Bisphosphonates reduce osteoclast activity and may decrease the prevalence of collapse. Studies show that surface modified gold nanoparticles have the potential to be effective as localized drug delivery vehicles for bisphosphonates in order to inhibit osteoclast proliferation and activity. Furthermore, gold nanoparticles show promise as markers to study the pathogenesis and repair process of osteonecrosis. There are a number of factors outstanding that will be determinants of the effectiveness of bisphosphonate therapy, one of which is in vivo application in disease models [35, 36]. The largest studies of alendronate with the longest duration of follow-up, as far as we know, demonstrated improved function and survivorship in 92% (364) of 395 hips and 87% (46) of 53 hips at a mean follow-up of 4 and 10 years, respectively [37, 38].

However, a Level-I multicenter randomized controlled trial found no effect of alendronate compared with placebo for preventing radiographic progression and total hip arthroplasty, as four of thirty-two hips treated with alendronate and five of thirty-three hips treated with a placebo had a total hip arthroplasty at a mean follow-up of 2 years [39].

Preexisting hypercholesterolemia itself induced by a cholesterol-rich diet does not increase the risk of developing steroid-induced osteonecrosis, but rather seems to diminish it. Lanolin may be the active anti-osteonecrosis component of the cholesterol diet. Low-level evidence has shown protective effects of cholesterol-rich diets [40].

The lipoic acid can significantly decrease the incidence of osteonecrosis in the steroid-treated rabbits. Inhibited oxidative stress and amendment of vascular endothelial dysfunction is a possible mechanism for this effect. The precise mechanism still requires a further in vivo study. The studies in humans that focus on the effect of the lipoic acid are required to determine the clinical effectiveness of the antioxidant on osteonecrosis. The administration of prophylactic agents timed so as to coincide with the period of greatest susceptibility to steroid-induced injury is thought to be important, with clinical application of this concept anticipated in the near future [41].

Enoxaparin has promise for treatment of primary osteonecrosis when initiated at Ficat Stages I or II, before segmental collapse of the femoral head. However, in osteonecrosis secondary to corticosteroid use, enoxaparin did not alter progression to Ficat Stages III or IV. Synergistic effects of thrombophilia or hypofibrinolysis or both and corticosteroid use renders osteonecrosis unresponsive to enoxaparin therapy [42].

A study confirmed the suppressive effects of simvastatin on PAI-1 expression and secretion from bone marrow adipocytes. Furthermore, pretreatment with simvastatin reversed dexamethasone-induced PAI-1 secretion. Simvastatin may thus exhibit preventive effects against steroid-induced osteonecrosis of the femoral head by suppressing PAI-1 secretion [43]. Lovastatin can prevent development of steroid-induced osteonecrosis in rabbits by inhibiting adipogenesis. Future evaluation on the effectiveness of lovastatin in the clinical practice is still necessary [44]. Pravastatin may prevent steroid-induced osteonecrosis of femoral head by suppressing PPARγ expression and activating Wnt signaling pathway [45].

Icaritin, a novel semisynthesized small molecule with osteoprotective potential, exerts dose-dependent effect on reducing incidence of steroid-associated osteonecrosis with inhibition of both intravascular thrombosis and extravascular lipid deposition. Suppression of the upregulated PPARgamma expression for extravascular adipogenesis of mesenchymal stem cells and protection from activated oxidative stress for intravascular endothelium injury were found to be involved in the underlying mechanisms [46].

When INFH was surgically induced in rats, an intraosseous injection of COMP-Ang1 preserved the trabecular framework of the osseous epiphysis and prevented femoral head deformities by promoting angiogenesis and bone remodeling [47]. A single local injection of rhFGF-2 microspheres promoted the repair of the osteonecrotic femoral head and inhibited femoral head collapse and osteoarthritis progression. rhFGF-2 may be a promising strategy for the treatment of osteonecrosis of femoral head [48].

Sodium ferulate has protective and apoptosis-intervening effects on excessive steroid-induced osteonecrosis in femoral head of cultured rabbits to regulate the expressions of caspase-3 and Bcl-2 [49].

The medicinal guide Ach improves the preventive and therapeutic effects of Huogu II Formula on experimental osteonecrosis model. The possible mechanism of this is related to its promoting effect on directional homing of BMSCs to the necrosis area [50].

A study demonstrated an increased number of empty osteocyte lacunae, which represent a pathologic feature of osteonecrosis, in the glucocorticoid-treated animal group. A decrease of empty lacunae was counted in the glucocorticoid-treated animal after additional treatment with a nitrate patch. This suggests a preventive effect of nitrate co-treatment for steroid-associated necrosis of femoral head [51].

And others [52–54] have been studied, but the results remain inconclusive.

Iloprost, a prostaglandin analogue, reduced pain and decreased lesion size in 65 of 117 bones in 50 patients (50 hips) and increased the Harris hip score by a mean of 27 points [55]. However, most evidence on these modalities is low (Level-IV) and limited, so these treatments are still experimental and we cannot give them high levels of recommendation.

A randomized controlled trial comparing therapy for femoral head osteonecrosis with hyperbaric oxygen in 10 patients and compressed air in 10 patients demonstrated more pain relief in the hyperbaric oxygen group after 20 and 30 treatment sessions than in the compressed air group. After 6 weeks, the air cohort was converted to hyperbaric oxygen. At 7 years of follow-up, all patients reported decreased pain and none had a total hip arthroplasty [56].

Pulsed electromagnetic field treatment may be indicated in the early stages of osteonecrosis of the femoral head (Ficat stages I and II). Pulsed electromagnetic field stimulation may be able to either preserve the hip or delay the time until surgery. The short-term effect of pulsed electromagnetic field stimulation may be to protect the articular cartilage from the catabolic effect of inflammation and subchondral bone marrow edema. The long-term effect of pulsed electromagnetic field stimulation may be to promote osteogenic activity at the necrotic area and prevent trabecular fracture and subchondral bone collapse [57].

Extracorporeal shock waves are acoustic waves of extremely high pressure and velocity. Shock waves can travel through fluid and soft tissue, and their effects occur at sites where there is a change in impedance, such as the bone–soft tissue interface. When shock waves are directed at bone, multiple interfaces between soft tissue and bone result in reflection and deposition of shock-wave energy. This deposition may be responsible for the osteogenesis and angiogenesis effects of this therapy [1, 53, 58–62].

Collapse of the femoral head or the presence of a large osteonecrotic lesion in the precollapse stages compromises the outcome of head-sparing procedures. Total hip arthroplasty is the surgical treatment that can most reliably achieve pain relief and provide prompt functional return with a single procedure in patients with femoral head collapse, especially when painful degenerative changes of the hip joint are present [2].

The durability of total hip arthroplasty in patients with osteonecrosis compared with that in patients with osteoarthritis has been questioned based on the younger age and increased activity of patients with osteonecrosis. Ortiguera et al. [74] reported that, at a mean follow-up of 17.8 years, patients with osteonecrosis had a significantly higher dislocation rate than did patients with osteoarthritis.

The tenet for core decompression with 10-mm trephines [75–77] and percutaneous drilling [78–85] is a reduction in intraosseous hypertension [86]. Favorable outcomes have been associated with hips with symptomatic, precollapse, smaller-sized lesions [85], and other factors may be responsible for the results of core decompression. It has been combined with arthroscopy [87–91], tantalum rods [92–99], calcium bone graft substitutes [100–102], platelet-rich plasma [88], cell-based therapies, and adjunctive therapies (bisphosphonates, ESWT, iloprost, etc.) [83, 103–106].

Osteotomies move the necrotic area away from the weight bearing region and include angular intertrochanteric and rotational transtrochanteric procedures [107–111] Rotational osteotomies had success rates ranging from 82 to 100% at 3–15 years of follow-up in nine reports (one Level-II, three Level-III, and five Level-IV investigations) [112–114]. Despite positive results, osteotomy usage is less frequent in western countries because of limited indications for small lesions. Osteotomies are associated with a higher rate of complications such as nonunion or delayed union and loss of fixation and/or position.

Nonvascularized bone-grafting has been used for precollapse and early postcollapse lesions [115]. Success relies on achieving necrotic segment decompression and providing structural support to allow healing and subchondral bone remodeling. These procedures are performed through a core track or window at the femoral neck base.

Mesenchymal stem cell treatment has received much interest, with many published reports [50, 52, 116–120]. Four randomized trials involving a total of 358 hips demonstrated mesenchymal stem cell treatment benefits [117–120]. They found a reduced time to collapse, pain score improvements and decreased lesion sizes with core decompression and mesenchymal stem cell treatments compared with core decompression alone at a mean follow-up of 24 and 60 months. Some issues are regulatory in nature because several countries have concerns regarding the use and manipulation of mesenchymal stem cell treatments. Other concerns include: (1) questionable potential osteogenic activity of mesenchymal stem cell treatments in patients with osteonecrosis, (2) the number of mesenchymal stem cell treatments needed for injection, (3) the optimal technique for cell delivery, (4) the fate of cells, and (5) ways of manipulating mesenchymal stem cell treatments to improve growth and regenerative activity. Currently, mesenchymal stem cell treatments studies are experimental and exact indications have not been defined.