affects the vertebrae. The condition may be either acute or chronic.
In acute osteomyelitis, the infection (which is usually caused by the bacterium Staphylococcus aureus) enters the bloodstream via a skin wound or as a result of infection elsewhere in the body. The infected bone and marrow become inflamed; pus forms, causing fever, severe pain and tenderness in the bone, and inflammation and swelling of the skin over the affected area.
Prompt treatment with high doses of antibiotic drugs, initially given intravenously and continued over several weeks or months, usually cures acute osteomyelitis. If the condition fails to respond, surgery has to be performed to remove infected and dead bone and drain away any pus.
Chronic osteomyelitis may develop if acute osteomyelitis is neglected or fails to respond to treatment; after a compound fracture; or due to infection of the bone with Mycobacterium tuberculosis, which causes tuberculosis. The condition causes constant pain in the affected bone.
Complications include persistent deformity and, in children, arrest of growth in the affected bone. Involvement of the spine can result in damage to the spinal cord if the condition is not treated. In the later stages of the disease, amyloidosis (abnormal deposits of a starchy substance in vital organs) may develop.
Chronic osteomyelitis requires surgical removal of all affected bone, sometimes followed by a bone graft; antibiotic drugs are also prescribed.
Osteomyelitis in detail -technical
Bacteria can obtain access to bone from a contiguous focus of infection (e.g. a diabetic foot ulcer) or by haematogenous spread. Osteomyelitis is most commonly caused by Staphylococcus aureus, β-haemolytic streptococci, and—in some situations—aerobic Gram-negative rods. An acute inflammatory response causes oedema within bone and soft tissue, and thrombosis in vessels that can result in bone infarction. Pus may form within cancellous bone and beneath the periosteum, stripping it from the bond and leading to extensive necrosis that sometimes involves an entire bone. The process may become chronic and relapsing.
Diagnosis—certain diagnosis of osteomyelitis requires the culture of bacteria from reliably obtained samples of bone, accompanied by histological evidence of inflammation, but this cannot be achieved in many cases and diagnosis is commonly made on the basis of clinical features and imaging. MRI is the standard and best method.
Clinical features—the condition predominantly affects the metaphyses adjacent to large weight-bearing joints, presenting as rapid onset of pain and loss of function in the affected limb, usually accompanied by high fever and malaise.
Treatment—acute osteomyelitis is an orthopaedic and medical emergency. Antibiotics (probably for at least 4 weeks) should be initiated on clinical suspicion, with appropriate initial regimens in most cases being a cephalosporin, a β-lactam/β-lactamase combination, or the combination of an antistaphylococcal penicillin and gentamicin. Vancomycin or an alternative will be necessary if the patient has risk factors for infection with methicillin-resistant S. aureus. Surgery is indicated if abscesses are present, or if the patient is failing to respond to medical measures.
Clinical features—presentation is more variable than acute osteomyelitis, but is typically painful unless there is underlying neuropathy. Wound or sinus tract drainage is usually present when the condition complicates ulceration, instrumentation, or other surgery. Bone may be visible, palpable with a gloved finger, or located with a sterile metal probe in the base of an ulcer or sinus.
Treatment—chronic osteomyelitis usually requires both (1) surgery—to remove dead bone and soft tissue, drain abscesses, eliminate cavities, ensure skeletal stability, and restore soft-tissue cover; and (2) antibiotics—as above, but guided by culture results, for weeks to many months.
Prognosis—a positive and coordinated approach from a multidisciplinary team can produce good results (90% cure rate with acute osteomyelitis and 80 to 90% with chronic osteomyelitis), a fact that stands in contrast to the negative experiences or views of many patients, carers, and health care workers.
Introduction and historical perspective
Osteomyelitis is an ancient disease with a formidable reputation for persistence and relapse. The changes of chronic osteomyelitis are even apparent in some dinosaur fossils, most notably in the fibula of a Tyrannosaurus rex specimen displayed in Chicago. It has been diagnosed in human fossil remains from the late Neolithic and was described by many classical medical writers including Hippocrates. While the term indicates inflammation of the marrow (the suffix ‘myelitis’) due to infection, it will be used here to indicate any infection of bone, even if confined to the cortex (sometimes called ‘osteitis’).
Management of osteomyelitis should, whenever possible, be multidisciplinary and involve orthopaedic surgeons, specialists in infection, radiologists, pathologists, therapists with skills in physical rehabilitation, and—as appropriate—adult physicians or paediatricians.
Aetiology, pathogenesis, and pathophysiology
The pathogens causing osteomyelitis are dominated by Staphylococcus aureus, but there are many other known causes. as shown below - to add.
An acute inflammatory response is elicited once bacteria gain access to bone and begin to multiply. This causes oedema within bone and soft tissue, and the procoagulant effect of inflammation may also cause thrombosis in vessels. The result can be bone infarction, possibly contributed to by bacterial toxins.The critical step in pathogenesis is the access of bacteria to the bone. This may occur from a contiguous focus such as chronic ulceration, surgery, trauma, or soft tissue infection. Alternatively, the route may be haematogenous, with bacteria reaching bone via the circulation. The exact mechanism by which this occurs is uncertain. It is believed that the tortuous capillary loops in the metaphyses of the long bones, a favoured site for haematogenous osteomyelitis, are particularly vulnerable to thrombosis, which provides a site for bacterial seeding. This is supported by a history of recent blunt trauma to the affected part in some 30% of haematogenous cases and by observations that in most animal models it is necessary to injure bone to infect it. Even minor bone and soft tissue trauma exposes components of blood clots, the extracellular matrix, and the bone matrix to the bloodstream. Many pathogens, notably S. aureus, can adhere to such host proteins through specific receptors and, hence, to tissues and cells, including endothelial cells and osteocytes.
As infection progresses, it propagates within the bone marrow and through the cortical bone via the haversian canals. Pus may form within cancellous bone and beneath the periosteum. It may break into the soft tissues and even extend to the surface as a sinus tract. Subperiosteal pus under pressure will strip off the overlying periosteum, tracking along the length of the bone and around its circumference. The vascular consequences of this are critical to the evolution of the disease, since the outer aspect of the cortical bone is vascularized by the periosteum, the inner by the endosteal circulation. If the endosteal blood supply is already compromised by the infection, periosteal stripping causes bone death. Thus, large pieces of bone, segments, or even whole long bones can die as the infection progresses.
Dead bone can potentially be revascularized and remodelled, but only if it remains in physical continuity with living bone. However, the action of bone-resorbing cells, recruited and activated by inflammation and some bacterial products, is frequently to separate dead from healthy bone. This produces a detached piece of dead bone called a sequestrum. Small sequestra can be extruded from sinuses or wounds and the episode of osteomyelitis may arrest spontaneously; larger sequestra result in continuing infection and inflammation. Over time, more bone tends to be involved, sometimes resulting in new sinuses, with extension into soft tissues and contiguous joints. As bone is resorbed and killed, the resulting loss of strength may lead to pathological fracture.
If periosteum has been stripped and remains viable, it produces new bone called the involucrum. This may develop circumferentially, producing a shell of living bone around the dead segment, thus preserving mechanical strength. Defects in the involucrum, through which sinuses communicate with sequestra, are called cloacae. Chronicity and relapse result both from this host response and from features of bacterial physiology. The body cannot mount effective inflammatory responses in dead tissue or chronic abscesses. Bacteria adhere to the inanimate surfaces of dead bone and, as in implant-related infections, form complex structures in which they are enmeshed in an antiphagocytic polysaccharide matrix, the whole being known as a biofilm. Their growth state alters within this, rendering them phenotypically resistant to almost all antibiotics. They may even be able to persist as metabolically crippled forms called small-colony variants: these can exist within cells and are also resistant to many antibiotics that would otherwise kill wild-type organisms.
Variations on this theme occur when flat bones or those of the spine are involved in haematogenous infection. In discitis and vertebral osteomyelitis, infection of the disc space is rapidly followed by involvement of the two adjacent vertebral bodies. The infection may arrest as disc material is replaced by granulation tissue, eventually leading to fusion of the two involved vertebral bodies. In flat bones such as the pelvis or the skull, infection can spread very rapidly in the cancellous bone between the two tables before exciting a periosteal reaction.
The inside-to-out nature of haematogenous osteomyelitis is in distinction to the outside-to-in nature of contiguous focus osteomyelitis. In this case, periosteum is destroyed as part of the same process that has destroyed the overlying soft tissues. Cortical bone is killed and infection can enter the medullary cavity, thereafter extending as for haematogenous disease. Sequestra may separate and be discharged, but the adverse biological factors that led to the initial soft tissue loss may impair subsequent healing and permit further bone infection to occur.
Classical acute haematogenous osteomyelitis has its peak incidence in childhood. Men are more commonly affected than women. In children, a greater incidence in the southern hemisphere and among certain racial groups (e.g. aboriginal Australians) has been described, with rates varying from 10 to 100:100 000/year. Socioeconomic factors may contribute to this variation. Acute osteomyelitis is also seen as a complication of infections of fractures and trauma, commonly seen in victims of military conflict and road traffic accidents or after orthopaedic instrumentation. Most acute bone infections now arise through these routes.
Chronic osteomyelitis is such a diverse disease that an overall incidence and prevalence rate is not available, but incidence rises with age due to numerous causes including diabetes, peripheral vascular disease, infirmity, and ulceration. Chronic osteomyelitis also results whenever acute osteomyelitis is not treated successfully. The global diabetes pandemic is particularly noteworthy, with an estimated 252 million people affected in 2007, leading to a huge burden of chronic osteomyelitis of foot bones complicating diabetic neuropathic ulceration.
Prevention and control
There are no proven means of preventing haematogenous osteomyelitis, but prompt treatment can prevent chronicity. Contiguous osteomyelitis can be prevented by the appropriate management of open fractures and of infective foci or chronic wounds whenever these are close to a bone or joint. Pressure-area care for immobile patients and appropriate foot care for people with diabetes can prevent ulceration and subsequent osteomyelitis.
Acute osteomyelitis presents as rapid onset of pain and loss of function in the affected limb, usually accompanied by high fever and malaise. It predominantly affects the metaphyses adjacent to the large weight-bearing joints, but any bone can be involved. Prostration, sweating, rigors, and vomiting from bacteraemia, which accompany 50% of cases, may also be present. In neonates and infants, an acute septic arthritis can be an early complication or a presenting feature of an acute osteomyelitis because the joint capsule encloses not only the joint but also the metaphyseal growth plate; infection may therefore track out from the bone into the joint cavity. In older children, the joint capsule is much tougher and inserts at the growth plate. In both age groups, the cartilage of the growth plate forms a barrier to the direct passage of infection from the metaphysis to the epiphysis and the joint.
Chronic osteomyelitis presents more variably. Pain is the rule, unless there is underlying neuropathy, and there may be severe disability in the context of an ununited fracture or when the spine is involved. Wound or sinus tract drainage is usually present when osteomyelitis complicates ulceration, instrumentation, or other surgery. Bone may be visible, palpable with a gloved finger, or located with a sterile metal probe in the base of an ulcer or sinus. There may be evidence of soft tissue swelling or induration and bony tenderness on palpation or percussion. Some patients experience repeated flares of fever and acute illness due to inadequate drainage of deep pus or rapid extension into previously uninvolved soft tissue or bone. Minor ill health is common, manifesting as loss of weight or appetite, general malaise, or poor glycaemic control in people with diabetes. This is often only noticeable in retrospect when infection has been treated.
Patients with vertebral osteomyelitis may present with bacteraemia and acute back pain (raising the possibility of spinal epidural abscess and the need for urgent diagnosis and treatment), but more often they present with chronic back pain and nonspecific illness. Differential diagnoses of degenerative back pain, osteoporotic fracture, metastatic disease, and myeloma should be considered. The presence of severe back pain at rest, or of night pain, should prompt consideration of the diagnosis. Pain is often of a deep and unremitting character that patients can distinguish from previous back pains. Spinal tenderness is an unreliable sign. Deformity and the development of neurological signs are late features suggestive of loss of mechanical stability or the formation of paraspinal or epidural collections or masses.
Osteomyelitis in the diabetic foot presents with overlying chronic ulceration. The location of the infection is linked to the biomechanical changes produced by neuropathy that cause ulcers in high pressure areas related to metatarsal heads, phalanges, interphalangeal joints, or—more rarely—the calcaneum or plantar area.
Special forms of osteomyelitis include chronic multifocal osteomyelitis (this presents with pain but, despite radiological and histological features of osteomyelitis, is culture-negative), unifocal osteomyelitis with a similar behaviour, and Brodie’s abscess (a well-defined chronic abscess in bone with a very indolent presentation).
Primary or metastatic tumours or fractures may mimic acute or chronic infection. Charcot’s neuro-osteoarthropathy can be difficult to distinguish from infection in patients with underlying neuropathy, a problem that is very common in diabetic foot osteomyelitis. A chronic periosteal reaction can arise from many causes, but commonly in the lower leg due to chronic venous insufficiency. Whilst a periosteal reaction in this situation is common, osteomyelitis is rare and is usually evident from other features such as massive soft tissue loss with obvious exposure of bone.
The white-cell count, erythrocyte sedimentation rate, and C-reactive protein, although generally elevated in acute infection and flares of chronic disease, are nonspecific and occasionally normal in chronic disease. It is helpful to see elevated inflammatory markers fall after treatment, but this may take several weeks. The alkaline phosphatase level is of no value, being neither sensitive nor specific for bone infection. Blood cultures are essential in acute infection, when they may be the only means of obtaininga microbiological diagnosis. Serological tests are useful for the diagnosis of syphilis, yaws, brucellosis, and occasionally bartonellosis.
Plain radiography of chronic osteomyelitis typically shows patchy osteopenia or frank bone destruction, loss of definition of the cortex, areas of sclerosis, or periosteal reaction with new bone formation. These changes take many weeks to develop fully. In acute infection, the earliest change visible on plain radiography is soft tissue swelling (minimum 2–3 days), which is followed by periosteal reaction (7 days) and (lastly) bone destruction (10 days). If radiographs are abnormal, the changes need to be distinguished from those of tumour, trauma, or degenerative bone disease. Repeat imaging at an interval (2–4 weeks) can sometimes help as osteomyelitis is usually an aggressive process with rapidly evolving radiology. For more rapid clarification of diagnosis, however, specialized imaging is needed.
Ultrasound can identify subperiosteal collections and soft tissue abscesses and can demonstrate sinuses. CT scanning may be able to identify cortical erosion that has been missed on plain films and can demonstrate sequestra within bone. Reformatted images make it possible to produce sagittal or coronal images (e.g. to view vertebral body endplates and the spinal canal in patients unable to undergo MRI scanning) and three-dimensional images for surgical planning. Soft tissue collections are easily identified. Other than a lack of sensitivity early in the disease, the principal pitfalls of CT scanning are the radiation dose, its lack of ability to determine the extent or activity of infection, and its sensitivity to image degradation from orthopaedic metalware.
Isotope scanning is widely used, but there is a lack of consensus on the utility of various tests. Conventional, three-phase, technetium bone scans are sensitive but nonspecific. Specificity may be increased by the addition of labelled leucocyte scanning. Other reagents include labelled immunoglobulins, antileucocyte monoclonal antibodies, and even radiolabelled antibiotics.
MRI is the standard and best method for diagnostic imaging of osteomyelitis. It can detect intra- and extraosseous oedema, abscesses, dead bone, and sinus tracts. It can distinguish active from inactive infection. MRI has the advantages that its costs are rapidly falling and its availability is increasing, but its use can be problematic, mainly because of its extreme sensitivity to physiological changes that may persist long after surgery or treatment and to metal artefacts from orthopaedic implants (and even to microscopic metallosis when implants have been removed).
The microbiological standard for the diagnosis of osteomyelitis is the growth of bacteria from samples of bone, taken with precautions to prevent contamination from superficial flora. Pus or soft tissue associated with infected bone may be acceptable, but sinus tract or wound swab cultures are not. The bacteria isolated from wounds are poorly predictive of the deep flora because of asymptomatic colonization. Cultures of this kind should be reserved for detecting multiresistant organisms (such as methicillin-resistant S. aureus (MRSA)) for infection control purposes. Fluid for microscopy and culture can be aspirated from periosteal or subperiosteal abscesses. In infants, needle aspiration of bone itself is safe and well tolerated if performed by someone experienced in the technique. Bone biopsy can be performed surgically or percutaneously (by needle biopsy). In neuropathic ulcers, bone can be obtained by curettage following debridement of the overlying ulcer material. The laboratory must be made aware of the importance and nature of any specimen sent so that it can be appropriately processed and interpreted. As epidemiologically appropriate, cultures for mycobacteria, brucellae and fungi may need to be requested.
Bone histology is also an important diagnostic test: the presence of inflammatory cells, dead bone, and active bone remodelling are hallmarks of infection. They may provide the only confirmation of infection in cases where the culture results are unhelpful and may suggest specific pathogens if the changes are granulomatous rather than pyogenic.
Criteria for diagnosis
Formal criteria, as defined for endocarditis and many inflammatory disorders, have not been agreed by consensus. The criterion standard is considered to be the culture of bacteria from reliably obtained samples of bone, accompanied by histological evidence of inflammation. However, these criteria can be difficult to satisfy in many cases, so it is common to make a clinical diagnosis based on a range of clinical and imaging features.
Acute osteomyelitis is an orthopaedic and a medical emergency that may respond to antibiotics alone, with good outcomes if treated before the onset of bone death or abscess formation. Treatment should be initiated on the basis of the clinical diagnosis, with investigations used to confirm the diagnosis once treatment has begun. Following blood cultures, high-dose intravenous antibiotics effective against S. aureus, β-haemolytic streptococci, and—in some situations—aerobic Gram-negative rods, should be given. Appropriate regimens include a cephalosporin, a β-lactam/β-lactamase combination (amoxicillin/clavulanate or ampicillin/sulbactam), or the combination of an antistaphylococcal penicillin and gentamicin. Vancomycin or an alternative will be necessary if the patient has risk factors for infection with MRSA. Antibiotics can be modified based on culture results. For patient comfort, the limb should be splinted and elevated and analgesia should be given.
Surgery is indicated if abscesses are present or if the patient is failing to respond to medical measures. Abscesses must be drained and, although controversial, drilling of the bone allows free drainage of contained pus. In acute infection, the surgeon aims to minimize damage to living bone and soft tissues and thereby avoid further devascularization and consequent excessive bone death.
The necessary duration of antibiotic therapy is unclear, but treatment for less than 4 weeks is associated with higher rates of relapse. In children, oral therapy can be considered when all of the following criteria are met: (1) the patient is afebrile after the initial 48 h to 72 h of intravenous treatment; (2) there is no evidence of abscess formation, metastatic infection, or bacteraemia; (3) there is no suspicion from the history or imaging that, prior to treatment, infection has been prolonged or is associated with dead bone; (4) the organism is sensitive to reliably bioavailable oral antibiotics; and (5) compliance with therapy can be assured.
Less information is available for adults. The greatly lower rates of bone blood flow and turnover make the revascularization and absorption of necrotic bone and the delivery of antibiotics and white cells less certain. Adult acute osteomyelitis may be treated with intravenous therapy for periods of at least 4 weeks (outpatient parenteral antibiotic therapy (OPAT) programmes are useful for this), but certain drugs, notably clindamycin and ciprofloxacin, are highly bioavailable and have proved useful in the oral treatment of osteomyelitis. There are no randomized studies to inform decisions about the necessary duration of intravenous therapy or total duration of antibiotic treatment.
To achieve long-term arrest of infection, the management of chronic osteomyelitis usually requires multiple, coordinated inputs. The aims of treatment are to:
- ◆ remove dead bone and soft tissue
- ◆ drain abscesses
- ◆ eliminate cavities (which act as surgical ‘dead spaces’)
- ◆ ensure skeletal stability
- ◆ restore soft tissue cover (if necessary using plastic surgery)
- ◆ define pathogens from high-quality specimens and administer appropriate antibiotics
- ◆ correct adverse local and systemic host factors
- ◆ support the patient physically and psychologically
- ◆ reconstruct the skeleton if need be
- ◆ rehabilitate the patient
- ◆ discitis and vertebral osteomyelitis—surgery is reserved for abscess formation, progressive pain or deformity, instability, spinal cord compression, or persistent sepsis
- ◆ tuberculous osteomyelitis—surgery is reserved for mechanical complications, pain, or persistent infection
- ◆ osteomyelitis of small bones such as the phalanges
- ◆ patients with diabetic foot osteomyelitis—some authorities quote that chronic osteomyelitis can be arrested in about 70% or 80% of cases with only by limited podiatric debridement of bone
Detailed consideration of surgical methods is beyond the scope of this article, but the importance of an expert surgical opinion in managing chronic osteomyelitis cannot be overstated, even if the conclusion of that input is that a surgical approach is not technically possible or in the patient’s overall interests. Recent major surgical advances include the use of free-tissue transfer and bone transport techniques to close very large bony and soft tissue defects. These permit much more radical approaches to the resection of diseased and dead tissues. In this way, surgery can potentially convert chronic infected wounds with dead bone and soft tissue into contaminated wounds of living bone with healthy soft tissue cover. This allows a reduction in the duration of antibiotic therapy in some situations and offers a greater range of patients the possibility of long-term arrest of infection.
These play an important role after surgery, although the ‘added value’ they confer is uncertain and may depend on the extent of surgical resection. Some conditions often respond well without surgery, including:
Antibiotics may also help when the patient refuses surgery, when there is no clearly definable surgical target, or when the risks and consequences of surgical resection would be worse than the disease itself.
The choice of antibiotics should be guided by the culture results. Intravenous therapy may need to be prolonged (for up to 6 weeks) where there is thought to be a risk of unreliable compliance, poor absorption, or lack of efficacy of oral therapy. As above, OPAT programmes are valuable for shortening the hospital stay for such patients. Periods of total antibiotic treatment vary from weeks to many months, but there is a growing trend to shorten the duration of treatment when an expert surgeon has achieved a radical surgical clearance, provided that local and systemic host factors are favourable. Antibiotics can also be delivered locally, by implanting antibiotic-loaded bone cement or collagen fleece at the time of surgery. The relative efficacies of intravenous, oral, or local antibiotics have received little attention and treatment protocols vary widely.
It is important to assess for, and if possible control, factors that may affect wound and bone healing. These include ischaemia due to peripheral vascular disease, anaemia, diabetes, hypoxia from respiratory or cardiac failure, peripheral oedema, poor nutrition, and smoking. Where neuropathy has contributed to ulceration, appropriate pressure relief is essential for healing and for secondary prevention. This must be continued indefinitely through the provision of specialist footwear, cushions, or beds. The patient must be taught about neuropathy and trained in methods to prevent further ulceration. Hyperbaric oxygen therapy has been widely employed with anecdotal success, but its effectiveness and its precise role are unclear, with definitive randomized trials still awaited. Given its expense, establishing a clear evidence base for hyperbaric oxygen should be a prerequisite for its commissioning and use.
More than 90% of cases of acute osteomyelitis that are amenable to medical treatment can be arrested. Chronic osteomyelitis can be arrested in about 80% or 90% of cases, usually when expert surgery has been combined with antibiotic treatment. Recurrence is most common within the first year, but may occur at any time, and recurrences have been described over 50 years after an initial infection has apparently been treated successfully. This poses major difficulties for the design of clinical trials, as extended follow-up is needed to make definitive statements about success or failure. Longstanding active chronic osteomyelitis may be associated with the eventual development of squamous metaplasia or carcinoma in a sinus and with the deposition of amyloid, but both these events are rarities, albeit important to consider.
Occupational, quality of life, and psychosocial aspects
Pain, chronic sepsis, and physical disability have a significant impact on quality of life. Psychological well being is further affected by issues common to all chronic diseases, together with anxiety and depression over risks of death, paralysis (e.g. in spinal infection), and limb loss, stigmatizing effects of chronic discharging wounds, and feelings of anger or failure where infection has resulted from an accident or surgery. The multidisciplinary team caring for the patient must have awareness and experience of dealing with these issues and access to appropriate rehabilitation resources to optimize long-term function and quality of life.
Likely developments in the near future
The rise in antimicrobial resistance is likely to make the antibiotic treatment of osteomyelitis more challenging and require the use of new agents, notably against MRSA. A major worldwide drive to decrease health care associated infections may bear fruit but be offset by increasing numbers of patients being injured through conflict or the effects of climate change. The aging populations of the industrialized world and the rising prevalence of diabetes are likely to result in further increases in the burden of diabetic foot and pressure sore osteomyelitis. For those able to afford them, there may be balancing advances in diagnosis using the polymerase chain reaction to detect microbial nucleic acid, microarrays to detect infection-specific host responses, and improved surgical reconstructive methods including the use of bone morphogenetic proteins to restore bone loss.