Variability in Patient-Incurred Costs and Protocols of Regenerative Medicine Procedures for Musculoskeletal Conditions in the United States

Abstract

Background: The use of regenerative medicine as an “off label” treatment for musculoskeletal conditions has increased in recent years. However, the literature is sparse regarding the costs of these treatments to patients. Purposes: We sought to determine the patient-incurred costs for regenerative medicine treatments performed by physicians for musculoskeletal conditions in the United States, according to primary specialty, geographic region, practice setting, and years in practice. We also sought to characterize pre- and posttreatment protocols and image guidance use. Methods: We performed a cross-sectional study with data collection occurring between April 2020 and April 2021. It began with the distribution of an online survey through an email campaign by the American College of Sports Medicine to its members. Approximately 90 emails were sent by our research team as well. Throughout the year, various participant recruitment methods were used (through Twitter, for example). Survey data included physician demographics, practice/training information, types/costs of regenerative medicine treatments performed, and pre-/postprocedure protocols. Results: One hundred physicians who self-reported performing standalone regenerative medicine procedures participated in this online survey. According to the responses, the most common treatments performed were platelet-rich plasma (PRP; 100%), bone marrow concentrate (BMC; 41%), microfragmented adipose grafting (36%), prolotherapy (33%), and bone marrow aspirate (BMA; 21%) administered to the peripheral joints, tendons/muscles, ligaments, and/or spine. Overall, the respondents reported large variations in treatment costs to patients; BMA and BMC were the most expensive and had the largest ranges in costs for all anatomical locations. Costs for PRP were lower than those for BMA and BMC, with less variation. Physicians in private practice reported higher PRP, BMC, and BMA costs in the peripheral joints than those in academic settings. Most physicians recommended avoiding non-steroidal anti-inflammatory drugs pre- and postprocedure, and 74% recommended physical therapy postprocedure. Conclusions: Findings from a survey of physicians who provide regenerative medicine procedures as off-label treatment for musculoskeletal conditions suggest that there is variation in related patient-incurred costs. Future studies should explore associations between treatment costs and outcomes.

Regenerative medicine treatments have been suggested to improve healing and pain subsequent to various cartilage, ligament, tendon, and bone pathologies [2]. These treatments have been promoted in both the lay press and the medical community without definitive evidence of their clinical efficacy. Many of these products are regulated by the U.S. Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER), and some are exempt from pre-market animal studies and clinical trials [2,4,6]. Regenerative medicine treatments are conducted with minimal oversight under the Public Health Service Act, section 361, which allows for the use of human cells, tissues, and tissue-based products if they are minimally manipulated and for homologous use.

While platelet-rich plasma (PRP) is currently FDA-approved for use in mixing bone graft materials, it is not approved for the treatment of any orthopedic conditions. Other regenerative medicine treatments also lack FDA approval for orthopedic uses; without this approval, insurance companies are not obligated to cover costs for off-label use, leaving patients responsible to pay for these procedures as out-of-pocket expenses. Thus far, only 1 study has examined the indications and costs for PRP procedures covered by 3rd party insurance [9]. Without insurance companies paying for these therapies, the price point is unregulated. This leads to large variations in costs to patients and creates an environment in which the average pricing range is unknown among providers and patients.

There is a wide variation in procedural technique, cost, outcomes, and indications. There are very few published studies on patient costs of regenerative medicine costs per procedure across the United States [1,4,5,9]. The studies that have been done only examined costs in orthopedic surgery or sports medicine practices [1,4,5,9]. Most of the studies have focused on PRP [1,4,5,9], but 2 of these look at “stem cells” broadly without adequately clarifying the specific cell populations [1,4]. In addition, these studies did not collect specific information about procedures, such as provider specialty, joint/tissue location, or use of image guidance. A more thorough study considering specific procedures and collecting procedural information across several specialties would help enlighten practitioners and patients alike.

Therefore, we aimed to survey physicians who provide regenerative medicine treatments for musculoskeletal conditions, which are performed by a wide range of physicians in the United States, and to establish the average costs of these treatments to patients. Our secondary aim was to evaluate fees for PRP, bone marrow aspirate (BMC), and bone marrow concentrate (BMA) treatments for peripheral joint osteoarthritis, according to primary specialty, geographic region, practice setting, and years in practice. The final aim was to characterize the use of image guidance and pre- and posttreatment protocols.

Methods

We conducted a cross-sectional study that was approved by the Institutional Review Board at our institution. Data collection took place between April 2020 and April 2021. An online survey was built on REDCap and distributed by the American College of Sports Medicine to its members; our research team distributed the survey through approximately 90 emails as well. Throughout the year, various participant recruitment methods were used—for example, the survey was shared through Twitter.

Before beginning the survey, potential participants were brought to a page that explained the purpose, procedures, and confidentiality. Clicking “yes” under the consent script served as informed consent to participate. Participants were required to confirm that they perform standalone regenerative medicine procedures, not procedures performed as an adjunct to a surgical intervention. Responses were collected anonymously, and no monetary compensation was offered.

Physician information was collected, including race, ethnicity, primary field of medicine, subspecialty, geographic region, years out of training, type of training (ie, residency, fellowship, conferences, self-taught, taught by colleagues in practice), and practice setting. Geographic regions were categorized into Northeast, South, Midwest, and West regions, as defined by the U.S. Census Bureau [8]. Physicians were asked to select the regenerative medicine treatments they provided from a list that included PRP, BMA, BMC, alpha-2 macroglobulin, prolotherapy, platelet lysate, microfragmented adipose grafting (Lipogems or Nanofat), stromal vascular fraction (SVF; enzymatically digested adipose tissue), perinatal tissue products (eg, dehydrated amniotic tissue injections, umbilical cord, blood, Wharton’s jelly, etc.), and Orthokine/Regenokine. For each treatment, the anatomical location (ie, peripheral joint, spine, tendons and/or muscles, ligaments), average cost charged by the physician to the patient, and pre- and postprocedure instructions were collected. Average costs charged by the physician excluded facility fees. In addition, physicians were asked if and when they conducted follow-ups, collected patient-reported outcomes, and published patient-reported outcomes.

Statistical Analysis

Descriptive statistics were employed for this study. Descriptive analysis of the physician population included reporting continuous data summarized as means and standard deviations. Discrete variables were summarized as frequencies and percentages. P < .05 was considered statistically significant. All analyses were performed with Stata, version 14.2.

Results

A total of 100 physicians completed the survey (Table 1). Most physicians identified as White (69%) and non-Hispanic/Latino (98%). The most common geographic locations were the Northeast (39%) and South (28%). Physical medicine and rehabilitation (PM&R) was the primary field of medicine for 53% of the physicians, and 79% reported a subspecialty of sports medicine. Almost half (46%) of the physicians were at least 10 years out of training. Approximately half reported that they either were self-taught or learned through conferences, whereas 35% of the physicians reported fellowship as the major source of their regenerative medicine training. More physicians were in an academic setting than in a private setting. In current practice, 47% of the physicians reported having trainees perform regenerative medicine procedures, and 8% reported having physician assistants or nurse practitioners perform regenerative medicine procedures. Sixty (60%) physicians had awareness of facility fees in addition to professional fees.

Table 1.

Physician characteristics.

Variable	N (%)
Race
White	69 (69)
Asian	18 (18)
Other	8 (8)
Black or African American	4 (4)
American Indian/Alaskan Native	1 (1)
Ethnicity
Not Hispanic/Latino	98 (98)
Hispanic/Latino	2 (2)
Geographic region
Northeast	39 (39)
South	28 (28)
West	23 (23)
Midwest	10 (10)
Primary field of medicine
Physical medicine and rehabilitation	53 (53)
Orthopedic surgery	22 (22)
Family medicine	19 (19)
Other	4 (4)
Emergency medicine	1 (1)
Radiology	1 (1)
Subspecialty
Sports medicine	79 (79)
Pain medicine	11 (11)
Other	6 (6)
None	4 (4)
Years out of training
0–2	12 (12)
2–5	21 (21)
5–10	21 (21)
10–15	11 (11)
Greater than 15	35 (35)
Source of majority of regenerative medicine training	N = 99
Residency	3 (3)
Fellowship	35 (35)
Conferences	23 (23)
Self-taught	27 (27)
Taught by colleagues in practice	11 (11)
Practice setting
Academic with clinical focus	52 (52)
Private practice	44 (44)
Academic with research focus	4 (4)

The most common treatments were PRP (n = 100; 100%), BMC (n = 41; 41%), microfragmented adipose grafting (n = 36; 36%), prolotherapy (n = 33; 33%), and BMA (n = 21; 21%). Orthokine/Regenokine and SVF were the least common; only 1 physician reported performing Orthokine/Regenokine treatments (Fig. 1). The top 5 most common regenerative medicine treatments were reported to have been performed in the peripheral joints, tendons and/or muscles, and ligaments. Some respondents reported performing all of these treatments, except for microfragmented adipose grafting, in the spine.

Fig. 1.

Regenerative medicine treatments. PRP platelet-rich plasma, BMC bone marrow concentrate, BMA bone marrow aspirate, SVF stromal vascular fraction.

Overall, there were large variations in treatment costs that physicians charged patients. These costs excluded fees related to facility use or image guidance. BMA was the most expensive treatment and had the largest range in costs for all anatomical locations (Fig. 2). BMC was the second most expensive treatment, with a similar wide range in costs. On average, PRP costs were lower than those for BMA and BMC, with less variation.

Fig. 2.

Costs to patients per procedure in the peripheral joints, spine, tendons/muscles, and ligaments. Boxplots of costs for each procedure in the (a) peripheral joints, (b) spine, (c) tendons/muscles, and (d) ligaments are shown. Upper and lower whiskers represent maximum and minimum values, respectively. Upper and lower lines of the box represent third and first quartiles, respectively. The line within the box represents the median, and the x represents the mean. The dots represent outliers. PRP platelet-rich plasma, BMC bone marrow concentrate, BMA bone marrow aspirate.

The costs of PRP, BMC, and BMA are further summarized in Table 2 by primary field, practice setting, region, use of image guidance, and number of years out of training. Variations in costs were observed for all variable designations. PRP treatment costs reported by PM&R physicians were higher than those reported by physicians in other fields. In general, PRP, BMA, and BMC treatment costs reported by physicians in private practice appeared to be higher than those in academic settings, regardless of anatomical location and type of treatment. The average cost of these procedures differed based on geographic region. Respondents reported the Northeast region to have the highest mean cost of PRP and BMC used in peripheral joints and the Western region to have the highest mean cost for BMA used in peripheral joints. No trends were observed for image guidance or number of years out of training. Additional stratification of mean cost by type of kit revealed large variations within each type of kit used for each treatment type (Table 3).

Table 2.

Peripheral joint costs to patients for PRP, BMC, and BMA.

	PRP		BMC		BMA
	N	Costs	N	Costs	N	Costs
Primary field
Physical medicine and rehabilitation	50	Mean: $991 ($341) Median: $900 ($449-$2000)	16	Mean: $3666 ($1465) Median: $3750 ($0-$6000)	6	Mean: $3717 ($749) Median: $3650 ($3000-$5000)
Orthopedic surgery	21	Mean: $757 ($223) Median: $800 ($250-$1000)	8	Mean: $3113 ($1190) Median: $3350 ($1000-$5000)	1	$1000a
All other	24	Mean: $829 ($288) Median: $850 ($0-$1400)	8	Mean: $5113 ($2079) Median: $4250 ($2800-$7600)	5	Mean: $4733 ($2477) Median: $4500 ($1500-$7600)
Practice setting
Academic	52	Mean: $863 ($343) Median: $800 ($0-$1800)	11	Mean: $3000 ($2828) Median: $3000 ($1000-$5000)	4	Mean: $3000 ($1633) Median: $3000 ($1000-$5000)
Private practice	43	Mean: $942 ($285) Median: $864 ($449-$2000)	21	Mean: $4155 ($1732) Median: $3500 ($2000-$7600)	9	Mean: $4411 ($2021) Median: $4000 ($1500-$7600)
Geographic location
Northeast	36	Mean: $972 ($356) Median: $1000 ($0-$1800)	7	Mean: $4500 ($3279) Median: $5000 ($1000-$7500)	4	Mean: $2950 ($1370) Median: $3400 ($1000-$4000)
South	26	Mean: $822 ($288) Median: $800 ($250-$1500)	15	Mean: $4060 ($1258) Median: $3600 ($3000-$7500)	5	Mean: $3900 ($2219) Median: $3500 ($1500-$7500)
Midwest	10	Mean: $807 ($202) Median: $825 ($500-$1000)	4	Mean: $3813 ($1103) Median: $3725 ($2800-$5000)	2	Mean: $3900 ($1556) Median: $3900 ($2800-$5000)
West	23	Mean: $910 ($320) Median: $850 ($542-$2000)	6	Mean: $3350 ($2671) Median: $2750 ($0-$7600)	2	Mean: $6300 ($1838) Median: $6300 ($5000-$7600)
Image guidance
Ultrasound	88	Mean: $900 ($327) Median: $850 ($0-$2000)	27	Mean: $4083 ($1627) Median: $4000 ($1000-$7600)	11	Mean: $4336 ($1869) Median: $4000 ($1500-$7600)
Fluoroscopy	22	Mean: $980 ($393) Median: $925 ($250-$2000)	13	Mean: $4662 ($2165) Median: $4500 ($0-$7600)	9	Mean: $4433 ($2002) Median: $4000 ($1500-$7600)
None	9	Mean: $900 ($179) Median: $900 ($600-$1200)	4	Mean: $3550 ($1226) Median: $3600 ($2000-$5000)	1	$1000a
Levels of training
<10 years	52	Mean: $911 ($365) Median: $857 ($0-$2000)	16	Mean: $3678 ($1861) Median: $3600 ($0-$7500)	5	Mean: $4100 ($2408) Median: $4000 ($1000-$7500)
10+ years	43	Mean: $884 ($256) Median: $850 ($400-$1500)	16	Mean: $4100 ($1561) Median: $3600 ($2000-$7600)	8	Mean: $3900 ($1807) Median: $3650 ($1500-$7600)

Results are mean (SD) and median (minimum-maximum).

PRP platelet-rich plasma, BMC bone marrow concentrate, BMA bone marrow aspirate.

^aOnly one physician in orthopedic surgery reported performing BMA in the peripheral joints. Only one physician reported using no image guidance for BMA in the peripheral joints.

Table 3.

Stratification of peripheral joint costs to patients for PRP, BMC, and BMA by type of kit.

	PRP		BMC		BMA
	N	Costs	N	Costs	N	Costs
Lipogems	4	Mean: $1050 ($311) Median: $950 ($800-$1500)	2	Mean: $2900 ($141) Median: $2900 ($2800-$3000)	0
Arthrex	41	Mean: $865 ($269) Median: $850 ($350-$1500)	7	Mean: $3736 ($791) Median: $3500 ($2950-$5000)	2	Mean: $2250 ($1768) Median: $2250 ($1000-$3500)
ACP	20	Mean: $920 ($330) Median: $850 ($350-$1800)	0		0
Harvest	10	Mean: $1040 ($365) Median: $925 ($500-$1500)	1	$0	1	$3000
Magellan	5	Mean: $844 ($374) Median: $660 ($600-$1500)	1	$5000	0
Angel	18	Mean: $982 ($251) Median: $1000 ($600-$1500)	7	Mean: $3857 ($1406) Median: $4500 ($1000-$5000)	1	$3500
Biomet GPS	3	Mean: $1100 ($346) Median: $900 ($900-$1500)	5	Mean: $3740 ($1144) Median: $3600 ($2000-$5000)	0
Other a	29	Mean: $925 ($378) Median: $900 ($0-$2000)	15	Mean: $4267 ($1732) Median: $4000 ($2000-$7500)	8	Mean: $4388 ($1489) Median: $4000 ($2800-$7500)

Results are mean (SD) and median (minimum-maximum).

PRP platelet-rich plasma, BMC bone marrow concentrate, BMA bone marrow aspirate.

^aOther types of kits include Emcyte, Regenexx, Mitek PEAK, and MarrowCellutions.

For pre-procedure protocols, 96% of the physicians recommended stopping non-steroidal anti-inflammatory drug (NSAID) use, with the most common duration being 1 week, and 75% recommended stopping the use of steroids. For postprocedure protocols, 91% of the physicians recommended avoiding NSAID use, the most common durations were 1 week and 3 weeks. The majority of physicians (89%) recommended the use of Tylenol for treatment-related pain management, and 58% recommended applying ice after the procedure. The majority (74%) also prescribed physical therapy after the procedure. Other pre- and postprocedure protocols are shown in Table 4.

Table 4.

Pre- and postprocedure protocols.

Variable	N (%)
Pre-procedure protocol	N = 95
Stop NSAIDs	91 (96)
Stop steroids	71 (75)
Stop smoking	44 (46)
Stop alcohol	28 (30)
Diet restrictions	17 (18)
Length of time for stopping NSAIDs pre-procedure	N = 89
1 day	3 (3)
2 days	5 (6)
1 week	69 (78)
3 weeks	12 (14)
Draw blood/fat aspirate/BMC by self	N = 95; 55 (58)
Post-procedure protocol	N = 98
Hold NSAIDs	89 (91)
Pain management using Tylenol	87 (89)
Progression of physical therapy	72 (74)
Apply cold	57 (58)
Use brace/crutches/immobilization	51 (52)
Pain management using prescription medication	49 (50)
Pain management using prescription opioids	42 (43)
No water exposure/bath	32 (33)
Apply warm	23 (24)
Diet restrictions	9 (9)
Other	1 (1)
Length of time for holding NSAIDs postprocedure	N = 86
2 days	1 (1)
1 week	33 (38)
3 weeks	31 (36)
Greater than 1 month	21 (24)
Follow-up with patients postprocedure	N = 100; 96 (96)
Follow-up time points	N = 96
2 weeks	40 (42)
4 weeks	33 (34)
6 weeks	9 (9)
8 weeks	29 (30)
12 weeks	23 (24)
6 months	10 (11)
12 months	6 (6)
Other	11 (12)
Collect patient-reported outcomes	N = 100, 61 (61)
Time points for patient-reported outcomes	N = 61
Baseline	47 (77)
2 weeks	15 (25)
4 weeks	26 (43)
8 weeks	24 (39)
12 weeks	38 (62)
6 months	45 (74)
12 months	40 (66)
Other	10 (16)
Publish patient-reported outcomes for procedures	N = 100, 20 (20)
Publication type	N = 20
Peer-reviewed publication	17 (85)
Office information	4 (20)
Other	1 (5)

NSAIDs non-steroidal anti-inflammatory drugs, BMC bone marrow concentrate.

Almost all physicians (96%) reported that they routinely carry out postprocedure follow-ups, with 2 weeks and 4 weeks as the most common time points. The collection of standardized patient-reported outcomes was reported by 61% of physicians. Patient-reported outcome time points are shown in Table 4. However, only 20 physicians (20% of overall cohort, 33% of those who reported collecting patient-reported outcomes) stated that they publish patient-reported outcomes for procedures, and 85% of these publications were in peer-reviewed journals.

Discussion

We surveyed physicians across the United States who reported performing regenerative medicine procedures and obtained information regarding cost to the patient, physician training, and protocols used. The 100 respondents reported a large variation in treatment costs for regenerative medicine procedures, with the highest cost for BMA and BMC, and lower costs for PRP. This was the first study looking at BMC, BMA, PRP, and other regenerative medicine procedures together. To our knowledge, no other study has looked at pricing based on administration of these treatments to the spine, peripheral joints, tendons, and ligaments. In doing so, we can provide a unique perspective on the range of costs of regenerative medicine procedures across the United States.

There are several limitations to this study. First, our survey distribution methods did not allow us to calculate a response rate; this limits the generalizability of our findings. In addition, not all respondents provided information about cost per procedure, and some noted that they did not know the exact costs. Also, relatively few physicians said they performed alpha-2 macroglobulin, SVF, platelet lysate, and Orthokine/Regenokine treatments; therefore, the costs we report may not be representative. We also did not obtain the cost of the kits used for these procedures, which can fluctuate in price and be quite expensive. Lastly, some physicians reported charging nothing for the treatments but gave no explanation for not charging the patient. We speculate that this may be due to the patient being enrolled in a clinical trial.

Previous studies investigating regenerative medicine costs have primarily focused on PRP and its use in knee osteoarthritis [1,4,5]. Piuzzi et al [5] contacted centers across the United States using a standardized script of a 52-year-old male patient with knee osteoarthritis and reported that the mean cost per unilateral knee same-day PRP injection was $714 (range: $380 to $1,390). Momaya et al [4] reported a similar mean cost of a PRP injection into the knee, with wider variability ($707; range: $175 to $4,973), across the United States. A study in south Florida showed a mean cost of $897 (range: $350 to $1,700) for PRP injections to the knee [1]. Two of these studies also assessed costs related to stem cell injections for knee osteoarthritis, with mean costs of $2,728 to $3,100; however, the exact definition of “stem cell” was not provided by either of these studies [1,4]. Zhang et al [9] used a national database of private insurance billing records to evaluate costs associated with PRP injections in different anatomical locations for various conditions and demonstrated a per-patient average cost of $1,755 per injection. Unlike previous studies, our study asked about 10 different types of regenerative medicine procedures: PRP, BMA, BMC, microfragmented adipose grafting, prolotherapy, perinatal tissue products, alpha-2 macroglobulin, platelet lysate, SVF, and Orthokine/Regenokine. We also looked at different anatomical locations: peripheral joints, spine, tendons/muscles, and ligaments. We found a wide variation in costs, both among different regenerative medicine procedures and among the same procedure for different anatomical regions. Overall, BMA and BMC were the most expensive treatments, with mean costs ranging from $3,688 to $4,379; these were higher than the costs of the stem cell injections reported by Momaya et al [4] and Alcerro et al [1], although “stem cell” could refer to a variety of interventions. Mean PRP treatment costs ranged from $899 in peripheral joints to $1,797 in the spine; these were also higher than the PRP treatment costs reported by previous studies [1,4,5].

A closer look at PRP, BMC, and BMA treatment costs in the peripheral joints revealed higher costs in private practice versus academic practice settings. This was opposite from the findings reported by Momaya et al [4], who found that academic practice settings reported higher PRP and stem cell treatment costs than private practice settings. The same study also reported higher PRP and stem cell treatment costs in the West [4]. Our results show that PRP and BMC treatment costs were highest in the Northeast, followed by PRP costs in the West and the BMC prices in the South. Piuzzi et al [5] demonstrated that states in both the Northeast and West had the highest costs of PRP injections for knee osteoarthritis. Furthermore, for PRP specifically, peripheral joint treatment costs reported by PM&R physicians were higher than those reported by orthopedic surgeons and other fields. This difference in cost among practitioners has not been previously reported.

In addition to costs, information about pre- and postprocedure protocols for regenerative medicine treatments was obtained from our study. Currently, the literature is limited regarding protocols for regenerative medicine treatments [3,7]. While it is often mentioned as a critical component, there is little data supporting 1 protocol over another. Protocols may include taking or discontinuing NSAIDs, rest or non-weight-bearing, and physical therapy [7]. We found that the majority of physicians recommended stopping NSAID use and steroid use prior to the procedures. For postprocedure protocols, almost all respondents said they recommend avoiding NSAID use. Most physicians said they recommend the use of Tylenol for pain management, and less than half recommended prescription opioids. A large percentage stated that they recommend physical therapy after the procedure. However, given the lack of research, there is no significant evidence that supports specific physical therapy recommendations at this time [3,6].

As regenerative medicine treatments continue to garner attention, it is critical that patients are well-informed on indications, efficacy, and cost. The out-of-pocket payment structure and direct-to-consumer advertising of these treatments make it vital that patients are well informed on the average price per procedure. Identifying price patterns based on procedures, location, and practice type is our first step in investigating regenerative medicine pricing. Future studies may focus on how pricing affects outcomes. Furthermore, given the potential for large profits, it is important that direct-to-consumer marketing be monitored to ensure it is in line with current scientific evidence.